Community-Acquired Pneumonia: Strategies for Management

Community-Acquired Pneumonia

Community-Acquired Pneumonia Strategies for Management Edited by

Antoni Torres

Hospital Cl´ınic de Barcelona, Spain

Rosario Men´endez Hospital Universitario La Fe, Valencia, Spain

Copyright  2008

John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex PO19 8SQ, England Telephone (+44) 1243 779777

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Library of Congress Cataloging-in-Publication Data Community acquired pneumonia : strategies for management / edited by Antoni Torres and Rosario Men´endez. p. ; cm. Includes bibliographical references and index. ISBN 978-0-470-05809-1 1. Community-acquired pneumonia. I. Torres Mart´ı, A. (Antoni) II. Men´endez, Rosario. [DNLM: 1. Pneumonia–diagnosis. 2. Pneumonia–therapy. 3. Community-Acquired Infections. WC 202 C7348 2008] RC771.C674 2008 616.2
41 – dc22 2008012124 British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library ISBN 978-0-470-05809-1 Typeset in 10.5/12.5 Times by Laserwords Private Limited, Chennai, India Printed and bound in Singapore by Markono Ltd

Contents Preface

vii

List of Contributors

ix

1

2

3

Epidemiology of Community-Acquired Pneumonia Outside Hospital Theo JM Verheij

1

Epidemiology of Adult Hospitalized Community-Acquired Pneumonia Mark Woodhead

5

Microbial Aetiology and Antibiotic Resistances in Community-Acquired Pneumonia G´erard Huchon

4

Microbiological Diagnosis of Community-Acquired Pneumonia Margareta Ieven

5

Empirical Treatment of Community-Acquired Pneumonia: Current Guidelines Javier Aspa, Olga Rajas, Felipe Rodr´ıguez de Castro, Jos´e Blanquer and Antoni Torres

6

Pathogen Directed Antimicrobial Treatment of Pneumonia Santiago Ewig and S¨oren Gatermann

7

General Pharmacological Considerations in Antibiotic Treatment of Community-Acquired Pneumonia Francesco Blasi, Mario Cazzola and Paolo Tarsia

8

β-Lactams in the Therapy of Community-Acquired Pneumonia Michael S. Niederman

21 43

63

101

127 153

vi

9 10

CONTENTS

Macrolides and Ketolides Javier Garau Role of Fluoroquinolones in the Treatment of Community-Acquired Pneumonia Tobias Welte

11

Non-Responding Pneumonia Rosario Men´endez

12

Influenza and Pneumococcal Vaccination for Prevention of Community-Acquired Pneumonia in Immunocompetent Adults ¨ ˚ Ortqvist Ake

13

Adjunctive Therapy in Community-Acquired Pneumonia Anna P. Lam and Richard G. Wunderink

Index

171

193 213

229 245 263

Preface Community-acquired pneumonia (CAP) is one of the most common respiratory infections, with an incidence that ranges from 8 to 50 cases per 1000 habitants per year. Obviously these figures depend on age and comorbidities. For example, patients older than 65 have incidences higher than 40 per 1000/year. With the overall increase of old patients, CAP represents one of the major problems in this population. Mortality is still very high ranging from 4 to 20 %. Patients requiring hospitalization have a high mortality (10–20 %) and patients with severe CAP requiring intensive-care-unit (ICU) admission have the highest, ranging from 20 to 50 %. Nowadays, the risk factors for mortality are very well known. Some of these factors are inherent to host comorbidities and microbial particularities. Some other factors are clearly related to antibiotic treatment; delay in administering antibiotics, inadequacy of empirical antibiotics and lack of adherence to guidelines are factors clearly associated with worse outcome, including mortality, length of stay, clinical stability and complications. All these factors are amenable to medical intervention. This book is mainly devoted to antibiotic treatment of CAP. As a first step the epidemiology and microbial aetiology of ambulatory and hospitalized CAP is reviewed by experts. This is necessary to understand the current antibiotic recommendations. The reader will find a review in depth of the three major classes of antibiotics used for the treatment of CAP: β-lactams, macrolides and quinolones. All of them have advantages and disadvantages that the experts have placed in perspective. Guideline recommendations are also assessed and this is crucial since guidelines are increasingly a requirement of health authorities for a good quality of care. Despite adequate antibiotic treatment, 10 % of hospitalized CAP patients present a lack of response to antibiotics. Needless to say that this population carries the highest mortality. This concept of lack of response is covered by experts that have investigated this particular problem. This population could benefit from adjunctive therapies, some of them still under investigation and also reviewed in this monograph.

viii

PREFACE

The editors hope that this book will be of help to all physicians dealing with the frequent clinical problem of CAP and very specifically in prescribing antibiotics correctly and adequately. The editors would like to express their enormous gratitude to all the authors who contributed to this book Antoni Torres and Rosario Men´endez December, 2007

List of Contributors Javier Aspa, MD, PhD Universidad Aut´onoma de Madrid, Servicio de Neumolog´ıa, Hospital Universitario de la Princesa, Madrid, Spain Jos´e Blanquer, MD, PhD Unidad de Cuidados Intensivos, Hospital Cl´ınic Universitari, Valencia, Spain Francesco Blasi, MD University of Milan, Institute Respiratory Diseases Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Fondazione IRCCS, Milan, Italy Mario Cazzola, MD University of Rome ‘Tor Vergata’, Department of Internal Medicine, Unit of Respiratory Diseases, Rome, Italy Felipe Rodr´ıguez de Castro, MD, PhD Universidad de las Palmas de Gran Canaria, Servicio de Neumolog´ıa, Hospital Dr. Negr´ın, Las Palmas de Gran Canaria, Spain Santiago Ewig, MD, FCCP Thoraxzentrum Ruhrgebiet, Kliniken f¨ur Pneumologie und Infektiologie, Evangelisches Krankenhaus Herne und Augusta-Kranken-Anstalt, Bochum, Gemany Javier Garau, MD, PhD Hospital Mutua de Terrassa, University of Barcelona, Spain S¨oren Gatermann, MD Institut f¨ur Medizinische Mikrobiologie, Ruhr-Universit¨at Bochum, Bochum, Gemany G´erard Huchon, MD Universit´e de Paris 5 Ren´e Descartes, Service de Pneumologie et R´eanimation, Hˆopital de l’Hˆotel-Dieu, Paris, France

x

LIST OF CONTRIBUTORS

Margareta Ieven, PhD Laboratory of Microbiology, Vaccine and Infectious Diseases Institute, Faculty of Medicine, University Hospital Antwerp, University of Antwerp, Belgium Anna P. Lam, MD Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Rosario Men´endez, MD, PhD Servicio de Neumolog´ıa, Hospital Universitario La Fe, Valencia, Spain Michael S. Niederman, MD Department of Medicine, SUNY at Stony Brook, Department of Medicine, Winthrop-University Hospital, Mineola, NY, USA ¨ ˚ Ake Ortqvist, MD, PhD Karolinska Institutet, Department of Medicine, Unit of Infectious Diseases, Solna, and Department of Communicable Diseases Control and Prevention, Stockholm County Council, Stockholm, Sweden Olga Rajas, MD, PhD Universidad Aut´onoma de Madrid, Servicio de Neumolog´ıa, Hospital Universitario de la Princesa, Madrid, Spain Paolo Tarsia, MD University of Milan, Institute Respiratory Diseases Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Fondazione IRCCS, Milan, Italy Antoni Torres Hospital Cl´ınic, Servei de Pneumolog´ıa i Al·lergia Respiratoria, Institut Cl´ınic del T´orax, Universitat de Barcelona, Barcelona, Spain Theo JM Verheij, MD, PhD, MRCGP Department of General Practice, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands Tobias Welte, MD, PhD Department of Respiratory Medicine, Medizinische Hochschule Hannover, Hannover, Germany Mark Woodhead, BSc, DM, FRCP Department of Respiratory Medicine, Manchester Royal Infirmary, Manchester, UK Richard G. Wunderink, MD Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

1 Epidemiology of Community-Acquired Pneumonia Outside Hospital THEO JM VERHEIJ Department of General Practice, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands

Introduction Information on community-acquired pneumonia (CAP) outside hospital is somewhat hampered by the use of different definitions. The International Classification of Primary Care indicates that the diagnosis pneumonia should be coded in the presence of signs of consolidation in lung tissue, either by physical examination or on a chest X ray (Bridges-Webb, 1998). Other publications define pneumonia as the presence of an infiltrate on a chest-X-ray or are just based on the diagnosis stated by the primary care physician. Appraising the literature on the epidemiology of CAP, the reader should realize that different definitions are used by the different sources.

Incidence and Complications The incidence of CAP in primary care is reported to be between five and ten cases per 1000 patients per year on average, but highly dependent on age (www.RIVM.nl/ vtv [accessed 2007]). Children up until 4 years of age show an incidence rate of around 20 per 1000 patients per year, after that age incidence drops to approximately one to four per 1000 per year in young adults and after the age of 40 Community-Acquired Pneumonia: Strategies for Management Edited by Antoni Torres and Rosario Men´endez  2008 John Wiley & Sons, Ltd

2

EPIDEMIOLOGY OF CAP OUTSIDE HOSPITAL

gradually rising to about 15 to 30 per 1000 in the 75 to 79 age group and between 40 and 60 in people over 85 years of age. Incidence rates are higher in men then in women (Figure 1.1). 70 Men Women

60

Incidence

50 40 30 20 10 0 4 0–

9

5–

4 9 4 9 9 4 9 9 9 4 4 4 4 4 9 –7 –5 –8 –7 –6 –5 –6 –4 –2 –3 –1 –3 –4 –2 –1 60 80 75 70 65 50 55 30 45 40 25 35 10 20 15

+ 85

Age

Figure 1.1 Incidence (per 1000 patients per year) of community-acquired pneumonia. (Source: RIVM National Kompas Volksgezondheid; http://www.rivm.nl/vtv/object document/o1848 n18080.html)

Usually it takes 2 to 4 weeks for the clinical syndrome to dissolve. Overall mortality of CAP in ambulatory patients is assumed to be between 3 and 5 % (Fine et al., 1996; Bont et al., 2007). Hospital admission rates differ somewhat between countries due to different routines and patient expectations. In The Netherlands around 15 % of patients with CAP are admitted to hospital.

Risk Factors for Pneumonia There are not many studies available that can provide an answer to the question of who is at risk from getting pneumonia. Obviously age and male gender are risk factors, as can be seen in Figure 1.1. In a Finnish study, alcoholism, chronic lung disease, immunosuppressive therapy, heart disease and institutionalism were found to be risk factors (Koivula et al., 2000). Having chronic lung disease was also found in a British study, and an American study showed that smoking and overweight were independent risk factors for getting pneumonia (Baik et al., 2000; Farr et al., 2000). A recent Dutch study showed that patients with diabetes also have an elevated risk for pneumonia (Muller et al., 2005). In summary one can say that apart from age, smoking and comorbid conditions, chronic lung diseases in particular, are the most important risk factors for CAP in

REFERENCES

3

outpatients. In addition, alcohol abuse and immunosuppressive therapy enhances the risk for pneumonia.

Prognosis of Patients with Pneumonia Although it is important to know which patients are at risk for getting pneumonia, in daily practice it is even more relevant to know which patients who actually have pneumonia are at risk for complications. As pointed out in Chapter 2, numerous studies have been done on assessment of disease severity in hospitalized patients. The information available on primary care patients is much less abundant. The most used prediction models in patients with lower respiratory tract infections are the so-called Pneumonia Severity Score (PSI) and the CURB-65 score. The PSI score is developed in hospital patients and contains some measurements such as pH and urea and sodium levels in blood that are not feasible in a primary care setting (Fine et al., 1997). From the CURB-65 score a simplified CRB-65 is derived that was validated in a cohort of both in- and outpatients (Bauer et al., 2006). This CRB-65 rule, however, only predicts mortality that is an uncommon complication in outpatients with CAP. Second, application of the rule means that every patient over 65 should be admitted to hospital, which is probably not necessary. Some other studies in primary care showed that apart from high age, confusion and blood pressure (the CRB-65 criteria), co-morbid conditions, in particular insulin-dependent diabetes and cardiac failure, hospitalization in the previous year, and the presence of tachypnoea also were predictive for a complicated course, hospitalization and death (Seppa et al., 2001; Bont et al., 2007). In short, the CRB-65 can be used in primary care patients, but other factors such as comorbidity and certain signs and symptoms should also be taken into account when assessing a patient’s risk for complications.

Conclusions Valid scientific information on important clinical issues regarding CAP outside hospital is scarce. Community-acquired pneumonia is a rather common disease in primary care, with more pronounced incidence rates in the very young and the very old. Important complications such as hospitalizations and death occur rather frequently in the very old, especially in those with chronic conditions. More studies should be done on occurrence and prognosis of CAP in primary care.

References Baik I, Curhan GC, Rimm EB, Bendich A, Willett WC, Fawzi WW. 2000. A prospective study of age and lifestyle factors in relation to community-acquired pneumonia in US men and women. Arch Intern Med 160(20): 3082–3088.

4

EPIDEMIOLOGY OF CAP OUTSIDE HOSPITAL

Bauer TT, Ewig S, Marre R, Suttorp N, Welte T. 2006. CRB-65 predicts death from community-acquired pneumonia. J Intern Med 260(1): 93–101. Bont J, Hak E, Hoes AW, Schipper M, Schellevis FG, Verheij TJ. 2007. A prediction rule for elderly primary-care patients with lower respiratory tract infections. Eur Respir J 29(5): 969–975. Bridges-Webb C (ed.). 1998. ICPC-2 The International Classification of Primary Care, an Introduction. Oxford (UK): Oxford University Press. Farr BM, Woodhead MA, Macfarlane JT, et al. 2000. Risk factors for community-acquired pneumonia diagnosed by general practitioners in the community. Respir Med 94(5): 422–427. Fine MJ, Smith MA, Carson CA, et al. 1996. Prognosis and outcomes of patients with community-acquired pneumonia. A meta-analysis. J Am Med Assoc 275(2): 134–141. Fine MJ, Auble TE, Yealy DM, et al. 1997. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med 336(4): 243–250. Koivula I, Sten M, Makela PH. 1994. Risk factors for pneumonia in the elderly. Am J Med 96(4): 313–320. Muller LM, Gorter KJ, Hak E, et al. 2005. Increased risk of common infections in patients with type 1 and type 2 diabetes mellitus. Clin Infect Dis 41(3): 281–288. Seppa Y, Bloigu A, Honkanen PO, Miettinen L, Syrjala H. 2001. Severity assessment of lower respiratory tract infection in elderly patients in primary care. Arch Intern Med 161(22): 2709–2713.

2 Epidemiology of Adult Hospitalized Community-Acquired Pneumonia MARK WOODHEAD Department of Respiratory Medicine, Manchester Royal Infirmary, Manchester, UK

Introduction Patients with community-acquired pneumonia (CAP) have been admitted to hospitals, probably since the first hospitals were built. Until about 30 years ago nearly all published material about the condition related to those admitted to hospital. Despite this there is little clear information, apart from death rates, about the epidemiology of this condition prior to the 1940s and 1950s. In particular, the precise reasons for admission to hospital are not stated, but in view of the absence of specific therapies and the recognized mortality of the condition, are likely to be mainly related to illness severity. Studies in Europe and North America suggest that rates of hospitalization for pneumonia are increasing. In England there was a 27 % rise in such admissions between 1991–1992 and 1999–2000 (http://www.sghms.ac.uk/depts/laia/laia.htm), while a 20 % increase in such admissions between 1988–1990 and 2000–2002 was seen for those aged 65 to 74 in the USA (Fry et al., 2005). The precise reasons for these changes have not been analysed, but the change is likely to be multifactorial in origin, with issues such as the ageing population, changes in patient expectations and possibly the frequency of comorbid diseases being important.

Community-Acquired Pneumonia: Strategies for Management Edited by Antoni Torres and Rosario Men´endez  2008 John Wiley & Sons, Ltd

6

EPIDEMIOLOGY OF ADULT HOSPITALIZED CAP

In the past 25 years there has been an explosion of information from studies of patients admitted to hospital with CAP, which will be described in this chapter. Accurate information about epidemiology can be obtained only from unselected patient populations. Any form of selection may introduce bias. In the literature it is difficult to find publications without some element of bias and the nature of this varies from study to study. I have selected recent studies describing the microbiology of CAP and severity scores as these are usually subject to the least bias. Many such recent studies are available from Europe (White et al., 1981; Macfarlane et al., 1982; McNabb et al., 1984; Berntsson et al., 1985; Aubertin et al., 1987; British Thoracic Society, 1987; Holmberg, 1987; Ausina et al., 1988; Levy ¨ et al., 1988; Hone et al., 1989; Ruf et al., 1989; Ortqvist et al., 1990; Blanquer et al., 1991; Burman et al., 1991; Falco et al., 1991; Pareja et al., 1992; Blasi et al., 1993; Ostergaard and Andersen, 1993; Bohte et al., 1995; Kauppinen and Saikku, 1995; Michetti et al., 1995; Gomez et al., 1996; Steinhoff et al., 1996; Logroscino et al., 1999; Men´endez et al., 1999; Ruiz et al., 1999; Socan et al., 1999; Sopena et al., 1999; Lorente et al., 2000; Jokinen et al., 2001; Lim et al., 2001, 2003; Roson et al., 2001; Arancibia et al., 2002; Espana et al., 2003; van der Eerden et al., 2004; Ortega et al., 2005; Capelastegui et al., 2006) and one from Australia (Buising et al., 2006), but few from North America. For North American data I have therefore used the hospital database used to derive the Pneumonia Severity Index (Fine et al., 1997) together with the inpatient arm of the Pneumonia Patients Outcomes Research Team (PORT) study (Fine et al., 1997) plus two other studies where epidemiological data were available (Mundy et al., 2003; Aujesky et al., 2005) and two large Canadian studies (Feagan et al., 2000; Marrie et al., 2003). No dataset is perfect and potential sources of bias will be discussed in the text.

Age As the age of the population has changed so has that for CAP admissions. This is graphically shown comparing the ages of admissions in the same hospital approximately 100 years apart (Figure 2.1). From a disease that predominantly affected 30 to 50 year olds it is now mainly a disease of those aged over 60 years. Nevertheless the incidence of CAP starts to rise from about the age of 50 upwards. In recent prospective studies the average patient age is usually between 60 and 64. The lowest mean age in recent studies has been 48 (British Thoracic Society, 1987) and the highest 69 (Arancibia et al., 2002) (Figure 2.2). The former is because patients above the age of 74 were not included in that study. Other variations between studies may reflect differences in the age make up of the local population. Age has been identified as an independent risk factor for hospitalization for pneumonia in elderly patients (LaCroix et al., 1989; Koivula et al., 1994).

GENDER 90 80 70 60 50 40 30 20 10 0

7

1878–1893 2002

20–29

30–39

40–49

50–59

>60

Figure 2.1 Age distribution of admissions for community-acquired pneumonia at Manchester Royal Infirmary – 1878–1893 compared with 2002 (unpublished data) (Leech, 1894)

70

Age

60

50

40 N America

Europe

Figure 2.2 Mean age for the incidence of community-acquired pneumonia. Each dot represents an individual study

Gender Hospital data from Manchester in the UK for the years 1878 to 1893 indicate a great male preponderance −78 % of cases (Leech, 1894) – Table 2.1. Studies in London and Edinburgh around the same time showed similar figures (Leech, 1894). Possible explanations are the structure of the population, social factors (females might have been less likely to go to hospital) and (perhaps less likely) a true sex difference in the frequency of the condition. However, Osler (1901) states that only 56 % of cases were male. More recent European studies usually document a male preponderance, but it is unusual for this to be greater than 70 % of cases. In the majority it is between 60 and 64 % of cases (Figure 2.3). This recent lower male preponderance presumably reflects better recent longevity in females and a higher

8

EPIDEMIOLOGY OF ADULT HOSPITALIZED CAP

Table 2.1 Sex distribution and mortality in UK hospitals 1870–1900 (Leech, 1894) Hospital St Thomas’s, London 1880–1890 St Bartholomew’s, London 1878–1892 Edinburgh 1874–1893 Manchester Royal Infirmary 1878–1893

Total

Male (%)

Female

Deaths (%)

708

542 (76)

166

143 (20)

2113

1573 (74)

600

395 (19)

947

728 (77)

219

257 (27)

832

653 (78)

179

240 (22)

%

70

60

50

40 N America

Europe

Figure 2.3 Proportion of males

female smoking incidence than in the past. Interestingly a more balanced gender ratio is present in North American studies.

Comorbid Conditions Whereas age and gender are nearly always documented in published studies, much variability surrounds the recording of comorbid diseases. Some comorbid conditions (e.g. HIV infection, malignant disease) are classed as exclusion factors in some studies since the pneumonia in these circumstances may not be truly community acquired or because the management may differ by virtue of the comorbid disease. In some studies such conditions are not documented at all. In those where they are documented a standardized system and standard definitions are not used. For example chronic lung disease is recorded in some studies but in others just chronic obstructive pulmonary disease is recorded. Another example is that of cardiac diseases where some studies record ischaemic heart disease, others just cardiac failure. This makes comparisons between studies and populations difficult. Recorded differences may reflect differences in the populations studied or may be simply because of lack of standardized definitions.

COMORBID CONDITIONS

9

Community-acquired pneumonia is predominantly a condition that occurs in those with other comorbid disease. The proportion of those without comorbidity (Figure 2.4) is almost certainly an overestimate for the reasons stated above and because a figure for absence of comorbidity is often not explicitly stated. In most studies less than 50 % of cases are in those without comorbidity and in those with higher proportions this is likely to be an overestimate. There is a suggestion that absence of comorbidity is less common in North American studies, but again this may be an artefact of documentation (Figure 2.4). 75

%

50

25

0 N America

Europe

Figure 2.4 Proportion with no comorbid onditions

55 50 45 40

%

35 30 25 20 15 10 5 IV H

S N C

al en

na n

R

cy

r ve M

al ig

Li

es

t D

ia

be t

ea r H

Lu n

g

0

Figure 2.5 Proportion with comorbid conditions (CNS, central nervous system)

The range of frequencies of comorbid disease is much greater between studies for the same reasons (Figure 2.5). Chronic lung disease is most common followed

10

EPIDEMIOLOGY OF ADULT HOSPITALIZED CAP

by chronic heart disease, as would be expected from the prevalence of these conditions in the general population. Bronchial asthma, lung disease, heart disease, immunosuppressive therapy (although the pneumonia in this setting would not be considered under the community-acquired heading by most authors) (Koivula et al., 1994) and chronic obstructive pulmonary disease (COPD), heart attack (men only), high blood pressure (women only) and diabetes (women only) (LaCroix et al., 1989) have been identified as independent predictors of hospital admission for pneumonia. If some of the differences in recorded frequencies of comorbid diseases genuinely represent differences in the populations included in the studies, the results of these studies may be affected by these differences and may be relevant only to the population under study. This is often forgotten when studies are compared.

Social Factors While measures of poverty and social deprivation might be expected to be related to hospital admission for CAP this has not been studied specifically. Smoking (and its consequences) is probably the most important risk factor for CAP, although its relation to hospitalization is not clear. It was the strongest independent risk factor for invasive pneumococcal disease in one study – a group of patients who mainly have pneumonia and who are mainly managed in hospital (Nuorti et al., 1998). Current smoking is recorded in between 22 (Ruiz et al., 1999) and 59 % (Macfarlane et al., 1982) of smokers in recent studies (Figure 2.6). This does not take into account the impact of cumulative exposure to tobacco smoke, which is certainly important as a risk factor for CAP if not specifically for hospital admission for this reason (Almirall et al., 1999). 60 50

%

40 30 20 10 0 Smoking

Alcoholism

IVDA

Figure 2.6 Social behaviours (IVDA, intravenous drug abuse)

Alcohol consumption is another important social factor that may be related to CAP, both because of its immunosuppressive effects and its potential to lower conscious level and thus to increase the risk of aspiration pneumonia. Some studies specifically exclude aspiration pneumonias and this might spuriously lower the

PRIOR MEDICATION

11

apparent frequency of alcoholism. Once again assessment of its impact is bedevilled by lack of definitions for what is recorded in recent studies. A history of ‘alcohol excess’ or ‘alcoholism’ was documented in between 6 (Lim et al., 2001) and 36 % (Levy et al., 1988) of cases in recent studies (Figure 2.6). In one study, although a risk factor for pneumonia, alcoholism was not found to increase risk of hospitalization(Koivula et al., 1994). In another study alcoholism was five times more frequent in those admitted to hospital for CAP compared with those admitted for other reasons (Fernandez-Sola et al., 1995). Intravenous drug abuse is a specific risk factor for pneumonia, however, the unique characteristics of pneumonia in this setting mean that most authors would not include such patients in studies of those with CAP. This behaviour was recorded in a small number of patients in two studies (Sopena et al., 1999; Roson et al., 2001) (Figure 2.6). Most patients with CAP dwell in their own home, but an increasing proportion of the elderly reside in long-term care facilities including nursing homes. North American studies suggest that Nursing Home acquired pneumonia (NHAP) has more in common with nosocomial pneumonia than CAP and is now considered by the American Thoracic Society under the heading of hospital-acquired pneumonia. This type of pneumonia has been little studied in Europe, but at least one study suggested, in contrast to North American studies, that pneumonias arising in this setting were similar to other CAPs in that age group (Lim and Macfarlane, 2001). Most CAP studies include a small proportion of patients from nursing homes, but this appears to be much more frequent in North American studies (Figure 2.7), possibly reflecting a difference in the size of the Nursing Home population or in the management of such patients when they become ill. 17.5 15.0

%

12.5 10.0 7.5 5.0 2.5 0.0 N America

Europe

Figure 2.7 Nursing Home residence

Prior Medication Influenza and pneumococcal vaccinations might be expected to influence hospitalization for CAP. Influenza vaccination has an efficacy of between 20 and 80 % in

12

EPIDEMIOLOGY OF ADULT HOSPITALIZED CAP

%

the prevention of hospital admission for influenza or pneumonia (Woodhead et al., 2005). The main impact of pneumococcal vaccination is the prevention of invasive disease, but in one study it was associated with a 43 % reduction in hospital admission for pneumonia compared with non-vaccinated subjects (Nichol et al., 1999). Vaccination history is infrequently quoted in CAP studies (only four of thirty-five) with influenza vaccination frequencies of 4 (Socan et al., 1999) to 41 % (Roson et al., 2001) and pneumococcal vaccination of 0 (Socan et al., 1999) to 15 % (Lim et al., 2001). Recently there has been much interest in potential reduction of CAP frequency through use of angiotensin converting enzyme (ACE) inhibitors (Okaishi et al., 1999; Ohkubo et al., 2004; Arai et al., 2005) or statins (Mortensen et al., 2005). Initial studies suggested that both were associated with a reduced pneumonia frequency, the former possibly related to the deletion of an allele of the ACE gene (Morimoto et al., 2002). A Canadian study of hospital admissions, however, failed to find any beneficial effect from statin therapy, attributing previously documented reductions in pneumonia frequency to a ‘healthy user effect’ (Majumdar et al., 2006). The same may be true of ACE inhibitors, as no protective effect against pneumonia could be found in a study from The Netherlands (van de Garde et al., 2006). Antibiotic therapy prior to hospital admission could be associated with both beneficial and harmful effects. Early antibiotic administration has been associated with improved outcome in CAP so a higher frequency of such use might be associated with better outcome. On the other hand those admitted despite prior antibiotic therapy might be a selected group of more severely ill patients where outcome might be worse or where the giving of outpatient antibiotics has inappropriately delayed hospital referral. Certainly the frequency of prior antibiotic therapy covers a very wide range from 11 (McNabb et al., 1984) to 62 % (Blasi et al., 1993) of cases (Figure 2.8) with on average about one-third of patients being treated before hospital. These differences probably reflect different healthcare structures and practices associated with the settings in which the studies were performed. These differences could have significant bearing on differences in results from these studies.

65 60 55 50 45 40 35 30 25 20 15 10 5 0

Figure 2.8 Proportion who had received antibiotics before hospital admission

ILLNESS SEVERITY

13

Illness Severity With the advent of objective severity scoring tools it is now, for the first time, possible to compare illness severity between different studies – a factor that could have a significant effect on outcomes. Two severity tools are in widespread use – the pneumonia severity index or PSI (Fine et al., 1997), which has five categories of increasing illness severity and the CURB or CURB-65 score (Lim et al., 2003), which has six categories. Two important issues are revealed by a comparison of studies. The first is that the pattern of severity classes is different for the two scoring systems (Figure 2.9). The number of patients gradually increases between PSI classes I to IV with slightly fewer in class V. The number of patients rises between CURB-65 scores 0, 1 and 2, but there are progressively fewer cases in scores 3, 4 and 5, with very few in the last group. The second issue is that the proportion of patients in each class varies considerably between different studies both in North America and other countries (Figure 2.10). For example, the proportion of cases in CURB-65 0 ranges from 14 to 33 % and PSI risk class V from 8 to 20 %. This suggests either that the patterns of CAP illness severity vary in different geographical localities or, more likely, that hospital admission practices vary considerably.

40

%

30 20 10 0 I

II

III

IV

V

40

%

30 20 10 0 0

1

2

3

4

5

Figure 2.9 A comparison of (top) pneumonia severity index (PSI) and (bottom) confusion, urea, respiratory rate, blood pressure and age 65 (CURB-65) scores at admission

14

EPIDEMIOLOGY OF ADULT HOSPITALIZED CAP

I

II

30

30

%

%

20 20

10 0

10 N America

Other

N America

IV

III 40

24 23 22 21 20 19 18 17 16 15

%

%

Other

30

20 N America

N America

Other

Other

V 25

%

20 15 10 5 0 N America

Other

Figure 2.10 Pneumonia severity index (PSI) score on admission

Intensive Care Unit Admission Between one in thirty and one in six patients are admitted to the intensive care unit (ICU; Figure 2.11). This may in part be due to the different spectrum of illness severity seen in different hospitals but may also reflect different ICU admission criteria and facilities (e.g. non-invasive ventilation may take place on the ICU in some hospitals, but on the general ward in others). In keeping with this is the much smaller variation in the proportion of patients receiving mechanical ventilation varying from 4 (Holmberg, 1987) to 11 % (Ruiz et al., 1999) of all hospital admissions for CAP.

CONCLUSIONS

15

17.5 15.0

%

12.5 10.0 7.5 5.0 2.5 0.0 ICU N America ICU Europe

MV Europe

Figure 2.11 Proportion of patients admitted to the intensive care unit (ICU; MV, mechanical ventilation)

Mortality Most patients survive their hospital admission, but a significant minority of those admitted to hospital with CAP will go on to die (Figure 2.12). Once again there is considerable variation between studies, with death occurring in from 3 (Logroscino et al., 1999) to 15 % (Macfarlane et al., 1982) of cases. Different case mix, severity mix and management practices may all contribute to this difference. 15

%

10

5

0

Figure 2.12 Proportion of admissions that died

Conclusions Considerable variability exists in epidemiological factors between studies of adults with CAP. Different study methodologies mean that it is not easy to distinguish which of these differences are due to genuine differences in study populations and

16

EPIDEMIOLOGY OF ADULT HOSPITALIZED CAP

which are artefacts of study design. Many of these variations could contribute to bias in study results. It is important for the future that such studies make methodology clear and describe these epidemiological characteristics in detail.

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Men´endez R, Cordoba J, de La CP, et al. 1999. Value of the polymerase chain reaction assay in noninvasive respiratory samples for diagnosis of community-acquired pneumonia. Am J Respir Crit Care Med 159: 1868–1873. Michetti G, Pugliese C, Bamberga M, et al. 1995. Community-acquired pneumonia: is there difference in etiology between hospitalized and outpatients. Minerva Med 86: 341–351. Morimoto S, Okaishi K, Onishi M, et al. 2002. Deletion allele of the angiotensin-converting enzyme gene as a risk factor for pneumonia in elderly patients. Am J Med 112: 89–94. Mortensen EM, Restrepo MI, Anzueto A, Pugh J. 2005. The effect of prior statin use on 30day mortality for patients hospitalized with community-acquired pneumonia. Respir Res 6: 82. Mundy LM, Leet TL, Darst K, Schnitzler MA, Dunagan WC. 2003. Early mobilization of patients hospitalized with community-acquired pneumonia. Chest 124: 883–889. Nichol KL, Baken L, Wuorenma J, Nelson A. 1999. The health and economic benefits associated with pneumococcal vaccination of elderly persons with chronic lung disease. Arch Intern Med 159: 2437–2442. Nuorti JP, Butler JC, Crutcher JM, et al. 1998. An outbreak of multidrug-resistant pneumococcal pneumonia and bacteremia among unvaccinated nursing home residents. N Engl J Med 338: 1861–1868. Ohkubo T, Chapman N, Neal B, Woodward M, Omae T, Chalmers J. 2004. Effects of an angiotensin-converting enzyme inhibitor-based regimen on pneumonia risk. Am J Respir Crit Care Med 169: 1041–1045. Okaishi K, Morimoto S, Fukuo K, et al. 1999. Reduction of risk of pneumonia associated with use of angiotensin I converting enzyme inhibitors in elderly inpatients. Am J Hypertens 12: 778–783. Ortega L, Sierra M, Dominguez J, et al. 2005. Utility of a pneumonia severity index in the optimization of the diagnostic and therapeutic effort for community-acquired pneumonia. Scand J Infect Dis 37: 657–663. ¨ Ortqvist A, Hedlund J, Grillner L, et al. 1990. Aetiology, outcome and prognostic factors in community-acquired pneumonia requiring hospitalization. Eur Respir J 3: 1105–1113. Osler W. 1901. Lobar pneumonia. In The Principles and Practice of Medicine. Edinburgh and London: Young J Pentland; 108–137. Ostergaard L, Andersen PL. 1993. Etiology of community-acquired pneumonia. Evaluation by transtracheal aspiration, blood culture or serology. Chest 104: 1400–1407. Pareja A, Bernal C, Leyva A, Piedrola G, Maroto MC. 1992. Etiologic study of patients with community-acquired pneumonia. Chest 101: 1207–1210. Roson B, Carratala J, Dorca J, Casanova A, Manresa F, Gudiol F. 2001. Etiology, reasons for hospitalization, risk classes, and outcomes of community-acquired pneumonia in patients hospitalized on the basis of conventional admission criteria. Clin Infect Dis 33: 158–165. Ruf B, Schurmann D, Horbach I, Fehrenbach FJ, Pohle HD. 1989. Incidence and clinical features of community-acquired legionellosis in hospitalized patients. Eur Respir J 2: 257–262. Ruiz M, Ewig S, Marcos MA, et al. 1999. Etiology of community-acquired pneumonia: impact of age, comorbidity, and severity. Am J Respir Crit Care Med 160: 397–405. Socan M, Marinic-Fiser N, Kraigher A, Kotnik A, Logar M. 1999. Microbial aetiology of community-acquired pneumonia in hospitalised patients. Eur J Clin Microbiol Infect Dis. 18: 777–782. Sopena N, Sabria M, Pedro-Botet ML, et al. 1999. Prospective study of community-acquired pneumonia of bacterial etiology in adults. Eur J Clin Microbiol Infect Dis. 18: 852–858. Steinhoff D, Lode H, Ruckdeschel G, et al. 1996. Chlamydia pneumoniae as a cause of community-acquired pneumonia in hospitalized patients in Berlin. Clin Infect Dis 22: 958–964.

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3 Microbial Aetiology and Antibiotic Resistances in Community-Acquired Pneumonia ´ GERARD HUCHON Universit´e de Paris 5 Ren´e Descartes, Service de Pneumologie et R´eanimation, Hopital de l’Hotel-Dieu, Paris, France ˆ ˆ

Introduction Community-acquired pneumonias (CAP) are of bacterial or viral origin, and much less frequently parasitic or fungal. Identification of microbial agents implies investigations usually carried out only in severe or potentially severe forms of CAP, or in case of resistance to initial antimicrobial treatment. Therefore, data on microbial aetiology rely only on studies performed either for primarily studying microbial epidemiology, or as satellite results of clinical trials testing antimicrobials or therapeutic strategies. The microbiological causes of CAP have been studied in outpatients, and in patients admitted to hospital or to the intensive care unit (ICU); most frequently involved pathogens are shown in Table 3.1 (Woodhead et al., 2005). Wide variations between studies in the frequency of each micro-organism can be explained by several factors, including differences in studied populations (e.g., age range or other risk factors), geographical area, studied samples and microbiological methods. The microbial aetiologies of mild infections in outpatients look similar to that of hospitalized patients (Woodhead et al., 2005): extracellular bacteria, especially Streptococcus pneumoniae, are in the first place, followed by Haemophilus influenzae, Staphylococcus aureus, Moraxella catarrhalis; among intracellular bacilli, Mycoplasma pneumoniae is the most common, followed in frequency by Legionella Community-Acquired Pneumonia: Strategies for Management Edited by Antoni Torres and Rosario Men´endez  2008 John Wiley & Sons, Ltd

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MICROBIAL AETIOLOGY AND ANTIBIOTIC RESISTANCES

Table 3.1 Percentage range of aetiologies of community-acquired pneumonia in adults in the community and in patients admitted to hospital and intensive care units (ICU) (After Woodhead et al., 2005) Community

Hospital

ICU

0–36 0–14 0–13 0–2 0–1 0–1 1–33 7–15 0–9 0–3 2–33 0–19

6–76 1–16 1–14 0–2 0–4 0–33 0–18 0–18 0–6 0–10.9 1–24 0–13

12–33 0–12 0–30 – 0–19 0–15 0–7 – 0–6 0–2 0–17 0–9

Streptococcus pneumoniae Haemophilus influenzae Legionella pneumophila Moraxella catarrhalis Staphylococcus aureus Gram-negative bacilli Mycoplasma pneumoniae Chlamydia pneumoniae Chlamydia psittaci Coxiella burnetii All viruses Influenza virus

and Chlamydia species; viruses are involved in 5–20 %. In ICUs, Staphylococcus aureus, Gram-negative bacilli and Legionella species are more frequently encountered.

Missing Microbial Agent The search for microbial agents responsible for CAP is usually not carried out in the community; in contrast, in the hospital evidence for microbial agents is extensively searched in patients with severe or resistant pneumonia or at risk of severe pneumonia. In those circumstances, as well as in clinical studies, the results are quite disappointing, since no pathogen is identified in a large proportion of cases (50 % overall). There are various explanations to that observation. For example, Ewig et al. (2002) observed in patients hospitalized for CAP that over the age 70 years, renal and cardiac comorbid illnesses and non-alveolar infiltrates were independently associated with a higher proportion of unknown aetiology. In many studies, all the appropriate tests have not been performed because they focused on extracellular bacteria, and others on intracellular bacteria or viruses. Furthermore, new infective agents and new microbial techniques are not usually applied without delay.

Bacterial Pneumonia Antibiotic Resistances Antibiotic resistance of bacteria is an increasing concern (Felmingham et al., 1998; Ewig et al., 1999b; Felmingham and Gruneberg, 2000; Marco et al., 2000; Schito et al., 2000; Groom et al., 2001; Marcos et al., 2006; Melo-Cristino et al., 2001;

BACTERIAL PNEUMONIA

23

EARSS, 2007), especially the resistance of S. pneumoniae, by far the most commonly documented cause of respiratory infection. There are large variations in resistance between areas. These variations in local resistance probably result from local habits in the use of antibiotics, inducing different selection pressures; they have to be identified and taken into account in guidelines on antibiotic strategies. Most epidemiological data on antibiotic resistance in this chapter were obtained from The Alexander Project, which is a world-wide continuing surveillance study, initiated in 1992, examining the susceptibility of pathogens involved in adult community-acquired respiratory tract infections to a range of antimicrobial agents (Felmingham and Gruneberg, 2000; Schito et al., 2000; Jacobs et al., 2003), and from the European Antimicrobial Resistance Surveillance System (EARSS; Bronzwaer et al., 1999; EARSS, 2007).

Streptococcus Species Streptococcus pneumoniae, the most common bacteria isolated from patients with CAP, easily proliferates when natural defences decline (ageing, alcoholism, diabetes, smoking, immunosuppression). Any S. pneumoniae pneumonia is a medical emergency, considering the fast rate of bacterial multiplication and the high risk of complications (empyema, meningitis, septicaemia and septic shock, adult respiratory distress syndrome). Other Streptococcus species are rarely involved in pneumonia. Among these, Streptococcus pyogenes pneumonia occurs more often in the young than in the elderly, usually after viral infections, both in infants (measles, rubella or varicella) and adults (influenza, measles or varicella). World-wide prevalence of resistance has been reported for S. pneumoniae (Jacobs et al., 2003; Felmingham, 2004; Jacobs, 2004). The penicillin resistance (penicillin MICs ≥ 2 mg/L) was 18.2 %, and the macrolide resistance (erythromycin MICs ≥ 1 mg/L) 24.6 % over the 1998–2000 period. Macrolide resistance exceeded penicillin resistance in 19 of 26 countries. Of the non-fluoroquinolone agents, the only oral agents to which over 90 % of S. pneumoniae isolates were susceptible were amoxicillin (95.1 %) and co-amoxiclav (95.5–97.9 %). The prevalence of fluoroquinolone-resistant S. pneumoniae (ofloxacin MICs ≥ 8 mg/L) was 1.1 %. Gemifloxacin was the most potent fluoroquinolone tested against S. pneumoniae (99.9 % susceptible). Data from global surveillance studies, however, indicate that resistance to penicillin (MIC ≥ 2 mg/L) among isolates of S. pneumoniae varies widely by geographical location (Felmingham, 2004; Trystram et al., 2004; EARSS, 2007). Rates exceed 20 % in the USA, Mexico, Japan, Saudi Arabia, Israel, Spain, France, Greece, Hungary and the Slovak Republic. In South Africa, Hong Kong, Taiwan and South Korea rates exceed 50 %. The proportion of isolates with Penicillin-Non-Susceptible Pneumococci (PNSP) exhibiting resistance and intermediate susceptibility (MIC 0.12–1 mg/L) was the highest in France (53 %), followed in decreasing order by Romania (50 %), Israel (38 %), Spain (33 %) and Poland (30 %); the PNSP rate was lower than 5 % in Austria, Denmark, Germany and The Nederland. Penicillin-Non-Susceptible Pneumococci is

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MICROBIAL AETIOLOGY AND ANTIBIOTIC RESISTANCES

frequently found in association with macrolide resistance, the prevalence of which is about 70–80 % in some Asian countries. The proportion of S. pneumoniae resistant to macrolide was the highest in Poland (67 %), followed by France (58 %), Belgium (34 %) and Italy (32 %). Trimethoprim-sulphamethoxazole (TMPSMX) and tetracycline resistance, either individually or combined with macrolide resistance as multiple resistance, is also associated with reduced susceptibility to penicillin. Antibiotic resistance of S. pneumoniae is of such concern that its impact in CAP has been studied extensively. However, consequences in term of morbidity and mortality are still debated. In a 10-year prospective study conducted in Spain, resistance or decreased sensibility of S. pneumoniae to penicillin and/or cephalosporin were not associated with an increased mortality in 204 patients with pneumococcal pneumonia, including 145 patients with penicillin-resistant strains and 31 with cephalosporin-resistant strains (Pallares et al., 1995). Similar results have been provided by other studies (Ewig et al., 1999a, b; Moroney et al., 2001; Valles et al., 2006). In one, there was no association of drug resistance with mortality and length of hospitalization, but mortality was associated with female gender, pleural effusion, and previous oral corticoid treatment (Valles et al., 2006). In another large study, mortality after day 4 was higher in patients with penicillin MIC > 4 µg/L or cephalosporin MIC > 2 µg/L (Feikin et al., 2000). Finally, a retrospective case-control study found a longer delay before response to treatment and an increased length of hospital stay when there were high levels of cephalosporin-resistance of S. pneumoniae (Ailani et al., 2002). Therefore, current levels of resistance of S. pneumoniae do not appear to impact significantly on the outcome of S. pneumoniae CAP. However, high levels of resistance to penicillin and cephalosporins might increase mortality after day 4, time-to-response and length of stay. There has been an international agreement on definitions of sensitivity (MIC ≤ 0.064 mg/L) and resistance (MIC ≥ 2 mg/L) of S. pneumoniae to bensylpenicillin for years; but, as mentioned above, it is also known that, for pneumonia, these breakpoints do not perfectly fit with clinical outcomes. Therefore, the European Committee on Antimicrobial Susceptibility Testing (www.antimicrobe.org) is discussing the possibility to consider sensitive and intermediate S. pneumoniae isolates as susceptible in pneumonia, whereas intermediate and resistant isolates should be considered as resistant in meningitis.

Haemophilus Influenzae Community-acquired pneumonia due to Haemophilus influenzae occurs usually after upper respiratory tract infection. Most invasive infections by H. influenzae result from strains encapsulated and typeable rather than non-encapsulated and non-typeable. The proportion of β-lactamase positive H. influenzae is 16.9 %, whereas the prevalence of β-lactamase-negative, ampicillin-resistant strains is low (0.2 %) (Schito et al., 2000; Jacobs et al., 2003). Using pharmacokinetic/pharmacodynamic

BACTERIAL PNEUMONIA

25

(PK/PD) breakpoints, the most active non-fluoroquinolone agents against H. influenzae are ceftriaxone (100 % susceptible), cefixime (99.8 %) and coamoxiclav (98.1–99.6 %). Haemophilus influenzae is susceptible to fluoroquinolones, including levofloxacin that has been available for the longest time.

Legionella Pneumophila About 30 Legionella species have been identified; they are aerobic Gram-negative intracellular bacilli, the most common being Legionella pneumophila (Cordes and Fraser 1980; Girod et al., 1982; Davis and Winn, Jr. 1987; Plouffe and File, 1999). Their natural reservoirs are water and air-conditioning systems, from where they spread by air. No transmission between human beings has been reported. Infection by L. pneumophila possibly may cause an asymptomatic seroconversion, a lone episode of pyrexia, or mild to severe pneumonia. Fever, chills, headache and upper respiratory tract symptoms might take place during Pontiac fever. Pneumonia occurs either sporadically or in small epidemics, and will more probably occur in immunocompromised hosts. Legionella pneumophila (8 % in patients under 80 years) rarely occur in the very old (1 % in patients over 80 years) (FernandezSabe et al., 2003).

Moraxella Catarrhalis Moraxella catarrhalis is a Gram-negative diplococcus frequently found in the oropharynx of normal subjects. Community-acquired pneumonia due to M. catarrhalis usually occurs in patients with comorbidities such as chronic obstructive pulmonary disease (COPD), congestive heart disease, or malignancy. Production of beta-lactams by M. catarrhalis is common world-wide (82–94 %) (Felmingham et al., 1998; Schito et al., 2000; Melo-Cristino et al., 2001; Jacobs et al., 2003) Co-amoxiclav, cefdinir and cefixime are the most active beta-lactams against M. catarrhalis which is also highly susceptible to the fluoroquinolones (Jacobs et al., 2003).

Staphylococcus Species Staphylococcal infection occurs by inhalation, aspiration, or haematogenous spread. Airborne contamination may take place after viral infection (influenza, measles), or be related to comorbidity such as COPD, carcinoma, laryngectomy, seizure, particularly in the elderly (Terpenning et al., 1994). Haematogenous spread results from bacteremia (endocarditis, infective foci flowing into the bloodstream, intravenous drug abuse). Methicillin-resistant S. aureus (MRSA), originally a nosocomial pathogen, appeared in recent times in the community, and are referred to as communityacquired MRSA (CA-MRSA). Resistance to methicillin is mediated by the gene mecA carried by the mobile genetic element staphylococcal cassette chromosome

26

MICROBIAL AETIOLOGY AND ANTIBIOTIC RESISTANCES

mec (SCCmec). Staphylococcal cassette chromosome mec type IV has been associated previously with the Panton–Valentine leukocidin (PVL) toxin, but new PVL-positive clones with novel SCCmec types may be arising and disseminating in the community (Berglund et al., 2005). Methicillin-resistant S. aureus has emerged as an infectious agent of increasing frequency associated with skin and soft-tissue infections in the community setting. For example, in a study performed in USA emergency departments (Moran et al., 2006), S. aureus was isolated from 76 % of patients with skin and soft-tissue infections; the prevalence of MRSA was 59 %, and SCCmec element type IV and the PVL toxin gene were detected in 98 % of MRSA isolates. In a study on the prevalence and risk factors for CA-MRSA (Beam and Buckley 2006), 85 % of hospital patients diagnosed with CA-MRSA and 47.5 % of healthy community members colonized with MRSA were found to have at least one health-care-associated risk factor: recent hospitalization, outpatient visit, nursing home admission, antibiotic exposure, chronic illness, injection drug use, and close contact with a person with risk factor(s). The challenge of the antibiotic treatment of S. aureus could be enhanced by the emergence and spread of S. aureus strains with reduced susceptibility to glycopeptides, i.e. vancomycin-intermediate S. aureus/glycopeptideintermediate S. aureus (VISA/GISA) and vancomycin-resistant S. aureus (VRSA) (de Lassence et al., 2006). Community-acquired MRSA can also lead to severe pulmonary infections, including necrotizing and haemorrhagic pneumonia, pneumothorax, pneumopyothorax, empyema, ventilatory failure and septicaemia (Lina et al., 1999; Gillet et al., 2002; Hageman et al., 2006; Hyvernat et al., 2007). It is more virulent compared with healthcare-associated MRSA isolates. Panton–Valentine leukocidin is a toxin that creates lytic pores in the cell membranes of neutrophils and induces the release of neutrophil chemotactic factors that promote inflammation and tissue destruction. Recently, Centers for Disease Control and Prevention (2007) have reported CA-MRSA associated with influenza virus infection or influenza-like illness; they reported 10 cases of severe MRSA CAP, including six deaths, among previously healthy children and adults in Louisiana and Georgia during December 2006 to January 2007.

Gram-Negative Bacilli Gram-negative bacilli (GNB) consist of various Enterobacteriaceae and Pseudomonadaceae, including Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa and Acinetobacter species. Gram-negative bacilli are a common cause of severe hospital-acquired pneumonia, but selective antimicrobial pressure and changes in the health-care environment have made GNB a more common cause of CAP (Terpenning et al., 1994, 2001). Oropharyngal colonization and inhalation or micro-aspirations of the bacilli may lead to pneumonia, particularly in the elderly (Preston et al., 1999; Terpenning et al., 2001). Comorbidities are usually considered as a risk factor for GNB pneumonias. Friedl¨ander’s pneumonia (K. pneumoniae) typically occurs in men over 40 years;

BACTERIAL PNEUMONIA

27

alcoholism, diabetes mellitus and pulmonary comorbidity are predisposing factors. Escherichia coli pneumonia and P. aeruginosa pneumonia usually occur in chronically ill patients. The risk factors for GNB CAP, and more specifically P. aeroginosa CAP, have been studied by Arancibia et al. (2002): probable aspiration, previous hospital admission, previous antimicrobial treatment and the presence of pulmonary comorbidity were independent predictors of GNB aetiology; pulmonary comorbidity and previous hospital admission were predictive of P. aeroginosa aetiology. Gram-negative bacilli were also an independent risk factor for death in patients with CAP. Pseudomonas pseudomallei, responsible for melioidosis, is an aerobic GNB found in soil, vegetation and water in tropical regions (Cheng and Currie, 2005). Humans and many animals are susceptible to melioidosis. Lung infection usually results from either the spread through the bloodstream of cutaneous infection or inhalation. The clinical presentation may be either acute or chronic.

Atypical Agents CAP due to M. pneumoniae, Chlamydia psittaci, Chlamydia pneumoniae, and Chlamydia burnetii (7 % in patients under 80 years) occur rarely in the elderly (1 % in patients over 80 years) (Fernandez-Sabe et al., 2003). Mycoplasma Pneumoniae

Mycoplasma are mucosal pathogens, living as a parasite in association with epithelial cells of the host, usually in the respiratory or urogenital tracts (Waites and Talkington, 2004; Blasi et al., 2005). Mycoplasma pneumoniae exclusively parasites humans and can be transmitted through aerosols from person to person and enhanced by close personal contact. Mycoplasma pneumoniae infection is able to involve the upper and the lower respiratory tracts and occur both endemically and epidemically world-wide in children and adults. The endemic disease transmission is punctuated by cyclic epidemics every 3 to 5 years. Outbreaks of M. pneumoniae infections tend to happen in the summer or early autumn. A prior upper respiratory tract infection is found in about 50 % of patients. Mycoplasma pneumoniae infections imitate the clinical presentation of viral respiratory infections with a longer incubation period (10 to 20 days). Chlamydia Species

Psittacosis is a pneumonia caused by an intracellular bacterium, Chlamydia psittaci, which is responsible for ornithosis in the domestic fowl. Chlamydia psittaci can be transmitted to humans by inhalation from infected birds, including canaries, parakeets, parrots, pigeons and turkeys (Kirchner, 1997). Pneumonia caused by C. psittaci probably occurs considerably more frequently than the few cases reported annually. Parrots and other birds still are the major reservoir of C. psittaci and most diagnosed patients own pet birds or work in a pet store (Gregory and Schaffner, 1997).

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Chlamydia pneumoniae was recognized as a human respiratory pathogen in 1985 (Hahn et al., 2002; Blasi et al., 2005). It has a unique biphasic life cycle characterized by an obligate intracellular (replicative) and an extracellular (infectious) form of the organism. Chlamydia pneumoniae infects the majority of the world’s population as a result of inhalation. If most acute human C. pneumoniae respiratory tract infections remain asymptomatic, about a third may have a more severe respiratory disease, such as CAP. After acute infection, C. pneumoniae stay in host cells, is metabolically inert, and then resistant to antibiotic. The role of C. pneumoniae as a cause of persistent infection in chronic respiratory diseases has been investigated, and the incidence of pneumonia due to C. pneumoniae remains uncertain: variations between studies are related to several factors such as the setting, age group and diagnostic methods. The absence of a gold standard for diagnosis jeopardizes the understanding of the prevalence and role of C. pneumoniae in acute and chronic respiratory infections. Coxiella Burnetii

Coxiella burnetii causes Q fever but is rarely reported (Cutler et al., 2007). It is the most frequent pathogen responsible for pneumonia among the Rickettsiaceae. It is distributed world-wide, except in New Zealand. Ticks are vector agents. Various wild and domestic animals (cattle, sheep, goats) are infected with no evidence of disease; C. burnetii multiplies in the placenta of pregnant animals and spreads during parturition. Although C. burnetii is present in numerous species of ticks, the main route of transmission is by inhalation.

Other Bacterial Agents Others bacteria may rarely cause CAP in special circumstances. Some of them could be used as biological weapons (Ligon, 2006). Nocardia asteroides and, to a lesser extent, Nocardia brasiliensis cause most cases of Nocardia pneumonia, which frequently present as subacute infections. Nocardia are aerobic, Gram-positive bacilli present mainly in soil. Nocardiosis occurs in both normal and immunocompromised hosts (Smeal and Schenfeld, 1986; Men´endez et al., 1997; Sopena et al., 1999). The diagnosis might be missed because of contamination of cultures and the need to extend culture periods. Because of this difficult diagnosis, the incidence of nocardiosis could be higher than published data suggest. Actinomyces and Arachnia species, and particularly Actinomyces israelii, can cause actinomycosis, which also often exhibits a subacute course (Morris and Sewell, 1994; Bassiri et al., 1996). They are anaerobic, Gram-positive, filamentous, branching bacilli, incorrectly considered as fungi for many years. Normally present in the oropharynx, they become invasive because there is a defect in the anatomic barrier or because they are inhaled. Then the infection may extend directly from one place to an adjacent area. Risk factors for pulmonary infection are bad dentition, bronchiectasis, COPD and male gender.

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Pasteurella multocida is a Gram-negative coccobacillus resident in oropharynx of mammals (Klein and Cunha, 1997). It causes cutaneous infection in humans after animal bites. Pneumonia has been reported in patients with chronic lung diseases. Francisella tularensis is a Gram-negative bacillus found in Northern Hemisphere mammals and insects (Sj¨ostedt, 2007; Vorou et al., 2007). Tularaemia is the consequence of a bite or contact with an infected animal. Yersinia pestis or Pasteurella pestis is a short Gram-negative rod that causes the three forms of plague: bubonic, septicemic and pneumonic (Koirala 2006; Ligon 2006; Eisen et al., 2007). That disease of rodents (squirrels, rabbits, rats) is transmitted to humans by flea bites or by person-to-person contact via aerosol inhalation. Initial symptoms are chills, fever, prostration, delirium, headache, vomiting and diarrhoea. Bacillus anthracis is a large Gram-positive rod that causes anthrax (cutaneous, intestinal, and pneumonic). Bacillus anthracis is present in soil, water and vegetation; it infects cows, sheep and horses, which in turn may infect humans. Bacillus cereus, which contains anthrax toxin genes, may be responsible for fatal pneumonia (Avashia et al., 2007). Brucella species are Gram-negative coccobacilli resident in the genitourinary tract of cows, pigs, goats and dogs (Gur et al., 2006). Contact with infected animals or ingestion of unpasteurized milk products cause brucellosis; thereafter the pathogen spreads in the body through the bloodstream.

Viral Pneumonia If pneumonia accounts for 20 % to 40 % of viral lower respiratory tract infections in children, incidence of viral pneumonia varies a lot in adult patients who are not immunocompromised, increasing with epidemics and ageing. Viral pneumonia may be caused by a direct action of virus or/and by consequences of a systemic infection. In hospitalized non-immunocompromised adults with CAP, the most common aetiological agents after S. pneumoniae (29 %) are respiratory viruses (23 %) (Marcos et al., 2006). In another study, CAP is due to viruses in 18 % (i.e., influenza, parainfluenza, respiratory syncytial virus and adenovirus), dominated by influenza in 12 % (de Roux et al., 2004); patients with cardiac heart failure (CHF) have an increased risk of acquiring a viral CAP. As sophisticated diagnostic tests become more widely available, the relative importance of additional viruses such as parainfluenza viruses, rhinoviruses, coronaviruses and metapneumoviruses will probably increase (Falsey and Walsh, 2006).

Influenza Virus Three types of influenza virus are identified: A, B and C (Cox and Subbarao, 1999). Types A and B are responsible for diseases, including the most severe and widespread, while type C looks harmless. Haemagglutinin and neuraminidase (sialidase) are the antigens of the virus envelope. In type A viruses, the former

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undergoes periodic changes, which may either lead to an entirely new gene by antigenic shifts following reassortments between strains, or result in antigenic drifts because of point mutations. Host immune response is mainly directed against haemagglutinin. Shifts are associated with pandemics if antigenic modifications lead to a decreased immune protection in the community. Drifts are usually associated with limited epidemics. Outbreaks of severe disease occur every one to three decades, with an excess mortality that may be as high as 10 000 patients per year. Transmission is by respiratory secretions (Brankston et al., 2007). Pneumonia may occur directly after the acute illness caused by the virus itself (primary pneumonia), or may result from bacterial superinfection, usually with S. pneumoniae, H. influenzae or S. aureus, after a period of improvement (secondary pneumonia). Influenza is responsible for at least half the viral pneumonias in immunocompetent adult subjects. Primary pneumonia occurs more in association with heart failure, and secondary pneumonia in elderly or patients with comorbidities, such as chronic cardiovascular or respiratory disease, diabetes mellitus, or chronic hepatic or renal failure.

Avian Influenza Virus Sporadic human infections by avian influenza virus A/H5N1 in various places in the world increase the risk for future pandemics (Beigel et al., 2005; Chotpitayasunondh et al., 2005; Boyd et al., 2006; Hsieh et al., 2006; Rajagopal and Treanor 2007). Avian influenza A/H5N1 infection in humans is much more severe than routine seasonal influenza, and is associated with severe illness and a > 50 % mortality rate, especially in people aged 10–39 years. Exposure to sick and dying fowls in an area where H5N1 is known or suspected to be has been reported in most patients, although the recognition of fowl outbreaks sometimes followed the recognition of human infections.

Parainfluenza Virus Four types of human parainfluenza viruses (HPIV) have been identified (HPIV-1 to HPIV-4) and are responsible for up to 20 % of the respiratory infections that occur in children (cold with fever, croup, bronchiolitis, pneumonia) but also infrequently in immunocompetent adults (Arden et al., 2006; Laurichesse et al., 1999). Reinfection with HPIV can occur in elderly and immunocompromised persons who are at a greater risk of serious complications; HPIV-1 has also been associated with secondary bacterial pneumonias in elderly persons. As with influenza, parainfluenza viruses are transmitted between humans via respiratory secretions. The incubation period lasts 2 to 6 days. Types HPIV-1 and HPIV-3 each cause pneumonias more frequently than HPIV-2 and HPIV-4. Type HPIV-1 infection has been associated with secondary bacterial pneumonias in elderly persons.

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Respiratory Syncytial Virus Being the principal cause of respiratory tract infection in children younger than 6 months, respiratory syncytial virus (RSV) is responsible for 25 % of hospital admissions for pneumonia and bronchiolitis. Almost all children older than 5 years have anti-RSV antibodies. In adults, mild to moderate upper respiratory tract illness is usual, but severe pneumonia may occur, particularly in the elderly with comorbidities or compromised immune status (Falsey et al., 2005; Falsey 2007). The incubation period lasts 4 to 6 days; epidemics occur in the late autumn and spring and usually last 1 to 5 months. Transmittal of RSV is by contaminated skin followed by autoinoculation in the conjunctiva or nose, or by aerosols produced by coughing or sneezing.

Adenovirus Adenoviruses are responsible for up to 10 % of pneumonias in children (CastroRodriguez et al., 2006) but account for less than 2 % of those in adults, especially in the immunocompromised host; with the exception of military recruits. Adenovirus respiratory infection may be the consequence of airborne or of faecal–oral contamination. The incubation period lasts 4 to 7 days.

Measles and German Measles Measles viruses belong to the paramyxoviridae family and therefore are similar to parainfluenza virus and RSV. Viruses enter humans by the respiratory tract and conjunctiva; 50 % of patients with measles have lower respiratory tract manifestations, mainly bronchitis and pneumonia, which may be complicated by bacterial superinfection 5–10 days after the onset of infection.

Varicella Varicella is a frequent contagious infection in childhood with growing incidence in adults. Pneumonia, even though rare, is the most serious complication that commonly affects adults (Mohsen and McKendrick, 2003). Epidemics occur in winter and spring, with infectivity rates that exceed 90 % during the initial 2 to 3 weeks after exposure, until lesions have crusted over.

Hantavirus The hantavirus pulmonary syndrome was first recognized in the USA in 1983, but the disease was retrospectively identified using serologic testing in patients who had a similar illness in 1959 (Miedzinski, 2005). The syndrome can result from several hantaviruses, such as Sin Nombre virus. Almost all cases have been

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reported in North and South America. Rodents (e.g., field mice, voles, chipmunks) serve as the reservoir, and transmission to human results from aeroionization of viruses contained in their faeces. Person-to-person spread rarely, if ever, occurs. Avoidance of areas where infected rodents live is the only preventive measure.

Severe Acute Respiratory Syndrome An outbreak of severe acute respiratory syndrome (SARS) was reported in 2002, mainly in Asian countries and Canada (Booth et al., 2003; Drosten et al., 2003; Hsu et al., 2003; Mandell 2005). The origin of the epidemic was probably the Guangdong province in China. None of the previously known respiratory pathogens was identified, and a new virus belonging to the coronaviridae family was found to be responsible. In 2004 and 2005, a second (CoV-NL63) and a third coronavirus (CoV-HKU1) were described. Considering that SARS is highly transmissible, patients have to be isolated in a single room possibly with negative pressure. Health-care personnel should put on gloves, gown, mask and eye protection, and wash their hands after removing their gloves. Health-care workers in contact with SARS patients should be limited in number.

Fungal and Parasitic Pneumonia Although fungal and parasitic pulmonary infections are frequently self-limited, recurrent or severe disease is common when cell-mediated immunity is impaired. However, pneumonias due to fungi and parasites may occur in the community in immunocompetent subjects with underlying lung disease. In those with a history of passing through endemic areas, the diagnosis of fungal pneumonia due to Histoplasma capsulatum, Blastomyces dermatitides or Coccidioides immitis, should be considered. Pneumonias due to opportunistic fungi (including species of Candida, Aspergillus and Phycomycetes) are also on the increase, and these arise mostly in compromised hosts.

Aspergillosis Aspergillus species are ubiquitous saprophytic fungi that produce toxic molecules (e.g., endotoxin, proteases). Airway colonization by Aspergillus is usually seen in patients with chronic lung alterations (bronchiectatic, fibrosis, tuberculosis sequelae, local host defence impairment). Invasive aspergillosis is an unusual finding in non-neutropenic patients but has been described in patients with chronic obstructive pulmonary disease on long-term steroid therapy, as well as in presumably healthy immunocompetent hosts (Clancy and Nguyen, 1998).

Cryptococcosis Found throughout the world in bird guano, Cryptococcus neoformans causes Cryptococcosis, particularly in immunocompromised patients, especially in AIDS and

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post-transplant patients. It is rare and usually asymptomatic and self-limited in immunocompetent patients. But there are a few case reports of pulmonary cryptococcosis in immunocompetent patients (Yang et al., 2006).

