Streptococcal Pharyngitis: Optimal Management (Issues in Infectious Diseases)

Streptococcal Pharyngitis

Issues in Infectious Diseases Vol. 3

Series Editors

Heinz Zeichhardt Brian W. J. Mahy

Berlin Atlanta, GA

Streptococcal Pharyngitis Optimal Management

Volume Editors

Jean Claude Pechère Geneva Edward L. Kaplan Minneapolis, Minn.

12 figures, 1 in color, and 54 tables, 2004

Basel · Freiburg · Paris · London · New York · Bangalore · Bangkok · Singapore · Tokyo · Sydney

Issues in Infectious Diseases

Library of Congress Cataloging-in-Publication Data Streptococcal pharyngitis : optimal management / volume editors, Edward L. Kaplan, Jean Claude Pechère. p. cm. – (Issues in infectious diseases, ISSN 1660–1890 ; v. 3) Includes bibliographical references and index. ISBN 3–8055–7602–1 (hbk.) 1. Streptococcal infections. 2. Throat–Diseases. 3. Pharyngitis. I. Kaplan, Edward L. II. Pechère. J.-C. (Jean Claude) III. Series. RC116.S84S778 2004 616.9⬘2–dc22 2003059534

Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents® and Index Medians. Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. © Copyright 2004 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland) www.karger.com Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel ISSN 1660–1890 ISBN 3–8055–7602–1

Contents

1 Introduction

3 Virulence Factors of Streptococcus pyogenes D.L. Stevens, Boise, Idaho 3 3 4 4 4 4 5 5 6 6 6 6 7 7 7 7 8 8 9 9 9 10

The Pathogen General Characteristics Microbiological Characteristics Virulence Factors Capsule Cell Wall M-Proteins Immunoglobulin Binding Proteins (M-Like Proteins) Fibronectin Binding Protein (Protein F) Protein SIC (Streptococcal Complement Inhibitory Protein) Opacity Factor Streptolysin O Streptolysin S Deoxyribonucleases A, B, C and D Hyaluronidase Nicotine-Adenine-Dinucleotidase (NADase) Streptokinase Pyrogenic Exotoxins General Pathogenic Mechanisms Anti-Phagocytic Properties Cytokine Induction The Pathogenesis of Pharyngitis

11 Pathogenic Mechanisms in Acute Rheumatic Fever 12 Post-Streptococcal Glomerulonephritis 12 References

16 Clinical Presentations of Pediatric Streptococcal Pharyngitis in Developed Countries R.R. Tanz, Chicago, Ill. 16 18 19 20 21

Typical Presentation Scarlet Fever Streptococcal Respiratory Tract Infection in Younger Children Conclusions References

22 Group A Streptococcal Pharyngitis in Adults: Diagnosis and Management G.S. Peter, A.L. Bisno, Miami, Fla. 22 22 23 23 24 28 30 32

Group A Streptococcal Pharyngitis in Adults: Diagnosis and Management Incidence Diagnosis of Group A Streptococcal Pharyngitis Signs and Symptoms of Streptococcal Pharyngitis Role of Clinical Criteria Laboratory Testing in the Diagnosis of Strep Pharyngitis in Adults Treatment References

36 Practical Experience with Clinical Algorithms for Reducing Unnecessary Antibiotic Use in the Management of Streptococcal Pharyngitis W.J. McIsaac, Toronto, Ont. 36 38 39 40 42 44 45 46 47 48

The Management of Sore Throat by Primary Care Physicians The Role of Clinical Error in Antibiotic Overuse Clinical Algorithms, Prediction Rules and the Reduction of Clinical Error The Sore Throat Score Management Approach Reliability in Different Clinical Settings The Potential Impact of the Score Approach on Unnecessary Antibiotic Prescriptions Limitations of the Score Approach Conclusions References Recommended Reading

49 Epidemiology, Clinical Presentations, and Diagnosis of Streptococcal Pharyngitis in Developing Countries of the World M.C. Steinhoff, A.W. Rimoin, Baltimore, Md. 49 Epidemiology 50 High Income Countries

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50 Low Income Countries 50 Incidence of GABHS Pharyngitis 51 Prevalence in Clinic Settings 53 Carriage Rates 53 Hemolytic Streptococcal Serogroups 53 GABHS Serotypes 55 Serology 56 Risk Factors 56 Age and Sex Distribution 56 Seasonality 57 Pharyngitis vs. Pyoderma 58 Relationship between GABHS and RF 59 Diagnostic Strategies 59 Clinical Prediction Rules 60 Throat cultures 61 Rapid Antigen Tests 62 Conclusions 62 References 66 The Group A Streptococcal Upper Respiratory Carrier. Diagnosis and Management E.L. Kaplan, Minneapolis, Minn. 66 Definitions 68 Pathophysiology of the Upper Respiratory Tract Carrier State 69 Epidemiology of the Group A Streptococcal Upper Respiratory Tract Carrier 69 Clinical Diagnosis of the Group A Streptococcal Upper Respiratory Tract Carrier 71 Do Group A Streptococcal Carriers Require Therapy? 71 Public Health Implications of the Group A Streptococcal Upper Respiratory Tract Carrier State 73 Conclusion 73 References 75 The Laboratory Diagnosis of Streptococcal Pharyngitis. Throat Cultures, Rapid Tests and Streptococcal Antibodies D.R. Martin, Porirua 75 76 77 78 80 80 81 82

Diagnosis of Streptococcal Pharyngitis Diagnostic Sensitivity of the Throat Swab Laboratory Culture Rapid Streptococcal Detection Tests (RADTs) Identification of Group A Streptococci Streptococcal Antibody Tests Anti-Streptolysin O (ASO) Anti-Deoxyribonuclease B

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82 Other Streptococcal Antibody Tests 82 Anti-Hyaluronidase Titer (AHT) 82 References 85 Diagnosis of Non-Suppurative Complications of Group A Streptococcal Pharyngitis P. Ferrieri, Minneapolis, Minn. 85 88 89 90 91 92 93 93

Acute Post-Streptococcal Glomerulonephritis Pathogenesis of Acute Post-Streptococcal Glomerulonephritis Acute Rheumatic Fever Epidemiology and Clinical Manifestations of Rheumatic fever Pathogenesis of Rheumatic Fever Post-Streptococcal Reactive Arthritis Pathogenesis of PSRA References

95 Diagnosis and Management of Suppurative Complications of Streptococcal Pharyngitis P. Gehanno, Paris 96 96 97 97 97 98 99 99 99 100 100 101 101 102

Collection of Pus Peritonsillar Abscess Parapharyngeal Abscesses Abscesses in the Prestyloid Space Abscesses in the Retrostyloid Space Extensive Cervical Cellulitis and Necrotising Fasciitis Constitutional Symptoms Local and Regional Manifestations Physical Findings Investigations Treatment and Course Type of Surgical Drainage Prognosis References

103 Antibiotic Treatment for Streptococcal Pharyngitis. Penicillin First? J.C. Salazar, Hartford, Conn. 103 Historical Perspective 104 Pharmacology 104 Chemical Composition and Mode of Action 105 Pharmacodynamics/Pharmacokinetics 105 Dosage and Route of Administration for GABHS Pharyngitis 106 Side Effects 107 Clinical Efficacy of Penicillin for Treatment of GABHS

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107 Prevention of Rheumatic Fever 107 Eradication of GABHS 109 Adherence 109 Copathogenicity 110 Antimicrobial Resistance 111 Penicillin Tolerance 111 Conclusions 112 References 115 Antibiotic Treatment for Streptococcal Pharyngitis. What is the Role of Oral Cephalosporins D. Adam, M. Helmerking, Munich 116 Antimicrobial Therapy 117 Other Explanations for Treatment Failure with Penicillin 117 The Role of Oral Cephalosporins 117 Effectiveness of Short Course Therapy 119 Clinical Efficacy 119 Resolution of Clinical Symptoms 119 Recurrence of Tonsillopharyngitis 119 Eradication of GABHS 120 Oral Antibiotics for Short Course Therapy 121 Antibiotic Prescription for Patients with Sore Throat 121 References 124 What is the Current Role of Macrolides and Ketolides in the Treatment of Group A Streptococcal Pharyngitis? A. Bryskier, Romainville; G. Cornaglia, Verona 124 125 125 125 126 126 127 129 130 132 133 133 133 135 135 135 136

Macrolide Antibiotics Microbiology In vitro Activities Against Susceptible S. pyogenes Impact on Oral Flora Pharmacokinetics Distribution in Tonsillar Tissue Concentrations in Saliva Clinical Efficacy Erythromycin Clarithromycin Azithromycin Roxithromycin Dirithromycin Flurithromycin Spiramycin Josamycin Telithromycin

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137 Conclusion 137 References 143 Mechanisms of Antibiotic Resistance in Streptococcus pyogenes N. Yamanaka, Wakayama Oral Antimicrobial Susceptibilities of Streptococcus pyogenes Mechanisms of Macrolides Resistance in Streptococcus pyogenes rRNA Methylases Efflux System Molecular Epidemiology of Erythromycin Resistance Genes in Streptococcus pyogenes 148 Conclusion 148 References 143 144 144 146 147

150 Macrolide Resistance of Streptococcus pyogenes G. Cornaglia, Verona; A. Bryskier, Romainville Mode of Action of 14- and 15-Membered Ring Macrolides and Ketolides Molecular Basis of Macrolide Resistance Modification of the Target Site Erythromycin A Efflux Laboratory Detection of Resistance Epidemiology of Erythromycin A Resistance Early Reports The Last Decade and the Spread of Macrolide Resistance in Europe Susceptibility Reports from Asia and Australia Susceptibility Reports from North America and Latin America Present Trends Role of Low-Level Resistance and Clinical Importance of the Different Macrolides 162 References 151 152 152 153 154 155 155 156 157 157 158 160

166 Cost Issues in Streptococcal Pharyngitis J.C. Pechère, Geneva 167 167 168 169 170 170 170 170 170 171 172 172

Is Microbiological Diagnosis of Streptococcal Pharyngitis Cost Effective? First Approaches Hypothetical Cohorts and Meta-Analysis Prospective Study in France Cost-Effectiveness of Antibiotic Therapy for Sore Throat The Western World Impact on Symptoms Impact on Complications Side Effects of Antibiotics Third World General Conclusion References

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173 Practical Problems Associated with the Prevention of Initial and Recurrent Attacks of Acute Rheumatic Fever in Developing Countries S.R. Zaher, A. Mandil, Alexandria 173 Governmental Involvement 174 Economic Constraints 175 Physicians’ Attitudes in Management 176 Negligence of Health Education 176 Reluctance in the Laboratory Diagnosis of Group A Streptococcal Pharyngitis 177 Inappropriate Reliance on the Anti-Streptolysin O Antibody Titer as a Diagnostic/Prognostic Test 177 Inappropriate Antibiotic Therapy for Group A Streptococcal Pharyngitis Once Diagnosed 178 Premature Discontinuation of Penicillin Prophylaxis 178 Social and Cultural Constraints 179 Patient Compliance with Treatment Protocols 179 Primary Prevention 179 Secondary Prevention 180 Health Education and Public Involvement 181 Pharmacokinetics of Benzathine Penicillin G 181 Technique of Injection 182 References 184 Streptococcal Pharyngitis: A Continuing Important Public Health Issue Worldwide T.E. Tupasi, Makati 185 186 188 190

Risk Groups for GAS Health and Economic Impact of GAS Public Health Approaches in the Control of Group A Streptococcal Infections References

192 Practical Management of Pharyngitis: The Costa Rica Experience and Its Impacts on Public Health A. Arguedas, E. Mohs, San José 193 The Costa Rican Experience 199 References 202 Vaccine Control Strategies against Group A Streptococcal Infections. Expectations, Hopes and Possible Impact M.F. Good, K.S. Sriprakash, D.J. Kemp, Herston 203 GAS Vaccine Approaches 203 The M Protein

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205 Fibronectin-Binding Proteins (FBPs) 206 C5a Peptidase 206 Spa18, Another Coiled-Coil Protein 207 Toxins 208 Is a Vaccine Against Scabies Possible? 208 The Need for a Scabies Vaccine 208 Evidence for a Role of Immunity in Self-Limiting Normal Scabies 209 Tick Vaccine Studies: ‘Concealed Antigens’ 210 House Dust Mite Allergens 210 A Vaccine Strategy for Scabies 210 Conclusion 211 References 215 Author Index 216 Subject Index

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Pechère JC, Kaplan EL (eds): Streptococcal Pharyngitis. Issues Infect Dis. Basel, Karger, 2004, vol 3, pp 1–2

Introduction

Among the many infections that confront clinicians every day, there is probably no more common and yet controversial one than pharyngitis/tonsillitis caused by group A beta hemolytic streptococcus (Streptococcus pyogenes). This illness concerns clinicians because not only is there an acute illness for an individual patient, but the potential spread of the organism and the resulting public health implications cannot be ignored either. The association of acute streptococcal pharyngitis with non-suppurative sequelae has provided the major stimulus for understanding and controlling these infections. Prompt diagnosis and effective antibiotic therapy have been documented to reduce the threat in a cost-effective and yet inexpensive manner. At the outset of the 21st century the group A streptococcus is unique in that – to date – there never has been a clinical isolate of this potentially virulent organism with demonstrated in vitro resistance to penicillin, perhaps the most inexpensive and readily available antibiotic all through out the world. Yet, the clinical management of these upper respiratory tract infections remains controversial. The clinical diagnosis often is not specific. Laboratory data can be misleading and frequently is misinterpreted. Despite the in vitro effectiveness of penicillin, it does not always eradicate the organism from a patient’s respiratory tract. Numerous newly introduced antibiotics, often expensive and not even available in many countries, continue to be promoted. Because of epidemiological evidence suggesting that these infections remain uncontrolled in all populations, because of the complexities of this infection, because of the remaining controversies, and because of the public health importance, we have asked an international group of colleagues including clinicians, epidemiologists, and clinical laboratory professionals to contribute to this volume in the hope of providing a relatively concise overview of the current aspects of group A streptococcal pharyngitis. The purpose of this collection of expert assessments is to assist the clinician. Where controversies exist, they are noted. Where information is lacking, it is clearly defined.

We are grateful to our colleagues for their important contributions to this book and for their patience as we compiled this collection. We hope it will be useful for the readers, whether they be experienced clinicians, public health authorities or students in the health care professions. Edward L. Kaplan, Minneapolis Jean-Claude Pechere, Geneva

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Pechère JC, Kaplan EL (eds): Streptococcal Pharyngitis. Issues Infect Dis. Basel, Karger, 2004, vol 3, pp 3–15

Virulence Factors of Streptococcus pyogenes Dennis L. Stevens Infectious Diseases Section, Veterans Affairs Medical Center, Boise, Idaho, USA

The Pathogen

Over the last 40 years streptococcal pharyngitis, erysipelas and scarlet fever have become milder diseases and the prevalence of acute rheumatic fever and post-streptococcal glomerulonephritis have reached all time lows in the western world. However, since 1985, several epidemics of rheumatic fever [1] and severe invasive group A streptococcal infections (reviewed in [2]) have been described from many sites around the world. In addition, the prevalence of streptococcal infections of all types remains high in undeveloped countries. Because the group A streptococcus can cause a wide variety of different types of infection and because the epidemiology of each varies temporally and geographically, it is important to understand the interaction between host and pathogen. General Characteristics

Streptococcus pyogenes, or group A streptococcus (GAS), is a facultative, gram-positive cocci which grows in chains and causes numerous infections in humans including pharyngitis, tonsillitis, scarlet fever, cellulitis, erysipelas, rheumatic fever, post-streptococcal glomerulonephritis, necrotizing fasciitis, myonecrosis and lymphangitis. The only known reservoirs for GAS in nature are the skin and mucous membranes of the human host. The clinical diseases produced by GAS have been well described, however, the pathogenic mechanisms underlying them are poorly understood, largely because each is the culmination of highly complex interactions between the human host defense mechanisms and specific virulence factors of the streptococcus.

Microbiological Characteristics

Group A streptococci require complex media containing blood products, grow best in an environment of 10% carbon dioxide and produce pinpoint colonies on blood agar plates which are surrounded by a zone of complete (beta) hemolysis. The exhaustive work of Rebecca Lancefield established the classification of streptococci into types A through O based upon acid extractable carbohydrate antigens of cell wall material [3]. In addition, GAS have also been subdivided based upon the surface expression of M and T antigens. Sub-typing strains of GAS has proven invaluable for epidemiological studies, in much the same way that phage typing has been useful to define the epidemiology of Staphylococcus aureus. High resolution genotyping provides a more specific determination of relatedness among strains isolated from outbreaks of GAS infections [4]. Finally, rapid sequencing of the gene encoding M-protein is providing a very fast definitive way of comparing M-typeable and M-non-typeable strains.