Pneumonias due to Soil-Dwelling Fungi After the contamination and growth of fungi in soil, infectious particles reach the lungs by inhalation. The spores in infective particles have usually an ideal size to reach the terminal airways. In the lung, multiplication converts the spores into yeasts. Histoplasmosis

Histoplasma capsulatum is found in soil contaminated by bird or bat faeces necessary for its growth (Wheat and Kauffman, 2003; Ansart et al., 2004). The disease is present in the central USA, Mexico and Puerto-Rico. Numerous occupations have an increased risk of exposure in rural communities as well as in urban settings that involve moving contaminated soil. Cellular immunocompromised patients are more susceptible to histoplasmosis and may present more severe disease. Subjects who inhale a larger numbers of spores develop abruptly 14 days later a syndrome that mimics influenza, bacterial pneumonia, tuberculosis, or even acute respiratory distress syndrome (ARDS). Blastomycosis

Blastomycosis is found in North America, Mexico, the Middle East, Africa and India and results from inhalation of Blastomyces dermatitidis (Bradsher et al., 2003). Blastomyces dermatitidis infection may be sporadic or epidemic. Depending on predominant inflammatory response, pyogenic or granulomatous, histopathological patterns may mimic bacterial infection, sarcoidosis or tuberculosis. After multiplication of the yeast in lungs, B. dermatitidis may spread to the other organs. Extrapulmonary manifestations may occur years after the initial infection. Coccidioidomycosis

Coccidioides immitis is endemic in the southwestern United States and northern Mexico and occurs mainly during hot, dry summers (DiCaudo, 2006). Inhalation of airborne spores leads to polymorphonuclear-mediated suppurative and cellmediated granulomatous inflammatory responses. The incubation period is 10 to 16 days. Paracoccidioidomycosis

Paracoccidioidomycosis results from the inhalation of Paracoccidioides brasiliensis found mainly in South and Central America and in Mexico (dos Santos et al., 2004). In non-immunocompromised patients, paracoccidioidomycosis presents as

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a chronic or subacute lung infection that is usually self-limited. In immunocompromised subjects, the clinical manifestations are those of an acute, severe disseminated infection.

Malarial Lung Pleuropulmonary complications result from Plasmodium falciparum, agent of the most severe form of malaria. Pulmonary involvement results from increased pulmonary capillary permeability and is usually associated with cerebral disease and marked parasitemia. Pulmonary oedema is the most important pulmonary manifestation of malaria. It may also occur rarely in milder disease (Taylor and White, 2002).

Pneumonias in Relation with Parasite Migration Pulmonary Ascariasis

The world-wide prevalence of infection by Ascaris lumbricoides is about 25 %. The normal adult worm lives in the jejunum, and infection follows ingestion of embryonated eggs. Maturation occurs during pulmonary migration and may be responsible for ascaris pneumonia, a disease occurring 4 to 16 days after ingestion and lasts for one to several weeks. Ascariasis is responsible for a L¨offler-like syndrome in approximately 20 % of cases. Strongyloidiasis and Ancylostomiasis

Strongyloides stercoralis is endemic in tropical and subtropical areas. Ancylostomiasis, or hookworm infection, may be caused by two nematodes: Ancylostoma duodenale and Necator americanus. The prevalence and life cycles of the parasites are similar to those of Ascaris lumbricoides. Patients may be asymptomatic or experience a L¨offler-like syndrome. Visceral Larva Migrans

Human visceral larva migrans is caused by Toxocara canis or Toxocara catis. The prevalence of infection in the dog is about 3 %. Humans are infected by ingestion of eggs in contaminated food or soil. Larvae migrate to the liver and lungs through lymphatics and blood vessels and induce an IgE-mediated immune response. In rare cases, other organs may be involved, such as the heart or the central nervous system.

Polymicrobial Pneumonias A substantial number of CAP may be attributed to more than one microbe. These situations can be divided into two groups: pure microbial pneumonia, involving two or more bacteria, two or more viruses, two or more fungi, or two or more

SUMMARY

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parasites; and mixed microbial pneumonia involving a combination of at least two kinds of microbes (bacteria, virus, fungi, parasite). In the community, polymicrobial pneumonia occurring in non-immunocompromised mainly implicate bacteria and virus. A better knowledge of the real incidence of polymicrobial infections in CAP could derive from advances in available diagnostic methods, which in turn could limit the field of studies to hospitalized patients. Polymicrobial infection could occur in more than 10 % of pneumonias. There is a lot of evidence from the paediatric world that respiratory viruses often pave the way for airway-colonizing bacteria. Several paediatric studies have evaluated the rate of polymicrobial infections in CAP: dual viral infection has been present in 0–14 %, dual bacterial infection in 0–14 %, and mixed viral – bacterial infection in 3–30 % (Korppi, 2002). Michelow et al. (2004) confirmed the frequent occurrence of bacterial and viral co-infections in children with pneumonia; CAP mixed bacterial – viral infections rate was 23 % in hospitalized children. Tsolia et al. (2004) have reported a high prevalence of viral (65 %) and mixed viral – bacterial (35 %) infections, which supports the notion that the presence of a virus, acting either as a direct or an indirect pathogen, may be the rule rather than the exception in the development of CAP in school-age children requiring hospitalization. Don et al. (2005) have prospectively surveyed children with pneumonia; a causative agent was detected in 66 (65 %) patients and evidence of bacterial, viral and mixed viral – bacterial infection was demonstrated in 44 %, 42 % and 20 % of the CAP cases, respectively; they conclude that the high proportion of mixed viral – bacterial infections highlights the need to treat all children with CAP with antibiotics. The picture looks different in adult patients, with rates of polymicrobial pneumonia ranging between about 5 and 25 %. Gutierrez et al. (2005) report that in CAP a single pathogen was detected in 45 % of the cases and two or more pathogens in 5.7 %; mixed infections were seen at all ages and as well in inpatients and outpatients. The most frequent combinations of pathogens were those of bacteria with an atypical organism (28.6 %) and of two bacteria (28.6 %). De Roux A et al. (2006) found among 256 consecutive hospitalized patients with established aetiology CAP that 26 (10 %) had mixed pneumonia; the most frequent co-pathogen was S. pneumoniae (12 patients) followed by C. pneumoniae (9 patients), and the most frequent combinations were mixed infections of S. pneumoniae and either influenza virus (5 patients) or parainfluenza virus (5 patients), and influenza virus with C. pneumoniae (5 patients). Other reports in adults hospitalized for CAP show that polymicrobial pneumonia rates may vary a lot from one study to another: 10.2 % (Liu et al., 2006), 12.5 % (Lauderdale et al., 2005), 17 % (Riquelme et al., 2006) and 25.9 % (Saito et al., 2006). Patients with mixed pneumonia probably have more comorbidities, and a more altered outcome (Gutierrez et al., 2005), which need to be comfirmed by further data.

Summary The search for microbial agents responsible for CAP is generally not carried out in the community; in contrast with the extensive search in the hospital setting in

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patients with severe or potentially severe pneumonia. The investigations are quite unsatisfactory, however, since no pathogen is identified in half the cases. Extracellular bacteria are in first place, especially S. pneumoniae, followed by H. influenzae, S. aureus and M. catarrhalis; as for intracellular bacilli, M. pneumoniae is the most common, followed by Legionella and Chlamydia species; viruses are implicated in 5 to 20 %, influenza viruses being at first place. Sporadic human infections by avian influenza virus A/H5N1 increase the risk for future pandemics. Community-acquired pneumonia due to fungi and parasites may occur in immunocompetent subjects with or without underlying lung disease. Polymicrobial infection could occur in more than 10 % of pneumonias: pure microbial pneumonia involves two or more bacteria, two or more viruses, two or more fungi, or two or more parasites; and mixed microbial pneumonia involves a combination of at least two kinds of microbes (bacteria, virus, fungi and parasite). In the community, polymicrobial pneumonia occurring in non-immunocompromised mainly implicate bacteria and virus. Antibiotic resistance of bacteria is an increasing concern, especially the resistance of S. pneumoniae. There are large variations in resistance between areas, variations that have to be identified and taken into account in guidelines on antibiotic strategies. Resistance to penicillin (MIC ≥ 2 mg/L) among isolates of S. pneumoniae exceed 20 % in the USA, Mexico, Japan, Saudi Arabia, Israel, Spain, France, Greece, Hungary and the Slovak Republic. In South Africa, Hong Kong, Taiwan and South Korea rates exceed 50 %. Penicillin-Non-Susceptible Pneumococci is frequently associated with macrolide resistance (70–80 % in some Asian countries). The impact of resistance of S. pneumoniae in CAP has been studied extensively in terms of morbidity and mortality; current levels of resistance of S. pneumoniae do not appear to have a significant impact on the outcome of S. pneumoniae CAP. Nevertheless, high levels of resistance to penicillin and cephalosporins might increase mortality after day 4, time-to-response and length of stay.

Conclusions A large number of microbial agents may cause CAP, but bacteria and virus will cause most of them. Ten percent or more of CAP have a polymicrobial origin. A serious concern is the resistance of bacteria to antibiotics, particularly the resistance of S. pneumoniae to various antibiotics. So far, however, the current levels of resistance have not been associated with a significant change in morbidity and mortality. New or mutant microbial agents are a threat, considering the potential of either a pandemic or a lethal untreatable disease.

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Gillet Y, Issartel B, Vanhems P, et al. 2002. Association between Staphylococcus aureus strains carrying gene for Panton–Valentine leukocidin and highly lethal necrotising pneumonia in young immunocompetent patients. Lancet 359(9308): 753–759. Girod JC, Reichman RC, Winn WC Jr, Klaucke DN, Vogt RL, Dolin R. 1982. Pneumonic and nonpneumonic forms of legionellosis. The result of a common-source exposure to Legionella pneumophilia. Arch Intern Med 142(3): 545–547. Gregory DW, Schaffner W. 1997. Psittacosis. Semin Respir Infect 12(1): 7–11. Groom AV, Wolsey DH, Naimi TS, et al. 2001. Community-acquired methicillin-resistant Staphylococcus aureus in a rural American Indian community. J Am Med Assoc 286(10): 1201–1205. Gur E, Frank M, Givon-Lavi N, et al. 2006. Community-acquired bloodstream infections in children > one month old in southern Israel 1992–2001: epidemiological, clinical and microbiological aspects. Scand J Infect Dis 38(8): 604–612. Gutierrez F, Masia M, Rodriguez JC, et al. 2005. Community-acquired pneumonia of mixed etiology: prevalence, clinical characteristics, and outcome. Eur J Clin Microbiol Infect Dis 24(6): 377–383. Hageman JC, Uyeki TM, Francis JS, et al. 2006. Severe community-acquired pneumonia due to Staphylococcus aureus: 2003–04 influenza season. Emerg Infect Dis 12(6): 894–899. Hahn DL, Azenabor AA, Beatty WL, Byrne GI. 2002. Chlamydia pneumoniae as a respiratory pathogen. Front Biosci 7: e66–e76. Hsieh YC, Wu TZ, Liu DP, et al. 2006. Influenza pandemics: past, present and future. J Formos Med Assoc 105(1): 1–6. Hsu LY, Lee CC, Green JA, et al. 2003. Severe acute respiratory syndrome (SARS) in Singapore: clinical features of index patient and initial contacts. Emerg Infect Dis 9(6): 713–717. Hyvernat H, Pulcini C, Carles D, et al. 2007. Fatal Staphylococcus aureus haemorrhagic pneumonia producing Panton–Valentine leucocidin. Scand J Infect Dis 39(2): 183–185. Jacobs MR. 2004. Streptococcus pneumoniae: epidemiology and patterns of resistance. Am J Med 117(Suppl 3A): 3S–15S. Jacobs MR, Felmingham D, Appelbaum PC, Gruneberg RN. 2003. The Alexander Project: 1998–2000: susceptibility of pathogens isolated from community-acquired respiratory tract infection to commonly used antimicrobial agents. J Antimicrob Chemother 52(2): 229–246. Kirchner JT. 1997. Psittacosis. Is contact with birds causing your patient’s pneumonia? Postgrad Med 102(2): 181–188. Klein NC, Cunha BA. 1997. Pasteurella multocida pneumonia. Semin Respir Infect 12(1): 54–56. Koirala J. 2006. Plague: disease, management, and recognition of act of terrorism. Infect Dis Clin North Am 20(2): 273–87, viii. Korppi M. 2002. Mixed microbial aetiology of community-acquired pneumonia in children. Acta Pathol Microbiol Immunol Scand 110(7–8): 515–522. Lauderdale TL, Chang FY, Ben RJ, et al. 2005. Etiology of community acquired pneumonia among adult patients requiring hospitalization in Taiwan. Respir Med 99(9): 1079–1086. Laurichesse H, Dedman D, Watson JM, Zambon MC. 1999. Epidemiological features of parainfluenza virus infections: laboratory surveillance in England and Wales: 1975–1997. Eur J Epidemiol 15(5): 475–484. Ligon BL. 2006. Plague: a review of its history and potential as a biological weapon. Semin Pediatr Infect Dis 17(3): 161–170. Lina G, Piemont Y, Godail-Gamot F, et al. 1999. Involvement of Panton–Valentine leukocidin-producing Staphylococcus aureus in primary skin infections and pneumonia. Clin Infect Dis 29(5): 1128–1132. Liu YN, Chen MJ, Zhao TM, et al. 2006. A multicentre study on the pathogenic agents in 665 adult patients with community-acquired pneumonia in cities of China. Zhonghua Jie He He Hu Xi Za Zhi 29(1): 3–8.

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Mandell LA. 2005. Update on community-acquired pneumonia. New pathogens and new concepts in treatment. Postgrad Med 118(4): 35–36. Marco F, Bouza E, Garcia-de-Lomas J, Aguilar L. 2000. Streptococcus pneumoniae in community-acquired respiratory tract infections in Spain: the impact of serotype and geographical, seasonal and clinical factors on its susceptibility to the most commonly prescribed antibiotics. The Spanish Surveillance Group for Respiratory Pathogens. J Antimicrob Chemother 46(4): 557–564. Marcos MA, Camps M, Pumarola T, et al. 2006. The role of viruses in the aetiology of community-acquired pneumonia in adults. Antivir Ther 11(3): 351–359. Melo-Cristino J, Fernandes ML, Serrano N. 2001. A multicenter study of the antimicrobial susceptibility of Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis isolated from patients with community-acquired lower respiratory tract infections in 1999 in Portugal. Microb Drug Resist 7(1): 33–38. Men´endez R, Cordero PJ, Santos M, Gobernado M, Marco V. 1997. Pulmonary infection with Nocardia species: a report of 10 cases and review. Eur Respir J 10(7): 1542–1546. Michelow IC, Olsen K, Lozano J, et al. 2004. Epidemiology and clinical characteristics of community-acquired pneumonia in hospitalized children. Pediatrics 113(4): 701–707. Miedzinski L. 2005. Community-acquired pneumonia: new facets of an old disease – Hantavirus pulmonary syndrome. Respir Care Clin N Am 11(1): 45–58. Mohsen AH, McKendrick M. 2003. Varicella pneumonia in adults. Eur Respir J 21(5): 886–891. Moran GJ, Krishnadasan A, Gorwitz RJ, et al. 2006. Methicillin-resistant S. aureus infections among patients in the emergency department. N Engl J Med 355(7): 666–674. Moroney JF, Fiore AE, Harrison LH, et al. 2001. Clinical outcomes of bacteremic pneumococcal pneumonia in the era of antibiotic resistance. Clin Infect Dis 33(6): 797–805. Morris JF, Sewell DL. 1994. Necrotizing pneumonia caused by mixed infection with Actinobacillus actinomycetemcomitans and Actinomyces israelii : case report and review. Clin Infect Dis 18(3): 450–452. Pallares R, Linares J, Vadillo M, et al. 1995. Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain. N Engl J Med 333(8): 474–480. Plouffe JF Jr, File TM Jr. 1999. Update of Legionella infections. Curr Opin Infect Dis 12(2): 127–132. Preston AJ, Gosney MA, Noon S, Martin MV. 1999. Oral flora of elderly patients following acute medical admission. Gerontology 45(1): 49–52. Rajagopal S, Treanor J. 2007. Pandemic (avian) influenza. Semin Respir Crit Care Med 28(2): 159–170. Riquelme OR, Riquelme OM, Rioseco ZM, Gomez MV, Gil DR, Torres MA. 2006. Etiology and prognostics factors of community-acquired pneumonia among adults patients admitted to a regional hospital in Chile. Rev Med Chil 134(5): 597–605. Saito A, Kohno S, Matsushima T, et al. 2006. Prospective multicenter study of the causative organisms of community-acquired pneumonia in adults in Japan. J Infect Chemother 12(2): 63–69. Schito GC, Debbia EA, Marchese A. 2000. The evolving threat of antibiotic resistance in Europe: new data from the Alexander Project. J Antimicrob Chemother 46(Suppl T1): 3–9. Sj¨ostedt A. 2007. Tularemia: History, epidemiology, pathogen physiology, and clinical manifestations. Ann NY Acad Sci 1105: 1–29. Smeal WE, Schenfeld LA. 1986. Nocardiosis in the community hospital. Report of three cases. Postgrad Med 79(8): 77–82. Sopena N, Sabria M, Pedro-Botet ML, et al. 1999. Prospective study of community-acquired pneumonia of bacterial etiology in adults. Eur J Clin Microbiol Infect Dis 18(12): 852–858.

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Taylor WR, White NJ. 2002. Malaria and the lung. Clin Chest Med 23(2): 457–468. Terpenning MS, Bradley SF, Wan JY, Chenoweth CE, Jorgensen KA, Kauffman CA. 1994. Colonization and infection with antibiotic-resistant bacteria in a long-term care facility. J Am Geriatr Soc 42(10): 1062–1069. Terpenning MS, Taylor GW, Lopatin DE, Kerr CK, Dominguez BL, Loesche WJ. 2001. Aspiration pneumonia: dental and oral risk factors in an older veteran population. J Am Geriatr Soc 49(5): 557–563. Trystram, D, Varon E, Grundmann H, Gutmann L, Jarlier V, Aubry-Damon H. 2004. R´eseau europ´een de surveillance de la r´esistance bact´erienne aux antibiotiques (EARSS): r´esultats 2002, place de la France. Bull Epidemiol Hebd 32–33: 1422–144. Tsolia MN, Psarras S, Bossios A, et al. 2004. Etiology of community-acquired pneumonia in hospitalized school-age children: evidence for high prevalence of viral infections. Clin Infect Dis 39(5): 681–686. Valles X, Marcos A, Pinart M, et al. 2006. Hospitalized community-acquired pneumonia due to Streptococcus pneumoniae: Has resistance to antibiotics decreased?. Chest 130(3): 800–806. Vorou RM, Papavassiliou VG, Tsiodras S. 2007. Emerging zoonoses and vector-borne infections affecting humans in Europe. Epidemiol Infect 1(17): 1–17. Waites KB, Talkington DF. 2004. Mycoplasma pneumoniae and its role as a human pathogen. Clin Microbiol Rev 17(4): 697–728, table. Wheat LJ, Kauffman CA. 2003. Histoplasmosis. Infect Dis Clin North Am 17(1): 1–19, vii. Woodhead M, Blasi F, Ewig S, et al. 2005. Guidelines for the management of adult lower respiratory tract infections. Eur Respir J 26(6): 1138–1180. Yang CJ, Hwang JJ, Wang TH, et al. 2006. Clinical and radiographic presentations of pulmonary cryptococcosis in immunocompetent patients. Scand J Infect Dis 38(9): 788–793.

4 Microbiological Diagnosis of Community-Acquired Pneumonia MARGARETA IEVEN Laboratory of Microbiology, Vaccine and Infectious Diseases Institute, Faculty of Medicine, University Hospital Antwerp, University of Antwerp, Belgium

Introduction The objectives of an aetiological diagnosis in community-acquired pneumonia (CAP) or lower respiratory tract infections (LRTI) are either patient oriented or community oriented. At the individual level they aim at: •

avoiding unnecessary use of antibiotics and thereby lowering the antibiotic pressure on the accompanying flora;

•

narrowing the spectrum of targeted antibiotic treatment;

•

administration of appropriate antiviral drugs if available;

•

possible cohorting of patients in case of hospitalization for respiratory syncytial virus (RSV) or other respiratory virus infections.

At the community level they mainly provide accurate epidemiological information to formulate recommendations for prevention and for vaccination. So far hardly any study has shown that initial microbiological studies affect the outcome of respiratory infections. Nevertheless many clinicians feel that investigations may be helpful in guiding treatment, particularly in the more severely ill patients, but diagnostic testing should not lead to delays (4–8 hours) in initiation of therapy. At this moment, even with extensive diagnostic testing a specific aetiology Community-Acquired Pneumonia: Strategies for Management Edited by Antoni Torres and Rosario Men´endez  2008 John Wiley & Sons, Ltd

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is identified mostly in only half of all patients and mostly at the earliest 1–2 days after the clinical diagnosis is made. With the advent of recently developed rapid techniques such as the immunochromatographic tests, the urinary antigen tests and particularly the nucleic acid amplification tests (NAATs) that produce results within 30 minutes or 4–5 hours, microbiological information is becoming clinically useful. Both bacteria and viruses and mixtures of these may be aetiological agents in CAP. Some clinical specimens may be more adequate for the detection of either bacterial or viral causes, others may be adequate for the detection of both bacteria and viruses. Besides the need to identify the most adequate clinical samples to be tested by the most appropriate technique, clinical laboratories should also optimize the strategy for handling the clinical specimens. All these aspects will be discussed.

Conventional Culture Techniques on Sterile and Non-Sterile Sampling Sites Sterile Sampling Sites Blood Culture

For the diagnosis of pneumonia, blood cultures have a very high specificity but are positive in only 4–18 % of untreated cases (Marrie et al., 1985; Macfarlane et al., 1993; Marston et al., 1997; Bishara et al., 2000). In the study by Waterer and Wunderink (2001) a direct correlation was found between the severity (based on the Fine Severity Index) of pneumonia and blood culture positivity rate: the value of routine blood cultures was questioned for CAP for patients in lower risk classes. Two blood cultures should be obtained as early as possible in the disease and before any antibiotic treatment is started. Kalin and Lindberg (1983) showed that 13/38 (34 %) blood cultures were positive when initiated within 4 days after the first symptoms of the illness and 3/26 (12 %) when initiated later. Streptococcus pneumoniae is identified in approximately 60 % of positive blood cultures and Haemophilus influenzae in various percentages from 2 % to 13 %. Other organisms are recovered in diminishing order of frequency from 14 % to 2 % and 1 %: Gram-negative aerobes, streptococci (S. pyogenes and others), Staphylococcus aureus, and mixtures of organisms (Kalin and Lindberg, 1983). For most of the latter it is difficult to decide whether they were present in the bloodstream or are skin contaminants. In recent years methicillin-resistant S. aureus originating in the community has been found responsible for rapidly necrotizing pneumonia in otherwise healthy young adults (Bradley, 2005). In HIV-infected patients blood cultures in liquid medium may detect Mycobacterium tuberculosis or Mycobacterium avium complex (Julander et al., 1998; Esteban et al., 2001). In conclusion despite their low sensitivity, blood cultures in CAP are considered the gold standard because the organisms are recovered from a normally sterile source. Results may be available after 24–48 hours.

CONVENTIONAL CULTURE TECHNIQUES ON STERILE

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Thoracentesis

In 40 % of CAP there may be an accompanying pleural effusion. Although specificity of pleural exudate culture is very high, the sensitivity is low because of the low incidence of invasion of the pleura (Skerrett, 1999). Gram stain or culture yielding bacterial pathogens from pleural fluid are likely to be an accurate reflection of the microbial cause of the pneumonia. Diagnostic thoracentesis should therefore be performed when a significant pleural effusion is present. Gram stain of pleural fluid may produce an indication of the nature of the infecting organism within 1 hour, with culture and identification requiring a further 24–48 hours. Thoracic Needle Aspiration

Although not used extensively, there has been in recent years resurgent interest and growing experience with thoracic needle aspiration (TNA) for microbial diagnosis of pneumonia, especially in patients with severe pneumonia (Garcia et al., 1999; Ishida et al., 2004; Ruiz-Gonzalez et al., 1997, 1999; Scott and Hall, 1999). Thoracic needle aspiration allows a specimen to be obtained from the infected focus without interference of commensal flora, except for possible skin contaminants. The puncture should be directed correctly. In studies reviewed by Skerrett (1999) TNA yielded a positive culture in 33–80 % of cases of patients with pneumonia. From 13 studies (Scott and Hall, 1999) in which the results of blood cultures were known as well, the sensitivity of lung aspiration was estimated at 74 % and that of blood cultures 37 %. Ruiz-Gonzales (1997) obtained through TNA a microbiological diagnosis in 36/55 (65 %) of patients with pneumonia of unknown aetiology by conventional methods (Ruiz-Gonzalez et al., 1999). The superiority of direct access to a lung lesion through TNA is also illustrated by the study of Clark et al. (2002), who identified an aetiology of infection in 12/18 (23 %) of infiltrates with a corresponding non-diagnostic bronchoalveolar lavage. Because of the inherent potential adverse effects, however, TNA can be considered only on an individual basis for some severely ill patients, with a focal infiltrate in whom less invasive measures have been non-diagnostic.

Non-Sterile Sampling Sites Bronchoscopic Protected Brush and Bronchoalveolar Lavage

The specificity of bronchoscopy for the diagnosis of bacterial pathogens in the lower respiratory tract infections (LRTI) is not high because of contamination with the upper airway flora, and the patient may be put at unnecessary additional risk because of already compromised oxygen saturation. Several techniques have been proposed to achieve accurate discrimination between colonization and infection. Diagnostic accuracy is improved by the use of a protected specimen brush (PSB) (Wimberley et al., 1979) and bronchoalveolar lavage BAL, at first performed through a bronchoscope, but later not taken bronchoscopically (NB-BAL) (Bello et al., 1996; Wearden et al., 1996). These procedures

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carry less risk and are usually more acceptable to patients than transtracheal aspiration and direct needle aspiration of the lung. A major criticism directed at the PSB technique is the relatively small amount of distal bronchial secretions examined, particularly in comparison with the BAL technique. Quantitative bacterial culture is important for the assessment of these techniques. The cut-off point for diagnosis of pneumonia has been set at 103 colony forming units (CFU)/mL or 103 –104 CFU/mL. (Thorpe et al., 1987; Meduri et al., 1991; Skerrett 1999; Pereira Gomes et al., 2000; Rasmussen et al., 2001). Using 103 CFU/mL as the threshold value for a positive culture, Cantral et al. (1993) determined the sensitivity and the specificity to be 90 % and 97 % respectively. With a threshold value for a positive culture of 104 CFU/mL the specificity of lavage cultures for potential pathogenic bacteria in relation to actual LRTI was 100 %. Therefore quantitative bacterial culture of potential pathogenic bacteria in BAL fluid is very specific but is positive in only about one-third of unselected immunocompetent adult patients with a LRTI (Rasmussen et al., 2001). The sensitivity of bronchoscopic BAL in ventilator associated pneumonia has been evaluated at 82–91 % by Chastre et al. (1984) and at 42–93 % by Torres and El Ebiary (2000). Introduction of NB-BAL in an emergency department allowed early identification of pathogens in severe CAP, leading to changes in antibiotic therapy (Rodriguez et al., 2001). Bronchoalveolar lavage (BAL) specimens are particularly useful for the diagnosis of different aetiologies of pneumonia in immunocompromised patients, especially those treated for haematological malignancies, and in bone marrow and solid organ recipients (Jain et al., 2004; Efrati et al., 2007; Joos et al., 2007). Sputum

Sputum specimens must be representative of lower respiratory secretions. The most widely used method to assess the acceptability in this regard is based on cytological criteria. The specimen should therefore be screened by microscopic examination for the relative number of polymorphonuclear cells and squamous epithelial cells in lower power (10×) field. Invalid specimens (≥10 squamous epithelial cells and ≤25 polymorphonuclear cells/field) should not be examined further. It may be difficult to obtain good quality, purulent sputum. Many pneumonia patients do not produce sputum, particularly older patients. Satisfactory sputum specimens can be obtained in 32 % (Gleckman et al., 1988), 39 % (Roson et al., 2000) or 55 % (Ewig et al., 2002) of patients. Inhalation of hypertonic saline may be helpful (Lagerstrom et al., 2004) Gram Stain

In good quality Gram stained sputum, the presence of a single or a preponderant morphotype of bacteria (±90 %) is diagnostic. This is based on the correspondence with the organisms recovered from blood cultures obtained in parallel, and which are the gold standard. The sensitivity and specificity for the detection of

RAPID ANTIGEN TESTS

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S. pneumoniae is about 35–79 % and 96 % respectively, and 42 % and 99 % respectively for H. influenzae (Gleckman et al., 1988; Roson et al., 2000; Garcia-Vazquez et al., 2004; Musher et al,, 2004; van der Eerden et al., 2005). Sputum with a mixed flora in the Gram stain has no diagnostic value. Sputum Culture

In contrast with widespread opinion, it is now also clear that sputum culture results are convincing when and only when the organism isolated is compatible with the morphology of the organism present in >90 % in the Gram stain (Drew, 1977; Kalin and Lindberg, 1983; Gleckman et al., 1988; Roson et al., 2000; Butler et al., 2003). In the absence of an informative Gram stain, the predictive value of sputum culture is very low. Sputum is the preferred clinical sample to detect Mycoplasma pneumoniae by DNA amplification (Templeton et al., 2003; Raty et al., 2005). Nucleic acid amplification tests on sputum are equivalent to those on rhinopharynx samples. The reader is referred to that paragraph. Sputum Gram stain can produce diagnostic useful information in 63–86 % of cases within 1 hour, culture and identification of the organism requiring 24–48 hours.

Rapid Antigen Tests Urinary Antigen Tests The value of the S. pneumoniae urinary antigen test in adults has been confirmed to have a sensitivity of 65–100 % and a specificity of 94 %, however, weak positive results should be interpreted with caution. A S. pneumoniae type specific urinary antigen detects the infecting bacterial serovars. (Leeming et al., 2005). The effect of pretreatment with antibiotics resulted in contradictory reports: a lower detection rate in one study (van der Eerden et al., 2005) and an increased detection rate if the test is performed 24–48 hours after initiation of antibiotic treatment (Korsgaard et al., 2005). The urinary antigen test may also be applied on pleural fluid with a sensitivity and specificity of almost 100 % (Dominguez et al., 2006) and on serum samples with a sensitivity of 50 % in bacteriemic patients and 40 % in nonbacteriemic patients (Dominguez et al., 2006). There is a relation between the degree of the S. pneumoniae urinary antigen test positivity and the pneumonia severity index (Ortega, et al., 2005). Vaccination does not result in a positive urinary antigen test (Vazquez et al., 2004). Urine specimens of children, carriers of S. pneumoniae in the nasopharynx, may test positive in the absence of evidence of pneumonia, and therefore the test cannot be applied in children (Esposito et al., 2004). For increasing the sensitivity in adults and for cost saving the test could be applied in a sequential manner with reservation of the test for high-risk patients for whom demonstrative results of a sputum Gram stain are unavailable (Gutierrez et al., 2003; Marcos et al., 2003; Smith et al., 2003; Butler et al., 2003; Ishida

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et al., 2004; Roson et al., 2004; Stralin and Holmberg, 2005; Andreo et al., 2006; Ercis et al., 2006; Genne et al., 2006; Lasocki et al., 2006; Kobashi et al., 2007). Urinary antigen test is currently the most helpful rapid test for the diagnosis of Legionella infections. Several test formats have been developed, the enzyme immunoassay (EIA) format being more suited to test a larger number of specimens and taking a few hours to complete. The immunochromatographic format is better suited for single specimens, and produces a result within minutes. The major limitation of urinary antigen tests is that currently available tests are intended to detect Legionella pneumophila serogroup 1 antigen, which is the most common cause of Legionella infection. The other serogroups of L. pneumophila, however, or the other species of Legionella are not reliably detected by this test although cross reactions with these species also do occur (Benson et al., 2000). These tests are particularly useful since culture of Legionella spp. is slow and takes 3–4 days. Legionella urinary antigen detection is frequently the first positive laboratory test in this infection. The sensitivity of the tests is 63.7 to 66.6 % in unconcentrated urine and 86.6 to 88.8 % after concentration of the specimen (Dominguez et al., 1998). Sensitivity of the immunochromatographic assay is 55.5 % and 97.2 % on unconcentrated and concentrated urine specimens, respectively (Dominguez et al., 1998). The assay may be negative in some patients during the first 5 days of the disease and remain positive for between 6 and 14 days (Bernander et al., 1994). For patients with mild Legionnaires’ disease, test sensitivities range from only 40 to 53 %, whereas for patients with severe Legionnaires’ disease who needed immediate special medical care, the sensitivities reach 88 to 100 % (Yzerman et al., 2002).

Antigen Tests on Pharyngeal Specimens Throat swabs are the specimens of choice for the diagnosis of bacterial pharyngitis, by culture and by rapid antigen tests. The rhinopharynx with its commensal flora functions both as a defence mechanism against airborne organisms and as a primary multiplication site for respiratory infections. Therefore throat specimens are important for the diagnosis of many LRTI, although the commensal pharyngeal flora constitutes a hindrance for the selective detection of pathogens, as well as for the examination of specimens from the lower respiratory tract, be they obtained by expectoration or by bronchoscopy, since, in the absence or precautionary measures, contamination by the rhinopharyngeal flora is inevitable. All bacteriological examinations of throat specimens must therefore distinguish between pathogens and organisms colonizing the rhinopharynx. Throat cultures of S. pneumoniae, H. influenzae and Moraxella catarrhalis in cases of LRTI are irrelevant since these bacteria are part of the local colonizing flora. On the contrary, for viral respiratory infections, the optimal specimen is the nasopharyngeal aspirate (NPA) obtained by slight suction on a catheter introduced consecutively in both nares, if necessary after introduction through the catheter of 1 mL of physiological saline. A nasopharyngeal specimen may also be collected by introducing a flexible pharyngeal stick into the nose until resistance is encountered.

NUCLEIC ACID AMPLIFICATION TESTS

49

Although NPAs are superior, many practitioners prefer to collect throat swabs (Covalciuc et al., 1999). During recent years a considerable number of previously unknown respiratory viral agents were discovered for which the in vitro culture is very slow or even unrealized: the human metapneumoviruses, the novel coronaviruses NL 63 and HKU1, and the human bocavirus (van Burik 2006; van den Hoogen et al., 2001; van Elden et al., 2004). Antigens of the many common respiratory viruses, influenza virus, respiratory syncytial virus (RSV), adenovirus and parainfluenza viruses can be detected by direct immunofluorescence (DIF) or by commercially available EIAs. The sensitivities of these tests vary from 50 to >90 % (Covalciuc et al., 1999; Henrickson, 2004; Landry and Ferguson, 2000). Several common respiratory viruses can be detected simultaneously by DIF through the use of pooled monoclonal antibodies. For the detection of influenza virus infections, the sensitivity of immunofluorescence can be increased by inoculation of the clinical sample on appropriate cells, followed by immunofluorescence after 48 hours. The sensitivity of the direct immunofluorescence test is lower in adults and older persons than in children (Steininger et al., 2002).

Nucleic Acid Amplification Tests Culture procedures for viruses and fastidious bacteria, Mycoplasma pneumoniae, Chlamydophyla pneumoniae, L. pneumophila, Bordetella pertussis, which normally do not colonize the human respiratory tract, are too insensitive and too slow to be therapeutically relevant and should be detected by NAATs. Their sensitivity is almost always superior to that of the traditional procedures and are considered as the gold standard (Weinberg et al., 2004). A multitude of reports have appeared on the epidemiology of LRTI but most are restricted to a few viruses (influenza, sometimes together with RSV, to rhino-, metapneumo- or coronaviruses) and/or restricted to some population groups (e.g. children, adults or elderly people). Great variations occur as a function of the time, place and age of the group studied (Guittet et al., 2003; Esper et al., 2004; McAdam et al., 2004; Monto, 2004; Tsolia et al., 2004). It appears that RSV is the most common cause of viral LRTI in very young children (Freymuth et al., 1987; Ieven et al., 1996; Drummond et al., 2000) and that RSV and rhino- and influenza viruses are common in older people (Nicholson et al., 1997; Falsey and Walsh, 2006). Coronaviruses and M. pneumoniae are also more prevalent than previously thought (Loens et al., 2003; Vallet et al., 2004). All these studies were done with the traditional NAATs that require at least 1–2 days, producing ‘a posteriori’ results that were unavailable to the clinician in time to have any possible impact on patient management. Real-time multiplex NAATs offer the solution. Templeton et al. (2004) developed a two tube real-time multiplex polymerase chain reaction (PCR) for the diagnosis of influenza A and B and RSV in a first tube and the four parainfluenza

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viruses in a second tube. The sensitivity was higher than culture or DIF test but no comparisons were made between multiplex reactions and monoreactions on the same samples. Gruteke et al. (2004) applied four multiplex reactions to detect 11 agents; Templeton (Templeton et al., 2005) covered 15 agents by six multiplex real-time reactions; and (Gunson et al., 2005) targeted 12 agents through four realtime multiplex reactions. Combined with traditional bacteriological techniques to diagnose S. pneumoniae infections, only 24 % of the infections remained aetiologically undefined in the study by Templeton et al. (2005) and only 14 % in the study by Gruteke et al. (2004). All studies were limited in time and were pilot trials. The wider application of multiplex reactions during recent years resulted in the detection of numerous simultaneous viral infections with widely varying incidences: from 3 % (Scheltinga et al., 2005) to 9 % (Guittet et al., 2003) to 23 % (Bellau-Pujol et al., 2005) and 35 % (Templeton et al., 2005). In the latter study, bacterial agents were also included. The divergent incidences may result from the variety of diagnostic panels applied. Combined viral and viral – bacterial infections were diagnosed but no preferential combinations. Only a few studies found combined infections to be associated with a more severe clinical status. Greensill et al. (2003) found severe bronchiolitis associated with the combination of human metapneumovirus (hMPV) and RSV and Templeton et al. (2005) found significantly more mixed infections, including bacteria, in patients with more severe pneumonia. Respiratory viruses have also been increasingly recognized as causes of severe LRTI in immunocompromised hosts (Ljungman, 1997; Whimbey et al., 1997). Respiratory infections are more common in solid organ recipients, particularly in lung transplant recipients (Kotloff et al., 2004). Infections are especially dangerous prior to engraftment and within three months after transplantation, in the setting of graft versus host disease. The origin of the infections is community acquired as well as nosocomial (Baron and Weinberg A, 2007).

Serological Tests The most reliable serological evidence of an ongoing infection is a fourfold rise in IgG antibodies during an illness. Therefore paired samples, collected at an interval of 2 to 3 weeks, are required. In practice, however, often only one serum sample, from the acute-phase of the illness is available or the two samples are collected within a too short a time interval to detect a titre rise. Since IgM antibodies appear earlier than IgG antibodies the detection of IgM in serum is a widely used approach for the early serological diagnosis of many acute infections. It should be realized that IgM antibodies are often not produced in children under 6 months of age, in a proportion of primary infections and during reinfections. The IgM response may also appear late and wanes with age. Solitary high IgG titres have no diagnostic meaning for an acute infection since the moment of the seroconversion is unknown and necessarily took place some time before the illness under observation started. Single high titres, for which a cut-off

OPTIMIZATION OF LABORATORY STRATEGY

51

value has to be determined by a local evaluation, are useful only in prevalence studies among population groups. The clinical significance of a serological test, for both IgM and IgG, should be defined by studies of patients with a documented infection and for whom detailed information concerning the time lapses between onset of disease and the collection of the serum specimens are known. The Table 4.1 shows the clinical significance of serological tests for influenza virus, RSV, L. pneumophila, M. pneumoniae and C. pneumoniae. It illustrates the low incidence of IgM antibodies in the acute phase serum specimens and importance of the delay between the two serum samples. The sensitivity and specificity of serological tests are related to the antigen used. For some respiratory agents a variety of tests are commercialized. Beersma et al. (2005) evaluated the sensitivity and specificity of 12 assays for the detection of M. pneumoniae IgM and IgG as well as the complement fixation test (CFT). Some of the assays had a low sensitivity (Novum and Immunocard IgM) while the best performances in terms of sensitivity and specificity were recorded for Ani Labsystems (77 % and 92 % respectively) SeroMP (77 % and 88 % respectively) and CFT (65 % and 97 % respectively). Petitjean et al. (2002) found similar IgM sensitivities with four M. pneumoniae tests in children: between 89 % and 92 %, but wide variations in adults: Platelia and BMD 16 %, Biotest 50 % and Sorin 58 %. The specifities of the four tests were 100 %, 90 %, 65 % and 25 % respectively. The latter two tests thus cannot be used for diagnosis. The sensitivities of the IgG tests in children were 55 % for Platelia, 66 % for BMD, 78 % for Biotest and 52 % for Sorin. The sensitivities for the IgG tests in adults were comparable: between 89 %, and 92 %. Clearly, serological tests cannot be helpful for the rapid diagnosis of LRTI since they lack specificity and require 2–3 weeks for a meaningful result to be available.

Optimization of Laboratory Strategy With the existing armamentarium it is hard to conceive that every hospital laboratory would perform a broad spectrum of available diagnostic tests on each patient with a LRTI, besides the question of their clinical usefulness. Strategies therefore will have to be developed in the function of clinical and public health requirements and the technical evolution of NAATs. Practical issues in the laboratory may limit the theoretical possibilities of rapid NAATs such as the necessity to handle specimens in batches, thereby losing some advantages of the rapidity of the tests. Moreover virology laboratories at present do not operate 24 hours, 7 days. Although this situation may change as more molecular tests may be required as an emergency, including outside the field of infectious diseases. Examples among infectious diseases are the aetiological diagnosis of meningoencephalitis and intrapartum detection of S. pyogenes. Such testing might be performed in a permanently functioning and greatly automated laboratory section.

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Table 4.1 Appearance of antibodies against respiratory agents Agent

Antibody detection

Influenza A EIA Influenza B EIA RSV EIA

IgM IgG IgM IgG IgM IgG

Legionella pneumophila IF Chlamydophila pneumoniae MIF

IgM

Mycoplasma pneumoniae Agglutination Mycoplasma pneumoniae CFT

Mycoplasma pneumoniae 11 antigens, EI Mycoplasma pneumoniae 4 antigens, EIA

Days after onset of disease

Positive result/ number examined

Percentage positive

18/39 24/39 13/37 33/36 15/31 14/31

–

21 28 6 28 10–14 Maximum levels at 20–30 days 7 14 21 2–3 weeks 6–8 weeks after onset of illness Acute phase

6/12

50

9/12

66

–

Convalescence phase 7–22 days

IgM IgG

IgM

7–10 days

IgG

2–3 weeks 3–4 weeks 1–6 days ≥ 16 days 3–4 weeks

IgM IgG

46 62 35 92 48 45

7.5 41 66

Reference

Rothbarth et al., 1999

Meddens et al., 1990

De Ory et al., 2000 Dowell et al., 2001

All 15 with titre rise confirmed by PCR 5/9 with persistent high titre confirmed by PCR

Talkington et al., 2004

Raty et al., 2005

14–45(x) 39–88 39–45

Beersma et al., 2005

7–23 24–86 47–63

Loens et al., 2003, 2005

a Abbreviations: EIA, enzyme immunoassay; CFT, complement fixation test; IF, immunofluorescence test; MIF, microimmunofluorescence test; PCR, polymerase chain reaction; RSV, respiratory syncytial virus. b Depending on antigen used.

A stratification of diagnostic laboratory services may be conceived. Nolte (2007) proposed the consideration of three levels of services to be provided by clinical laboratories: level 1 to perform only Food and drug Administration (FDA) approved tests, level 2 to perform FDA approved and research-use-only tests and protocols

OPTIMIZATION OF LABORATORY STRATEGY

53

that are adequately approved by other laboratories, and level 3 to design, develop and verify in-house tests. Alternatively, to cover public health needs, a reference laboratory functioning in close contact with an in- and out- patient clinic and a group of general practitioners could apply the broad spectrum diagnostic panel on their group of patients and produce the required global epidemiological information. The reference laboratory should make its results available on a daily basis. Regional and local laboratories might limit their investigations to the antibiotic treatable, bacterial infections: i.e. the classic bacteria and M. pneumoniae, C. pneumoniae and L. pneumophila. More elaborated protocols can be envisaged in which Gram staining of sputum is performed together with NAATs for the atypical bacterial causes of CAP. A positive result may lead to adaptation of antibiotic therapy, when these results are negative, tests for viral causes are initiated. At present most clinicians do not stop antibiotics in patients negative for a bacterial cause. Falsey and Walsh (2006) propose different protocols during the summer and the winter months. During the summer months PCR and viral testing is performed in cases of severe illness only. During the winter months the strategy is different whether influenza epidemic is ongoing or not. Since in our region important acute respiratory infection (ARI) viral agents are also active only during the winter months, the diagnostic procedures could be limited to, for example, influenza and RSV between November and March. In the presence of an influenza epidemic, efforts could be entirely concentrated on transferring the local isolates to the reference laboratory for subtyping. Nucleic acid amplification tests are not required for every purpose. For cohorting RSV infected paediatric patients the DIF tests can be as sensitive as a RT-PCR (Henrickson, 2004) with results available within 60 minutes (and at lower cost than with NAATs). Very rapid chromatographic tests with fast results (Ohm-Smith et al., 2004; Reina et al., 2004; Slinger et al., 2004) are also available for RSV that can be done in the laboratory outside the virology laboratory operating hours (Cazacu et al., 2004). These tests, however, lack sensitivity when applied on respiratory samples of adult patients (Landry and Ferguson, 2000). Thoroughly investigated specimens from infections remaining without a known infectious cause should be stored for studies aimed at the discovery of yet unidentified pathogens. Indeed there are still missing pieces in the puzzle of the causes of respiratory infections since studies on the aetiological spectrum of ARI leave a considerable proportion of cases without a known cause, although in the studies by Templeton et al. (2005) and Gruteke et al. (2004) this fraction was reduced to 24 % and 14 %, respectively. Since the organisms discovered more recently multiply poorly in tissue cultures it may be surmised that agents remaining to be discovered might not grow at all in tissue cultures or that novel types of tissue cultures will be required. This is illustrated by the recent discovery of previously unknown coronaviruses (Yam et al., 2003; van der Hoek L. et al., 2004; Kleines et al., 2007)

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Cost Benefit Amplification techniques are at present more expensive than conventional approaches, with the most expensive being the fluorogenic-based real-time detection systems. However, improvements in standardization and automation for sample preparation and technical advances in thermocyclers allowing multiple runs of PCR to be performed simultaneously or in a very short time will lead to increased use of amplification methods and cost reductions to rates competitive with conventional methods. It remains to be studied whether a comprehensive approach is patient friendly, allows streamlining of management, is cost effective and reduces the antibiotic pressure in the hospital and the community. The approach may be considerably educative as illustrated for example by the high frequency of rhinovirus causing bronchiolitis (Gruteke et al., 2004) Several studies tended to show cost efficiency of rapid diagnosis of ARI resulting from reduced antibiotic use and complementary laboratory investigations but most significantly from shorter hospitalization and reduced isolation periods of patients (Barenfanger et al., 2000; Welti et al., 2003; Hueston and Benich III, 2004; Rocholl et al., 2007; Woo et al., 1997). During epidemics it may be as important to rule out a particular infection. A considerable saving in diagnostic procedures in ARI is possible by the abolishment of tissue cultures and serological tests. Serological diagnosis of those cases that remain undetected by the NAATs is of no clinical use since it is always available after many days or even weeks. Oosterheert et al. (2003) pointed out that the lack of cost reduction in available studies results from the small impact of microbiological investigations on the therapeutic decisions. A closer collaboration between clinicians and the laboratory has a high priority.

Conclusions A number of subjects remain to be investigated. The implementation of quantitative tests could shed further light on the relation between virus load and the seriousness of the disease (DeVincenzo et al., 2005) produce useful prognostic information and may help in the differentiation between colonization and infection. Since NAATs are more sensitive than tissue culture tests, they could offer more precise information on the length of the post-infection carrier state as well as on the importance of subclinical infections and how prone these are for spreading infections. The importance of LRTI viruses in chronic respiratory diseases such as COPD and cystic fibrosis should also be better evaluated. Several other agents responsible for respiratory infections should be considered separately because of the specific clinical picture for which they are responsible: C. psittaci, B. pertussis and B. parapertussis, Coxsiella burnetii and Pneumocystis jirovecii. The rapid molecular characterization of the previously unknown severe acute respiratory syndrome (SARS) coronavirus within a few weeks after the appearance

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of the disease and the recent discovery of bocavirus illustrate the potency of NAATs for broadening the knowledge on ‘hidden’ viruses remaining to be discovered. Furthermore in the organizational framework of the diagnostic laboratory, NAAT panels directed at other clinical syndromes such as meningoencephalitis, sepsis, sexually transmissible infections, hepatitis and others will have to be included.

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Smith MD, Derrington P, Evans R, et al. 2003. Rapid diagnosis of bacteremic pneumococcal infections in adults by using the Binax NOW Streptococcus pneumoniae urinary antigen test: a prospective, controlled clinical evaluation. J Clin Microbiol 41(7): 2810–2813. Steininger C, Kundi M, Aberle SW, Aberle JH, Popow-Kraupp T. 2002. Effectiveness of reverse transcription-PCR, virus isolation, and enzyme-linked immunosorbent assay for diagnosis of influenza A virus infection in different age groups. J Clin Microbiol 40(6): 2051–2056. Stralin K, Holmberg H. 2005. Usefulness of the Streptococcus pneumoniae urinary antigen test in the treatment of community-acquired pneumonia. Clin Infect Dis 41(8): 1209–1210. Talkington DF, Shott S, Fallon MT, Schwartz SB, Thacker WL. 2004. Analysis of eight commercial enzyme immunoassay tests for detection of antibodies to Mycoplasma pneumoniae in human serum. Clin Diagn Lab Immunol 11(5): 862–867. Templeton KE, Scheltinga SA, Graffelman AW, et al. 2003. Comparison and evaluation of real-time PCR, real-time nucleic acid sequence-based amplification, conventional PCR, and serology for diagnosis of Mycoplasma pneumoniae. J Clin Microbiol 41(9): 4366–4371. Templeton KE, Scheltinga SA, Beersma MF, Kroes AC, Claas EC. 2004. Rapid and sensitive method using multiplex real-time PCR for diagnosis of infections by influenza A and influenza B viruses, respiratory syncytial virus, and parainfluenza viruses 1, 2, 3, and 4. J Clin Microbiol 42(4): 1564–1569. Templeton KE, Scheltinga SA, van den Eeden WC, et al. 2005. Improved diagnosis of the etiology of community-acquired pneumonia with real-time polymerase chain reaction. Clin Infect Dis 41(3): 345–351. Thorpe JE, Baughman RP, Frame PT, Wesseler TA, Staneck JL. 1987. Bronchoalveolar lavage for diagnosing acute bacterial pneumonia. J Infect Dis 155(5): 855–861. Torres A, El Ebiary M. 2000. Bronchoscopic BAL in the diagnosis of ventilator-associated pneumonia. Chest 117(4 Suppl 2). 198S–202S. Tsolia MN, Psarras S, Bossios A, et al. 2004. Etiology of community-acquired pneumonia in hospitalized school-age children: evidence for high prevalence of viral infections. Clin Infect Dis 39(5): 681–686. Vallet S, Gagneur A, Talbot PJ, Legrand MC, Sizun J, Picard B. 2004. Detection of human Coronavirus 229E in nasal specimens in large scale studies using an RT-PCR hybridization assay. Mol Cell Probes 18(2): 75–80. Van Burik JA. 2006. Human metapneumovirus: important but not currently diagnosable. Ann Intern Med 144(5): 374–375. Van den Hoogen BG, de Jong JC, Groen J, et al. 2001. A newly discovered human pneumovirus isolated from young children with respiratory tract disease. Nat Med 7(6): 719–724. Van der Eerden MM, Vlaspolder F, de Graaff CS, Groot T, Jansen HM, Boersma WG. 2005. Value of intensive diagnostic microbiological investigation in low- and high-risk patients with community-acquired pneumonia. Eur J Clin Microbiol Infect Dis 24(4): 241–249. Van der Hoek L, Pyrc K, Jebbink MF, et al. 2004. Identification of a new human coronavirus. Nat Med 10(4): 368–373. Van Elden LJ, van Loon AM, van Alphen F, et al. 2004. Frequent detection of human coronaviruses in clinical specimens from patients with respiratory tract infection by use of a novel real-time reverse-transcriptase polymerase chain reaction. J Infect Dis 189(4): 652–657. Vazquez EG, Marcos MA, Vilella A, Yague J, Bayas JM, Mensa J. 2004. Assessment of a commercial rapid urinary antigen test to detect Streptococcus pneumoniae in patients who received 23–valent pneumococcal polysaccharide vaccine. Eur J Clin Microbiol Infect Dis 23(12): 927–929. Waterer GW, Wunderink RG. 2001. The influence of the severity of community-acquired pneumonia on the usefulness of blood cultures. Respir Med 95(1): 78–82.

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Wearden PD, Chendrasekhar A, Timberlake GA. 1996. Comparison of nonbronchoscopic techniques with bronchoscopic brushing in the diagnosis of ventilator-associated pneumonia. J. Trauma 41(4): 703–707. Weinberg GA, Erdman DD, Edwards KM, et al. 2004. Superiority of reverse-transcription polymerase chain reaction to conventional viral culture in the diagnosis of acute respiratory tract infections in children. J Infect Dis 189(4): 706–710. Welti M, Jaton K, Altwegg M, Sahli R, Wenger A, Bille J. 2003. Development of a multiplex real-time quantitative PCR assay to detect Chlamydia pneumoniae, Legionella pneumophilia and Mycoplasma pneumoniae in respiratory tract secretions. Diagn Microbiol Infect Dis 45(2): 85–95. Whimbey E, Englund JA, Couch RB. 1997. Community respiratory virus infections in immunocompromised patients with cancer. Am J Med 102(3A): 10–18. Wimberley N, Faling LJ, Bartlett JG. 1979. A fiberoptic bronchoscopy technique to obtain uncontaminated lower airway secretions for bacterial culture. Am Rev Respir Dis 119(3): 337–343. Woo PC, Chiu SS, Seto WH, Peiris M. 1997. Cost-effectiveness of rapid diagnosis of viral respiratory tract infections in pediatric patients. J Clin Microbiol 35(6): 1579–1581. Yam WC, Chan KH, Poon LL, et al. 2003. Evaluation of reverse transcription-PCR assays for rapid diagnosis of severe acute respiratory syndrome associated with a novel coronavirus. J Clin Microbiol 41(10): 4521–4524. Yzerman EP, den Boer JW, Lettinga KD, Schellekens J, Dankert J, Peeters M. 2002. Sensitivity of three urinary antigen tests associated with clinical severity in a large outbreak of Legionnaires’ disease in The Netherlands. J Clin Microbiol 40(9): 3232–3236.

5 Empirical Treatment of Community-Acquired Pneumonia: Current Guidelines ´ JAVIER ASPA1 , OLGA RAJAS2 , FELIPE RODRIGUEZ DE CASTRO3 , JOSE´ BLANQUER4 AND ANTONI TORRES5 ´ Hospital Universidad Autonoma de Madrid, Servicio de Neumologıa, ´ Universitario de la Princesa, Madrid, Spain 2 Universidad Autonoma de Madrid, Servicio de Neumologıa, ´ Hospital ´ Universitario de la Princesa, Madrid, Spain 3 Universidad de las Palmas de Gran Canaria, Servicio de Neumologıa, ´ ´ Las Palmas de Gran Canaria, Spain Hospital Dr. Negrın, 4 ´ Unidad de Cuidados Intensivos, Hospital Clınic Universitari, Valencia, Spain 5 Hospital Clınic, ´ ´ ´ Servei de Pneumologıa i Al·lergia Respiratoria, Institut Clınic del Torax, Universitat de Barcelona, Barcelona, Spain ´ 1

Introduction Community-acquired pneumonia (CAP) is not a reportable condition, and it is, therefore, impossible to determine its exact incidence. Nevertheless, estimates of the frequency of CAP in different European populations have ranged from 5 to 11 cases per 1000 persons per year, although the rate is substantially higher in the elderly (Woodhead et al., 1987; Jokinen et al., 1993). Management of pneumonia has aroused considerable interest in recent years and various different scientific associations have consequently published a great number of guidelines in order to optimize its control (Bartlett et al., 2000; Mandell et al.,

Community-Acquired Pneumonia: Strategies for Management Edited by Antoni Torres and Rosario Men´endez  2008 John Wiley & Sons, Ltd

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2000, 2003, 2007; Anon., 2001, 2005; Niederman et al., 2001; Alfageme et al., 2005; Woodhead et al., 2005; Torres, 2006). The evidence on which the guidelines were based has increased and the methods for guideline development have been refined. The following are the principal factors that have given rise to this interest. 1. Community-acquired pneumonia places a tremendous pressure on health-care resources: in the USA the estimated cost of treatment is more than $20 billion (in US dollars) per year (File et al., 2004a), while in the UK this annual cost has been calculated to be more than £40 million (Brown and Lerner, 1998). In Spain, the cost of hospitalization alone due to CAP was estimated at $137 million (in US dollars) per annum in, 2001 (Monge et al., 2001). The percentage of patients with CAP that are admitted to the hospital varies greatly, from 22 % to 61 % (Almirall et al., 2000), with hospital admittance being the greatest health cost factor due to this illness. A 1-day reduction in length of stay in hospital might yield substantial cost-savings (Fine et al., 2000). 2. Patients affected by CAP show a high morbidity and mortality rate. A metaanalysis, carried out over a total of 33 148 patients in 127 studies, showed an overall CAP mortality of 14 %, reaching 37 % in ICU-admitted patients, whilst less than 2 % of the patients that did not need to be admitted to hospital died (Fine et al., 1996). 3. In a relatively short period of time new antibiotics whose activity is adapted to the main CAP-causing germs have been incorporated into the therapeutic arsenal. We could use telithromycin, ertapenem and linezolid as examples. Some of these new antibiotics are subject to controversy and also their correct position in accordance with their pharmological activity and pre-existing antibiotic resistances, or the avoidance of rapidly generated new ones, is difficult to determine. 4. Pneumococcal antibiotic resistances towards different families of antibiotics continue to be a much debated issue (Tleyjeh et al., 2006), above all when evaluating the role they play in the progress of and prognosis for CAP patients. Such resistances have been shown to vary greatly in a geographical context (Johnson et al., 2006). 5. In spite of the increasingly more common usage of microbiological techniques for early aetiological detection (pneumococcal and legionella urinary antigens), initial CAP treatment is still empirical. It should be taken into account that strong evidence to support individual recommendations has generally been found to be lacking. Individual antibiotic studies do not capture all outcomes of importance in antibiotic management, and there may be variations in factors, such as the prevalence of antibiotic resistance of leading pathogens such as Streptococcus pneumoniae, that might determine different antibiotic recommendations in different geographical locations (Woodhead et al., 2005).

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6. Hospitals have been found to handle CAP patients in very different ways (McCormick et al., 1999; Capelastegui et al., 2005). It has equally been demonstrated that managing these patients in accordance with quality criteria and standardized guidelines has improved their prognosis (Men´endez et al., 2002; Capelastegui et al., 2004, 2006). In this chapter, an update on the empirical treatment of CAP is provided by analysing the Spanish Guidelines (Alfageme et al., 2005), the European Guidelines (Woodhead et al., 2005), those of the Infectious Diseases Society of America (IDSA; Mandell et al., 2007) and, likewise, other recent studies. As has recently been pointed out (File et al., 2004a), a number of key differences exist between North American and European guidelines, mainly in the outpatient setting. The North American approach is to use initial antimicrobial therapy which provides coverage for S. pneumoniae plus atypical pathogens. On the other hand, Europeans tend to focus on providing pneumococcal coverage with less emphasis on coverage for atypical pathogens. Syndromic approaches (typical versus atypical) have not been useful in predicting the aetiology of CAP (Helms et al., 1979; Woodhead and Macfarlane 1987; Farr et al., 1989; Fang et al., 1990; Kauppinen et al., 1996; Marrie et al., 1996; Ruiz et al., 1999a; Alfageme et al., 2005; Woodhead et al., 2005). The prognosis is most directly related to severity of illness and allows for the distinction of: (1) low-risk patients who can safely be treated as outpatients (mild pneumonia); (2) patients at increased risk who should be hospitalized (moderate pneumonia); and (3) patients at high risk of mortality who should be admitted to the intensive care unit (ICU; severe pneumonia) (Alfageme et al., 2005; Woodhead et al., 2005; Mandell et al., 2007). The rapid initiation of appropriate antimicrobial treatment has been shown to be a crucial factor in order to ensure treatment success (Tang and Macfarlane, 1993; Meehan et al., 1997; Simpson et al., 2000).

Likely Pathogens of Community-Acquired Pneumonia In general, the aetiological diagnostic rate of CAP is not more than 40–60 %. Table 5.1 lists the most common causes of CAP (Woodhead, 2002; File, 2003). Streptococcus pneumoniae has been consistently shown to represent the most frequent causative agent of CAP. Prospective studies have reported an incidence of pneumococcal pneumonia of about 30–40 % (Ruiz et al., 1999b). Moreover, there is some evidence that most episodes without established aetiology are in fact due to S. pneumoniae (Ruiz et al., 1999b). The principal groups at risk of developing pneumococcal infections are immunocompetent adults with chronic illnesses (cardiovascular, lung, or liver diseases), patients with functional or anatomic asplenia, patients with lymphoproliferative illnesses (chronic lymphatic leukaemia, multiple myeloma and non-Hodgkin lymphoma), and those with congenital deficits of

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Table 5.1 Most common aetiologies of community-acquired pneumoniaa Ambulatory patients Streptococcus pneumoniae Mycoplasma pneumoniae Haemophilus influenzae Chlamydophyla pneumoniae Respiratory virusesb

a Based

Hospitalized (non-intensive care unit) Streptococcus pneumoniae Mycoplasma pneumoniae Chlamydophyla pneumoniae Haemophilus influenzae Legionella spp. Aspiration Respiratory virusesb

Severe (intensive care unit) Streptococcus pneumoniae Staphylococcus aureus Legionella sp. Gram-negative bacilli Haemophilus influenzae

on collective data from recent studies (Woodhead, 2002; File, 2003) A and B; adenovirus; respiratory syncytial virus; parainfluenza.

b Influenza

immunoglobulin synthesis. Cigarette smoking is the strongest independent risk factor for invasive pneumococcal disease among immunocompetent, non-elderly adults (Nuorti et al., 1998). In the past, approximately 80 % of hospitalized patients with bacteremic pneumococcal infections died of their illness (Austrian and Gold, 1964). With effective antimicrobial agents, mortality has decreased, but it remains at nearly 20 % for elderly adults (Austrian and Gold, 1964; Kramer et al., 1987; Whitney et al., 2000). Other bacterial causes of CAP include non-typeable Haemophilus influenzae and Moraxella catarrhalis, generally in patients who have underlying bronchopulmonary disease, and Staphylococcus aureus, especially during an influenza outbreak. Risk factors for Gram-negative enterobacteria (GNEB) and Pseudomonas aeruginosa, as aetiologies for CAP, are structural lung diseases, such as bronchiectasis, or repeated exacerbations of severe chronic obstructive pulmonary disease (COPD) leading to frequent steroid and/or antibiotic use, as well as prior antibiotic therapy, alcoholism and suspected aspiration (Arancibia et al., 2000, 2002; Paganin et al., 2004). Two or more of these criteria increase the risk considerably and highly prevalent areas should lead to consideration of antipseudomonal treatment. Pseudomonas aeruginosa should also be a concern in any patient with a smoking history and rapidly progressive pneumonia (Hatchette et al., 2000, Woodhead et al., 2005). Less common causes of pneumonia include Streptococcus pyogenes, Neisseria meningitidis, Pasteurella multocida and H. influenzae type B. Chlamydophyla pneumoniae and respiratory viruses are also frequent causes of mild pneumonia. Influenza remains the predominant viral cause of CAP in adults, whilst other commonly recognized viruses include respiratory syncytial virus (RSV), adenovirus, human metapneumovirus, simple herpes virus, severe acute respiratory syndrome (SARS) associated coronavirus, and measles (Bartlett et al., 2000; Mandell et al., 2003; Falsey et al., 2005). In a recent study (de Roux et al., 2004) viruses appear to be involved in up to 18 % of cases, and in 9 %, a respiratory virus was the only pathogen identified. Studies that include outpatients find viral pneumonia rates as high as 36 % (Templeton et al., 2005). The frequency of other aetiological agents (Mycobacterium tuberculosis, Chlamydophyla psitacci,

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Coxiella burnetii, Francisella tularensis, Bordetella pertussis, and endemic fungi), is determined by the epidemiological setting, and by the intensity with which the search for them is carried out, but it rarely exceeds 2–3 % of the cases (Ruiz et al., 1999a; Falguera et al., 2001). Although epidemic outbreaks of Legionella spp. are not infrequent, these bacteria can also sporadically appear throughout the entire year. Anaerobic coverage is clearly indicated in the classic aspiration syndrome in patients with a history of previous loss of consciousness due to alcohol/drug overdose or following seizures in patients with concomitant gingival disease or oesophageal motility disorders (Ruiz et al., 1999a). Antibiotic trials have not demonstrated a need to specifically treat these organisms in the majority of CAP cases. Small-volume aspiration at the time of intubation should be adequately handled by standard empirical treatment for severe CAP and by the oxygen tension provided by mechanical ventilation (Sirvent et al., 1997). Mixed infections have been reported to be present in 5–38 % of cases (Lieberman et al., 1996; Neill et al., 1996). Consequently it can be said that mild pneumonia is basically caused by S. pneumoniae and Mycoplasma pneumoniae, without forgetting the role of viruses in this setting. In moderate pneumonia, besides S. pneumoniae and M. pneumoniae, H. influenzae, aspiration syndrome and Legionella spp should be kept in mind. In cases of severe pneumonia, S. pneumoniae and Legionella spp are responsible for approximately 50 % of cases, although GNEB and S. aureus must also be considered. Pathogens that should be considered in various specific epidemiological situations are detailed in Table 5.2 (Bartlett et al., 2000; Mandell et al., 2003; Alfageme et al., 2005; Woodhead et al., 2005).