Virulence Factors

Capsule Some strains of S. pyogenes possess thick capsules of hyaluronic acid resulting in large mucoid colonies on blood agar. Luxuriant production of M-protein may also impart a mucoid colony morphology, a trait which has been associated most commonly with M-18 strains [5]. Utilizing an isogenic mutant of an M-18 strain, Wessels et al. [6] showed that the strains producing hyaluronic acid capsule were resistant to phagocytosis and were virulent in mice, whereas the hyaluronic acid-deficient strain was non-virulent and readily killed by phagocytes. Interestingly, the non-hyaluronic acid producing strain adhered to macrophages with greater avidity than the mucoid strain [6]. This suggests that hyaluronic acid capsule, like M-protein confers resistance to phagocytosis but that such capsules also interfere with adherence to eukaryotic cells. Streptococci possessing hyaluronic acid capsule adhere to keratinocytes through specific receptors (CD44) [7]. Cell Wall The cell wall is comprised of a peptidoglycan backbone with integral lipoteichoic acid components. The main function of these components is structural stability of the microbe, though the exact function of lipoteichoic acid is unknown. Lipoteichoic acid may play a role in pathogenesis by facilitating the adherence of GAS to pharyngeal epithelial cells [8]. Peptidoglycan, like

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endotoxin from gram-negative bacteria, is capable of activating the alternative complement pathway [9–11]. M-Proteins Over 80 different M-protein types of GAS are currently described. The protein is a coiled-coil consisting of four regions of repeating amino acids (A–D), a proline/glycine-rich region which serves to intercalate the protein into the bacterial cell wall, and a hydrophobic region which acts as a membrane anchor [12]. Region A near the N-terminus is highly variable, and antibodies to this region confer type-specific protection. Within the more conserved B–D regions lies an area which binds one of the complement regulatory proteins (factor H), stearically inhibiting antibody binding and complement-derived opsonin deposition, and effectively camouflaging the organism against humoral immune surveillance [13]. M-protein also protects the organism against phagocytosis by polymorphonuclear leukocytes [14], though this property can be overcome by type-specific antisera [3, 12, 15]. Observations by Lancefield suggest that the quantity of M-protein produced decreases with passage on artificial media but increases rapidly with passage through mice [3]. In humans, the quantity of M-protein produced by an infecting strain progressively decreases during convalescence and with prolonged carriage [3]. Non-typeable strains of GAS may express minute amounts of M-protein, may lack M-protein altogether, or may be of a totally new M-type. Recently, 60 non-typeable strains which had been isolated from upper respiratory sources in southeast Asia were found to be resistant to phagocytosis in normal serum or plasma, suggesting that these strains do in fact produce M-protein [16]. These data are compatible with the view that new M-types are constantly emerging. This could result from mutational events within the emm gene, producing novel M-proteins which no longer cross react with standard polyvalent typing sera. Evidence that heterogeneity within this gene locus does in fact occur has recently been demonstrated among strains typed as M-1 [17]. In subsequent studies by these investigators, roughly 50% of randomly collected human sera opsonized 7 strains of M-1 GAS [18]. In contrast, the remaining 50% of serum samples opsonized only some of these strains, prompting the authors to conclude that opsonic antibody may not be type specific, but rather strain specific [18]. Immunoglobulin Binding Proteins (M-Like Proteins) Group A streptococcus produces a family of proteins which share structural similarities to M-proteins and also bind immunoglobulins including IgG, IgM and IgA. Unlike M-protein, these molecules do not inhibit phagocytosis in the absence of type specific antibody. Nonetheless, these molecules, like M-protein, may play a role in pathogenesis by interfering with complement activation.

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This was nicely shown recently by Tern et al. [19] who demonstrated that IgG binding protein from GAS selectively bound C4b binding protein (C4BP), a protein that is intimately involved in the regulation of the complement system. The authors concluded that this protein might interfere with opsonization by down-regulating complement activation, but acknowledged that it could also serve as a ligand between GAS and host cells [19] and thus may actually facilitate non-immune phagocytosis. Fibronectin Binding Protein (Protein F) Binding of GAS to fibronectin appears to enhance the adherence of GAS to epithelial surfaces. Recently, Hanski and Capron [20] described protein F, a 659 amino acid protein with two fibronectin binding domains [20]. It was suggested that protein F might be found in abundance in isolates from patients with invasive GAS infections [21]. Yet studies which defined the distribution of protein F among various M-types indicated that M-types 1 and 3, the two most common strains isolated from patients with invasive GAS infections, did not produce this protein [21]. These authors were able to demonstrate that high carbon dioxide concentrations increase the expression of protein F. Thus, protein F or perhaps other fibronectin binding proteins might play an important role in the adhesion of GAS to mucosal or skin surfaces. Protein SIC (Streptococcal Complement Inhibitory Protein) Recently, Akesson et al. [22] described a novel, extracellular protein of 305 amino acid residues which inactivates the membrane attack complex of complement. SIC was found only in M-types 1 and 57. In addition, the sic gene is located in the mga regulon of M-type 1 GAS, directly adjacent to the emm gene [22]. Clearly, through this mechanism the organism could evade destruction by the membrane attack complex (C5–C9) generated by either the alternative or classical complement pathway. Opacity Factor The opacity factor (OF) has been found largely in GAS but has recently also been detected in Group G and C streptococci, S. dysgalactiae, and S. equisimilis [23]. OF is a type-specific lipoprotein lipase whose role in pathogenesis is unknown. Recent evidence suggests a relationship with the presence of OF and arrangement of specific emm genes. Specifically, OF is associated with M-types which are largely skin strains [24]. Streptolysin O Streptolysin O belongs to a family of oxygen-labile, thiol-activated cytolysins, and causes the broad zone of hemolysis surrounding colonies of

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S. pyogenes on blood agar plates [25]. Thiol-activated cytolysins bind to cholesterol on eukaryotic cell membranes creating toxin-cholesterol aggregates that contribute to cell lysis via a colloid-osmotic mechanism. Cholesterol inhibits both toxicity in isolated myocytes and hemolysis of red blood cells in vitro. In situations where serum cholesterol is high (i.e. nephrotic syndrome), falsely elevated ASO titres may occur because both cholesterol and anti-ASO antibody will ‘neutralize streptolysin O’. Striking amino acid homology exists between streptolysin O and thiol-activated cytolysins from other gram-positive bacteria [26]. Streptolysin O contributes to pathogenesis of streptococcal infections in several ways. First, in high concentrations, it is cytotoxic. In lower concentrations, it activates a variety of cells such as PMNL and endothelial cells, and acts synergistically with other streptococcal factors (e.g. pyrogenic exotoxins) to induce cytokine production. Streptolysin S Streptolysin S is a cell-associated hemolysin which does not diffuse into the agar media. Purification and characterization of this protein has been difficult and its only role in pathogenesis may be through direct, contact dependent, cytotoxicity [27]. Deoxyribonucleases A, B, C and D Expression of deoxyribonucleases (DNases) in vivo, especially DNase B, elicits production of anti-DNase antibody following either pharyngeal or skin infection. Hyaluronidase This extracellular enzyme hydrolyzes hyaluronic acid in deeper tissues and may facilitate the spread of infection along fascial planes. Anti-hyaluronidase titres rise following S. pyogenes infections, especially those infections involving the skin. Nicotine-Adenine-Dinucleotidase (NADase) This extracellular enzyme also called NAD glycohydrolase has been produced by many strains of GAS [28]. It is not know what function this enzyme has for the organism per se and it is also unclear what role NADase may play in pathogenesis of any GAS infection. Recently, it was shown that NADase is expressed in M-1 and M-3 strains of GAS, but not in non-invasive strains [29]. Interestingly, in a survey done 20 years ago NADase was not found in M-1 strains [28]. NADase likely contributes to pathogenesis by directly attenuating leukocyte functions such as chemotaxis and phagocytosis [29].

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Streptokinase Streptokinase is produced by all strains of GAS and is located in the extracellular milieu. In contrast, a plasminogen binding site is found on the surface of strains of GAS [30]. Once plasminogen is bound, streptokinase proteolytically converts bound plasminogen to active plasmin [30]. Plasmin then cleaves fibrin into fragments known as fibrin degradation products, or FDPs. Interestingly, bound plasmin can not be inhibited by endogenous anti-proteases such as alpha-l anti-trypsin [30]. The role of streptokinase in GAS infections is unclear, though it may play a role in post-streptococcal glomerulonephritis. Pyrogenic Exotoxins Streptococcal pyrogenic exotoxins (SPE) type A, B, and C, also called scarlatina or erythrogenic toxins, induce lymphocyte blastogenesis, potentiate endotoxin-induced shock, induce fever, suppress antibody synthesis, and act as superantigens [31]. The identification of these three different types of pyrogenic exotoxins may in part explain why some individuals may have multiple attacks of scarlet fever. The gene for pyrogenic exotoxin A (speA) is transmitted by bacteriophage, and stable production depends upon lysogenic conversion in a manner analogous to toxin production by Corynebacterium diphtheria [32]. Control of SPEA production is not yet understood, though this is likely an important mechanism since it is well established that the quantity of SPEA produced by strains varies dramatically from decade to decade. In addition, point mutations in the SPEA gene result in dramatic changes in the potency of this toxin [33]. Historically, streptococcal pyrogenic exotoxin A- and B-producing strains have been associated with severe cases of scarlet fever and more recently, with streptococcal toxic shock syndrome (StrepTSS) [34, 35]. Although all strains of GAS are endowed with the gene for streptococcal pyrogenic exotoxin B (speB), not all strains produce SPEB and even among those strains which produce this toxin, the quantity produced varies greatly from strain to strain [32, 34, 36, 37]. Pyrogenic exotoxin C (SPEC), like SPEA, is bacteriophage-mediated and expression is likewise highly variable. Recently, mild cases of scarlet fever in England and the United States have been associated with SPEC-positive strains [37]. Two new superantigens, mitogenic factor (MF) [38, 39] and streptococcal superantigen (SSA) [40] have recently been described; however, their roles in pathogenesis have not been fully investigated. Pyrogenic exotoxins induce fever in humans and animals and also participate in shock by lowering the threshold to exogenous endotoxin [41]. SPEA and SPEB induce human mononuclear cells to synthesize not only tumor necrosis factor-␣ (TNF␣) [42] but also interleukin-1␤ (IL-1␤) [43] and interleukin-6 (IL-6) [43–45], suggesting that TNF could mediate the fever, shock and organ

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failure observed in patients with StrepTSS [35] (see ‘Cytokine Induction’ below).

General Pathogenic Mechanisms

Anti-Phagocytic Properties M-protein contributes to invasiveness through its ability to impede phagocytosis of streptococci by human polymorphonuclear leukocytes (PMNL) [3]. Conversely, type specific antibody against the M-protein enhances phagocytosis [3]. Following infection with a particular M-type, specific antibody confers resistance to challenge with viable GAS of that M-type [3]. Recently, Boyle’s group [46] have shown that GAS protease cleaves the terminal portion of the M-protein, rendering the organism more susceptible to phagocytosis by normal serum but protecting it from opsonization by type specific antibody. While strains of M-types 1 and 3 have accounted for the vast majority of strains isolated from cases of StrepTSS, many other M-types, including some non-typeable strains, have also been isolated from such cases. M-types 1 and 3 are also commonly isolated from asymptomatic carriers, and patients with pharyngitis or mild scarlet fever [36, 47]. There may be major differences in susceptibility to opsonization by anti-M-type antibody among strains of a given M-type [18, 48], raising further questions regarding the potential efficacy of M-protein vaccines. Cytokine Induction There is strong evidence suggesting that SPEA, SPEB and SPEC activity as superantigens and stimulate T cell responses through their ability to bind to both the class II MHC complex of antigen presenting cells and the V␤ region of the T cell receptor [49]. The net effect is induction of T cell proliferation (via an IL-2 mechanism) with concomitant production of cytokines (e.g. IL-1, TNF␣, TNF␤, IL-6, IFN␥) that mediate fever, shock, and tissue injury. Recently, Hackett and Stevens demonstrated that SPEA induced both TNF␣ and TNF␤ from mixed cultures of monocytes and lymphocytes [50] supporting the role of lymphokines (TNF␤) in shock associated with strains producing SPEA. Kotb et al. [51] have shown that a digest of M-protein type 6 can also stimulate T cell responses by this mechanism. Interestingly, quantitation of such V␤ T cell subsets in patients with acute StrepTSS demonstrated deletion rather than expansion, suggesting that perhaps the life-span of the expanded subset was shortened by a process of apoptosis [52]. In addition, the subsets deleted were not specific for SPEA, SPEB, SPEC, or MF suggesting that perhaps an as yet undefined superantigen may play a role in streptococcal infections such as toxic shock syndrome [52].

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Peptidoglycan, lipoteichoic acid [53] and killed organisms [54, 55] are also capable of inducing TNF␣ production by mononuclear cells in vitro [41, 55, 56]. Exotoxins such as SLO are also potent inducers of TNF␣ and IL-1␤. SPEB, a proteinase precursor, has the ability to cleave pre-IL-1␤ to release preformed IL-1␤ [57]. Finally, SLO and SPEA together have additive effects in the induction of IL-1 by human mononuclear cells [50]. Whatever the mechanisms, induction of cytokines in vivo is likely the cause of shock and SLO, SPEA, SPEB, SPEC as well as cell wall components, etc., are potent inducers of TNF and IL-1 [58]. Finally, a cysteine protease formed from cleavage of SPEB may play an important role in pathogenesis by the release of bradykinin from endogenous kininogen and by activating metalloproteases involved in coagulation [59].

The Pathogenesis of Pharyngitis

Adherence of GAS to respiratory epithelial cells is necessary for development of pharyngitis, and fibronectin binding protein (protein F) facilitates this association, though peptidoglycan and M-protein may also contribute [20]. Protein F is found most abundantly in strains isolated from the skin and throat and is not found in blood isolates [21]. Adherence and growth of GAS on pharyngeal mucosal surfaces is probably sufficient to cause the clinical entity of streptococcal pharyngitis. It is unclear what role, if any, the ‘anti-phagocytic’ properties of M-protein play in simple pharyngitis since invasion of tissues and blood is uncommon. In contrast, local extention to tonsils, lymph nodes and peritonsillar areas could be facilitated by virulence factors which attenuate the ability of phagocytes to opsonize, ingest and kill GAS. In addition to M-protein, M-like proteins, C5a peptidase, hyaluronic acid capsule and streptococcal complement inhibitory protein (SIC) may also contribute to local invasion (see also the specific virulence factors described above). GAS has been found intracellularly in tonsillar tissue from patients with chronic tonsillitis undergoing tonsillectomy and in vitro studies have clearly shown that GAS can not only adhere to, but invade, respiratory epithelial cell lines in tissue culture. Some studies have demonstrated that only certain strains of M-1 GAS invade cells efficiently [60], yet others have not confirmed these findings [61, 62]. However, there is no data suggesting that invasion of respiratory epithelial cells occurs during the course of acute pharyngitis. Does in vitro invasion of cell lines by GAS correlate with demonstration of intracellular organisms in tonsils of patients with chronic tonsillitis? First, tonsils are generally not removed from patients with acute tonsillitis and in fact, the standard of care would be to require several episodes of recurrent tonsillitis before surgical excision would be considered. Thus, in those human tonsillar

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tissues that contain intracellular streptococci, the infection has been of long duration. Further, these are not patients who have been bacteremic or who have had local extension into the neck, sinuses, etc. Thus, there is little to support the concept that invasion of respiratory epithelial cells correlates with acute infection, spreading of infection to adjacent tissues or bacteremia. In addition, in cases of chronic tonsillitis, sufficient time should have elapsed for development of anti-M-protein antibody. Thus, enhanced opsonization and ingestion of GAS by macrophages in pharyngeal tissue, lymphatic tissue and tonsils would be expected. If GAS is found in non-professional phagocytes in vivo in tonsillar tissue, then the question is ‘Is this process antibody-enhanced endocytosis or invasion or both?’ In this scenario, one wonders what roles anti-protein F or anti-M-protein antibody would play and whether these antibodies would be protective or detrimental. It may be a situation where adherence is inhibited by anti-protein F antibody, but internalization by either professional or nonprofessional phagocytes could be enhanced. Regardless of the mechanism, such an intracellular environment could have a number of consequences. First, export of GAS virulence factors could result in prolonged antigenic stimulation necessary for development of post-infectious sequelae such as rheumatic fever (see below). Second, production of virulence factors could result in effects on the host cell that directly contribute to the symptoms and signs of acute pharyngitis. While this may be possible, it seems quite clear that in human infection, few if any pharyngeal cells are actually destroyed. If the latter were true, it would be expected that ulcerations and necrosis of tissue, similar to that seen in diphtheria, would be manifest. Since this is not the case, it seems that invasion of pharyngeal epithelial cells in acute pharyngitis must be a limited process if it occurs at all. Whether or not intracellular GAS plays any role in acute pharyngotonsillitis, such a location could protect the bacterium from antibody, complement, leukocytes and some antibiotics. Clearly, all these factors could make eradication of GAS more difficult in these chronic situations.

Pathogenic Mechanisms in Acute Rheumatic Fever

The pathogenesis of acute rheumatic fever involves an intimate interplay between streptococcal virulence factors and the susceptible host. That T cells play an integral role was demonstrated by obtaining T-cell clones from valvular tissue of patients with rheumatic fever and demonstrating that these clones were responsive to specific epitopes of type 5 M-protein [63]. That B-lymphocytes play an important role is suggested by the demonstration that antibodies raised against particular M-protein digests cross react with cardiac tissue including

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myosin and endothelium [64]. Interestingly, anti-myosin antibodies also react strongly to cardiac endothelium [65]. Thus, as antibody against M-protein develops in a patient with antecedent group A streptococcal pharyngitis, antibody could fix complement, thereby damaging and activating the endothelium yielding cytokines and chemokines which attract and activate T-lymphocytes. Thus, molecular mimicry between specific epitopes on M-protein and cardiac tissue results in damage to endothelium on the heart valve mediated by specific B and T lymphocytes. Post-Streptococcal Glomerulonephritis

It is clear that only certain strains of streptococci are capable of causing poststreptococcal glomerulonephritis. The best hypothesis at the present time is that proteins with unique antigenic determinants produced only by ‘nephritogenic strains’, intercalate into the lipid bilayer of the glomerular basement membrane during the course of pharyngitis or impetigo. Recent studies suggest that streptokinase, which has certain lipophilic regions may be the streptococcal virulence factor responsible. Once streptokinase is membrane bound, complement is activated directly. Further glomerulus-bound streptokinase interacts with circulating anti-streptococcal antibodies, resulting in further complement fixation and glomerular damage [66]. References 1 2 3 4 5 6 7

8 9 10

Veasy LG, Wiedmeier SE, Orsmond GS: Resurgence of acute rheumatic fever in the intermountain area of the United States. N Engl J Med 1986;316:421–427. Stevens DL: Streptococcal toxic shock syndrome: Spectrum of disease, pathogenesis and new concepts in treatment. Emerg Infect Dis 1995;1:69–78. Lancefield RC: Current knowledge of type specific M antigens of group A streptococci. J Immunol 1962;89:307–313. Stanley J, Desai M, Xerry J, Tanna A, Efstratiou A, George R: High-resolution genotyping elucidates the epidemiology of group A streptococcus outbreaks. J Infect Dis 1996;174:500–506. Stevens DL: Streptococcus pyogenes infections; in Stein JH (ed): Internal Medicine, ed 4. St. Louis, Mosby-Year Book, 1994, pp 2078–2086. Wessels MR, Moses AE, Goldberg JB, DiCesare TJ: Hyaluronic acid capsule is a virulence factor for mucoid group A streptococci. Proc Natl Acad Sci USA 1991;88:8317–8321. Schrager HM, Albertis S, Cywes C, Dougherty GJ, Wessels MR: Hyaluronic acid capsule modulates M protein-mediated adherence and acts as a ligand for attachment of group A streptococcus to CD44 on human keratinocytes. J Clin Invest 1998;101:1708–1716. Hasty DL, Itzhak O, Courtney HS, Doyle RJ: Minireview: Multiple adhesions of streptococci. Infect Immun 1992;60:2147–2152. Greenblatt J, Boackle RJ, Schwab JH: Activation of the alternate complement pathway by peptidoglycan from streptococcal cell wall. Infect Immun 1978;19:296–303. Verhoef J, Kalter E: Bacterial Endotoxins: Structure, Biomedical Significance and Detection with the Limulus Amebocyte Lysate Test. Liss, New York, 1985.