Pneumococcal Resistance to β-Lactam Agents The use of antimicrobials, appropriate or not, encourages the development of resistance in bacterial strains. In recent decades, bacteria have demonstrated their almost limitless ability to adapt to different circumstances, specifically to the ecological pressure caused by different antimicrobial agents. Bacteria can evade antimicrobial action by adopting diverse mechanisms. The main mechanism of resistance in clinical isolates of S. pneumoniae involves the alteration of penicillin target proteins, the so-called penicillin-binding proteins (PBPs), which causes reduced affinities and/or binding capacities for the antibiotic molecule (Klugman, 1990). Therefore, the antibiotic is neither modified nor destroyed by hydrolysis (-lactamases), but poorly recognized (Chenoweth et al., 2000; Musher, 2000; Garau, 2002). Alterations to the penicillin-binding properties of these proteins are brought about by the transfer of portions of the genes encoding the PBPs from other streptococcal species, resulting in mosaic genes (Markiewicz and Tomasz, 1989; Baquero et al., 1998; Musher, 2000).

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Table 5.2 Additional risk factors for consideration when selecting initial empirical antimicrobial treatment (Modified from Alfageme et al., 2005; Woodhead et al., 2005) Risk factor COPD and/or bronchiectasis Recent hospitalization Recent antimicrobial treatment Silent aspiration Gross aspiration Influenza Exposure to cattle Exposure to birds IVDA Recent travel to Mediterranean coast Chronic steroid treatment Recent travel to midwest and southern USA Presence of two or more of: COPD/bronchiectasis recent hospitalization recent antimicrobial treatment suspected aspiration

Pathogen Haemophilus influenzae, GNEB, Pseudomonas aeruginosa GNEB, Pseudomonas aeruginosa GNEB, Pseudomonas aeruginosa Mixed infections, anaerobes GNEB, Pseudomonas aeruginosa, anaerobes Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae Coxiella burnetii Chlamydophyla psitacci Staphylococcus aureus (MSSA or MRSA) Legionella spp. Aspergillus capsulatum Hystoplasma capsulatum Increased risk for GNEB or Pseudomonas aeruginosa

COPD, chronic obstructive pulmonary disease; GNEB, Gram-negative enterobacteria; IVDA, intravenous drug abuse; MSSA, methicillin-sensitive Staphylococcus aureus; MRSA, methicillin-resistant Staphylococcus aureus.

The following PBPs have been identified in penicillin-susceptible pneumococci: 1a, 1b, 2x, 2b and 3 (Appelbaum, 2002). The final resistance level will depend on the combined action of the different PBPs or, in other words, the resistance phenotype of each strain depends on the genotype of all the PBPs involved (Baquero et al., 1998). Loss of susceptibility affects all -lactams, but to different degrees, depending on the affinity of each drug for the altered PBPs. Resistance to thirdgeneration cephalosporins requires alterations mainly in PBP 2x and 1a, but they rarely produce a lower susceptibility to penicillin. Conversely, mutations in PBP 2b are determinant for the development of high-level penicillin resistance, but not for cephalosporins. Gene mutations in PBP 1a, PBP 2x and PBP2b should be considered highly penicillin-resistant mutants (Baquero et al., 1998). Mutations in PBP 3 could very slightly alter the minimum inhibitory concentration (MIC) of penicillin and cephalosporins; this protein seems to be the target of clavulanate acid, although the consequences of this interaction do not seem to be immediately followed by any antibiotic effect. The penicillin non-susceptible S. pneumoniae have, to a greater or lesser degree, cross-resistance to all -lactam antibiotics. This resistance affects all -lactam antibiotics that target PBP 1 and PBP 3, but it does not affect imipenem or other carbapenems that preferentially target PBP 2b. The addition of clavulanate, sulbactam

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or tazobactam does not affect the MICs of the parent -lactam compound (Baquero et al., 1998). Penicillin non-susceptible S. pneumoniae are far more likely to be resistant to non--lactam antibiotics (e.g., macrolides, clindamycin, tetracyclines, chloramphenicol and trimethoprim-sulphamethoxazole) (Doern et al., 1998; Zhanel et al., 2003; Aspa et al., 2004), so it could be considered that penicillin resistance is a marker of resistance to other antimicrobial agents (Linares et al., 1992). Knowing risk factors is essential for the clinician to suspect resistance to S. pneumoniae and to select appropriate empirical antimicrobial treatment (Niederman, 2001).

Risk Factors for Infection by Penicillin-Resistant Streptococcus Pneumoniae Various authors have found that patients with penicillin-resistant pneumococci have a significantly higher incidence of: use of -lactam antibiotics during the previous 3–6 months, hospitalization during the previous 3 months, nosocomial pneumonia, suspected aspiration, episodes of pneumonia during the previous year, alcoholism, non-invasive disease, and an initially critical condition. Additional risk factors include age less than 5 years or greater than 65 years, white race, closed communities (military camps or schools), attendance in day-care centres, and the presence of chronic underlying disease (mainly COPD) (Nava et al., 1994; Clavo-Sanchez et al., 1997; Campbell and Silberman, 1998; Ewig et al., 1999; Aspa et al., 2004). It has also been shown that paediatric residents in long-term care facilities may be an important reservoir of penicillin-resistant penumococci (Pons et al., 1996; Ekdahl et al., 1997). A French multicentre study reported (Bedos et al., 1996) that age less than 15 years, isolation of the organisms from the upper respiratory tract and human immunodeficiency virus (HIV) infection are risk factors for pneumonia caused by antibiotic-resistant S. pneumoniae.

Pneumococcal Resistance to Macrolide Agents Resistance to the macrolide antibiotics (e.g., erythromycin, clarithromycin and azithromycin) has escalated in association with penicillin resistance. In addition, macrolide resistance can develop independently from penicillin resistance. Taking into account the current levels of S. pneumoniae macrolide resistance, in hospitalized patients with moderate or moderately severe CAP, empirical monotherapy with a macrolide is not optimal (Lynch and Zhanel, 2005). In the case of macrolide agents, antibiotic resistance occurs as a consequence of two main mechanisms, namely a macrolide efflux pump mechanism (mef gene; the M resistance phenotype) or a mechanism involving methylation of the ribosomal binding site (erm gene) (Leclercq and Courvalin, 1991; Sutcliffe et al., 1996; Feldman, 2004). The former translates into lower levels of resistance (MICs in the range of 1–32 µg/mL) and only confers resistance to 14 and 15 membered macrolides, whereas the latter mechanism translates into high-level resistance (MICs in the range of 64 µg/mL or greater) (Feldman, 2004). This is a conformational change

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in the ribosome that reduces the affinity of MLS (macrolides, lincosamides, streptogramin) antibiotics for the binding site. Streptogramin A-type antibiotics are unaffected, and synergy between the two components of streptogramin against MLS-resistant strains is maintained (Chabbert and Courvalin, 1971). This phenotype is referred to as the MLSB phenotype (Leclercq and Courvalin, 1991; Montanari et al., 2001); it is prevalent in Europe (in Spain it is the predominant phenotype) and South Africa (Johnston et al., 1998; Montanari et al., 2001; Pallares et al., 2003). While some have suggested that infections caused by isolates with efflux-pumpmediated mechanisms of resistance may be overcome by using high doses of macrolides/azalides, most authors would consider that it is the level of macrolide resistance (MIC level of the isolate) rather than the mechanism of resistance that is likely to dictate the probability of the success or failure of macrolide therapy (Feldman and Anderson, 2006). Pneumococci resistant to erythromycin by either mechanism are also resistant to azithromycin, clarithromycin and roxithromycin.

Risk Factors for Macrolide-Resistant Streptococcus Pneumoniae Risk factors for pneumonia caused by erythromycin-resistant pneumococci have been assessed in a prospective Spanish study (Aspa et al., 2004). Previous hospital admissions (odds ratio (OR) 1.89) and resistance to penicillin (OR 15.85) were identified as independent risk factors. Age less than 5 years, white race and a nosocomial origin of the infection have also been reported as risk factors for antibiotic resistance (Moreno et al., 1995; Hyde et al., 2001; Aspa et al., 2004; see Table 5.3).

Pneumococcal Resistance to Quinolone Agents Rates of fluoroquinolone resistance have increased dramatically within the past decade among both nosocomial and community pathogens. Resistance to fluoroquinolones is generally unrelated to penicillin susceptibility (Schrag et al., 2004; Vanderkooi et al., 2005), although there is some evidence of an association between resistance to penicillin and resistance to fluoroquinolones (Chen et al., 1999; Linares et al., 1999; Ho et al., 2001) and, in Spain, because of its high prevalence, also to macrolides (Linares et al., 1999; Garcia-Rey et al., 2000). Some studies have also reported higher rates of fluoroquinolone resistance among penicillin non-susceptible S. pneumoniae (de la Campa et al., 2004; Doern et al., 2005). Once inside the cell, the antimicrobial action of the fluoroquinolones is mediated through the inhibition of two DNA topoisomerase enzymes, DNA gyrase (also termed ‘topoisomerase type II’) and topoisomerase IV. Resistance to quinolones occurs (Hooper and Wolfson, 1993) by mutation in the genes that encode DNA gyrase and topoisomerase IV, or by lowering intracellular drug content through an active efflux mechanism (Janoir et al., 1996; Munoz and De La Campa, 1996; Drlica and Zhao, 1997).

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Table 5.3 Risk factors for the existence of Streptococcus pneumoniae resistant to penicillin, erythromycin and quinolones Pneumococcal resistance risk factors β-lactams

Macrolides (Aspa et al., 2004, Hyde et al., 2001; Moreno, 1995) Quinolones (Ho et al., 2001)

Previous β-lactam treatment (Bedos et al., 1996, Clavo-Sanchez et al., 1997, Nava et al., 1994, Pallares et al., 1987) Nosocomial infection (Bedos et al., 1996, Pallares et al., 1987) Previous hospitalization (Aspa et al., 2004, Pallares et al., 1987) CAP in previous year (Pallares et al., 1987) Serious illness (Pallares et al., 1987) HIV infection (Aspa et al., 2004, Bedos et al., 1996) Alcohol abuse (Clavo-Sanchez et al., 1997) Comorbidities (≥ 2) (Aspa et al., 2004) Age < 5 and > 65 years old (Aspa et al., 2004, Clavo-Sanchez et al., 1997, Karlowsky et al., 2003) Others (children, closed institutions) (Bauer et al., 2001) Chronic pulmonary disease (Aspa et al., 2004) Suspected aspiration (Aspa et al., 2004) Age < 5 years old Nosocomial pneumonia White race Previously hospitalized Penicillin resistance Previous exposure to quinolones Age > 65 years old Nursing home Nosocomial pneumonia Isolates in sputum Penicillin resistance Chronic obstructive pulmonary disease (COPD)

With respect to the first resistance mechanism or altered target sites, bacteria develop resistance to fluoroquinolones through chromosomal mutation in the target enzymes of fluoroquinolone action, DNA gyrase and topoisomerase IV. Because of the different preferential targets of various fluoroquinolone molecules, pneumococcal resistance could theoretically be conferred by mutations in either the gyrA or gyrB genes (encoding DNA gyrase) or in the parC or parE genes (encoding DNA topoisomerase IV) (Appelbaum, 1992; Munoz and De La Campa, 1996; Pan et al., 1996; Pestova et al., 1999; Tankovic et al., 2003). The fluoroquinolones also differ in target site affinity and according to the mechanisms of action, gatifloxacin, moxifloxacin and gemifloxacin would be expected to preferentially select gyrA mutations, whereas ciprofloxacin and levofloxacin would select mutations in parC (Fukuda and Hiramatsu, 1999). Importantly, a ‘first-step’ parC mutation in the quinolone resistance determinant region (QRDR) increases the risk for subsequent mutations (e.g., gyrA) that confer high-level resistance to fluoroquinolones (Lim et al., 2003b). The use of less potent fluoroquinolones (e.g., ciprofloxacin) or low doses of newer fluoroquinolones (e.g.,

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levofloxacin 500 mg qd) may amplify the risk of fluoroquinolone resistance development (Tillotson et al., 2001; Low, 2004, 2005; Lynch and Zhanel, 2005). Resistance to fluoroquinolones in S. pneumoniae arises primarily by spontaneous point mutations in the QRDR of either or both parC and gyrA (Bast et al., 2000). Low-level resistance to ciprofloxacin typically develops from mutations altering parC. High-level fluoroquinolone resistance strains typically have dual mutations in QRDRs affecting both parC and gyrA (Bast et al., 2000). However, once a first-step parC mutation exists, the probability for developing a gyrA mutation with exposure to fluoroquinolones increases (Gillespie et al., 2003; Smith et al., 2004). Dual mutations (parC and gyrA) are associated with high-grade resistance to ciprofloxacin (MICs ≥ 16 µg/L) and confer resistance to levofloxacin, gatifloxacin and moxifloxacin and, most of the time, to gemifloxacin (Brueggemann et al., 2002; de la Campa et al., 2004). First-step mutations will not be detected by conventional susceptibility testing and may reflect the ‘tip of the iceberg’ for fluoroquinolone resistance. Further, secondary mutations are acquired more rapidly than first-step mutations and may result in isolates that are highly resistant to all fluoroquinolones (Smith et al., 2004). Theoretically, the use of more potent fluoroquinolones (particularly gemifloxacin or moxifloxacin), as well as high doses of levofloxacin (750 mg qd), may reduce the emergence of resistance (Tillotson et al., 2001).

Risk Factors for Quinolone-Resistant Streptococcus Pneumoniae The following risk factors have been established for quinolone resistance: previous exposure to quinolones, old age, nursing homes, nosocomial acquisition of the infection, isolates in sputum, penicillin resistance and COPD (Ho et al., 2001). The nasopharynx is considered the main reservoir of penicillin and macrolideresistant pneumococci. It has been suggested that, similarly, the airways of elderly COPD patients may have the same role for fluoroquinolone-resistant pneumococcal strains (Ho et al., 2001; See Table 5.3).

Impact of Antimicrobial Resistance on the Morbidity and Mortality of Pneumococcal Pneumonia Microbial resistance causes a great deal of confusion when choosing an empirical treatment for pneumonia. Strictly speaking, the term resistance refers to the in vitro susceptibility of a pathogen to various antibiotics; however, in vitro data do not necessarily translate into in vivo efficacy. Favourable pharmacokinetic/pharmacodynamic (PK/PD) parameters and high concentrations of antimicrobials at the site of infection may explain the good clinical outcomes achieved despite MIC values in vitro that appear to be ‘resistant’ or ‘non-susceptible’. In recent years, there has been a greater concern to know the extent to which antimicrobial resistance may come to influence the morbidity and mortality of pneumococcal infections, specifically pneumonia.

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Concerns have been raised owing to the rapid emergence of resistance of this microorganism to several of the first-line antimicrobial agents recommended for the treatment of these infections (Metlay, 2002; Metlay and Singer, 2002; File, 2003; Aspa et al., 2004; Feldman, 2004; Fuller et al., 2005; Lynch and Zhanel, 2005; Feldman and Anderson, 2006). While there is an extensive body of literature on the prevalence of, risk factors for and mechanisms of antibiotic resistance, a more important consideration is whether antimicrobial resistance has any impact on the outcome of these infections (Metlay and Singer, 2002; Metlay, 2004). Complicating our ability to determine the true impact of antibiotic resistance on the outcome of patients with CAP is the knowledge that some patients, even those infected with susceptible microorganisms, who receive appropriate antimicrobial therapy still die (Feldman and Anderson, 2006). Treatment failures due to drug resistance have been reported with meningitis (Sloas et al., 1992; Catalan et al., 1994) and otitis media (Poole, 1995; Jacobs, 1996), but the relationship between drug resistance and treatment failures among patients with pneumococcal pneumonia is less clear (Buckingham et al., 1998; Choi and Lee, 1998; Deeks et al., 1999; Dowell et al., 1999; Turett et al., 1999; Feikin et al., 2000). There are a number of important issues that need to be addressed when studying the impact of antibiotic therapy on outcome, which are often not considered in individual studies. These include the need to use an appropriate end point to study; most investigations have used death alone as the important parameter (Metlay and Singer, 2002), but mortality is also an inprecise outcome measurement for the impact of antibiotic resistance. Additional factors that should be taken into account when evaluating outcome include the age of the patients, the presence or absence of underlying comorbid conditions and the severity of the infection (Metlay, 2002; Feldman and Anderson, 2006). These factors alone may impact significantly on the outcome of pneumonia, irrespective of whether there is antibiotic resistance among the isolates or not. Resistance can be linked to adverse outcome only if the patient received discordant therapy, such as treatment with an antibiotic or antibiotics to which the organism was resistant (Metlay, 2002; Metlay and Singer, 2002; Feldman and Anderson, 2006). At least one recent prospective observational study of the outcome of bacteremic pneumococcal pneumonia concluded that discordant antibiotic therapy was associated with a worse outcome (Lujan et al., 2004). While a number of studies suggest limited or no impact of -lactam resistance (Klugman and Feldman, 2001; Yu et al., 2003; Aspa et al., 2004; File et al., 2004b; Song et al., 2004; Bonnard et al., 2005; Feldman and Anderson, 2006), there are a number of studies that purport to show an impact of antibiotic, and in particular penicillin resistance, on the outcome of pneumococcal infections treated with standard -lactam antibiotics (Turett et al., 1999; Feikin et al., 2000; Metlay et al., 2000; Klugman and Feldman, 2001; Falco et al., 2004). This has also been reported in a recent systematic review and meta-analysis demonstrating the apparent impact of penicillin resistance on outcomes (Tleyjeh et al., 2006). However, the conclusions of this study are unlikely to significantly change the antimicrobial prescribing habits and/or recommendations of the various CAP guidelines,

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since these already take into account antimicrobial resistance (File et al., 2006). One recently conducted critical review of medical literature concluded that there has been only one reported microbiological failure of appropriate parenteral penicillin therapy (appropriate choice of agent and dosage), being the appearance of a resistant pneumococcus (MIC of the microorganism was 8 µg/mL) in the pleural fluid of a patient receiving amoxicillin/clavulanate for pneumococcal pneumonia (Garau, 2005; Peterson, 2006). However, failures have occurred with several other β-lactam agents, which were predictable according to our current understanding of the pharmacodynamic (PD) and pharmacokinetic (PK) principles of antimicrobial therapy (Peterson, 2006). Among such agents are ticarcillin, cefazolin, cefuroxime, cefamandole and ceftazidime (Peterson, 2006). Neither ticarcillin nor ceftazidime are considered to be appropriate antipneumococcal β-lactam agents and are therefore never recommended for use in such infections. With regard to cefuroxime, a number of failures have been reported with its discordant use in cephalosporinresistant infections (Yu et al., 2003; Feldman, 2004; Feldman and Anderson, 2006). Owing to the small numbers of strains with high-level resistance (MIC ε 4 mg/L) observed, current studies are underpowered to establish the impact of infections with these strains on outcome. As a result, the Drug-Resistant Streptococcus pneumoniae Therapeutic Group (Heffelfinger et al., 2000) has recommended that penicillin susceptibility categories be shifted upward so that the susceptible categories include all isolates with MICs of ≤ 1 mg/L, the intermediate categories include isolates with MICs of ≥ 2 mg/L, and the resistant category includes isolates with MICs of ≥ 4 µg/mL. In conclusion, in the treatment of β-lactam-resistant pneumococcal infections, the use of standard antipneumococcal β-lactam agents (e.g., penicillins, aminopenicillins and cephalosporins such as cefotaxime and ceftriaxone) is unlikely to impact negatively on the outcome of CAP when appropriate agents are given in sufficient doses, at least in the case of infections with isolates with intermediate resistance (Feldman, 2004; Garau, 2005). However, in a recent meta-analysis, Tleyjeh et al. (2006) suggest that resistance may need to be reconsidered as an independent predictor of poor prognosis. In contrast to the β-lactam agents, there has been a relatively larger number of failures of macrolide/azalide agents used for the treatment of infections with macrolide-resistant isolates (Feldman and Anderson, 2006). Some authors have reported failure while using a macrolide to treat a pneumococcal infection caused by a macrolide-resistant strain (Moreno et al., 1995; Fogarty et al., 2000; Kelley et al., 2000; Waterer et al., 2000; Lonks et al., 2002). In a recent review (Klugman, 2002), it was stated that there is increasing evidence of bacteriologically confirmed macrolide failure in pneumococcal pneumonia therapy at MICs ε 4 µg/mL. This is particularly important in Europe, where the predominant mechanism of resistance is typically of a high level (Aspa et al., 2004). To add to the confusion, the emergence of resistance to macrolide agents during treatment has been reported (Musher et al., 2002). Approximately 20 % of pneumococcal strains are naturally resistant to macrolides not related to antibiotic use.

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Thus, in areas of high prevalence of high-level macrolide resistance, empirical monotherapy with a macrolide is not optimal for the treatment of hospitalized patients with moderate or moderately severe CAP. In countries where prevalence and levels of resistance are lower, macrolides have been recommended as alternative monotherapy for outpatient treatment of younger patients without comorbid illness and/or risk factors for macrolide-resistant isolates (Feldman and Anderson, 2006; Volturo et al., 2006). On the other hand, these agents are the treatment of choice for pneumonia caused by so-called atypical pathogens and are also recommended for use as part of combination antibiotic therapy (together with standard β-lactam agents) for more seriously ill cases requiring admission to hospital for the management of their CAP. The fluoroquinolones represent valuable alternatives for the therapy of pneumococcal infections, since their activity is not affected by resistance to other antimicrobial classes (Critchley et al., 2002). However, although they have not reached the high resistance levels that other antibiotic classes present, resistance to quinolones is increasing progressively. This coincides with the increased use of ciprofloxacin in adults. During the 1990s, pneumococcal infections resistant to fluoroquinolones only represented some 2–3 % of the strains in North America (Chen et al., 1999; Whitney et al., 2000) and Spain (Linares et al., 1999); however, a tendency towards an increase in resistance is being observed now and fluoroquinolone resistance among S. pneumoniae is becoming more prevalent (Doern et al., 2005). As stated for macrolides, a number of failures of fluoroquinolone agents have been documented in the management of resistant pneumococcal pneumonia. These have occurred with either ciprofloxacin or levofloxacin (Fuller and Low, 2005). These failures were predictable on the basis of our understanding of PK/PD parameters and antibiotics. In the first instance, ciprofloxacin is not considered to be an appropriate antipneumococcal fluoroquinolone and is not recommended for use in such infections, particularly with the availability of the new-generation fluoroquinolones with enhanced antipneumococcal activity. In the case of levofloxacin, these failures have mainly occurred at a dose of 500 mg daily (Fuller and Low, 2005). The currently recommended appropriate levofloxacin dose is 750 mg daily (where this formulation is available) or alternatively 500 mg twice daily, which is unlikely to be associated with treatment failure at current levels of fluoroquinolone resistance. However, there are data from some studies that suggest that this assumption may not be entirely correct (Ambrose et al., 2004). More recently, Endimiani et al. (2005) have described a treatment failure of levofloxacin (500 mg bid) in a patient with pneumococcal CAP. The current National Committee for Clinical Laboratory Standards’ criteria for resistance in pneumococci indicate that those strains with a MIC of 8 µg/mL or more are considered levofloxacin-resistant and those with a MIC of 2 µg/mL or less are considered susceptible (Ambrose et al., 2004). At least, one study has indicated that 59 % of strains regarded as levofloxacin susceptible contain a single-step mutation in their QRDR, which can easily mutate to further levels of fluoroquinolone non-susceptibility (Lim et al., 2003a; Ambrose et al., 2004). Resistance is much more likely to emerge with fluoroquinolone agents that have lower area under the curve/MIC ratios.

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Therefore, in the case of fluoroquinolone resistance, links between phenotypically defined resistance (consequence of two mutations in the QRDR) and clinical failure are clear. However, there are convincing data demonstrating that a first-step mutation on the par C/gyr A gene, not producing MIC-defining phenotypic resistance, can lead to clinical failure. The risk of clinical failure depends more on the presence of a mutation than on the phenotypic definition of resistance. Unfortunately, percentages of levofloxacin intermediate resistance, as well as frequencies of single mutants within the population of susceptible strains are often unknown or not reported (Ambrose et al., 2004). One last overall point of importance to make with regard to antimicrobial resistance is that it is essential to be aware of previous exposure to antibiotics, since the single most important risk factor for development of resistance to a particular antibiotic is the previous use of an antibiotic from the same class. (Vanderkooi et al., 2005). Many guidelines thus recommend that antibiotics from the same class should not be used for the current infection if the patient has been exposed to that class of antibiotics in the past three months (Feldman and Anderson, 2006). At this time, it is generally believed that the current prevalence and levels of resistance of pneumococci to penicillins in most areas of the world do not indicate the need for significant treatment changes in the management of CAP.

Multidrug-Resistant Streptococcus Pneumoniae Multiresistance is defined as resistance to at least three or more classes of antibiotics. Jacobs et al. (1978) reported the emergence of pneumococci resistant to multiple antimicrobial agents in Durban, South Africa in 1978, and in recent years, multiresistant pneumococci have spread world-wide (Friedland and McCracken, 1994; Hofmann et al., 1995; Butler et al., 1996; Chen et al., 1999; Verhaegen and Verbist, 1999; McCullers et al., 2000; Appelbaum, 2002; ). Factors associated with CAP caused by multidrug-resistant S. pneumoniae (MDRSP) have not been extensively studied. Non--lactam antibiotic resistance tends to be more common among strains not susceptible to penicillin (Hofmann et al., 1995; Butler et al., 1996). Between 1995 and 1998, the proportion of MDRSP increased from 9 % to 14 % in the USA (Whitney et al., 2000). As part of the Alexander Project (global surveillance study, 1992–2001; Mera et al., 2005), an increase of 15.3 % has been recently reported in the MDRSP rate, and that three out of four penicillin-resistant S. pneumoniae isolates are also multiresistant. A report from the SENTRY Antimicrobial Surveillance Program (1997–2003; Pottumarthy et al., 2005) showed that the multiple resistance rate ranged from 17.6 % (penicillin and erythromycin resistance only) to 5.7 % (resistance to five drugs). An evaluation of 6362 S. pneumoniae isolates collected during the 2000–2001 community-acquired respiratory tract infection season showed that 88.1 % and 80.2 % of the 1077 isolates with high-level penicillin-resistance were also resistant to trimethoprimsulphamethoxazole and azithromycin, respectively (Kelly, 2001). The Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromicyn

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(PROTEKT) study also showed a steady rise in pneumococcal resistance among common antibiotics, as well as an increase in MDRSP (Karchmer, 2004; Doern et al., 2005). Doern et al. (2005) and Karchmer (2004) reported that in 1817 S. pneumoniae isolates obtained from patients with community-acquired respiratory tract infections in 44 USA medical centres (2002–2003), 22.2 % of isolates were multidrug resistant. In Spain, Fenoll et al. (1998) have also described increasing multiple drug resistance, with rates ranging from 1.1 % in 1979–1984 to 7.7 in 1985–1989 and 12.5 in 1990–1996 (9.5 % in 1990 to 16.6 % in 1996).

Recently Introduced Antibiotics for Community-Acquired Pneumonia Telithromycin Telithromycin belongs to a new type of antibiotics, the Ketolides, which are derived from the family of macrolides, and it is active against S. pneumoniae resistant to other kinds of antibiotics (penicillin, macrolides and fluoroquinolones). It has been shown, in several published studies, to be equivalent to its comparative antibiotics (amoxicillin, clarithromycin and trovafloxacin; Hagberg et al., 2003; Pullman et al., 2003; Mathers Dunbar et al., 2004; Tellier et al., 2004; Carbon et al., 2006). This agent has similar efficacy to the new macrolides for H. influenzae and available information suggests that telithromycin plays a role in the treatment of CAP caused by drug-resistant S. pneumoniae (van Rensburg et al., 2005). Postmarketing reports of associated hepatotoxicity should also be considered (Clay et al., 2006; Graham, 2006). At present, the committee of the recent IDSA/ATS guidelines (Mandell et al., 2007) is awaiting further evaluation of the safety of this drug by the Food and Drug Administration before making its final recommendation.

Ertapenem Two randomized double-blind studies showed ertapenem to be equivalent to ceftriaxone (Vetter et al., 2002; Ortiz-Ruiz et al., 2004). Ertapenem also has an excellent activity against drug-resistant S. pneumoniae, anaerobic microorganisms and most enterobacteriaceae (but not P. aeruginosa).

Cefditoren pivoxil Cefditoren pivoxil is an oral cephalosporin with an excellent activity against S. pneumoniae, acting in a similar way to the classic third-generation parenteral cephalosporins (ceftriaxone, cefotaxime) and it also has an excellent activity against enterobacteriaceae (Soriano et al., 2003, 2004). In various published works it has also been shown to be equivalent to comparative agents (amoxicillin–clavulanate, cefpodoxime) (Fogarty et al., 2002; van Zyl et al., 2002). It could also turn out

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to be a good choice in switch therapy for the outpatient treatment of inpatients treated with parenteral cephalosporins.

Community-Acquired Pneumonia Due to Methicillin-Resistant Staphylococcus Aureus Recently, a high incidence of CAP due to methicillin-resistant Staphylococcus Aureus (MRSA) has been published, pointing out the existence of strains with an epidemiologically, genotypically and phenotypically distinct pattern from hospitalacquired strains (Mongkolrattanothai et al., 2003; Deresinski, 2005; Mandell et al., 2007). In a large study of community-acquired MRSA (CA-MRSA) in three communities, 2 % of CA-MRSA infections were pneumonia (Fridkin et al., 2005). Community-acquired pneumonia due to MRSA remains rare in most communities but is expected to be an emerging problem in CAP treatment (Mandell et al., 2007).

Combination Antibiotic Therapy Over the past few years, several retrospective studies have been published, both on CAP in general and on the subset of patients with bacteremic pneumococcal pneumonia in particular, which have suggested that the outcome of patients with CAP requiring hospital admission may shorten hospital stays and reduce mortality rates if they are treated with combination antibiotic therapy as part of the initial antimicrobial treatment rather than their being treated with single agents alone (Garcia Vazquez et al., 2005, Gleason et al., 1999, Mufson and Stanek, 1999; Stahl et al., 1999; Waterer et al., 2001; Brown et al., 2003; Martinez et al., 2003; Sanchez et al., 2003; Baddour et al., 2004; Weiss et al., 2004; Waterer, 2005; Weiss and Tillotson, 2005), even when S. pneumoniae is finally identified as the causative organism. However, many aspects of the apparently beneficial effects of the combined therapy remain unclear and/or controversial. There are inconsistencies in reported outcomes and confusing biases that may have influenced these results. The most common combination reported in these studies has been the use of a macrolide agent together with standard β-lactam therapy. However, in some of the studies the outcome has been improved with various other combinations as well (Epstein and Gums, 2005). This understanding is further complicated by additional studies indicating that combination antibiotic therapy has either no, or limited, benefit in pneumococcal pneumonia (Harbarth et al., 2005; Aspa et al., 2006). Other studies have suggested that fluoroquinolone monotherapy may be as effective as β-lactam/macrolide combinations and may even be associated with faster clinical improvement (Finch et al., 2002; Katz et al., 2004; Portier et al., 2005; Torres, 2005; Welte et al., 2005), contrasting with a more recent study suggesting that combination therapy with a β-lactam and a fluoroquinolone is associated with an

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increased short-term mortality in patients with severe pneumonia in comparison with the use of other guideline-concordant antibiotic regimes (Mortensen et al., 2005). Many of the studies of combination therapy versus antibiotic monotherapy have significant limitations, including being retrospective and/or observational and/or non-randomized in design, having incomplete microbiological data, and/or limited data on antibiotic administration, route and dosing, and with severity of illness being a retrospective constructed variable (Waterer, 2005). There have been a number of suggestions as to why adding a macrolide to standard β-lactam therapy may be associated with an improved outcome in CAP (Waterer, 2005; Feldman and Anderson, 2006). One reason may be that the inclusion of the macrolide provides for possible cover for so-called atypical pathogens. Another possible reason for the benefit of combination therapy includes potential cover for polymicrobial infections (Waterer, 2005). Perhaps, one of the most important reasons for the benefits of combination therapy may well be due to the non-antimicrobial, immunomodulatory, anti-inflammatory activities of the macrolide/azalide group of antibiotics, which have been very well documented (Waterer, 2005; Waterer and Rello, 2006). Combining a β-lactam with an inhibitor of bacterial protein synthesis represents a logical strategy to improve the antimicrobial therapy of patients with severe CAP (Feldman and Anderson, 2006). However, two meta-analyses evaluating the advantages of adding a macrolide to a -lactam in the treatment of CAP patients have recently been published, and no additional benefits were found for this combination (Mills et al., 2005; Shefet et al., 2005). From a microbiological point of view, laboratory studies and some animal experiments have suggested that rather than having a synergistic activity, adding macrolides to penicillin may be associated with antagonism. Johansen et al. (2000) have reported antagonism for the combination of penicillin-erythromycin with S. pneumoniae both in vitro and in animal models of invasive disease, suggesting that -lactam antibiotics and macrolides should not be administered together unless pneumococcal infection is ruled out. Other authors have suggested that the existence of antagonism depends on the order in which the antibiotics are combined. In conclusion, despite the fact that there is no gold-standard evidence of the benefits of combination therapy over antibiotic monotherapy, most international guidelines recommend combination therapy, most commonly the addition of a macrolide to standard β-lactam therapy, for the treatment of patients with more severe CAP.

Empirical Antimicrobial Therapy The choice of antibiotics for CAP should be based on the following factors: consideration of the local prevalence and resistance patterns of the area, since resistances vary noticeably according to the geographical region; contemplation of the possible presence of other CAP-causing pathogens despite there being a very high suspicion of pneumococcal aetiology. Moreover, it is necessary to take into account

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age, presence of comorbidities and other factors indicating severity of illness. In the latter case, it is important to get the initial therapy right since the probability of death is higher during the first 48–72 hours before knowing the results from bacterial cultures. The following will show the recommendations that the Spanish Society of Pneumology (Alfageme et al., 2005), the European Respiratory Society (Woodhead et al., 2005), and the Infectious Diseases Society of America/American Thoracic Society (IDSA/ATS; Mandell et al., 2007) established for every type of pneumonia and the level of scientific evidence on which they are based.

Mild Community-Acquired Pneumonia Spanish Guidelines

The recommended treatment for patients in this group is telithromycin 800 mg/day or one of the new fluoroquinolones, such as levofloxacin 500 mg/day or moxifloxacin 400 mg/day, taken orally. Another possible option are high doses of oral amoxicillin (at least 1 g every 8 hours) – a regimen effective against most pneumococcal strains having reduced sensitivity to β-lactam antibiotics – plus a macrolide, such as oral azithromycin 500 mg daily or oral clarithromycin 500 mg every 12 hours. In view of the high incidence of macrolide-resistant pneumococci in Spain and the predominant mechanism of resistance, monotherapy with macrolides should not be prescribed. A subset of patients is suitable for outpatient management despite having concurrent chronic diseases or other risk factors for Gram negative microorganisms (H. influenzae, enterobacteria). In such cases, the first line treatment is singledrug therapy with an oral fluoroquinolone providing effective pneumococcal cover (levofloxacin or moxifloxacin). Amoxicillin–clavulanic acid could be used as an alternative treatment always bearing in mind its lack of activity against atypical microorganisms. European Guidelines

Lower respiratory tract infection: • Preferred–amoxicillin or tetracyclines; • Alternative, to be used in the presence of hypersensitivity to preferred drug or widespread prevalence of clinically relevant resistance in the population being treated – co-amoxiclav, macrolide, levofloxacin, moxifloxacin. IDSA/ATS Guidelines

1. Previously healthy and no risk factors for drug-resistant S. pneumoniae (DRSP) infection: • a macrolide (azithromycin, clarithromycin or erythromycin) (strong recommendation; level I evidence) • doxycycline (weak recommendation; level III evidence)

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2. Presence of comorbidities, such as chronic heart, lung, liver, or renal disease; diabetes mellitus; alcoholism; malignancies; asplenia; immunosuppressing conditions or use of immunosuppressing drugs; use of antimicrobials within the previous 3 months (in which case an alternative from a different class should be selected); or other risks for DRSP infection: • a respiratory fluoroquinolone (moxifloxacin, gemifloxacin or levofloxacin [750 mg]) (strong recommendation; level I evidence) • β-lactam plus a macrolide (strong recommendation; level I evidence) (highdose amoxicillin [e.g., 1 g three times daily] or amoxicillin–clavulanate [2 g two times daily] is preferred; alternatives include ceftriaxone, cefpodoxime and cefuroxime [500 mg two times daily]; doxycycline [level II evidence] is an alternative to the macrolide) 3. In regions with a high rate (> 25 %) of infection with high-level (MIC ≥ 16 µg/mL) macrolide-resistant S. pneumoniae, consider the use of alternative agents listed above for any patient, including those without comorbidities. (Moderate recommendation; level III evidence.)

Moderate Community-Acquired Pneumonia Spanish Guideline

Initial empirical treatment should include one of the following regimens: a thirdgeneration cephalosporin (cefotaxime 1 g/6 hour or ceftriaxone 1–2 g/24 hour, administered intravenously); or amoxicillin–clavulanic acid 1000/200 mg/8 hour in combination with a macrolide, both administered intravenously. The combination of a macrolide with amoxicillin clavulanic acid, 2000/125 mg/12 hour can be used to treat many patients. If the urinary antigen test for L. pneumophila is negative, the macrolide may be omitted and the patient treated with β-lactam antibiotics alone. However, it has been suggested that the combination of a β-lactam with a macrolide is more effective than monotherapy with a β-lactam alone because it reduces mortality in patients with CAP, especially in those with bacteremia. This is still controversial, and randomized studies are necessary to clarify this issue (level II evidence). Another, equally valid, treatment option could be to use an antipneumococcal fluoroquinolone, such as levofloxacin or moxifloxacin (level II evidence). The fact that this regimen has been reported to be associated with a lower risk of treatment failure justifies its use in these cases. European Guidelines

•

Preferred, in regions with low resistance rates (in no special order) – penicillin G ± macrolide; aminopenicillin ± macrolide; aminopenicillin/β-lactamasa inhibitor ± macrolide; nonantipseudomomonal cephalosporin II or III ± macrolide.

•

Alternative, in regions with increased resistance rates or intolerance to preferred drugs (in no special order) – levofloxacin; moxifloxacin.

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Woodhead et al. (2005) remark that although experience with ketolides is limited, they may offer an alternative when oral treatment is adequate. New macrolides are preferred to erythromycin. Within the fluoroquinolones, moxifloxacin has the highest antipneumococcal activity. IDSA/ATS Guidelines

1. A respiratory fluoroquinolone (strong recommendation; level I evidence). 2. A β-lactam plus a macrolide (strong recommendation; level I evidence) (preferred β-lactam agents include cefotaxime, ceftriaxone and ampicillin; ertapenem for selected patients; with doxycycline [level III evidence] as an alternative to the macrolide; a respiratory fluoroquinolone should be used for penicillin-allergic patients). Increasing resistance rates have suggested that empirical therapy with a macrolide alone can be used only for the treatment of carefully selected hospitalized patients with non-severe disease and without risk factors for infection with drug-resistant pathogens. However, such monotherapy cannot be routinely recommended.

Severe Community-Acquired Pneumonia Spanish Guidelines

These patients should be treated with high doses of a third-generation cephalosporin (cefotaxime 2 g/6–8 hours or ceftriaxone 2 g/24 hours, administered intravenously), always in combination with a macrolide (clarithromycin 500 mg/12 hours or azithromycin 500 mg/day, administered intravenously) or an antipneumococcal fluoroquinolone (intravenous levofloxacin 500 mg/day). European Guidelines

• No risk factors for P. aeruginosa –nonantipseudomonal cephalosporin III + macrolide or; nonantipseudomonal cephalosporin III + (moxifloxacin or levofloxacin). • Risk factors for P. aeruginosa –(antipseudomonal cephalosporin or acylureidopenicillin/β-lactamase inhibitor or carbapenem) + ciprofloxacin. Woodhead et al. (2005) remark that evidence in favour of combination therapy for P. aeruginosa remains inconclusive. Aminoglycoside therapy is associated with increased toxicity and monotherapy often leads to the development of resistance against that antibiotic. Therefore, combination therapy with a β-lactam plus a fluoroquinolone is advocated.

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IDSA/ATS Guidelines

1. A β-lactam (cefotaxime, ceftriaxone or ampicillin–sulbactam) plus either azithromycin (level II evidence) or a fluoroquinolone (level I evidence) (strong recommendation). (For penicillin-allergic patients, a respiratory fluoroquinolone and aztreonam are recommended.) 2. For Pseudomonas infection, use an antipneumococcal, antipseudomonal βlactam (piperacillin–tazobactam, cefepime, imipenem or meropenem) plus either ciprofloxacin or levofloxacin (750-mg dose) • or the above β-lactam plus an aminoglycoside and azithromycin • or the above β-lactam plus an aminoglycoside and an antipneumococcal fluoroquinolone (for penicillin-allergic patients, substitute aztreonam for the above β-lactam). (Moderate recommendation; level III evidence.)

Pseudomonas Aeruginosa Spanish Guidelines

In cases with risk factors for infection with P. aeruginosa (broad-spectrum antibiotic therapy for more than 7 days in the preceding month, the presence of bronchiectasis, malnutrition, or diseases and treatments associated with neutrophil dysfunction), the patient must be treated with combined therapy including effective coverage against P. aeruginosa, Legionella species, and potentially resistant S. pneumoniae. This can be achieved with a fourth-generation cephalosporin (cefepime 1–2 g/12 hours), piperacillin–tazobactam (4000/500 mg/8 hours), imipenem or meropenem (0.5– 1 g/68 hours) in combination with a fluoroquinolone (ciprofloxacin 400 mg/8 hours or levofloxacin 500 mg/12 hours), all administered intravenously. Some authors suggest that the carbapenem–fluoroquinolone combination should be avoided because of the potential risk of acquired cross-resistance. The combination of a β-lactam with an aminoglycoside (preferably tobramycin or amikacin) is another alternative; in this regimen, the synergistic effect of the two antibiotics compensates for the poor pulmonary penetration of the aminoglycosides. IDSA/ATS Guidelines

•

Preferred antimicrobials: antipseudomonal β-lactam plus ciprofloxacin or levofloxacin or aminoglycoside.

•

Alternative: aminoglycoside plus ciprofloxacin or levofloxacin.

Community-Acquired Methicillin-Resistant Streptococcus Aureus European Guidelines

•

Vancomycin, teicoplanin ± rifampin, linezolid.

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IDSA/ATS Guidelines

• For CA-MRSA infection, add vancomycin or linezolid. (Moderate recommendation; level III evidence.)

Anaerobic Organisms Spanish Guidelines

When an infection with anaerobic microorganisms is suspected (necrosis or cavitation on chest radiography or suspected aspiration), amoxicillin–clavulanic acid should be administered (with high doses of amoxicillin, 2 g). Other alternatives include clindamycin plus a third-generation cephalosporin or single-drug therapy with ertapenem or moxifloxacin. If admission to the ICU is necessary, the cephalosporin should be replaced by a combination of piperacillin and tazobactam. IDSA/ATS Guidelines

• β-lactam/β-lactamase inhibitor (piperacillin–tazobactam, ticarcillin-clavulanate, ampicillin–sulbactam or amoxicillin–clavulanate), or clindamycin. carbapenem.

Comparison Among Different Guidelines The European and Spanish guidelines date from 2005, while the IDSA/ATS guidelines are very recent, published at the beginning of 2007. Basically, in the three documents the CAP treatment rests on β-lactams and quinolones. Promising drugs for the management of CAP outpatients which were included in the Spanish guidelines, such as telithromycin, are not incorporated in the IDSA/ATS guidelines because of their hepatic toxicity described after their introduction in the market, as we have said earlier. Equally, more recently introduced drugs, such as ertapenem and linezolid, find their place in therapeutic protocols. In countries, such as Spain, with a very high rate of resistance in pneumococci, there is no room for monotherapy with macrolides and tetracyclines. Among the β-lactams, high-doses of amoxicillin, ceftriaxone and cefotaxime are preferable; within the quinolone group, the choice depends on the availability of the drugs among the different countries but, in general, levofloxacin, moxifloxacin and gemifloxacin are among the common preferences. As we have said, in countries where it is available, doses of 750 mg qd of levofloxacin are recommended. Overall, respiratory quinolones are considered very useful drugs in the treatment of lower respiratory tract infections in general, and particularly in CAP. Its use is widely generalized and its drawbacks are not in its efficacy but rather in that resistances become widespread. There is an overwhelming number of published guidelines on the management of CAP but very few variations among them concerning the recommended antibiotics. Although it has been demonstrated that the management of CAP according to

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published guidelines is beneficial for the patients, the pharmaceutical companies’ encouragement for its publication cannot be ruled out. Based on the above mentioned data, a consensus alternative is proposed in Table 5.4. Table 5.4 Recommended empirical antibiotics for community-acquired pneumonia (CAP) Treatment of community-acquired pneumonia Outpatient–mild CAP Inpatients (non-intensive care unit) – moderate CAP Inpatients (intensive care unit) – severe CAP

For Pseudomona aeruginosa

For community-acquired methicillin-resistant Staphylococcus aureus For anaerobic organism

Pneumococcal CAP–definitive treatment (MIC for penicillin)

Moxifloxacin or levofloxacin. Amoxicillin plus macrolides β-lactam (ceftriaxone, cefotaxime, amoxicillin–clavulanate) plus macrolides. Respiratory fluoroquinolones β-lactam (cefotaxime, ceftriaxone, cefepime) plus either azithromycin or respiratory fluoroquinolones. For penicillin-allergic patients, a respiratory fluoroquinolones and aztreonam are recommended Antipneumococcal, antipseudomonal β-lactam (piperacillin–tazobactam, cefepime, imipenem, meropenem) plus either ciprofloxacin or levofloxacin. Above β-lactam plus an aminoglycoside plus azithromycin. Above β-lactam plus an aminoglycoside plus an anti-pneumococcal fluoroquinolone. For penicillin-allergic patients: aztreonam plus an aminoglycoside and either a fluoroquinolone or a macrolide Add vancomycin or linezolid

Amoxicillin–clavulanate (high dose of amoxicillin). Clindamycin plus a third-generation cephalosporin. Ertapenem Minimum inhibitory concentration (MIC) < 0.06 mg/L: penicillin at conventional doses amoxicillin or ampicillin MIC 0.12–1 mg/L: high dose of penicillin, amoxicillin or ampicillin MIC 2–4 and > 4 mg/L: third-generation cephalosporins (cefotaxime or ceftriaxone) respiratory fluoroquinolones (third and fourth generation) vancomycin carbapenems

Duration of Antibiotic Treatment The duration of antibiotic treatment is difficult to substantiate. Normally CAP is treated for 10–14 days, although some studies have shown good responses and shorter treatment periods (5–7 days) using antibiotics with a longer serum half-life and good intracellular penetration (Plouffe et al., 2000; Dunbar et al., 2003). In the light of current knowledge, patients with mild pneumonia ought to take antibiotics

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for 7–10 days, whereas in cases of moderate CAP, antimicrobials should be taken for longer periods (10–14 days; (Mandell and File, 2003). In CAP caused by L. pneumophila, S. aureus and P. aeruginosa, treatment should be administered for a period of not less than 14 days, and for as much as 4 weeks in cavitated CAP with suspected anaerobic infection (Siegel et al., 1996).

Switch Therapy Given that hospital stay is the factor that most contributes to the health-care cost of caring for these patients, being able to safely switch from an intravenous antibiotic treatment to an oral one is an important aspect of their management. In order to do this, it is necessary that two conditions be fulfilled: firstly that the patient’s condition is stable and secondly that antibiotics with adequate PK/PD parameters, that allow for a sequential switch from intravenous to oral therapy, are available. The average time needed for achieving CAP patient stability is 2–4 days (Siegel et al., 1996; Halm et al., 1998; Men´endez et al., 2004a). The patient must comply with a series of criteria for this sequential therapy to be able to be carried out. They must be capable of oral ingestion, not have a high temperature (< 37.8◦ C), show improvement in or recovery from pneumonia symptoms and signs, not suffer from mental confusion or unstable comorbidities and lack infection in other areas or not suffer from other active infections (Siegel et al., 1996; Halm et al., 1998; Rhew et al., 2001). Hospital release could be safely given within 24 hours of fulfilling these requirements and once oral treatment has been established and tolerated.

Additional Therapies Low Molecular Heparin Low molecular heparin should be administered to all patients with acute respiratoty failure (Samama et al., 1999). Its use reduces thromboembolic instances from 14.9 % to 5.5 % and at the same time prevents embolic complications.

Steroids There is currently insufficient evidence to enable firm recommendations to be made with respect to the use of corticosteroids in patients with severe pneumococcal disease (Feldman and Anderson, 2006). Confalonieri et al. (2005) published data on the largest series of patients in a multicentre, randomized, double-blind, placebocontrolled trial. In this study (Confalonieri et al., 2005), 46 patients with CAP and ICU admission received either IV hydrocortisone or placebo for 7 days (together with appropiate antibiotics). Steroid administration was associated with significant improvement in PaO2 /FiO2 ratio and chest X-ray, as well as significant reductions in the concentration of circulating C-reactive protein, multiple organ dysfunction

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score, length of hospital stay and mortality. The final conclusion of this study supports the original hypothesis that control of inflammation with prolonged lowdose hydrocortisone infusions hastens recovery from pneumonia and prevents the development of sepsis-related complications. This study lays the foundations for future larger studies. In the opinion of the authors and that of others (Confalonieri et al., 2005; Feldman and Anderson, 2006) it will be necessary that, in future works, a series of variables, such as the participation of a larger number of patients, stratification of patients according to the initial mode of mechanical ventilation, adherence to recent guidelines for the management of patients with severe sepsis and septic shock, stringent recording of time of initial administration of antibiotics, and serial management of circulating pro-inflammatory cytokines are monitored. In addition, the measurements of other systemic indices of severity of infection and intensity of neutrophil activation, such as procalcitonin, TREM-1 and CD64 at the time of presentation, would be highly interesting (Christ-Crain et al., 2006).

Non-Invasive Ventilation The use of non-invasive ventilation has been shown to be efective in COPD patients with pneumonia (Confalonieri et al., 1999; Alfageme et al., 2005; Woodhead et al., 2005). Its use in patients with comorbidities other than COPD remains controversial (Jolliet et al., 2001); although it initially improves oxygenation figures, intubation is later required in 66 % of cases.

Management of Non-Responding Pneumonia It seems practical to differentiate between non-resolving pneumonia (failure to respond to initial treatment) and slowly resolving pneumonia–failure to be completely resolved (Woodhead et al., 2005). In the case of non-resolving CAP patients, all efforts should be made to reinvestigate the patient intensively; the carrying out of computed tomography scanning or bronchoscopy must be individualized (Arancibia et al., 2000). The most important diagnoses to exclude are empyema, abscess formation, pulmonary embolism and fluid overload (Alfageme et al., 2005; Woodhead et al., 2005). For patients with slowly resolving pneumonia, the decision to embark on reinvestigation should be based on a careful estimation of factors influencing symptom resolution and the likelihood of identifying a specific diagnosis. The possibility of an alternative diagnosis or infection by an uncommon germ should be kept in mind. Recently, a prospective multicentre cohort study, undertaken to quantify the incidence of failure of empirical treatment in CAP, to identify risk factors for treatment failure and to determine the implications of treatment failure on the outcome, was performed on 1424 hospitalized patients from 15 hospitals (Men´endez et al., 2004b). Early treatment failure (< 72 hours), late treatment failure and inhospital mortality were recorded. Treatment failure occurred in 15.1 % of patients (early failure in 62.3 % and late failure in 37.7 %). The causes were infectious in

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40 %, non-infectious in 15.8 % and undetermined in the rest. The independent risk factors associated with treatment failure in a stepwise logistic regression analysis were liver disease, pneumonia risk class, leucopenia, multilobar CAP, pleural effusion and radiological signs of cavitation. Independent factors associated with a lower risk of treatment failure were influenza vaccination, initial treatment with fluoroquinolones and COPD. Mortality was significantly higher in patients with treatment failure (25 % vs 2 %). Failure of empirical treatment increased the mortality of CAP elevenfold after adjustment for risk class.

Prevention • All persons ε 50 years, others at risk because of influenza complications, household contacts of high-risk persons and health-care workers should receive inactivated influenza vaccine (Smith et al., 2006). • Pneumococcal polysaccharide vaccine is recommended for persons ε 65 years and for those with selected high-risk concurrent diseases according to current Advisory Committee on Immunization Practices (ACIP) guidelines (Benin et al., 2003). • Smoking cessation should be a goal for smokers hospitalized with CAP.

Summary 1. The aetiology of CAP can differ between several groups of patients (outpatients; non-ICU inpatients; ICU inpatients.) although S. pneumoniae is the most frequent microorganism in all of them. 2. Antimicrobial treatment will be basically empirical and its administration should be based on the following factors: severity of illness, most probable aetiology and local microorganism resistances. 3. Antibiotic treatment must be started as early as possible. 4. Treatment time will be 7–10 days in cases of mild CAP and 10–14 days in the case of inpatients. 5. The recommended empirical antibiotics for CAP are the following: • Outpatient treatment: moxifloxacin or levofloxacin amoxicillin + macrolides. • Inpatients, non-ICU treatment: respiratory fluoroquinolone β-lactam + a macrolide • Inpatients, ICU treatment

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a β-lactam (cefotaxime, ceftriaxone, cefepime) PLUS either azithromycin OR a respiratory fluoroquinolone. (For penicillin-allergic patients, a respiratory fluoroquinolone and aztreonam are recommended.)

6. All persons ε 50 years, others at risk because of influenza complications, household contacts with high-risk persons and health-care workers should receive inactivated influenza vaccine (Smith et al., 2006). 7. Pneumococcal polysaccharide vaccine is recommended for persons ε 65 years and for those with selected high-risk concurrent diseases according to current ACIP guidelines (Benin et al., 2003). 8. Smoking cessation should be a goal for smokers hospitalized with CAP.

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6 Pathogen Directed Antimicrobial Treatment of Pneumonia ¨ SANTIAGO EWIG1 AND SOREN GATERMANN2 1

Thoraxzentrum Ruhrgebiet, Kliniken fur ¨ Pneumologie und Infektiologie, Evangelisches Krankenhaus Herne und Augusta-Kranken-Anstalt, Bochum, Gemany 2 ¨ Bochum, Bochum, Institut fur ¨ Medizinische Mikrobiologie, Ruhr-Universitat Gemany

Introduction Targeted treatment of pneumonia is an issue difficult to comply with. The usual approach to the treatment of pneumonia is an empirical one, based on the most probable microbial pattern in the given condition of the patient and on local peculiarities of the treatment setting (Woodhead et al., 2005). The rationale behind this approach is the low diagnostic yield of microbial investigation and the need for a broad-spectrum initial combination treatment in severe, life-threatening pneumonia in order to preclude discordant initial coverage which is associated with considerable excess mortality. Even in studies with vigorous diagnostic protocols of hospitalized patients with community-acquired pneumonia, a pathogen can be identified in not more than 50–60 % of cases. In routine practice, standard diagnostic protocols are rarely applied, and, therefore, an aetiological diagnosis is probably only rarely made. This is certainly even more true for outpatients. Diagnostic efforts made in patients with nosocomial pneumonia are usually higher, however, as due to the many uncertainties associated with a definite aetiological diagnosis in this condition, only few cases will be attributed to a specific pathogen. On the other hand, once a broad Community-Acquired Pneumonia: Strategies for Management Edited by Antoni Torres and Rosario Men´endez  2008 John Wiley & Sons, Ltd

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spectrum is administered and the patient is doing better, many physicians remain reluctant to change the effective combination treatment. As a result, discouraging experiences with microbial investigation and encouraging experiences with effective broad-spectrum combination treatment may lead to a general disregard of the potentials for targeted, pathogen directed antimicrobial treatment. Another objection frequently made against targeted treatment is the potential for the presence of mixed infections. As a consequence, targeted treatment may effectively treat one pathogen but fail to cover a second or third possibly even more important one. Concerns about the potential of unidentified copathogens for treatment failures of targeted treatment are not supported by the literature, although it has to be admitted that this issue is difficult to study and, therefore, data even for hospitalized patients are scarce (de Roux et al., 2006). Conversely, there are at least three arguments in favour of targeted antimicrobial treatment. First, targeted treatment is the only way to ensure that the most potent agent against a given pathogen is administered. For example, penicillin G continues to be the most active agent for pneumococcal infection but is only rarely used in empirical broad-spectrum combination treatment regimens. Second, the emergence of microbial resistance world-wide does not allow us to ignore one major target for intervention, i.e. the judicious use of antimicrobial agents in order to reduce selection pressure. This includes different concepts such as de-escalation after identification of a pathogen, sequential treatment after clinical improvement and limitation of overall antimicrobial treatment duration (H¨offken and Niederman, 2002). Finally, targeted treatment opens a considerable potential for cost savings, an argument which should finally convince also habitual sceptics. As a result, recent recommendations for antimicrobial stewardship have a main focus on the optimal implementation of de-escalation strategies for antimicrobial treatment (Dellit et al., 2007). Thus, at least in hospitalized patients, there are good reasons to adjust microbial treatment of pneumonia according to the results of microbial investigation. In the following, we will review the options for targeted pathogen directed treatment of bacterial pneumonia in the non-immunosuppressed host based on the most recent data available in the literature.

Gram-Positive Cocci Streptococcus pneumoniae The Challenge of Pneumococcal Resistance

Up to the beginning of the 1990s, pneumococci appeared to be almost universally susceptible to penicillin. Since then, the emergence and spread of pneumococcal resistance to penicillin (and, likewise, to other ß-lactams and macrolides) has questioned the general recommendation of treatment with a ß-lactam. However, the relevance of penicillin and macrolide resistance for the treatment of pneumonia has continued to be a matter of debate. Prospective observational and

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most retrospective case-control studies (12 of 15) did not find a difference in outcome when the effects of discordant treatment were controlled for main confounders such as age and severity of disease (Metlay, 2004). Several studies were underpowered and subject to possible type-II error. However, the largest series, which applied the most vigorous methodology, did not find an effect of outcome in the presence of penicillin resistance (Yu et al., 2003). In contrast, some authors could identify high-level resistance of > 2 mg/dL as risk factors for excess mortality. For example, in 5837 patients studied, mortality was associated with penicillin minimum inhibitory concentration (MIC) ≥ 4 µg/mL or cefotaxime MIC > 2 µg/mL when deaths during the first four hospital days were excluded (adjusted odds ratio (OR) for penicillin 7.1, 95 % confidence interval (CI) 1.7–30, and for cefotaxime OR 5.9, 95 % CI 1.1–33) (Feikin et al., 2000). Comparable findings were made by another smaller study including 462 cases (Turett et al., 1999). Only recently, a meta-analysis of 10 studies including 3430 patients (most of whom were hospitalized) found that the combined risks of all-cause mortality for the penicillin-non-susceptible, intermediate and resistant S. pneumoniae groups as compared to the penicillin-susceptible group were 1.31 (95 % CI 1.08–1.58), 1.34 (95 % CI 1.13–1.6) and 1.29 (95 % CI 1.01–1.66), respectively (Chang et al., 2003). The authors concluded that penicillin resistance is associated with a higher mortality rate than is penicillin susceptibility in hospitalized patients with pneumococcal pneumonia. In line with this conclusion, macrolide use in patients with bacteremic pneumococcal pneumonia due to macrolide-resistant pneumococci was found to be associated with treatment failures. The interpretation of these data remains conflictive. To begin with the noncontroversial, there are no data indicating that resistance to penicillin or macrolides in patients with mild pneumonia might be associated with adverse outcomes. Therefore, in contrast to current American Thoracic Society (ATS) guidelines, there is no reason to abandon ß-lactam monotherapy or to shift to combination treatment of ß-lactams with other antimicrobial agents in patients with mild pneumococcal pneumonia. Penicillins should, however, be used in a high dosage, e.g. amoxicillin 1 g thrice daily. The response to treatment should be carefully monitored and treatment should be re-evaluated in case of non-response after 72 hours of treatment duration. Judgement of the relevance of penicillin resistance in hospitalized patients with moderate to severe disease is far more complicated. Theoretically, the cut-offs for resistance (MIC 0.12–1 µg/mL for intermediate and ≥ 2 µg/mL for high level resistance), originally designed in view of pneumococcal meningitis, are less appropriate in patients with pneumonia. The critical determinant of success for ß-lactam antimicrobials is the duration of time that serum or tissue levels exceed the MIC, and success is predictable when the free-drug concentration is above that of the MIC for at least 40–50 % of the dosing interval. Moreover, local drug levels up to 1 mg/dL should regularly be reached in patients with pneumonia. Thus, dosages of 8–20 million units of penicillin G given daily in four to six divided doses should be effective. These pharmacological considerations have questioned

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current thresholds of susceptibility (Heffelfinger et al., 2000) and finally led to a revision of susceptibility categories for non-meningeal pneumococcal infections by the Clinical Laboratory Standards Institute (formerly the National Committee for Clinical Laboratory Standards). Specifically, susceptibility is defined as MIC ≤ 1 µg/mL, intermediate susceptibility as MIC 2 µg/mL, and resistance as MIC ≥ 4 µg/mL. These cut-offs also apply to the cephalosporins cefotaxime and ceftriaxone. However, it is important to remember that in the presence of pneumococci intermediately resistant to penicillin according to traditional breakpoints (MIC 0.12–1 µg/mL), susceptibility to macrolides, cefuroxime and doxycycline is usually decreased, whereas ceftriaxone remains active. This theoretical concept is challenged by the recent meta-analysis. However, several inherent limitations of the meta-analysis need to be stated. The ability to control for confounding factors in the studies included remains questionable. Given the many confounding factors which may determine mortality from pneumococcal disease, separating out the impact of resistance to penicillin is difficult. Possible explanations for a presumed excess mortality are widespread. These may relate to organism virulence, age and comorbidity of the host, severity of illness and discordant antimicrobial treatment. However, the association of resistance and virulence is not established, and only one study found an association of discordant antimicrobial treatment (low dose cefuroxime) with mortality (Yu et al., 2003). In view of these limitations, we continue to rely on the theoretical framework and the results of most single studies that penicillin resistance can be overcome by adequate high-dose ß-lactam treatment up to a MIC of 2 µg/mL. As in nonsevere pneumonia, the response to treatment should be carefully evaluated and treatment should be changed in case of non-response after 72 hours of treatment at the latest. Data assessing the impact of macrolide resistance on clinical outcomes are scarce. In addition to the confounders already present when investigating the relevance of penicillin resistance, favourable pharmacokinetics and pharmacodynamics, high concentrations at sites of infections and additional anti-inflammatory properties of macrolides may obscure the predictive potential of in vitro MICs to predict clinical failures. Moreover, the two mechanisms of resistance (modification (methylation) of ribosomal RNA (erm) or active drug efflux (mef )) confer different grades of resistance. Obviously, the latter probably can be overridden in vivo. The only way to achieve definite insights into the relevance of macrolide resistance are prospective, randomized, clinical trials with sufficient power, which have not been performed and are highly unlikely to be performed in the future. However, several retrospective studies and case reports have been published which demonstrate failure of discordant treatment followed by successful resolution with another antimicrobial agent (Lynch et al., 2002). Moreover, the observation of breakthrough bacteremia in patients with discordant treatment strongly supports the idea that macrolide resistance is relevant in vivo (Lonks et al., 2002). It should be noticed that all these data refer to patients with moderate to severe bacteremia and/or pneumonia. No data are available for patients with mild pneumonia.