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Bisno AL: Alternate complement pathway activation by group A streptococci: role of M-protein. Infect Immun 1979;26:1172–1176. Fischetti VA: Streptococcal M protein. Sci Am 1991;264:58–65. Fischetti VA, Horstmann RD, Pancholi V: Location of the complement factor H binding site on streptococcal M6 protein. Infect Immun 1995;63:149–153. Peterson PK, Schmeling D, Cleary PP, Wilkinson BJ, Kim Y, Quie PG: Inhibition of alternative complement pathway opsonization by group A streptococcal M protein. J Infect Dis 1979;139: 575–585. Dale J, Chiang E: Intranasal immunization with recombinant group A streptococcal M protein fragment fused to the B subunit of Escherichia coli labile toxin protects mice against systemic challenge infections. JID 1995;171:1038–1041. Tran PT, Johnson DR, Kaplan EL: The presence of M protein in nontypeable group a streptococcal upper respiratory tract isolates from southeast Asia. J Infect Dis 1994;169:658–661. Single LA, Martin DR: Clonal differences within M-types of the group A streptococcus revealed by pulsed field gel electrophoresis. FEMS Microbiol Lett 1992;91:85–90. de Malmanche SA, Martin DR: Protective immunity to the group A streptococcus may be only strain specific. Med Microbiol Immunol 1994;183:299–306. Thern A, Stenberg L, Dahlback B, Lindahl G: Ig-binding surface proteins of Streptococcus pyogenes also bind human C4b-binding protein (C4BP), a regulatory component of the complement system. J Immunol 1995;154:375–386. Hanski E, Caparon M: Protein F, a fibronectin-binding protein, is an adhesin of the group A streptococcus Streptococcus pyogenes. Proc Natl Acad Sci USA 1992;89:6172–6176. Natanson S, Sela S, Moses A, Musser J, Caparon M, Hanski E: Distribution of fibronectin-binding proteins among group A streptococci of different M types. J Infect Dis 1995;171:871–878. Tuomanen E, Liu H, Hengstler B, Zak O, Tomasz A: The induction of meningeal inflammation by components of the pneumococcal cell wall. J Infect Dis 1985;151:859–868. Katerof V, Lindgren P, Totolain A, Schalen C: Serum opacity factor activity among Group C and Group G streptococci. Program and Abstracts of the ASM Conference on Streptococcal Genetics,1998. Bessen DE, Sotir CM, Readdy T, Hollingshead SK: Genetic correlates of throat and skin isolates of group A streptococci. J Infect Dis 1996;173:896–900. Alouf JE, Geoffroy C: Structure activity relationships in sulfhydryl-activated toxins; in Freer JH, Jeljaszewicz J (eds): Bacterial Protein Toxins. London, Academic Press, 1984, pp 165–171. Tweten RK: Nucleotide sequence of the gene for perfringolysin O (theta-toxin) from Clostridium perfringens: Significant homology with the genes for streptolysin O and pneumolysin. Infect Immun 1988;56:3235–3240. Nizet V, Beall B, Bast DJ, Datta V, Kilburn L, Low DE, DeAzavedo JCS: Genetic locus for streptolysin S production by group A streptococcus. Infect Immun 2000;68:4245–4254. Lutticken R, Lutticken D, Johnson DR, Wannamaker LW: Application of a new method for detecting streptococcal nicotinamide adenine dinucleotide glycohydrolase to various M types of Streptococcus pyogenes. J Clin Microbiol 1976;3:533–536. Stevens DL, Salmi DB, McIndoo ER, Bryant AE: Molecular epidemiology of nga and NAD glycohydrolase/ADP-ribosyltransferase activity among Streptococcus pyogenes causing streptococcal toxic shock syndrome. J Infect Dis 2000;182:1117–1128. Lottenberg R, Broder CC, Boyle MDP: Identification of a specific receptor for plasmin on a group A streptococcus. Infect Immun 1987;55:1914–1928. Barsumian EL, Schlievert PM, Watson DW: Non-specific and specific immunological mitogenicity by group A streptococcal pyrogenic exotoxins. Infect Immun 1978;22:681–688. Nida SK, Ferretti JJ: Phage influence on the synthesis of extracellular toxins in group A streptococci. Infect Immun 1982;36:745–750. Kline JB, Collins CM: Analysis of the superantigenic activity of mutant and allelic forms of streptococcal pyrogenic exotoxin A. Infect Immun 1996;64:861–869. Hauser AR, Stevens DL, Kaplan EL, Schlievert PM: Molecular analysis of pyrogenic exotoxins from Streptococcus pyogenes isolates associated with toxic shock-like syndrome. J Clin Microbiol 1991;29:1562–1567.

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Stevens DL, Tanner MH, Winship J, Swarts R, Reis KM, Schlievert PM, Kaplan E: Reappearance of scarlet fever toxin A among streptococci in the Rocky Mountain West: Severe group A streptococcal infections associated with a toxic shock-like syndrome. N Engl J Med 1989;321:1–7. Kohler W, Gerlach D, Knoll H: Streptococcal outbreaks and erythrogenic toxin type A. Zentralbl Bakteriol Mikrobiol Hyg 1987;266:104–115. Hallas G: The production of pyrogenic exotoxins by group A streptococci. J Hyg (Camb) 1985;95: 47–57. Iwasaki M, Igarashi H, Hinuma Y, Yutsudo T: Cloning, characterization and overexpression of a Streptococcus pyogenes gene encoding a new type of mitogenic factor. FEBS Lett 1993;331: 187–192. Norrby-Teglund A, Newton D, Kotb M, Holm SE, Norgren M: Superantigenic properties of the group A streptococcal exotoxin SpeF (MF). Infect Immun 1994;62:5227–5233. Mollick JA, Miller GG, Musser JM, Cook RG, Grossman D, Rich RR: A novel superantigen isolated from pathogenic strains of Streptococcus pyogenes with aminoterminal homology to staphylococcal enterotoxins B and C. J Clin Invest 1993;92:710–719. Stevens DL: Invasive group A streptococcus infections. Clin Infect Dis 1992;14:2–13. Fast DJ, Schlievert PM, Nelson RD: Toxic shock syndrome-associated staphylococcal and streptococcal pyrogenic toxins are potent inducers of tumor necrosis factor production. Infect Immun 1989;57:291–294. Hackett SP, Schlievert PM, Stevens DL: Cytokine production by human mononuclear cells in response to streptococcal exotoxins. Clin Res 1991;39. Norrby-Teglund A, Norgren M, Holm SE, Andersson U, Andersson J: Similar cytokine induction profiles of a novel streptococcal exotoxin, MF, and pyrogenic exotoxins A and B. Infect Immun 1994;62:3731–3738. Muller-Alouf H, Alouf JE, Gerlach D, Fitting C, Cavaillon JM: Cytokine production by murine cells activated by erythrogenic toxin type A superantigen of Streptococcus pyogenes. Immunobiology 1992;186:435–448. Raeder RH, Woischnik M, Podbielski A, Boyle MD: A secreted streptococcal cysteine protease can cleave a surface expressed M1 protein and alters its immunoglobulin-binding properties. Res Microbiol 1998;149:539–548. Johnson DR, Stevens DL, Kaplan EL: Epidemiologic analysis of group A streptococcal serotypes associated with severe systemic infections, rheumatic fever, or uncomplicated pharyngitis. J Infect Dis 1992;166:374–382. Villasenor-Sierra A, McShan WM, Salmi D, Kaplan EL, Johnson DR, Stevens DL: Variable susceptibility to opsonophagocytosis of group A streptococcus M-1 strains by human immune sera. J Infect Dis 1999;180:1921–1928. Mollick JA, Rich RR: Characterization of a superantigen from a pathogenic strain of Streptococcus pyogenes. Clin Res 1991;39:213A. Hackett SP, Stevens DL: Streptococcal toxic shock syndrome: Synthesis of tumor necrosis factor and interleukin-1 by monocytes stimulated with pyrogenic exotoxin A and streptolysin O. J Infect Dis 1992;165:879–885. Kotb M, Tomai M, Majumdar G, Walker J, Beachey EH: Cellular and biochemical responses of human T lymphocytes stimulated with streptococcal M protein. XIth Lancefield International Symposium on Streptococcal Diseases, Sienna, 1990, abstr L77. Watanabe-Ohnishi R, Low DE, McGeer A, et al: Selective depletion of V␤-bearing T cells in patients with severe invasive group A streptococcal infections and streptococcal toxic shock syndrome. J Infect Dis 1995;171:74–84. Stevens DL, Bryant AE, Hackett SP: Gram-positive shock. Curr Opin Infect Dis 1992;5:355–363. Hackett S, Ferretti J, Stevens D: Cytokine induction by viable group A streptococci: Suppression by streptolysin O. Program and Abstracts American Society for Microbiology, Las Vegas, 1994, abstr B-249. Muller-Alouf H, Alouf JE, Gerlach D, Ozegowski JH, Fitting C, Cavaillon JM: Comparative study of cytokine release by human peripheral blood mononuclear cells stimulated with Streptococcus pyogenes superantigenic erythrogenic toxins, heat-killed streptococci and lipopolysaccharide. Infect Immun 1994;62:4915–4921.

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Hackett SP, Stevens DL: Superantigens associated with staphylococcal and streptococcal toxic shock syndromes are potent inducers of tumor necrosis factor beta synthesis. J Infect Dis 1993;168: 232–235. Kappur V, Majesky MW, Li LL, Black RA, Musser JM: Cleavage of Interleukin 1␤ (IL-1␤) precursor to produce active IL-1␤ by a conserved extracellular cysteine protease from Streptococcus pyogenes. Proc Natl Acad Sci USA 1993;90:7676–7680. Chaussee MS, Liu J, Stevens DL, Ferretti JJ: Genetic and phenotypic diversity among isolates of Streptococcus pyogenes from invasive infections. J Infect Dis 1996;173:901–908. Burns EH, Marciel AM, Musser JM: Activation of a 66-kilodalton human endothelial cell matrix metalloprotease by Streptococcus pyogenes extracellular cysteine protease. Infect Immun 1996;64: 4744–4750. Dombek PE, Cue D, Sedgewick J, Lam H, Ruschkowski S, Finlay BB, Cleary PP: High-frequency intracellular invasion of epithelial cells by serotype M1 group A streptococci: M1 proteinmediated invasion and cytoskeletal rearrangements. Mol Microbiol 1999;31:859–870. Hagman MM, Stevens DL: Comparison of adherence to and penetration of a human laryngeal epithelial cell line by group A streptococci of various M protein types. FEMS Immunol Med Microbiol 1999;23:195–204. Molinari G, Chhatwal GS: Invasion and survival of Streptococcus pyogenes in eukaryotic cells correlates with the source of clinical isolates. J Infect Dis 1998;177:1600–1607. Guilherme L, Cunha-Neto E, Coelho V, et al: Human heart-infiltrating T cell clones from rheumatic heart disease patients recognize both streptococcal and cardiac proteins. Circulation 1995;92:415–420. Quinn A, Kent W, Fischetti VA, Hemric M, Cunningham MW: Immunological relationship between the class I epitope of streptococcal M protein and myosin. Infect Immun 1998;66:4418–4424. Gulizia JM, Cunningham MW, McManus BA: Immunoreactivity of anti-streptococcal monoclonal antibodies to human heart valves: Evidence for multiple cross-reactive epitopes. Am J Pathol 1991;138:285–301. Nordstrand A, Norgren M, Ferretti JJ, Holm SE: Streptokinase as a mediator of acute poststreptococcal glomerulonephritis in an experimental mouse model. Infect Immun 1998;66:315–321.

Dennis L. Stevens, PhD, MD Chief, Infectious Diseases Section, Veterans Affairs Medical Center 500 West Fort Street (Bldg 45), Boise, ID 83702 (USA) Tel. ⫹1 208 422 1599; Fax ⫹1 208 422 1365, E-Mail [email protected]

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Pechère JC, Kaplan EL (eds): Streptococcal Pharyngitis. Issues Infect Dis. Basel, Karger, 2004, vol 3, pp 16–21

Clinical Presentations of Pediatric Streptococcal Pharyngitis in Developed Countries Robert R. Tanz Northwestern University Feinberg School of Medicine, Children’s Memorial Hospital, Chicago, Ill., USA

Pharyngitis refers to inflammation of the structures of the pharynx. The tonsils are most often affected. The terms pharyngitis, tonsillitis, tonsillopharyngitis, and pharyngotonsillitis are interchangeable and do not imply an etiology. Most episodes of pharyngitis (up to 85%) are caused by viruses. Pharyngitis caused by Streptococcus pyogenes is the most common bacterial pharyngitis diagnosed in developed countries. Streptococcal pharyngitis most often occurs in the late winter and early spring. It affects school-age children, particularly those 5–11 years old, but children and adults of all ages can be infected with group A streptococci. The signs and symptoms of streptococcal pharyngitis overlap with those of other causes of pharyngitis; definitive diagnosis requires laboratory evaluation of either a throat culture or an antigen detection test. Pharyngeal infection with streptococci can present simply as pharyngitis or as scarlet fever. In younger children, a syndrome commonly called streptococcosis can occur. Typical Presentation

The typical patient with acute streptococcal pharyngitis is a school-age child with sudden onset of fever and sore throat in the late winter or spring (table 1). Headache, malaise, abdominal pain, nausea, and vomiting occur frequently. Cough, rhinorrhea, stridor, hoarseness, conjunctivitis, and diarrhea are distinctly unusual. The pharynx is erythematous. Petechiae may be seen on the soft palate. Tonsils are enlarged and red, with patchy exudates. The papillae of the tongue may be red and swollen (strawberry tongue). Tender, enlarged

Table 1. Classical features of acute streptococcal pharyngitis in children Age: 5–11 years Season: late winter or early spring Symptoms (sudden onset) Sore throat Fever Headache Abdominal pain, nausea, vomiting Signs Pharyngeal erythema with enlarged tonsils and exudate Tender, enlarged anterior cervical nodes Palatal petechiae and/or ‘doughnut lesions’ Scarlet fever rash Absence of cough, rhinitis, stridor, hoarseness, conjunctivitis, diarrhea

anterior cervical nodes are common. Any of these ‘classic’ symptoms and signs may be absent in a particular patient; reliable diagnosis requires swabbing the throat for culture or a group A carbohydrate antigen detection test. Fever was documented in more than 90% of patients with streptococcal pharyngitis reported by Stillerman and Bernstein [1]. The fever may be low-grade, 37.8–38.0⬚C, or as high as 40⬚C. In a large study from our institution 40 years ago [2], 30% of children had temperature greater than 38.3⬚C. Very young children may have a less impressive febrile response than older children [3, 4]. Sore throat is usually thought of as the sine qua non symptom of the illness, occurring in 74–79% of children reported in studies of symptoms [1, 2, 5, 6]. However, sore throat is the primary or chief complaint in as few as 56% of patients [1]. Streptococcal sore throat is often described as a raw feeling, exacerbated when liquids are swallowed. Dysphagia can be so severe that the child refuses to eat or drink and some children may drool rather than swallow their saliva. Ear pain may occur with the sore throat. Many patients complain of abdominal pain, nausea, and vomiting. However, diarrhea does not occur. These symptoms do not mimic an acute surgical abdomen and do not warrant investigation in the clinical context of pharyngitis. Headache is often present at the onset of the illness, commonly occurring with the nausea and vomiting. Mental status is normal and there are not complaints of photophobia or posterior neck pain. Malaise and generalized aching are common. Physical examination reveals the throat to be erythematous, often described as deep or beefy red. The uvula may also be swollen and red. Typically there is

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exudate on the tonsils. The tonsillar exudate can be white, grayish, or slightly yellow, and it can be blood-tinged. It can be fairly localized to a single tonsil or be more diffuse, but extensive membranes are not usually seen. As many as 10% of patients have petechiae on the soft palate [1]. In addition, the soft palate may exhibit small, red follicular or punctate lesions that have slightly yellow centers. These ‘doughnut lesions’ are sometimes mistaken for petechiae [3]. Either of these palatal findings is highly suggestive of streptococcal infection when present [1, 3]. The papillae of the tongue may be swollen and red, giving it the appearance of the surface of a strawberry. Early in the illness the tongue is often coated white, and with the swollen papillae it is called a white strawberry tongue. After several days the white coating is gone, the tongue is often quite red, and then it is called a red strawberry tongue. Usually, the tympanic membranes appear normal, even when the child complains of otalgia. Swelling of the anterior cervical lymph nodes occurs frequently. During the acute illness they are firm and tender. Kernig and Brudzinski tests are negative. Abdominal examination is normal despite vomiting and abdominal pain. The presence of hepatomegaly or splenomegaly should alert the physician to consider infectious mononucleosis as these findings do not occur with streptococcal pharyngitis. Petechiae may be seen on the skin, even without a scarlet fever rash. Absence of both sore throat and signs of pharyngitis, especially without fever, should lead the clinician to doubt group A streptococcal infection as the cause of the illness. The presence of cough, coryza, stridor, hoarseness, conjunctivitis, or diarrhea in a school-age child suggests that a viral infection is more likely than streptococcal pharyngitis. Positive throat culture or antigen detection test in the context of either of these scenarios most likely represents chronic streptococcal carriage in a child with a viral upper respiratory tract infection. Scarlet Fever When rash accompanies streptococcal pharyngitis, the syndrome is called scarlet fever, because of the characteristic red exanthema. Whereas scarlet fever was once considered a potentially life-threatening condition (called fulminating toxic or malignant scarlet fever in its most severe form) [7], today it is merely streptococcal pharyngitis with rash. In fact, streptococcal pharyngitis was once called ‘scarlatina sine eruptione’ (scarlatina without rash) [7, 8]. Scarlet fever is rarely seen in children less than 3 years old [3, 8–10]. The fine, diffuse scarlet fever rash is caused by infection with a group A streptococcus that contains a bacteriophage encoding for production of an erythrogenic toxin, usually erythrogenic (or pyrogenic) exotoxin A. The scarlet fever rash feels somewhat like sandpaper and blanches with pressure. The rash begins on the

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Table 2. Characteristics of streptococcal upper respiratory tract infection in children ⬍3 years old

Insidious onset Low-grade fever Rhinitis, often purulent Diffuse cervical adenopathy Otitis media Pharyngitis less prominent, but can occur Exposure at home or day-care Absence of scarlet fever

face and becomes generalized after 24 h. The area around the mouth often appears pale in comparison to the extremely red cheeks, giving the appearance of circumoral pallor. Accentuation of erythema occurs in flexor skin creases, especially in the antecubital fossae, axillae, and inguinal creases (Pastia’s sign or Pastia’s lines). On close examination, Pastia’s lines may appear petechial or slightly hemorrhagic. An increase in petechiae distal to a tourniquet or other constriction is commonly seen evidence of capillary fragility (positive tourniquet test or Rumpel-Leeds phenomenon). Erythema begins to fade within a few days, and within a week of onset desquamation can occur, first on the face, progressing downward, and often resembling a resolving mild sunburn. Occasionally, sheet-like desquamation occurs around the free margins of the fingernails. Pharyngitis in association with a scarlet fever rash is almost always due to group A streptococci. Diseases that may mimic some features of scarlet fever are Arcanobacterium haemolyticum pharyngitis, Kawasaki disease, measles, and staphylococcal toxic shock syndrome. Symptoms and signs of streptococcal pharyngitis resolve fairly rapidly, even without antibiotic treatment. Vomiting, nausea, abdominal pain, and headache are usually gone after the first day of illness. The severity of sore throat diminishes over one to three days and usually resolves, along with fever, by the fourth day. In most untreated cases all symptoms of streptococcal pharyngitis are absent by the fourth or fifth day of illness. Similarly, by the third day of illness physical signs of the disease are waning and by the fifth day they are gone, except for desquamation in scarlet fever.

Streptococcal Respiratory Tract Infection in Younger Children

Younger children (less than 3 years old) may have coryza, with crusting below the nares, more generalized adenopathy, and a more chronic course, a syndrome now called streptococcosis (table 2). In the youngest infants (less than 6 months old) this syndrome may be indistinguishable from a viral upper

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respiratory tract infection. Among those 6 months to 3 years old, lowgrade fever, purulent nasal discharge, cervical adenitis, otitis media, and sinusitis may occur. Impetigo may also be present, presumably as a result of self-inoculation from the rhinitis. Studies of the characteristics of childhood streptococcal disease in the 1940s referred to this syndrome as ‘streptococcic (or streptococcal) fever, childhood type’ and emphasized its insidious onset and indolent course with persistence for several weeks [8–10] (these publications used ‘streptococcosis’ to refer to the entire spectrum of streptococcal disease in all age groups). Persistence of the rhinitis has been observed less often in more recent studies [4, 11], possibly related to changes in healthcare-seeking behavior and the availability of antibiotics. Culture of the nares may be more sensitive than throat culture in children less than 3 years old [4]. Children less than 3 years old can also develop culture-positive streptococcal pharyngitis. Exposure to someone with the disease at home, such as a sibling, is a risk factor [4, 12]. Coryza, cough, and hoarseness occur more frequently than they do among older children [4, 11]. An outbreak and subsequent screening study in a day-care center found that young children with streptococcal infection tend to have fever and symptoms consistent with sore throat [13]. In that report throat cultures infrequently yielded group A streptococci in children less than 21/2 years old. Clearly, children younger than 3 years old can harbor group A streptococci in their upper respiratory tracts, but at a lower rate than noted in older children [13, 14]. Symptoms and signs of illness may resemble those seen in viral infections or may be similar to the presentation in older children, except that scarlet fever is very uncommon [8–10]. Because acute rheumatic fever is exceedingly unusual in children less than 3 years old, the principal reason to recognize streptococcosis or streptococcal pharyngitis in young children is to decrease contagion as nasal secretions are particularly contagious.

Conclusions

Streptococcal pharyngitis is predominantly a disease of school-age children. In contrast to dramatic changes in our understanding of the disease, its treatment, and the prevention of sequelae, clinical presentation has changed little in the last 75 years. In its most classic presentation, children have sudden onset of fever and sore throat accompanied by malaise, abdominal pain, headache, nausea, and vomiting. Exudative tonsillitis and cervical adenitis are frequent findings; palatal petechiae and scarlatina may occur. Younger children may present with acute pharyngitis or with a less dramatic onset of rhinitis and adenopathy.

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References 1 2

3 4 5 6 7 8 9 10 11

12 13 14

Stillerman M, Bernstein SH: Streptococcal pharyngitis: Evaluation of clinical syndromes in diagnosis. Am J Dis Child 1961;101:476–489. Siegel AC, Johnson EI, Stollerman GH: Controlled studies of streptococcal pharyngitis in a pediatric population. 1. Factors related to the attack rate of rheumatic fever. N Engl J Med 1961;265:559–566. Breese BB, Hall CB: Beta Hemolytic Streptococcal Diseases. Boston, Houghton Mifflin, 1978. Levin RM, Grossman M, Jordan C, Ticknor W, Barnett P, Pascoe D: Group A streptococcal infection in children younger than three years of age. Pediatr Infect Dis J 1988;7:581–587. Moffett HL, Cramblett HG, Smith A: Group A streptococcal infections in a children’s home. II. Clinical and epidemiologic patterns of illness. Pediatrics 1964;33:11–17. Breese BB, Disney FA: The accuracy of diagnosis of beta streptococcal infections on clinical grounds. J Pediatr 1954;44:670–673. Dick GF, Dick GH: Scarlet Fever. Chicago, Year Book, 1938. Powers GF, Boisvert PL: Age as a factor in streptococcosis. J Pediatr 1944:25:481–504. Boisvert PL, Darrow DC, Powers GF, Trask JD: Streptococcosis in children: A nosographic and statistical study. Am J Dis Child 1942;64:516–534. Bearg PA, Boisvert PL, Darrow DC, Powers GF, Trask JD: ‘Streptococcosis’ and ‘streptococcic fever.’ Am J Dis Child 1941;62:431–436. Gerber MA, Kaplan EL, Gastanuduy AS, McKay C, Wannamaker LW: The immunologic response to group A streptococcal upper respiratory infections in very young children. J Pediatr 1980;96:374–379. Schwartz RH, Hayden GF, Wientzen R: Children less than three-years-old with pharyngitis: Are group A streptococci really that uncommon? Clin Pediatr 1986;25:185–188. Smith TD, Wilkinson V, Kaplan EL: Group A streptococcus-associated upper respiratory tract infections in a day-care center. Pediatrics 1989;83:380–384. Alpert JJ, Pickering MR, Warren RJ: Failure to isolate streptococci from children under the age of 3 years with exudative tonsillitis. Pediatrics 1966;38:663–666.

Robert R. Tanz, MD Division of General Academic Pediatrics, Children’s Memorial Hospital 2300 Children’s Plaza, Box 16, Chicago, IL 60614 (USA) Tel. ⫹1 773 880 3830, Fax ⫹1 773 281 4237, E-Mail [email protected]

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Pechère JC, Kaplan EL (eds): Streptococcal Pharyngitis. Issues Infect Dis. Basel, Karger, 2004, vol 3, pp 22–35

Group A Streptococcal Pharyngitis in Adults: Diagnosis and Management Garnet S. Peter, Alan L. Bisno Department of Medicine, University of Miami School of Medicine, Miami Veterans Affairs Medical Center, Miami, Fla., USA

Group A Streptococcal Pharyngitis in Adults: Diagnosis and Management

Because acute streptococcal pharyngitis is predominantly an illness of children, the disease has been studied much less intensively in civilian adults. Nevertheless, accurate clinical assessment of adults presenting with acute pharyngitis remains crucial in selecting further laboratory tests, determining optimal treatment, and avoiding overuse of antibiotics. This chapter will therefore focus on the approach to diagnosis and treatment of acute pharyngitis in adults. Incidence

The most detailed studies of streptococcal infection in young adults have been conducted in the military [1]. Military training camps bring together large numbers of young men (and more recently women) from diverse ethnic and socioeconomic backgrounds from far-flung geographic areas who are housed in close quarters and subjected to intense physical stress. Such conditions are ideal for person-to-person transmission of respiratory pathogens, and epidemics of streptococcal pharyngitis, scarlet fever and acute rheumatic fever have been a serious concern to the armed forces. Indeed, the classic studies conducted at Fort Warren in Wyoming in the years following World War II provide the basis for much of our understanding of the ecology of streptococcal infections in semi-closed populations [2, 3]. For further discussion of streptococcal infections in the military, the reader is referred to other sources [2, 4].

Data are lacking on the incidence of GABHS pharyngitis in adult civilians. According to the National Ambulatory Care Survey, adults with a chief complaint of sore throat accounted for approximately 6.7 million annual visits to primary care physicians between 1989 and 1999; antibiotics were prescribed in 73% of the visits [5]. If even 5% of all visits were due to GABHS infections, then the incidence would approximate 335,000 cases per year. The frequency with which adults develop streptococcal pharyngitis is influenced by season [6], epidemiologic setting [7–12], exposure to a school-aged child at home [13], and age. McIsaac et al. [11] found that the prevalence of positive GABHS throat cultures in sore throat patients in Toronto decreased from 36.2% in children under the age of 15 to 10.7% in patients between 15 and 44 years and to 1.3% in the 45- to 76-year age group (p ⬍ 0.001). This trend has been corroborated by other investigators [6, 8]. Therefore, any consideration of GABHS pharyngitis must take into account the age range of the population being sampled. Many studies investigating streptococcal pharyngitis in ‘adults’ include patients as young as 15 years. The reported prevalence of positive GABHS cultures in adults with acute pharyngitis differs widely (table 1). At a university student health service, for example, a prevalence of 5% for patients with sore throats has been documented [7]. Other ambulatory care sites (e.g. HMO clinics, hospital-based ambulatory care practices, and family medicine offices in the community or affiliated with a university) found GABHS-positive cultures in as low as 8–15% [8, 9, 11, 12] and as high as 29% of patients [14]. In comparison, a prevalence of 17–44% has been reported in patients presenting to emergency departments [10, 13, 15, 16].

Diagnosis of Group A Streptococcal Pharyngitis

Signs and Symptoms of Streptococcal Pharyngitis Clinical manifestations of streptococcal pharyngitis in adults are quite similar to those in children. Adults with this disease are likely to have had recent exposure to persons with streptococcal infection [8] and to manifest pain on swallowing and myalgias [9]. They are also less likely to complain of cough [8, 9, 15], rhinorrhea [8, 9] or itchy eyes [9] than patients whose throat cultures are negative for group A streptococci. In the authors’ experience, abdominal pain and vomiting (features seen with slightly increased frequency in children [17]) are rare in adults. Signs associated with adult streptococcal pharyngitis include pharyngeal erythema, pharyngeal or tonsillar exudates, tonsillar swelling, tender and swollen anterior cervical lymph nodes, fever [8, 9, 15], which may exceed 101⬚F, and a white blood cell count of ⬎10,000 [9].

Streptococcal Pharyngitis in Adults

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Table 1. Prevalence of group A strep pharyngitis in adults Reference

Ages years

Prevalence %

Number of patients

Setting

US state or country

Walsh et al. [1975] Centor et al. [1981] Poses et al. [1985] Komaroff et al. [1986]

ⱖ15

15

418

HMO clinic

NH

ⱖ16

17

234

VA

Wigton et al. [1986] Clancy et al. [1988]

ⱖ12

26

516

ⱖ17

34

517

40

720

9

189

Emergency Department University student health service 2 HMO clinics 2 hospital-based ambulatory care centers Emergency Department Emergency Department (ER1) Emergency Department (ER2) Student health service (SH) University-affiliated family medicine center General practice

ⱖ17

4.9

308

ⱖ16

9.7

693

McIsaac et al. [1998]1 (CMAJ)

ⱖ15

8

413

Dagnelie et al. [1998]1 Woods et al. [1999] McIsaac et al. [2000]1

ⱖ15

28.6

479

30–65

44

148

ⱖ15

10.7

441

Emergency Department Community-based family practices

PA RI; MA

Nebraska VA

Canada

Netherlands VA Canada

1

Data for children included in the study are not reported here.

Role of Clinical Criteria Several investigators have focused on developing clinical prediction rules to aid in the assessment of pharyngitis patients and to help predict the need for further diagnostic testing or antimicrobial therapy. Existing clinical algorithms vary in predictive strength (table 2). Walsh et al. [8] identified separate risk groups according to the presence or absence of five clinical findings. The chance of obtaining a positive throat culture in the high, medium, and low-risk groups was 28, 15 and 4%, respectively. Komaroff et al. [9] studied 693 adult pharyngitis patients and found the prevalence of positive throat cultures to

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Table 2. Prediction rules for group A pharyngitis in adults (ⱖ15 years) Reference Prediction rule

Walsh [1975]1

Centor [1981]1

Poses [1986] (AIM)

Komaroff et al. [1986]1

Wigton et al. [1986]

Branching algorithm Risk group High Moderate Low Predictors Score 4 (10%) 3 (20%) 2 (25%) 1 (30%) 0 (15%) Walsh model Branching algorithm Centor predictors 4 3 2 1 0 Risk group High (2%)

Sensitivity/ Positive Receiverspecificity predictive operating % value % characteristic (ROC) curve area 0.69 ⫾ 0.032

54.7/74 35.9/63.3 9.4/62.7

28 15 4 0.793

32.5/94.8 37.5/83.5 22.5/74.5 11.25/66.2 2.5/82.5

56 32 15 6.5 2.5 0.69 ⫾ 0.07

14 9 1 2 0

0.77 ⫾ 0.06

42

Moderate (51%)

71.6/51.3

13.5

Low (37%)

13.4/60.5

3.4

54.4 44.7 23.1 13.9 2.6

Streptococcal Pharyngitis in Adults

LR3 6.3 2.1 0.75 0.3 0.16

10 2 2

9/98.7

Centor criteria 4 3 2 1 0

Likelihood ratio (LR)

Comments

Predictors Enlarged or tender lymph nodes Pharyngeal exudates Exposure to strep. Temperature ⱖ101⬚F Absence of cough Four predictors Tonsillar exudate Swollen or tender anterior cervical nodes Fever history Lack of cough Evaluation of various prediction rules in a population with 5% GABHS prevalence

High risk Tonsillar exudate, swollen anterior cervical lymph nodes, and temp. ⬎100⬚F Moderate risk One or two of the above findings Low risk Neither of the above 0.72

25

Table 2 (continued) Reference Prediction rule

Clancy et al. [1988]

McIsaac, et al. [1998] (CMAJ)4

Scoring system according to presence and severity of fever history, difficulty swallowing, and cough Scoring system according to Centor criteria Score of 0–4 based on age and Centor criteria (score prevalence*) 4 (3.4%) 3 (7.3%) 2 (19.1%) 1 (31.5%) 0 (38.7%)

Sensitivity/ Positive Receiverspecificity predictive operating % value % characteristic (ROC) curve area

Likelihood ratio (LR)

ER 1: 0.700 ⫾ 0.024 ER 2: 0.714 ⫾ 0.022 SH: 0.742 ⫾ 0.069

Comments

ER 1 and 2 refers to: Two different emergency rooms SH refers to: Student health center

ER 1: 0.719 ⫾ 0.023 ER 2: 0.743 ⫾ 0.022 SH: 0.783 ⫾ 0.057

24.2/98.4 24.2/94.2 21.2/81 18.2/67.4 12.1/58.9

57.1 26.7 8.9 4.6 2.5

6.43 2.49 0.84 0.32 0.14

In patients younger than 15 years, the highest possible score was 5 --------------------LR calculated from data that included children

1

Sensitivity and specificity calculated by present authors. From Poses et al. [21]. 3 From Ebell et al. [58]. 4 Sensitivity, specificity and *score prevalence in adults calculated by present authors. 2

be 9.7%. Forty-two percent of their subjects presenting with tonsillar exudates, cervical lymphadenopathy and fever and positive cultures, compared to only 3.4% of patients lacking all three signs. Only 2% of the patients, however, demonstrated all three clinical findings. Centor et al. [15] evaluated four clinical features in predicting a positive throat culture for GABHS in adults with acute pharyngitis presenting to an emergency room. These characteristics included a history of fever, tonsillar exudate, cervical lymphadenopathy, and the absence of cough. The study group consisted of 234 patients, of whom 17% subsequently proved to have a positive culture. The positive predictive value (PPV) ranged from 56% in the presence of all four predictors, to 2.5% when none of the predictors was present.