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Similar conclusions may be drawn from the few data reported from patients with quinolone resistance. Overall, it appears that discordant treatment is associated with treatment failures (Davidson et al., 2002). Combination Treatment for Severe Pneumococcal Pneumonia

Another conflicting issue is the potential advantage of combination treatment for severe bacteremic pneumococcal pneumonia even in the presence of fully penicillin-susceptible isolates. Data from three retrospective analyses of patients with bacteremic pneumococcal pneumonia suggest that combination treatment is associated with reduced mortality as compared with monotherapy (Mufson and Stanek, 1999; Waterer et al., 2001; Martinez et al., 2003). Two of these studies focused on the addition of a macrolide to a ß-lactam treatment (Mufson and Stanek, 1999; Martinez et al., 2003). In the following, a large prospective observational multicentre study of 844 adult patients with bacteremic pneumococcal pneumonia from 21 hospitals in 10 countries showed a dramatic reduction of 14-day mortality in the critically ill group receiving combination treatment (23.4 versus 55.3 %). Of note, microbial resistance in monotherapy or combination treatment did not affect the outcome (Baddour et al., 2004). However, the authors pointed out several limitations. First, the study had not a blinded, randomized design. Second, neither the selection nor the duration of antimicrobial combination treatment were standardized. Third, no specific advantage for a given combination treatment could be identified, and thus, the rationale behind a superiority could not be cleared. Nevertheless, while awaiting further prospective trials, it appears prudent to administer directed treatment for severe pneumococcal pneumonia as combination treatment of a ß-lactam with a macrolide or a respiratory quinolone for 3–5 days. Directed Treatment of Pneumococcal Pneumonia

The directed treatment of pneumococcal pneumonia (Table 6.1) has become more complex than in the past. Microbial resistance and severity of illness have to be taken into account. For mild disease, penicillin resistance is not relevant unless the MIC goes beyond 2 µg/mL. However, amoxicillin must be administered at high dosages (1 g three times daily). Macrolide resistance is probably of minor significance but macrolide treatment should nevertheless be avoided in the presence of resistance. If both high-level resistance to penicillin (MIC ≥ 2 µg/mL) and macrolide resistance is present, or if the patient is intolerant to both, respiratory quinolones are the drugs of choice. Doxycycline and telithromycin may be an alternative if proven as susceptible. Trimethoprim–sulphamethoxazole should be avoided because of its toxicity. In hospitalized patients who are not critically ill, treatment must be directed according to the level of penicillin resistance. Patients with susceptible or intermediately resistant pathogens should preferably be treated with penicillin G or a third-generation cephalosporin (e.g., ceftriaxone). In patients infected with pneumococci expressing high-level resistance to penicillin (MIC ≥ 2 µg/mL), ß-lactam treatment may still be adequate (Roson et al., 2001). However, it seems prudent

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Table 6.1 Targeted antimicrobial treatment of pneumonia due to Streptococcus pneumoniae: MIC, minimum inhibitory concentration Disease category

Antimicrobial agent

Dosage

Mild

Amoxicillin Clarithromycin Azithromycin Telithromycin Levofloxacina Moxifloxacina

3 × 1 g orally (7 days) 2 × 500 mg orally (7 days) 2 × 250 mg orally (3 days) 1 × 800 mg orally (7 days) 1 × 500 mg orally (7 days) 1 × 400 mg orally (7 days)

Penicillin G

4 × 5 million units iv (7 days, sequential treatment with amoxicillin) 1 × 2 g iv (7 days) 1 × 500 − 750 mg iv (7 days, sequential treatment) 1 × 400 mg iv (7 days, sequential treatment) 1 × 500 mg iv (7 days) 1 × 400 mg iv (7 days) 2 ×1g

Moderate (hospitalized patients, not critically ill) Fully susceptible up to intermediately resistant to penicillin (MIC < 0.1 up to 1.2 µg/mL)

Ceftriaxone Levofloxacinb Moxifloxacinb

High-level resistance to penicillin (MIC ≥ 2 µg/mL) Severe (patients admitted at the ICU, critically ill) Fully susceptible to penicillin Reduced susceptibility to penicillin

Levofloxacin Moxifloxacin Vancomycin

Penicillin G plus clarithromycin or azithromycin Two fully active agents out of ß-lactam, macrolides, quinolones or othersc

a Treatment

of choice in patients with intolerance to penicillin and macrolides or high-level resistance to penicillin (MIC ≥ 2 µg/mL) together with macrolide resistance. b Treatment of choice in patients with intolerance to ß-lactams. c Vancomycin, clindamycin, linezolid.

to rely mainly on respiratory quinolones as the treatment of choice at this level of resistance (Tleyjeh et al., 2006). This is certainly true for MIC ≥ 4 µg/mL. In this rare latter condition, other options behind these standard agents include vancomycin, clindamycin, and linezolid. Finally, critically ill patients admitted to the intensive care unit (ICU) with pneumococcal pneumonia by fully susceptible pathogens should receive a combination treatment of penicillin G plus a macrolide or plus a respiratory quinolone. Because these patients are at highest risk of death, treatment should be guided by the selection of the most active antipneumococcal agents regardless of the uncertainty about the true relevance of resistance. Combination treatment can be de-escalated to monotherapy after the clinical condition of the patient has improved (usually after three to five days).

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Staphylococcus aureus Patterns of Resistance

Staphylococcus aureus may prove resistant to virtually all antimicrobial agents available. The most prevalent resistance is to penicillin conferred by penicillinase. Penicillinase-producing S. aureus emerged rapidly after penicillin was introduced into clinical practice in the 1940s. They represent at least 80 % of the isolates. Nevertheless, since the MIC of penicillin G for susceptible S. aureus is 0.01 mg/L and thereby about tenfold lower than that of penicillinase-stable drugs, penicillin G remains the drug of choice against rare penicillin-susceptible staphylococci. Otherwise, penicillinase-stable ß-lactams (oxacillin, first- and second-generation cephalosporins) are the treatment of choice for methicillin-susceptible Staphylococcus aureus (MSSA). Almost at the same time (i.e. in the late 1950s) the first penicillinase-stable ß-lactams became available, methicillin-resistant Staphylococcus aureus (MRSA) emerged as a novel threat. The prevalence of MRSA progressively increased thereafter, with great geographical variations. In European countries such as The Netherlands or the Scandinavian countries, MRSA prevalence remains remarkably low, whereas in Germany, France, Italy, Spain and Portugal, for example, MRSA prevalence is steadily increasing, reaching 25–50 %. Similar differences are evident in America; whereas the USA and Latin American MRSA reach a prevalence of about 35 %, it remains as low as about 6 % in Canada. Resistance to macrolides and lincosamides is also prevalent. The most prevalent mechanism is modification of ribosomal RNA by the erm genes (ermA and ermC ). In the wild type, this gene is expressed only in the presence inducing drugs, macrolides being a perfect inducer. However, mutants expressing the gene constitutively are readily selected and these mutants are also resistant to lincosamides and streptogramin B. Thus, an isolate resistant to macrolides but inducibly resistant to lincosamides and streptogramins B must never be treated with clindamycin because of selection of constitutive MLSB resistant mutants. Hospital-acquired MRSA frequently (> 90 %) exert constitutive macrolide–lincosamide–streptogramin B resistance (MLSB ); therefore, these drugs should not be considered in the treatment of MRSA. Isolates that show resistance to erythromycin only and lack inducible resistance to lincosamides may be treated with clindamycin because the underlying resistance mechanism is msrA, an exporter pump that is inactive against clindamycin. Quinolones should not be used against MRSA since development of resistance is likely. Only recently has MRSA emerged in community-acquired infections (CAMRSA). Evidently, CA-MRSA does not share the typical risk factors for hospitalacquired MRSA (HA-MRSA), reflecting that the two types of organisms are not identical. In fact, in contrast to HA-MRSA, CA-MRSA usually occurs in otherwise healthy patients and presents as severe necrotizing pneumonia due to (among other mechanisms) Panton–Valentine leucocidin (PVL) production. Importantly, although CA-MRSA is more invasive than HA-MRSA, it is less resistant.

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Glycopeptide-resistant MRSA (intermediately resistant, GISA, or fully resistant, VRSA) have as yet not been described to cause pneumonia. Choices of Treatment

Vancomycin is the classic drug active against MRSA (Table 6.2). It is important to state that the use of vancomycin should be restricted to patients with suspected or proven MRSA because in the presence of MSSA, treatment outcome of penicillinase-stable ß-lactams (oxacillin) is superior to vancomycin (Chang et al., 2003; Gonzales et al., 1999; Stryjewski et al., 2007). On the other hand, there are concerns about the validity of vancomycin monotherapy of pneumonia because of the unfavourable pharmacokinetics of this drug, mainly a result of limited tissue penetration. Therefore, based on synergisms observed in vitro, combination treatment with rifampin is frequently advocated. However, there are virtually no clinical data to support this practice. New options of MRSA treatment include quinupristin–dalfopristin, linezolid and tigecycline. Several other agents active against MRSA are currently under investigation. Table 6.2 Targeted antimicrobial treatment of pneumonia due to Staphylococcus aureus

Methicillinsusceptible Staphylococcus aureus

Methicillinresistant Staphylococcus aureus

Antimicrobial agent

Dosage

Oxacillin Cefazolin Cefuroxime Clindamycin Levofloxacin Moxifloxacin Vancomycin + rifampin Vancomycin + trimethoprim– sulphmethoxazole Vancomycin + fosfomycin Linezolid Quinupristin–dalfopristin Tigecycline

6 × 2 g iv (7–10 days) 3 × 2 g iv (7–10 days) 3 × 1.5 g iv (7–10 days) 3 × 600–900 mg iv (7–10 days)b 1 × 500–750 mg iv (7 days)b 1 × 400 mg iv (7 days)b 2 × 1 g + 1 × 600 mg iv (7–10 days) 2 × 1 g + 15 − 20 mg/kg iv (7–10 days) 2 × 1 g + 2 × 5 g iv (7–10 days) 2 × 600 mg iv (7–10 days)b 3 × 7.5 mg/kg iv (7–10 days) 100 mg loading dose, then 2 × 50 mg iv (7–10 days)

a

All notes on treatment duration refer to patients without abscess formation. Patients with staphylococcal abscesses have to be treated significantly longer, usually until complete clearance of chest radiograph. b Consider sequential treatment.

Antimicrobial Treatment of Methicillin − Susceptible Staphylococcus aureus

Pneumonia due to MSSA should be treated with oxacillin or a first- or secondgeneration cephalosporin. Alternatively, in case of ß-lactam intolerance, clindamycin or a respiratory quinolone appear effective. The duration of treatment has not been formally assessed. In the absence of abscess formation, 7–10 days of treatment should be sufficient. Otherwise, treatment should be continued until full clearance of the abscess in chest-radiograph.

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Antimicrobial Treatment of Methicillin − Resistant Staphylococcus aureus

To compare quinupristin–dalfopristin with vancomycin for the treatment of ventilator-associated pneumonia due to MRSA, 298 patients with nosocomial pneumonia were enrolled in a prospective, randomized, open-label multicentre study. A subgroup of 171 were evaluable for the major efficacy end-points. Cure or improvement was achieved in 49 (56.3 %) of the patients receiving quinupristin–dalfopristin and 49 (58.3 %) patients receiving vancomycin (difference, −2.0 % [95 % CI −16.8 % to 12.8 %]) in the bacteriologically evaluable population. The bacteriological response showed equivalent clinical success rates for Streptococcus pneumoniae, MSSA and MRSA. Overall, quinupristin–dalfopristin was shown to be equivalent to vancomycin in the treatment of nosocomial pneumonia caused by Gram-positive pathogens (Fagon et al., 2000). These encouraging results were somewhat devalued by the launch of linezolid, a drug which compared favourably in terms of pharmacokinetics and oral availability. In two double-blind prospective studies evaluating the treatment of staphylococcal infections with linezolid as compared with vancomycin in patients with nosocomial pneumonia, both regimens were found to be equivalent (Rubinstein et al., 2001; Stevens et al., 2002). However, in two retrospective analyses of these studies, linezolid was found to be highly superior in patients with proven MRSA pneumonia. In the first study comprising 339 patients with documented S. aureus pneumonia (S. aureus subset) and 160 patients with documented MRSA pneumonia (MRSA subset), clinical cure rates for linezolid versus vancomycin (excluding indeterminate or missing outcomes) were 59.0 % (36 of 61 patients) vs 35.5 % (22 of 62 patients) for the MRSA subset (p < 0.01). Logistic regression analysis confirmed that the difference favouring linezolid remained significant after adjusting for baseline variables (OR, 3.3; 95 % CI 1.3–8.3; p = 0.01) (Wunderink et al., 2003). In the second study, comprising 264 with documented Gram-positive ventilator-associated pneumonia (VAP) and 91 with methicillinresistant S. aureus (MRSA) VAP, clinical cure rates assessed 12–28 days after the end of therapy and excluding indeterminate or missing outcomes significantly favoured linezolid in the Gram-positive and MRSA subsets. Logistic regression showed that linezolid was an independent predictor of clinical cure with ORs of 1.8 for all patients, 2.4 for Gram-positive VAP, and 20.0 for MRSA VAP. Kaplan–Meier survival rates favoured linezolid in the MRSA subset. Logistic regression showed that linezolid was an independent predictor of survival with ORs of 1.6 for all patients, 2.6 for Gram-positive VAP and 4.6 for MRSA VAP (Kollef et al., 2004). These results led the authors and many other authorities to judge linezolid as superior to vancomycin in the treatment of MRSA pneumonia. However, there are a lot of concerns which should be appreciated. First, this was a retrospective analysis of subgroups, a design which frequently has been shown to result in erroneous conclusions. Second, to keep in line with the study design linezolid would have to be administered empirically in any patient with suspected MRSA, a practice which is clearly unacceptable. Finally, the Kaplan–Meier plots in the first study show that patients in the inferior vancomycin group die far beyond two weeks of

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treatment, implying that late mortality is prevented by linezolid. This unexpected finding cannot be accepted as conclusive evidence in favour of linezolid without another confirmatory study. In the meantime, vancomycin plus rifampin remains the mainstay of treatment also for HA-MRSA pneumonia. Alternatives may include a combination of vancomycin with trimethoprim–sulphamethoxazole, vancomycin plus fosfomycin, linezolid or quinupristin–dalfopristin. Experience with tigecycline is very limited yet, but this may emerge as another option in the near future. The treatment of CA-MRSA may offer a broader battery of alternatives since these pathogens are more susceptible. Nevertheless, the main options are identical with those given for HA-MRSA. As regards treatment duration, the same considerations apply to MRSA as to MSSA.

Gram-Negative Rods Haemophilus influenzae Pneumonia due to Haemophilus influenzae is usually caused by non-typeable strains. The drug of choice is an aminopenicillin, or, in case of intolerance to penicillin, a second or third generation cephalosporin (cefuroxime or ceftriaxone). In case of aminopenicillin resistance (almost invariably due to ß-lactamase production), the combination of an aminopenicillin plus a ß-lactamase inhibitor (amoxicillin plus clavulanic acid or ampicillin plus sulbactam) or a second- or third generation cephalosporin is indicated. For patients intolerant to ß-lactams, quinolones (levofloxacin and moxifloxacin) represent an excellent alternative (Table 6.3). Macrolides (as well as ketolides) do not exert optimal activity in vitro, and although this failure may be somewhat compensated by anti-inflammatory properties, macrolides (and ketolides) are not recommended for directed treatment of H. influenzae pneumonia. Azithromycin has the relatively best activity among the macrolides but should also be avoided for directed treatment. Several oral cephalosporins such as cefaclor, loracarbef, cefuroxime axetil, cefixime and cefpodoxime are active in vitro but do not offer significant advantages as compared with aminopenicillins. The optimal duration of treatment is unknown, however, treatment should be confined to one week.

Gram-Negative Enterobacteriaceae (GNEB) Escherichia coli Escherichia coli was usually easily treated by aminopenicillins, second- and thirdgeneration cephalosporins, quinolones and aminoglycosides. Currently, the prevalence of ampicillin resistance is very high. The option of quinolones is also

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111

Table 6.3 Targeted antimicrobial treatment of pneumonia due to Haemophilus influenzae Disease category Mild Susceptible to aminopenicillin ß-lactamase-producing strains Intolerance to penicillin Severe Susceptible to aminopenicillin ß-lactamase-producing strains

Intolerance to penicillin a Ideal

Antimicrobial agent

Dosage

Amoxicillin

3 × 1 g orally (7 days)

Amoxicillin–clavulanic acid Sultamicillin Levofloxacin Moxifloxacin

3 × 625 mg 2 × 750 mg 1 × 500 mg 1 × 400 mg

Ampicillin Cefuroxime Ceftriaxone Amoxicillin–clavulanic acid Ampicillin–sulbactam Cefuroxim Ceftriaxone Levofloxacin Moxifloxacin

3 × 1 g iv (7 days)a 3 × 1.5 g iv (7 days) 1 × 2 g iv (7 days) 3 × 2.2 g iv (7 days)a 3 × 3 g iv (7 days)a 3 × 1.5 g (7 days) 1 × 2 g iv (7 days) 1 × 500 mg iv (7 days)a 1 × 400 mg iv (7 days)a

orally orally orally (7 days) orally (7 days)

choice for sequential treatment.

severely challenged by raising resistance rates, currently up to 30 %. Most E. coli are still susceptible to third-generation cephalosporins, carbapenems and aminoglycosides.

Klebsiella spp. The most frequent Klebsiella species involved in pneumonia are Klebsiella pneumoniae and Klebsiella oxytoca. All Klebsiella spp. are resistant to ampicillin because of the presence of a chromosomal gene encoding a penicillin-specific ß-lactamase. Nosocomial strains frequently are multiresistant due to the acquisition of multidrug resistance (MDR) plasmids. The most prominent example is a plasmid encoding extended-spectrum ß-lactamases (ESBLs). As a result, usual Klebsiella spp. may be treated with first-generation cephalosporins, penicillin plus ß-lactamase-inhibitors and quinolones. For ESBL, carbapenems are the treatment of choice. In a prospective multicentre study of 85 episodes of Klebsiella pneumoniae bacteremia due to an ESBL-producing organism, failure to use an antibiotic active against ESBL-producing K. pneumoniae was associated with a high excess mortality. Use of a carbapenem (primarily imipenem) was associated with a significantly lower 14-day mortality than was use of other antibiotics active in vitro. Accordingly, multivariate analysis including other predictors of mortality showed that use of a carbapenem during the 5-day period after onset of bacteremia due to an ESBL-producing organism was independently associated with lower mortality (Paterson et al., 2004; Ramphal and Ambrose, 2006). Alternatives

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are quinolones, if the isolate is susceptible, and probably tigecycline (Table 6.4). Fourth-generation cephalosporins should be avoided. Table 6.4 Targeted antimicrobial treatment of pneumonia due to Gram-negative Enterobacteriaceae (Escherichia coli, Klebsiella pneumoniae and Enterobacter spp.) Enterobacteriaceae

Antimicrobial agent

Dosage

Escherichia coli

Ciprofloxacin Ceftriaxone Cefazolin Amoxicillin–clavulanic acid Ampicillin–sulbactam Levofloxacin Moxifloxacin Imipenem or Meropenem Ertapenem Tigecycline

3 × 400 mg iv (8 days) 1 × 2 g iv (8 days) 3 × 2 g iv (8 days) 3 × 2.2 g iv (8 days)a 3 × 3 g iv (8 days)a 1 × 500 mg iv (8 days)a 1 × 400 mg iv (8 days)a 3 × 1 g iv (8 days) 1 × 1 g iv (8 days) 100 mg loading dose, then 2 × 50 mg iv (8 days) 3 × 1 g iv (8 days) 1 × 1 g iv (8 days)

Klebsiella pneumoniae –nonmultidrug resistant

Klebsiella pneumoniae – multidrug resistant, particularly extendedspectrum ß-lactamases Enterobacter spp. a Consider

Imipenem or Meropenem Ertapenem

sequential treatment.

Enterobacter spp. The Enterobacter species most frequently involved in pneumonia are E. cloacae and E. aerogenes. All strains are intrinsically resistant to ampicillin and firstand second-generation cephalosporins due to an inducible AmpC chromosomal ßlactamase. Moreover, mutants overexpressing the chromosomal ß-lactamase readily arise during treatment. These mutants show resistance to penicillins and thirdgeneration cephalosporins. Thus, isolates that appear susceptible to penicillins and third-generation cephalosporins should not be treated with these drugs since stably derepressed resistant mutants may arise (Chow et al., 1991). The AmpC ßlactamase cannot be inhibited by currently available ß-lactamase inhibitors. Finally, also plasmids encoding MDR may be present. As a result, at least in severe pneumonia, penicillins and cephalosporins should be avoided. Instead, Enterobacter spp. should be treated with carbapenems. In patients who do not tolerate ß-lactams tigecycline may be an alternative. Again, fourth-generation cephalosporins should be avoided (Table 6.4).

Serratia spp. Serratia marcescens and, rarely, Serratia liquefaciens may appear as pathogens of nosocomial pneumonia. Similar to Enterobacter spp., Serratia spp. are resistant to ampicillin and first-generation cephalosporins due to an inducible, chromosomal AmpC ß-lactamase. Furthermore, mutants producing high amounts of these

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enzymes may arise during treatment as a result of stable derepression. Plasmids may carry the potential for resistance to other ß-lactams, carbapenems, and aminoglycosides. Resistance to quinolones is also common (Hejazi et al., 1997).

Others There are several other GNEB such as Citrobacter spp., Hafnia alvei, Proteus spp., Providencia spp. and Morganella spp. which are very infrequently encountered in pneumonia but may play a role in ventilator-associated pneumonia. Except for Proteus mirabilis, which is usually susceptible to most common antimicrobial agents, these pathogens share similar susceptibility patterns to Enterobacter and Serratia spp.

Non-Fermenters Pseudomonas aeruginosa Available antipseudomonal drugs include acylureido-penicillins (mainly piperacillin), third and fourth generation cephalosporins (ceftazidime and cefepime), carbapenems (imipenem and meropenem), quinolones (ciprofloxacin and levofloxacin) as well as aminoglycosides (tobramycin, amikacin). Older agents which are currently attracting new interest in the treatment of multiresistant pseudomonal pneumonia include polymyxins (colistin = polymyxin E, and polymyxin B) and, to a limited extent, aztreonam. Aminoglycosides, although exerting a high activity against P. aeruginosa in vitro, have several disadvantages which explain their high failure rate when used as single agents. These include low antibiotic levels achieved in the airways (Odio et al., 1975), inactivation of aminoglycosides in the acidic environment of the lungs (Bryant and Hammond, 1974) and binding of drugs to human mucus (Ramphal et al., 1988). Several strains of P. aeruginosa develop resistance during antipseudomonal treatment, particularly against carbapenems and quinolones, usually after the first five days of treatment (Fink et al., 1994). This resistance is mostly due to changed permeability of the outer membrane. Treatment of Susceptible Strains

Traditionally, combination treatment with two different classes of antimicrobial agents, usually a ß-lactam and an aminoglycoside, was considered first choice treatment for pseudomonal pneumonia. However, several studies and meta-analyses have proven that the combination treatment of ß-lactam and aminoglycoside for immunocompetent patients with sepsis (Paul et al., 2004), cancer, and neutropenia (Maschmeyer and Braveny, 2000; Paul et al., 2003; Glasmacher et al., 2005), for Gram-negative bloodstream infections (Leibovici et al., 1997, Safdar et al., 2004),

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as well as P. aeruginosa infections (including pneumonia) (Chamot et al., 2003), is not more effective compared with monotherapy (Klibanov et al., 2004). In a large Cochrane analysis comparing clinical outcomes for ß-lactam–aminoglycoside combination therapy versus ß-lactam monotherapy for sepsis, 64 trials (7586 patients) were included. Twenty trials compared the same ß-lactam in both study arms, while the remaining compared different ß-lactams using a broader spectrum ß-lactam in the monotherapy arm. In studies comparing the same ß-lactam, there was no difference between study groups with regard to all-cause fatality, relative risk (RR) 1.01 (95 % CI 0.75–1.35) and clinical failure, RR 1.11 (95 % CI 0.95–1.29). In studies comparing different ß-lactams, there was an advantage to monotherapy: all cause fatality RR 0.85 (95 % CI 0.71–1.01), clinical failure RR 0.77 (95 % CI 0.69–0.86). No significant disparities emerged from subgroup and sensitivity analyses, including the assessment of patients with Gram-negative and P. aeruginosa infections. Also no differences in the rate of resistance development were found. Adverse events rates did not differ significantly between the study groups overall, although nephrotoxicity was significantly more frequent with combination therapy, RR 0.30 (95 % CI 0.23–0.39). The authors concluded that the addition of an aminoglycoside to β-lactams for sepsis should be discouraged since all-cause fatality rates remained unchanged and combination treatment carried a significant risk of nephrotoxicity (Paul et al., 2006). Another argument frequently made in favour of a combination treatment is the control of emerging resistance during treatment. A recent meta-analysis including a total of eight randomized controlled trials addressed this issue. However, ß-lactam monotherapy was not associated with a greater emergence of resistance than was the aminoglycoside–ß-lactam combination (OR 0.90; 95 % CI 0.56–1.47). Actually, ß-lactam monotherapy was associated with fewer superinfections (OR, 0.62; 95 % CI 0.42–0.93) and fewer treatment failures (OR, 0.62; 95 % CI 0.38–1.01). Rates of treatment failure attributable to emergence of resistance (OR, 3.09; 95 % CI 0.75–12.82), treatment failure attributable to superinfection (OR, 0.60; 95 % CI 0.33–1.10), all-cause mortality during treatment (OR, 0.70; 95 % CI 0.40–1.25) and mortality due to infection (OR, 0.74; 95 % CI 0.46–1.21) did not differ significantly between the two regimens (Bliziotis et al., 2005). It should, however, be noted that the studies included in these meta-analyses used aminoglycosides in a twice- or thrice daily dosing at low levels. The failure to appreciate the concentration-dependent killing mediated by aminoglycosides may explain the lack of efficacy demonstrated in these studies. Thus, antimicrobial treatment directed against a pseudomonal strain with proven susceptibility should be monotherapy with an antipseudomonal ß-lactam, cephalosporin, carbapenem or quinolone. Treatment must be administered intravenously except for quinolones which may be given as sequential treatment or even oral treatment in selected cases. Treatment should not be extended to more than eight days because of the risk for induction of resistance during treatment (Chastre et al., 2003). If treatment must be prolonged for some reason, a change of antimicrobial agent class and a repeated sampling for culture and susceptibility testing is mandatory.

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Treatment of Multiresistant Strains

Multiresistant P. aeruginosa are defined as strains resistant against ß-lactams, carbapenems, quinolones and aminoglycosides. Pseudomonas aeruginosa now carries multiple genetically based resistance determinants. Among others, these include the Bush group 1 class of ß-lactamases and ESBL, mutations that increase the levels of a number of efflux systems and mutations leading to a lack of expression or decreased production of OprD, thereby limiting the penetration in the periplasmatic space. The only drugs with activity against multiresistant P. aeruginosa are the polymyxins (Evans et al., 1999; Levin et al., 1999; Markou et al., 2003). Polymyxin B is considered to be more nephrotoxic than polymyxin E. Whereas older studies reported generally discouraging results of polymyxins in the treatment of pseudomonal infections, both in terms of efficacy as well as nephrotoxicity, more recent reports were more favourable. Nevertheless, the scant data available do not allow for a definite judgement. Other experimental approaches to the treatment of multiresistant pseudomonal strains include the combination of drugs to which the strain is resistant, e.g. aztreonam and amikacin (Oie et al., 2003; Song et al., 2003). Aerosolized preparations of aminoglycosides and colistin have been suggested for treatment of multiresistant strains. However, although these might provide adequate drug levels in the tracheobronchial tree, there is no reason to believe that the drugs would penetrate into the consolidated lung. Initial Treatment in Patients at High Risk

Nevertheless, combination treatment is still advisable as initial treatment (e.g., for the first 48 hours) for the reason that it decreases the probability of inadequate treatment, a failure that is known to be associated with an excess mortality, regardless whether active agents are introduced after cultures become available. In a retrospective cohort analysis using automated patient medical records and the pharmacy database at Barnes-Jewish Hospital, three hundred and five patients with P. aeruginosa bloodstream infection were identified over a 6-year period. Hospital mortality was statistically greater for patients receiving inappropriate initial antimicrobial treatment compared with appropriate initial treatment (30.7 % vs 17.8 %; p = 0.018). Multiple logistic regression analysis identified (among others) inappropriate initial antimicrobial treatment as independent determinants of hospital mortality (OR 2.04). Appropriate initial antimicrobial treatment was administered statistically more often among patients receiving empirical combination antimicrobial treatment for Gram-negative bacteria compared with empirical monotherapy (79.4 % vs 65.5 %; P = 0.011). Inappropriate initial empirical antimicrobial treatment was associated with greater hospital mortality among patients with P. aeruginosa bloodstream infection. Thus, inappropriate antimicrobial treatment of P. aeruginosa bloodstream infections may be minimized by increased use of combination antimicrobial treatment until susceptibility results become known

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(Micek et al., 2005). These results support previous data from a retrospective study (Klibanov et al., 2004). Combination treatment should primarily include an antipseudomonal ß-lactam, cephalosporin or carbapenem with a quinolone. The primary use of aminoglycosides should be discouraged. In any case, if these are considered, they should be administered at single high doses, and drug-levels should be monitored. Therapeutic options and dosages for pseudomonal pneumonia are given in Table 6.5. Table 6.5 Targeted antimicrobial treatment of pneumonia due to Pseudomonas aeruginosa Treatment category

Antimicrobial agent

Dosage

Susceptible strains

Piperacillin Ceftazidime Imipenem Meropenem Ciprofloxacin

3 × 4 g iv (8 days) 3 × 2 g iv (8 days) 3 × 1 g iv (8 days) 3 × 1 g iv (8 days) 3 × 400 mg iv 2 × 750 mg orally (sequentially or primarily orally in selected cases) (8 days) 1 × 750 mg or 2 × 500 mg iv 1 × 750 mg orally (sequentially or primarily orally in selected cases) (8 days) 1 × 5–7 mg/kg iv (8 days) 1 × 15 mg/kg iv (8 days) 2.5–5 mg/kg iv in 2–3 divided doses (8 days) 2.5–3 mg/kg iv in 4 divided doses (8 days) 2 × 2 g iv (8 days)

Levofloxacin

Multiresistant strains a Not

Tobramycina Amikacina Colistin Polymyxin B Aztreonam

regularly indicated in combination treatment, not suitable for monotherapy.

Acinetobacter spp. Currently, carbapenems are the drugs with the lowest MIC among available antimicrobial agents, whereas ampicillin/sulbactam are the most active of the remaining ßlactams (Visalli et al., 1997). In addition, cephalosporins (ceftazidime), quinolones (ciprofloxacin, levofloxacin) and aminoglycosides may remain active. However, cephalosporins may induce ß-lactamases and are not recommended. Quinolones should not be used as monotherapy. Alternatives usually include trimethoprim – sulphamethoxazole, doxycycline and polymyxins (Table 6.6). The recently marketed glycylcycline tigecycline shows remarkable activity, however, it has not yet been approved for use in pneumonia. Most strains are nowadays resistant against ampicillin and cefotaxime. More recently, sulbactam has emerged as an effective drug against carbapenem(multidrug-) resistant strains. In vitro data suggest bactericidal synergy of carbapenems or ß-lactam/ß-lactamase-inhibitors or quinolones plus aminoglycosides

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Table 6.6 Targeted antimicrobial treatment of pneumonia due to Acinetobacter spp. Treatment category

Antimicrobial agent

Dosage

Carbapenemsusceptible strainsa Multiresistant strainsb

Imipenem Meropenem Ampicillin–sulbactam Colistin

3 × 1 g iv (8 days) 3 × 1 g iv (8 days) 3 × 3 g iv (8 days) 2.5–5 mg/kg iv in 2–3 divided doses (8 days) 100 mg loading dose, then 2 × 50 mg iv (8 days)

Tigecycline a Consider b Consider

combination with an active aminoglycoside, or a quinolone combination with an active aminoglycoside or rifampin.

in multidrug-resistant strains (Marques et al., 1997, Corbella et al., 1998, Bajaksouzian et al., 1997). As is the case in P. aeruginosa, resistance may emerge during monotherapy of an originally susceptible strain. Likewise, relapses have been observed. Mild to moderately severe pneumonia may respond to monotherapy alone. A carbapenem may be considered the drug of choice. Severe infections might be treated by a combination of a carbapenem plus a quinolone or an active aminoglycoside. The use of sulbactam may exert a more rapid bactericidal effect when combined with an active aminoglycoside or even rifampin. According to a small study, intravenous colistin can be used effectively in multidrug-resistant Acinetobacter pneumonia (Garnacho-Montero et al., 2003).

Stenotrophomonas maltophilia Trimethoprim–sulphamethoxazole and ticarcillin – clavulanic acid are the only agents with consistent therapeutic activity against S. maltophilia isolates. It is important to note that in vitro sensitivity of S. maltophilia (particularly with regard to trimethoprim–sulphamethoxazole) may reveal results which are in negative contrast to the favourable clinical outcome of patients that have been treated with these agents (Carroll et al., 1998). Minocycline has excellent in vitro activity, however, there is very limited clinical experience with this drug. A new alternative may be the glycylcycline tigecycline (Table 6.7).

Table 6.7 Targeted antimicrobial treatment of pneumonia due to Stenotrophomonas maltophilia pneumonia

First choice Alternatives

Antimicrobial agent

Dosage

Trimethoprim–sulphamethoxazole Ticarcillin–clavulanic acid Tigecycline

15–20 mg/kg iv (8 days) 6 × 3.1 g (8 days) 100 mg loading dose, then 2 × 50 mg iv (8 days)

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Atypical Bacterial Pathogens Legionella spp. Legionella spp. are intracellular pathogens, mostly affecting monocytic phagocytes. Therefore, antimicrobial agents effective against these pathogens must penetrate and remain active intracellularly. Whereas all macrolides, quinolones and tetracyclines (and rifampin) meet these criteria, none of the ß-lactams, monobactams and aminoglycosides are active for this condition. Important insights about the effectiveness of antimicrobial drugs against Legionella spp. originate from cell culture and experimental animal studies, particularly using the guinea pig model. It could be shown that macrolides (except azithromycin) and tetracyclines inhibit intracellular growth of Legionella spp. and cure the animals but are not bactericidal and do not clear the bacterium from infected guinea pigs. Obviously, quinolones, azithromycin and ketolides are much more effective in terms of activity and bactericidal effects, which may result in shorter length of treatment, and smaller dose required for cure and amount of residual lung inflammation. In addition, a considerable post-antibiotic effect and anti-inflammatory activity may contribute to the superior results of these drugs, particularly in the case of azithromycin (Edelstein, 1995). Comparative clinical data of the treatment for Legionella pneumonia originate from small uncontrolled and underpowered studies and from retrospective analyses of community-acquired or nosocomial outbreaks. In the 1976 Philadelphia epidemic, mortality from pneumonia was 10 % for erythromycin (and tetracycline) compared with 20–40 % for other antimicrobial drugs (Fraser et al., 1977). As a consequence, erythromycin was recommended as standard of care for years. The addition of rifampicin in severe cases was often recommended without any clinical evidence for the superiority of a combination treatment. In aggregate, in patients with mild to moderate disease good treatment results could be achieved when using any macrolide, any quinolone, and a ketolide (telithromycin) (Hamedani et al., 1991; Edelstein, 1995). However, these studies are difficult to interpret due to the limited patient numbers studied and the generally favourable outcome. Studies including more severely ill patients are more conclusive. A small study could show a superiority of pefloxacin compared with erythromycin in severe Legionella pneumonia (Doumon et al., 1990). In a more recent study of patients with severe Legionella pneumonia, patients who received early treatment with a quinolone had better outcomes than those with delayed onset of treatment or than those treated with any other regimen, including erythromycin (Gacouin et al., 2002). Two recent studies support the superiority of quinolones compared with macrolides as regards time to treatment response. In an observational, prospective, non-randomized study of patients with Legionella pneumonia during the Murcia outbreak, macrolides were compared with levofloxacin. In addition, to assess the potential effects of adjuvant therapy with rifampicin, 45 case patients treated with levofloxacin plus rifampicin were evaluated and compared with 45

ATYPICAL BACTERIAL PATHOGENS

119

control pairs who were treated with levofloxacin alone. There were no significant differences between treatment groups in clinical outcome for patients with mild-to-moderate pneumonia, whereas in patients with severe pneumonia, levofloxacin was associated with fewer complications (3.4 % vs 27.2 %) and shorter mean hospital stays (5.5 vs 11.3 days, p = 0.04). Addition of rifampicin to the treatment regimen for patients receiving levofloxacin for severe pneumonia did not provide additional benefit (Blazquez-Garrido et al., 2005). In another observational study of 139 cases of L. pneumophila pneumonia, patients who received levofloxacin had a faster time to defervescence (2.0 vs 4.5 days; p < 0.001) and to clinical stability (3 vs 5 days; p = 0.002). No differences were found regarding the development of complications (25 % vs 25 %; P = 0.906) and case-fatality rate (2.5 % vs 5 %; P = 0.518). The median length of hospital stay was 8 days in patients treated with levofloxacin and 10 days in those who received macrolides (p = 0.014) (Turrett et al., 1999; Mykietiuk et al., 2005). It appears that levofloxacin is efficacious at both 500 mg for 7 to 14 days and 750 mg for 5 days (Yu et al., 2004). Immunocompetent patients with mild to moderate Legionella pneumonia should preferably be treated with a macrolide (azithromycin) or a respiratory quinolone (levofloxacin, moxifloxacin). A ketolide (telithromycin) or doxycycline may be alternatives. Patients with severe pneumonia or immunocompromised patients with pneumonia of any severity should receive the drugs currently recognized as the most effective ones, azithromycin or levofloxacin (Table 6.8). Table 6.8 Targeted antimicrobial treatment of pneumonia due to Legionella spp. Disease category Mild-to-moderate disease, immunocompetent host First choice

Alternatives

Severe and/or immunocompromised host a Consider

Antimicrobial agent

Dosage

Azithromycin Levofloxacin Moxifloxacin Telithromycin Doxycycline

1 × 500 mg orally (3–5 days) 1 × 500 mg orally (7–10 days) 1 × 400 mg orally (7–10 days) 1 × 800 mg orally (7–10 days) 200 mg load orally, then 2 × 100 mg orally (14–21 days) 1 × 500 mg iv (7–10 days)a 1 × 750 mg iv (10–14 days)a

Azithromycin Levofloxacin

sequential treatment.

The optimal duration of treatment has not been established. Over the years, with the establishment of agents other than erythromycin and doxycycline, there is a clear trend to shorter duration of treatment. In mild disease, treatment with azithromycin may be as short as three to five days (Myburgh et al., 1993; Matute et al., 2000), and there is no evidence that more than one week at most is required for treatment with quinolones. Longer treatment of 10–14 days may be required in patients with immunosuppression, in order to prevent relapses.

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Mycoplasma pneumoniae Antimicrobial treatment of pneumonia due to Mycoplasma pneumoniae is effective in shortening the duration of illness and in reducing the spread of infections in contacts. Whether the many rare extrapulmonary syndromes of M. pneumoniae infection can be influenced by antimicrobial treatment is unknown. Microbial resistance is not recognized as a problem in infections due to Mycoplasma spp. Comparative clinical data for the treatment of M. pneumoniae are not available. Thus, treatment must be tailored according to in vitro susceptibility patterns. Mycoplasma pneumoniae has no cell wall and, therefore, ß-lactams are not active against this pathogen. Erythromycin and tetracyclines are highly active and cheap. As a consequence, they are frequently referred to as the drugs of choice. However, erythromycin especially is poorly tolerated. Therefore, in view of a usually mild and self-limiting disease, the activity of antimicrobial drugs must be balanced against tolerability and cost. The alternatives of newer macrolides (azithromycin and clarithromycin), ketolides (telithromycin) and quinolones (levofloxacin and moxifloxacin) are better tolerated but are considerably more costly (Table 6.9). Table 6.9 Targeted antimicrobial treatment of pneumonia due to Mycoplasma pneumoniae and Chlamydophila pneumoniae Disease category

Antimicrobial agent

Dosage

First choice

Azithromycin Clarithromycin Doxycycline

Intolerance to ß-lactams

Levofloxacin Moxifloxacin Telithromycin Azithromycin Levofloxacin

1 × 500 mg orally (3–5 days) 2 × 250 mg orally (7–14 days) 200 mg load orally, then 2 × 100 mg orally (7–14 days) 1 × 500 mg orally (7–14 days) 1 × 400 mg orally (7–14 days) 1 × 800 mg orally (7–14 days) 1 × 500 mg iv (7–10 days) 1 × 750 mg iv (10–14 days)

Severe disease and/or immunocompromised host

It must be realized that both tetracyclines and quinolones are contraindicated in children. Thus, it appears that new macrolides (azithromycin or clarithromycin) may confer the best relation of effectiveness, tolerance and cost in children as well as in adults. Doxycycline is a reasonable alternative in adults. The optimal duration of treatment is unknown. Most patients should be treated effectively within a seven day course of treatment. Azithromycin may be administered for a shorter duration of three to five days. A treatment longer than one week might be considered according to the response to treatment.

Chlamydophila spp. The treatment of Chlamydophila pneumoniae is very similar to M. pneumoniae. Again, treatment is mainly guided by in vitro susceptibility patterns, with macrolides and tetracyclines as the mainstay of treatment. Azithromycin and clarithro-

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mycin are an excellent alternative to erythromycin in terms of tolerance. Newer quinolones (levofloxacin and moxifloxacin) may be used as alternatives in patients with intolerance to macrolides and tetracyclines (Table 6.9). Studies evaluating antimicrobial treatment of Chlamydophila pneumoniae have used clinical success and nasopharyngeal culture as endpoints (usually among children). Overall, each study could document the outcome of a handful of patients. In aggregate, these studies indicate that all macrolides and tetracyclines are able to cure the vast majority of patients. It has been observed that clinical cure can also be achieved in patients in whom eradication of the pathogen could not be achieved. As in most other pathogens, the optimal duration of treatment is unknown. However, in view of intracellular pathogens it appears prudent to consider a 14 day treatment at least in patients with delayed or incomplete response.

Other Pathogens Directed treatment of other, usually less frequent and important, pathogens is summarized in Table 6.10. Table 6.10

Targeted antimicrobial treatment of pneumonia due to other pathogens

Pathogen

Antimicrobial agent

Comment

Bacillus anthracis

Ciprofloxacin or doxycycline, each plus one of the following: penicillin, clarithromycin, clindamycin, rifampin, vancomycin, imipenem Aminopenicillin + ß-lactamase-inhibitor cephalosporin II or III, respiratory quinolone Ceftazidime or carbapenem ± trimethoprim–sulphamethoxazole

Penicillin and ampicillin should not be used alone (due to constitutive or inducible ß-lactamases) Usually ß-lactamase producers

Moraxella catarrhalis Burkholderia pseudomallei (Melioidosis)

Yersinia pestis (Plague) Nocardia spp. Coxiella burnetii

Aminoglycosides (streptomycin, gentamicin), doxycycline, chloramphenicol Trimethoprim–sulphamethoxazole Imipenem + Amikacin Doxycycline, respiratory quinolones

Eradication treatment – minimum 3 months: trimethoprim – sulphamethoxazole ± doxycycline

Several alternatives Consider addition of rifampin

Summary Despite concerns regarding the possible presence of mixed infections, targeted pathogen directed antimicrobial treatment after identification of underlying

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pathogens represents a major issue within the de-escalation treatment strategy of pneumonia. In order to comply with this challenge, this review presents recommendations for targeted treatment of bacterial pathogens of pneumonia in nonimmunosuppressed patients according to the most recently published data. Overall, solid data from controlled studies are scarce. Recommendations for several pathogens have to be made exclusively based on in vitro susceptibility patterns. Three major pathogens posing a particular challenge for clinicians are particularly focused. Although penicillin resistance of S. pneumoniae is of concern, resistance up to 2 mg/µL may still be overcome with high-dose ß-lactam treatment. Thus, ß-lactams provide the mainstay of treatment of pneumococcal pneumonia. Treatment of MRSA remains a difficult task. Unfortunately, although several new agents active against MRSA are available, optimal treatment remains poorly defined. The double-coverage of P. aeruginosa with ß-lactam and aminoglycosides has been challenged by recent meta-analyses and is no longer the treatment of choice. An initial combination of ß-lactams and preferably antipseudomonal quinolones remains, however, a prudent choice for initial treatment in face of the fact that inadequate treatment is associated with an excess mortality. Gram-negative enterobacteriaceae exerting ESBL activity should be treated primarily with carbapenems. Finally, it is time to recognize that erythromycin with or without rifampin is no longer the treatment of choice for legionellosis. Instead, both new macrolides and respiratory quinolones confer significant advantages. In the near future, we expect controlled studies to answer many unresolved issues in the treatment of frequent and/or difficult to treat pathogens.

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7 General Pharmacological Considerations in Antibiotic Treatment of Community-Acquired Pneumonia FRANCESCO BLASI1 , MARIO CAZZOLA2 AND PAOLO TARSIA3 1

University of Milan, Institute Respiratory Diseases Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Fondazione IRCCS, Milan, Italy 2 University of Rome ‘Tor Vergata’, Department of Internal Medicine, Unit of Respiratory Diseases, Rome, Italy 3 University of Milan, Institute Respiratory Diseases Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Fondazione IRCCS, Milan, Italy

Introduction Antimicrobial agents are the cornerstone of bacterial pneumonia therapy. Initial antibiotic choice should be based on expected aetiological pathogens, but pharmacological characteristics of the antibiotic itself, such as microbiological activity (bactericidal or bacteriostatic mode of action) and the spectrum of activity of the compound are equally relevant in the choice of treatment. The ability to pass from the capillary bed to the bronchial lumen across a series of membranes and diffusional paths (the so-called blood–bronchoalveolar barrier), as well as the frequency of side-effects and the interference with immunological homeostasis, also influence the choice of the antibiotic to be used (Cazzola and Matera, 2003). Community-Acquired Pneumonia: Strategies for Management Edited by Antoni Torres and Rosario Men´endez  2008 John Wiley & Sons, Ltd

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Pharmacokinetics and Pharmacodynamics of Antibiotics The potential therapeutic efficacy of an antibiotic depends not only on its spectrum of action, but also on the concentration that it reaches in the bloodstream and in the site where the infection is developing. In patients with bacterial pneumonia, the site of infection is in the alveolar spaces or in the pulmonary interstitium. With the improvements in the technique of bronchoalveolar lavage (BAL), it has been possible to obtain samples from the alveolar lining (epithelial lining fluid or ELF) and alveolar macrophages. The alveolar lining is considered an important site of extracellular infection in pneumonia, whereas macrophages are an important site in intracellular infections. The concentrations reached by antibiotics in these two distal sites should be excellent predictors of their clinical efficacy in the treatment of pneumonia (Cazzola et al., 2004a). There are significant differences in the penetration of different classes of antibiotics into these two pulmonary compartments.

Antibiotic Penetration into the Epithelial Lining Fluid The ELF is regarded as an important site of extracellular infection in pneumonia. The concentrations reached by antibiotics into this site are excellent predictors of their clinical efficacy in the treatment of pneumonia (Valcke et al., 1990). The alveolar epithelial membrane is a significant barrier that separates the alveolar lining from blood. Thus, the alveolar lining constitutes an important microenvironment. Clinical efficacy, particularly with pathogens that are confined to sites separated from blood by significant barriers, may be more closely related to drug concentrations at actual sites of infection (Olsen et al., 1996). Unfortunately, the technique for performing BAL can cause evaluation errors that must always be kept in mind. To perform BAL, four 50-mL aliquots of heated normal saline must be instilled into the lungs by means of a bronchoscope, and each must immediately be aspirated into a trap. It is preferable to discard the first aliquot as it corresponds primarily to lavage of the proximal airways. From the remaining three aliquots, roughly 60–70 mL are retrieved, on which it is possible to perform the determination of antibiotic levels (Baldwin et al., 1990a). Data obtained are generally not reliable, due to the dilution produced by saline introduced into airways, which makes it difficult to compare the concentration of antibiotics in aspirate lavage fluid and in blood (Valcke et al., 1990). To overcome this problem, the drug levels in blood and in BAL are compared with a reference substance, usually urea or creatinine, used as a marker of dilution (Braude et al., 1983; Rennard et al., 1986; Baldwin et al., 1990a). These substances have a low molecular weight and diffuse rapidly across the alveolar–capillary membrane. It is felt that, in conditions of equilibrium, the concentration of urea in the blood is equal to that in alveolar lavage (Braude et al., 1984). Comparing the ratio between the concentration of the antibiotic and that of the reference substance in BAL with the same ratio in blood, it is possible to calculate the relative penetration coefficient of the antibiotic into alveolar fluid. It must, however,

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be highlighted that the urea method does not account for the partial movement of the solute from pulmonary capillaries to the alveolar space, thus causing an underestimate of the concentration of the drug. In fact, although epithelial permeability to urea is low, redistribution of the dilution marker during lavage due to its absorption, cell binding, or metabolism may cause erroneous estimation of the ELF volume and the corresponding drug concentrations (Chinard, 1992). Moreover, it has been known for some time that urea transport in human red blood cells occurs largely by facilitated diffusion (Macey, 1984), which may also be present in the alveolar and airway epithelium. In any case, although it is well known that use of urea as an endogenous marker for estimation of ELF dilution results in overestimation of ELF volume, it is still widely used due to its simplicity. A method has been developed more recently, based on the equilibration of technetium-99m diethylenetriaminepentaacetic acid (99m Tc-DTPA) between blood and ELF, which accounts for the diffusion of the indicator during lavage (Bayat et al., 1998) in an attempt to overcome the problems with urea, and efforts have been made using this technique for measuring antibiotic concentrations in ELF (Bayat et al., 2004). It has been repeatedly stressed that the fluid introduced by a bronchoscope stagnates in the lungs for the time that is necessary to gather the distal alveolar lining. This interval allows the diffusion of urea from the interstitium and the blood and falsely increases its levels in the fluid obtained with BAL. This causes an overestimate of the alveolar lining volume of 100–300 % after only 1 minute of stagnation (Marcy et al., 1987). To overcome this limitation, the microlavage technique has been suggested. This procedure involves the introduction into the lungs of smaller volumes of saline solution by means of a minute catheter enabling the quick sampling of small quantities of fluid. However, there is the possibility of contamination with blood following mechanical trauma if personnel lacking in expertise perform this procedure (Baldwin et al., 1990a) and, moreover, microlavage yields lower ELF volume. More recently, Yamazaki et al. (2003) have described a novel method of sampling intrapulmonary drug concentrations using bronchoscopy with a bronchoscopic microsampling probe. This microsampling method uses a polyethylene sheath containing an inner polyester fibre probe that immediately adsorbs fluid. The probe is advanced into a distal airway and ELF is directly sampled through adsorption of fluid onto the probe; the volume of ELF and corresponding drug concentrations are easily determined through simple laboratory procedures. When compared with standard methods using BAL, for example, levofloxacin concentrations determined by the microsampling method were approximately one-half the concentrations determined through lavage (Yamazaki et al., 2003). It must be highlighted that the technique of BAL has several major drawbacks. For example, many substances distribute into the ELF within minutes after entering the systemic circulation but this technique lacks the ability to monitor rapid changes in concentrations of drugs in the ELF of the lung in a single subject. Furthermore, due to the nature of the sampling process and each lavage altering the composition of the ELF, this makes frequent multiple sampling from an individual patient difficult. Therefore, this technique is not generally well suited for

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pharmacokinetic studies. Consequently, in order to ascertain ELF drug penetration, clinical trial designs randomize patients to different drug doses and sampling times. Analysis of these data is often limited to obtaining ratios of drug concentrations into ELF to those determined simultaneously in blood. For drugs with multicompartental behaviour, these ratios will change as a function of the sampling time. Such time dependency makes this measure a poor one for understanding the penetration behaviour of a drug (Drusano et al., 2002). Moreover, due to the difficulty of confining the instilled fluid to a limited area within the lung, saline distributes freely throughout the available space during lavage. As a result, the technique lacks spatial resolution and usually presents data averaged over a segment of the lung. The accuracy of the estimate can also be adversely affected by the influx of the fluid from the interstitium during lavage. The movement of antibiotics across the blood-alveolar barrier is extremely difficult as the capillary endothelium of the pulmonary circulation is non-fenestrated and the alveolar membranes are relatively impermeable due to the presence of many tight junctions (zonulae occludens) (Staehelin, 1974). As a consequence, antimicrobials penetrate less in the alveolar lining than in the bronchial mucosa (Baldwin et al., 1990b). However, fluoroquinolones appear to concentrate more in alveolar lavage than in the bronchial mucosa and this behaviour makes it seem probable that this class of compound possesses additional mechanisms that allow the crossing of the membrane (Rennard et al., 1986). There are substantial differences in the concentration into ELF among the different classes of antimicrobials, and even among compounds of the same class (Just et al., 1984; Unertl et al., 1985; Saux et al., 1986; Benoni et al., 1987a, b; Vlahov et al., 1987; Panteix et al., 1988; Perea et al., 1988; Morita et al., 1989; Reid et al., 1989; Baldwin et al., 1990b, 1992; Bergogne-Berezin, 1992; Martin et al., 1992; Valcke et al., 1992; Lamer et al., 1993; Cazzola et al., 1994, 1995, 2001; Cook et al., 1994, 1996; Conte et al., 1995, 1996, 2005, 2006; Patel et al., 1996; Andrews et al., 1997a,b, 2003; Matera et al., 1997; Sch¨uler et al., 1997; Imaizumi et al., 1998; Nix, 1998; Carcas et al., 1999; Honeybourne et al., 1999, 2001; Soman et al., 1999; Allegranzi et al., 2000; Gotfried et al., 2001; Khair et al., 2001; Rodvold et al., 2003; Bayat et al., 2004; Burkhardt et al., 2005) (Table 7.1). This is certainly true for macrolides, which are tissue-directed antibiotics (Amsden, 2001). Macrolides have been found to concentrate into ELF (Morita et al., 1989; Baldwin et al., 1990b; Cazzola et al., 1994; Patel et al., 1996; Matera et al., 1997), with azithromycin showing a 7-fold and clarithromycin a 5.7-fold increase compared with serum levels. In particular, it has been documented that clarithromycin was concentrated in ELF (range, 72.1 ± 73.0 mg/L at 8 hours to 11.9 ± 3.6 mg/L at 24 hours), whereas the concentrations of erythromycin in ELF were low at 4, 8 and 12 hours following the last dose of the drug (range, 0–0.8 ± 0.1 mg/L) (Conte et al., 1996). In another study, the azithromycin concentrations in ELF were less than half those of clarithromycin (Sch¨uler et al., 1997). The higher apparent volume of distribution of azithromycin may explain these results. It can presumably be caused by a larger distribution of this azalide to extracellular sites than clarithromycin. Concentration in ELF of the ketolide telithromycin, a semisynthetic

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Table 7.1 Antibiotic levels in serum and epithelium lining fluid (ELF) Antibiotic Amoxicillin Clavulanic acid Cefuroxime axetil Cefpodoxime proxetil Ceftibuten Cefdinir Ceftazidime Cefepime Cefpirome Imipenem Meropenem Tobramycin Erythromycin Clarithromycin Azithromycin Dirithromycin Roxithromycin Telithromycin Pefloxacin Clinafloxacin Lomefloxacin Trovafloxacin Temafloxacin Sparfloxacin Levofloxacin Gatifloxacin Moxifloxacin Garenoxacin Vancomycin Linezolid Tigecycline

Dose

Route

500 mg 250 mg 613 mg 220 mg 400 mg 600 mg 1g 1g 1g 1g 1g 300 mg 250 mg 500 mg 500 mg 500 mg 300 mg 800 mg 800 mg 200 mg 400 mg 200 mg 600 mg 400 mg 500 mg 400 mg 400 mg 600 mg 15 mg 600 mg 100 mg

PO MD PO MD PO MD PO PO PO IM IV IV IV IV IM PO MD PO MD PO MD PO MD PO MD PO MD PO PO PO MD PO MD PO MD MD PO PO PO PO IV MD PO MD PO MD

Serum (mg/L−1 )

1.85 ± 0.82 15.2 4.20 39.89 40.4 34.5 19.0 ± 1.1 25.98 5.5 1.57 3.96 0.13 ± 0.05 0.61 1.86 7.46 ± 0.25 1.54 3.2 1.41 9.6 ± 1.22 1.2 ± 0.4 6.6 3.96 3.2 10.0 24 7.3 ± 4.9 0.72 ± 0.24

ELF (mg/L−1 ) 2.56 ± 1.41 1.33 ± 0.65 1.04 ± 0.66 0.22 ± 0.13 1.6 0.49 2.71 3.4 7.2 24.1 ± 51.4 7.07 3 0.97 20.46 1.4 2.37 2.0 ± 1.7 14.89 97.7 ± 30.0 2.71 6.9 4.8 6.5 ± 3.6 115.0 ± 8.3 10.9 6.16 20.7 14.3 4.5 64.3 ± 33.1 0.37

Penetration (%)

12 10 11 7 8 21 127 27 55 62 512 1076 388 800 1305 176 216 340 276 1250 165 155 647 143 19 881 51

PO, per os; MD, multiple doses; IV, intravenous; IM, intamuscular.

derivative of the 14-membered ring macrolides, is eight times higher than in serum (Khair et al., 2001). A recent study that has evaluated the bronchopulmonary concentrations of intravenous levofloxacin and azithromycin in healthy adults, showed that levofloxacin 500 and 750 mg achieved significantly higher concentrations in steady-state ELF than azithromycin 500 mg during the 24 hours after drug administration. This difference was despite the values of azithromycin at 24 hours sampling being higher than those of levofloxacin (Rodvold et al., 2003). Intriguingly, data suggest that penetration of levofloxacin into the lung is not dose-dependent (Conte et al., 2006). With tigecycline, an investigational glycylcycline antibiotic, at all time periods, serum and ELF concentrations are not significantly different (Conte et al., 2005).

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The hydrophilic nature of ß-lactams leads to poor penetration into the relatively impermeable alveolar space and the ELF, with levels reaching only 12–50 % of serum concentration (Baldwin et al., 1992; Cook et al., 1994, 1996; Cazzola et al., 1995; Gotfried et al., 2001; Burkhardt et al., 2005) . Also aminoglycosides penetrate poorly into ELF and high peak serum concentrations of aminoglycosides are necessary to obtain microbiologically active concentrations at the alveolar level. In fact, because of their hydrophilicity, polycationic charge and relatively large size, these antibiotics are able to diffuse only sparsely across biological membranes without active transport mechanisms (Chiu and Amsden, 2002). In patients with pneumonia, the ratio ELF to serum concentration of tobramycin at peak serum time was 0.30 (Carcas et al., 1999), whereas that of netilmicin was 0.46 (BergogneBerezin, 1992).

Antibiotic Penetration into Alveolar Macrophages Although the neutrophil is the prevalent cell in bacterial infections, in vitro studies show that alveolar macrophages (AMs) concentrate antibacterials in a manner similar to a neutrophil. Consequently, the determination of antibacterial concentration in AMs is a valid model for evaluating antibiotic levels in the site of infections caused by intracellular pathogens such as Legionella pneumophila or Chlamydia pneumoniae (Honeybourne and Baldwin, 1992). The quantity of antimicrobials passed into cells is determined using AMs isolated from lavage fluid by rapid centrifugation and following equally rapid ultrasonication. The possibility of a rapid effusion of the antibiotic from AMs is a potential source of evaluation error. It has been shown that even cells that contain a high concentration of a drug rapidly lose great amounts if they are not placed in a medium containing the drug itself. This is what happens during BAL; the extracellular concentration of the antibiotics falls by at least 100-fold. In vitro studies have generally shown that a considerable loss of the drug takes place within 10 minutes from the suspension of the cellular culture in a medium lacking in antibiotic (Chiu and Amsden, 2002). The efflux of fluoroquinolones is particularly relevant because these antimicrobials rapidly leave the cells, whereas the efflux of ß-lactams is difficult to assess considering that they penetrate very poorly into cells. Macrolides vary in their efflux capacity (Rennard et al., 1986); erythromycin exits rapidly (Honeybourne and Baldwin, 1992), whereas the uptake of azithromycin is slow and the release rate is even slower (Johnson et al., 1980). The technique for obtaining BAL is fairly long and is conditioned by the clinical situation of each single patient. It is therefore preferable to wait for a complete equilibrium between the fluid obtained by BAL and the cellular component, even though some studies indicate that the release of antibiotics during BAL does not proceed at the same rate observed in vitro. There are, obviously, some discrepancies between antibiotic levels quantified in macrophages in vitro and those determined in BAL (Tulkens, 1991). Alternatively, AMs must be separated in a fast manner in order to minimize the efflux of drugs from intracellular compartments into extracellular BAL fluid.

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Placing the samples on ice and centrifugation of the sample as quickly as possible helps to diminish this loss (Gladue et al., 1989). The accurate quantification of the number of macrophages is also important since high degrees of variability in the cell count will lead to varying concentrations (Mattie et al., 1987). β-Lactams diffuse but do not accumulate into phagocytes, probably because of their acidic character; their activity at this site is negligible due to the low pH. However, clavulanate, but not amoxicillin, is detectable in AMs (Rodvold et al., 2003). Aminoglycosides are too polar to pass across membranes and are therefore only taken up slowly by endocytosis. Lincosamides, macrolides and fluoroquinolones all accumulate in phagocytes (Tulkens, 1991). Levels of azithromycin are up to 23 times and clarithromycin 70 times higher than in serum (Patel et al., 1996), whereas levofloxacin shows an 8-fold (Andrews et al., 2003), gatifloxacin a 35fold (Honeybourne et al., 2001) and moxifloxacin a 50-fold increase (Soman et al., 1999) compared with serum levels. In 36 healthy, non-smoking adult subjects, the concentrations in AM following intravenous administration of five doses of levofloxacin (500 or 750 mg) and azithromycin (500 mg) once daily were higher than concentrations in plasma (Rodvold et al., 2003). However, azithromycin achieved significantly higher concentrations in AM than levofloxacin. Linezolid concentrations in AMs are less than those observed in plasma and ELF, suggesting that the drug is excluded or rapidly removed from this compartment (Conte et al., 2002). A similar partitioning for pyrazinamide has been reported (Conte et al., 1999). In general, the concentration of antimicrobials in AMs is greater in inflamed airways due to macrophage activation and the fact that alveolar–capillary barrier permeability can dramatically increase in lung inflammation. Moreover, smokers present higher levels since their macrophages reach a higher level of activation (Hand et al., 1985). It is important to highlight that antibiotic disposition varies within cells (Table 7.2). Consequently, very large differences in intracellular concentrations exist between antibiotics. This has an impact on the choice of the antimicrobial treatment. Some bacteria (e.g. Legionella sp. and Chlamydia sp.) are found within subcellular compartments, such as the phagosomes. Others, such as Staphylococcus aureus, are mostly located within phagolysosomes. Table 7.2 Antibiotic intracellular penetration, accumulation, localization and release Antibiotic

Penetration

Accumulation

Localization

Release

Aminoglycosides

Very slow (days)

Very slow

Lysosomes

β-lactams Fluoroquinolones

Very limited Rapid, similar for all compounds Slow (1–2 hours) drug dependant

Absent Four- to eightfold

Cytosol Phagosomes, Lysosomes Lysosomes > 90 %

Very slow (weeks) Rapid Rapid (minutes) Slow (days)

Macrolides

May reach > 100-fold drug dependent

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Fluoroquinolones appear to be entirely soluble in cells, and lincosamides concentrate in both phagosomes and lysosomes. On the contrary, macrolides accumulate principally in lysosomes because the pH in these sites is extremely low and induces a high rate of protonation and aminoglycosides result in an exclusively lysosomal localization (Carlier et al., 1987; De Duve et al., 1974). The macrolide molecule becomes more polar when it is protonated and therefore is less capable of exiting the cell (Tulkens, 1991). It is still not known whether drugs withheld in the lysosomes are truly capable of carrying out their antimicrobial activity. A relatively new hypothesis that has started to gain acceptance is that the concentrations achieved by the macrolides within the actual phagocytic cells that will clear infecting bacteria (i.e. neutrophils, monocytes, macrophages) are the drug levels that should be considered (Amsden, 1999). The fact that intraphagocytic concentrations of these drugs are multiple logs higher than the corresponding serum concentrations and are maintained at this level for a prolonged period, either through cellular retention (azithromycin) or dosing (erythromycin, clarithromycin), helps explain how all macrolides are active not only against susceptible bacterial isolates, but also potentially against those bacteria with ‘resistant’ minimum inhibitory concentrations (MICs) (Chiu and Amsden, 2002).