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Copper et al. [18] and Snow et al. [19] have published a clinical practice guideline for management of acute pharyngitis in adults that utilizes the Centor criteria as a guide to diagnostic prediction and selection of patients for antimicrobial therapy. This guideline is endorsed by the Centers for Disease Control and Prevention, American Academy of Family Physicians, and the American College of Physicians-American Society of Internal Medicine. The authors suggest that patients with only one or none of the four Centor criteria should not be tested or treated because of the very low probability of streptococcal infection. They also eschew the use of the throat culture in favor of a rapid antigen detection test (RADT) (see below) when the test sensitivity exceeds 80%. These recommendations appear sound and practical based upon the published literature regarding pharyngitis in adults. The Cooper and Snow recommendations regarding management of patients who present with two to four of the Centor criteria are, however, more controversial. Among several proposed strategies they include the options of treating patients presenting with three or four of the Centor criteria without any diagnostic tests. While it is true that the authors allow options for using the RADT, it is extremely unlikely that clinicians will elect to perform such a test when the guideline allows decision-making on clinical grounds alone. The authors state that a major goal of their guideline is ‘dramatically decreasing antibiotic use’ [19]. In the Centor study, however, only 10% of ‘adult’ (i.e. age ⬎ 15 years) pharyngitis patients presenting to an urban emergency room manifested all four predictive factors; in this group the probability of a positive group A streptococcal throat culture was 56%. In the 20% of subjects exhibiting only three factors, the probability of a positive culture was only between 30 and 34%. Therefore, the PPV associated with having either 3 or 4 clinical predictors would be approximately 40%. Consequently, 60% of patients for whom antibiotics are prescribed using this guideline would have had negative microbiologic tests (throat culture/RADT) for the group A streptococcus. We must conclude, therefore, that the proposed algorithm-based strategy would result in antimicrobial treatment of an unacceptably large number of adults with non-streptococcal pharyngitis. This is a particularly undesirable result in an age group with low prevalence of streptococcal pharyngitis and exceedingly low current risk (in developed countries) of acute rheumatic fever. It should be pointed out that the proposed clinical practice guideline has not been endorsed by the Infectious Diseases Society of America (IDSA) and indeed is at variance with the IDSA’s own official recommendations [20]. When compared to the Centor study, Mclsaac et al. [11] found similar predictive values in their 1998 analysis. In the adult subgroup, scores between 0 and 4 were assigned based on age as well as presence of tender anterior cervical

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27

lymphadenopathy, tonsillar swelling or exudate, temperature ⬎38⬚C, and absence of cough. A clinical score of four had a PPV of 57%, whereas a score of three was associated with a 26.7% probability of a positive culture. About 11% of the patients had a score of three or four. In patients older than 15 years, a score of either three or four would be associated with a PPV of 36%. This number is very close to that for the Centor algorithm, despite a lower prevalence (8%) of positive GABHS cultures. The positive or negative predictive value of an algorithm or a test is strongly influenced by prevalence. Thus, with regards to clinical predictors, the probability of a positive culture might be overestimated in populations with lower prevalence of streptococcal pharyngitis. In a population with a GABHS prevalence of 5%, for example, posterior probability of infection was only 24% in patients with all four Centor criteria [21]. This finding stands in contrast to a PPV of 56% demonstrated in a population in which 17% of throat cultures were positive for GABHS [15]. Formulas exist that allow correcting for differences in prevalence [16]. However, clinicians would have to be familiar with the prevalence of GABHS within the population of interest to predict the effect of pretest probability on predictive values. In contrast, likelihood ratios are not influenced by prior probability and thus seem to constitute a more suitable measure for comparing strength of clinical predictors. Unfortunately, only few studies have determined likelihood ratios for comparison of prediction rules (table 2). In summary, the use of clinical criteria alone in the diagnosis of streptococcal pharyngitis has been limited by the low and variable positive predictive values of clinical indicators. Even those algorithms with the highest positive predictive values would tend to result in significant overuse of antibiotics. In contrast, algorithms may well be of use in identifying adults in whom the probability of GABHS infection is remote and in whom neither further testing nor antimicrobial therapy is required [12, 22]. Laboratory Testing in the Diagnosis of Strep Pharyngitis in Adults The signs and symptoms of group A streptococcal and other (most frequently viral) pharyngitides overlap broadly. Therefore, unless the physician is able confidently to exclude the diagnosis of streptococcal pharyngitis on epidemiologic and clinical grounds (see above), a laboratory test should be performed to determine whether group A streptococci are present in the pharynx [20]. The ‘gold standard’ is the throat culture. A positive throat culture cannot definitively differentiate an acutely infected individual from an asymptomatic pharyngeal streptococcal carrier. Nevertheless, in a patient with a compatible history plus signs and symptoms of acute pharyngitis, a positive culture is considered, for clinical purposes, to confirm the diagnosis of ‘strep throat’.

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A disadvantage of the conventional blood-agar plate throat culture is the delay (overnight or longer) in obtaining definitive results. Rapid antigen detection tests, in contrast, can detect the presence of group A streptococcal cell-wall carbohydrate directly from throat swabs within minutes. Prompt identification and treatment of patients with streptococcal pharyngitis can reduce the risk of the spread of GABHS as well as the acute morbidity of this illness [23–25]. The use of RADTs in certain populations (e.g. emergency rooms) has been shown to significantly increase the number of patients appropriately treated for streptococcal pharyngitis when compared with the use of traditional throat cultures [26]. Most commercially available RADTs have an approximate specificity of 95% of greater when compared with blood-agar plate cultures [23]. A recent study in adults reporting lower specificities [27] has not as yet been confirmed. Because false-positive test results are unusual, a positive RADT can be considered for management purposes equivalent to a positive throat culture. Unfortunately, the sensitivity of most RADT is between 80 and 90% or even lower when compared with the blood-agar plate culture. Recently introduced RADTs using optical immunoassay (OAI) and chemiluminescent DNA probes have been reported to approximate the sensitivity of the throat culture [28–30], but there are conflicting data [31]. The reader is referred to pp 75–84 for a more detailed discussion of these tests as well as the potential limitations imposed by the Clinical Laboratory Improvement Act of 1988 [32] on their use in the physician’s office. Because of their lower sensitivity, it has been recommended that negative RADT should be confirmed by a throat culture [20]. Since the majority of pharyngitis patients seen in primary care practice do not have group A streptococcal infection, the necessity to back up the RADT in most patients is a disincentive to use of the rapid tests. Moreover, some observers feel that the gain in sensitivity obtained by backing up RADT with throat culture may not justify the cost and inconvenience nor necessarily translate into better patient outcomes in areas in which the incidence of acute rheumatic fever is quite low [33]. The proportion of adult pharyngitis patients whose illness is streptococcal is considerably lower than that in children. In several studies the figure is as low as 5–10% [7, 9, 34]. Moreover, the risk of development of acute rheumatic fever in adults is much lower than in children, even if a streptococcal infection should go undiagnosed and untreated. Given these epidemiologic features, it seems reasonable for clinicians to rely either upon a throat culture or a high-sensitivity RADT without culture backup in adults. The high specificity of the rapid tests (very few false-positive results) should help prevent the promiscuous prescribing of antimicrobial agents in the great majority of adults with acute pharyngitis [5].

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Table 3. Antimicrobial therapy of group A streptococcal pharyngitis in adults Antimicrobial agent

Dose

Duration1

Oral Penicillin V (phenoxymethyl penicillin)

250 mg q.i.d. or 500 mg b.i.d.2

10 days

Intramuscular Benzathine penicillin G

1.2 million units

once

Oral agents for penicillin-allergic patients Erythromycin3 1st generation cephalosporins5

varies with formulation4 varies with agent

10 days 10 days

1 Shorter courses of certain third-generation cephalosporins have been reported to be effective for treating group A streptococcal upper respiratory tract infections. However, due to their broader spectra and substantially increased costs (even in shorter courses) compared to penicillin, these agents are not recommended for therapy. 2 Data on twice daily dosing of these agents in adults are limited. 3 Treatment with azithromycin may be considered in patients unable to tolerate oral erythromycin and in whom cephalosporins are contraindicated, but even in FDA-approved 5-day courses, such therapy is quite costly. Macrolide antimicrobials should not be used to treat streptococcal pharyngitis in non-penicillin-allergic patients (see text). 4 Available as stearate, ethyl succinate, estolate or base. Cholestatic hepatitis may rarely occur in patients, primarily adults, receiving erythromycin estolate. The incidence is increased in pregnant women, who should not receive this formulation. 5 These agents should not be used in patients with immediate-type hypersensitivity to betalactam antibiotics.

Treatment

The treatment goals in adults with acute streptococcal pharyngitis include alleviating symptoms, decreasing the duration of illness (provided antimicrobial therapy is initiated early in the illness), limiting household spread of the infection, preventing suppurative complications, and preventing acute rheumatic fever. The authors’ recommendations for antimicrobial therapy of GABHS in adults are presented in table 3. Symptomatic therapy – including warm saline gargles, antipyretics and analgesics (e.g. acetaminophen, aspirin, and nonsteroidal anti-inflammatory agents) – remains an important component of the management of sore throat. In the great majority of cases, GABHS pharyngitis is a self-limited illness, even if no antimicrobial therapy is given. Antibiotics seem to hasten the resolution of clinical illness, but only if administered early in the course of the

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disease [35–38]. DeMeyere et al, in a carefully designed randomized, placebocontrolled trial, showed that sore throat symptoms resolved approximately one day earlier in the penicillin-treated group of patients with streptococcal pharyngitis when compared to controls [36]. A subsequent study showed a decrease in the duration of sore throat and fever, but no hastening of return to school of work [38]. Sore throat duration was shorted by about 1–2 days. The last two studies included children as well as adults, but similar results were seen in a group limited to adult patients [39]. The group A streptococcus has remained uniformly and exquisitely susceptible to penicillin [40], and this time-honored agent is effective in both primary [41, 42] and secondary prevention of acute rheumatic fever. Both the American Heart Association [43] and IDSA [20], recommend either a single intra-muscular injection 1.2 million units of benzathine penicillin G or a 10-day course of penicillin V (phenoxymethyl penicillin) as the antimicrobial treatment of choice for non-penicillin-allergic patients with GABHS pharyngitis. In current medical practice, the benzathine regimen is usually reserved for adults whose adherence to the 10-day oral regimen is judged questionable or who have a history of acute rheumatic fever. Most studies evaluating antibiotic regimens for the treatment of streptococcal pharyngitis are limited to or include children. Several investigators have evaluated antibiotic regimens in abbreviated courses specifically in the adolescent and adult population. In particular, a 5-day course of cefotiam hexetil, cefpodoxime proxetil, or cefdinir as well as a 6-day course of amoxicillin have all been reported to achieve clinical and bacteriologic response rates comparable to a ten-day course of penicillin [44–47]. Azithromycin (500 mg p.o. on day 1, followed by 250 mg p.o. QD on days 2–5) has also been reported to be equivalent in safety and efficacy to a 10-day course of penicillin V [48] and has been approved by the FDA for this indication [49]. Conversely, Kaplan et al. [50] found that a 10-day course of clarithromycin resulted in greater eradication rates than a 5-day course of azithromycin. Further confirmatory data on these short course regimens are required. Moreover, the antimicrobial spectra of these agents are broader than that of penicillin, and in most cases the regimens are considerably more expensive than penicillin, even when administered for short courses. Therefore, we do not recommend these short-course regimens at this time. Once- and twice-daily cefdinir for 10 days produced response rates that were superior to penicillin V in adolescents and adults [51], but also resulted in more adverse reactions. In children [52] and a limited number of adults [53], amoxicillin 750 mg once a day for 10 days appears to be as effective as penicillin V three times a day. Once-a-day amoxicillin could be a very attractive alternative to penicillin V in the treatment of adult streptococcal pharyngitis, although more randomized controlled trials are needed before further recommendations can be made.

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The penicillin-allergic adult may be treated with erythromycin (table 3) [34, 43]. One of the available formulations, erythromycin estolate has been associated with cholestatic hepatitis. Although rare and usually reversible, this complication appears to be more frequent in adults and particularly so in pregnant women, in whom the drug is relatively contraindicated. Macrolides, including azithromycin and clarithromycin, should not be used to treat streptococcal pharyngitis in patients who are not allergic to penicillin. Extensive use of this group of antimicrobials can result in community-wide increases in the frequency of erythromycin-resistant group A streptococci. In Finland, for example, macrolide-resistance increased from 4 to 24% between 1988 and 1990 [54] concomitant with accelerating macrolide use. Similarly in Italy, approximately 28% of GABHS isolates had developed resistance to erythromycin in 1995 compared to about 3.4% in 1993 [55]. In the US, only 2.6% of 301 of GABHS isolates from over twenty states were macrolideresistant between 1994 and 1997 [40]. Canada reported a comparable rate of resistance, 2.1% in over 3,000 isolates in 1997 [56]. Recently, however, erythromycin resistance was detected in between 30% and 48% of GABHS isolates from the community and from primary school children in Pittsburg, PA, respectively [57]. In addition to selecting for macrolide-resistant GABHS, overuse of macrolides increases the potential for antimicrobial resistance in other bacterial strains. A 5-day course of azithromycin, for example, was associated with an increase in erythromycin-resistant pneumococci from 2 to 8% [58]. In summary, penicillin is generally well tolerated. It remains a narrowspectrum and very cost-effective antibiotic compared to many cephalosporins. In addition, GABHS has not developed resistance to penicillin, as has been seen with macrolides. Azithromycin, as well as any of the broader antibiotics, are more likely to increase selection for anti-microbial resistance in both GABHS as well as other organisms including Streptococcus pneumoniae. Although several antibiotics appear to be effective in eradicating oropharyngeal streptococci, the current recommendation continues to be a 10-day course of penicillin or erythromycin for penicillin-allergic patients.

References 1 2

3 4

Denny FW Jr: A 45-year perspective on the streptococcus and rheumatic fever: The Edward H. Kass lecture in infectious disease history. Clin Infect Dis 1994;19:1110–1122. Rammelkamp CH, Denny FW, Wannamaker LW: Studies on the epidemiology of rheumatic fever in the armed services; in Thomas L (ed): Rheumatic Fever. Minneapolis, University of Minnesota Press, 1952, pp 72–89. Rammelkamp CH, Wannamaker LW, Denny FW: The epidemiology and prevention of rheumatic fever: 1952. Bull NY Acad Med 1997;74:119–133. Gray GC: Acute respiratory disease in the military. Fed Pract 1995;Jan:27–29, 33.

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15 16 17 18

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30 31

32 33 34 35 36 37 38

39

40

41 42

43

44

45 46

47

48 49 50

Steed LL, Korgenski K, Daly JA: Rapid detection of Streptococcus pyogenes in pediatric patient specimens by DNA probes. J Clin Microbiol 1993;31:2996–3000. Schlager TA, Hayden GA, Woods WA, Dudley SM, Hendley JO: Optical immunoassay for rapid detection of group A beta-hemolytic streptococci. Arch Pediatr Adolesc Med 1996;150:245–248. Schwartz B, Fries S, Fitzgibbon AM, Lipman H: Pediatricians’ diagnostic approach to pharyngitis and impact of CLIA 1988 on office diagnostic tests. JAMA 1994;271:234–238. Webb KH: Does culture confirmation of high-sensitivity rapid streptococcal tests make sense? A medical decision analysis. Pediatrics 1998;101:E2. Bisno AL: Acute pharyngitis. N Engl J Med 2001;344:205–211. Merenstein JH, Rogers KD: Streptococcal pharyngitis: Early treatment and management by nurse practitioners. JAMA 1974;227:1278–1282. de Meyere M, Mervielde Y, Verschraegen G, Bogaert M: Effect of penicillin on the clinical course of streptococcal pharyngitis in general practice. Eur J Clin Pharmacol 1992;43:581–585. Del Mar C: Managing sore throat: A literature review. II. Do antibiotics confer benefit? Med J Aust 1992;156:644–649. Dagnelie CF, van der Graaf Y, de Melker RA: Do patients with sore throat benefit from penicillin? A randomized double-blind placebo-controlled clinical trial with penicillin V in general practice. Br J Gen Pract 1996;46:589–593. Zwart S, Sachs AP, Ruijs GJ, Gubbels JW, Hoes AW, de Melker RA: Penicillin for acute sore throat: Randomised double blind trial of seven days versus three days treatment or placebo in adults. BMJ 2000;320:150–154. Kaplan EL, Johnson DR, Del Rosario MC, Horn DL: Susceptibility of group A beta-hemolytic streptococci to thirteen antibiotics: Examination of 301 strains isolated in the United States between 1994 and 1997. Pediatr Infect Dis J 1999;18:1069–1072. Denny FW, Wannamaker LW, Brink WR, Rammelkamp CH, Custer EA: Prevention of rheumatic fever: Treatment of the preceding streptococcic infection. JAMA 1950;143:151–153. Wannamaker LW, Rammelkamp CH Jr. Denny FW, Brink WR, Houser HB, Hahn EO: Prophylaxis of acute rheumatic fever by treatment of preceding streptococcal infection with various amounts of depot penicillin. Am J Med 1951;10:673–695. Dajani A, Taubert K, Ferrieri P, Peter G, Shulman S: Treatment of acute streptococcal pharyngitis and prevention of rheumatic fever: A statement for health professionals. Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young, the American Heart Association. Pediatrics 1995;96:758–764. Carbon C, Chatelin A, Bingen E, Zuck P, Rio Y, Guetat F, et al: A double-blind randomized trial comparing the efficacy and safety of a 5-day course of cefotiam hexetil with that of a 10-day course of penicillin V in adult patients with pharyngitis caused by group A ␤-haemolytic streptococci. J Antimicrob Chemother 1995;35:843–854. Portier H, Chavanet P, Gouyon JB, Guetat F: Five day treatment of pharyngotonsillitis with cefpodoxime proxetil. J Antimicrob Chemother 1990;26(suppl E):79–85. Tack KJ, Henry DC, Gooch WM, Brink DN, Keyserling CH: Five-day cefdinir treatment for streptococcal pharyngitis. Cefdinir Pharyngitis Study Group. Antimicrob Agents Chemother 1998;42:1073–1075. Peyramond D, Portier H, Geslin P, Cohen R: 6-day amoxicillin versus 10-day penicillin V for group A beta-haemolytic streptococcal acute tonsillitis in adults: A French multicentre, open-label, randomized study. The French Study Group Clamorange. Scand J Infect Dis 1996;28: 497–501. Hooton TM: A comparison of azithromycin and penicillin V for the treatment of streptococcal pharyngitis. Am J Med 1991;91(suppl 3A):A3–A23. Committee on Infectious Diseases: Group A streptococcal infection; in Pickering LK, (ed): 2000 Red Book. Elk Grove Village, American Academy of Pediatrics, 2001, pp 526–536. Kaplan EL, Gooch WM III, Notario GF, Craft JC: Macrolide therapy of group A streptococcal pharyngitis: Ten days of macrolide therapy (Clarithromycin) is more effective in streptococcal eradication than five days (azithromycin). J Infect Dis 2001;32:1798–1802.

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51

52 53 54 55

56

57 58

Nemeth MA, McCarty J, Gooch WM III, Henry D, Keyserling CH, Tack KJ: Comparison of cefdinir and penicillin for the treatment of streptococcal pharyngitis. Cefdinir Pharyngitis Study Group. Clin Ther 1999;21:1873–1881. Feder HMJ, Gerber MA, Randolph MF, Stelmach PS, Kaplan EL: Once-daily therapy for streptococcal pharyngitis with amoxicillin. Pediatrics 1999;103:47–51. Shvartzman P, Tabenkin H, Rosentzwaig A, Dolginov F: Treatment of streptococcal pharyngitis with amoxycillin once a day. BMJ 1993;306:1170–1172. Seppala H, Nissinen A, Jarvinen H, Huovinen S, Henriksson T, Herva E, et al: Resistance to erythromycin in group A streptococci. N Engl J Med 1992;326:292–297. Cornaglia G, Ligozzi M, Mazzariol A, Masala L, Lo Cascio G, Orefici G, et al: Resistance of Streptococcus pyogenes to erythromycin and related antibiotics in Itlay. Clin Infect Dis 1998;27(suppl 1):S87–S92. De Azavedo JC, Yeung RH, Bast DJ, Duncan CL, Borgia SB, Low DE: Prevalence and mechanisms of macrolide resistance in clinical isolates of group A streptococci from Ontario, Canada. Antimicrob Agents Chemother 1999;43:2144–2147. Martin JM, Green M, Barbadora KA, Wald ER: Erythromycin – resistant group A streptococci in Pittsburgh. N Eng J Med 2002;346:1200–1206. Morita JY, Kahn E, Thompson T, Laclaire L, Beall B, Gherardi G, et al: Impact of azithromycin on oropharyngeal carriage of group A streptococcus and nasopharyngeal carriage of macrolideresistant Streptococcus pneumoniae. Pediatr Infect Dis J 2000;19:41–46.

Alan L. Bisno, MD Chief, Medical Service Miami VA Medical Center 1201 NW 16th Street Miami, FL 33125 (USA) Tel. ⫹1 305 324 3264, Fax ⫹1 305 324 3147, E-Mail [email protected]

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Pechère JC, Kaplan EL (eds): Streptococcal Pharyngitis. Issues Infect Dis. Basel, Karger, 2004, vol 3, pp 36–48

Practical Experience with Clinical Algorithms for Reducing Unnecessary Antibiotic Use in the Management of Streptococcal Pharyngitis Warren J. McIsaac Mt. Sinai Family Medicine Centre, Department of Family and Community Medicine, University of Toronto, Toronto, Ont., Canada

After assessing a child or an adult complaining of a sore throat, the physician or health care provider is faced with a decision; should I prescribe an antibiotic or not? In the past, the answer to this question was frequently ‘yes’ as the risks of side effects from unnecessary antibiotic treatment were generally judged to be less than the consequences of untreated streptococcal infections. In addition, physicians wanted to offer patients relief from uncomfortable symptoms that early antibiotic treatment might afford. The decade of the 1990s brought with it the recognition of a worldwide problem with antibiotic resistance [1]. A large body of evidence pointed to the overuse of antibiotics in the management of community acquired respiratory infections as a prime contributor to the development of resistance. As a result, physicians are now faced with a new consideration when deciding whether or not to prescribe an antibiotic to a person complaining of a sore throat; how do I make sure those that need antibiotics most receive them while at the same time limiting unnecessary antibiotic prescriptions?

The Management of Sore Throat by Primary Care Physicians

The only generally accepted indication for antibiotic treatment in persons complaining of a sore throat is a group A streptococcal infection. While the prevalence of infection in primary care settings that treat both children and adults is generally between 10 and 20% [2], prescribing rates for upper

Table 1. Surveys and studies assessing sore throat management practices of primary care physicians* Study

Holmberg (1983) Cochi (1984) Arthur (1984) Berger (1987) McIsaac (1996)

Setting

Number of MDs

Throat culture, % usually

selectively

Start antibiotics before results %

Find culture results not timely %

USA

491

50

45

87

44

USA

567

18

46

52

54

USA

921

23

–

–

–

Canada

85

53

–

78

56

Canada

128

70

16

*Adapted from Family Practice 1997;14:34–39.

respiratory tract infections, pharyngitis and tonsillitis in developed countries range from 50% to more than 90% [3, 4]. How do primary care physicians approach patients complaining of a sore throat such that over prescribing results? Table 1 includes some of the studies that have assessed physician management of patients complaining of a sore throat [2]. Whereas expert groups advise physicians to take a throat swab and await the results before making a prescribing decision, no more than half of physicians report they usually take a throat swab. Most report they make a selective decision about the need for a throat swab based on the clinical picture. Low rates of throat culture use are also common in some European countries, Australia and the United States [4–6]. One reason for this may be the view expressed by these physicians that culture results are not timely in informing treatment decisions. As a result, the majority of physicians in these surveys reported they would make a decision about the need for antibiotics, prior to the availability of culture results, based on their clinical judgement. What is the accuracy of clinical judgement as a basis for deciding about the need for antibiotics? Studies from a variety of settings have found the sensitivity of clinical judgement to range from 45 to 90% and specificity from 30 to 80% (table 2) [7, 8]. This suggests that in many primary care settings, physicians may miss up to one-half of the cases of group A streptococcus when they rely on clinical judgment. The false-positive rate for prescribing decisions based on clinical judgment is generally in the range from 20 to 40%.

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Table 2. The Accuracy of clinical judgement in the diagnosis of streptococcal pharyngitis* Study

Setting

Hart (1976) Shank et al (1984) Vandepitte (1990) Kljakovic (1993) Centor (1981) Cebul (1986) Siegel (1961) Fujikawa (1985)

General practice, Canada General practice, USA General practice, Belgium General practice, New Zealand Emergency Department USA Student Health Service, USA Paediatric Hospital, USA Paediatric Hospital, Japan

Number of patients

Prevalence of GAS on Culture %

Sensitivity %

Specificity %

540

10

56

57

3,982

16

45

80

648

27

45

74

329

12

93

26

286

17

72

76

310

5

53

67

2,545

48

55

73

271

40

90

71

*Adapted from Can Fam Physician 1997;43:485–493, with permission of the publisher.

As the prevalence of group A streptococcus in patients complaining of a sore throat in general practice settings is most often from 10 to 20%, the vast majority of patients with a sore throat do not have a streptococcal infection. However, the relatively low specificity and resulting high false-positive rate mean that a large proportion of the 80–90% of all sore throat patients without a group A streptococcal infection will be considered for antibiotic treatment when clinical judgement is relied upon. As this is the preferred approach of most physicians, this suggests that clinical error in estimating the chance that a given patient has a streptococcal infection could contribute to unnecessary antibiotic use.

The Role of Clinical Error in Antibiotic Overuse

Physicians generally overestimate the chance that a given person has a group A streptococcal infection and their estimate of risk is strongly related to their prescribing decision [9]. In a study of children and adults with a URI and

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Table 3. Rate of unnecessary antibiotic prescriptions in children and adults complaining of a sore throat in relation to the error by family physicians in estimating the likelihood of a group A streptococcal (GAS) infection* Difference between the Physician’s estimate and the true risk of GAS %

Rate of unnecessary antibiotic prescriptions %

⬍10 ⫹10 to 29 ⫹30 to 49 ⱖ50

5.1 16.0 35.6 78.3

*Adapted from Med Decis Making 2000;20:33–38, with permission of the publisher.

a sore throat, Canadian family physicians were asked to estimate the likelihood that a given patient had a group A streptococcal infection [10]. Each of these patients had a throat swab taken for culture. The physicians’ estimates were compared to the true likelihood that the patient had a streptococcal infection, by examining the rate of positive cultures in groups of patients with similar findings (table 3). When the estimate by the physician of the likelihood of a group A streptococcal infection was close to the true risk of infection, the rate of unnecessary antibiotic prescriptions were low. As the error in the physicians’ estimate increased, the rate of unnecessary antibiotic use increased in a graded fashion, suggesting a strong association between clinical error and antibiotic overuse in the management of patients complaining of a sore throat. Sixty-three percent of all unnecessary antibiotic prescriptions in this study were attributable to a clinical error by the physician in estimating the likelihood of a streptococcal infection of more than 10%.

Clinical Algorithms, Prediction Rules and the Reduction of Clinical Error

A number of clinical algorithms and prediction rules were developed to address the problem of diagnostic error in the clinical evaluation of patients complaining of a sore throat. While it was clear that individual clinical findings were not sufficiently precise to differentiate between viral and bacterial infections, physicians generally considered multiple clinical findings when

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arriving at a diagnosis. Early approaches looked at groups of symptoms and signs that were more common in patients with group A streptococcal infections [11, 12]. The next step was to more formally incorporate these into algorithms and scoring systems to take into account the number of findings present in arriving at a management decision [13, 14]. An advance in this area was the application of mathematical modeling techniques. In the now classic study, Centor et al. [15] used logistic regression to create a simple model for the prediction of group A streptococcal infection in adults presenting to the emergency room. Problems with this approach were that it was not valid in children and was subject to variable performance when applied in other settings where the prevalence of group A streptococcus was different than in the emergency room [16]. In addition, physicians trained to provide better estimates of the likelihood of a group A streptococcal infection using this approach did lot lower their antibiotic prescribing rates [17]. As the majority of sore throat presentations in many countries are managed by general practitioners and family physicians who look after both children and adults, we conducted a study to determine if the Centor score could be modified for use in general practice settings. The remainder of this chapter will be spent discussing the results of this research and its implications for reducing unnecessary antibiotic use in the management of patients complaining of a sore throat in the developed world. For a more detailed discussion of the strengths and weaknesses of other sore throat prediction rules, as well as issues in their application in the developing world, additional references are provided [see ‘Recommended Reading’].

The Sore Throat Score Management Approach

An initial study was conducted in a family medicine teaching centre in Canada. Family physicians assessed 512 children and adults for the presence of more than 20 clinical findings and a throat culture was obtained in each case [18]. The method of Centor was used in applying logistic regression modeling to determine the individual clinical findings most predictive of a positive throat culture. Taking into account all possible findings, only the following clinical features were independently associated with being more likely to have a positive culture: a history of a temperature ⬎38⬚C (odds ratio ⫽ 2.37, 95% confidence interval 1.10, 5.10), absence of a cough (OR ⫽ 2.36, 95% CI ⫽ 1.09, 5.10), tonsillar swelling or exudate (OR ⫽ 4.35, 95% CI ⫽ 2.02, 9.38) and tender, anterior cervical adenopathy (OR ⫽ 2.81, 95% CI ⫽ 1.20,6.60). Each of these clinical findings was assigned one point to reflect the relatively equal weighting of these factors in the model, as indicated by the

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overlapping confidence intervals. The rate of positive culture in children aged 3–14 in this study was 36.2% compared to 10.7% in adults aged 15–44 years and 1.3% in adults aged 45 years or more. As a result, children were assigned 1 extra point for their higher prevalence of infection and one point was subtracted for older adults. Total scores were then calculated for each person in the study and the rates of positive cultures in relation to the number of findings or ‘points’ present determined. The following shows the results from this study of children and adults in comparison to Centor’s original results in adults: Proportion of rate of positive throat cultures Total score

Sore throats (%)

McIsaac [18] (%)

Centor [15] (%)

0 or less 1 2 3 4 or more

31.8 27.4 19.5 10.7 10.5

2.5 5.1 11.2 27.8 52.8

2.5 6.0–6.9 14.1–16.6 30.1–34.1 55.7

Because physicians did not lower their antibiotic prescribing rates when using a similar prediction rule to estimate the likelihood of a group A streptococcal infection [17], explicit management recommendations were developed and linked to the estimates of the likelihood of infection [19]. For those with a total score of 0 or 1 where the prevalence of a positive throat culture was less than 10%, no antibiotic and no throat culture were advised. The rationale was that the gold standard for diagnosis in clinical practice was a single throat swab. The sensitivity of this had been estimated at 90% compared to 2 throat cultures, suggesting that up to 10% of positive cultures would be missed if all sore throat patients underwent a throat culture. If the total score was 2 or 3, a throat culture was recommended and physicians were advised to await the culture results before deciding about the need for antibiotics. More than 70% of patients in this group have negative cultures so that prescribing at the time of the office visit would result in an unacceptable number of unnecessary prescriptions. For a score of 4 or more, either initiating antibiotic treatment or a throat culture was advised. This group comprised only 10% of all presentations and randomized trials indicated the effect of antibiotic treatment on symptom relief was likely greatest in those with more severe presentations who were seen early in the course of their illness [7]. In addition, this addressed the preference of physicians to initiate treatment before culture results based on their clinical judgement in selected cases. The resulting score ‘approach’ (estimates for the probability of infection linked to explicit management recommendations) is illustrated in figure 1.

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Criteria

Points

Temperature ⬎38ºC 1 No cough 1 Tender, anterior cervical nodes 1 Tonsil swelling or exudate 1 Age ⬍15 1 Age 45 or older ⫺1 Score total

Chance of ‘strep’ infection in general practice (%)*

Suggested management

0 or less 1

0–3 4–10

No culture or antibiotic required

2 3

10–19 24–40

Culture all; treat only if culture positive

4 or more

43–60

Treat with penicillin on clinical grounds**

*Based on 95% confidence intervals combining data of original and validation study [18, 20]. **If patient has high fever or clinically unwell and early in disease course. Otherwise a culture is appropriate. Use erythromycin if penicillin allergy Adapted from Can Med Assoc J 1998;158:75–83.

Fig. 1. Age-appropriate sore throat score and management recommendations.

Standards for the validation of prediction rules recommend evaluations in different clinical settings to ensure reliability and validity for use in clinical practice.

Reliability in Different Clinical Settings

Two studies were conducted in separate patient populations to determine the reliability of the score approach in different clinical settings and what the impact would be on unnecessary antibiotic use if adopted by physicians into routine clinical care [18, 20]. As this method was developed to assist general practitioners and family physicians in reducing unnecessary antibiotic use, these studies were conducted in the offices of family physicians (table 4). The first study was conducted in an academic family medicine centre in a major metropolitan city in Canada. The center is part of the University of Toronto Department of Family and

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Table 4. Reliability of sore throat score estimates for the likelihood of a group A streptococcal infection in Canadian children and adults complaining of a sore throat in different settings

Setting

Number of physicians Number of patients Prevalence of GAS on culture, % Positive cultures in each score category 0 1 2 3 4 Sensitivity, % Specificity, %

Study 1

Study 2

Academic family Medicine Residency Centre, Toronto 31 503 12.9

Community-based Family Physicians’ Offices, Ontario 97 600 17.0

2.5% (4/160) 5.1% (7/138) 11.2% (11/98) 27.8% (15/54) 52.8% (28/53) 83.1 94.3

1.0% (2/179) 10.0% (13/134) 17.0% (18/109) 35.0% (28/81) 51.0% (39/77) 85.0 92.1

Community Medicine and trains approximately 18 residents per year who become family physicians. The second study was conducted in a different time period and involved 97 community-based family physicians from all regions of the province of Ontario, the largest province in Canada. The practices of these physicians were nonacademic for the most part and many were situated in small urban or rural areas. The prevalence of group A streptococcal infections were similar in the two settings and within the range generally reported in other general practice settings [2]. In each study, the clinical elements needed to determine the score were assessed by the treating physician and a throat swab for culture was obtained in all cases. Physicians were free to make prescribing decisions as they felt appropriate. Score totals were calculated for all patients and the rate of positive cultures for each score category was determined to assess the reliability of the estimates in different settings. To determine the accuracy of the score approach in identifying cases of group A streptococcal infection, sensitivity and specificity was determined as follows; if the score approach recommended an antibiotic or a throat swab and the subsequent culture was positive, then the patient was classed as having been appropriately identified (sensitivity of overall management). If the score approach did not recommend an antibiotic or a throat swab and the culture was negative, or a throat swab was recommended but no

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Table 5. Potential impact of following a score approach on unnecessary antibiotic use and throat swab utilization compared to usual care

Total patients Antibiotic prescriptions Unnecessary prescriptions Throat swab use

Observed care by physicians

Score Approach

Reduction [95 % CI]

1,136 24.8% (278/1,138) 16.0% (179/1,1191) 46.1% (520/1,128)

1,083 12.1% (131/1,083) 5.9% (64/1,083) 31.6% (342/1,083)

– ↓50% [40%, 59%] ↓63% [51%, 72%] ↓31% [24%, 39%]

1

Denominators differ due to missing throat culture results and information about use of throat swabs.

antibiotic prescribed and the culture was negative, then the patient was also considered to have been appropriately managed (specificity). The proportions of positive cultures in each score category were similar in the two studies, as were the overall estimates for the sensitivity and specificity of the score approach. These studies suggested that, through a combination of prescribing and swabbing, the score approach could achieve a sensitivity for identifying group A streptococcal infection of 84.8% [95% confidence interval ⫽ 79.3%, 90.3%] and a specificity of 93% [95% CI ⫽ 92.8%, 93.2%] in a population of children and adults presenting to family physicians. The sensitivity of the score approach in children was higher than in adults in these studies. In the first study, the sensitivity in children was 96.9% and in the second study, 92.6% [18]. The comparable figures for adults were 69.7 and 76.1%. As the risk of rheumatic fever in children is generally higher than in adults, a high sensitivity is desirable. In addition, the overall sensitivity of the score approach appears to be at least as high or higher than physicians relying on usual clinical judgment (table 2). The Potential Impact of the Score Approach on Unnecessary Antibiotic Prescriptions

Table 5 displays the combined data from the two studies comparing observed management by the family physicians in these studies and what would have happened had the score approach been followed. It is relevant to note that in the second study, physicians were provided with information about the score

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approach although they were not compelled to follow it. However, the performance of the physicians in this latter study was somewhat better than physicians in the first study in terms of identification of group A streptococcal infections [20]. As a result, the estimated reductions in unnecessary antibiotic use in table 5 may be conservative. Overall antibiotic prescriptions would have been reduced by 50% while unnecessary antibiotic prescriptions would have been reduced by 63%. Unnecessary prescriptions were defined as antibiotics prescribed to a patient at the time of the office visit where the subsequent throat culture was negative. As up to 50% of physicians report that they would not necessarily discontinue antibiotics when faced with a negative culture report [2], it is important to affect these initial prescribing decisions if unnecessary antibiotic use in the community is to be reduced. It is also important that these reductions in antibiotic use could be achieved without any need to increase throat culture utilization. By following the score approach, throat swab use would have been reduced by 31%.