Therapeutic Significance of Pulmonary Disposition of Antibacterials The therapeutic significance of antibacterial concentrations is debatable (Cazzola et al., 2002). However, some studies have suggested that efficient antimicrobial penetration into potential sites of pulmonary infection and its protracted permanence in active form are advantageous (Honeybourne, 1997). This is particularly true when the infection has not spread beyond the lung and there are no existing barriers to adequate lung penetration, such as lung abscess or necrotizing pneumonia. The results of clinical trials of the intravenous azalide azithromycin in patients with community-acquired pneumonia (CAP) are paradigmatic of this assumption. These trials have revealed that clinical outcomes were similar in bacteremic patients and in a control group treated with cefuroxime with or without erythromycin (Plouffe et al., 2000). Since serum concentrations of azithromycin fall rapidly but antibacterial concentrations in the lung parenchyma and phagocytes rise by several-fold, these results support the concept that pulmonary antibacterial levels may be a significant pharmacokinetic factor in the cure of patients with CAP. An in vitro computer-controlled pharmacodynamic simulation of human azithromycin concentrations in serum and ELF has documented that the suggested breakpoint for susceptibility (≤ 2 mg/L) may be adequate to predict Streptococcus pneumoniae eradication with ELF but not with serum concentrations obtained after an intravenous azithromycin 500 mg once daily regimen (Sevillano et al., 2006). Other studies (Bergogne-B´er´ezin, 1995a) have shown that drugs that penetrate well and remain for long periods at the pulmonary site of infection often induce therapeutic responses greater than that expected on the basis of in vitro data. This finding seems to be independent of the class of antibacterials used. Fluoroquinolones, which concentrate in pulmonary tissues and fluids, reach levels that

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are sufficient to overcome a good percentage of cases of infective processes caused by S. pneumoniae which present high MICs toward these antibiotics, provide an interesting documentation of the importance of effective pulmonary disposition of antimicrobials. For example, although the serum level of ciprofloxacin (1.19 ± 0.16 mg/L) is below the MIC90 of S. pneumoniae (2.0 mg/L), the concentrations reached in ELF are ≈ 3 mg/L (Baldwin et al., 1993). Similarly, the mean concentration of pefloxacin is 88.2 ± 10 mg/L in the ELF, whereas the mean serum concentration is 6.67 ± 0.47 mg/L (Panteix et al., 1994), which is below the MIC90 of S. pneumoniae (8.0 mg/L). However, failures of ciprofloxacin and pefloxacin in the treatment of pneumococcal pneumonia have been described notwithstanding the relevance of their accumulation in the lower respiratory tract. It has been suggested that subtherapeutic intrapulmonary concentrations might be responsible for these failures (Baldwin et al., 1993), and, moreover, that experimentally determined ‘total tissue concentrations’ are not good indicators of activity since they represent average values including unspecifically bound drugs and not the concentrations actually present at the site of action (Bergogne-B´er´ezin, 1995b). For the same reason, the concept of ‘tissue partition coefficients’ for antibiotics is inadequate since it implies homogeneous tissue concentrations. It is the aqueous unbound concentration at the site of infection in the tissue that is most relevant for the magnitude of antibiosis (Cazzola et al., 2004a). Thus, if overall concentrations are measured, effective site concentrations of drugs that equilibrate exclusively with the extracellular space, such as ß-lactams, may be underestimated. This, in turn, will also lead to an overestimation of effective site concentrations of drugs that accumulate intracellularly. Unfortunately, the tissue–blood ratio is also equally considered relatively unimportant. In fact, the clinical utility of penetration ratios is somewhat misleading since bacterial eradication is a function of the drug concentration at the site of infection rather than penetration ratios. Substantially, pulmonary pharmacokinetics are a very useful tool for describing how drugs behave in the human lung, but do not promote an understanding of the pharmacological effects of a drug. More important, instead, is the correlation between pulmonary disposition of the drug and its MIC values for the infectious agent (Cazzola et al., 2002; Cazzola et al., 2004a). In vivo bacteria are not exposed to constant, but to constantly changing antibiotic concentrations, with peaks and troughs. Therefore, at the pulmonary site of infection, the pathogens are exposed to a gradient of antibiotic concentrations according to the pharmacokinetics of the drug (Cazzola et al., 2000). The addition of bacteriological characteristics to in vivo pharmacokinetic studies has triggered a ‘pharmacodynamic approach’. Pharmacodynamic parameters integrate the microbiological activity and pharmacokinetics of an anti-infective drug by focusing on its biological effects, in particular growth inhibition and killing of pathogens. Therefore, they allow a better evaluation of the dosage regimen in conjunction with its clinical response (Delacher et al., 2000). The duration of time that concentrations exceed MIC should be the pharmacodynamic parameter that best correlates with therapeutic efficacy of ß-lactam antibiotics and, consequently, avoids resistance (Craig, 1998). Experimental research has shown that

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cephalosporins exert an in vivo bacteriostatic effect even when their concentrations are above MIC for only 40 % of the time between administrations, whereas maximal bactericidal effect is obtained when concentrations are above MIC for 60–70 % of the time (Vogelman et al., 1988). Therefore, the aim for a highly effective dosing regimen would be to provide levels above the MIC for at least 70 % of the dosing interval (Craig, 1995). On the other hand, aminoglycosides and fluoroquinolones exhibit concentration-dependent killing and prolonged postantibiotic effects (PAEs). The goal of a dosing regimen for these drugs would be to enhance drug concentrations. Widely spaced administration of large doses would be possible because of the prolonged PAEs. Thus, peak serum concentration (Cmax ) to MIC and/or area under the concentration time curve over 24 hours (AUC0 – 24 ) to MIC would be expected to be the major pharmacodynamic parameters correlating with efficacy for these drugs (Dalla Costa and Derendorf, 1996; p Craig, 1998). With fluoroquinolones, pharmacodynamic studies data indicate that a Cmax to MIC ratio of 10:1 or greater and/or AUC0 – 24 to MIC ratio greater than 100–125, maximize bacterial eradication and prevent resistance in critically ill patients with nosocomial lower respiratory infections caused by Gram-negative bacilli (e.g. Pseudomonas aeruginosa), whereas in mild–moderately ill patients with communityacquired respiratory infections such as CAP caused by S. pneumoniae, free-drug AUC0 – 24 /MIC ratios of 25–34 are appropriate for bacterial eradication and hence favourable clinical outcome (Noreddin et al., 2004). It must be highlighted that it is extremely difficult to define the real impact of the interrelationship between pulmonary pharmacokinetics and pharmacodynamics on clinical and microbiological outcomes. The majority of studies have, in fact, only examined the interrelationship between serum pharmacokinetics and pharmacodynamics in patients with CAP, probably because it is easier and ethical to sample blood than ELF or AMs (Cazzola et al., 2002). Nonetheless, some interesting papers have addressed this important issue. Thus, Boselli et al. (2005a) have documented that in critically ill patients who are receiving mechanical ventilation and have severe CAP and creatinine clearance of > 40 mL/min, the administration of 500 mg of intravenous levofloxacin, which is a concentration-dependent antimicrobial, once and twice daily allows for the exceeding of pharmacodynamic thresholds predictive of outcome (i.e., peak concentration to MIC ratio of > 10 or AUC0 – 24 to MIC ratio of > 125 hours) both in serum and ELF for pathogens with MIC values of ≤ 1 mg/L and > 1 mg/L, respectively. The same group of researchers (Boselli et al., 2006) has shown that intravenous administration of ertapenem, a time-dependent antibiotic, 1 g once daily to critically ill patients with early-onset ventilator-associated pneumonia (VAP) and no known risk factors for multidrug resistant pathogens provides satisfactory pharmacokinetic results in this particular subset of patients, with a free ertapenem percentage penetration in ELF of approximately 30–40 % and concentrations exceeding the MIC of the targeted pathogens in both serum and ELF during 50–100 % of the time. Moreover, it has been documented that during the treatment of severe nosocomial pneumonia, a regimen of piperacillin–tazobactam 4 g/0.5 g every 8 hours might provide insufficient concentrations into ELF to exceed the MIC of many

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causative pathogens (Boselli et al., 2004). This suggests that higher doses of piperacillin–tazobactam should be administered in order to maximize the antibiotic concentration at the site of infection, or that a second antimicrobial agent should be used in association. On the contrary, a dosage of 600 mg linezolid administered intravenously twice daily to critically ill patients with Gram-positive VAP would achieve success against organisms with MICs as high as 2–4 mg/L in both plasma and ELF (Boselli et al., 2005b).

Interaction Between Antibiotics and the Host Natural Defences Recovery following a bacterial infection requires the combined activity of host resistance and antimicrobial therapy. The ability of powerful antibiotics has improved the results of antimicrobial therapy, but host resistance is still the most important determinant of outcome (Cazzola and Matera, 2003). It is well recognized that the inflammation associated with bacterial infections generally occurs as a host defence mechanism against the bacterial infection. For example, exposure of macrophages to bacterial products triggers the production of key inflammatory mediators including tumour necrosis factor (TNF) and, via induction of the inducible nitric oxide synthase (iNOS) protein, nitric oxide (NO). More than 95 % of lipopolysaccharide (LPS) activated monocytes or macrophages produce IL-1β, TNF-α and IL-6. Transcription of these biological and active peptides, notably in response to endotoxin, is regulated by a variety of signals including cytokines, immune stimuli, mediators of inflammation and bacterial cell-wall components that can activate macrophages or monocytes directly. Unfortunately, excessive production of these inflammatory mediators may cause serious damage to the host organ. Recent investigations have demonstrated that some antibiotics, in addition to their antimicrobial effects, can interfere with cytokine production and play an important role in controlling this process. Substantial data now exist on the direct or indirect effects of antibacterial agents on the immune system (Table 7.3). The synergistic interactions, which occur between the host immune system and antimicrobial agents, contribute to the successful outcome of antimicrobial chemotherapy (Fernandes et al., 1984). Antibacterial agents can be classified into four groups: A. Those that do not modify host defences (e.g. most β-lactams and chloramphenicol). B. Those that depress immune functions in vitro and ex vivo (tetracyclines, aminoglycosides, sulphonamides, teicoplanin and rifampicin). C. Those that display synergy with the immune system (i.e. co-operate with the host antibacterial system, particularly as a result of intracellular penetration (macrolides and quinolones).

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Table 7.3 Antibiotics and the host defence system Antibiotic

Effect

Effects on human phagocyte motility: Doxycycline Rifampicin Cotrimoxazole Effects on phagocyte oxidative burst: Josamycin Rokitamycin Dirithromycin Effects on phagocytosis and bacterial killing by human phagocytes: Tetracycline Sulphonamides Cefpimizole Cefotaxime Cefodizime Ceftriaxone Cefaclor Cefetamet Macrolides Effect on the specific immune system: Ciprofloxacin Grepafloxacin Moxifloxacin Cefotaxime Cefodizime Cefaclor Cefetamet Ceftazidime Ceftriaxone Macrolides Daptomycin Linezolid Intracellular bioactivity: Macrolides

IL-1α, TNF-α and IFN-γ IL-1α and IL-1β IL-1α and TNF-α IL-1 IL-1, IL-8 IFN-γ IL-6, TNF-α IL-6 and TNF-α IL-6 and TNF-α ≈ ≈ IL-2 and IL-5 TNF-α IL-1β, IL-6, TNF-α and IL-1ra

D. Those that enhance immune function in either healthy individuals or immunocompromised patients (Labro, 1990). In a general sense, immunomodulatory effects of drugs fall into one of the following four categories (or combinations thereof):

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1. Stimulation of the inflammatory response (e.g. by increasing the proinflammatory cytokine status or by augmenting phagocyte or T-cell function). 2. Inhibition of the counter-regulatory, anti-inflammatory response (e.g. by inhibiting anti-inflammatory cytokines such as IL-10, IL-4 and TGF β). 3. Inhibition of the inflammatory response (e.g. by decreasing the proinflammatory cytokine status, by inhibiting phagocyte or T-cell function or by inducing apoptosis of inflammatory cells). 4. Promotion of the counter-regulatory, anti-inflammatory response (e.g. by increasing anti-inflammatory cytokines as IL-10, IL-4 and TGF β) (van der Meer, 2003). In vivo Data Seem To Concur With The In vitro Studies. Unfortunately, The Contradictory Nature Of Several In vitro Observations And The Small Number Of In vivo Studies Preclude Any Unequivocal Conclusion Regarding The Role of antibiotics as potential immunomodulators in the treatment of inflammatory diseases.

Fluoroquinolones By way of illustration, clinically relevant concentrations of most quinolones seem to have no direct effect on isolated immune parameters such as phagocytic cell functions, lymphocyte proliferation, immunoglobulin production, interferon (IFN)-γ secretion and bone marrow progenitor cell proliferation (Shalit, 1991). Nevertheless, synergistic phagocytosis and intracellular killing of Klebsiella pneumoniae is observed in the presence of macrophages and subinhibitory concentrations (onehalf MIC) of pefloxacin. Pretreatment of bacteria with pefloxacin leads to an increase in both bacterial uptake and microbicidal activity of phagocytes. Exposure of the macrophages to pefloxacin does not affect any phagocyte functions (Cuffini et al., 1992). All quinolones modestly but significantly impair rat macrophage chemotaxis in a concentration-dependent manner. The effects of 4-quinolones on mediator (cytokine) production by monocytes are widely documented. The production of certain cytokines (interleukin (IL)-1, IL-2) and granulocyte-colony stimulating factor (G-CSF) by stimulated lymphocytes and splenocytes is enhanced in the presence of clinically achievable concentrations of the drug (Petit et al., 1987), probably because they enhance IL-2 gene induction (Riesbeck et al., 1994). However, levofloxacin increases IL-2 production in a concentration-dependant manner with a significant increase at concentrations of 10 µg/mL or more and granulocyte–macrophage-colony stimulating factor (GM–CSF) only at concentrations exceeding 50 µg/mL (Yoshimura et al., 1996). It is interesting to highlight that ciprofloxacin has a post-transcriptional differential effect on the production of IL-1α and IL-1β, reducing the total amount of IL-1β produced by LPS-stimulated human monocytes, while IL-1α is unaffected (Bailly et al., 1990). Ciprofloxacin also modulates IL-6 and IL-8 expression in a differential manner (Galley et al., 1997).

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Moreover, it increases the concentrations of nuclear factor of activated T cells (NFAT-1) and AP-1. Thus, ciprofloxacin interferes with the regulative pathway common to several cytokines (Tufano et al., 1992). Intriguingly, ciprofloxacin exerts an inhibitory effect on increased LPS- and TNF-related inflammatory responses in the treatment of Gram-negative bacterial pneumonia (Kawai et al., 2006), and this agent is considered to be useful for controlling these excessive inflammatory responses that exacerbate the pneumonia. Recently, it has been documented that ciprofloxacin also inhibits the pro-inflammatory cytokine (IL-1α, TNF-α, IFN-γ)induced NO production in a concentration-dependent manner, via the inhibition of the cytokine-induced NO synthase iNOS mRNA expression (Kolios et al., 2006). Grepafloxacin in vitro inhibits the production of IL-1α and IL-1β, and the expression of IL-1α, IL-1β, TNF-α, IL-6 and IL-8 mRNA (Ono et al., 2000). It has been suggested that the inhibitory effect of grepafloxacin be exerted, in part, at the gene transcription level. It has been shown that moxifloxacin also has immunomodulatory activity through its capacity to alter the secretion of IL-1α and TNF-α by human monocytes (Araujo et al., 2002). In an in vitro model of transendothelial migration, levofloxacin, moxifloxacin, and gatifloxacin had a significant inhibitory effect on neutrophils and monocytes when endothelial cells were activated either by infection via Chlamydia pneumoniae or stimulation via TNF-α (Uriarte et al., 2004). Moxifloxacin and gatifloxacin produced a significant decrease in IL-8 in C. pneumoniae-infected and TNF-α-stimulated cells; however, moxifloxacin was the only fluoroquinolone that produced a significant decrease in monocyte chemotactic protein (MCP)-1 levels. Mechanisms of neutrophil and monocyte inhibition by fluoroquinolone antibiotics are unknown but may be partially due to inhibition of IL-8 and MCP-1 production, respectively. It must be highlighted that any of the reports regarding the effect of quinolone antibacterial agents on cytokine production involves in vitro studies with concentrations higher than those seen in clinical use, except those showing stimulation of IL-2 production (Shalit, 1991). In any case, ciprofloxacin and moxifloxacin, administered to cyclophosphamide-injected mice, revert some of the immune suppressive effects of this agent (Shalit et al., 2001).

β-Lactams Immunomodulation in vitro with β-lactams has also been studied, but to a lesser degree. Cephalosporins may modulate mediator release from various cells, e.g. basophils, mast cells, polymorphonuclear neutrophils (Tufano et al., 1992). Cefodizime at the high concentrations of 200 µg/mL exerts a marked inhibitory activity on TNF-α release from human peripheral mononuclear cells (Ritts, 1990). At concentrations as low as 50–100 µg/mL, cefodizime inhibits the release of TNF-α and IL-6 and shows a significant stimulatory activity on IL-8 release (Meloni et al., 1995). Cefodizime also induces a significant dose-dependent increase in GM–CSF release from human bronchial epithelial cells (Pacheco et al., 1994). This cephalosporin influenced the pulmonary inflammatory response to heat-killed

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K. pneumoniae in mice (Bergeron et al., 1999). It up-regulated the early Klebsiellainduced secretion of TNF-α, as well as the number and phagocytic efficacy of AMs. By contrast, the late polymorphonuclear neutrophil recruitment and levels of IL-1α and IL-6 were reduced. Also ceftazidime administration modulates the concentration of pro-inflammatory cytokines in vivo (Alkharfy et al., 2000). In a rat model of sepsis, IL-6 concentrations were significantly elevated (100 to 200 times the baseline) 6 hours after ceftazidime administration in both septic and non-septic (control) rats, whereas TNF-α concentrations increased significantly in non-septic (∼40 times the baseline) rats but not septic (∼ 2 to 3 times the baseline) rats. Ceftazidime administration was not associated with an increase in endotoxin concentrations. These findings suggest that ceftazidime modulation of pro-inflammatory cytokine concentrations may be independent of its antimicrobial properties. This is not a surprise because several in vitro and in vivo studies have found that antimicrobials with high affinity for the penicillin-binding protein class 3 (PBP 3) have a marked potential to activate cytokine transcription (Jackson and Kropp, 1992; Prins et al., 1995). Cefetamet and cefaclor decrease the secretion of IL-6 and TNF-a from human lymphocyte–monocyte–basophil suspension, but cefaclor does not alter the production of mRNA for IL-6 and TNF-α (Scheffer et al., 1992). Recently, the amoxicillin–clavulanic acid combination, which increases the phagocytic and microbicidal activity of PMNs, was shown also to elicit the production of IL-1β and IL-8 by LPS- and Klebsiella-stimulated PMNs (Reato et al., 1999). Three chemically unrelated β-lactams (cefmetazole, imipenem and cefoxitin) had similar stimulatory effects on various PMN functions (phagocytosis, oxidative burst and antibody-dependent toxicity) and displayed chemoattractant activity (Rodriguez et al., 1991a, b, c): these antibiotics also significantly stimulated protein carboxy methylation, increased intracellular cyclic GMP levels and decreased ascorbate content. Cefetamet, cefpodoxime and cefaclor suppress the generation of LTB4 from human neutrophil granulocytes (Scheffer and K¨onig, 1993). LTB4 is one of the most potent chemotactic factors for polymorphonuclear leukocytes. Recently, Brooks et al. (2005) have tested a selection of penicillins, cephalosporins, a monobactam (aztreonam), a β-lactamase inhibitor (clavulanic acid), a carbapenem (meropenem) and the non-β-lactam penicillin derivative D-penicillamine for their effect on IFN-γ activity. Clavulanic acid, cefoxitin and cefaloridine were the most potent inhibitors of IFN-γ activity, followed by cefotaxime, ceftriaxone and phenoxymethylpenicillin. Ampicillin was less inhibitory than penicillin G, whereas meropenem and aztreonam had the least effect and D-penicillamine had no effect. The modulatory effect of these compounds was not due to a direct effect on CD54 induction. It must be highlighted that the β-lactam antibiotics cause release of proinflammatory bacterial cell-wall structures. The magnitude of TNF-α and IL-1β induction is dependent on the concentration of penicillin relative to the MIC, but is not critically dependent on the bacterial growth stage (Moore et al., 2005). It has been suggested that there may be enhanced TNF-α release in patients who are treated with β-lactams, especially if sub-MIC concentrations exist, for example during the dosing interval (Craig, 1995) or during penicillin-resistant infections (Knudsen et al., 1995; Fuursted et al., 1997). The consequential inflammatory

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effects of TNF-α may be due to the altered morphologies of sub-MIC-treated bacteria.

Macrolides Macrolides are a class of antibiotics taken up and concentrated by cells; consequently, they can reach intracellular concentrations far higher than those attained in the extracellular medium (Labro, 1997). This property may alter the function of phagocytes, which are crucial for both antibacterial defence and inflammation. Macrolides are particularly attractive in the treatment of infectious asthma because they dose-dependently inhibit microvascular leakage and neutrophil recruitment induced by LPS (Tamaoki et al., 1994; Cazzola et al., 2004b). A body of evidence highlights that they may not only enhance the host defence system through increased cytokine synthesis by host cells, but also exhibit anti-inflammatory activity by including anti-inflammatory cytokines (Amsden, 2005). Roche et al. (1988) have shown that high concentrations (100 µg/mL) of erythromycin enhance extracellular IL-1 activity from human monocytes in vitro. Kita et al. (1990) have shown that the administration of erythromycin to mice enhanced the production of IL-1 by macrophages and production of IL-2 and IL-4 by splenocytes. A 28-day treatment with roxithromycin induced an increased synthesis of IL-1 and TNF-α production by macrophages and the production of IL-2, IL-4 and IFN-γ by spenocytes (Kita et al., 1993), but a longer term (for 42 days) administration inhibited both IL-1 and IL-2 production (Konno et al., 1992). Erythromycin and clarithromycin have been reported to exert a suppressive effect on IL-6 expression in human bronchial epithelial cells (Takizawa et al., 1995). This finding contrasts with results of Bailly et al. (1991) who showed that spiramycin and, to a lesser extent, erythromycin increased total IL-6 production without affecting IL-1α and IL-1β or TNF-α production, whereas roxithromycin had no effect. Moreover, erythromycin and clarithromycin, both 14-member macrolides, but not 16-member macrolide josamycin, have an inhibitory effect on IL-8 expression and suppress the release of IL-8 from normal and inflamed human bronchial epithelial cells (Takizawa et al., 1997). Considering that IL-8 induces the migration of neutrophils to inflammatory sites, the impaired production and/or secretion of this cytokine may reduce neutrophil accumulation. Both 14-member and 16-member macrolides suppress the proliferative response of peripheral blood mononuclear cell stimulated by polyclonal T-cells mitogens and the IL-2 production by T cells but not the expression of IL-2 receptor (CD25) (Morikawa et al., 1994). An interesting study has shown that the incubation of human bronchial epithelial cell cultures in presence of 0.1–10 µg/mL erythromycin significantly blocked the H. influenzae endotoxin-induced release of IL-6, IL-8 and soluble intercellular adhesion molecule (sICAM)-1 (Khair et al., 1995). Moreover, preincubation with erythromycin prevented the endotoxin-induced expression of c-fos, c-jun and NF-κB that are fundamental for the transcriptional regulation of the TNF-α gene in monocytes (Sung et al., 1991). Recent work demonstrates that the decreased mortality and length of stay seen with macrolide-based CAP treatment regimens may also be due to short-term immunomodulatory effects of the

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macrolides. It has been demonstrated that a 3-day course of azithromycin appears to have a biphasic effect, where it enhances the immune system’s response to bacteria initially. After that it shuts it down, once the bacteria have been eradicated, thereby eliminating the inflammatory response as quickly as possible. However, before this mechanism can be referred to as ‘gospel’, it needs to be replicated in at least an animal model of CAP (Amsden, 2005).

New Classes of Antimicrobials Also new classes of antimicrobials can modulate the inflammatory response. Daptomycin, a novel cyclic lipopeptide antimicrobial active against resistant Grampositive pathogens including MRSA and vancomycin-resistant enterococci, alone or in combination with vancomycin or oxacillin (compared with vancomycin or oxacillin alone) is able to decrease macrophage inflammatory response with diminished TNF secretion and reduced accumulation of iNOS protein (English et al., 2006). The mechanisms responsible for this effect of daptomycin are not known but may include the diminished release of pro-inflammatory bacterial components. Linezolid, a novel oxazolidinone antibiotic, has potent concentration-dependent suppressive effects on cytokine (IL-1β, IL-6, TNF-α and IL-1ra) production by LPS-stimulated monocytes in vitro, modifying the acute-phase inflammatory response by disturbing the cytokine cascade (Garcia-Roca et al., 2006).

Therapeutic Value of the Synergistic Interactions Between the Host Immune System and Antimicrobial Agents It is unknown whether the efficacy of antimicrobial therapy can be improved by support of the impaired host resistance. The biological response-modifying activity of such drugs has not been proved to be of clinical significance except for the intracellular activity of those agents that have the ability to enter cells. The direct modification of immune responses is still a matter of debate; in fact, it remains difficult to relate the clinical situation to in vitro findings (Labro, 2000). For example, patients with Gram-negative nosocomial pneumonia have high plasma concentrations of lipopolysaccharide, IL-6 and TNF-α, but antibiotic therapy with ceftazidime or imipenem did not significantly modify these concentrations. In any case, TNF-α plasma concentrations were significantly higher in the group treated with ceftazidime compared with the group treated with imipenem at the baseline and 4 hours later, but these differences were not statistically significant after 12 hours of initiation of both treatments (Maskin et al., 2002). It is probably advisable to use antibiotics with immunomodulating activity for practical and timely treatment of patients with pneumonia, particularly those with diminished immune capacity or those who insidiously develop septic syndrome. In effect, antibiotics that enhance host resistance and protect the host through direct or indirect effects on inflammation, in addition to their bactericidal properties, hopefully will contribute to improving therapy of threatening infections.

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Adverse Events Antimicrobial agents are associated with side-effects, which are usually tolerated because the benefits of treatment outweigh the toxic effects. Common side-effects are gastrointestinal symptoms, skin rashes and thrush; specific effects include nephrotoxicity associated with aminoglycosides and staining of the teeth attributable to tetracyclines. Although all the reviewed randomized controlled trials of antibiotic therapy collected data about adverse events, such studies, given their small size, are likely to detect only the most common occurrences (Barlow et al., 2003). Rare but more important side-effects may be detected only during postlicensing surveillance. In 1992, temafloxacin was withdrawn from the market, 6 months after it had been launched, because of a risk of haemolysis, liver and kidney failure and clotting disorders (the ‘temafloxacin syndrome’). The incidence of this syndrome was very high, at one case per 3500 treatments. Three years later, sparfloxacin saw its indications restricted because of severe phototoxicity. Trovafloxacin, first released onto the market in December 1997, was withdrawn in June 1999 because of the risk of fatal cytolytic hepatitis; this time, however, the risk was low, at about 0.006 %. Finally, grepafloxacin, registered in November 1997, was withdrawn by the company in October 1999 because of cases of QT prolongation (seven deaths in Germany); the estimated frequency was below 0.0001 %. By contrast, observational antibiotic studies rarely report adverse events, perhaps owing to the difficulty of obtaining accurate data from case-notes or administrative databases. Between one and five thousand subjects would have to be treated to observe at least one case of a rare adverse event (frequency between 0.01 and 0.1 %), while this number rises to between fifty thousand and half a million when the adverse effect is exceptional (frequency between 0.001 and 0.01 %). It is, therefore, impossible to catalogue every potential adverse effect of a new antibiotic before it is released onto the market. Unfortunately, these adverse effects are usually unpredictable because of their idiosyncratic nature, due to innate individual hypersensitivity (Rouveix, 2003). To be able to evaluate and prevent these iatrogenic risks, we need to understand the underlying mechanisms and to identify individual contributory factors. This type of toxicity remains difficult to prevent. Among the most important outstanding questions is whether the molecular structure of an antibiotic is responsible for its toxicity and if its metabolism is genetically modulated (role of type 2 acetylation, cytochrome P450 2D6 or 2C19, glutathione 5-transferase, etc.). Traditional studies based on animal models and cell culture have successfully identified the toxic metabolite, both in standard conditions and after stimulation of their production through enzyme induction or by creating a detoxification deficiency (glutathione depletion, inhibition of epoxide hydrases, etc.). Finally, prevention implies the need to assess individual susceptibility. Acquired factors (multiple drug therapy, drug interactions, old age, malnutrition, alcoholism, etc.) and genetic factors (phenotyping and genotyping for antibiotics with genetic polymorphism) should be looked for (Rouveix, 2003).

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Conclusions The lung is the organ with the largest epithelial surface area in contact with the external environment. The airways are repeatedly exposed to microorganisms and infectious respiratory disorders are therefore an important part of the daily activity of physicians. Antibiotic treatment is a key factor in the management of these diseases. Optimal treatment would be an antibiotic regimen specifically suited for a specific patient and infecting pathogen in order to assure the best therapeutic outcome. The choice of an antibiotic should be based on several parameters including bacteriological efficacy, pharmacokinetics and pharmacodynamics, costs, tolerability and safety, ending with an individualized dosing. The application of this knowledge will lead to a better treatment and to a cost-effective management of lower respiratory tract infections.

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8

β-Lactams in the Therapy of Community-Acquired Pneumonia MICHAEL S. NIEDERMAN Department of Medicine, SUNY at Stony Brook, Department of Medicine, Winthrop-University Hospital, Mineola, NY, USA

Introduction Since its introduction in the early 1940s penicillin has been regarded as an important therapeutic option, and by some it is the drug of choice for patients with community-acquired pneumonia (CAP), an illness most commonly caused by Streptococcus pneumoniae (Garau, 2005; Chiou, 2006; Peterson, 2006). Following the development of penicillin, a variety of other agents have appeared that have modifications of the basic β-lactam ring, including a wide range of penicillins, cephalosporins, monobactams and carbapenems, all with utility in the therapy of pneumonia.

Overview of the β-Lactam Class of Antibiotics Definitions and a Listing of Specific Agents The β-lactams are a group of bactericidal antibiotics that have in common the presence of a β-lactam ring, which is bound to a five-membered thiazolidine ring in the case of the penicillins and to a six-membered dihydrothiazine ring in the case of the cephalosporins. Modifications in the thiazolidine ring can lead to agents such as the penems (imipenem and meropenem), whereas absence of the second ring structure characterizes the monobactams (aztreonam) (Niederman, 2008). These agents can also be combined with β-lactamase inhibitors such Community-Acquired Pneumonia: Strategies for Management Edited by Antoni Torres and Rosario Men´endez  2008 John Wiley & Sons, Ltd

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as sulbactam, tazobactam or clavulanic acid, to create the β-lactam–β-lactamase inhibitor drugs. The β-lactamase inhibitors extend the antimicrobial spectrum of the β-lactams by providing a substrate (sulbactam, clavulanic acid, tazobactam) for bacterial β-lactamase enzymes, thereby preserving the antibacterial activity of the parent compound. B-lactam antibiotics work by interfering with the synthesis and cross-linking of bacterial cell-wall peptidoglycans by binding to bacterial penicillin-binding proteins. The penicillins used for respiratory tract infections include the natural penicillins (penicillin G and V), the aminopenicillins (ampicillin, amoxicillin), the antistaphylococcal agents, the anti-pseudomonal agents, and the β-lactam–β-lactamase inhibitor combinations. The anti-pseudomonal penicillins include: the older carboxypenicillins (ticarcillin) and the ureidopenicillins (piperacillin, azlocillin, mezlocillin), with piperacillin and azlocillin being the most active agents against P. aeruginosa. The β-lactamase inhibitor combinations include: clavulanic acid with either amoxicillin or ticarcillin; and sulbactam with ampicillin; and tazobactam with piperacillin. Although Staphylococcus aureus is not a common cause of CAP, it can occur after influenza and the anti-staphylococcal penicillins include methicillin, nafcillin and oxacillin. These agents are not active against methicillinresistant S. aureus (MRSA). The cephalosporins were first developed in 1948, and the currently available agents span from first to fourth generation (Garau, 2005). The earlier agents were generally active against Gram-positives, but did not have activity that extended to the more complex Gram-negatives, or anaerobes, and were susceptible to destruction by bacterial β-lactamases. The newer generation agents are generally more specialized, with broad spectrum activity, and with more mechanisms to resist breakdown by bacterial enzymes. The second generation and newer agents are resistant to bacterial β-lactamases. The third-generation agents that are active against drug-resistant pneumococci (DRSP) include ceftriaxone and cefotaxime, while ceftazidime is active against P. aeruginosa, but not highly effective against DRSP. Specific third-generation agents are effective in the therapy of CAP, but may induce the production of extended-spectrum and type 1 bacterial β-lactamases among certain Gram-negatives (such as the Enterobacteriaceae), and thus promote the emergence of resistance during monotherapy (Chow et al., 1991) The fourthgeneration agent, cefepime, is active against pneumococci (including DRSP), and P. aeruginosa, but is also less likely to induce resistance among the Enterobacteraceae than the third-generation agents (Yakolev et al., 2006). A new cephalosporin ceftobiprole is currently under development, but is unusual because it provides good in vitro coverage of both MRSA and P. aeruginosa, thus spanning the spectrum from resistant Gram-positives to resistant Gram-negatives with a single agent. Imipenem and meropenem are the broadest spectrum β-lactams, being active against Gram-positives, anaerobes and Gram-negatives, including P. aeruginosa. They have shown efficacy for patients with severe pneumonia, both communityacquired and nosocomial (Siempos et al., 2007). Aztreonam is a monobactam that is so antigenically different from the rest of the β-lactams that it can be used

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in penicillin allergic patients. It is only active against Gram-negative organisms, having a spectrum very similar to the aminoglycosides, and its application in CAP is primarily as part of a multidrug regimen for those penicillin-allergic patients who are admitted to the intensive care unit (ICU).

Antimicrobial Activity, Pharmacokintetics and Pharmacodynamics of β-Lactams Bactericidal and Antimicrobial Activity

The β-lactam antibiotics are generally considered to be bactericidal agents, but the terms bactericidal and bacteriostatic are broad categorizations, and may not apply for a given agent against all organisms, with certain antimicrobials being bactericidal for one bacterial pathogen but bacteriostatic for another (Finberg et al., 2004). Bactericidal antibiotics kill bacteria, generally by inhibiting cell-wall synthesis or by interrupting a key metabolic function of the organism, and as mentioned, β-lactams act by the former mechanism. The use of a specific agent is dictated by the susceptibility of the causative organism(s) at the site of infection. However, when neutropenia is present, or if there is accompanying endocarditis or meningitis, the use of a bactericidal agent is preferred. Thus, for most patients with CAP, it is not essential to choose a bactericidal agent, but the bactericidal nature of the β-lactams may in part account for their high degree of reliability in the therapy of pneumonia caused by DRSP (Peterson, 2006). Antimicrobial activity is often described by the terms minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). The term MIC defines the minimum concentration of an antibiotic that inhibits the growth of 90 % of a standard sized inoculum, leading to no visible growth in a broth culture. At this concentration not all the bacteria have necessarily been killed. The term MBC refers to the minimum concentration needed to cause a 3-logarithmic decrease (99.9 % killing) in the size of the standard inoculum, and generally all pathogenic bacteria are killed at this concentration. The MIC is used to define the sensitivity of a pathogen to a specific antibiotic, under the assumption that the concentration required for killing (the MIC) can be reached at the site of infection in vivo. However, these terms must be interpreted cautiously in the treatment of pneumonia, because the clinician must consider the MIC data in light of the penetration of an agent into lung tissues, and β-lactams may only reach 40–50 % of their serum level at the alveolar level (Andes et al., 2004). This is because these drugs are poorly lipid soluble, and their entry into the epithelial lining fluid is inflammation dependent. In recent years, concern about antimicrobial resistance has led to a new term, the mutant prevention concentration (MPC) (Andes et al., 2004). The MPC is defined as the lowest concentration of an antimicrobial that prevents bacterial colony formation from a culture containing greater than 1010 bacteria. At lower than MPC concentrations, spontaneous mutants can persist and be enriched among the organisms that remain during therapy. The concept has been most carefully studied with

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pneumococcus and the fluoroquinolones, but may apply to the β-lactams as well. In general the MPC is higher than the MIC, implying that it is possible to use an antimicrobial to successfully treat an infection, but not to prevent the remaining organisms (which are not causing illness) from emerging as resistant, and persisting and spreading to other patients. Antibiotic Pharmacokinetics and Pharmacodynamics

β-lactams are bactericidal in relation to how long they stay above the MIC of the target organism (time-dependent killing), unlike the quinolones which are effective in relation to the peak concentration achieved (concentration-dependent killing) (Andes et al., 2004). Because antibiotic killing is time dependent, dosing schedules should be chosen to achieve the maximal time above the MIC of the target organism. The rate of killing is saturated once the antibiotic concentration exceeds four times the MIC of the target organism. Therefore, the optimal dosing strategy is to dose often and not to let trough concentrations fall below the MIC of the target organism. With these considerations in mind, continuous infusion of β-lactams is under study to optimize treatment with β-lactam agents. There are few studies of continuous infusion of β-lactams in the therapy of pneumonia. Bryan et al. (1997) has calculated that if penicillin were administered to a patient with normal renal function, at a loading dose of 3 million units, followed by infusion of 24 million units per day, a serum level of 20 mg/L would be achieved, a level far above any degree of pneumococcal resistance. In spite of these considerations, for many organisms, the concentration of the antibiotic only needs to be above the MIC for 40–50 % of the dosing interval, and possibly for as little as 20–30 % of the interval in the case of carbapenems. For this reason, some new formulations of penicillins have appeared (high-dose amoxicillin–clavulanate) which are able to stay above the MIC for a long enough time period, because the initial peak concentrations achieved are so high (Garau, 2005). Optimization of dosing is possible for penicillins because the penicillins have linear pharmacokinetics, whereas other agents (such as cephalosporins) which do not, are not able to achieve the doses needed to maximize time above MIC (Garau, 2005). In addition, the cephalosporins may predispose to higher levels of pneumococcal resistance than the penicillins (Bryan et al., 1997). Recently, some investigators have suggested that antibiotic therapy be chosen on the basis of another property of certain agents: their ability to stimulate inflammation and cytokine production in response to the presence of the bacterial cell-wall lysis products that they generate (Finberg et al., 2004). It has been known for many years that certain antibiotics in the β-lactam class liberate bacterial cell-wall products that can interact with cytokine-producing cells, stimulating the production of high levels of cytokines such as tumour necrosis factor. In theory, this could lead to the development, or worsening, of the sepsis syndrome in patients immediately after therapy for pneumonia is started, a phenomenon seen in the therapy of Pneumocystis jirovecii pneumonia and pneumococcal meningitis, leading to recommendations to use corticosteroids with antibiotics when treating these infections. Other than in these situations, it is unclear if cytokine release is clinically

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relevant. However, β-lactams that are cell-wall active, and that kill slowly, have been associated with the greatest cytokine release. In particular, if an antibiotic has a high affinity for bacterial penicillin-binding protein 2, compared with those with a high affinity for penicillin–binding protein 3, it may kill slowly and be a more potent stimulus for cytokine release. Although there are not much clinical data on this issue, one study of Gram-negative infection demonstrated more endotoxin release when therapy was given with ceftazidime than when therapy was given with imipenem (Prins et al., 1995).

Efficacy of β-Lactams in Community-Acquired Pneumonia Overview Although North American guidelines recommend that β-lactams be used as part of a combination regimen for the empirical therapy of CAP, there is a rich database demonstrating the reliability and efficacy of β-lactam monotherapy in this illness (Peterson, 2006). For example, in Sweden, monotherapy with either a penicillin or cephalosporin is common in CAP, and in one study, 80 % of 982 CAP patients received these agents (50 % penicillin, 30 % cephalosporins), generally as a single agent, and the overall mortality rate was only 3.5 % (Hedlund et al., 2002). Garau (2005) has reviewed clinical trials of β-lactam therapy of CAP, including inpatients and outpatients, extending from 1978 to 2003, and observed clinical success rates of 75–100 %, with no trend of a decrease in efficacy over time, as drug resistant pneumococci have become more common. In fact, Peterson (2006) reviewed the role of penicillins in the therapy of pneumococcal pneumonia, and concluded that current levels of in vitro pneumococcal resistance are not clinically relevant and that documented failure of penicillin, when dosed correctly, remains ‘virtually non-existent’. Most of the failures of β-lactam therapy in the setting of CAP and in vitro pneumococcal resistance have been associated with inadequate dosing or else primarily with the cephalosporins such as ceftazidime, cefazolin, cefuroxime and cefamandole (Peterson, 2006). The third-generation agents ceftriaxone and cefotaxime are more reliable, even in the setting of documented DRSP infection (Lujan et al., 2004). Peterson observed in his review of the literature that there was only one documented case of clinical and microbiological failure associated with the use of a penicillin. This case involved a patient who failed therapy with 2 g of amoxicillin every 8 hours (with clavulanate) by developing an empyema with an organism having an MIC of 8 mg/L, although this level of resistance was no higher than the pretreatment level, implying that this high level should not have been treated with a penicillin alone. In general, most studies have demonstrated no impact of discordant therapy of DRSP with adverse outcome, nor have they correlated adverse outcomes with the use of a specific therapy, or with the identification of microbiological (as opposed to clinical) failure. When a patient with a resistant organism fails therapy of CAP, it can only be attributed to ineffective therapy, as opposed to patient-related factors, if there is also persistence or emergence of a resistant organism after therapy.

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Efficacy of β-Lactams against Drug-Resistant Pneumococci Frequency of Pneumococcal Resistance to β-Lactams and its Clinical Relevance

Pneumococcus (Streptococcus pneumoniae) is the most common aetiological pathogen for CAP, in any patient population, in or out of the hospital, possibly even among those without an aetiology recognized by routine diagnostic Although pneumococcal resistance in CAP has been recognized since the 1970s, the frequency of this problem has been increasing since the mid-1990s, with resistance in vitro being reported for penicillins and cephalosporins among the β-lactams, and also with resistance to other antibiotic classes, including the macrolides, trimethoprim–sulphamethoxizole, and now even the quinolones (Mandell et al., 2007). Although drug-resistant pneumococci may be present in at least 40 % of these organisms, in the USA, a large number of penicillin resistant organisms are of the ‘intermediate’ type (penicillin minimum inhibitory concentration, or MIC, of 0.1 to 1.0 mg/L) and not of the high-level type (penicillin MIC of 2.0 or more). As already mentioned, it is difficult to show a clinical impact of in vitro resistance on outcomes such as mortality in large numbers of patients. There are certain features from the history of a patient with CAP that identify the patient as being at risk for infection with DRSP. These include: age > 65 years, β–lactam therapy within the past 3 months, alcoholism, immune suppressive illness (including therapy with corticosteroids), multiple medical comorbidities and exposure to a child in a day-care facility. In addition, a high frequency of DRSP in the community may also be a risk factor for DRSP infection (Niederman et al., 2001). A recent study in the USA indicated that the trend of rising rates of DRSP may be coming to an end, and that we may be ‘turning the corner’ on resistance to β-lactam agents (Doern et al., 2005). The study examined 1817 respiratory isolates of pneumococci, from 44 medical centres in 2002–2003, that were judged to be clinically relevant (but not all from patients with pneumonia), and resistance rates to 27 antimicrobials were evaluated. Penicillin resistance was present in 34.2 % (15.7 % intermediate level, 18.5 % high level), while ceftriaxone resistance was in 6.9 %, and resistance was also present to other antimicrobials such as macrolides (29.5 %) and clindamycin (9.4 %). Although quinolone resistance was uncommon, more than 20 % of the isolates already had quinolone resistance determinant genes present, implying a risk for future mutations that could lead to a high rate of quinolone resistance. The authors compared the findings to trend analysis dating back to 1994–1995 and concluded that β-lactam resistance may have plateaued or even begun to decline. Similar data recently appeared in a Spanish study that found a decreasing rate of penicillin and cephalosporin resistance in patients treated from 1999–2002, compared with earlier studies (Valles et al., 2006). In one of the earliest studies of the relevance of DRSP, investigators from Spain found no impact on mortality, after adjusting for severity of illness in a population with nearly a 30 % frequency of in vitro resistance (Pallares et al., 1995). In another Spanish study, 638 cases of pneumococcal CAP were included, of which 35.7 % had minimum inhibitory concentration (MIC) to penicillin of ≥ 0.12 µg/mL (three isolates had a MIC of 4 µg/mL) (Aspa et al., 2004). In a logistic

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regression model, chronic pulmonary disease (odds ratio [OR], 1.44), human immunodeficiency virus infection (OR, 1.98), clinically suspected aspiration (OR, 2.12) and previous hospital admission (OR, 1.69) were related to decreased susceptibility to penicillin. While pneumococcal resistance was not a risk for mortality, the patients with penicillin MICs ≥ 0.12 µg/mL, had a predominance of serotype 19 which was associated with a higher mortality rate. On the other hand, disseminated intravascular coagulation, empyema and bacteremia were significantly more frequent among patients with penicillin-susceptible pneumococcus. A recent report from Spain also showed no statistically significant increase in mortality for patients with DRSP, compared with those with sensitive organisms, and the risk factors for mortality were patient factors such as female gender, pleural effusion and prior oral corticosteroid therapy (Valles et al., 2006). In spite of these findings, some studies have shown that resistance can affect outcomes, including mortality, but only in a select number of patients. In a group of patients with pneumococcal bacteremia, of which more than half were HIV positive, high-level resistance was a predictor of mortality (Turett et al., 1999). While other investigators did not find an increased risk of death from infection with resistant organisms in other populations, they did find an enhanced likelihood of suppurative complications (empyema), and a more prolonged hospital length of stay (Plouffe et al., 1996; Metlay et al., 2000). These conflicting data may have been the result of studying relatively few patients, many of whom did not have high levels of in vitro resistance. One large study evaluated more than 5000 patients with pneumococcal bacteremia and CAP and found an increased mortality for patients with a penicillin MIC of at least 4 mg/L or greater, or with a cefotaxime MIC of 2.0 mg/L or more (Feikin et al., 2000). However, this increased mortality was present only if patients who died in the first 4 days of therapy were excluded from analysis. Fortunately, very few organisms are currently at this level of resistance, which may explain the conflicting findings in various studies. More recently, another study using both a cohort and matched control methods, found that severity of illness, and not resistance or accuracy of therapy, was the most important predictor of mortality (Moroney et al., 2001). In some studies, severity of illness was greater in patients without resistant organisms, implying a loss of virulence among organisms that become resistant, a finding echoed in other studies that have found that the absence of invasive illness is a risk factor for pneumococcal resistance Efficacy of Specific Agents: Discordant Therapy

While an adverse clinical impact of DRSP is difficult to demonstrate consistently, there are few studies that have examined this issue in relation to the accuracy of the therapy that was chosen. However, when investigators have evaluated this issue, most have not demonstrated that therapy with a β-lactam to which the aetiological isolate of pneumococcus has in vitro resistance (discordant therapy) is associated with a worse outcome in CAP. In one study of 101 patients with pneumococcal pneumonia, drug resistance to either penicillin, cephalosporins or macrolides was present in 52 (Ewig et al., 1999). In this population of patients with pneumococcal infection, 49 % had penicillin resistance (33 % high level,

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16 % intermediate), 31 % cephalosporin resistance (9 % high level with MIC values ≥ 2 mg/L), 27 % with macrolide resistance (MIC ≥ 1 mg/L) and 17 % ciprofloxacin resistance (MIC ≥ 2 mg/L, including 3 % with MIC ≥ 4 mg/L), with many of the strains resistant to multiple agents. Resistance was more common in patients with immune suppression, although this difference was not significant. In immune competent patients, the risk factor for cephalosporin resistance was age > 65 years, while the risk factor for penicillin resistance was multiple (> 2) medical comorbidities. In the immune suppressed group, the presence of bacteremia was inversely correlated with penicillin and cephalosporin resistance, implying a loss of virulence when resistance was present. Outcomes such as length of stay, severity of pneumonia, complications and mortality were the same with and without resistance, and when resistance was present, the use of discordant therapy was not associated with an increased risk of death. Another study from the USA evaluated 146 patients who were hospitalized with invasive pneumococcal pneumonia and found that only 4 of 22 who received discordant therapy died (18 %) compared with 17 % with concordant therapy, and in a multivariate model, the use of discordant therapy was not associated with an increased risk of dying (Moroney et al., 2001). One explanation for these findings may have been that many patients were treated with cefotaxime or ceftriaxone, and the MIC values defining resistance may not be identifying a level of resistance that is clinically relevant. This possibility is supported by the findings in a Spanish study that does show an adverse outcome of in vitro resistance if discordant therapy is given, but suggests that the use of ceftriaxone or cefotaxime (which was very common) would be unlikely to lead to discordant therapy (Lujan et al., 2004). In the study, discordant therapy was defined as failure to administer an antibiotic with in vitro activity against an isolated bacteremic strain of pneumococcus within 24 hours of hospital admission. Of 100 patients with bacteremic pneumococcal pneumonia, 29 had penicillin-resistant strains, but in the entire study, discordant therapy was documented in only ten patients, five of whom died. In contrast to this 50 % mortality rate, the mortality in patients receiving concordant therapy was 14 % (13 of 90). Nursing home residence (OR = 14.8) and immunocompromise (OR = 11.5) were independently (p < 0.05) associated with discordant therapy. The multivariate analysis found that discordant therapy was independently associated with death, with an OR = 27.3, and the excess mortality for initial discordant therapy was estimated to be 35.6 % (95 % confidence interval, 3.73–67.4). However, while discordant therapy was a mortality predictor, the risk of discordant therapy was significantly higher (p < 0.05) when empirical therapy did not include cefotaxime or ceftriaxone (OR = 10.4). Thus, the authors concluded that it is very unlikely that discordant therapy would be given if ceftriaxone or cefotaxime were used for empirical therapy. Since these drugs are commonly used, and because current in vitro definitions of resistance to them may not be clinically relevant, it is not surprising to see low rates of discordant therapy, and very little impact of current levels of resistance. While the third-generation cephalosporins cefotaxime and ceftriaxone may be reliable choices, some data suggest that discordant therapy with cefuroxime may

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be more problematic (Yu et al., 2003). In a prospective observational, multi-centre, international study of 844 patients with pneumococcal bacteremia, which included 15 % with intermediately susceptible organisms, and 9.6 % with high level resistance, the presence of penicillin resistance was not a risk factor for mortality nor was discordant monotherapy, unless the therapy was with cefuroxime, which was associated with an increased risk of death in patients who received monotherapy. In addition, there was a trend to prolonged fever in patients treated with discordant therapy involving cefuroxime, but not with any other therapies. One recent review found six prospective studies that compared clinical effectiveness of concordant and discordant therapy with the same β-lactam as monotherapy in patients with pneumococcal pneumonia (Falagas et al., 2006). There was no statistically significant difference in mortality (19 % concordant vs 21 % discordant) or in clinical or microbiological success when comparing these two types of therapy. Another recent meta-analysis found an increased mortality for CAP due to DRSP, compared with infection due to non-resistant organisms, but the use of discordant therapy was not associated with any higher mortality than the use of concordant therapy (Tleyjeh et al., 2006). The authors considered the possibility that the presence of drug-resistance was itself a prognostic indicator and probably a marker of the presence of host factors that can adversely affect outcome, but that from a mortality perspective, current therapy choices did not need to be changed to account for the presence of DRSP. Impact of Recent β-Lactam Therapy

Several recent studies have clarified the finding that recent β-lactam therapy is a risk factor for DRSP. In a study of 303 patients with pneumococcal bacteremia, of which 98 were with penicillin-non-susceptible strains (65 intermediate resistant, 33 high-level resistance), the investigators found that the use of penicillins, sulphonamides and macrolides within either 1 or 6 months before infection were associated with an increased risk of bacteremia with penicillin non-susceptible pneumococci (PNSP). The odds ratio of increased risk was 3.3 for β-lactam therapy in the preceding month, and rose to 6.4 for β-lactam therapy within the past 6 months. (Ruhe and Hasbu, 2003). When the issues of repeated therapy and prolonged therapy were examined, they were additional risks for infection with PNSP. Prolonged therapy was a particular risk for β-lactams inducing bacteremia with PNSP, and the use of at least two courses of therapy was a risk for all three classes (β-lactams, sulphonamides, and macrolides). One limitation to the data analysis is that many patients received multiple antibiotics simultaneously, so the exact impact of an agent was hard to estimate. While the impact of prior β-lactam therapy on subsequent pneumococcal resistance has been well-established by a number of studies, the exact impact of time of exposure has not been worked out. It is difficult to understand the biological plausibility of therapy 6 months earlier still having an impact on subsequent penicillin susceptibility in patients with pneumococcal CAP. Another study examined 563 patients with invasive pneumococcal infection and recent antibiotic therapy in the past 3 months (156 with a penicillin and 123 with a cephalosporin) and found that

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therapy in this time frame with penicillins, macrolides and quinolones increased the risk that a subsequent episode of infection would be with an organism resistant to the agent recently used (Vanderkooi et al., 2005). Penicillins had less of an effect than other agents, but they still were associated with an OR of subsequent resistance of 2.47. Interestingly, recent cephalosporin use was not a risk factor for subsequent penicillin resistance. Based on data such as these, new guidelines and recommendations for empirical therapy of CAP have suggested taking a history of antibiotic use in the preceding 3 months and choosing an agent from a different class if there has been recent therapy with a penicillin, macrolide or quinolone (Mandell et al., 2007).

The Role of β-Lactams in Community-Acquired Pneumonia Guidelines Monotherapy vs Combination Therapy In North American guidelines, β-lactams are a therapeutic option for all inpatient and outpatient subgroups, but never as monotherapy, because of the recommendation that all patients receive therapy that covers atypical pathogens, either as the primary aetiology or as a co-infection, in addition to pneumococcus and other possible aetiological organisms (Mandell et al., 2007). This recommendation is based on large studies, mostly involving hospitalized patients, but also some involving outpatients, that demonstrate improved outcomes, including mortality, when a macrolide is added to a β-lactam, compared with when a β-lactam is used alone (Gleason et al., 1999; Houck et al., 2001). In contrast to these recommendations, the guidelines from the British Thoracic Society and the European Respiratory Society allow both outpatients and inpatients to receive β-lactams as sole therapy, with macrolides as an alternative in some settings or as an optional second drug for more severely ill individuals (British Thoracic Society, 2001; Woodhead et al., 2005). Only in the ICU admitted patient population do all guidelines agree that a β-lactam (or any other agent) as monotherapy is not sufficient, and all such patients require combination therapy. The recommendation to provide routine atypical pathogen coverage and not use β-lactams as monotherapy is controversial, and this explains why not all guidelines agree on this point. In the USA, several large studies have shown reduced mortality when a macrolide is added to a cephalosporin, either a second- or third-generation agent. In one study, the benefit of adding a macrolide only applied if it was added to a cephalosporin, but not if it was added to a β-lactam–β-lactamase inhibitor combination (Gleason et al., 1999). Most of the data on this issue have come from studies of Medicare patients, but at least one large study included nearly 15 000 patients less than age 65, and reached the same conclusions (Brown et al., 2003). The reason for benefit of the addition of a macrolide is uncertain, but in one study, the use of a second agent reduced mortality in only one of three calendar

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years examined, suggesting that even if there is a benefit due to atypical pathogen co-infection treatment, the frequency of this type of infection may vary over time (Houck et al., 2001). Although the necessity of using a macrolide with a β-lactam has been questioned, particularly in European guidelines, a recent study has suggested that the findings in North America are also applicable in Spain (Vazquez et al., 2005). In a retrospective analysis of 1391 non-ICU CAP patients, with therapy chosen by the physicians, 270 received β-lactam monotherapy, while 918 received a β-lactam with a macrolide. The mortality rate was 13.3 % in those treated with monotherapy, compared with 6.9 % in those receiving a combination therapy. An aetiological diagnosis was established in 36 % of patients, of whom 58.6 % were pneumococcus. Interestingly, the mortality benefit of adding a macrolide applied to patients in all pneumonia severity classes, and also to those with documented pneumococcal infection. In another multicentre Spanish study, the choice of empiric therapy, including the issue of whether a macrolide is added to a β-lactam, or a β-lactam used alone, showed no impact on CAP mortality (Aspa et al., 2006). However, for those patients with a Pneumonia Severity Index (PSI) class of > III, the addition of a macrolide to a β-lactam did reduce mortality (OR for mortality of 1.49 with p = 0.04 for monotherapy vs combined therapy). In another analysis of only patients with severe CAP, non-adherence to guidelines (which often meant the use of monotherapy and not a combination regimen) was associated with a prolonged duration of mechanical ventilation (Shorr et al., 2006). In another study that included patients from North America, Europe, South America, Asia and Africa, the incidence of atypical pathogen infection in CAP was similar, but the use of therapies to cover these pathogens was variable in different regions of the world (Arnold et al., 2007). However, the use of therapy directed at atypical pathogens (vs such therapies as β-lactams used alone), was associated with patient benefits, including reduced time to clinical stability, decreased length of stay, decreased overall mortality and decreased CAP-related mortality. The need for routine atypical pathogen coverage has been questioned by the findings of two meta-analyses (Mills et al., 2005; Shefet et al., 2005). One study examined 18 double- blind randomized registration studies of agents active against atypicals compared with β-lactam monotherapy in 6749 patients without severe illness (Mills et al., 2005). There was no difference in per cent with clinical cure or improvement, and no difference in mortality, but the mortality rate for all patients was low at 1.9 %. There was a treatment benefit of atypical pathogen coverage when Legionella was present. The other study evaluated 24 trials of 5015 inpatients with CAP, comparing β-lactam therapy to therapy including atypical pathogen coverage (Shefet et al., 2005). There were no differences in mortality with atypical pathogen coverage, but there was a trend to more clinical and bacteriological success with this type of therapy, especially with a quinolone, and with documented Legionella infection. The problem with all of these analyses is they only included patients enrolled in registration studies, and not all individuals presenting with CAP, thus raising questions about the general applicability of the findings.

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Recommended Agents for Outpatients and Inpatients Outpatients

In the new American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) CAP guidelines, recommended therapy for outpatients is divided into therapies for those who were previously healthy and have no history of antibiotic use in the past 3 months, those with comorbidities or with recent antibiotics in the past 3 months, and those living in regions with high rates of DRSP. A β-lactam is an option (as is monotherapy with a fluoroquinolone) for patients who have comorbid illness, recent antibiotic therapy or other risks for DRSP, but as mentioned above, the β-lactam is not used empricially as monotherapy, but must be combined with a macrolide or doxycycline (Mandell et al., 2007). Recommended oral β-lactams for these patients are ampicillin (1 g three times daily), amoxicillin–clavulanate 2 g twice daily, cefpodoxime and cefuroxime. In some practice settings therapy can be given initially to outpatients with intravenous ceftriaxone. If an oral β-lactam is used for a patient who is not at risk for DRSP infection, the new ATS/IDSA CAP guidelines also allow for therapy with cefdinir, cefditoren or cefprozil. In the British Thoracic Society (BTS) recommendations, outpatient therapy can be given with amoxicillin alone and quinolones are not recommended, while in the European Respiratory Society (ERS) recommendations, outpatient therapy can be with amoxicillin monotherapy (British Thoracic Society, 2001; Woodhead et al., 2005). Inpatients

Inpatient therapy is divided into therapy for those admitted to the hospital without severe CAP, and those admitted to the ICU. In North American Guidelines, for those admitted to the hospital, β-lactam therapy can be used, along with a macrolide, as an alternative to a fluoroquinolone for patients with comorbid illness or with risk factors for DRSP. The recommended β-lactams are cefotaxime, ceftriaxone, ampicillin and ertapenem (for selected patients at risk for Gram-negative CAP) (Mandell et al., 2007). The ICU population is divided into those at risk for pseudomonal pneumonia and those who are not, with the risk factors being: structural lung diseases, such as bronchiectasis; repeated exacerbations of severe COPD leading to frequent steroid and/or antibiotic use, or recent antibiotic therapy. For those admitted to the ICU, and not with risk factors for P. aeruginosa, recommended therapy is a β-lactam (cefotaxime, ceftriaxone, ampicillin–sulbactam) with a macrolide or quinolone. For penicillin-allergic patients, therapy should be aztreonam plus a respiratory quinolone (levofloxacin or moxifloxacin). For the ICU patient at risk for P. aeruginosa infection, therapy should be with an antipseudomonal β-lactam (cefepime, imipenem, meropenem, piperacillin–tazobactam) plus ciprofloxacin or levofloxacin or alternatively an aminoglycoside plus a respiratory quinolone or macrolide. For penicillin allergic patients, therapy should be with aztreonam plus levofloxacin or aztreonam plus an aminoglycoside plus a macrolide or moxifloxacin.

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The recommendations from the BTS and the ERS are similar to the North American guidelines, with a few exceptions (British Thoracic Society, 2001; Woodhead et al., 2005). The BTS guidelines allow for β-lactam monotherapy out of the ICU, and cefuroxime is one of the recommended β-lactams. For non-ICU patients, the ERS recommendations allow for oral β-lactam therapy, have cefuroxime as a recommended agent, and make macrolide combination optional. In the ICU admitted patient the ERS recommendations are similar to the North American therapy options, while the BTS recommendations do not allow for monotherapy, but also do not specifically recommend pseudomonal therapy.

Other Controversies in the Use of β-Lactams for Community-Acquired Pneumonia Monotherapy vs Combination Therapy for Pneumococcal Bacteremia The role of combination therapy for all patients with CAP has already been examined, but there are also data to suggest that combination therapy may have a particular role in reducing the mortality of CAP patients with documented pneumococcal bacteremia. One of the earliest studies evaluated a 20-year experience with pneumococcal bacteremia in a single geographical location and included 328 adults, with the group as a whole having a mortality rate of 20.3 %. However, those older than age 50 who were treated with a macrolide, combined with a penicillin or cephalosporin, had the lowest case fatality rate of only 6 % (Mufson and Stanek, 1999). Waterer et al. (2001) conducted a retrospective review of 225 patients with pneumococcal bacteremia, and observed that 99 received single effective therapy, 102 dual effective therapy and 24 received more that dual effective therapy. Even though multiple drugs were given to sicker patients as reflected by the Acute Physiology and Chronic Health Evaluation (APACHE) score and the PSI, the odds ratio for death was threefold higher for those who received single effective therapy. Those who got dually effective therapy generally received a β–lactam plus either a macrolide or quinolone. The mechanism for benefit of combination therapy remained unclear from the data analysis, with possibilities being atypical pathogen coverage in the setting of co-infection, synergistic effects of the two drugs, or an anti-inflammatory effect of macrolide therapy. Three other studies have also shown benefit of combination therapy for pneumococcal bacteremia (Weiss and Tillotson, 2005). In one study that retrospectively analysed prospectively collected data from a multicentre study, combination therapy had no impact on the mortality rate of the 844 patients with pneumococcal bacteremia. However, when the 94 critically ill patients were examined, combination therapy dramatically reduced mortality from 55.3 % to 23.4 % (Baddour et al., 2004). When combination therapy was used, it was almost always with a β-lactam, but the second agents included macrolides, aminoglycosides, vancomycin, a quinolone, trimethoprim–sulphamethoxizole, chloramphenicol, or even a second

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β-lactam. The frequency of penicillin-resistance did not differ between those receiving monotherapy compared with those receiving combination therapy. A retrospective study from Spain looked at 409 patients with pneumococcal bacteremia of whom 238 received a β-lactam with a macrolide, while 171 received a β-lactam without a macrolide (64 % of these were as monotherapy), and found a reduction in mortality when a macrolide was added to a β-lactam (Martinez et al., 2003). The absence of a macrolide with a β-lactam increased the OR for death to 3.1 in a logistic regression analysis. However, as pointed out in the accompanying editorial, the findings do not make it clear that there is value in continuing dual therapy once the blood culture results are known, since the study only looked at outcomes in relation to initial empirical therapy (File and Mandell, 2003). In a smaller Canadian retrospective study, monotherapy with a β-lactam was associated with a higher mortality than combination therapy with a β-lactam and a macrolide (Weiss and Tillotson, 2005). In that study, the mortality was 26 % for the 42 patients who received monotherapy, compared with only 7.5 % for the 53 who receieved combination therapy. There was no impact of the presence of pneumococcal resistance on the observed outcomes. The problem with all of these findings is that the studies were retrospective database analyses and there was no existing protocol for when to use dual therapy in any of the experiences. In addition, as mentioned, the implications for continued therapy once blood culture results are known is unclear. However, since bacteremia may represent more severe illness than non-bacteremic illness, and especially because of the benefit of dual therapy in critically ill patients in one of the studies, it seems prudent to at least start with combination therapy, not using a β-lactam as monotherapy, for severely ill CAP patients.

Duration of Therapy Traditionally CAP has been treated for 7–14 days, with some patients with Legionella being treated for up to 21 days. In the new ATS/IDSA CAP guidelines, the recommendation is to treat patients for a minimum of 5 days, with at least 48–72 hours being afebrile (Mandell et al., 2007). Longer durations may be needed for patients with extrapulmonary infection and for those infected with MRSA or P. aeruginosa. Although most of the recent studies of short-duration therapy of CAP have involved quinolones, there have been some studies with β-lactams. In one recent study, 3-day therapy with intravenous amoxicillin was compared with 8-day therapy (IV then oral) in hospitalized patients, and the short-duration therapy was comparable to longer duration therapy for clinical success (El Moussaui et al., 2006). However, the study only included patients with mild–moderate illness, and patients only received short-duration therapy if they improved substantially with intravenous therapy by day 3, so they could be randomized to 5 days of oral placebo or oral amoxicillin. In fact, 38 of 186 patients enrolled had not improved enough by day 3 to be randomized to the intervention. Thus, we do not know optimal duration of therapy for patients who are slower to respond. However, it is interesting that prolonged therapy added no benefit in those with a good early response, possibly reflecting the rapid bactericidal effect of β-lactam therapy on

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common CAP pathogens. One correlate of these findings is that a hospitalized patient who becomes clinically stable with intravenous therapy could be safely discharged, without continued inpatient observation.

Summary β-lactams remain a mainstay in the therapy of CAP, and are a part of all guideline recommendations for outpatients, inpatients and even for those admitted to the ICU. The impact of in vitro pneumococcal resistance to outcomes of β-lactam therapy is uncertain, and may not be relevant except at high levels of resistance, which remain uncommon. Penicillin failures in pneumococcal pneumonia have been more difficult to identify than the occasional failures that have been observed with certain cephalosporins. The role of discordant β-lactam therapy for CAP outcomes is also uncertain and patient factors may be more important than drug selection in determining mortality risk. When β-lactams are used for CAP patients, a number of controversies remain, including whether these drugs should be used alone, or as part of a combination regimen, with or without a second agent that provides atypical pathogen coverage. Even in the setting of documented pneumococcal bacteremia, β-lactams may be most effective when used as part of a combination regimen. Finally, β-lactams have been particularly effective in CAP therapy because they are rapidly bactericidal to such pathogens as pneumococcus, and this may explain their ability to effectively treat pneumonia with therapy durations as short as 3 days.