Limitations of the Score Approach

The score approach is less sensitive for identifying group A streptococcal infections than a policy of throat swabbing all children and adults complaining of a sore throat. However, it is clear that physicians have not followed this approach over the last few decades and nonetheless, rates of rheumatic fever in developed countries remain at their lowest levels in history. As the score approach is at least as sensitive as usual physician care, this suggests that rheumatic fever rates are unlikely to be adversely affected with such an approach. The score approach presented here was specifically developed to help primary care physicians who care for both children and adults to reduce their antibiotic use while still identifying the majority of group A streptococcal infections. In Canada, family physicians account for 80% of antibiotic prescriptions written for the management of respiratory infections [21]. However, this approach may be less applicable in other settings such as pediatric clinics or student health services. In the subgroup of children in the two studies (n ⫽ 257), antibiotic prescriptions would not have been reduced compared to usual care. The proportion of visits where an unnecessary antibiotic was prescribed by physicians was 17.2% overall compared to 19.2% had the score approach been followed (p ⫽ 0.56). However, the score approach would have identified a greater proportion of group A streptococcal infections in children (94%) than physicians did (80%, p ⫽ 0.006) [18]. Given the higher prevalence of group A streptococcal infections in children, it may be difficult to decrease unnecessary antibiotic

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use further without compromising the detection of infections. An alternative is to increase reliance on bacteriologic testing, although physicians have tended to reject this approach [6]. Further research examining predictive clinical models in children may be helpful in guiding those who care for children only [22]. The problem of disease prevalence affecting the performance of clinical scores has been noted previously [see ‘Recommended Reading’]. The prevalence in most general practice settings is reported to be between 10 and 20% [2]. At these endemic levels, the score approach is reliable. However, in countries where the prevalence of group A streptococcal infection exceeds this, the approach cannot be relied upon unless adjustments for the differing prevalence of disease are made [see ‘Recommended Reading’]. This is also the case in populations that continue to be affected by rheumatic fever, such as some aboriginal populations and countries of the developing world. In these situations, alternative approaches may be needed (see this book, p. 173 and p. 192 – Practical problems associated with the prevention of initial and recurrent attacks of acute rheumatic fever in developing countries; Practical management of pharyngitis: the Costa Rica Experience and its impact on the public health).

Conclusions

The emergence of antibiotic resistance as a global threat has necessitated a re-examination of the antibiotic prescribing practices of physicians for patients complaining of a sore throat. Most physicians have rejected a strategy of taking a throat swab for all patients and instead rely on their clinical judgement to make a selective decision about the need for a throat culture or an antibiotic. While this has been compatible with low levels of rheumatic fever in developed countries, antibiotic prescription rates are higher than is necessary given the relatively low prevalence of group A streptococcal infections. The sore throat score approach provides for more precise estimates of the likelihood of a group A streptococcal infection in a given patient, and therefore allows the physician to more appropriately classify a person as being at a low, moderate or high risk of infection. When linked to explicit management recommendations, this approach has the potential to reduce unnecessary antibiotic use in the management of patients complaining of a sore throat. This can be accomplished while maintaining or even achieving higher levels of detection of group A streptococcal infections than is the case with current management practices. As a result, rheumatic fever rates are unlikely to be adversely affected. There is an urgent need to reduce unnecessary antibiotic use to combat further increases in antibiotic resistance. The sore throat score approach is a

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practical and reliable method that general practitioners and family physicians can use to help them accomplish this goal. References 1 2 3 4

5 6 7

8 9

10 11 12 13 14 15 16 17 18 19 20 21 22

World Health Organization: Report on Infectious Diseases. Removing Obstacles to Healthy Development. Publication code WHO/CDS/99.1, 1999. McIsaac WJ, Goel V: Sore throat management practices of Canadian family physicians. Family Pract 1997;14:34–39. Gonzales R, Steiner JF, Sande MA: Antibiotic prescribing for adults with colds, upper respiratory tract infections, and bronchitis by ambulatory care physicians. JAMA 1997;278:901–904. Touw-Otten FWMM, Johansen KS: Diagnosis, antibiotic treatment and outcome of acute tonsillitis: Report of a WHO Regional Office for Europe study in 17 European Countries. Family Pract 1992;9:255–262. Carr NF, Wales SG, Young D: Reported management of patients with sore throat in Australian general practice. Br J Gen Pract 1994;44:515–518. Mainous AG III, Zoorob R, Kohrs F, Hagen MD: Streptococcal diagnostic testing and antibiotics prescribed for pediatric tonsillopharyngitis. Pediatr Infect Dis J 1996;15:806–810. McIsaac WJ, Goel V, Slaughter PM, Parsons GW, Woolnough KV, Weir PT, Ennet JR: Reconsidering sore throats. 1. Problems with current clinical practice. Can Fam Physician 1997;43:485–493. Vandepitte J: Streptococcal pharyngitis: A Belgian perspective. Pediatr Infect Dis J 1991;10: S64–S67. Poses RM, Cebul RD, Collins M, Fager SS: The accuracy of experienced physicians’ probability estimates for patients with sore throats. Implications for decision making. JAMA 1985;254: 925–929. McIsaac WJ, Butler CC: Does clinical error contribute to unnecessary antibiotic use? Med Decis Making 2000;20:33–38. Honikman LH, Massell BF: Guidelines for the selective use of throat cultures in the diagnosis of streptococcal respiratory infection. Pediatrics 1971;48:573–582. Forsyth RA: Selective utilization of clinical diagnosis in treatment of pharyngitis. J Fam Prac 1975;2:173–177. Walsh BT, Bookheim WW, Johnson RC, Tompkins RK: Recognition of streptococcal pharyngitis in adults. Arch Intern Med 1975;135:1493–1497. Breese BB: A simple scorecard for the tentative diagnosis of streptococcal pharyngitis. Am J Dis Child 1977;131:514–517. Centor RM, Witherspoon JM, Dalton HP, Brody CE, Link K: The diagnosis of strep throat in adults in the emergency room. Med Decis Making 1981;1:239–246. Poses RM, Cebul RD, Collins M, Fager SS: The importance of disease prevalence in transporting clinical prediction rules: The case of streptococcal pharyngitis. Ann Intern Med 1986;105:586–591. Poses RM, Cebul RD, Wigton RS: You can lead a horse to water-improving physicians’ knowledge of probabilities may not affect their decisions. Med Decis Making 1995;15:65–76. McIsaac WJ, White D, Tannenbaum D, Low DE: A clinical score to reduce unnecessary antibiotic use in patients with sore throat. Can Med Assoc J 1998;158:75–83. McIsaac WJ, Goel V: Effect of an explicit decision-support tool on decisions to prescribe antibiotics for sore throat. Med Decis Making 1998;18:220–228. McIsaac WJ, Goel V, To T, Low DE: The validity of a sore throat score in family practice. Can Med Assoc J 2000;163:811–815. Health Protection Branch, Laboratory Centre for Disease Control. Controlling antimicrobial resistance. An integrated action plan for Canadians. CCDR 1997;(supplement)23s7. Wald ER, Green MD, Schwartz B, Barbadora K. A streptococcal score card revisited. Pediatric Emerg Care 1998;14:109–111.

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Recommended Reading Ebell MH, Smith MA, Barry HC, Ives K, Carey M: The rational clinical examination. Does this patient have strep throat? JAMA 2000;284; 2912–2918. Steinhoff MC, Abd El Khalek MK, Khallaf N, Hamza HS, El Ayadi A, Orabi A et al: Effectiveness of clinical guidelines for the presumptive treatment of streptococcal pharyngitis in Egyptian children. Lancet 1997;350:918–921. Morise AP, Diamond GA, Detrano R, Bobbio M, Gunel E: The effect of disease-prevalence adjustments on the accuracy of a logistic prediction model. Med Decis Making 1996;16:133–142.

Warren J. McIsaac, MD MSc 600 University Ave, Suite 413 Toronto, Ont., M5G 1X5 (Canada) Tel. ⫹1 416 586 5373, Fax ⫹1 416 586 3175, E-Mail [email protected]

McIsaac

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Pechère JC, Kaplan EL (eds): Streptococcal Pharyngitis. Issues Infect Dis. Basel, Karger, 2004, vol 3, pp 49–65

Epidemiology, Clinical Presentations, and Diagnosis of Streptococcal Pharyngitis in Developing Countries of the World M.C. Steinhoff, A.W. Rimoin Bloomberg School of Public Health, Department of International Health, Department of Epidemiology, and School of Medicine, Department of Pediatrics, Johns Hopkins University, Baltimore, Md., USA.

This chapter will review selected epidemiological and clinical features of streptococcal pharyngitis seen in low-income developing regions of the world. Because pharyngitis data are scant and not directly comparable across all parts of the world, we will also review and compare selected data on acute rheumatic fever and rheumatic carditis. We reviewed original articles, reviews, textbook chapters and performed a MEDLINE search to identify relevant published material. Current understanding of the epidemiology of group A streptococcal pharyngitis derives largely from studies conducted in high income, (mostly Northern or temperate climate) countries where pharyngitis is a common complaint in pediatric practice. In low-income countries (mostly, though not all, tropical), there are few prospective studies that provide data on group A streptococcal pharyngitis, its epidemiology and clinical presentation. As a result, it is problematic to determine the magnitude of true differences between geographic settings, and to assess if apparent differences are related to socioeconomic, biological, geographic/climatological or other factors. Epidemiology

Long-term studies in North America show the proportion of pharyngitis that is streptococcal has not varied for over 50 years, although the incidence of rheumatic fever and rheumatic carditis have declined remarkably [1].

In higher income regions rheumatic fever was first described in 1898 and its association with group A streptococcus noted in the 1930s. The descriptive epidemiology of streptococcal disease in low income tropical regions has not been well defined. Early in the modern colonial period up to the 1920s, it was thought by colonial observers that rheumatic fever and carditis were rare in the tropics. Reports of rheumatic carditis as an important tropical problem first appeared in the medical literature only in the 1930s to 1950s. It has since become clear that post-streptococcal rheumatic disease occurs in low income regions at rates similar to or greater than the rates reported in the early 20th century from countries with high incomes. As with other infections, such as tetanus or pertussis, it is likely that high-income temperate, and low-income tropical environments were more similar in disease experience at the beginning of the 20th century than at the end. For example, in the late 1980s reports from Ethiopia suggest that the prevalence of rheumatic heart disease among children was essentially identical to rheumatic heart disease prevalence rates from the US four decades previously [2]. It is also known that some low-income regions with increasing economic resources have shown a remarkable decline in rheumatic disease [3], similar to the historical patterns reported in high-income regions. High Income Countries In high-income countries pharyngitis is common in children ages 3–15 years. On average in the USA, each child has approximately one GABHS pharyngitis infection by age 5, with a mean of 3 episodes (range 1–8) by 13 years of age, [4]. Before the availability of penicillin in the 1940s, ARF rates declined by 50% from 1900. From 1935 to 1960, the incidence of acute rheumatic fever in the USA ranged between 40 and 65/100,000 in all age groups. From the late 1960s, there was a marked decline in ARF; since 1970s, incidence of rheumatic fever has ranged from 0.023 to 1.88 per 100,000 population [5–7]. Localized outbreaks of ARF were reported in parts of the USA in the 1980s. Low Income Countries Few studies have been conducted to ascertain the incidence and prevalence of GABHS in developing countries. The studies we reviewed used varying and non-standardized methods for throat cultures, ASO titers or rapid antigen tests for diagnosis. Incidence of GABHS Pharyngitis Few precise estimates of the incidence of GABHS pharyngitis in lowincome countries are available. The reported incidence of culture-proven GABHS pharyngitis in prospective studies in a few sites appears to be much higher than that reported from the United States in the 1950s: up to 900 versus

Steinhoff/Rimoin

50

Cases per child-year

2

India

1.6

USA

1.2 0.8 0.4 0 1

3

5

7

9

11

13

15

Age (years)

Fig. 1. Age-specific incidence of group A streptococcal pharyngitis in India and the USA [8, 9].

Table 1. Incidence of streptococcal pharyngitis by prospective surveillance studies Author

Site

Year

Age group years

n

Incidence/ 1,000 child-years

Throat culture

ASO

Nandi et al. [8] Dingle et al. [9]

India Cleveland, USA Egypt Mexico USA

1995–1996 1948–1957

5–11 ⱕ16

536 271

950 214

yes yes

no no

1970 1970–1982 1955–1959

6–12 ⱕ15 6–12

156 150 64

310 193 175–195

yes yes yes

no no no

El Kholy et al. [10] Leon et al. [11] Cornfeld et al. [12]

approximately 200 per 1,000 child-years of observation (fig.1; table 1) [8–12]. A recent study reported a high rate of 950 [8]. These apparently elevated rates of infection suggest high rates of carriage and transmission. Since streptococci are spread through the respiratory route, and low income regions are characterized by crowded housing, these data are not surprising. Prevalence in Clinic Settings Interpretation of studies of streptococcal pharyngitis carried out in clinics and hospitals can be difficult because of the conflation of categories of ‘infection’, ‘carriage’ and ‘streptococcal pharyngitis’. Clinical studies in Kuwait, Egypt, Ethiopia, and India have shown that prevalence rates of GABHS pharyngitis in clinics range from 0.3 to 37% (table 2) [2, 11, 12, 15–21]. However, some estimates of GABHS pharyngitis may be low, as it has been suggested that in some countries patients with symptoms of pharyngitis may not seek care

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Table 2. Positive throat cultures for GABHS in patients with pharyngitisa Authors

Site

Year

Age group years

n

Rate, % (95% CI)

Ogunbi et al. [17] Steinhoff et al. [16] Koshi et al. [18] Gubbay et al. [19]

Lagos, Nigeria Cairo, Egypt Vellore, India Buenos Aires, Argentina Mexico City, Mexico France USA MN, USA

1971 1993 1973–1974 1997

6 2–13 ⬍15 4–10

5,300 451 44 4,147

0.3 (0.26, 0.35) 24 (26, 35) 8.75 (1, 17) 26.8 (25.8, 27.8)

1985

6–12

547

21.4 (18.4, 24.4)

1992 1955–1959 1964–1967

3–16 6–12 ⬍15

307 64 624

36.8 (31.8, 41.8) 20.7 (16.2, 25.2) 34.9 (31.2, 38.6)

Leon et al. [11] Cohen et al. [20] Cornfeld et al. [12] Kaplan et al. [21] a

Clinical definitions varied between sites.

at health facilities or complain of sore throat due to economic, cultural or other factors [22]. Reviews of data from some developing countries suggest that a lower percentage of children presenting with pharyngitis have positive GABHS throat cultures than in the USA [1, 22]. In addition, clinical experience suggests that classic textbook cases of streptococcal pharyngitis with enlarged tonsils, exudate and large, tender nodes are infrequently seen in clinics in some regions. El Kholy from Egypt [23] stated ‘in this 3 year study on schoolchildren, monthly history and clinical examinations indicated a very low occurrence of typical acute exudative streptococcal pharyngitis. In the absence of clinical recognizable exudative streptococcal pharyngitis, bacteriological and serological data were employed to determine the attack rates of streptococcal infections.’ Muller noted from Liberia [24]: ‘In the experience of one of the authors… streptococcal illness such as sore throats and scarlet fever were hardly if ever seen among the plantation population. He had never seen tonsils which necessitated tonsillectomy.’ A study in India found that of 53 children with GABHS isolated from the pharynx, 54% had serological evidence of infection, yet none of these patients had complaints of symptoms typically associated with streptococcal pharyngitis [25]. One cannot distinguish if this apparent low proportion of classical clinical presentation of GABHS pharyngitis is related to regional differences in the organism, variation in the host responses, or to patterns of care seeking and referral, although the latter is the least well studied factor.