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Niederman MS, Mandell LA, Anzueto A, et al. 2001. Guidelines for the management of adults with community-acquired lower respiratory tract infections: Diagnosis, assessment of severity, antimicrobial therapy and prevention. Am J Respir Crit Care Med 163: 1730–1754. Pallares R, Linares J, Vadillo M, et al. 1995. Resistance to penicillin and cehpalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain. N Engl J Med 333: 474–480. Peterson LR. 2006. Penicillins for treatment of pneumococcal pneumonia: Does in vitro resistance really matter? Clin Infect Dis 42: 224–233. Prins JM, van Agtmael MA, Kuijper EJ, van Deventer SJ, Speelman P. 1995. Antibioticinduced endotoxin release in patients with Gram-negative. urosepsis: a double-blind study comparing imipenem and ceftazidime. J Infect Dis 172: 886–891. Ruhe JJ, Hasbu R. 2003. Streptococcus pneumoniae bacteremia: Duration of previous antibiotic use and association with penicillin resistance. Clin Infect Dis 36: 1132–1138. Shefet D, Robenshtok E, Paul M, Leibovici L. 2005. Empirical atypical coverage for inpatients with community-acquired pneumonia: Systematic review of randomized controlled trials. Arch Intern Med 165: 1992–2000. Shorr AF, Bodi M, Rodriguez A, et al. 2006. Impact of antibiotic guideline compliance on duration of mechanical ventilation in critically ill patients with community-acquired pneumonia. Chest 130: 93–100. Siempos II, Vardakas KZ, Manta KG, Falagas ME. 2007. Carbapenems for the treatment of immunocompetent adult patients with noscomial pneumonmia. Eur Resp J 29: 548–560. Tleyjeh IM, Tlaygeh HM, Hejal R, Montori VM, Baddour LM. 2006. The impact of penicillin resistance on short-term mortality in hospitalized adults with pneumococcal pneumonia: A systematic review and meta-analysis. Clin Infect Dise. 42: 788–797. Turett GS, Blum S, Fazal BA, Justman JE, Telzak EE. 1999. Penicillin resistance and other predictors of mortality in pneumococcal bacteremia in a population with high human immunodeficiency virus seroprevalence. Clin Infect Dis 29: 321–327. Valles X, Marcos A, Pinart M, et al. 2006. Hospitalizad community-acquired pneumonia due to Streptococcus pneumoniae. Has resistance to antibiotics decreased? Chest 130: 800–806. Vanderkooi OG, Low DE, Green K, Powis JE, McGeer A, et al. 2005. Predicting antimicrobial resistance in invasive pneumococcal infections. Clin Infect Dis 40: 1288–1297. Vazquez EG, Mensa J, Martinez JA, et al. 2005. Lower mortality among patients with community-acquired pneumonia treated with a macrolide plus a beta-lactam agent versus a beta-lactam agent alone. Eur J Clin Microbiol Infect Dis 24: 190–195. Waterer GW, Somes GW, Wunderink RG. 2001. Monotherapy may be suboptimal for severe bacteremic pneumococcal pneumonia. Arch Intern Med 161: 1837–1842. Weiss K, TIllotson GS. 2005. The controversy of combination vs. monotherapy in the treatment of hospitalized community-acquried pneumonia. Chest 128: 940–946. Woodhead M, Blasi F, Ewig S, et al. 2005. Guidelines for the management of adult lower respiratory tract infectiosn. Eur Resp J. 26: 1138–1180. Yakolev SY, Stratchounski LS, Woods GL, et al. 2006. Ertapenem versus cefepime for initial empiric treatment of pneumonia acquired in skilled-care facilities or in hospitals outside the intensive care unit. Eur J Clin Microbiol Infect Dis 25: 633–641. ¨ Yu VL, Chiou CC, Feldman C, Ortqvist A, et al. 2003. An international prospective study of pneumococcal bacteremia: Correlation with in vitro resistance, antibiotics administered, and clinical outcome. Clin Infect Dis 37: 230–237.

9 Macrolides and Ketolides JAVIER GARAU Hospital Mutua de Terrassa, University of Barcelona, Spain

Introduction Erythromycin, the first macrolide antibiotic discovered, has been used extensively since the 1950s for the treatment of respiratory tract infections caused by susceptible organisms, especially in penicillin-allergic patients. Macrolide antibiotics were originally isolated from various Streptomyces spp., and can be synthesized by condensation of acetate, propionate and butyrate units. The final structure is characterized by a macrocyclic lactone ring attached to two or more sugar moieties. Fourteen-membered macrolides include erythromycin, oleandomycin, troleandomycin, dirithromycin, roxithromycin and clarithromycin. Fifteen-membered macrolides are represented by azithromycin, an azalide. Sixteen-membered macrolides include spiramycin, tylosin, josamycin, midecamycin, and rokitamycin. The spectrum and activity of these compounds are, in general, similar to erythromycin, but with important differences in activity, resistance to inactivation and pharmacological properties are observed for certain derivatives. Newer macrolide antimicrobials have been synthesized by altering the erythromycin base, resulting in compounds with improved pharmacokinetics and extended spectrums of activity. Two of these new advanced macrolides, clarithromycin and azithromycin, were approved for clinical use early last decade. Ketolides, a new class of macrolides, share many of the characteristics of the advanced macrolides. Additionally, their in vitro spectrum of activity includes Gram-positive organisms (Streptococcus pneumoniae, Streptococcus pyogenes), which are macrolide resistant. Telithromycin, specifically developed for the treatment of respiratory tract infections, and more recently cethromycin, are the first compounds of this class to be considered for clinical use. This chapter reviews the pharmacokinetics, antimicrobial activity, clinical use in respiratory tract infections and adverse effects of these antimicrobial agents, with emphasis in clarithromycin, azithromycin and telithromycin.

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Activity Mechanism of Action The macrolide antimicrobials exert their antibacterial effects by reversibly binding to the 50S subunit of the bacterial ribosome. They inhibit RNA-dependent protein synthesis at the step of chain elongation in susceptible prokaryotic organisms; erythromycin A bind to sequences on domain V of the 23S rRNA that is a component of the 50S subunit of the bacterial ribosome (Allen, 2002; Leclercq and Courvalin, 2002). That binding site is near the peptidyl transferase centre, and peptide chain elongation is thereby prevented by blocking of the polypeptide exit tunnel (Allen, 2002; Leclercq and Courvalin, 2002; Edelstein, 2004). Limited studies suggest that azithromycin, clarithromycin, and erythromycin bind to the same receptor on the bacterial 50S ribosomal subunit and inhibit RNA-dependent protein synthesis by the same mechanism (Allen, 2002; Piscitelli et al., 1992). Azithromycin has greater activity than the 14-member macrolides erythromycin and clarithromycin against Gram-negative bacteria (especially for Moraxella catarrhalis and Haemophilus influenzae) and therefore appears to better penetrate the outer envelope of those organisms. Depending on drug concentration, microbial species, phase of growth and inoculum density, macrolides are bacteriostatic or bactericidal. Bacterial killing is favoured by higher antibiotic concentrations, lower bacterial density and rapid growth; bactericidal activity is easily demonstrated in vitro against such species as S. pyogenes, S. pneumoniae and H . influenzae. Due to the better penetration of non-ionized drugs through the bacterial cell wall, the activity of the weak base macrolides is increased with alkaline pH.

Spectrum of Activity The antibacterial activity of erythromycin is mainly directed against Gram-positive bacteria, including staphylococci, streptococci, corynebacteria, Listeria monocytogenes, some Erysipelothrix rhusopathiae, Bacillus spp. and certain species of Clostridium, Actinomyces and Mycobacterium. Its Gram-negative spectrum includes Neisseria gonorrhoeae, Neisseria meningitidis, Brucella, Campylobacter, Bacteroides spp. Legionella, Mycoplasma spp., Chlamydia, Rickettsiae and treponemes. Table 9.1 lists the common pathogens implicated in community respiratory diseases and corresponding susceptibility data for each drug. Clarithromycin has equal or better activity against Gram-positive organisms compared with erythromycin. The modal minimum inhibitory concentration (MIC) values for macrolide-susceptible strains of S. pneumoniae are 0.03–0.06 µg/mL for clarithromycin, 0.06 µg/mL for erythromycin and 0.12 µg/mL for azithromycin. The Clinical and Laboratory Standards Institute (CLSI) MIC interpretative criteria for macrolides versus S. pneumoniae for erythromycin and clarithromycin are: S ≤ 0.25; I, 0.5; R ≥ 1 µg/mL. The MICs are generally two- to fourfold lower against most streptococcal and methicillin-sensitive Staphylococcus aureus. Azithromycin is two- to fourfold less active than erythromycin against these Gram-positive organisms but the MICs are

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Table 9.1 In vitro susceptibilities to macrolides of selected respiratory pathogens (Sources: Barry et al., 1988; Hardy et al., 1992; Inderlied et al., 1993; Maurin et al., 1993; Zuckerman, 2004) Organism Streptococcus pneumoniae Pen S Pen I Pen R Streptococcus pyogenes Staphylococcus aureus Corynebacterium diphtheriae Moraxella catarrhalis Haemophilus influenzae Bordetella pertussis Neisseria meningitidis Mycoplasma pneumoniae Chlamydia trachomatis Chlamydophila pneumoniae Legionella pneumophila Coxiella burnetii Mycobacterium avium-intracellulare

Erythromycin MIC90

Clarithromycin MIC90

Azithromycin MIC90

1.0 > 64 > 64 0.06 > 128 0.02 0.25 8 0.06 1 ≤ 0.01 0.12 0.25 0.5 >8 ND

0.25 > 64 > 64 0.06 > 128 0.006 0.25 16 0.06 0.5 < 0.01 < 0.01 < 0.01 0.04 2–4 4–8

1.0 > 64 > 64 0.25 2.0 0.05 0.06 2.0 0.06 1.0 < 0.01 0.25 0.25 0.5 ND 32

still within achievable therapeutic levels. Streptococci and staphylococci that are resistant to erythromycin are also resistant to clarithromycin and azithromycin. The newer macrolides have enhanced activity against Gram-negative organisms. Azithromycin is the most active of these agents against H. influenzae, with a MIC four- to eightfold lower than erythromycin. On the other hand, the existence of efflux pumps leads to loss of susceptibility to macrolides in more than 98 % of H. influenzae strains (Peric et al., 2003). It appears that the vast majority (> 98 %) of H. influenzae strains have a macrolide efflux mechanism, with a few of these being hyperresistant (1.3 %) due to one or several ribosomal mutations. Occasional hypersusceptible strains (1.8 %) are found without any underlying mechanism of resistance appeared to be the only truly macrolide-susceptible variants of H. influenzae. Clarithromycin appears more active than azithomycin and erythromycin in vitro against Legionella pneumophila and Chlamydia pneumoniae, whereas azithromycin demonstrates better activity against Moraxella catarrhalis and Mycoplasma pneumoniae. Clarithromycin is approximately 10-fold more active than erythromycin against Chlamydia trachomatis, whereas azithromycin activity is similar to that of erythromycin. Clarithromycin and azithromycin have little activity against Mycobacterium tuberculosis but demonstrate good activity against other Mycobacterium species. Clarithromycin’s MIC90 against M. avium complex (MAC) is 4–8 µg/mL, significantly lower than azithromycin (MIC90, 32 µg/mL). Despite the high MIC of azithromycin, it still plays a role in treating MAC infections because high levels of drug accumulate in macrophages. However, macrolide-resistant populations of

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M. avium emerge frequently after treatment of experimentally infected beige mice with clarithromycin or azithromycin (Bermudez et al., 1998).

Resistance Mechanisms Macrolide-resistance in S. pneumoniae occurs by two main mechanisms: targetsite modification or efflux of the drug out of the cell. In the most common form of target-site modification, a specific adenine residue on the 23S rRNA (A2058) is dimethylated by an rRNA methylase. The predominant methylase responsible for macrolide-resistance in S. pneumoniae is encoded by erm(B). This methylation is thought to lead to conformational changes in the ribosome resulting in decreased binding of all macrolide, lincosamide and streptogramin antibacterials (the so-called MLSB phenotype) (Roberts et al., 1999; Leclercq et al., 2002; Edelstein, 2004). Pneumococci harbouring erm(B) gene exhibit high to very high levels of resistance to all macrolides with MIC90 of both clarithromycin and azithromycin of 256 µg/mL or more. Other genotypes responsible of target modification as erm(A) subclass erm(TR), common in S. pyogenes, have also recently been reported in S. pneumoniae (Brown et al., 2004). Macrolide efflux is mediated by the product of the mef (A) gene, which usually causes MICs lower than the erm(B) isolates (MICs of 1–32 µg/mL) and retain susceptibility to clindamycin (the so-called M-phenotype) (Leclercq et al., 2002; Edelstein, 2004). The acquisition of both a methylase and an efflux mechanism in the same strain has been also described (Farrell et al., 2004a). An increasing number of erythromycin resistant isolates, either obtained in vitro after serial passages in macrolide-containing media or found in clinical isolates that lack mef (A) or erm(B) genes are being recognized. Mutations at different positions in domains V and II of 23S rRNA and in genes that encode the ribosomal proteins L4 and L22 have been identified in such strains (Farrell et al., 2004b). On the other hand, and as mentioned above, the existence of efflux pumps leads to loss of susceptibility to macrolides in more than 98 % of H. influenzae strains (Peric et al., 2003). It appears that the vast majority (> 98 %) of H. influenzae strains have a macrolide efflux mechanism, with a few of these being hyperresistant (1.3 %) due to one or several ribosomal mutations. Macrolide-resistant M. pneumoniae mutants can easily be selected in vitro (Stopler et al., 1980; Lucier et al., 1995; Okazaki et al., 2001); such mutants typically exhibit the macrolide–lincosamide–streptogramin B (MLSB) type resistance, rendering lincosamines and streptogramin B inactive in addition to all macrolides. Macrolide resistance can occur due to point mutations leading to A-to-G transitions in the peptidyl transferase loop of domain V of the 23S rRNA gene at positions 2063 and 2064, which reduces the affinity of these antibiotics for the ribosomes (Lucier et al., 1995; Okazaki et al., 2001). The likelihood of M. pneumoniae developing resistance to macrolides by this mechanism under natural conditions may be enhanced, since there is only a single rRNA operon in the M. pneumoniae genome (Gobel et al., 1984). This may be taking place in Japan. Although resistance to erythromycin was observed many years ago in a few M. pneumoniae strains, when the investigation

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of macrolide resistance among ca. 300 isolates was carried out in Japan from 1983 to 1998, no erythromycin-resistant strain was found among them (Matsuoka et al., 2004). In contrast, in a recent Japanese study, ca. 20 % of M. pneumoniae strains isolated from patients from 2000 to 2003 were found to be erythromycinresistant (Matsuoka et al., 2004). Of 76 strains of M. pneumoniae isolated in three different areas in Japan during 2000 to 2003, 13 (17 %) strains were erythromycinresistant, most highly resistant (MIC, ≥ 256 µg/mL); 10 strains had an A-to-G transition at position 2063 in domain V of 23S rRNA, indicating that transition is the predominant type of mutation in M. pneumoniae (Matsuoka et al., 2004). Within Legionella species, strains with low-level resistance to erythromycin have been described (MIC values between 0.5 and 8 µg/mL) (Nielsen et al., 2000). The prevalence of these strains differs between the few studies available. Some studies report no resistant strains; perhaps, the fact that some investigators use breakpoints ≤ 1 µg/mL for susceptible strains accounts for this discrepancy. With selection experiments, development of resistance to erythromycin is possible, and strains with MIC values up to 256 µg/mL have been produced, and not confined to one species (Dowling et al., 1985). Whether the presence of low-level resistance to erythromycin has any clinical significance is unclear. The ease with which erythromycin-resistant strains (some with high-level of resistance) have been obtained on exposure to modest concentrations of the antibiotic raises the possibility that resistant strains could be selected during patient therapy (Nielsen et al., 2000).

Clinical Pharmacology Pharmacokinetics Table 9.2 provides pharmacokinetic data for macrolides based on serum concentrations (Kees et al. 1990; Dunn and Barradell., 1996; Alvarez-Elcoro and Enzler, 1999). Excellent tissue and body penetration is the hallmark of macrolides except for cerebrospinal fluid. Clarithromycin is well absorbed after oral administration, and Table 9.2 Comparative pharmacokinetics of macrolides (Adapted from: Kees et al.,1990; Foulds et al., 1991; Piscitelli et al., 1992; Dunn and Barradell, 1996; Alvarez-Elcoro and Enzler, 1999; Zhanel et al., 2001) Erythromycin Clarithromycin Azithromycin 500 mg 500 mg 500 mg Cmax (µg/mL) Tmax (hours) T1/2 (hours) AUC0 – 24 (mg/L × hours) Bioavailability (%)

0.3–2 3–4 2–3 8 25

2.1–2.4 2 3–5 12.1 55

0.4 2 40–68 4.5 37

Cmax , peak serum concentration; Tmax , time to peak serum concentration; T1/2 , serum half-life; AUC, area under plasma concentration time curve.

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is approximately 50 % bioavailable (Piscitelli et al., 1992). When taken with meals the bioavailability of clarithromycin is increased up to 25 %. Mean peak serum concentrations in the steady state with oral doses of 250 and 500 mg every 12 hours are 1 and 2–3 µg/mL, respectively. The elimination half-life of clarithromycin of 4–5 hours necessitates twice-daily dosing. Clarithromycin is appreciably metabolized in the liver; the major metabolite, 14-hydroxyclarithromycin, has antibacterial activity and accounts for 20 % of the metabolites (Piscittelli et al., 1992). Clarithromycin serum protein binding is approximately of 65–70 %. In the presence of renal insufficiency with creatinine clearances of less than 30 mL/minute, there is a marked increase in half-life of clarithromycin (Hardy et al., 1992). Dose adjustment is necessary for patients in severe renal failure, including recommendations for a 500-mg loading dose followed by 250 mg once or twice daily depending on the type of infection being treated (Hardy et al., 1992). In chronic liver disease, when severe, there is an increase in the renal clearance of clarithromycin associated with a decrease in metabolic clearance, to the extent that no dosage adjustment is recommended at present (Hardy et al., 1992). Concentrations of clarithromycin and its 14-hydroxy metabolite in middle ear fluids of children with acute otitis media exceeded the plasma concentrations several-fold. Concentrations generally exceed the MIC of most strains of middle ear pathogens. Available is an extended-release dosage form of clarithromycin, which achieves a peak of 2.5 lg/mL and half-life of 1216 hours, to provide sufficient drug exposure with once-daily dosing (Guay et al., 2001). The oral bioavailability of azithromycin after a single 500-mg dose is 37 % (Schentag and Ballow, 1991). Food decreases the absorption by 50 %; therefore, the dose should be taken at least 1 hour before or 2 hours after a meal (Hopkins, 2001). The drug should not be taken simultaneously with magnesiumor aluminium-containing antacids, which decrease the rate of absorption and therefore the peak serum concentration but do not change the extent of absorption (i.e., the area under the curve, AUC) (Foulds et al., 1991). The peak serum concentration following a single 500-mg oral dose is approximately of 0.4 µg/mL; protein binding of azithromycin in serum varies between 7 % and 50 % depending on the drug concentration (Piscitelli et al., 1992). Azithromycin is widely distributed in tissues, and for most the drug concentration exceeds that in serum by 10- to 100-fold (Schentag and Ballow, 1991), particularly in sputum and lung. Very high concentrations can be found in alveolar macrophages and neutrophils (Ballow et al., 1992). The average half-life in many tissues is between 2 and 4 days (Schentag and Ballow, 1991) so that it is estimated that significant antibacterial activity against many pathogens persists in tissue for at least 5 days after a 5-day course of treatment (Schentag and Ballow, 1991). The average terminal half-life is 68 hours, consistent with a slow release of drug from tissues followed by elimination from the vascular compartment. The serum elimination of azithromycin is particularly slow. This is presumably because of the slow efflux of azithromycin from the cellular compartment into extracellular fluid (Johnson et al., 1990). Because of the slow and sustained release of azithromycin, once-daily dosing and shorter 5-day treatment regimens have been used. Azithromycin elimination is primarily in the

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faeces by way of biliary excretion and urinary excretion is minimal. Dosing modifications do not appear to be necessary in patients with mild or moderate hepatic impairment. The newer macrolides penetrate extensively into mammalian tissue, especially pulmonary tissue. This property has made these agents particularly useful in respiratory tract infections. The epithelium lining fluid (ELF) and alveolar macrophages (AM) represent sites in the lung where extracellular bacteria and intracellular pathogens reside, respectively. In ELF, clarithromycin achieves significantly higher concentrations relative to serum, with ratios ranging from 11 to 31 (Patel et al., 1996). Azithromycin and erythromycin also penetrate into ELF, although to a much lesser degree than clarithromycin (Conte et al., 1995; Patel et al., 1996). Clarithromycin, erythromycin and azithromycin all concentrate intracellularly; however, a much greater degree of penetration into AM relative to serum is observed with clarithromycin and azithromycin.

Pharmacodynamics There is no consensus among investigators as to which pharmacodynamic parameter best correlates with antimicrobial efficacy for macrolides. In general, macrolides, but not azithromycin, have been categorized as time-dependent agents (Gladue et al., 1989). Studies have suggested that 50 % teicoplanin (T) greater than MIC should be sufficient in immunocompetent patients (Khair et al., 1992; MullerSerieys et al., 2001). Evaluation of erythromycin pharmacodynamics using a murine infection model (Novelli et al., 2002) supports that %T greater than MIC is the important pharmacodynamic parameter for efficacy. In contrast, evaluation of azithromycin in a pneumococcal mouse peritonitis model showed a trend for increased survival with less frequent administration. In an in vitro pharmacokinetic model by the same investigators, peak drug concentration was most predictive of success (Hardy et al., 1992). Interdependence among the pharmacodynamic parameters seems to exist for clarithromycin. All three pharmacodynamic parameters evaluated (peak-MIC, AUC-MIC and %T greater than MIC) correlated closely with reduction in bacterial density and with survival.

Epidemiology of Macrolide Resistance Macrolide resistance is particularly frequent in penicillin-resistant pneumococci and has been detected at a variable rate in different epidemiological settings, with a clear trend toward increasing resistance in many parts of the world, putting into question the efficacy of these agents in the treatment of pneumococcal pneumonia. Macrolide resistant pneumococci remained rare until the last decade when resistance rates rose to levels of approximately 27 % in the USA. In the past 5 years, macrolide resistant rates seem to have stabilized and currently exist at an overall rate of approximately 30 %. In Europe (Figure 9.1) there is a great difference of resistance rate in the different countries. In the northern European countries, resistance among invasive isolates is less than 5 %. In contrast, in France, Italy,

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Figure 9.1 Prevalence of resistance to erythromycin among invasive Streptococcus pneumoniae isolates in Europe in 2005: LU, Luxembourg; MT, Malta. (From European Antimicrobial Resistance Surveillance (EARSS): http://www.rivm.nl/earss/)

Spain, the resistance rates have been found to be as high as 30 %. Two-thirds of macrolide resistant strains in the USA have mef (A)- mediated efflux as the resistance mechanism; the remaining 30–40 % are of the MLSB phenotype as a result of harbouring the erm gene. These differences likely reflect the result of different profiles of antibiotic use and differing circulating clones in different countries. There is an increase of erm(B)-positive isolates of pneumococci that are also mef positive. Thus, today, in the USA, nearly half of erm(B)-positive isolates also harbour the mef (A) gene. Macrolide resistance, like β-lactam and multidrug resistance with pneumococci, occurs most frequently among isolates from paediatric patients and in certain geographical areas. The different macrolides are distinguishable from one another in terms of their likelihood of promoting the emergence of macrolide resistance with pneumococci and further, among the macrolides, azithromycin usage has been most responsible for the emergence of macrolide resistance. As mentioned above, macrolide-resistant M. pneumoniae strains have been increasingly recognized in Japan since early this decade. A recent report indicates that of a total of 195 M. pneumoniae strains collected between 2002 and 2004

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from paediatric outpatients with respiratory tract infections, 12 strains showed highlevel resistance to erythromycin, clarithromycin and azithromycin with MICs of ≥ 32 µg/mL (Morozumi et al., 2005); interestingly enough, MICs of telithromycin, josamycin and midecamycin ranged from 2 to ≥ 64 µg/mL. Thus, macrolideresistant M. pneumoniae is spreading in Japan. Studies of susceptibility of M. pneumoniae to macrolides in other parts of the world are urgently needed.

The Clinical Significance of Macrolide Resistance Despite the numerous reports of resistance, there is limited information on the clinical relevance of macrolide resistance. Also, some authors have debated the clinical relevance of macrolide resistant pneumococci. For example, Amsden (1999) in a recent review stated that in vitro resistance is not a problem because macrolides and azalides achieve high intracellular concentrations,. Dixon (1967) reported the first case of a patient infected with a macrolide resistant pneumococcus that failed to respond to macrolide therapy. In the past 15 years, there have been an increasing number of reports of macrolide treatment failure for pneumococcal infections with macrolide-resistant isolates. Sanchez et al., (1992) reported two patients with pneumonia who failed to respond to erythromycin. Needle aspiration of the lung grew a macrolide-resistant pneumococcus. Both patients were treated with a -lactam antibiotic and improved. Lonks et al., (1993) reported that a young man, 32 years of age, who while taking oral erythromycin for lobar pneumonia presented to the hospital because he was getting worse. Blood cultures grew an erythromycin-resistant pneumococcus. Recently, there have been reports of breakthrough bacteremias in patients taking azalides as well as macrolides. Fogarty et al., (2000) reported that three patients who failed to respond to azithromycin had breakthrough bacteremia. Kelley et al., (2000) reported the clinical failure of oral azithromycin in three patients and oral clarithromycin in one patient. Five of the seven isolates had the M phenotype; one isolate was available for genotyping and contained the mef gene. These reports are, however, anecdotal and do not prove that the clinical failures were due to the antibiotic resistance. Breakthrough bacteremias may have occurred because of non-compliance in taking the antibiotic or poor absorption. Although it is not surprising that highly resistant strains (MIC, ≥16 mg/mL) may lead to clinical failure, the relevance of low-level resistance (MIC, 0.5–8 mg/ mL) has been brought into question. A matched case-control study of patients with bacteremic pneumococcal infections investigated whether development of breakthrough bacteremia during macrolide treatment was related to macrolide susceptibility of the isolate (Lonks et al., 2002). Breakthrough bacteremia with an erythromycin resistant isolate occurred in 18 (24 %) of 76 patients taking a macrolide compared with none of the 136 matched patients with bacteremia with an erythromycin-susceptible isolate. These results establish that macrolide resistance among pneumococci is a cause of failure of outpatient pneumonia therapy.

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A more recent population-based case-control study from Toronto confirms these results (Daneman et al., 2006). Macrolide resistance contributes to an increased risk of macrolide failure, irrespective of the underlying resistance mechanism or of the degree of elevation in erythromycin MIC. Therefore, it would be wise to avoid empirical macrolide therapy when a patient is at risk of being infected with a macrolide-resistant pathogen, either as a result of patient-specific characteristics or the overall rate of resistance in the community. Clinical parameters associated with macrolide resistance among pneumococci include macrolide exposure within the previous 3 months, recent use of a penicillin or trimethroprim–sulphamethoxazole, extremes of age, HIV infection and exposure to siblings colonized with resistant isolates (Doern, 2006).

Adverse Effects and Drug Interactions Adverse reactions to clarithromycin and azithromycin are rare. Gastrointestinal intolerance (diarrhoea, nausea, abdominal pain) is the primary adverse side effect of these agents, but occurs at a significantly reduced rate when compared with erythromycin. Abnormalities in liver function are occasionally encountered in patients treated with these drugs, and reversible cholestatic hepatitis has been reported with azithromycin (Chandrupatla et al., 2002). With the high doses of these drugs used in the treatment of M. avium complex, tinnitus, dizziness and reversible hearing loss have been reported (Wallace et al., 1992; Kolkman et al., 2002). Rarely, severe allergic reactions have occurred with the use of azithromycin. The risk of macrolide-associated torsade de pointes has been associated with increasing age, female sex and concomitant drug use, especially with cisapride (Shaffer et al., 2002). Acute psychosis or ‘mania’ has been reported in patients receiving clarithromycin (Cone et al., 1996). Adverse events related to the intravenous infusion of azithromycin were pain at the injection site (6.5 %) and local inflammation (3.1 %) (Garey and Amsden, 1999). Clarithromycin and azithromycin, like erythromycin, may occasionally lead to digoxin toxicity (Guerriero et al., 1997). Clarithromycin, like erythromycin, is oxidized by the cytochrome P-450 system, primarily the CYP3A4 subclass of hepatic enzymes; this interaction inhibits the CYP3A4 enzymes resulting in decreased clearance of other agents given concurrently that are metabolized by the same enzyme system; azithromycin interferes poorly with this system (Westfal, 2000). The concurrent use of cisapride, pimozide, terfenadine and astemizole with clarithromycin is contraindicated because of the possible cardiotoxic effects of these agents and the occurrence of torsade de pointes. Other medications, such as benzodiazepines, statins such as lovastatin, simvastatin and atorvastatin, class 1A antiarrhythmic agents (quinidine, disopyramide), theophylline, carbamazepine, warfarin, ergots and cyclosporine should be used cautiously when given with clarithromycin. These drug–drug interactions are less likely to occur with azithromycin because it is not a potent inhibitor of the CYP3A enzymes.

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Clinical Uses in Respiratory Tract Infections Lower Respiratory Tract Infections Numerous randomized trials have demonstrated the efficacy of erythromycin, clarithromycin and azithromycin for treatment of lower respiratory tract infections, including acute bronchitis, acute exacerbation of chronic bronchitis (AECB) and community-acquired pneumonia (CAP). Erythromycin administered orally is poorly tolerated because of gastrointestinal side effects; therefore, the more expensive macrolides, azithromycin and clarithromycin are often used instead. Most of the studies involved patients who were not hospitalized.

Community-Acquired Pneumonia Comparative trials for the outpatient treatment of CAP have shown equivalent efficacy between clarithromycin, 500 mg twice a day for 10 days and moxifloxacin, and clarithromycin extended-release tablets (two 500 mg tablets once daily for 7 days) and levofloxacin or trovafloxacin (Hoeffken et al., 2001; Gotfried et al., 2002; Sokol et al., 2002). Comparable efficacy has also been shown between the once-daily dosing of the extended-release formulation of clarithromycin and the twice-daily dosing of the immediate-release formulation for the treatment of lower respiratory tract infections (Adam et al., 2001; Allin et al., 2001). In two comparative studies, azithromycin (500 mg daily for 3 days) was as efficacious as clarithromycin (250 mg twice a day for 10 days) in the treatment of patients with lower respiratory tract infections (Bradbury, 1993; O’Doherty et al., 1998). A meta-analysis of randomized controlled trials of azithromycin compared with other antibiotics showed superior efficacy in the treatment of CAP (ContopoulosIoannidis et al., 2001). Azithromycin and clarithromycin have also been shown to be effective in the treatment of CAP in patients requiring hospitalization (Plouffe et al., 2000). Monotherapy with intravenous azithromycin was equally as effective as cefuroxime plus or minus erythromycin followed by their oral equivalents to complete a 7- to 10-day course of therapy (Vergis et al., 2000). The recommended dose of intravenous azithromycin for the treatment of CAP is 500 mg daily for at least 2 days followed by oral azithromycin, 500 mg daily, to complete a 7- to 10-day course. Legionella pneumophila pneumonia is susceptible in vitro to the macrolides. The ability of this class of antimicrobials to concentrate intracellularly makes them effective in the treatment of this condition. Erythromycin was the most effective antimicrobial in the treatment of Legionnaire‘s disease in the historical outbreak in Philadelphia more than 30 years ago (Fraser et al., 1977). In a non-comparative trial, clarithromycin (500 to 1000 mg twice a day for 14 to 35 days) was effective in 43 of 44 patients with Legionella pneumonia (Hamedani et al., 1991). Azithromycin has demonstrated superior results in an animal model

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of that infection (Fitzgeorge et al., 1991) Azithromycin successfully treated 96 % (22 of 23) of patients hospitalized with L. pneumonia with a mean total duration of antibiotic therapy (intravenous plus oral) of 8 days (Pflouffe et al., 2003). It is the preferred macrolide for this indication and the suggested dose for this condition for adults is 500 mg orally or intravenously for 5 to 15 days (Stout and Yu, 1997). For infections caused by M. pneumoniae or Chlamydia psittaci, azithromycin is equivalent to erythromycin (Sch¨onwald et al., 1990). Macrolides are a good alternative to tetracyclines in the treatment of other intracellular bacteria including C. pneumoniae; azithromycin eradicates C. pneumoniae from the nasopharynx of adults and children with pneumonia in 70 % (7 of 10) and 83 % (19 of 23), respectively (Roblin and Hammerschlag, 1998); iti is also effective in C. burnetii infection (Gikas et al., 2001). Outpatient therapy in the Infectious Diseases Society of America (IDSA) guidelines for patients who have not received antibiotics within the previous 3 months includes any macrolide (erythromycin, azithromycin, or clarithromycin) for previously healthy individuals (Mandell et al., 2007). In the European guidelines, newer macrolides are only considered in the case of hypersensitivity as good alternatives in countries with low pneumococcal macrolide resistance (Woodhead et al., 2005). Azithromycin monotherapy is no longer recommended by the IDSA/ATS (American Thoracic Society) guidelines for hospitalized patients. The generally recommended empirical therapy for community-acquired pneumonia requiring hospitalization includes the combination of a macrolide and a β-lactam; this recommendation is based on observational studies that indicated that treatment with this combination as the initial regimen is associated with a reduced length of stay and a lower mortality than treatment with a cephalosporin alone (Gleason et al., 1999; Houck et al., 2001). In addition, several retrospective studies have consistently shown that in cases of bacteremic pneumococcal pneumonia, dual antimicrobial therapy, including a macrolide, reduce mortality (Mufson and Staneket al., 1999; Waterer et al., 2001; Martinez et al., 2003). However, other contemporaneous studies have not shown any survival advantage (Harbarth et al., 2005; Dwyer et al., 2006) using this combination. The possible benefit of adding a macrolide to a β-lactam agent in the treatment of bacteremic pneumococcal pneumonia may result from several factors, including antimicrobial synergism, macrolide-induced attenuation of cytokine production (Aoki and Kao, 1999), diminished adherence of pneumococci to respiratory epithelial cells, inhibition of the production of pneumolysin even in the setting of macrolide resistant strains (Anderson et al., 2007), and the coexistence of atypical pathogens. However, in vitro studies have not shown antimicrobial synergism (Lin et al., 2003), and have demonstrated in vitro and in vivo in the animal model antagonism between penicillin and erythromycin against S. pneumoniae, possibly caused by the inhibitory activity of erythromycin on the growth rate of the bacteria, attenuating the bacterial activity of penicillin (Johansen et al., 2000). It is clear that the issue is not settled and independent prospective, randomized studies are urgently needed for hospitalized patients with severe CAP.

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Acute Exacerbation of Chronic Bronchitis Clinical cure rates for the treatment of AECB have been found to be similar between a 10-day course of clarithromycin, levofloxacin or cefuroxime axetil, and also between a 7-day course of extended-release tablets of clarithromycin or amoxicillin–clavulanic acid (Weiss, 2002; Martinot et al., 2001; Anzueto et al., 2001). In a comparative trial between 5 days of gemifloxacin and 7 days of clarithromycin for the treatment of AECB, clinical and bacteriological cures were similar but significantly more patients in the gemifloxacin group remained free of AECB recurrences (Wilson et al., 2002). A meta-analysis of randomized controlled trials of azithromycin compared with other antibiotics showed comparable clinical cures in the treatment of acute bronchitis and AECB (Contopoulos-Ioannidis et al., 2001). A recent trial demonstrated equivalent efficacy between a 5-day course of azithromycin and a 7-day course of levofloxacin for the treatment of AECB (Amsden et al., 2003). An alternative regimen for the treatment of AECB is 500 mg daily for 3 days.

Pertussis Bordetella pertussis is susceptible in vitro to erythromycin, azithromycin and clarithromycin (Hoppe and Bryskier, 1998). The purpose of antibiotic therapy for pertussis is to eradicate the bacteria from the nasopharynx; therapy does not substantially alter the clinical course unless given early in the catarrhal phase of the disease. the American Academy of Pediatrics recommends erythromycin as the antimicrobial agent of choice for treatment of and prophylaxis against pertussis (Pickering, 2000). In adults, clarithromycin, 500 mg bid for seven days or azithromycin, 500 mg on day one and 250 mg subsequently for 5 days have been recommended as alternatives to erythromycin. Cystic fibrosis, bronchiectasis. Macrolides have both antibacterial and immuno modulatory properties. Macrolides have less marked immunosuppressive properties than corticosteroids, and effects include decreasing mucous production, inhibiting virulence factors and biofilm formation of P. aeruginosa, decreasing leukocyte numbers and altering inflammatory mediator release (King, 2007). Macrolides have been shown to be very effective in the treatment of diffuse panbronchiolitis in Japan and the results are very reproducible; some studies show improvement of lung function and symptoms in cystic fibrosis (CF) (Nguyen et al., 2007). They can have a role in the treatment of bronchiectasis. Results of a double-blind, placebocontrolled trial of low-dose, long-term erythromycin (500 mg bid for 8 weeks) showing improvement in patients with bronchiectasis has been published (Tsang et al., 1999). In 11 patients who received erythromycin, forced expiratory volume (FEV) 1 and forced vital capacity (FVC) increased while sputum volume over 24 hours decreased significantly compared with those receiving placebo. The data obtained from cystic fibrosis and bronchiectasis, however, although positive, have been highly variable to date and more research needs to be conducted.

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Mycobacterium Avium-Intracellulare Complex Clarithromycin and azithromycin have been shown to be effective in preventing and treating disseminated M. avium complex disease in HIV infected patients. Azithromycin is effective as prophylaxis against disseminated M. avium complex disease in patients with CD4 counts less than 100 cells/mm3 . Compared with placebo, a 1200-mg weekly dose decreased the incidence of disseminated M. avium complex from 24.7 % to 10.6 % (Oldfield et al., 1998). However, the use of the macrolides alone is often associated with clinical relapse and the emergence of macrolide-resistant organisms (Chaisson et al., 1994). Clarithromycin (500 mg orally twice daily) or azithromycin (500 mg orally once daily) in addition to ethambutol with or without rifabutin should be considered the drugs of choice in the treatment of disseminated M. avium complex infections in patients with AIDS. US Public Health Service–IDSA guidelines recommend azithromycin, 1200 mg weekly, or clarithromycin, 500 mg twice a day, as the preferred regimens for M. avium complex prophylaxis in HIV-infected individuals with a CD4 count less than 50 cells/mm3 (Kaplan, et al., 2002).

Ketolides The ketolides, semisynthetic 14-membered ring macrolides represent a new subclass of agents in the macrolide–lincosamide–streptogramin group. The substitution of the L-cladinose sugar with a 3-keto group on the erythronolide A ring is the major differing structural component of the ketolides. This change confers greater acid stability and prevents induction of macrolidelincosamide–streptogramin B resistance (Douthwaite and Champney, 2001). Telithromycin is synthesized by cycling of the C11–12 positions to form a carbamate ring with an imidazo-pyridyl group attachment. The carbamate extension enhances binding to the bacterial ribosome and in vitro activity. Telithromycin, unlike the macrolides, has a greater affinity to bind to domain II of the 23S rRNA enabling it to maintain antimicrobial activity against bacterial strains that are macrolide resistant because of alterations in the domain V binding site (Douthwaite et al., 2000). Resistance by methylation of an adenine residue in domain V of the 23S rRNA is mediated by the erythromycin ribosome methylase (erm) genes. Methylation prevents binding of the macrolides and ketolides to domain V and results in highlevel macrolide resistance (MICs ≥64 mg/L). Ketolides presumably maintain their antimicrobial activity by virtue of their ability to bind to domain II of the 23S rRNA. This is perceived to be important since penicillin and macrolide nonsusceptible Streptococcus pneumoniae strains continue to increase in prevalence according to in vitro studies. Methylase may be either induced or constitutively expressed. Both clarithromycin and azithromycin can induce methylase production resulting in resistance. Telithromycin, however, does not induce methylase production. Ketolides show greater activity than clarithromycin and azithromycin against erythromycin-susceptible strains of S. pneumoniae, and against erythromycin-resis

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tant strains of S. pneumoniae, ketolides have higher MIC values (compared with erythromycin-susceptible strains) but retain good activity (Wootton et al., 1999; Jalava et al., 2001). Telithromycin has excellent penetration into bronchopulmonary tissues. Levels in alveolar macrophages exceed plasma levels 8 hours after dosing and maintained elevated levels 24 and 48 hours after dosing. Concentrations of telithromycin in bronchial mucosa and epithelial lining fluid exceeded for 24 hours the mean MIC90 of S. pneumoniae, M. catarrhalis, and M. pneumoniae (Khair et al., 2001). Ketolides are similar to, or slightly more active than the macrolides against Chlamydophila pneumoniae, M. pneumoniae and L. pneumophila. Telithromycin is approximately 60 % bioavailable, and is eliminated by multiple pathways including unchanged drug in faeces (7 %) and urine (13 %) and the remainder by hepatic metabolism by the CYP3A4 and 1A isoenzymes (Zhanel et al., 2001). In patients with mild to moderate renal impairment, there was no significant change in the pharmacokinetics of telithromycin. Dosing modifications are not necessary when administering telithromycin to patients with hepatic impairment because pharmacokinetics are not significantly changed due to a compensatory increase in renal excretion (Cantalloube et al., 2003). The MIC90 for telithromycin against S. pneumoniae strains with the mef (A) gene was ≤ 0.25 mg/L compared with 1–4 mg/L for macrolides, and against strains expressing the erm(B) gene, the MIC90 was 0.5 mg/L, compared with a MIC90 > 64 mg/L for the macrolides (Zhanel et al., 2001; Ubukata et al., 2003). Telithromycin has a concentration dependent post-antibiotic effect. Telithromycin has demonstrated excellent clinical efficacy in the outpatient treatment of CAP. It has been shown to be at least as effective when compared with either a 10-day course of high-dose amoxicillin, or twice-daily clarithromycin (Zuckerman, 2004). Forty-four of 55 patients with erythromycin-resistant S. pneumoniae infections were cured including 8 of 10 patients with bacteremia (Zuckerman, 2004). Eradication rates for H. influenzae have been lower for telithromycin (66 %) than comparators (88 %) (Carbon, 2003). Telithromycin inhibits the CYP3A4 pathway, increasing the risk for drug–drug interactions. Patients with myasthenia gravis experienced worsening dyspnea and muscle weakness within hours of first taking telithromycin (Anonymous, 2003). The cause of this serious side effect is unknown, but the effect may be similar to the problems with ciliary body function that can lead to difficulties in visual accommodation, causing blurred vision in apparently healthy young persons. An analysis of the Food and Drug Administration’s post-marketing database has revealed a 3.5 to 11 times higher incidence of acute liver failure associated with telithromycin compared with other antimicrobials (Graham, 2006), and a reported rate of 167 cases of acute liver failure per 1 million person-years of telithromycin use has been documented (Graham, 2006). As a consequence, the indications for acute bacterial exacerbations of chronic bronchitis (ABECB) and bacterial sinusitis were removed, and a black-box warning contraindicating the use of telithromycin in patients with myasthenia gravis has been added. Finally, warnings regarding liver toxicity, visual disturbances and loss of consciousness have been strengthened.

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Wallace Jr RJ, Brown BA, Griffith DE. 1993. Drug intolerance to high-dose clarithromycin among elderly patients. Diagn Microbiol Infect Dis 16: 215–221. Waterer GW, Somes GW, Wunderink RG. 2001. Monotherapy may be suboptimal for severe bacteremic pneumococcal pneumonia. Arch Intern Med 161: 1837–1842. Weiss LR. 2002. Open-label, randomized comparison of the efficacy and tolerability of clarithromycin, levofloxacin, and cefuroxime axetil in the treatment of adults with acute bacterial exacerbations of chronic bronchitis. Clin Ther 24: 1414–1425. Westphal JF. 2000. Macrolide-induced clinically relevant drug interactions with cytochrome P-450A (CYP): 3A4: an update focused on clarithromycin, azithromycin and dirithromycin. Br J Clin Pharmacol 50: 285–95. Wilson R, Schentag JJ, Ball P, et al. 2002. A comparison of gemifloxacin and clarithromycin in acute exacerbations of chronic bronchitis and long-term clinical outcomes. Clin Ther 24: 639–52. Woodhead M, Blasi F, Ewig S, et al. 2005. Guidelines for the management of adult lower respiratory tract infections. Eur Respir J 26: 1138–1180. Wootton M, Bowker KE, Janowska A, et al. 1999. In-vitro activity of HMR 3647 against Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and betahaemolytic streptococci. J Antimicrob Chemother 44: 445–453. Zhanel GG, Dueck M, Hoban DJ, et al. 2001. Review of macrolides and ketolides: focus on respiratory tract infections. Drugs 61: 443–498. Zuckerman JM. 2004. Macrolides and ketolides: azithromycin, clarithromycin, telithromycin. Infect Dis Clin N Am 18: 621–649.

10 Role of Fluoroquinolones in the Treatment of Community-Acquired Pneumonia TOBIAS WELTE Department of Respiratory Medicine, Medizinische Hochschule Hannover, Hannover, Germany

Introduction Pneumonia is a world-wide serious threat to health, and an enormous socioeconomic burden for the health-care systems. According to recent World Health Organization (WHO) data, 3 to 4 million patients die from pneumonia each year, a large proportion of whom are children or elderly people. Pneumonia is the third most common cause of death among infectious disease in the world (Lopez and Murray, 1998). In 2007, the CAPNETZ project was the first presenting reliable data about the incidence of community-acquired pneumonia (CAP) in Germany (Schnoor et al., 2007). Depending on the statistical method, the incidence is estimated at 3.7 to 10.1 per 1000 inhabitants, resulting in a number of 400 000 to 680 000 cases in Germany each year. According to the national agency for statistics (Statistisches Bundesamt), 250 000 patients are treated each year with the diagnosis community-acquired pneumonia. Community-acquired pneumonia is the sixth most frequent reason for dying, and there is an increase of 0.5 to 1 % per year (Bundesgesch¨aftsstelle f¨ur Qualit¨atssicherung, 2006). The increase is caused by the growing life expectancy, by ageing of the population, and by a better treatment of chronic diseases. Elderly people with concomitant diseases are more susceptible to infectious diseases (Bartlett et al., 2000), and typically have a spectrum of pathogens Community-Acquired Pneumonia: Strategies for Management Edited by Antoni Torres and Rosario Men´endez  2008 John Wiley & Sons, Ltd

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(Gram-negative enterobacteriaceae, staphylococci, legionella, bacteriaemic pneumococci) which is associated with higher mortality (Lim et al., 2001; Arancibia et al., 2002). These prevalences are similar to data from the USA, where 2 to 3 million cases of CAP occur each year, leading to around 10 million doctor – patient contacts (Center for Disease Control and Prevention, 1997). If an estimated proportion of 20 % (0.5 million) of these patients were hospitalized, the incidence is 258 hospital admissions per 100 000 inhabitants. The requirement for hospitalization depends on age, with the highest rates observed for patients over age 65, among whom the necessity for hospital admissions rises by a factor of four to around 1000 per 100 000 inhabitants (Marston et al. 1997). In total, it is estimated that the costs of pneumonia treatment reach eight billion dollars in the USA. The largest proportion of this amount is spent on elderly and hospitalized patients. Community-acquired pneumonia results in a remarkable mortality, which is low in outpatients (1 %) but can rise to up to 20 % in hospitalized patients Fine et al. (1996).

Definition Community-acquired pneumonia has its onset not in a hospital, but ‘in the community’. Due to the incubation period of the most important pathogens, occurrence of pneumonia in the first 48 hours after hospital admission is still seen as community acquired. Pneumonia occurring within 7 days after discharge from the hospital is still recognized as nosocomial-acquired pneumonia.

Aetiology The spectrum of pathogens and resistances varies widely between continents and countries. Universal guidelines for diagnosing and treatment are for rough orientation only, the treatment must be adapted to the specific local situation. Even under optimized diagnostic conditions, sufficient sputum specimen can be obtained in only 50 % of all patients (Metlay et al., 1997). In the early phase of the infection, sputum production may be normal. In about one third of all cases, the specimen do not meet international quality standards, which require a high proportion of leukocytes and a low proportion of squamous cells (Bartlett-criteria; Bartlett et al., 2000). Depending on the patient group (all patients, all patients with positive results in the specimen, all patients who were able to expectorate sputum, all patients who produced purulent sputum), very different distributions of pathogens had been reported. According to results from CAPNETZ (Welte et al., 2004), a reliable microbiological diagnosis can be established in only 20 % of all cases (Welte et al., 2006). In a global view, the most important pathogen is Streptococcus pneumoniae, followed by Haemophilus influenzae. The prevalence and importance of ‘atypical’ pathogens such as Mycoplasma pneumoniae, Chlamydiae pneumonia

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and Legionella pneumophila are still under debate. Most of the epidemiological data come from serological testing. Studies using polymerase chain reaction (PCR) show lower prevalences (Wellinghausen et al., 2006). This could be due to the fact that titres of IgA and IgM antibodies remain elevated for a long time, even when the infection is cured. Serological testing does not seem to be helpful after an acute infection. A recently published international study, including 2878 patients from 39 hospitals in 11 countries demonstrates prevalences of 12 % for Mycoplasma, 7 % for Chlamydia and 5 % for Legionella (Arnold et al., 2007). Legionella can be associated with a severe clinical course of the disease and an excess mortality. Infections with other Gram-negative pathogens are more common in patients from nursing homes, elderly patients and multimorbid patients (cardiac and kidney diseases, neurological disorders and chronic obstructive pulmonary disease, COPD). The mortality of these patients is much higher than in patients who are living in the normal community (El-Solh et al., 2001). The most important determinants for the acquisition of such pathogens seem to be previous antibiotic treatment and previous hospitalization (in the past 3–6 months, possibly in the past year) (Carratal`a et al., 2007). Some publications reveal significant rates of Pseudomonas aeruginosa in CAP (Micek et al., 2007). This pathogen seems to play a role in patients with certain defined risk factors only (Table 10.1). Staphylococcus aureus may also cause severe CAP, and infection with this species is an important differential diagnosis in patients developing pneumonia after influenza infection. Some recent reports of methicillin-resistant S. aureus acquired outside the hospital (cMRSA) have demonstrated an increasing prevalence in some regions in the USA. However, European countries with very low resistance patterns (The Netherlands, Germany) have also reported first case series of cMRSA, suggesting a more important role of this pathogen in the future.

Table 10.1 Risk factorsa for the acquisition of Pseudomonas aeruginosa Pulmonary comorbidities such as chronic obstructive pulmonary disease (COPD) in Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage IV, bronchiectasis, cystic fibrosis Regular treatment with prednisolon (> 10 mg/day) Hospitalization of more than 2 days in the previous 3 months Aspiration Treatment with broad-spectrum antibiotics over more than 7 days in the previous month a The probability of P. aeruginosa infection rises exponentially with the number of risk factors (more than 50 % with three and more risk factors).

Viruses had been found in a number of studies (with or without PCR) in 10–15 % of all CAP cases (De Roux et al., 2004; Welte et al., 2005). The question, whether viruses are the responsible pathogen for CAP, or whether the virus-induced damage of the bronchial epithelia is the precursor of bacterial infection, is still open. In winter time, influenza viruses are most important (70 % of all viruses), underlining

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the importance of influenza vaccination in the elderly for the prevalence and severity of pneumonia. Large-scale trials revealed that vaccination results in lower rates of pneumonia (Nichol et al., 1998). Similar results could not be obtained for the vaccination against S. pneumoniae, since the vaccinate did not cover all serotypes of this pathogen (Watson et al., 2002). Bacteriaemic infections could be prevented, ¨ but there is no local protection (Ortqvist et al., 1998). American studies revealed that vaccination of children reduced the incidence of severe pneumonia in adults, albeit that different serotypes play the dominating role (Witney et al., 2003).

Resistances Problems with resistances of the most important pathogens, especially pneumococci, vary widely between the different countries (Felmingham et al., 2002). Modifying factors that place patients at risk for infection with drug-resistant S. pneumoniae (DRSP) include age > 65 years, receipt of β-lactam therapy within the past 3 months, alcoholism, immune suppression (which includes receipt of corticosteroid therapy), multiple medical comorbidities, and exposure to a child in day care. In southern Europe and in South Africa, more than half of all S. pneumoniae isolates are penicillin-resistant. The main reasons are differences in the consumption of antibiotics. There is a direct correlation between the use of antibiotic and resistances in many countries (Goossens et al., 2005). The significance of pathogen resistances for the outcome of a patient is controversial. Increasing resistances of pneumococci against penicillin, even when treatment with penicillin was continued, did not affect the mortality until organisms reach a penicillin minimum inhibitory concentration (MIC) of at least 4 mg/L, a level that, fortunately, is uncommon. On the other hand, resistances against cefuroxim had been found to worsen mortality of pneumonia patients (Yu et al., 2003). Altogether, the use of a wide range of antibiotics still leads to a good clinical response in patients with CAP due to DRSP. However, a much more important rationale for using highly active pneumococcal therapy for patients with risk factors for infection with DRSP is to manage the problem of future resistance. Recent case series have shown the emergence of resistances during therapy with certain lessactive antipneumococcal agents; thus, it is probably important to assure rapid and complete eradication of even intermediate resistant organisms. This approach could minimize the risk of persistent drug-resistant organisms, which could spread to others in the community. The success of vaccination with the seven-valent vaccinate in newborns and children, which resulted not only in a reduction of pneumococcal infections, but owing to the minimized colonization in children, also to a reduction of DRSP, underlines the importance of this measure (Stephens et al., 2005). Pneumococci resistance against macrolides seems to be associated with higher rates of bacteriaemia (Daneman et al., 2006), but the impact on mortality in unclear. Fluroquinolones can induce pneumococcal resistance to these agents. A Canadian study (Chen et al., 1999) collecting 7500 pneumococcal isolates over the course of a 10-year period documented that, as quinolone use increased over

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time, so did the development of quinolone-resistant pneumococci. However, these pneumococci were resistant to ciprofloxacin but many remained susceptible to other, more active, antipneumococcal quinolones. These data suggest that, if naturally occurring quinolone resistant pneumococci do emerge in the community, the use of more-active agents such as levo- or moxifloxacin might still be effective in eradicating these organisms. In another report, two unusual isolates of fluoroquinolone-resistant pneumococci recovered from patients who had received levofloxacin for exacerbations of chronic obstructive pulmonary disease (Urban et al., 2001) were documented. These organisms were initially resistant to most quinolones, except for gemifloxacin and moxifloxacin, but the investigators were able to induce resistance to all quinolones in vitro by inducing another mutation on top of the two naturally occurring mutations that were present in these isolates. Other case series supported these results (Davidson et al., 2002), however, a significant increase in resistance over the time has not been reported, even in countries in which fluoroquinolon consumption is high. Unpublished data from the German CAPNETZ were not able to document an increase in one-step mutants during a 5-year time period (2001–2006). While nearly no resistances have been reported for atypical pathogens, the resistance rates are growing in Gram-negative pathogens important for the development of pneumonia. Enterobacteriaceae (Escherichia coli, Klebsiella pneumoniae) can produce extended spectrum betalactamases (ESBL), resulting in a resistance against penicillins and cephalosporins. In recent years, new multiresistant pathogens such as Acinetobacter spp. had been detected in the outpatient setting.

Respiratory Fluoroquinolones In the light of increasing resistances of S. pneumoniae and other Gram-negative pathogens, progress in the development of new fluoroquinolones became more and more important for the treatment of airway infections. Ciprofloxacin has been a reliable antibiotic against nearly all Gram-negative pathogens in the past 20 years, however, due to its limited efficacy against S. pneumoniae, it should not be applied in community-acquired pulmonary infections. Newer quinolones, the so-called respiratory fluoroquinolones provide much better treatment effects. Examples are levofloxacin, moxifloxacin, gatifloxacin (this drug has been removed from the European market recently due to its effects on glucose homeostasis; in the USA its usage is contraindicated in patients with diabetes), gemifloxacin and some other derivatives which are under development. Examples are garenoxacin and sitafloxacin. These new derivatives have a broad antibacterial spectrum that retains good activity against gram-negative bacteria (with the exception of P. aeruginosa, against which ciprofloxacin – and perhaps levofloxacin – is still the most active quinolone), ‘atypical’ pathogens, clinically important Gram-positive organisms and anaerobes. Their activity provides excellent coverage of major respiratory pathogens (Table 10.2), including resistant strains such as penicillin- and macrolide-resistant pneumococci

0.12–0.25 0.03–0.06 0.06–0.12 0.12 0.06–1.0 0.015

1.0 0.015–0.03 0.06 0.15–1.0 0.15–1.0 0.015

Streptococcus pneumoniae Pen S and Pen R Haemophilus influenzae β-lactamse- and β-lactamase+ Moraxella catarrhalis Mycoplasma pneumoniae Chlamydophila pneumoniae Legionella pneumophila

Moxifloxacin MIC90 (mg/L)

Levofloxacin MIC90 (mg/L)

Bacteria

0.03 0.12–0.25 0.25 0.015–0.03

0.015

0.05

Gatifloxacin MIC90 (mg/L)

0.015–0.03 0.12 0.25 0.015–0.03

0.008–0.015

0.03–0.06

Gemifloxacin MIC90 (mg/L)

0.03 1.0–4.0 1.0–2.0 0.03

0.015

1.0–2.0

Ciprofloxacin MIC90 (mg/L)

Table 10.2 Comparative antibacterial activity of some newer fluoroquinolones against community respiratory pathogens (Adapted from Zhanel et al., 2002; Dalhoff and Schmitz, 2003; Saravolatz and Leggett, 2003)

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and β-lactamase producing H. influenzae and M. catarrhalis (Zhanel et al., 2002; Dalhoff and Schmitz, 2003). In addition, the excellent penetration into respiratory tract tissues and fluids, the optimal oral bioavailability and the highly bactericidal effect are major advantages of these groups of drugs (Andrews et al., 1997; Soman et al., 1999; Grasela et al., 2000). An additional pharmacodynamic effect of fluoroquinolones is the post-antibiotic effect (PAE), which is a continued suppression of the organisms’ growth that persists after exposure to the antibiotic. Fluoroquinolones exhibit prolonged PAEs with a large variety of bacteria (Pickerill et al., 2000). Fluoroquinolones display concentration-dependent PAEs against both Gram-positive and Gram-negative bacteria, generally in the range of 1.5–3 h (Ferrara et al., 2005). This persistent antibacterial activity allows infrequent dosing of these agents even when the drug concentrations fall below the MIC. Prolonged PAEs protect against bacterial regrowth. Finally, levofloxacin, moxifloxacin and gemifloxacin have acceptable safety profiles similar to those of established agents. Recently, the experience with more than 18 000 outpatients was reported (Faich et al., 2004). About 1300 of CAP patients received 400 mg of moxifloxacin p.o. once daily for at least 10 days. Adverse events were relatively uncommon. A total of 13 % of patients had drug-related adverse events, which included headaches, nausea, diarrhoea, vomiting and occasional dizziness. In that study, there were no reports of ventricular arrhythmias, and there were six deaths, which were not considered to be related to arrhythmias. A comparative study of moxifloxacin and levofloxacin for the therapy of elderly patients with CAP enrolled 195 patients treated with moxifloxacin, and 199 patients treated with levofloxacin (Morganroth et al., 2005). All patients underwent a baseline EKG test, 72 hour Holter monitoring and then a second EKG test. All patients were older than 65 years, 75 % had cardiac disease, and only one patient (treated with levofloxacin) had torsade de pointes; one patient with moxifloxacin had non-lethal sustained ventricular tachycardia. Fluoroquinolones have been studied extensively in comparison to other established antibiotics in patients with CAP. The efficacy and safety of a 7–14 days levofloxacin treatment cycle was compared with ceftriaxone and/or cefuroxime axetil in a prospective, multicentre, randomized trial including 456 CAP patients (File et al., 1997). Patients received either intravenous and/or oral levofloxacin (500 mg once daily, 226 patients) or i.v. ceftriaxone (1 or 2 g, once or twice daily, 230 patients) and/or oral cefuroxime axetil (500 mg twice daily). Erythromycin or doxycyclin may have been added – investigator discretion – to the comparator arm. Clinical success at day 5 to 7 was superior in the levofloxacin group (96 %), compared with the ceftriaxone and/or cefuroxime axetil group (90 %, Figure 10.1). Patients with typical respiratory pathogens, producing respiratory secretions suitable for microbiological evaluation, revealed better overall bacteriological eradication rates with levofloxacin (98 %), compared with the ceftriaxone and/or cefuroxime axetil group (85 %). Levofloxacin eradicated 100 % of the most frequently reported respiratory pathogens (i.e., H. influenzae and S. pneumoniae) and provided a > 98 % clinical success rate in patients with atypical pathogens. Both levofloxacin and ceftriaxone – cefuroxime axetil eradicated 100 % of the S. pneumoniae detected in blood culture.

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FLUOROQUINOLONES IN THE TREATMENT OF CAP Clinical success CE

Clinical success ME

Eradication ME

100 80 60 40 20 0 Levofloxacin

Ceftriaxone

Figure 10.1 Levofloxacin versus ceftriaxone/cefuroxime. Clinical success and microbiological eradication (CE = clinically evaluable; ME = microbiologically evaluable). (Adapted from File et al., 1997)

In another multicentre, open-label, randomized trial the relative efficacy and tolerability of levofloxacin (500 mg p.o. or i.v. q 24 hours, 110 Patients) monotherapy, and a combination between azithromycin (500 mg i.v. q 24 hours for at least 2 days, 114 patients) and ceftriaxone (1 g i.v. q 24 hours for 2 days) was assessed in hospitalized adults with moderate to severe CAP (Frank et al., 2002). The minimum duration of treatment was 10 days in both treatment groups. At the end of treatment, the clinical success rate (cured or improved) in clinically evaluable patients was 94.1 % in the levofloxacin group and 92.3 % in the azithromycin group. The respective post-therapy microbiological eradication rates were 89.5 % and 92.3 %. This findings were confirmed in a second open-label multicentre trial with either a combination of intravenous ceftriaxone 1 g and i.v. azithromycin 500 mg daily, or a monotherapy with i.v. levofloxacin 500 mg daily (Zervos et al., 2004). Patients who improved clinically were switched to oral follow-on therapy with either azithromycin 500 mg/day or levofloxacin 500 mg/day. Favourable clinical outcomes were demonstrated in 91.5 % of patients treated with ceftriaxone plus azithromycin, and in 89.3 % of patients treated with levofloxacin at the end of therapy visit, and in 89.2 % and 85.1 % patients, respectively, at the end of study visit. The majority of the patients in these trials were in Pneumonia Severity Index (PSI) Class I to III, although many of them were hospitalized. This raises concerns whether levofloxacin as a monotherapy could also be effective in more severely ill patients. In a multinational controlled open-label study, patients who had been admitted to the intensive care unit (ICU) with severe CAP without shock were randomized to either levofloxacin (500 mg i.v. q 12 hours, 139 patients) monotherapy, or to a combination therapy with cefotaxim (1g i.v. q 8 hours, 132 patients) and ofloxacin (200 mg i.v. q 12 hours) for 10 to 14 days (Leroy et al., 2005). In the per protocol analysis, clinical success was observed in 79.1 % of patients (L group) and in 79.5 % of patients (C + O group). A satisfactory bacteriological response was present in 73.7 % of L-group patients and in 77.5 % of C + O-group

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patients, including responses of 75.7 % and 70.3 %, respectively, in the L group and C + O group in the S. pneumoniae-documented population. This demonstrated the efficacy of levofloxacin monotherapy in the treatment of a subset of patients with CAP requiring ICU admission. However, due to the exclusion criteria used in this study, this conclusion could not be extrapolated to patients requiring mechanical ventilation or vasopressors (i.e., those patients in shock). Moxifloxacin showed comparable clinical and microbiological results as reported for levofloxacin in several randomized clinical trials. The most important of these are described in detail below. The so called ‘TARGET’ trial compared efficacy, safety and tolerability of moxifloxacin (400 mg) given intravenously once daily followed by oral moxifloxacin (400 mg) for 7 to 14 days with the efficacy, safety and tolerability of co-amoxiclav (1.2 g) administered intravenously three times a day followed by oral co-amoxiclav (625 mg) three times a day, with or without clarithromycin (500 mg) twice daily (intravenously or orally), for 7 to 14 days in adults with CAP requiring initial parenteral therapy (Finch et al., 2002). Although the trial was designed to demonstrate the equivalence of both regimens, the results showed statistically significant higher clinical success rates for moxifloxacin (93.4 %), vs 85.4 % for the comparator regimen. Bacteriological success rates were 93.7 % for patients treated with moxifloxacin versus 81.7 % for the comparator group. This superiority was seen irrespective of the severity of pneumonia, and whether or not the combination therapy included a macrolide. The time to resolution of fever was also statistically significantly shorter for patients who received moxifloxacin (median time, 2 vs 3 days), and the duration of hospital admission was approximately 1 day less for patients who received moxifloxacin. The treatment was switched to oral application immediately after the initial mandatory 3-day period of intravenous administration for a larger proportion of patients in the moxifloxacin group than for patients in the comparator group (151 [50.2 %] vs 57 [17.8 %] patients, respectively). There were fewer deaths (9 [3.0 %] vs 17 [5.3 %]), and fewer serious adverse events (38 [12.6 %] vs 53 [16.5 %], respectively) in the moxifloxacin group than in the comparator group. This results are in line with the largest retrospective ‘real life’ analysis from a USA hospital database using records from 12 945 Medicare inpatients (≥ 65 years of age) with CAP (Gleason et al., 1999). Treatment with a non-pseudomonal, thirdgeneration cephalosporin alone – the current standard – was used as reference group. Initial treatment with a fluoroquinolone alone (hazard ratio (HR) 0.64; 95 % confidence interval (CI) 0.43–0.94) was independently associated with a lower 30day mortality, and was as effective as the combination therapy of cephalosporin and macrolide. Adjusted mortality among patients initially treated with these drugs was significantly lower than in the reference group beginning 2, 3 and 7 days after hospital admission. Use of a β-lactam/β-lactamase inhibitor plus macrolide (HR, 1.77), and an aminoglycoside plus another agent (HR, 1.21) was associated with an increased 30-day mortality (Figure 10.2). One of the possible explanations for the inferiority of the β-lactam/β-lactamase inhibitor therapy was underdosing of these

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Cefuroxime/M

Ceftriaxone/M

Amp+I/M

FQ

Aminoglykoside +

1.8 Adjusted mortality

1.6 1.4 1.2 1 0.8 0.6 0.4 0.2 0 0

5

10

15 Days

20

25

30

Figure 10.2 Association between initial antimicrobial therapy and 30-day mortality (M = macrolide; Amp + I = ampicillin + β-lactamase inhibitor; FQ = fluoroquinolones). (Adapted from Gleason et al., 1999)

antibiotics, mainly in elderly patients. However, as a consequence of these studies, cephalosporins were preferred for hospital-admitted patients in some countries. In another multicentre, randomized controlled, open-labelled trial in Germany, the efficacy, safety, and speed and quality of defervescence of sequential, intravenous or oral moxifloxacin (400 mg i.v. once daily, possibly followed by tablets) and high-dose ceftriaxone (2 g i.v. once daily) with or without erythromycin (1 g i.v. every 6–8 hours) for patients with community-acquired pneumonia requiring parenteral therapy were investigated (Welte et al., 2005). One hundred and thirty-eight (85.7 %) of 161 moxifloxacin-treated patients, and 135 (86.5 %) of 156 patients in the comparator group (37.8 % of whom received combination therapy) revealed clinical resolution. An additional analysis of these trials demonstrated the efficacy of moxifloxacin against atypical pathogens, compared with macrolides (Hoeffken et al., 2004). Of 101 intention-to-treat patients with atypical pathogens, a total of 39 moxifloxacintreated and 47 comparator-treated subjects were microbiologically evaluable, and included into the analysis. Clinical and bacteriological success rates were 95 % for the moxifloxacin-treated and 94 % for the comparator-treated patients. As mentioned above, data for severely ill patients treated with moxifloxacin are scarce. Results of the so-called ‘MOTIV’ study, which has been presented in abstract form only, compared monotherapy with moxifloxacin and a combination therapy between levofloxacin and ceftriaxone in patients in PSI Class IV and V. Both regimen were of comparable efficacy and safety, either for clinical or microbiological parameters. However, similar to the above described levofloxacin study, only a small number of patients suffered from septic shock or needed mechanical ventilation. Therefore, fluoroquinolone monotherapy cannot be recommended for this patient group.

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One of the studies of major interest for the use of the fluoroquinolones was the ‘Community-Acquired Pneumonia Recovery in the Elderly (CAPRIE) study’, including mainly elderly patients, a population which may be of increasing interest in the future. For the majority of available antibiotics, no data are available about efficacy and safety in the elderly. In this prospective, double-blind, randomized, controlled trial patients received treatment with either intravenous/oral moxifloxacin (400 mg daily, 141 patients), or intravenous/oral levofloxacin (500 mg daily, 140 patients) for 7–14 days (Anzueto et al., 2006). The mean age of the patients was 77.4 years. Cure rates at test-of-cure were 92.9 % in the moxifloxacin arm and 87.9 % in the levofloxacin arm. In the moxifloxacin group, cure rates were 92.6 % for patients with mild or moderate CAP, and 94.7 % for patients with severe CAP, compared with cure rates of 88.6 % and 84.6 %, respectively, in the levofloxacin group (p = not significant). Cure rates in the moxifloxacin arm were 90.0 % for patients aged 65–74 years and 94.5 % for patients aged ≥ 75 years, compared with 85.0 % and 90.0 %, respectively, in the levofloxacin arm (p = not significant) (Figure 10.3).

92.6 88.6

100

94.7 84.6

80 60 40 20 n = 122

n = 114

n = 19

n = 26

Clinical cure (% of patients)

Clinical cure (% of patients)

100

90.0

94.5

84.6

85.0

80 60 40 20 n = 45

n = 51

n = 92

n = 80

0

0 Severe CAP Mild/moderate CAP CAP severity

65 to <75 Age (years)

>75

Figure 10.3 Clinical cure rates in the Community-Acquired Pneumonia Recovery in the Elderly (CAPRIE) study stratified for severity of the disease (A) and for age (B) (black bars = moxifloxacin, white bars = levofloxacin). (Adapted from Anzueto et al., 2006)

Gatifloxacin and gemifloxacin have not been studied as extensively as levoor moxifloxacin. Both are not available in all western countries, and their use is restricted to adverse events as mentioned above. However, clinical results are comparable to the other respiratory fluoroquinolones. Due to the minor importance of these substances, only two studies on their clinical efficacy are presented here. In a double-blind, double-dummy, multicentre, multinational, parallel-group study oral gatifloxacin (400 mg once-daily) and oral co-amoxiclav (amoxicillin 500 mg + clavulanic acid 125 mg three-times) were compared in the treatment of patients with mild-to-moderate community-acquired pneumonia (Lode et al., 2004). Overall, a successful clinical response was achieved in 86.8 % of gatifloxacintreated patients, compared with 81.6 % of those receiving co-amoxiclav, while

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corresponding rates of bacteriological efficacy (eradication plus presumed eradication) were 83.1 % and 78.7 %, respectively. In a very similar but open-labelled study in adults hospitalized with a clinical and radiological diagnosis of CAP, patients were randomized to receive either oral gemifloxacin 320 mg once daily (116 patients, 7–14 days) or ceftriaxone 2 g i.v. once daily (121 patients, 1–7 days), followed by oral cefuroxime 500 mg twice daily (1–13 days) for a total of 14 days (Lode et al., 2002). Patients receiving ceftriaxone – cefuroxime were allowed to receive concomitant macrolide treatment. Clinical success rates in the clinically evaluable (CE) population at follow-up (day 21–28 post-therapy), the primary end point, were 92.2 % for gemifloxacin and 93.4 % for ceftriaxone – cefuroxime. In patients in PSI risk classes IV and V, the clinical success rate was 87.0 % (20/23) for gemifloxacin versus 83.3 % (20/24) for ceftriaxone – cefuroxime. No difference in clinical response was detected for those who used additional macrolides. Bacteriological success rates at follow-up in the bacteriologically evaluable (BE) population were 90.6 % (58/64) for gemifloxacin and 87.3 % (55/63) for ceftriaxone – cefuroxime. Another double-blind, double-dummy, parallel group Phase III study compared gemifloxacin 320 mg once daily for 7 days with oral amoxicillin – clavulanate 1 g/125 mg three times daily for 10 days. Gemifloxacin was found to be clinically, bacteriologically and radiologically as effective as 10 days of amoxicillin – clavulanate 1 g/125 mg three times daily for the treatment of suspected pneumococcal CAP. Specifically, penicillin- and macrolide-resistant strains of S. pneumoniae were studied in these trial and were eradicated in 95.7 % of the cases with gemifloxacin (L´eophonte et al., 2004). Altogether, the new respiratory fluoroquinolones demonstrated in all clinical studies at least equivalence in comparison to β-lactam antibiotics. In more severe cases of CAP (PSI classes IV and V) mainly levofloxacin and moxifloxacin seem to be as effective as a combination therapy with a β-lactam and a macrolide. In these studies, clinically important adverse events could not be detected between fluoroquinolones and the comparators. The efficacy against a broad spectrum of pathogens, the good clinical response rates, together with an acceptable safety profile made fluoroquinolones an attractive alternative for the treatment of community-acquired pneumonia. The following section highlights the role of fluoroquinolones in actual recommendations for CAP management.

Risk stratification Current CAP recommendations use a risk stratification approach for CAP therapy. The risk factors for excess CAP mortality are age, the number of concomitant diseases and the place of living before admission to the hospital (patients from nursing homes had an eight-fold higher risk for dying than patients coming from ‘regular’ homes) (Micek et al., 2007).

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Different scores for the estimation of the prognosis of patients with CAP have been evaluated to substantiate the decision for hospital admission, and the decision where to treat the patient (regular ward, intermediate care unit, intensive care unit). Many scores designed for hospital patients (PSI, Fine et al., 1997; CURB score [confusion, urea, respiratory rate and blood pressure], Lim et al., 2003) have the disadvantage that they need laboratory testing, which is not available in the outpatient setting. Recent data have revealed that a simple clinical score (CRB-65: C, confusion; R, respiratory rate > 30/minute; B, blood pressure < 90 mmHg; 65, age > 65 years) allows assignment of patients into a low, moderate or high mortality risk groups (Bauer et al., 2006; Capelastegui et al., 2006). The risk within the hospital can be best assessed with the ATS Score (Ewig et al., 2004), which has been modified in the new Infectious Diseases Society of America/American Thoracic Society (ISDA/ATS) guidelines (Mandell et al., 2007). The criteria for severe CAP, needing close observation in an intensive care unit, are listed in Table 10.3. Table 10.3 Criteria for severe community-acquired pneumonia: bold, newly introduced criteria; italic, criteria used by the CURBa score. If one major criterion or two minor criteria are present, then intermediate or intensive care treatment is necessary Major criteria Septic shock which requires vasopressor therapy Respiratory rate ≥ 30/minute

Minor criteria Invasive mechanical ventilation PO2/FiO2 ≤ 250 Multilobular infiltrates in chest X-ray Confusion Uraemia (BUN b >20 mg/dL) Leucopenia (< 4000/mm3 ) Thrombocytopenia (< 100 000/mm3 ) ◦ Hypothermia (<36 C core temperature) Hypotension (requiring fluid therapy)

a Confusion, b Blood,

urea, respiratory rate and blood pressure. urea, nitrogen.

Therapy The primary treatment should consider the presence of S. pneumoniae and atypical pathogens. The above-mentioned paper of Arnold et al. (2007) revealed a relevant number of non-responders for the initial treatment, if atypical pathogens were not covered. The recommendations in all guidelines separate patients with low risk of dying (see above), who may be treated in the outpatient setting, and patients with high risk, who need to be hospitalized. In addition, specific risk factors of the patient and the pathogen must be taken into account. In the new ISDA/ATS guidelines for outpatient treatment in previously healthy patients without risk factors for DRSP, macrolides or doxycyclin are drugs of

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the first choice. The efficacy of macrolides has been demonstrated in large trials, while only few observations exist for doxycyclin. With respect to low resistances of S. pneumoniae against doxycyclin, and the sufficient effect against atypical pathogens, doxycyclin is recommended. When comorbidities, such as chronic heart, lung, liver, or renal disease, diabetes mellitus, alcoholism, malignancies, or asplenia are present, or when immunosuppressant conditions or use of immunosuppressant drugs, or use of antimicrobials within the previous 3 months (in which case an alternative from a different class should be selected), or other risks for DRSP infection are probable, an escalation of therapy is necessary. Therefore a respiratory fluoroquinolone (moxifloxacin, gemifloxacin or levofloxacin), or a ß-lactam plus a macrolide combination therapy are recommended. In regions with a high rate (> 25 %) of infections with high-level (MIC > 16 mg/mL) macrolide-resistant S. pneumoniae, the use of alternative agents active against atypicals should be considered. For hospitalized patients who are not in an ICU, and without risk factors for P. aeruginosa, respiratory fluoroquinolone or a ß-lactam plus a macrolide are recommended. Patients in the ICU should be treated with a combination therapy of a ß-lactam plus azithromycin or plus fluoroquinolone. For penicillin-allergic patients, a respiratory fluoroquinolone and aztreonam are recommended. For Pseudomonas infection, use of an antipneumococcal, antipseudomonal ßlactam (piperacillin – tazobactam, cefepime, imipenem or meropenem) plus either ciprofloxacin or levofloxacin is necessary. Alternatively, the above ß-lactam plus an aminoglycoside and azithromycin or the above ß-lactam plus an aminoglycoside and an antipneumococcal fluoroquinolone could be a choice. For penicillin-allergic patients, aztreonam could be a substitute for the above ß-lactam. For community-acquired methicillin-resistant S. aureus infection (cMRSA) there are only few data available. Vancomycin or linezolid are the best evaluated drugs which should be used. Whether a combination therapy between these two drugs, or with rifampicin, or fosfomycin is effective, remains open. Most of the clinical studies investigating fluoroquinolones used an approach with a 7–10 day treatment. The ISDA/ATS guidelines reduced the duration of therapy for the first time to a minimum of 5 days, if patients are afebrile for 48–72 hours, and show no more than 1 CAP-associated sign of clinical instability (Table 10.4) before discontinuation of therapy. Fluoroquinolone short course therapy has been investigated in several studies. Taking into account that levofloxacin demonstrates concentration-dependent bactericidal activity most closely related to the pharmacodynamic parameters of the ratio of area under the concentration-time curve (AUC) to MIC and the ratio of peak plasma concentration (C(max)) to MIC an increase of the dose to 750 mg may allow a shorter course of treatment without diminishing therapeutic benefit. This was demonstrated in a multicentre, randomized, double-blind investigation that compared levofloxacin dosages of 750 mg per day for 5 days with 500 mg per day for 10 days for the treatment of CAP. Clinical success rates were 92.4 %

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Table 10.4 Criteria for clinical stability (Adapted from Halm et al., 2002) Temperature ≤ 37.8◦ C Heart rate ≤ 100 beats/minute Respiratory rate ≤ 24 breaths/minute Systolic blood pressure ≥ 90 mm Hg Arterial oxygen saturation ≥ 90 % or pO2 ≥ 60 mm Hg on room air Ability to maintain oral intakea Normal mental statusa a

Important for discharge or oral switch decision but not necessarily for determination of non-response.

(183 of 198 persons) for the 750-mg group and 91.1 % (175 of 192 persons) for the 500-mg group. Microbiological eradication rates were 93.2 % and 92.4 % in the 750-mg and 500-mg groups, respectively (Dunbar et al., 2003). A subgroup analysis of this study was focused on atypical pathogens, for which a longer treatment duration (10 to 21 days) were recommended. The 750-mg, 5-day course of levofloxacin was at least as effective as the 500-mg, 10-day regimen for atypicals. In addition, the 750-mg therapy resulted in more rapid symptom resolution, with a significantly greater proportion of patients experiencing resolution of fever by day 3 of therapy (Dunbar et al., 2004). One of the above-mentioned studies (Welte et al., 2005) demonstrated that defervescence and relief of symptoms, such as chest pain, occurred significantly earlier in the moxifloxacin-treated group than in the ceftriaxone – macrolide-treated group. Most of the patients in this study showed clinical stability after 5 days of treatment. The efficacy and safety of 5- versus 7-day courses of 320 mg of oral gemifloxacin for outpatient treatment of mild – moderate CAP has been studied in a multicentre, randomized, double-blind, parallel group trial. Over 95 % of all patients in each cohort had a PSI score of less than 4. Gemifloxacin once daily for 5 days was not inferior to 7 days with respect to clinical, bacteriological and radiological efficacy (Figure 10.4; File et al., 2007). Shorter treatment duration could be responsible for cost effectiveness of an antibiotic, although the drug is more expensive than the comparators. In a recently published study symptom resolution, side effects and processes of care between the use of clarithromycin and gatifloxacin for the treatment of radiographically confirmed CAP were investigated (Dean et al., 2006). Gatifloxacin monotherapy was compared with clarithromycin alone or combined with ceftriaxone for patients with multiple risk factors. No significant difference was found in return to usual activities, pneumonia-specific symptom scores and 12-item short-form health survey scores. The rates of hospital admission and length of stay were similar. The cost of antibiotic was higher in the clarithromycin group: $257 versus $110 for gatifloxacin. Gatifloxacin Monotherapy was found to be similar to clarithromycin given with or without ceftriaxone for the treatment of CAP, except that antibiotic cost, bad taste and injection site soreness favour the use of gatifloxacin.

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Percentage of afebrile patients

50

40

30

20 L 500 mg L 750 mg

10

M 400 mg 0 Day 3 of therapy for CAP

Day 2 of therapy for CAP

Figure 10.4 Percentage of patients treated for community-acquired pneumonia (CAP) who became afebrile at day 3 of treatment with either 500 or 750 mg of levofloxacin (L) (Dunbar et al., 2003) or at day 2 of treatment with 400 mg moxifloxacin in a separate trial (Welte et al., 2005)

This study confirmed the results of a naturalistic, prospective and open study enrolling 580 patients in Germany. Major determinants of costs were length of hospital stay and ICU admission, whereas costs for staff and hotel were major contributors to direct costs. Initial antibiotic therapy with moxifloxacin resulted in similar clinical efficacy and direct costs compared with non-standardized therapy; however, patients treated with moxifloxacin benefited with an earlier hospital discharge (Baur et al., 2005).

Conclusion Due to their efficacy against a broad spectrum of pathogens, the good clinical response rates together with an acceptable safety profile fluoroquinolones clearly have a variety of important roles in the management of CAP. Because of their high bioavailability, fluoroquinolones can help avoid hospitalization for some patients who are otherwise borderline for hospital admission. As agents for oral therapy, fluoroquinolones allow for the rapid initiation of therapy for moderately ill patients and achieve serum levels that are highly effective. For patients who have clinical risk factors for infection with resistant pathogens, fluoroquinolones are a reliable monotherapy and serve as an effective alternative to combination therapy with a β-lactam and a macrolide. Finally, due to the more rapid resolution of fever and other clinical symptoms, fluoroquinolones transition may facilitate the switch from

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intravenous to oral therapy for hospitalized patients and may shorten the duration of hospital stay and may help therefore to reduce health-care cost. Although rate of fluoroquinolone resistance among pneumococci is low at the moment, development of such patterns has to be observed carefully in the future, mainly in countries with high consumption of these drugs.

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11 Non-Responding Pneumonia ´ ROSARIO MENENDEZ ´ Hospital Universitario La Fe, Valencia, Spain Servicio de Neumologıa,

Introduction Community-acquired pneumonia (CAP) is the most frequent infectious cause of death in developed countries, although the state of this infection is usually updated by scientific societies and antimicrobial therapies have been greatly improved. The rate of mortality has remained similar during the past decades and is not expected to decline within the near future (Minino and Smith, 2001; Kaplan et al., 2002). Several reasons have been recognized to explain the sustained mortality of CAP: the progressive ageing of the population, the higher survival of patients with debilitating comorbid diseases, and the larger population with immunosuppression. The probability of death may be estimated at diagnosis using the Fine prognostic scales (Fine et al., 1997) and CURB-65 (confusion, urea, respiratory rate and blood pressure, age 65) (Lim et al., 2003). These scales estimate the probability of death depending on several initial parameters; however, after antimicrobial treatment some patients respond to the therapy whereas others do not, with the latter group demonstrating a worse prognosis (Men´endez et al., 2004). The term non-responding pneumonia is used to define a clinical situation in patients with inadequate clinical response despite antibiotic treatment. Nonetheless there is no clear-cut, validated definition in the literature or even in the guidelines, thereby making non-response difficult to study and to compare publications. In the first publications non-responding pneumonia was arbitrarily and differently defined by several authors (Fein et al., 1993; Kuru and Lynch, 1999). With the appearance of more studies on clinical stability (Halm et al., 1998) and treatment failure in CAP, scientific guideline have proposed a new, more structured and practical approach to define non-responding pneumonia.

Community-Acquired Pneumonia: Strategies for Management Edited by Antoni Torres and Rosario Men´endez  2008 John Wiley & Sons, Ltd

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Concept and Classification A key issue is to define when a patient should be considered to have non-responding CAP. This diagnosis must take into account the time the antibiotic treatment requires to take effect and also the causal microorganisms, the initial severity of the infection and the condition of the host. In addition, it should be taken into account that out- and in-patients respond differently to antibiotic treatment as do patients in the hospitalization ward or in the intensive care unit (ICU). In the latest Infectious Diseases Society of America/American Thoracic Society (ISDA/ATS) consensus (Mandell et al., 2007) a systematic classification of causes of non-responding has been proposed according to the time of onset of infection and type of failure. For hospitalized CAP, 72 hours is the period most frequently used to evaluate response to therapy, agreeing with the median time required to achieve clinical stability (Halm et al., 1998), the time required to reduce bacterial concentration in the airways (Montravers et al., 1993), or the time suggested ¨ to proceed to obtain further samples and perform bronchoscopy (Ortqvist et al., 1990). Two different patterns of non-responding pneumonia have been described in hospitalized non-ICU patients (Mandell et al., 2007). 1. Progressive pneumonia is considered in cases with clinical deterioration with acute respiratory failure requiring ventilatory support and/or the appearance of septic shock, usually occurring within the first 72 hours of hospital admission. 2. Persistent or non-responding pneumonia is defined as absence of or delay in achieving clinical stability. The term early failure employed in two recent studies was used even before 72 hours of treatment and it was similar to that of progressive pneumonia. The definition of treatment failure by Roson et al. (2004) also included the need for a change in therapy or for thorax drainage. Studies by Men´endez et al. (2004) also included hemodynamic instability, worsening of or the appearance of respiratory failure, or a new foci of infection in the definition. The term non-resolving pneumonia has been proposed for persistence of pulmonary infiltrates 30 days after diagnosis (Mandell et al., 2007).

Incidence and Prognosis The incidence of non-responding CAP has not been clearly established although ¨ several publications have evaluated treatment failure (Ortqvist et al., 1990; Arancibia et al., 2000; Men´endez et al., 2004; Roson et al., 2004). In a multicentre study in hospitalized CAP, 15 % of the patients were found to have a lack of response to empirical antibiotic treatment (8 % early and 7 % late failure) (Men´endez et al., 2003). Roson et al. (2004) found 6 % with early failure (48–72 hours) in CAP, and up to 39 % of patients with non-responding pneumonia in CAP developed progressive pneumonia (Arancibia et al., 2000). The risk of inadequate response

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or even deterioration after stabilization in patients admitted to the ICU is higher (Arancibia et al., 2000). The mortality of patients with non-responding CAP depends on the cause of the treatment failure. The mortality rate is high (88 %) if the cause is a nosocomial infection, 38 % in cases with primary infection, 40 % in persistent infection and 27 % when no diagnosis is found (Arancibia et al., 2000).

Causes of Non-Responding Pneumonia The causes of non-responding pneumonia are classified according to the aetiology: as infectious, non-infectious and of unknown origin. Arancibia et al. (2000) proposed the following more complete classification within the infectious subgroup. 1. Primary infection when a pathogen is not covered by the usual empiric treatment, i.e. virus or unusual pathogens. 2. Definitive persistent pathogens when a pathogen is demonstrated in initial and posterior microbiological studies. 3. Possible persistent pathogens when the pathogen is found in the initial but not in repeated investigations. 4. New nosocomial infection on the appearance of a different or new pathogen in posterior investigations. Examples include both infection in the lung and/or other localizations such as an intravenous line, indwelling urinary catheter, or colitis by Clostridium difficile. In the latest IDSA/ATS guidelines a systematic classification has been proposed (Table 11.1). Table 11.1 Classification of non-responding pneumonia. Modified from Mandell et al. 2007 Deterioration or progression 1. Early <72 hours • Resistant microorganism • Metastatic infection • Alternative diagnosis 2. Delayed • Nosocomial superinfection • Exacerbation of comorbid condition • Intercurrent non-infectious disease Failure to improve 1. Normal response if early <72 hours 2. Delayed • Resistant microorganism • Pleural effusion • Non-infectious causes

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Infectious Causes Infections account for 40 % of non-responding CAP. The most frequent microorganisms found are: Streptococcus pneumoniae, Legionella (Roson et al., 2004), Staphylococcus aureus, and Pseudomonas (Arancibia et al., 2000; Men´endez et al., 2003). In institutionalized elderly patients, El-Solh et al. (2002) reported methicillin-resistant S. aureus (MRSA) (33 %), enteric Gram-negative bacilli (24 %) and Pseudomonas aeruginosa (14 %). Streptococcus pneumoniae resistance does not seem to be the cause of treatment failure when the treatment is appropriate, adheres to guidelines and the minimal inhibitory concentration of penicillin is <4 µg/mL (Ewig et al., 1999). However, there have been isolated cases of treatment failure with resistance to the new fluoroquinolones, specifically levofloxacin (Chen et al., 1999), and to macrolides (Kelley et al., 2000). Recently, the presence of community-acquired MRSA (Panton–Valentine leukocidin strains) has been recognized in severe CAP which evolves with cavitary lesions and sepsis (Micek et al., 2005). The presence of rarer, or unusual, microorganisms in CAP may be a cause of non-responding pneumonia (Men´endez et al., 1997), as they may not be adequately covered by the recommended initial empirical therapy.

Non-Infectious Causes Several diseases can mimic CAP and behave as non-responding pneumonia, including: pulmonary haemorrhage, diseases of inflammatory origin such as bronchiolitis obliterans with organizing pneumonia (BOOP), thromboembolic diseases, pulmonary eosinophilia, hypersensitivity pneumonitis, and others (Kuru and Lynch, 1999). Pulmonary neoplasia, formerly considered relatively frequent, is estimated to ¨ account for 1 % of the cases (Ortqvist et al., 1990; Arancibia et al., 2000; Men´endez et al., 2003; Roson et al., 2004). In a study from an ICU, Jacobs et al. (1999) found 19 % of non-infectious causes, including drug-induced pneumonitis, aspiration of gastric contents, adult respiratory distress syndrome, pulmonary embolism, carcinomatous lymphangitis and cardiogenic pulmonary oedema.

Factors Related to Non-Responding Pneumonia Host Factors The impact of age and comorbid conditions on response to treatment has recently been studied by multivariate analyses (Table 11.2). It was found that compared with non-failure, early treatment failure was lower in those >65 years of age (OR, odds ratio: 0.35; Roson et al., 2004) and twofold higher in patients with liver disease (Men´endez et al., 2004), whereas, curiously, chronic obstructive pulmonary disease (COPD) improved prognosis (Men´endez et al., 2004). This surprising finding has no current explanation, although it is remarkable that the mortality of CAP in patients with COPD is low at around 8 % (Torres et al., 1996), and, in fact, this

FACTORS RELATED TO NON-RESPONDING PNEUMONIA

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Table 11.2 Independent factors related to any treatment failure and early failure Factor Host-related factors: -Age >65 years -Influenza vaccination -COPD -Liver disease Microorganism-related factors: -Legionella -Gram negative Factors related to extension/severity of CAP -Pleural effusion -Multilobar CAP -Cavitation -Fine risk class Treatment-related factors: -Discordant therapy -Fluoroquinolone therapy

Any failure OR* (95 % CI)

Early failure OR* (95 % CI) 0.2 (0.1–0.4)

0.3 (0.2–0.4) 0.6 (0.4–0.9) 2.1 (1.1–3.5) 2.7 (1.4–5.3) 4.3 (1.04–18) 2.7 2.1 4.1 1.3

(1.1–4.2) (1.4–2.9) (1.3–13.5) (1.1–1.5)

2.7 (1.8–4.2) 2.15 (1.4–3.4) 1.8 (1.11–2.9) 2.51 (1.61–3.94)

0.5 (0.3–0.9)

*OR: odds ratio

disease is not included in the PSI score (Fine et al., 1997). Concomitant treatment with steroids may play a protective role in the regulation of pro-inflammatory cytokine response of the host (Monton et al., 1999; Nelson, 2001; Skerrett and Park, 2001). In recent years the influence of host inflammatory response against infection and its impact on the patient prognosis has been studied. Indeed, sufficient inflammatory response must be produced to overcome the proliferation and dissemination of the microorganism in the lung. However, the release of an excessive inflammatory production of cytokines and their disseminates into the systemic circulation may lead to a hemodynamic disorder and/or multi-organ failure. Research in the past decade has brought about a better understanding of the systemic and local inflammatory response in CAP and other severe infections, especially sepsis (Bonten et al., 1997; Nelson, 2001; Skerrett and Park, 2001). However, it is not as yet known what factors cause excessive inflammatory response with deleterious effects, although it has been associated both to the host and the bacterial load and to the virulence of the microorganisms. The genetic variability in the production of pro-inflammatory cytokines has also been studied (Waterer and Wunderink, 2005). Polymorphisms in the TNF-alpha gene have received considerable attention. The presence of the TNF-308A allele is associated with a higher TNF-alpha production and mortality (Waterer et al., 2001), while the G allele is associated with a lower production of TNF and a lower incidence of shock. There are fewer studies regarding interleukin-6. Nevertheless, the GG genotype of IL-6 (GG genotype of the IL-6-174 polymorphism) is associated with a lower production of IL-6 and greater survival in sepsis (Schluter

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et al., 2002). The absence of the protein (SP)-B+1580 of the surfactant increases the susceptibility to lung injury. The CC and CT genotypes at the SP-B+1580 site are associated with an increased risk for mechanical ventilation requirement, respiratory distress and septic shock (Quasney et al., 2004). Furthermore, the polymorphisms of interleukin IL-10 have also been studied. Interleukin IL-10 has an important anti-inflammatory effect and participates in the resolution phase of the inflammation. However, if the microorganism has not been cleared this cytokine can have a damaging effect if it prematurely disrupts the inflammatory process. It has been reported that stimulated IL-10 release is higher in IL-10 homozygous G patients, who have the highest risk for septic shock (Schaaf et al., 2003), and a higher frequency of the IL-10 G allele has been reported in CAP patients who died (Gallagher et al., 2003).

Factors Related to the Aetiology and Severity of Community-Acquired Pneumonia Non-responding CAP is more frequent in severe pneumonia measured by the Fine risk class (Men´endez et al., 2004; Roson et al., 2004) (Table 11.2) as well as in patients admitted to the ICU. It has also been reported that bacteremic pneumonia and local metastatic infection such as pleural effusion is independently associated with a higher probability of non-responding CAP. In CAP due to Legionella pneumonia or Gram-negative microorganisms (Roson et al., 2004), the probability of treatment failure increases two- and fourfold, respectively. Legionella CAP can initially behave as a progressive pneumonia, with high mortality, and takes longer to resolve (Muder et al., 1987). Moreover, when the aetiology of CAP is mixed, the resolution of the infection is delayed (Kauppinen et al., 1996).

Treatment-Related Factors Discordant treatments (Roson et al., 2004) as well as treatments which do not adhere to the guidelines (Men´endez et al., 2005) have been associated with treatment failure and a higher mortality (Dudas et al., 2000; Feagan et al., 2000; Dean et al., 2001; Men´endez et al., 2002). We recently reported that when the initial antibiotic treatment is selected by a pneumologist or by the clinical resident, treatment failure is lower than when selected by a non-pneumology specialist (Men´endez et al., 2005). Interestingly, treatment failure is lower in influenza-vaccinated patients. This vaccine has a favourable impact against the appearance of pneumonia and on the reduction of hospitalization and mortality (Gross et al., 1995). The percentage of influenza-vaccinated patients is also lower among those with early failure (Roson et al., 2004).

DIAGNOSTIC EVALUATION OF TREATMENT FAILURE

219

Diagnostic Evaluation of Treatment Failure Diagnostic Management of Non-Responding Community-Acquired Pneumonia The approach to a patient with treatment failure requires several steps and the assessment of several aspects such as host factors that may explain delayed resolution, the degree of clinical compromise and the evolution of infiltrates in radiographs (Figure 11.1). The first evaluation of the clinical response of a patient takes place within the first 3 days if there is no amelioration of symptoms or even before in cases with early failure. The first step recommended comprises a careful review of the clinical history and the initial microbiological results in order to confirm the diagnosis of CAP. Important epidemiological clues may orientate the differential diagnosis such as the presence of unusual microorganisms related to previous journeys, pets, hobbies and others. Complete re-evaluation of clinical history may lead to other alternative non-infectious diagnoses and guide the differential diagnosis. Non-responding CAP Clinical re-evaluation

Non-invasive samples Sputum Blood culture Antigens Other cultures

Bronchoscopy

Chest X-ray/CT

PBS BAL Biopsy

Empirical herapeutic change Adjust treatment to microbiological results

Figure 11.1 Approach to a patient with treatment failure PBS: protected brush specimen BAL: bronchoalveolar lavage

On confirmation of CAP without unusual microorganism, host factors may explain the slower resolution of infectious parameters. In addition, elderly patients with comorbid conditions or immunosuppression may explain a slower resolution of symptoms. In these cases and if there is no clinical deterioration a conservative approach with clinical observation and serial radiographs would be enough. Chest radiographs may show pleural effusion, lung abscess and/or new infiltrates. Pleural effusion is a frequent cause of treatment failure and requires thoracocentesis. Non-invasive microbiological studies may rule out the persistence of infection, the

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appearance of resistance during treatment or the appearance of a new nosocomial infection. Furthermore, the demonstration of Legionella spp., bacteremic pneumonia and other aetiologies may explain a protracted clinical course and delayed resolution. An aggressive approach is necessary when microbiological aetiology is not found or in cases without host-related delayed resolution and/or clinical deterioration. In addition to further radiological studies and non-invasive samples, endoscopic methods should be performed to evaluate the airways and to obtain samples for microbiological tests and other studies. Bronchoscopy allows direct observation of the airways and the recovery of samples directly in the infected lobe. In fact, the diagnostic yield of protected brush specimen (PBS) and bron¨ choalveolar lavage (BAL) is 41 % in patients with treatment failure (Ortqvist et al., 1990; Arancibia et al., 2000; Roson et al., 2004). A complete processing of BAL for microbiological and non-microbiological studies also provides useful diagnostic information. The approach to persistence of infiltrates in radiographs after treatment is another clinical setting which usually does not require urgent management. The therapeutic approach may be more conservative on the reduction of the infiltrates on radiographs, an amelioration of the symptoms and fewer than 6 weeks have passed (Kuru and Lynch, 1999). However, if the infiltrate has not reduced after 6 weeks or if the symptoms persist, a more complete evaluation with bronchoscopy and computed tomography (CT) may be indicated.

Microbiological Assessment Although routine initial microbiological studies do not demonstrate any impact on patient outcome, they may provide useful information if the diagnosis is confirmed (Luna et al., 1997; Sanyal et al., 1999; Pereira Gomes et al., 2000) and they allow appropriate treatment in almost 40–50 % of non-responding CAP. Microbiological evaluation (Table 11.3) should begin with assessment of samples obtained from non-invasive techniques, to search for infrequent and/or resistant microorganisms. More recent techniques such as polymerase chain reaction in blood, urine and airway samples allow the identification of S. pneumoniae and Legionella (Men´endez et al., 1999; Welti et al., 2003) as well as Chlamydia pneumoniae and Mycoplasma pneumoniae and viruses in pharyngeal swabs. However, these techniques have not been completely standardized and are still under development. In processing BAL fluid Gram staining should be performed after centrifugation. This stain is useful to identify the microorganism and has predictive value for bacterial growth and also provides information on the differential diagnosis of noninfectious causes. Procedures for microbiological evaluation should include stains and cultures for the usual bacteria, fungi, viruses and opportunistic germs, including conventional and modified Ziehl for Nocardia spp., and direct immunofluorescence and subsequent culture for the investigation of Legionella. To differentiate between colonization and infection by the usual bacteria, the colony count method is used

MICROBIOLOGICAL ASSESSMENT

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Table 11.3 Microbiological assessment indicated for non-responding or progressive pneumonia Non-invasive samples -Sputum • Gram stain and bacteria culture • Legionella DIF • Ziehl and Giemsa stain • Stain for fungi -Blood • Two sets -Urine • Legionella and pneumococcal antigen Invasive samples -Tracheal aspirate, PBS and/or BAL • Bacterial cultures with colony counts • Mycobacterial stain and cultures • Fungi stain and cultures • Opportunists DIF: direct immunofluorescence

but should be interpreted in combination with other tests, since previous antibiotic treatment can reduce the counts below the established cut-off of 103 CFU/mL for PBS and 104 CFU/mL for BAL. In patients undergoing mechanical ventilation, the tracheal aspirate provides a good diagnostic yield in non-responding pneumonia (sensitivity of 93 % and specificity of 80 % for a cut-off of 105 CDU/mL; Wu et al., 2002). It remains to be demonstrated whether the information obtained from the analysis of biological samples and the subsequent changes of treatment in CAP reduces mortality. The results available from studies of nosocomial pneumonia show the usefulness of these evaluations to select antibiotic treatment, but not to improve the prognosis (Niederman, 2000).

Diagnostic Studies of Non-Infectious Aetiology Several authors have reported the frequency of this diagnosis in non-responding pneumonia to be around 20 % (Arancibia et al., 2000; Men´endez et al., 2004). With the use of the May–Gr¨unwald Giemsa stain for cellular identification and the Perls’ stain to evaluate hemosiderin, Jacobs et al. (1999) suspected a non-infectious origin in a group of ICU patients with pneumonia. Arancibia et al. (2000) found 22 % of non-infectious causes in non-responding CAP using bronchoscopy. The study and cell count obtained from BAL are very useful in the orientation of diagnosis towards non-infectious causes (Jacobs et al., 1999).Thus, in the presence of >20 % eosinophils it is mandatory to rule out causes such as

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pulmonary eosinophilia, fungal infection, drug-induced pneumonitis or others. Pulmonary haemorrhage is suggested by the presence of blood or hemosiderin-loaded macrophages (>20 %), and an increase in lymphocyte count suggests hypersensitivity pneumonitis, sarcoidosis or pulmonary fibrosis. Although not very frequent lung carcinoma may be the reason for unresolved images (Fein et al., 1993). Feinsilver et al. (1990) reported that bronchoscopy was most likely to yield a specific diagnosis in non-smoking patients with multilobar infiltrates of long duration and may be avoided in older, smoking, or otherwise compromised patients with lobar or segmental infiltrates. The value of bronchial and transbronchial biopsy in treatment failure has not been clearly established and depends on the pre-test probability of other diagnoses. If abnormalities in the airways are found, a bronchial biopsy should be obtained. The role and indication of transbronchial biopsy are not clear. This procedure should be indicated if airway examination rules out other findings and if there is no evidence of infection because other diagnoses can be made. Arancibia et al. (2000) obtained up to 57 % of diagnoses with transbronchial biopsy in non-responding pneumonia, although this procedure was done only in 25 % of their cases. They concluded that it was particularly useful in cases of non-infectious causes including neoplasia, BOOP and histiocytosis X. Van der Eerden et al. (2005) reported that the use of bronchoscopy in patients with treatment failure or non-sputum showed a diagnostic yield of 52 % and 49 %, respectively. Open lung biopsy is indicated when other diagnostic methods have been unsuccessful. Nonetheless, Dunn et al. (1994) pointed out that the procedure seldom provides relevant information to improve prognosis. However, Feinsilver et al. (1990) found that diagnosis by open lung biopsy was reached in 2 out of 35 cases of non-responding pneumonia with previous negative bronchoscopy results.

Radiological Studies In non-responding pneumonia, plain chest X-ray can show pleural effusion, cavitation and/or new infiltrates (Franquet, 2001). These findings are more evident on CT scan, which allows detailed study of the parenchyma, interstitium, pleura and mediastinum. Pulmonary CT scan findings may orient towards some specific microorganisms, even though the radiographic images are not pathognomic. Images of nodules surrounded by a halo of ground-grass attenuation, with involvement near the pleura, are suggestive of pulmonary aspergillus and/or Mucor infection. Similar nodular images have been described in infections by Candida or cytomegalovirus, Wegener’s granulomatosis, Kaposi’s sarcoma and haemorrhagic metastases. As a characteristic feature Pneumocystis jiroveci pneumonia shows ground-glass opacity or images of interstitial pneumonia. Images of nodules or multiple masses with or without cavitation can be caused by Nocardia spp., Mycobacterium tuberculosis or Q fever. Diffuse or mixed interstitial infiltrates may be due to virus or M. pneumoniae. Distinguishing infectious from non-infectious aetiology with the use of imaging studies is a field of investigation that is currently under development. Tomiyama

SUMMARY

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et al. (2000) were able to correctly classify the aetiology of acute lung diseases as infectious or not in 90 % of the patients using only high-resolution CT scan. Perfusion–ventilation gammagraphy and/or helicoidal CT should be performed if pulmonary embolism is suspected, especially in the absence of microorganisms and in the presence of other risk factors such as prolonged immobilization, signs of deep vein thrombosis and right ventricular overload or dilatation.

Therapeutic Approach Since infections are the most frequent causes of treatment failure, empirical adjustment of antibiotic therapy is mandatory. An interval of 72 hours is usually recommended before this change, except if there is severe clinical deterioration and/or worsening of the radiological infiltrates. In early treatment failure, broad-spectrum antibiotic therapy may be administered even before 72 hours. If possible new invasive samples should be obtained for microbiological studies prior to adjusting antibiotic therapy even though results may not be available for up to 48 hours. In non-responding CAP, the new antibiotic regime must broaden the spectrum to cover not only the usual bacteria, but also resistant S. pneumoniae, P. aeruginosa, S. aureus and anaerobic bacteria. The treatment should include anti-pseudomonal β-lactams (cefepime, imipenem, meropenem, piperacillin–tazobactam) and intravenous fluoroquinolones. In cases of community-acquired MRSA (Panton–Valentine leukocidin strains) antimicrobial treatment should, depending on susceptibility tests, include linezolid, clindamicin, vancomycin or combinations of these with or without rifampicin (Micek et al., 2005). In severe COPD patients with prolonged steroid treatment or in patients treated with immunosuppressants, antifungal therapy covering Aspergillus spp. should be considered while awaiting microbiological results. Non-antibiotics treatments recommended in the latest ATS/IDSA guidelines should be drotrecogin alfa activated in early failure with physiological severe compromise. Promising results have been achieved in ongoing investigation on the possibility of modulating the excess inflammatory response with steroids in patients with severe CAP who have the greatest probability of failure. Future studies must determine the target population in whom these treatments should be directed and the usefulness of biological markers in failure to achieve therapeutic response.

Summary Non-responding pneumonia is defined as a clinical condition with inadequate response to antimicrobial therapy. Inadequate response may proceed as progressive pneumonia with severe acute respiratory failure and/or septic shock or as failure in achieving clinical stability. The incidence of treatment failure in communityacquired pneumonia is about 10–15 %. Causes of non-responding CAP include

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resistant and unusual microorganisms, persistent infections and also non-infectious reasons. The factors associated with a lack of response to empirical antibiotic treatment are not completely known. It has been recently recognized that an excessive pro-inflammatory systemic response in patients with sepsis and severe CAP is associated with deleterious effects and a worse prognosis. The excess of pro-inflammatory cytokines has mainly been associated with initial severity and possibly the genetic susceptibility of each individual. Diagnostic management depends on the clinical deterioration, patient characteristics, comorbid conditions and the onset of failure. A conservative approach with clinical observation and serial radiographs could be recommended in elderly patients with comorbid conditions that may explain delayed response. Invasive studies with bronchoscopy to obtain protected brush specimen and bronchoalveolar lavage are indicated in cases of clinical deterioration or failure to stabilize. The diagnostic yield of a systematic approach with imaging procedures and non-invasive and invasive samples reaches almost 70 %. An empirical change in antibiotic therapy to cover a wider microbial spectrum is required in patients not responding to therapy. The mortality of patients with non-responding pneumonia is increased nearly fivefold.

Conclusions Lack of response to treatment in CAP represents a threatening condition with high mortality. Although there is no clear-cut definition or time to consider a CAP as non-responding, a recent proposal has been released by an ATS/IDSA consensus. Infectious and non-infectious reasons may cause lack of response; a complete reevaluation obtaining invasive respiratory samples have a diagnostic yield around 70 %. However, improvement in diagnosis does not mean better survival. Recently, much attention has been directed to the inflammatory response of the host, mainly focusing in innate response against microorganisms and its genetic polymorphisms. Research with non-antibiotic treatments capable of modulating the response of the host is ongoing. Future studies must determine the target population to whom these treatments should be directed and the usefulness of biological markers for early identification.

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12 Influenza and Pneumococcal Vaccination for Prevention of Community-Acquired Pneumonia in Immunocompetent Adults ¨ ˚ AKE ORTQVIST Karolinska Institutet, Department of Medicine, Unit of Infectious Diseases, Solna, and Department of Communicable Diseases Control and Prevention, Stockholm County Council, Stockholm, Sweden

Introduction This chapter will discuss the role of influenza and pneumococcal vaccines as preventive measures of community-acquired pneumonia (CAP) in immunocompetent adults. The current vaccines, their immunogenicity, safety, efficacy and effectiveness will be reviewed.

Influenza Vaccination Among adults the risk for complications to seasonal influenza is highest among those who are 65 years of age or older. In this age group secondary lower respiratory infections, especially pneumonia, are common and also an important causes of death (Smith et al., 2006). The temporal relationship between influenza peaks and an increase in cases of bacterial pneumonia has been well known clinically for

Community-Acquired Pneumonia: Strategies for Management Edited by Antoni Torres and Rosario Men´endez  2008 John Wiley & Sons, Ltd

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a long time and has been well described both during seasonal influenza (Foy et al., 1979) and pandemic influenza, such as the Hong Kong in 1969 (Schwarzmann et al., 1971).

Current Vaccines The influenza vaccines used today are mostly based on ‘inactivated’ virus (IV), i.e. highly purified egg-grown viruses that have been made non-infectious. Vaccines are basically of three types: whole virion vaccines consisting of whole inactivated or killed virus; subunit vaccines made of the H (haemaggluttinin) and N (neuraminidase) surface antigens; and split virion vaccines where the viral structure has been broken up resulting in both internal and surface antigens being included in the vaccine. The IV vaccines are administered by intramuscular administration. Recently, live attenuated influenza vaccines (LAIV), which can be administered non-invasively by nasal application, have been evaluated in clinical studies (Beyer et al., 2002). Both IV and LAIV vaccines are trivalent, i.e. they include the predicted antigenic elements for two influenza A types (usually A H3N2 and A H1N1) and one influenza B type.

Immunogenicity and Safety A haemagglutinin-inhibiting (HI) titre of ≥ 40 after vaccination is the normally accepted surrogate marker for protective efficacy against clinical influenza (Beyer et al., 2002). While vaccination with IV induces a ‘protective’ HI titre against influenza A and B in 70–100 % of healthy adults, the response in the elderly is less good and only between 30 and 70 % reach a HI titre of > 1:40 (Iorio et al., 1992; Govaert et al., 1994a; Bernstein et al., 1999). New formulations or additions of different adjuvants, such as IL-2 supplemented liposomal vaccine (Ben Yehuda et al., 2003) and the MF59 oil-in-water emulsion (Squarcione et al., 2003; Puig-Barbera et al., 2004), may improve immunogenicity in older people or other persons at risk. Live attenuated vaccines do not reach as high HI titres, as the inactivated, but induce significantly higher local IgA titres in the nasal mucosa (Beyer et al., 2002). Both IV and LAIV vaccines are safe (Demicheli et al., 2004). Systemic reactions after vaccination with IV are seen in less than 10 % of vaccinated, which is comparable to persons receiving placebo (Beyer et al., 2002), while mild local reactions, such as ‘a sore arm’, are more common after vaccination with IV than after placebo, 15–20 % vs 5–10 %, respectively (Margolis et al., 1990; Govaert et al., 1993; Allsup et al., 2001). Whole virion vaccines are generally associated with more frequent local reactions than split-virion vaccines (al Mazrou et al., 1991). After nasal administration of LAIV, local reactions, such as a couple of days of ‘runny nose’, are quite common and occur in about 40 %, as compared with about 25 % in those who receive placebo (Nichol et al., 1999).

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Annual revaccination with IV vaccines is safe and does not lead to either a decreasing immune response or a less good protection (Beyer et al., 1999; Buxton et al., 2001).

Vaccine Efficacy and Effectiveness Healthy Adults

A Cochrane analysis evaluating 25 randomized or quasi-randomized studies including close to 60 000 vaccinees, found the preventive efficacy of influenza vaccination against serologically verified influenza in healthy adults 14–60 years of age to be 70 % (95 % confidence interval (CI) 56–80) for IV and 48 % (95 % CI 24–64) for LAIV (Demicheli et al., 2004). For clinical influenza the effectiveness was smaller, 15 % (95 % CI 8–21) for LAIV and 25 % (95 % CI 13–35) for IV. This is not surprising since influenza-like illness may be caused by many different viruses. Although vaccination with IV significantly reduced time off work for clinical influenza, it was only by 0.16 days (95 % CI 0.04–0.29). A few, mostly older studies, including in total about 20 000 persons, attempted to estimate the efficacy of the vaccine in preventing complications to influenza in healthy adults (Demicheli et al., 2004). However, the complication rate, overall and for hospital admissions, was very low (in general under 1 %) and there was no difference between the groups in any of the studies, nor in the meta-analysis. Health-Care Workers

There is some evidence from two cluster-randomized studies that influenza vaccination of health-care workers (HCW) may reduce mortality of elderly people in long-term hospitals, although no difference in the proportion of elderly positive for influenza was seen (Potter et al., 1997; Carman et al., 2000). Two systematic reviews have confirmed these results, but at the same time stressed the presence of methodological problems, such as selection biases and generalizability (Burls et al., 2006; Thomas et al., 2006). Evidence supporting the effectiveness of vaccinating HCWs for protection of residents was provided by a recent cluster-randomized controlled trial in nursing and care homes in the UK (Hayward et al., 2006). During two consecutive influenza seasons, 2003–04 and 2004–05, the vaccine uptake among staff in intervention and control homes was 48 % vs 6 % and 43 % vs 4 %, respectively. There was only a 4 % difference in vaccine coverage of residents between the intervention and control homes. During the first season there was a significant decrease in mortality of residents in intervention homes, compared with control homes (−5 per 100 residents, 95 % CI–7 to −2). There was also a significant reduction in influenza-like illness and in consultation by GPs and admission to hospitals for influenza-like illness. No difference was seen between the groups during the non-influenza period of the first season, or during the second influenza season when there was very little influenza circulating.

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High-Risk Adults < 65 Years of Age

There are no randomized trials specifically studying this patient group. In a large Dutch nested case-control study about 10 000 primary care patients 18–64 years with different high-risk medical conditions were evaluated during the 1999–2000 influenza epidemic (Hak et al., 2005). After adjustments, for covariates and confounding by indication, vaccination prevented 26 % (7–47) of GP visits and 87 % (39–97) of hospitalizations for acute respiratory or cardio-vascular disease, and 78 % (39–92) of all-cause deaths. Elderly Persons

Only one high-quality randomized placebo-controlled trial (RCT) has been performed in the elderly (Govaert et al., 1994b). This trial was not designed to analyse protection against complications from influenza, but clearly showed that in persons 60 years of age, or older, without any high-risk conditions, a split-virion vaccine conferred significant protection against serological influenza (50 %), clinical influenza (47 %) and against the combination of serological and clinical influenza (58 %). Numerous observational studies over the years have investigated the efficacy of the influenza vaccine and most of those have been included in one or more of the three meta-analyses performed between 1995 and 2005. The first meta-analysis by Gross et al. (1995) included 20 cohort studies published up to 1992, the second by Vu et al. (2002) included 15 studies, one RCT and 14 cohort or case-control studies, up to 31 December 2000, and the third by (Jefferson et al., 2005) included 64 studies, five RCTs, 49 cohort and 10 case-control studies up to 31December 2004. The total number of observations varied between about 30 000 (Gross et al., 1995) to several millions (Jefferson et al., 2005) and there were significant differences in viral circulation, vaccine matching, and study quality between single studies included in the three meta-analyses. Despite this, the main results of the three meta-analyses are quite consistent concerning serious complications to influenza (Table 12.1). Vaccination seems to be most effective in persons living in homes for the elderly by preventing about 45–50 % of pneumonia, hospital admission from influenza or pneumonia, and deaths from influenza or pneumonia, and by preventing about 60–70 % of all-cause deaths. In elderly living in the community well-matched vaccines were shown to, after adjustments of confounders, prevent for hospital admissions from influenza or pneumonia (vaccine efficacy [VE] 27 %, 21–33 %) respiratory diseases (VE 22 %, 15–28 %), and cardiac disease (VE 24 %, 18–30 %), and for all-cause mortality VE 47 %, 39–54 %) (Jefferson et al., 2005). In a couple of recent observational studies no consistent protective effect of the vaccine against pneumonia could be demonstrated. In a Dutch population-based cohort study, including about 26 000 subjects, the effects of annual vaccination on the occurrence of lower respiratory tract infections (LRTI) were studied during 1996 to 2002 (Voordouw et al., 2006). No protective effect was observed after a first vaccination. However, in persons without comorbidity revaccination reduced the risk for LRTI by 33 % (95 % CI 8–52) and for pneumonia by 50 % (95 % CI

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Table 12.1 Efficacy (in per cent with 95 % confidence interval within parentheses) of inactivated influenza vaccine in elderly persons according to three meta-analyses performed between 1995 and 2005 Environment/outcome

Gross et al. (1995)

Elderly living in the community Prevention of pneumonia Prevention of hospitalization for influenza or pneumonia Prevention of death from influenza or pneumonia Prevention of death all causes Institutionalized elderly Prevention of pneumonia Prevention of hospitalization Prevention of death from influenza or pneumonia Prevention of death all causes

NDa

a Not b No

Vu et al. (2002)

Jefferson et al. (2005)

ND 33 (27–38)

NSb 27 (21–33)

47 (25–62)

NS

50 (45–56) ND

47 (39–54)

53 (35–66) 50 (28–65) ND

46 (30–58) 45 (16–64) 42 (17–59)

68 (56–76)

60 (23–79)

included in the analysis. statistically significant preventive effect shown.

7–73) during epidemic periods. Among patients with comorbidity, who accounted for about 90 % of all LRTI and pneumonia cases during epidemic periods, no preventive effect was seen. In an Australian study, using a case-cohort design, the multivariate analysis demonstrated a relative risk of CAP of 0.98 (95 % CI 0.84–1.15) for those who were vaccinated with influenza vaccine vs no vaccination (Skull et al., 2007). Finally, a study from the USA evaluated the impact of prior influenza vaccination on in-hospital mortality among about 17 000 adults with CAP (Spaude et al., 2007). In more than half the patients the vaccination status was unknown, while the vaccinated group accounted for a little less than 10 % and the unvaccinated for about 30 % of the patients. After adjustments for comorbidity and pneumococcal vaccination the authors found that all-cause mortality was significantly lower in vaccine recipients, than in unvaccinated (odds ratio (OR) 0.61; 95 % CI 0.43–0.87). It must be kept in mind that all the above-cited data on the preventive effect of vaccination on influenza complications in high-risk or elderly persons are based on observational studies. People who seek or accept vaccination may have a riskpattern for pneumonia or death that is different from that of individuals who abstain from vaccination (Jefferson et al., 2005). While a concomitant chronic disease may increase the likelihood of being vaccinated (‘confounding by indication’), the same may apply to a high degree of health consciousness among healthy individuals (‘healthy-user bias’). Further, the propensity for being vaccinated may not be the same among all persons suffering from the same underlying disease. Adjustment for differences in base-line factors by multiplicative models does not fully circumvent such selection bias, so these have to be addressed by other methods, such as

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using vaccinated and unvaccinated subjects as their own reference by comparing the mortality during the influenza epidemic with that during a period with no circulating influenza (Jackson et al., 2006; Mangtani et al., 2004). We addressed this problem in a population based prospective cohort study in Stockholm County, Sweden, including all persons 65 years, or older, (n ≈ 260 000) during three influenza ¨ seasons, 1998–99, 1999–00, and 2000–01 (Ortqvist et al., 2007a). The relative risks for mortality among vaccinated versus unvaccinated were estimated using Cox’ proportional hazards regression, adjusted for, and stratified by, demographic factors and comorbidity during and out of, respectively, each of the three seasons. Similar to most other studies, influenza vaccination was associated with an unadjusted reduction in all-cause mortality by around 40–50 % during all three seasons. Adjustment for demographic factors and comorbidity reduced these estimates by only some 5 %. However, after adjustment also for differences in mortality between vaccinated and unvaccinated after the influenza season the reduction of all-cause mortality among vaccinated persons decreased to 14 %, 19 % and 1 %, respectively, during the three seasons (Table 12.2). A healthy-user bias, i.e. that vaccination uptake in our cohort was higher among persons with lower risk of death within each strata of adjustment (age, sex, socio-economic status and comorbidities), was probably the reason for the falsely high effectiveness, despite adjustment for demographics and comorbidity. This phenomenon was particularly evident during the 2000–2001 season when vaccinated subjects, after adjustment for known confounders, had a 37 % reduced risk of death during the influenza season despite that there was no or little influenza circulating in the community. However, when the reduced out-of-season mortality was taken into account no preventive effect of the vaccine against death could be demonstrated that season. Table 12.2 Effectiveness of influenza vaccination in prevention of death all causes among elderly in Stockholm County (n ≈ 260 000) during three consecutive influenza seasons (95 % confidence interval given in parentheses)

Unadjusted ( %) Adjusted for demographics and co-morbidity (%) Adjusted for demographics and co-morbidity and mortality during non-influenza season (%) Number needed to vaccinate to prevent one death Influenza activity Match between vaccine and circulating strain

1998–1999

1999–2000

2000–2001

50 44

46 40

42 37

14 (5–23)

19 (11–27)

1 (−10–11)

297 (212495)

158 (123–222)

743 (314–8)

Moderate Good

Moderate-high Good

Low Good

Jackson et al. (2006) found that the relative difference in mortality between vaccinated and unvaccinated was largest in the period before the influenza season,

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indicating a preferential receipt of vaccine by relatively healthy elderly persons. Our study could confirm their findings and we concluded that there are, at least, two ¨ principally different selection processes involved (Ortqvist et al., 2007a). The first is that persons with a high likelihood of dying within a few weeks are unlikely to seek or receive vaccination. The second mechanism is a more general association between the probability of dying and the probability of having a vaccination at all, illustrated by the observed difference in mortality after the influenza season, which could not be explained with differences in demographics or comorbidity.

Pneumococcal Vaccination Streptococcus pneumoniae remains the most common cause of community-acquired pneumonia (CAP) in patients admitted to hospital, the most common cause of pneumonia requiring intensive care treatment, and accounts for more deaths, than any ¨ other pathogen, among patients with CAP (Ortqvist, 2001a).

Current Vaccines There are currently two types of pneumococcal vaccines available, a 23-valent capsular polysaccharide vaccine (23-PV) and a 7-valent protein-polysaccharide conjugate vaccine (7-PCV). The polysaccharide vaccine, which has been available for more than 20 years, includes 25 µg purified capsular polysaccharide antigens from each of the 23 serotypes (serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F) that represent ¨ about 90 % of all serotypes that cause invasive pneumococcal disease (Ortqvist, 2001b). Pneumococcal polysaccharide-protein (CRM197) conjugate vaccines have been developed to induce antibody production and an immunological memory also in very young children with an immature immune system, since they respond poorly to polysaccharide antigens (Oosterhuis-Kafeja et al., 2007). The 7-valent pneumococcal conjugate vaccine (7-PCV), which has been on the market since the end of the 1990s, was developed with a focus on the serotypes that were the most common among children in the USA and often also associated with lowered susceptibility to penicillin, namely serotypes 4, 6B, 9V, 14, 18C, 19F and 23F. The amount of purified capsular polysaccharide antigens is 2 µg for all serotypes except for 6B, which include 4 µg. Conjugate vaccines including 10 to 13 serotypes are currently under evaluation in clinical trials.

Immunogenicity Ninety different serotypes of S. pneumoniae are described, based on antigenic differences of the capsular polysaccharide (Henrichsen, 1995). Capsular polysaccharide antigens induce type-specific antibodies, by a T-cell-independent mechanism,

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which enhances opsonization, phagocytosis and killing of pneumococci by ¨ phagocytic cells (Ortqvist, 2001b). Vaccination of adults induces a twofold or greater rise of serotype-specific antibodies within about 3 weeks (Musher et al., 1990). There is generally a good antibody response also in older persons (Hedlund et al., 1994; Sankilampi et al., 1996), although a subset may respond only to some serotypes (Rubins et al., 1998, 1999). The response may also be less good in persons with chronic underlying illnesses, e.g. bronchiectasis (van Kessel et al., 2005). Serotype-specific IgG antibody concentrations correlate with the quality of anticapsular antibodies, measured by their activity in the opsono-phagocytosis assay (Goldblatt et al., 2005; Musher et al., 1986). The correlation may be poor among certain serotypes and higher pre- and post-polysaccharide immunization antibody levels may be needed to support opsono-phagocytosis in elderly subjects compared with young adults (Romero-Steiner et al., 1999; Yu et al., 1999). In a recent study, elderly patients who developed a culture-verified pneumococcal pneumonia after being vaccinated with the 23-PV responded with a significant increase of antibody concentration (> 1 ug/mL) post-vaccination, and equally well as controls, to most ¨ serotypes, but not to the infecting serotype (Ortqvist et al., 2007b). Neither was there any significant difference in the opsono-phagocytosis assay post-vaccination between patients and controls. This indicates that the 23-valent pneumococcal vaccine should be regarded as 23 different vaccines, rather than one, so that an older person who fails to respond to one serotype may well be protected against infection by the other 22 serotypes. From the peak antibody concentration, about 3 weeks after vaccination, there is a gradual decline to pre-vaccination levels. The duration of the antibody rise above the pre-vaccination level has varied in different studies from 3–4 years to more than 5–10 years (Konradsen, 1995; Sankilampi et al., 1997). The immune response to revaccination with 23-PV has been relatively little studied using modern techniques. In one large study, patients who were revaccinated obtained as high antibody concentrations for two out of three serotypes measured, as those receiving their primary dose (Jackson et al., 1999). In another study, the antibody concentration was measured in the same 61 patients after primary vaccination and after revaccination about 5 years later (Torling et al., 2003). At revaccination 60 % of the patients responded with an antibody fold increase > 2 to > 2 of 6 serotypes, although both antibody levels and antibody fold increases were significantly lower than after the primary vaccination. So far immunogenicity studies of 7-PCV in the elderly, or other high-risk adults, have been largely inconclusive. In contrast to in children, a single injection of protein-conjugated polysaccharide vaccine does not seem to consistently elicit a better antibody response than the 23-PV vaccine alone in older persons, and vaccination with protein-conjugated vaccine followed by polysaccharide vaccine alone does not induce a booster effect (Abraham-Van Parijs, 2004).

Safety Mild local reactions, such as a slight soreness and/or redness or swelling may occur in up to 50 % of the cases after primary vaccination with 23-PV, but are

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mostly very mild and short-lived (Jackson et al., 1999). Severe soreness, swelling (> 10 cm) or redness occurs in about 2–3 % and usually resolves within a few days, while serious reactions are extremely rare (Honkanen et al., 1996; Jackson et al., 1999). After revaccination, mild local reactions are even more common, than after primary vaccination, but most resolve within 48 hours (Jackson et al., 1999, 2005; Rutherford et al., 1995; Torling et al., 2003). The frequency of major local reactions has varied between 10 and 15 % and the risk seems to be higher in younger age groups and in persons with high pre-vaccination antibody levels.

Vaccine Efficacy and Effectiveness of the 23-PV The efficacy of the 23-PV has been evaluated in eight systematic reviews, the latest including studies up to 2003 (Fine et al., 1994; Hutchison et al., 1999; Moore et al., 2000; Cornu et al., 2001; Watson et al., 2002; Dear et al., 2003; Conaty et al., 2004; Melegaro and Edmunds, 2004). The results as well as the quality of these systematic reviews differ due to when they were performed and differences in methodology. The three most recent systematic reviews are the most comprehensive and have also included a systematic review of observational studies of invasive pneumococcal disease (Dear et al., 2003; Conaty et al., 2004; Melegaro and Edmunds, 2004). After 2003, several new observational cohort studies and an open RCT on the effectiveness of 23-PV have been published (Andrews et al., 2004; Christenson et al., 2004; Dominguez et al., 2005; Vila-Corcoles et al., 2005, 2006; Alfageme et al., 2006; Fisman et al., 2006; Musher et al., 2006; Mykietiuk et al., 2006; Skull et al., 2007). Young and Healthy Adults

Early RCTs have indicated that the 23-PV is 70–80 % effective in prevention of bacteraemic pneumococcal pneumonia in young healthy adults (Austrian et al., 1976; Smit et al., 1977). In these trials, which included populations with a very high incidence of pneumococcal disease in South Africa and Papua New Guinea, there was also a moderate protective effect against presumptive pneumococcal pneumonia and against death in pneumonia overall. Elderly Persons and Other Risk Groups

Invasive pneumococcal disease The two latest systematic reviews of RCTs (Conaty et al., 2004; Melegaro and Edmunds, 2004) clearly indicate that the 23-PV is about 50 % efficacious in prevention of invasive pneumococcal disease (IPD) in the general elderly population and in other persons with moderate risk for acquiring pneumococcal disease (Table 12.3). When including observational studies in their meta-analyses, either together with RCTs (Melegaro and Edmunds, 2004), or in separate analysis (Conaty et al., 2004), the authors found that the estimates of protection against IPD were consistent, homogeneous and compatible with those of RCTs. Also three more

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Table 12.3 Vaccine efficacy (in per cent with 95 % confidence interval within parentheses) of the 23-PV against invasive pneumococcal disease in elderly persons and/or persons with chronic underlying diseases according to two meta-analyses of randomized control studies and observational studies Source

Randomized controlled trials (RCTs)

RCTs + casecontrol studies

Melegaro and Edmunds (2004) Conaty et al. (2004)

44 (−45 to 79)

47 (30–60)

49 (−23 to 79)

Case-control studies

55 (44–64)

Cohort studies

47 (19–65)

recent observational studies support the efficacy of the 23-PV in prevention of IPD (Dominguez et al., 2005; Musher et al., 2006; Mykietiuk et al., 2006). Pneumonia There is no evidence from systematic reviews of RCTs that the 23-PV prevents against pneumonia in the elderly or other risk groups. However, in a recent open RCT performed in adults with COPD a high degree of protection against CAP, due to S. pneumoniae or unknown aetiology, was seen in persons less than 65 years of age, and especially in those with severe functional obstruction (forced expiratory volume (FEV) 1 < 40 %; Alfageme et al., 2006). Results from observational studies on the efficacy of 23-PV in prevention of CAP in the elderly have been conflicting. One of the systematic reviews of observational studies did in fact demonstrate a moderate protective efficacy of about 30 % against all-cause pneumonia, but it should be noted that the meta-analysis included only five, quite heterogeneous studies (Conaty et al., 2004). Findings from two more recent cohort studies support that the 23-PV may be associated with a reduction of pneumonia overall, and also with a reduction of pneumococcal pneumonia, hospitalization for pneumonia and death due to pneumonia (Christenson et al., 2004; Vila-Corcoles et al., 2005, 2006). In a large prospective cohort study, including all persons of 65 years of age or above (about 260 000 persons), in Stockholm County, Sweden, pneumococcal vaccination was associated with a 9 % (95 % CI 0–18) lower risk for being admitted to hospital with pneumonia, compared with those who were unvaccinated, during an observation period of 1 year (Christenson et al., 2004). This risk was even lower, 29 % (25–35), in persons who had received both influenza and pneumococcal vaccines, indicating a possible additive effect of the two vaccines. In another prospective cohort study, of about 11 000 persons 65 years of age, or older, in Taragona, Spain, pneumococcal vaccination, compared with no vaccination, was associated with a 21 % (95 % CI 2–36) lower overall pneumonia rate, 45 % (95 % CI 12–66) lower risk of pneumococcal pneumonia, 26 % (95 % CI 8–41) lower risk of hospitalization for pneumonia, and a 59 % (95 % CI 28–67) lower risk of death due to pneumonia (Vila-Corcoles et al., 2006). There are also two recent studies indicating that patients vaccinated

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with 23-PV, compared with unvaccinated, have a more favourable outcome when hospitalized for CAP (Fisman et al., 2006; Mykietiuk et al., 2006). In contrast, no protective effect of the 23-PV against non-bacteremic pneumococcal pneumonia was found in a case-control study performed in a Veterans Affairs Medical Center in Texas, USA (Musher et al., 2006). Neither could any protective effect of the 23-PV against CAP in the elderly be demonstrated in a large study using a casecohort design from Australia (Skull et al., 2007). In a multivariate analysis these authors found the relative risk for CAP for those being vaccinated with 23-PV vs no 23-PV vaccination to be 1.01 (95 % CI 0.87–1.16). However, this study, like some other ‘negative’ studies, was not designed to exclude the possibility of a small protective effect, less than 15–20 %, in prevention of CAP. The studies of (Christenson et al., 2004) and (Vila-Corcoles et al., 2006) did demonstrate VEs of that magnitude, 9 % and 21 %, respectively. Since S. pneumoniae is the cause of 25–40 % of all CAP in the elderly (Woodhead et al., 2005), a 10–20 % protective efficacy of the 23-PV against CAP would indicate a VE against pneumococcal pneumonia of 40–80 %. Effectiveness of Vaccination of Children with the 7-PCV on Pneumonia and Pneumococcal Disease in Adults

Vaccination of children with 7-PCV has been shown to be of benefit also for adults. Since the start of vaccination of children in the USA in the year 2000 a marked reduction of IPD has been noted both in the vaccinated cohorts and in adults, overall as well as for serotypes associated with reduced susceptibility to penicillin (Whitney et al., 2003; Kyaw et al., 2006). This ‘herd immunity’ effect has been most marked in the age groups of parents (20–39 years of age) and grandparents (above 65 years of age). A recent ecological study also demonstrated that vaccination of children with 7-PCV had an effect on the need for hospital treatment for pneumonia among adults (Grijalva et al., 2007). In the age group of 18–39 years, the incidence of hospital treatment for pneumonia overall and for pneumococcal pneumonia was 26 % (95 % CI 4–43) and 30 % (95 % CI 9–47) lower, respectively, at the end of 2004, compared with before the start of vaccination in 1997–1999.

Conclusions Influenza Vaccination Influenza vaccination is safe and protects adults of all age groups against influenza and influenza-like illness. In healthy adults, below 65 years of age, the risk for complications is small and the effectiveness of vaccination too limited to merit a general recommendation of vaccination. However, annual vaccination is recommended in HCWs in settings where elderly or other high-risk groups are treated or living, since this may reduce influenza complications among the residents/patients. In elderly persons, and other high-risk groups, influenza complications, such as pneumonia, are common and can clearly be prevented by vaccination. Although

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data from observational studies may overestimate the effectiveness somewhat, it is clear that vaccination remains the mainstay for the prevention of influenza and its complications in the elderly and other high-risk groups. Vaccination should be given yearly and of the currently available vaccines an inactivated split-virion or subunit vaccine is recommended.

Pneumococcal Vaccination Vaccination with the 23-PV is safe and offers a moderate to good protection in adults of all age groups against invasive pneumococcal disease (IPD). Elderly persons, and other high-risk groups, should be vaccinated with 23-PV since it reduces the risk for IPD by about 50 %. Whether or not 23-PV protects against non-bacteremic pneumococcal pneumonia in older persons remains controversial, but some observational studies do indicate that vaccination is associated with a slightly lowered risk for all-cause pneumonia. In young healthy adults the risk for severe pneumococcal disease is too low to recommend a general vaccination. Most elderly respond to revaccination, although the antibody rise may be less good than after primary vaccination, and severe side-effects are very rare. One revaccination, > 5 years after the primary dose, may therefore be considered.

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13 Adjunctive Therapy in Community-Acquired Pneumonia ANNA P. LAM1 AND RICHARD G. WUNDERINK2 1

Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA 2 Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

Introduction The advent of widespread use of penicillin in the 1940s and the resultant substantial reduction in mortality from community-acquired pneumonia (CAP) promised to herald a golden era in the treatment of pneumonia. However, despite significant advances in medical science, CAP remains the most common cause of death from infection and the seventh overall leading cause of death (Centers for Disease Control and Prevention, 1995). Mortality rates for CAP range from 5.1 % for ambulatory patients to 36.5 % for intensive care unit (ICU) patients (Fine et al., 1996). Modern intensive care has only made a small difference to the mortality in patients with severe pneumonia (Hook et al., 1983). Although the ageing population, increased number of patients with severe comorbid illnesses and the human immunodeficiency virus (HIV) epidemic have certainly contributed to the persistently high mortality rate (Plouffe et al., 1996; Watanakunakorn and Bailey, 1997; Torres et al., 1998), apparently healthy, immunocompetent patients continue to die from CAP, particularly with bacteremic pneumococcal and methicillin-resistant Staphylococcus aureus pneumonia (Burman et al., 1985; Watanakunakorn and Bailey, 1997; Gillet et al., 2002, Francis et al., 2005). Consistent with these findings, a recent British Thoracic Society study concluded that most deaths from CAP in Community-Acquired Pneumonia: Strategies for Management Edited by Antoni Torres and Rosario Men´endez  2008 John Wiley & Sons, Ltd

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young adults are not preventable by current available therapies (Simpson et al., 2000). While some causative microorganisms, such as Pseudomonas, and some strains of common causative microorganisms appear to be more virulent, the majority of CAP patients who die are infected with the same organisms as survivors and sensitive to commonly prescribed antibiotics. Given that most patients with CAP die despite microbiological confirmation that they received appropriate antibiotic therapy, the introduction of new antibiotic classes is unlikely to reduce mortality further. For this reason, research has been directed into non-antibiotic therapeutic measures. The current state of adjunctive therapy for CAP, including pneumonia-specific immunomodulatory therapies (see Table 13.1) and other advances in the intensive care management of patients with severe CAP, will be discussed. Table 13.1 Potential immunomodulatory therapies in community-acquired pneumonia Corticosteroids Prostaglandin inhibitors: indomethacin acetylsalicylic acid Immunoglobulin enhancement: immunoglobulin therapy pneumococcal vaccination anti-pseudomonal antitoxin antibodies Macrophage enhancement: interferon gamma Activated protein C Tissue factor pathway inhibitor Macrolides Statins Angiotensin converting enzyme inhibitors

Pneumonia Specific Immune Therapies Corticosteroids The use of corticosteroids in pneumonia remains highly controversial. The best evidence of benefit for corticosteroids comes from studies in specific, narrowly defined groups of patients with CAP caused by less common pathogens, of which Pneumocystis carinii/jerovicii pneumonia has been the most studied. Randomized, controlled trials have shown that corticosteroids reduce mortality in AIDS patients with Pneumocystis carinii /jerovicii pneumonia and significant hypoxia, if instituted at or prior to the onset of antibiotic therapy (Bozzette et al., 1990;

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Gagnon et al., 1990). Small cohort studies and case reports have suggested that corticosteroids may also improve the outcome of severe Varicella pneumonia (Mer and Richards, 1998; Lau, 1999; Ahmed et al., 2002; Popara et al., 2002; Adhami et al., 2006). Anecdotally, corticosteroids are frequently used in the setting of severe fungal pneumonia, particularly due to Histoplasmosis (Bradsher, 1996; Goldman et al., 1999). For the treatment of severe CAP (SCAP), Marik and colleagues studied the effect of a single 10 mg/kg dose of hydrocortisone 30 minutes prior to antibiotic therapy in a small randomized, placebo-controlled trial of 30 adult patients (Marik et al., 1993). Hydrocortisone had no detectable effect on the tumour necrosis factor TNF-α production in the following 12 hours, length of ICU stay, or mortality (only four deaths). Of note, the finding from this study that β-lactam antibiotics did not result in a significant increase in serum TNF-α levels suggests that rapid antigen release due to bacterial lysis is probably not a cause of deterioration in patients with SCAP, as previously postulated (Klugman, 1990). To evaluate the possible systemic and pulmonary immunomodulatory effects of intravenous methylprednisolone in SCAP, Mont´on and co-workers measured bronchoalveolar lavage fluid (BALF) and serum cytokines in 20 mechanically ventilated patients with severe nosocomial pneumonia or CAP (Monton et al., 1999). The eleven patients who received corticosteroids had significantly lower serum and BALF TNF-α, interleukin (IL)-1β, IL-6, and C-reactive protein levels. There was also a non-significant trend to lower mortality in the steroid treated group (36 % vs 67 %). Most recently, Confalonieri and colleagues compared intravenous hydrocortisone (200 mg bolus followed by 10 mg/hour for 7 days) with placebo in a randomized, double-blinded, placebo-controlled trial of 46 patients with SCAP admitted to the ICU (Confalonieri et al., 2005). The trial was stopped early after an interim analysis showed statistically significant improvement in oxygen and mortality benefit favouring the steroid group (0 % vs 30 %). However, the mortality difference was driven by deaths after day 8 and a high incidence of “delayed septic shock”. This clinical scenario has not been seen in any other SCAP study. The difference in percentage of patients who received non-invasive ventilation rather than endotracheal intubation and mechanical ventilation also confounds the data regarding a beneficial effect of steroids on gas exchange, especially given the fact that non-invasive ventilation has been shown by the same group to decrease mortality compared with invasive ventilation (Confalonieri et al., 1999). Unfortunately, the early closure of the study severely limits the ability to exclude confounding factors that may explain the mortality difference. In addition, the surprising lack of fatalities in the corticosteroid group also raises concern about bias in patient selection and whether the control or case cohorts are accurately representing patients with SCAP. Despite the considerable limitations of these studies, the existing body of literature suggests a trend towards benefit with corticosteroids. Clearly, further clinical studies are needed to definitively address the role of corticosteroids in SCAP.

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Immunoglobulin Enhancement Before the advent of antibiotic therapy, passive immunization with serum was used with some success in patients with pneumonia (Dowling and Lepper, 1951). Mortality was reduced by approximately 10 % in most age groups with a diminishing effect in patients over the age of 60. With the exception of patients with specific immunoglobulin deficiencies, this therapy has largely been abandoned due to the much greater efficacy of antibiotics, in addition to the difficulty and cost of obtaining sufficient serum. The development of new antiviral drugs has also largely obviated the anecdotal use of hyperimmune serum in cytomegalovirus and varicella pneumonitis. While the overall efficacy of pneumococcal immunization is unclear, especially in the elderly with some comorbid illnesses, several studies and a meta-analysis have suggested that even if pneumococcal pneumonia is not prevented, the incidence of invasive pneumococcal disease is decreased (Cornu et al., 2001; Fisman et al., 2006). The use of specific antipseudomonal exotoxin antibodies has been tried as an adjunct to antibiotics with some success in mice (Kohzuki et al., 1993) and guinea pigs (Hector et al., 1989), and pseudomonas-specific vaccines have enhanced antibiotic response in guinea pigs (Pennington et al., 1981). Antipseudomonal antibodies appeared safe in human subjects, with evidence of increased opsonophagocytic activity in a small phase I study of 20 subjects (Saravolatz et al., 1991), but further studies are required to determine whether they have any clinically relevant effect. In human sepsis studies, generic anti-endotoxin strategies have so far been disappointing (Greenman et al., 1991; Ziegler et al., 1991). Although they have not specifically been studied in pneumonia, the primary site of sepsis in many of the patients in these studies was the lung, indicating a low likelihood of benefit.

Macrophage Enhancement Legionella pneumophila is consistently identified as a leading cause of CAP, particularly in patients with SCAP (Klimek et al., 1983; Aubertin et al., 1987; Fang et al., 1990; Lieberman et al., 1996). Unlike pneumococcal pneumonia, the immune response to Legionella infection is predominantly of a TH1 type (Tateda et al., 1998) and bacterial killing is predominantly by macrophages (Friedman et al., 1998). Interferon gamma (IFN-γ) is a potent stimulator of macrophage function (Nathan et al., 1984; Murray, 1988). When Skerrett and Martin administered IFN-γ as an intratracheal bolus in rats with experimental L. pneumophila pneumonia, there was marked reduction in the replication of L. pneumophila in corticosteroid-treated rats but no detectable effect in immunocompetent rats or when given intraperitoneally (Skerrett and Martin, 1994). Recombinant IFN-γ can be given by aerosol, thus not only avoiding unwanted systemic side effects but also achieves much higher intrapulmonary levels compared with systemic administration (Debs et al., 1988; Jaffe et al., 1991). Clinical trials of nebulized IFN-γ in patients with pulmonary legionellosis are awaited.

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Drotrecogin Alfa (Activated Protein C) Recombinant activated protein C (drotrecogin alfa activated) was the first nonantimicrobial agent to show a reduction in mortality in severe sepsis (Bernard et al., 2001). In the large randomized, double blinded, placebo-controlled trial, the 28-day mortality was clearly better in subgroups of patients who received drotrecogin alfa activated, but the subgroup with community-acquired pneumonia accounted for the majority of the benefit of the drug (Laterre et al., 2005), with the greatest reduction in mortality seen with Streptococcus pneumoniae infection (relative risk (RR) = 0.56; 95 % confidence interval (CI) 0.35–0.88). The availability of rapid urinary antigen detection for S. pneumoniae allows this association to enter clinical decision (Smith et al., 2003; Roson et al., 2004). Drotrecogin alfa activated appeared to have a greater effect in single organ failure than multiple (≥ 2) organ failure, but clearly has its greatest benefit in patients who have the highest acuity of illness (acute physiology and chronic health evaluation [APACHE II] score > 25; Abraham et al., 2005). Worsening thrombocytopenia, suggestive of early disseminated intravascular coagulation, appears to be another important indicator for patients likely to respond to drotrecogin alfa activated (Ely et al., 2003). While different criteria for the administration of drotrecogin alfa activated have been established in different institutions around the world, the presence of pneumonia and shock should prompt physicians to consider its early use as adjunctive therapy.

Tifacogin (Recombinant Tissue Factor Pathway Inhibitor) Following on the heels of the success of drotrecogin alfa activated and the current understanding of the contribution of the procoagulant cascade to the pathogenesis of severe sepsis, the optimized phase 3 tifacogin in multicentre international sepsis trial (OPTIMIST) was designed to study the safety and efficacy of tifacogin (recombinant tissue factor pathway inhibitor [rTFPI]) in severe sepsis (Abraham et al., 2003). While the trial did not demonstrate a survival benefit for rTFPI in the general cohort, subgroup analysis indicated that patients with SCAP who were not receiving heparin therapy had a favourable response to treatment (51.5 % vs 29.3 %, uncorrected p = 0.015; Wunderink et al., 2006). This subgroup analysis of the OPTIMIST trial was used to design a large prospective phase III trial of tifacogin specifically in SCAP patients. Final results from the phase III studies will provide better insights into the exact role of rTFPI in the treatment of SCAP.

Macrolide Antibiotics Macrolides are known to possess a myriad of immunomodulatory effects, including alterations in leukocyte function, cytokine expression and mucus production. In vitro and animal studies have shown inhibitory effects of macrolides on neutrophil migration and superoxide generation by neutrophils (Labro et al., 1989; Joone et al., 1992; Mitsuyama et al., 1995; Tamaoki et al., 1997; Yamasawa et al.,

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2004). Interestingly, the presence of bacteria seems to alter the effects of macrolides on the immune system. In lipopolysaccharide-primed neutrophils, clarithromycin inhibits cytokine expression in the absence of bacteria but exposure to Klebsiella pneumoniae results in clarithromycin-enhanced cytokine expression (Reato et al., 2004). Similarly, azithromycin induces apoptosis of neutrophils in healthy volunteers, but co-incubation with Streptococcus pneumoniae prevents azithromycininduced neutrophil apoptosis (Koch et al., 2000). Azithromycin also interferes with ERK 1/2 and NF-κB signalling that leads to increased production of the MUC5AC gene, which encodes the major core protein of mucin secreted from the airway surface epithelium, in a Pseudomonas aeruginosa model (Imamura et al., 2004). The non-antimicrobial effects of macrolides were first clinically demonstrated with the remarkable success in the treatment of diffuse panbronchiolitis (Kudoh et al., 1998). No direct evidence presently exists to support the use of macrolides as immunomodulatory therapy in CAP. However, data from the literature (Figure 13.1) suggested improved outcomes when CAP was treated with macrolide-containing antibiotic regimens (Amsden, 2005). Retrospective analysis of a hospital claims database revealed that combination therapy with a macrolide significantly decreased overall mortality compared with monotherapy with a βlactam or fluoroquinolone antibiotic in CAP patients (Brown et al., 2003). Another database analysis found that the lack of inclusion of a macrolide to the initial antibiotic regimen was independently associated with death (p = 0.03; Martinez et al., 2003). In both retrospective case series (Waterer et al., 2001; Weiss et al., 2004) and prospective observational trials (Mufson and Stanek, 1999; Martinez et al., 2003; Baddour et al., 2004), addition of a macrolide to a cephalosporin is associated with improved outcome from bacteremic pneumococcal pneumonia, even when the pneumococcus was sensitive to the cephalosporin (see Figure 13.1).

Mortality odds ratio

1.2 1

1 0.8 0.6 0.4

0.4

0.42

0.3

0.29

0.22 0.2 0 Waterer

Mufson Martinez Baddour

Weiss

Harbarth

Figure 13.1 Odds ratio for death in bacteremic pneumococcal pneumonia when treated with macrolide combination therapy (Mufson and Stanek, 1999; Waterer et al., 2001; Martinez et al., 2003; Baddour et al., 2004; Weiss et al., 2004; Harbarth et al., 2005)

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The only study not showing a survival advantage was a retrospective analysis of placebo-treated patients qualifying for a severe sepsis interventional trial (Harbarth et al., 2005). This does not appear to be due to coverage of atypical pathogen coinfection, since quinolone–cephalosporin combination therapy has been suggested to have an increased mortality (Mortensen et al., 2005b). In addition, bacteremic patients with erythromycin-resistant or intermediately resistant isolates of S. pneumoniae who were treated with a macrolide had a mortality rate of 0 % versus 18 % (p = 0.06) in those patients who did not receive macrolide therapy (Lonks et al., 2002). Prospective studies are needed to evaluate the immunomodulatory role of macrolides in CAP.

Statins and Angiotensin Converting Enzyme Inhibitors The observations from patients who were taking statins at the time of development of pneumonia or other infection noted a lower likelihood of developing sepsis, death from sepsis or complications leading to ICU admission (Liappis et al., 2001; Almog et al., 2004; Fernandez et al., 2006; Hackam et al., 2006; Kruger et al., 2006; Thomsen et al., 2006). A retrospective cohort study of 787 patients with discharge diagnosis of pneumonia by Mortensen and colleagues showed that the use of statins at presentation was associated with decreased 30-day mortality (odds ratio (OR) 0.36, 95 % CI 0.14–0.92; Mortensen et al., 2005a). However, the largest prospective cohort study to date by Majumdar and co-workers, evaluating 3415 patients with CAP admitted to the hospital, found no benefit with statin use in mortality or need for ICU admission (Majumdar et al., 2006). Similar associations have been observed with prior angiotensin converting enzyme (ACE) inhibitor use and CAP, in particular with Japanese cohorts with specific ACE genotypes (Okaishi et al., 1999; Takahashi et al., 2005; Mortensen et al., 2005c). Large cohort studies in predominantly white populations did not find this association with ACE inhibitors (van de Garde et al., 2006; Etminan et al., 2006). Given the conflicting data, it is unclear whether or not prior or concurrent use of statins or ACE inhibitors has a protective role in CAP. However, none of the studies can be used to justify initiation of treatment with statins or ACE inhibitors after the development of CAP. A separate clinical trial is needed to validate this intervention.

Other Supportive Measures The supportive therapies unique to CAP are improved oxygenation and secretion clearance. The remainder of supportive care is not different than that for other critically ill patients with infection.

Prostaglandin Inhibitors The use of prostaglandin antagonists in the treatment of pneumonia has been studied in both animals and humans. In dogs with lobar pneumonia, indomethacin

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reduced the intrapulmonary shunt fraction from 29 % to 21 %, with a corresponding decrease in the consolidated lung regions (Light, 1986). Acetylsalicylic acid had a similar effect, reducing the shunt fraction from 38 % to 23 %. The mechanism is unclear but may be due to reversal of prostaglandin inhibition of the hypoxiainduced pulmonary vasoconstriction. The follow-up study in 10 human patients with bacterial pneumonia requiring mechanical ventilation studied the effect of indomethacin (1 mg/kg) on gas exchange (Hanly et al., 1987). Five subjects had substantial improvement in oxygenation with a small improvement in three additional patients. Improvement tended to occur in the patients with the greatest degree of hypoxemia. In contrast, Ferrer and co-workers found that a 2 g intravenous infusion of acetylsalicylic acid (ASA) resulted in no improvements in arterial oxygenation for seven patients with severe unilateral pneumonia (Ferrer et al., 1997). Although intrapulmonary shunting did decrease by a modest amount (28 % ± 17 % vs 23.5 % ± 13 %), the lack of clinically apparent benefit was discouraging. Several possible explanations were proposed to explain the discrepancy between this and the prior studies. Differences in efficacy between ASA and indomethacin may be the cause, but clear conclusions are difficult to draw given the limited data. Future studies should consider indomethacin in preference to ASA.

Positioning Therapy Community-acquired pneumonia is one of the most common causes of severe hypoxic respiratory failure. The addition of positive end expiratory pressure (PEEP), a common method to improve oxygenation, may actually worsen oxygenation in patients with severe asymmetrical lung disease such as CAP. High PEEP may overdistend the unaffected lung, thus increasing pulmonary vascular resistance on the local area. This overdistension may then lead to greater blood flow to the pneumonic area, especially if hypoxic vasoconstriction has been blocked by some bacterial product, and worsening shunt physiology. With extensive unilateral pneumonia, positioning the ventilated patient in the lateral decubitus position with the affected lung up has been demonstrated to improve oxygenation (Remolina et al., 1981). Positioning increases perfusion to the dependant, non-involved lung, increases secretion clearance from the affected lung, and may allow addition of PEEP without increasing shunt because the dependent lung is now less compliant and less likely to become overdistended.

Differential Lung Ventilation Differentially ventilating each lung by means of a dual lumen endotracheal tube may also be beneficial (Carlon et al., 1978; Hillman and Barber, 1980). This method allows the use of higher levels of PEEP in the less compliant, affected lung while maintaining lower levels of PEEP in the normal lung, thus theoretically reducing the risk of barotrauma. Ranieri and colleagues demonstrated a correlation between the level of PEEP and pro-inflammatory cytokine production, further

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supporting this approach to protect the ‘normal’ lung (Ranieri et al., 1999). Since this severe hypoxemia appears to be somewhat limited in duration, positional therapy, and possibly use of indomethacin, can usually temporize long enough for the normal hypoxic vasoconstriction to be restored and oxygenation to improve. A subgroup analysis of surfactant supplementation in patients with acute respiratory distress syndrome (ARDS) found that the subgroup with severe ARDS secondary to pneumonia or aspiration benefited, despite no overall difference in mortality. Once again, a prospective phase III trial to confirm this subgroup analysis is underway (ClinicalTrials.gov Identifier: NCT00074906).

Extracorporeal Membrane Oxygenation Extracorporeal membrane oxygenation (ECMO), a modification of cardiopulmonary bypass, was designed to provide oxygenation in patients with severe respiratory failure. Although available since the 1970s, initial poor results from a National Institutes of Health-sponsored prospective, multicentre randomized trial limited the use of ECMO to research centres (Zapol et al., 1979). However, a significant reduction in complications has led to resurgence in interest in ECMO as a means of providing oxygenation when all other means have failed. The role of ECMO has most extensively been studied in neonates. In newborn infants with respiratory failure unresponsive to other therapy, it has proven highly effective with an overall survival of 80 % in over 10 000 neonates, in which nearly 100 % mortality would be expected (ELSO, 1997). Modification of the neonatal ECMO technique has also been effective in some paediatric patients with respiratory failure (Green et al., 1996), including those with pneumonia from both bacterial (Masiakos et al., 1999) and viral (Meyer and Warner, 1997) pathogens. As would be expected, as the duration of ECMO required increases, the prognosis decreases (Masiakos et al., 1999). While in the NIH-sponsored ECMO trial, adults with viral pneumonia did particularly poorly, a retrospective review by Kolla and colleagues of 100 adults with severe acute respiratory failure supported with ECMO revealed a 53 % survival rate in the 49 patients with a primary diagnosis of pneumonia (Kolla et al., 1997). Although this mortality seems high, patients selected for ECMO had an expected mortality in excess of 90 %. Predictors of poor response to ECMO were increasing age, days of ventilation prior to commencement of ECMO, and the degree of respiratory failure as measured by the Pa02/Fi02 ratio. Cases of successful intervention in adults with severe Legionella (Nakajima et al., 1997; Ichiba et al., 1999; Harris et al., 2002), pneumococcal (Codispoti et al., 1995) and Varicella pneumonia (Lee et al., 1997) have all been reported. The clearest indication for ECMO in adults may be the Hantavirus Pulmonary Syndrome (HPS). With no effective antiviral therapy, care is entirely supportive. In a small series, the dramatic but time-limited cardiovascular and pulmonary haemorrhagic manifestations of HPS appeared to be well supported by ECMO (Crowley et al., 1998). Extracorporeal membrane oxygenation may have a role in the care of some patients with severe respiratory failure secondary to pneumonia. However, the

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timing, duration and patient selection for an expensive, labour-intensive therapy remain to be determined by prospective studies.

Other Therapies Liquid ventilation with volatile hydrocarbons has been studied in the management of ARDS. Few data are currently published on its use specifically in human subjects with pneumonia. In rats given lethal doses of pneumococci, partial liquid ventilation in combination with perfluorocarbon doubled survival compared with antibiotics alone (Dickson et al., 1998). Nitric oxide (NO) inhalation has also been studied as adjunctive therapy of ARDS, as well as some forms of severe pulmonary hypertension. While no studies specifically address human patients with pneumonia, in dogs with Escherichia coli pneumonia, inhaled NO had a minimal effect on oxygenation and no effect on sepsis-induced pulmonary hypertension (Quezado et al., 1998). As an effector molecule released by macrophages to kill bacteria (Anggard, 1994), inhaled NO has a potential antibacterial effect. Hoehn and colleagues studied the bacteriostatic effect of NO on bacterial cultures from neonate (Hoehn et al., 1998). At 120 ppm (greater than the usual dose range of 40–80 ppm), NO inhibited the growth group B Streptococcus, Staphylococcus epidermidis and E. coli but not Pseudomonas aeruginosa or Staphylococcus aureus. Further studies will be required to determine whether inhaled NO has any real bacteriostatic effect in vivo, particularly as it may have deleterious effects on the neutrophil function (CholletMartin et al., 1996). Aerosolized prostacyclin has also been shown by Walmrath and colleagues to improve oxygenation by reducing shunt and pulmonary hypertension in patients with pneumonia (Walmrath et al., 1995). Twelve patients with severe pneumonia (Pa02/Fi02 < 150), six of whom had interstitial lung disease (ILD), received varying doses of prostacyclin. Patients with ILD required substantially larger doses of prostacyclin to produce a clinical effect.

Clearance of Secretions Significant accumulation of mucopurulent secretions can occur in CAP, particularly in patients on mechanical ventilation. Mucus impaction can lead to obstruction, ranging in severity from linear atelectasis to complete lobar collapse. Physical Removal

Clearly the most effective secretion clearance is a spontaneous cough. However, the respiratory compromise often attendant to severe CAP may prevent an effective cough. Support with non-invasive ventilation (NIV) may benefit the patient by both improving respiratory mechanics while allowing the patient to spontaneously expectorate (Confalonieri et al., 1999). However, retained secretions are one of the causes of failure of NIV. An important strategy to avoid this complication is to

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avoid continuous application of NIV and actively encourage the patient to cough during periods off NIV. In mechanically ventilated CAP patients, removal of secretions by regular suctioning is essential. The use of percussion or vibration in ventilated patients has been associated with worsening of gas exchange, and the benefit in non-intubated CAP patients is unclear. The benefit of bronchoscopy for secretion removal is also poorly supported. Bronchoscopy for secretion removal has been associated with an increased risk of development of subsequent nosocomial pneumonia (Joshi et al., 1992). Therefore, its therapeutic use should be limited. One of the few studies on this topic has suggested that if lobar atelectasis is accompanied by an air bronchogram, bronchoscopy is unlikely to find a mucus plug or benefit the patient (Marini et al., 1979). Vibrational Therapy

High frequency chest wall oscillation (HFCWO) administered via a vest system to mobilized secretions has been evaluated with unsuccessful results in preventing pulmonary complications in a small group of patients with amyotrophic lateral sclerosis with chronic respiratory failure on non-invasive mechanical ventilation (Chaisson et al., 2006). In patients hospitalized for cystic fibrosis exacerbation, use of HFCWO resulted in similar outcomes as conventional chest physiotherapy (Arens et al., 1994). Other studies of HFCWO in patients with cystic fibrosis have been directed at prevention of disease progression rather than during acute exacerbation. One study of continuous oscillating beds in the intensive care unit showed borderline survival improvement only in those patients with acute physiology and chronic health evaluation (APACHE) II scores of ≥ 20 (Traver et al., 1995).

Mucolytics Changing the rheological properties of thick tenacious mucus is often attempted with little scientific support. Avoidance of dessication and inspissation of secretions does appear to be important. Adequate hydration may be the most effective therapy. Intubated CAP patients with significant secretions are poor candidates for heat and moisture exchangers and should usually have ventilation initiated with heated humidification. The pharmacological intervention most often attempted is N-acetylcysteine. Most support for this therapy is an extension of results from the literature for cystic fibrosis patients. Whether the same benefit can be achieved in CAP patients is unclear as there is no published data of N-acetylcysteine use in this setting. The potential benefit is also partially offset by induction of bronchial irritation and bronchospasm in some patients. Preliminary data on agents with more physiological support, such as uridine 5
-triphosphate (UTP) (Olivier et al., 1996), are encouraging but need further study. Guaifenesin has limited data in non-pneumonia patients

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and is unlikely to have a major benefit in intubated CAP patients. Although a variety of other mucolytic agents are available, including bromohexine, rhDNase and polymyxin B, there are no data to support their use in general patients with CAP.

Conclusion In the twenty-first century, CAP remains, as in the preceding centuries, a significant health problem, despite new antibiotic therapies. Research into the development of modifiers of the host immune response, both anti- and pro-inflammatory approaches, has yet to deliver successful therapies to improve outcome. The current state of adjunctive treatment of CAP is limited. With regard to immunomodulator therapy, recombinant activated protein C and tissue factor pathway inhibitor may modify the disease course in some patients. Cytokine delivery directly to the lung, such as with nebulized IFN-γ, is a particularly promising way of achieving the desired pulmonary effect without systemic side effects. However, which of the multitude of cytokines to deliver remains an important question. Of the available treatments, corticosteroids alone have a proven role in the therapy of pneumonia due to P. carinii/jerovicii. The wider therapeutic indication for corticosteroids in SCAP awaits further research. Once respiratory failure has ensued, supportive measures such as patient positioning and differential lung ventilation may improve in some patients, particularly those with severe unilateral pneumonia. At available facilities, ECMO may be beneficial in selected patients when all other means of providing respiratory support have failed. The role of inhaled NO and partial liquid ventilation is also currently unclear and requires further study. As the understanding of the pathophysiological mechanisms of severe pneumonia improves, rational design of immunomodulatory drugs will tailor specific therapies for particular patient groups in order to avoid deleterious effects and finally improve outcome in community-acquired pneumonia.

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Index ‘CAP’ refers to ‘community-acquired pneumonia.’ Page numbers in italics refer to figures, those in bold refer to tables. N-acetylcysteine 255 acetylsalicylic acid 252 Acinetobacter antibiotic resistance 197 antibiotic treatment 116–17 Actinomyces 28 Actinomyces israelii 28 activated protein C 249 acute respiratory distress syndrome (ARDS) 253, 254 acute respiratory infections (ARI) 53 rapid diagnosis 54 adenovirus 31 diagnosis 49 adjunctive therapy 245–56 adverse drug events antibiotics 144 macrolides 180 telithromycin 185 age, hospital admissions 6, 7 AIDS patients Pneumocystis jiroveci pneumonia 246–7 see also HIV infection alcohol abuse CAP risk 2, 3 risk factor 10–11 Alexander Project 23 alveolar macrophages antibiotic penetration 132–4

macrolide concentrations 177 telithromycin penetration 185 aminoglycosides Acinetobacter treatment 116 concentration in epithelial lining fluid 132 E. coli treatment 110, 111 guidelines for empirical treatment 83 H. influenzae therapy 110, 111 P. aeruginosa treatment 115 pharmacodynamic approach 136 aminopenicillin 154 E. coli 110 guidelines for empirical treatment 81 amoxicillin dosage 105 guidelines for empirical treatment 80 amoxicillin–clavulanic acid, guidelines for empirical treatment 81, 84 ampicillin host natural defence interactions 141 resistance in Serratia 112 Ancylostoma duodenale (ancylostomiasis) 34 angiotensin-converting enzyme (ACE) inhibitors 251 prior medication 12 anthrax 29

Community-Acquired Pneumonia: Strategies for Management Edited by Antoni Torres and Rosario Men´endez  2008 John Wiley & Sons, Ltd

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antibiotic(s) administration route 86 adverse events 144 alveolar macrophage penetration 132–4 combination therapy 78–9 duration of treatment 85–6 empirical therapy 79–85 host natural defence interactions 137–43 movement across blood–alveolar barrier 130 MRSA treatment 108, 109–10 new 64, 77–8 host natural defence interactions 143 non-responding pneumonia 223 pathogen-directed treatment 101–22 penetration into epithelial lining fluid 128–32 pharmacodynamic approach 135–6 pharmacodynamics 128–37 pharmacokinetics 128–37 pharmacology 127–45 previous exposure 76 prior medication 12 pulmonary disposition 134–7 sensitivity definition 24 of pathogen 155 switch therapy 86 synergistic interaction therapeutic value 143 see also named drugs and groups; non-responding pneumonia antibiotic resistance 22–3, 36, 196–7 definition 24 macrolides 174–5, 177–80 multidrug 76–7 pneumococcal 23–4, 36, 64, 67–78, 102–5 third-generation cephalosporins 154 significance 196 antigen tests, pharyngeal specimens 48–9 antigenic drifts 30 antigenic shifts 30 anti-inflammatory response 139 antipseudomonal exotoxin antibodies 248 Arachnia 28

Ascaris lumbricoides (ascaris) 34 Aspergillus (aspergillosis) 32 asthma, comorbidity 10 avian influenza virus A/H5N1 30 azalides, pneumococcal resistance 74–5 azithromycin 171 adverse effects 180 alveolar macrophage penetration 133 C. pneumoniae treatment 120–1 clinical uses 181–4 drug interactions 180 epithelial lining fluid concentration 130–1 guidelines for empirical treatment 83 H. influenzae treatment 110 immunomodulation 250 Legionella treatment 118, 119 lower respiratory tract infections 181 lung parenchyma concentrations 134 M. pneumoniae treatment 120 mechanism of action 172 MIC for H. influenzae 173 for S. pneumoniae 172, 173 phagocyte concentrations 134 pharmacodynamics 177 pharmacokinetics 175, 176–7 resistance 178, 179 spectrum of activity 172–4 aztreonam, activity 154–5 Bacillus anthracis 29 Bacillus cereus 29 bacterial pneumonia 22–9 airway-colonizing 35 atypical agents 27–8, 53, 118–21 treatment 75 extracellular organisms 35 Gram-negative bacilli 26–7, 110–13 Gram-positive cocci 102–10 human parainfluenza virus association 30 intracellular organisms 35 non-fermenters 113–17 superinfection 30 beta-lactams see β-lactams bias, epidemiology studies 6 biopsy 222 Blastomyces dermatitidis (blastomycosis) 33

INDEX

blood cultures 44 blood–alveolar barrier, antibiotic movement across 130 Bordetella pertussis (pertussis) 183 British Thoracic Society (BTS) guidelines 162, 164, 165 bronchial biopsy 222 bronchiectasis, macrolide use 183 bronchiolitis obliterans with organizing pneumonia (BOOP) 216, 222 bronchitis, acute exacerbation 183 bronchoalveolar lavage (BAL) 46, 132 drawbacks of technique 129–30 epithelial lining fluid antibiotic penetration 128–9 non-responding pneumonia 220, 221 bronchoscopy non-responding pneumonia 220, 221, 222 secretion clearance 255 Brucella (brucellosis) 29 carbapenem Acinetobacter treatment 116, 117 E. coli 110, 111 Enterobacter treatment 112 guidelines for empirical treatment 84 P. aeruginosa treatment 116 cardiac disease, comorbidity 8, 10 cardiac heart failure (CHF), viral CAP 29 cefditoren pivoxil 77–8 cephalosporins 154 Acinetobacter treatment 116 E. coli 110, 111 fourth-generation 154 guidelines for empirical treatment 81, 82, 83 H. influenzae treatment 110 host natural defence interactions 140–1 macrolide combination 162–3 minimum inhibitory concentration 68 P. aeruginosa treatment 116 pharmacodynamic approach 135–6 resistance Enterobacter 112 S. pneumoniae 24, 160–1 Serratia 112 third-generation 154

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discordant therapy 160–1 treatment failure 157 cethromycin 171 children human parainfluenza virus 30 M. pneumoniae treatment 120 pneumococcal vaccines 235, 236, 239 polymicrobial pneumonias 35 respiratory syncytial virus 31, 49 varicella virus 31 Chlamydophila (Chlamydia) 22, 27–8 Chlamydophila (Chlamydia) pneumoniae 28, 66–7 antibiotic treatment 120–1 co-pathogen activity 35 importance 194–5 serological tests 51, 52 Chlamydophila (Chlamydia) psittaci 27, 66–7 macrolide use 182 chromatographic tests 53 chronic lung disease CAP risk 2, 3 comorbidity 8, 9–10 chronic obstructive pulmonary disease (COPD) comorbidity 8, 10 non-responding pneumonia 216 ciprofloxacin antibacterial activity 198 epithelial lining fluid levels 135 guidelines for empirical treatment 82, 83 host natural defence interactions 139–40 resistance 197 clarithromycin 171 adverse effects 180 C. pneumoniae treatment 120–1 clinical uses 181–4 concentration in epithelial lining fluid 130 drug interactions 180 host natural defence interactions 142 immunomodulation 250 lower respiratory tract infections 181 M. pneumoniae treatment 120 mechanism of action 172 MIC for S. pneumoniae 172, 173

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clarithromycin (continued ) penetration into alveolar macrophages 133 pharmacodynamics 177 pharmacokinetics 175–6 resistance 179 spectrum of activity 172–4 clavulanic acid amoxicillin–clavulanic acid guidelines for empirical treatment 81, 84 host natural defence interactions 141 ticarcillin–clavulanic acid 117 clindamycin, guidelines for empirical treatment 84 clinical stability criteria 206, 207 Coccidioides immitis (coccidioidomycosis) 33 colistin, P. aeruginosa treatment 115 community-acquired pneumonia (CAP) aetiology 194–6 complications 1–2 definition 194 incidence 1–2 prevalence 194, 195 prevention 88 prognosis 3 severe 247 comorbid conditions 206 hospital admissions 8–10 non-responding pneumonia 216 complement fixation test (CFT) 51 computed tomography (CT) 222 coronaviridae 32 corticosteroids see steroids Coxiella burnetii 28 Cryptococcus neoformans (cryptococcosis) 32–3 culture techniques non-sterile sampling sites 45–7 sterile sampling sites 44–5 threshold value for positive culture 46 CURB-65 score 3, 13, 213 cystic fibrosis, macrolide use 183 cytochrome P-450 system 180 cytokines 137 fluoroquinolone effects 139–40 β-lactam induced release 156–7 macrolide effects 142 pro-inflammatory 217–18

daptomycin, host natural defence interactions 143 diabetes comorbidity 10 pneumonia risk 2 diagnostic laboratory services 52–3 direct immunofluorescence (DIF) 49, 53 disseminated intravascular coagulation (DIC) 249 DNA gyrase 71 doxycycline guidelines for empirical treatment 80 β-lactam combination 164 Legionella treatment 119 drotrecogin alfa 223, 249 drugs, immunomodulatory effects 138–9 efflux pumps 174 elderly people fluoroquinolone use 203 human parainfluenza virus 30 influenza vaccination 196, 229–30, 232–5 mortality 231, 234–5 pneumococcal vaccination 237–9 susceptibility 193–4, 195 empirical treatment 63–89 additional therapies 86–7 antibiotic resistance 67–77 combination antibiotic therapy 78–9 failure 87–8, 102 guidelines for antibiotic therapy 79–86 non-responding pneumonia 223 pathogens 65–7 recently introduced antibiotics 77–8 endotoxins 137 Enterobacter 112 enzyme immunoassay (EIA) 48, 49 epidemiology adult hospitalized CAP 5–16 bias in studies 6 outside hospital 1–3 epithelial lining fluid antibiotic penetration 128–32 ciprofloxacin levels 135 ertapenem 136 macrolide concentrations 177 pefloxacin levels 135 piperacillin–tazobactam 136–7

INDEX

erm(B) gene 174, 178 ertapenem 77, 136 erythromycin 171 clinical uses 181–4 host natural defence interactions 142 lower respiratory tract infections 181 M. pneumoniae treatment 120 mechanism of action 172 MIC for S. pneumoniae 172, 173 penetration into alveolar macrophages 132 pharmacodynamics 177 pharmacokinetics 175, 177 resistance 70, 71, 178–9 spectrum of activity 172–4 Escherichia coli 26, 27 antibiotic resistance 197 antibiotic treatment 110–11 NO inhalation 254 European Antimicrobial Resistance Surveillance System (EARSS) 23 European guidelines for antibiotic empirical therapy 80, 81–2, 83 European Respiration Society, guidelines 162, 164, 165 extended-spectrum β-lactamases (ESBLs) 111, 197 extra-corporeal membrane oxygenation (ECMO) 253–4 Fine prognostic scales 213, 217, 218 fluoroquinolones 193–209 guidelines for empirical treatment 80, 81, 82, 83 host natural defence interactions 139–40 β-lactam combination 78–9 mortality rate 201–2 penetration into alveolar macrophages 132, 133, 134 pharmacodynamic approach 136 post-antibiotic effect 199 pulmonary tissue accumulation 134–5 resistance 70–2, 75–6 pneumococcal 196–7 respiratory 197, 198, 199–204, 206 risk stratification 204–5 severely ill patients 200–1, 202, 204

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short course therapy 206–7 therapy 205–8 Food and Drug Administration (FDA), diagnostic testing 52–3 Francisella tularensis 29 Friedl¨ander’s pneumonia 26–7 fungal pneumonia 32–4, 221 soil-dwelling fungi 33–4 garenofloxacin 197 gatifloxacin 197, 198 efficacy 203–4 host natural defence interactions 140 monotherapy 207 gemifloxacin 197, 198 efficacy 203, 204, 207 safety 207 short course therapy 207 gender, hospital admissions 7–8 German measles 31 Gram stains 46–7, 220 Gram-negative bacilli (GNB) 26–7 aetiology 195 antibiotic resistance 197 antibiotic treatment 110–13 blood cultures 44 treatment failure 218 Gram-negative enterobacteria (GNEB) antibiotic treatment 110–13 incidence 67 risk factors 66 Gram-positive cocci, treatment 102–10 grepafloxacin 140 guaifenesin 255–6 guidelines for empirical treatment 63–89 comparisons 84–5 European 80, 81–2, 83 IDSA/ATS 80–1, 83, 84 Spanish 80, 81, 82, 83, 84 guidelines for treatment British Thoracic Society (BTS) 162, 164, 165 European Respiration Society 162, 164, 165 β-lactams 162–5 non-adherence 218 see also IDSA/ATS guidelines for antibiotic therapy

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haemagglutinin 29–30 Haemophilus influenzae 21, 22, 24–5 aminoglycoside therapy 110, 111 antibiotic sensitivity 24–5 antibiotic treatment 110 blood cultures 44 bronchopulmonary disease 66 importance 194 incidence 67 macrolide activity 173 macrolide resistance 174 superinfection 30 haemosiderin 221 hantavirus 31–2 hantavirus pulmonary syndrome 253 health-care resources 64 health-care workers, influenza vaccination 231 heparin, low molecular weight 86 high frequency chest wall oscillation (HFCWO) 255 high-risk patients, influenza vaccination 232 histiocytosis X 222 Histoplasma capsulatum (histoplasmosis) 33, 247 HIV infection blood cultures 44 cryptococcosis 32–3 M. avium-intracellulare complex 184 Pneumocystis carinii/jiroveci pneumonia 246–7 hookworm infection 34 hospital(s), patient management 65 hospital admissions age 6, 7 comorbid conditions 8–10 gender 7–8 prognosis scoring 205 rates 2 hospitalized adult CAP 5–16 host inflammatory response 139 non-responding pneumonia 217, 218 human metapneumovirus (hMPV) 50 human parainfluenza virus (HPIV) 30 hydrocarbons, volatile 254 hydrocortisone 247 hypertension, comorbidity 10

IDSA/ATS guidelines for antibiotic therapy 164 classification of causes of non-responding 214 duration 166 empirical therapy 80–1, 83, 84 fluoroquinolones 206 macrolide use 182 non-responding pneumonia 223 outpatient guidelines 205–6 risk stratification 205 illness severity, hospital admission 13, 14 imipenem activity 154 guidelines for empirical treatment 83 immunochromatographic tests 44 immunocompromised patients cryptococcosis 32–3 histoplasmosis 33 immunoglobulin enhancement 248 immunoglobulin G (IgG), serological tests 50–1 immunoglobulin M (IgM), serological tests 50–1 immunomodulatory therapy 246–52 immunosuppressive therapy CAP risk 2, 3 comorbidity 10 indomethacin 251–2 Infectious Diseases Society of America/American Thoracic Society see IDSA/ATS guidelines for antibiotic therapy infiltrates in radiographs 220 inflammatory response 139, 217, 218 influenza epidemics 53 mortality 234–5 S. aureus CAP 66 influenza vaccination 11–12, 196, 229–35, 239–40 elderly people 196, 229–30, 232–5 health-care workers 231 high-risk patients 232 infection prevention 88 lower respiratory tract infection impact 232–3 mortality 233, 234–5 nursing homes 231, 232 residential care 231, 232

INDEX

revaccination 231 treatment failure rate 218 influenza vaccine efficacy/effectiveness 231–5 haemagglutinin-inhibiting (HI) titre 230 immunogenicity 230–1 intravenous 230, 231 safety 230–1 types 230 influenza virus 29–30, 195–6 bacterial superinfection 30 diagnosis 49 incidence 66 serological tests 51, 52 intensive care unit admission 14, 15 antibiotic treatment 106 combination therapy 106, 206 critically ill patients 106 β-lactams combination therapy 162, 164–5 monotherapy 165 mortality 245 interferon γ (IFN-γ), recombinant 248 interleukin 1β (IL-1β) 137 interleukin 6 (IL-6) 137 interleukin 10 (IL-10) 218 interstitial lung disease 254 intravenous drug abuse, risk factor 11 invasive pneumococcal disease (IPD) 237–8, 239, 240 ketolides 171, 184–5 H. influenzae treatment 110 Legionella treatment 118, 119 Klebsiella oxytoca, antibiotic treatment 111–12 Klebsiella pneumoniae 26–7 ampicillin resistance 111 antibiotics resistance 197 treatment 111–12 ESBLs 111 β-lactamases, extended-spectrum (ESBLs) 111, 197 β-lactams Acinetobacter treatment 116

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agents 153–5 alveolar macrophage penetration 132, 133 antimicrobial activity 155–6 bactericidal activity 155–6 combination therapy 162–3 pneumococcal bacteraemia 165–6 concordant therapy 160 cytokine release 156–7 definitions 153–5 discordant therapy 159–61 doxycycline combination 164 drug-resistant pneumococci efficacy 158–62 duration of therapy 166–7 efficacy 157–62 epithelial lining fluid concentration 132 failures 157 fluoroquinolone combination 78–9 guidelines for treatment 162–5 empirical 81, 82, 83, 84 H. influenzae treatment 110 high dose in penicillin resistance 104 hospitalized patients 206 host natural defence interactions 140–2 inpatient treatment 164–5 killing rate/time 156–7 macrolide agent combination 78, 79, 105, 162–3, 164 MIC 156 monotherapy 103, 157, 162–3 pneumococcal bacteraemia 165–6 Moraxella catarrhalis 25 outpatient treatment 164 P. aeruginosa treatment 114, 116 pharmacodynamics 156–7 pharmacokinetics 156–7 pneumococcal bacteraemia 165–6 pneumococcal resistance 67–9, 73–4 recent therapy impact 161–2 resistance 158–62 Legionella (Legionnaires’ disease) 22 antibiotic therapy 118–19 duration of therapy 166 epidemic outbreaks 67 incidence 67 macrolides resistance 175

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Legionella (Legionnaires’ disease) (continued ) use 181–2 macrophage enhancement 248 non-responding pneumonia 215 urinary antigen test 48 Legionella pneumophila 25 importance 195 macrophage enhancement 248 serological tests 51, 52 treatment failure 218 urinary antigen tests 48 levofloxacin 197, 198 alveolar macrophage penetration 133 C. pneumoniae treatment 121 efficacy 199, 200, 208 elderly people 203 epithelial lining fluid concentration 131 guidelines for empirical treatment 81, 82, 83 H. influenzae treatment 110 host natural defence interactions 140 Legionella treatment 118–19 monotherapy 200–1 pharmacodynamics 136 resistance 197 safety 199 severely ill patients 200–1, 204 short course therapy 206–7 lincosamides penetration into alveolar macrophages 133, 134 S. aureus resistance 107 linezolid alveolar macrophage penetration 133 guidelines for empirical treatment 83, 84 host natural defence interactions 143 MRSA treatment 109–10 lipopolysaccharide 137 live attenuated influenza vaccines (LAIV) 230, 231 L¨offler-like syndrome 34 lower respiratory tract infections 48–9 influenza vaccination impact 232–3 macrolide use 181 viral 50 lung biopsy, open 222

INDEX

lung carcinoma 222 lung ventilation, differential 252–3 macrolides 171–84 activity 172–5 acute exacerbation of chronic bronchitis 183 adverse effects 180 alveolar macrophage penetration 132, 133, 134, 177 bronchiectasis 183 C. pneumoniae treatment 120–1 cephalosporin combination 162–3 clinical uses 181–4 cystic fibrosis 183 drug interactions 180 epithelial lining fluid concentration 130–1 penetration 177 guidelines for empirical treatment 80, 81, 82 H. influenzae treatment 110 hospitalized patients 206 host natural defence interactions 142–3 immunomodulation 249–51 β-lactam combination 78, 79, 105, 162–3, 164 Legionella treatment 119 lower respiratory tract infections 181 M. avium-intracellulare complex 184 mechanism of action 172 non-antimicrobial effects 250 pertussis 183 pharmacodynamics 177 pharmacokinetics 175–7 pneumococcal resistance 69–70, 74–5, 104, 105, 160 bacteraemia 179–80, 182, 196 mechanisms 104 prior medication 162 resistance 107 clinical significance 179–80 epidemiology 177–80 mechanisms 174–5 S. aureus resistance 107 spectrum of activity 172–4 macrophages 137 enhancement 248

INDEX

malaria 34 measles 31 mechanical ventilation 14, 15 indomethacin use 252 intensive care unit 14, 15 secretion clearance 255 medication, prior antibiotic resistance 76 pneumococcal resistance 161–2 risk factor 11–12 mef (A) gene 174, 178 melioidosis 27 meningitis, treatment failures 73 meningoencephalitis, emergency diagnosis 51 meropenem activity 154 guidelines for empirical treatment 83 metapneumovirus (MPV) 50 metastatic infection 218 methicillin-resistant Staphylococcus aureus (MRSA) 25–6 community-acquired 26, 78, 107 guidelines for empirical treatment 83–4 non-responding pneumonia 216, 223 treatment 206 glycopeptide-resistant 108 hospital-acquired 107 resistance patterns 107–8 treatment 108–10 methylprednisolone 247 microbiological causes of CAP 21–36 polymicrobial pneumonias 34–5, 36 microbiological diagnosis 43–55 cost–benefit 54 culture techniques 44–7 cut-off point 46 non-responding pneumonia 220–3 nucleic acid amplification tests 49–50 optimization of laboratory strategy 51–3 rapid antigen tests 47–9 serological tests 50–1, 52 summer protocols 53 winter protocols 53 minimum bactericidal concentration (MBC) 155

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minimum inhibitory concentration (MIC) 155 azithromycin for H. influenzae 173 for S. pneumoniae 172, 173 cephalosporins 68 clarithromycin for S. pneumoniae 172, 173 erythromycin for H. influenzae 173 for S. pneumoniae 172, 173 β-lactams 156 telithromycin for S. pneumoniae 185 Moraxella catarrhalis 21, 22, 25 bronchopulmonary disease 66 morbidity 64 antimicrobial resistance impact on pneumococcal pneumonia 72–6 mortality 2, 64, 194 antimicrobial resistance impact on pneumococcal pneumonia 72–6 elderly people 231, 234–5 fluoroquinolone use 201–2 hospital admissions 15 influenza epidemics 234–5 vaccination 233, 234–5 intensive care unit 245 penicillin resistance 103 prediction 3 rate 213, 245, 246 risk scoring 205 moxifloxacin 197, 198, 199 C. pneumoniae treatment 121 costs 208 efficacy 201, 202, 208 elderly people 203 guidelines for empirical treatment 81, 82 H. influenzae treatment 110 host natural defence interactions 140 Legionella treatment 119 safety 201, 202 severely ill patients 204 tolerability 201 mucolytics 255–6 mutant prevention concentration (MPC) 155–6 Mycobacterium avium, blood cultures 44

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Mycobacterium avium-intracellulare complex, macrolide use 184 Mycobacterium tuberculosis, blood cultures 44 Mycoplasma pneumoniae 22, 27 antibiotic treatment 120 importance 194–5 incidence 67 macrolide resistance 174–5, 178–9 macrolide use 182 serological tests 51, 52 sputum culture 47 N-acetylcysteine 255 nasopharyngeal aspirate (NPA) 48–9 Necator americanus 34 neuraminidase 29–30 nitric oxide (NO) 137 inhalation 254 nitric oxide synthase, inducible (iNOS) 137 Nocardia asteroides 28 Nocardia brasiliensis 28 non-responding pneumonia 87–8 nucleic acid amplification tests (NAATs) 44, 49–50, 51 atypical bacteria 53 real-time multiplex 49–50 nursing home acquired pneumonia (NHAP) prevalence 195 risk factor 11 nursing homes, influenza vaccination 231, 232 organ transplantation, cryptococcosis 33 Panton–Valentine leukocidin 26, 216, 223 Paracoccidioides brasiliensis (paracoccidioidomycosis) 33–4 parainfluenza virus 30 diagnosis 49 parasitic pneumonia 34 Pasteurella multocida 29 Pasteurella pestis 29 pathogens 21–2, 65–7 identification 101 sensitivity to antibiotics 155 unidentified copathogens 102

see also bacterial pneumonia; microbiological causes of CAP; microbiological diagnosis; named pathogens; viral pneumonia pefloxacin epithelial lining fluid levels 135 Legionella treatment 118 penicillin 154 anti-pseudomonal 154 drug-resistance pneumococci 158–9 guidelines for empirical treatment 81 minimum inhibitory concentration 68 prior medication 161–2 resistance 71, 103–4 Enterobacter 112 high-dose β-lactams 104 S. pneumoniae 24, 36, 158–60 susceptibility categories 74 penicillin G 102 penicillin-binding proteins (PBPs) 67–9 Penicillin-Non-Susceptible Pneumococci (PNSP) 23–4, 36 perfloxacin, host natural defence interactions 139 perfusion–ventilation gammagraphy 222 pertussis, macrolide use 183 phagocytes antibiotic accumulation 133, 134 azithromycin concentrations 134 piperacillin–tazobactam epithelial lining fluid levels 136–7 guidelines for empirical treatment 83 plague 29 plain chest X-ray 222 Plasmodium falciparum 34 pleural effusion 218 pneumococcal infection see Streptococcus pneumoniae pneumococcal vaccination 11–12, 235–9, 240 children 235, 236, 239 efficacy/effectiveness 237–9, 248 immunogenicity 235–6 reactions 236–7 safety 236–7 pneumococcal vaccine polysaccharide 88, 235 types 235

INDEX

Pneumocystis carinii/jiroveci pneumonia (PCP) 246–7 pneumonia aspiration 10–11, 67 bacteraemic 218 early failure 214 non-responding 213–24 aetiology 218 causes 215–16 classification 214, 215 diagnostic evaluation 219–20 host factors 216–18 incidence 214–15 microbiological assessment 220–3 non-infectious 216, 221–2 prognosis 214–15 radiological studies 222–3 severity 217, 218 therapeutic approach 223 treatment-related factors 218 parasitic 34 polymicrobial 34–5, 36 progressive 214 secondary 30 ventilator-associated 109, 136–7 see also bacterial pneumonia; viral pneumonia Pneumonia Severity Index (PSI) 3, 13, 14 S. pneumoniae urinary antigen test positivity 47 pneumonitis drug-induced 221 hypersensitivity 216 polymicrobial pneumonias 34–5, 36 positioning therapy 252 positive end-expiratory pressure (PEEP) 252 post-antibiotic effects 136 prostacyclin, aerosolized 254 prostaglandin inhibitors 251–2 protected brush specimen (PBS) 45–6 non-responding pneumonia 220, 221 Pseudomonas aeruginosa 26, 27 antibiotic treatment 113–16 duration of therapy 166 guidelines for empirical treatment 83 high-risk patients 115–16 multiresistant strains 115

273

non-responding pneumonia 216 prevalence 195 risk factors 66, 195 susceptible strains 113–14 third-generation cephalosporins 154 Pseudomonas pseudomallei 27 psittacosis 27 pulmonary eosinophilia 216, 221 pulmonary haemorrhage 221 pulmonary hypertension 254 pulmonary neoplasia 216, 222 pulmonary oedema, malarial 34 Q fever 28 quinolone agents Acinetobacter treatment 116 C. pneumoniae treatment 121 H. influenzae treatment 110 K. pneumoniae treatment 112 Legionella treatment 118, 119 macrolide resistance 105 penicillin resistance 105 pneumococcal resistance 70–2, 105, 106 prior medication 162 resistance 75–6 see also fluoroquinolones quinolone resistance determinant region (QRDR) 71–2 point mutations 72, 76 quinupristin–dalfopristin, MRSA treatment 109 rapid antigen tests 47–9 reference laboratories 53 residential care influenza vaccination 231, 232 risk factor 11 respiratory syncytial virus children 31, 49 diagnosis 49–50 respiratory syncytial virus (RSV) 31, 43 diagnosis 49 serological tests 51, 52 rifampicin guidelines for empirical treatment 83 vancomycin combination 110 risk factors for CAP 2–3 macrolide-resistant S. pneumoniae 70

274

risk factors for CAP (continued ) penicillin-resistant S. pneumoniae pneumococcal 65–6, 69, 70, 72 quinolone-resistant S. pneumoniae

INDEX

69 72

secretion clearance 254–5 sepsis/sepsis syndrome drotrecogin alfa 249 macrolides 251 non-responding pneumonia 217 tissue factor pathway inhibitor 249 worsening after antibiotic therapy 156 serological tests 50–1, 52 Serratia 112–13 serum, passive immunization 248 severe acute respiratory syndrome (SARS) 32 Sin Nombre virus 31 sitafloxacin 197 smoking cessation 88 risk factor 10, 66 social factors 10–11 Spanish guidelines for antibiotic empirical therapy 80, 81, 82, 83, 84 spiramycin, host natural defence interactions 142 sputum culture 47 Gram staining 53 sputum specimens 46 staphylococcal cassette chromosome mec (SCCmec) 25–6 Staphylococcus aureus 21, 22, 25–6, 195 blood cultures 44 incidence 67 influenza outbreak 66 macrolide activity 172–3 methicillin-susceptible 108 non-responding pneumonia 216 resistance patterns 107–8 superinfection 30 see also methicillin-resistant Staphylococcus aureus (MRSA) Staphylococcus epidermidis 254 statins 251 prior medication 12 Stenotrophomonas maltophila, antibiotic treatment 117

steroids 86–7, 246–7 non-responding pneumonia 223 Streptococcus group B 254 Streptococcus pneumoniae 21, 22, 23–4 antibiotic resistance 23–4, 36, 64, 67–78, 102–5, 154 β-lactam discordant therapy 159–61 β-lactam efficacy 158–62 risk factors 196–7 azalide resistance 74–5 bacteraemia β-lactam use 165–6 macrolide use 179–80, 182, 196 blood cultures 44 combination treatment 105 co-pathogen activity 35 directed treatment 105–6 ertapenem activity 78 erythromycin resistance 70, 71 fluoroquinolone use 197, 198 immunoglobulin enhancement 248 importance 194 incidence 65–6, 67 invasive disease 237–8, 239, 240 β-lactam resistance 67–9, 73–4, 158–62 recent therapy impact 161–2 macrolides activity 172, 173 resistance 69–70, 74–5, 174, 177–8 morbidity/mortality with antimicrobial resistance 72–6 multidrug-resistance 76–7 non-responding pneumonia 215–16 penicillin non-susceptible 68–9 penicillin-resistant 69, 71 penicillin-susceptible 68 quinolone resistance 70–2, 75–6 superinfection 30 susceptibility categories 104 telithromycin action 78 urinary antigen tests 47 see also pneumococcal vaccination Streptococcus pyogenes blood cultures 44 emergency intrapartum detection 51

INDEX

Strongyloides stercoralis (strongyloidiasis) 34 sulbactam, Acinetobacter treatment 116–17 teicoplanin guidelines for empirical treatment 83 pharmacodynamics 177 telithromycin 77, 171, 184–5 adverse effects 185 concentration in epithelial lining fluid 130–1 drug interactions 185 guidelines for empirical treatment 80 Legionella treatment 119 MIC for S. pneumoniae 185 temafloxacin, adverse events 144 tetracyclines C. pneumoniae treatment 120–1 guidelines for empirical treatment 80 M. pneumoniae treatment 120 thoracic needle aspiration (TNA) 45 thoracocentesis 45 throat swabs 48–9 thrombocytopenia 249 thromboembolic disease 216 ticarcillin–clavulanic acid 117 tick-borne disease, Q fever 28 tifacogin 249 tigecycline Enterobacter treatment 112 epithelial lining fluid concentration 131 K. pneumoniae treatment 112 S. maltophilia treatment 117 tissue factor pathway inhibitor, recombinant 249 tissue partition coefficients 135 topoisomerase IV 71 Toxocara canis/catis 34

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transbronchial biopsy 222 treatment discordant 218 β-lactams 159–61 empirical 63–89 failure 213–24 diagnostic evaluation 219–20 non-adherence to guidelines 218 non-responding pneumonia 223 trimethoprim–sulphamethoxazole 117 trovafloxacin, adverse events 144 tularaemia 29 tumour necrosis factor (TNF) 137 tumour necrosis factor α (TNF-α) 217 uridine 5
-triphosphate (UTP) 255 urinary antigen tests 44, 47–8 vancomycin guidelines for empirical treatment 83, 84 MRSA treatment 108 rifampicin combination 110 Varicella pneumonia 247 varicella virus 31 ventilation differential lung 252–3 non-invasive 87, 254–5 volatile hydrocarbons 254 see also mechanical ventilation ventilator-associated pneumonia 109 antibiotic pharmacodynamics 136–7 vibrational therapy 255 viral pneumonia 29–32, 195–6 airway-colonizing bacterial entry 35 incidence 67 visceral larva migrans 34 Yersinia pestis 29