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Table 3. Carriage prevalence: throat cultures positive for GABHS in asymptomatic schoolchildren Author

Site

Year

Age n years

Positive, % (95% CI)

Tewodros et al. [2]

Addis Ababa, Ethiopia Liberia Vellore, India Delhi, India Kuwait Cairo, Egypt Sapporo, Japan Waikato, New Zealand Prague, Czechoslovakia Copenhagen, Denmark Philadelphia, USA

1992

0–12

816

17 (14, 20)

1965 1965–1967 1990–1991 1977–1978 1967–1979 1979 1978

ⱖ5 0–15 5–15 6–16 6–12 8–9 5–11

455 6,651 749 1,041 300 124 272

20 (16, 24) 34 (33, 35) 18.8 (16, 22) 47 (44, 50) 24 (19, 29) 17 (10, 24) 34.5 (28.9, 41.1)

Valkenburg et al. [24] Koshi et al. [18] Gupta et al. [25] Karoui et al. [26] El Kholy et al. [10] Maekawa et al. [27] Wallace et al. [28] Duben et al. [29] Hoffman et al. [30] Cornfeld et al. [12]

1966–1971 all

4,000 5.7 (5, 6.4)

1983–1984 ⱕ14

129

10.9 (4.9, 16.9)

1955

64

13.1 (4.8, 2.14)

6–12

Carriage Rates As shown in table 3 [2, 10, 12, 18, 24–30], asymptomatic carriage of GABHS appears to be more common in low-income tropical countries than in higher income countries with temperate climates, with the exception of NewZealand [31]. This could be related to variations in transmission dynamics of streptococci or possibly to lower access to antibiotic therapy. Hemolytic Streptococcal Serogroups In many low income countries, isolation rates of group C and G streptococci from the pharynx of asymptomatic schoolchildren are higher than those for group A. Group A streptococci were found in approximately 60% of GABHS-positive throat cultures in temperate climates compared to 30% in tropical countries (table 4) [10, 19, 24, 26, 32, 33]. Serogroups C and G are associated with pharyngitis, but are not associated with rheumatic fever. The reasons for these geographical differences are not known and require further study [22, 31]. GABHS Serotypes There is limited information from low-income countries on M type prevalence. Recently, Kaplan et al. compared the percentage of typability and

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Table 4. Percent asymptomatic children with beta-hemolytic streptococcal (BHS) serogroups Author

Country

Year

Climate

n

Age years

BHS carrier rate %

A %

C %

G %

Other %

Valkenburg et al. [24] Myers and Koshy [32] Karoui et al. [26] Valkenburg et al. [24] Pike and Fashena [33] Valkenburg et al. [24] Gubbay et al. [19] El Kholy et al. [10]

Liberia

1965–1966

tropical

72

5–14

49

10

18

14

7

South India

1957–1958

tropical

1,313

6–10

24.3

7

6.1

10.8

0.4

Kuwait

1978–1979

arid desert

1,041

6–16

47

10

352

2

Netherlands1

1959–1964

temperate

1,065

6⫹

21.9

21.9

United States 1944–1945

temperate

900

0–14

42

25

11

6

Nigeria

1967

tropical

125

5–14

12

3

2

2

5

Argentina

1991–1995

subtropical

23,250

0–16

20.6

17.6

0.9

0.9

1.2

Egypt

1969–1970

arid desert

156

2–12

24

24

Climate classifications based on Koppen climate classification. Adults and children. 2 Reported as C + G. 1

serotype distributions of GABHS isolates from pharyngitis patients in the United States and Thailand. They reported that whereas 80% of the US isolates could be M or opacity factor (OF) typed, less than 20% of the isolates from Thailand could be similarly characterized. They also demonstrated a statistically significant difference in the percentage of strains that could be characterized by the T agglutination pattern, and there were marked differences in the distribution of the serotypes among identifiable strains between the two countries [34]. El Kholy and co-workers found of 591 strains of GABHS isolated from the pharynx of carriers that only 47% were M-typable. The most common types isolated in the pharynx in Egypt were 5, 12, 14, 41, 46 and 58 (table 5) [10, 15, 34, 35]. Two studies in the United States showed that the most common M types associated with uncomplicated pharyngitis in the United States were 1, 2, 4 and 12 [34, 36]. One of these studies was also conducted in Thailand and showed that the prevalent serotypes in Thailand were 1, 4, 11, 12, 55 and 81 [34]. These studies indicate that worldwide, many of the same serotypes are seen in cases of pharyngitis [15, 23, 34, 35].

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Table 5. Distribution of M-types in selected countries Author

Country

Year

Isolates n

Typing sera n

Typable serotypes %

Prevalent serotypes

El Kholy et al. [10] Majeed et al. [15] Kaplan et al. [34] Kaplan et al. [34] Ameen et al. [35]

Egypt Kuwait Thailand USA UAE

1967–1968 1989 1989 1992 1994–1995

591 407 123 866 100

57 57 57 57 36

47 53 15 80 76

5, 12, 14, 41, 46, 58 1, 4, 12, 48 1, 4, 11, 12, 55, 81 1, 4, 12 1, 2, 6, 22, 28, 75

Table 6. Distribution of anti-streptolysin O titers in children in selected tropical countries (1972) [40]

Country

% ASO titer over 200 units

Thailand Pakistan Burma Mongolia Algeria Kenya Nigeria

17.7 18.4 37.2 52.3 36.4 40.6 53.3

It is known that some GABHS serotypes are more ‘rheumatogenic’ than others. Studies in high income countries show association of increased risk of rheumatic fever with M types 1, 3, 5, 6, 12 and 21 [37–39]. Serology Serologic surveys for streptococcal antibodies provide indirect data on the recent occurrence of streptococcal infection. Though serological data cannot distinguish pharyngeal from skin exposure, a survey carried out in 1972 by the World Health Organization revealed that mean ASO antibody titers were generally higher in children in low income countries than in children from richer countries (table 6) [40]. The mean anti-streptolysin O (ASO) titer in healthy children living in temperate, high income countries is approximately 200 units, lower than the mean in low income regions [22, 31]. The relative role of respiratory pharyngitis versus skin (impetigo or pyoderma) exposure in the elevated ASO titers has been discussed by some authorities [22] (see ‘Pharyngitis vs. Pyoderma’).

Epidemiology, Clinical Presentations, and Diagnosis of Streptococcal Pharyngitis

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Risk Factors Crowding is associated with increased risk of acquiring streptococcal pharyngitis. This is because transmission of GABHS occurs primarily in large droplet inhalation or by direct contact with respiratory secretions [41]. Studies conducted in the 1940s at Warren Air Force Base among military recruits showed an inverse relationship between acquisition rates and distance to the nearest case. The acquisition rate of GABHS pharyngitis was ⬎60/100,000 person-weeks when the distance of beds from the nearest infected person was ⬍5 feet, and was ⬍20 when the distance was ⱖ30 feet [42]. Low socioeconomic status has been associated with increased rates of acute rheumatic fever in many settings, likely due to either increased transmission of GABHS or perhaps decreased access to care, or to malnutrition, and other factors that are associated with low socioeconomic status [16, 25]. It is not clear that ethnicity or race considered independent of socioeconomic status is associated with increased risk of infection or sequelae [43]. There is preliminary evidence that certain HLA genetic elements are associated with increased risk of ARF [44]. Age and Sex Distribution In high income countries GABHS pharyngitis is common in children ages 3–15 years. In low-income countries, there is limited data on the age distribution of GABHS pharyngitis in children. A recent study in India indicated that the peak age for GABHS pharyngitis was at 11 years, possibly because this is the age of transfer to secondary school (fig. 1) [8]. Most reports of GABHS pharyngitis do not present sex-specific data. It is likely that there are no remarkable differences between boys and girls [16]. In all sites, GABHS pharyngitis occurs in infancy, although the risk of subsequent acute rheumatic fever appears lower in children less than 3 years of age [37, 39]. Many reviews of RF in lower income regions note a higher proportion of RF cases in younger children than reported from high income regions [1, 22]. Seasonality In temperate regions GABHS pharyngitis generally peaks in the late winter and early spring months. Studies conducted in North America have shown that carriage rates tend to increase during the early winter and peak in the spring months [5, 12]. GABHS pharyngitis generally peak during the cooler seasons of tropical countries as well [8, 22, 23]. A study by Sarkar et al. [45] in Varanasi, India, suggests a significant increase in cases of GABHS pharyngitis during the cooler months, similar to more recent data from Nandi et al. [8] from northern India and from Koshi et al. [18] in Vellore, India (fig. 2; table 7).

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Incidence of sore throat

Incidence per child-year

1.2

Incidence of GAS sore throat 1 0.8 0.6 0.4 0.2 0 April May June July Aug. Sep. Oct. Nov. Dec. Jan. Feb. Mar. Month

WHO 01.47

Fig. 2. Monthly incidence of pharyngitis and GABHS pharyngitis in a north Indian population [8].

Table 7. Seasonality of pharyngitis: cross-sectional study in rural schoolchildren in South India [18] Season

Summer Rainy Winter

Population examined

Sore throats n

%

1,061 978 1,050

177 195 284

16.68 19.93 27.05

␹2=37.04; d.f. ⫽ 2; p ⬍ 0.001 (summer or rainy vs. winter season).

Carriage also appears to be seasonal. El Kholy et al. [10] reported from Egypt a pattern of highest monthly GABHS carrier rate during the late autumn and early winter and the minimal rate in the summer (fig. 3). We did not find a description of the relationship of GABHS infection or carriage with tropical monsoon patterns. Pharyngitis vs. Pyoderma In some tropical countries, pyoderma is frequent, rates of apparent streptococcal pharyngitis are low, and the incidence of acute rheumatic fever is high. These observations led to the speculation that acute rheumatic fever may also be caused by GABHS pyoderma and not pharyngitis. However, it is possible that this phenomenon could be related to underreporting of GABHS pharyngitis,

Epidemiology, Clinical Presentations, and Diagnosis of Streptococcal Pharyngitis

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T3

Carriers of group A streptococci (per cent.)

40 35

T5 T3

30

T3 T3

T4 T5

25 T6

20

T5

T5

T5

T3

T4

T3

T5 T3

T6

15 T3

10

T3

T4

T3

T5

5 0 S N J1 M1 M2 J2 S D M1 M2 J2 S N J1 M1 M2 J2

1967–68

1968–69

1969–70

School year and month

Fig. 3. GABHS carrier rate by month in an Egyptian population [10].

and the lack of culture diagnosis and adequate laboratory facilities, rather than pyoderma being the cause of ARF [46]. Relationship between GABHS and RF One estimate of the pattern of acute rheumatic fever in low income settings suggests that for every 1,000 episodes of pharyngitis, 300 might be group A streptococcal, leading to 10 cases of rheumatic fever, 7 cases of RHD and 2–3 deaths due to RHD. Assuming high levels of exposure, these estimates would suggest an RHD prevalence of 7–10 per 1,000 children [47]. In fact, surveys of schoolchildren report prevalence rates of RHD of 10 to 15/1,000 in South America, Africa and Asia [48, 49]. This would imply that there is virtual universal exposure, with development of manifest cardiac disease and sequela in the expected proportion of patients. As mentioned above, the current situation in lower income regions may be similar to the picture a hundred years ago in high income countries. Epidemics of RF have rarely been reported from developing countries. Data are not available to distinguish if these epidemics do not occur or are simply not reported.

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Table 8. Selected clinical prediction rules for streptococcal infections in children Author

Country

Year

Age years

n

Culture positive %

Score

Sen. %

Spec. %

PPV %

NPV %

Breese [52]

USA

1977

children

670

54

ⱖ26 ⱖ30 ⱖ32

98 83 68

40 72 85

66 78 84

94 78 69

McIsaac et al. [53]

Canada

1998

3–14

90

36

2⫹ 3⫹ 4⫹

97 84 63

12 38 67

38 43 51

87 81 76

Wald et al. [54]

USA

1998

2–16

365

48

3⫹ 4⫹ 5⫹ 6⫹

98 92 64 22

7 28 65 93

51 55 64 75

76 77 65 55

Steinhoff et al. [16]

Egypt

1997

2–13

451

24

rule WHO

84 12

40 94

30 38

89 77

Attia et al. [55]

USA

1999

6 months– 18 years

297

29

high low

95 15

PPV ⫽ Positive predictive value; NPV⫽ negative predictive value.

Diagnostic Strategies

In some high income countries, it is recommended that a specific laboratory diagnosis of streptococcal infection be made before offering antibiotic treatment of pharyngitis. However, in other high income countries (including in Europe), virtually all pharyngitis cases are treated with antibiotics [50]. It is interesting to note that substantial proportions of pediatricians and physicians in the United States do not follow the recommended practices of lab testing followed by treatment for proven cases. Because bacteriological culture is not readily available, clinicians in most low income countries make a clinical diagnosis and offer presumptive treatment. Clinical Prediction Rules While a variety of clinical decision-making rules have been proposed and evaluated (mostly in high income regions), these rules appear to be more useful in adults than in children in high income countries [51]. There are numerous studies on GABHS pharyngitis diagnosis in the literature, but there are only a few which describe clinical prediction rules for GABHS pharyngitis in children who are at highest risk for sequeae, and very few studies outside of North America (table 8) [16, 51–55].

Epidemiology, Clinical Presentations, and Diagnosis of Streptococcal Pharyngitis

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There have been some studies in adults that have produced apparently useful clinical prediction rules for GABHS pharyngitis [14, 56, 57]. Decision analyses for the illness in adults suggest that some clinical prediction rules may be accurate enough to treat presumptively without culture [58, 59]. In children, there are limited evaluations of clinical prediction rules. The earliest studies done on the subject were those by Breese and Disney [60] and Stillerman and Bernstein [61] who correlated clinical findings with culture results. However, they selected cases for study on the basis of clinical features suggesting GABHS pharyngitis. This may have introduced an overestimate of prevalence, as well as of the sensitivity and specificity of clinical findings. Further, they validated the individual signs and symptoms against a throat culture for GABHS. Defining pharyngitis by culture alone will include a considerable number of GABHS carriers and thus may confound the identification of predictors of true infection [4]. Kaplan et al. [21] studied 624 children less than 15 years of age with uncomplicated pharyngitis and compared clinical features both with throat culture and antibody rise. He found that 35% of cases were GABHS culture positive, but only 43% of these showed an antibody rise, indicating a true infection prevalence of 15%. The World Health Organization Acute Respiratory Infections (ARI) treatment program suggests that, in the absence of other guidelines for children under 5 years of age, acute streptococcal pharyngitis should be suspected and presumptively treated when pharyngeal exudate plus enlarged and tender cervical lymph nodes are found [62]. When these recommendations were evaluated in a prospective study, the guidelines were shown to be highly specific, but not very sensitive. Steinhoff et al. [62] studied 451 children 2–13 years of age complaining of sore throat and pharyngeal erythema in an urban pediatric clinic in Egypt. The prevalence rate of GABHS pharyngitis by culture was 24%, and serology was not reported. The clinical features most highly associated with positive throat culture were pharyngeal exudate and enlarged anterior cervical lymph nodes. Presence of one or both of these signs had a high sensitivity of 0.84 but a low specificity of 0.40 (fig. 4) [16]. A clinical evaluation in Turkey has shown the Breese clinical scoring system appeared less useful in younger children [63]. There is a need for careful validation in children of existing clinical decision rules, and for development of improved rules. These new rules should be developed and evaluated in a variety of environments to determine their local utility in situations of varying clinical presentation. Throat cultures Diagnosis of GABHS pharyngitis is made by throat culture in some high income countries, which is said to be accurate in 90–97% of the cases in detecting the presence of GABHS in the pharynx. However, more than 50% of

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History of fever

Large node Exudate or large node (proposed guideline) Tender node

Exudate Exudate and a large and tender node (WHO ARI guideline) 100 80

60

40

20

% positive throat cultures treated Black bar⫽Sensitivity

0

20

40

60

80 100

% negative throat cultures not treated

White bar ⫽ Specificity

Fig. 4. Using simple clinical guidelines, percentage of children who would receive appropriate treatment for GABHS [16].

culture-positive patients may be carriers, with no increased risk of ARF [64]. Nevertheless, US recommendations are for treatment if culture alone is positive. Culture requires 24–48 h for a report, and the family must telephone or re-visit the clinic; neither may be feasible in low income settings with limited availability of or access to health care. Rapid Antigen Tests There are a numerous rapid antigen detection tests, some of which have reported high levels of sensitivity and specificity [65–67]; these are generally too expensive (cost USD 4.85–12.50) for routine use in low income countries [59, 68]. Whether any of these antigen detection technologies can be adapted for low cost production in low income countries with industrial capacity remains to be seen. Countries with relatively elevated rates of rheumatic fever and an improving economic status could consider increasing culture availability, or providing low cost kits to allow laboratory confirmation and specific treatment of streptococcal pharyngitis. Although Costa Rica [3] and other countries have had seeming success with presumptive antimicrobial treatment of all pharyngitis, this strategy will predictably lead to increased rates of antimicrobial resistance in Streptococcus pneumoniae and other bacterial species carried by the treated children [69]. A recent cost-benefit review of strategies for prevention of acute rheumatic heart disease suggested that for many low-income countries, primary prevention is

Epidemiology, Clinical Presentations, and Diagnosis of Streptococcal Pharyngitis

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not cost-effective [46]. However, the level of income and economic development at which primary prevention is cost effective has not been defined. In addition, an analysis of costs of primary prevention using effective clinical decision rules has not been done. Conclusions

There are numerous areas of similarity between high income and low income regions with regard to group A streptococcal pharyngitis. The limited data that allows comparisons between the two environments suggest that there are higher incidences of pharyngitis and streptococcal pharyngitis as well as much higher rates of post-streptococcal sequelae in low income regions. Asymptomatic carriage of group A appears to be increased in low income regions. In contrast, in clinics, the proportion of pharyngitis cases that are culturepositive for GABHS may be lower in low income regions. Additionally, the classical textbook clinical presentation is apparently rare in some of these clinical settings. With regard to the organism in low income regions, there is increased frequency of streptococcus non-group A infections, and the GABHS M-serotypes appear to be more varied. Overall, ASO antibody titers appear to be higher in each age group. Risk factors including low socioeconomic status, and crowding, but not sex or ethnic/racial groups, appear to be similar in both environments, as does seasonality. In terms of diagnosis, more data are needed regarding the variations in the spectrum of clinical presentation, and the applicability of clinical prediction rules developed in higher income regions. As is true of microbiological culture, the role of rapid diagnostic tests appears to be limited by cost.

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8

9

10

11 12 13

14 15

16

17

18 19 20

21

22

23

24

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Nandi S, Kumar R, Ray P, Vohra H, Ganguly NK: Group A streptococcal sore throat in a periurban population of northern India: A one-year prospective study. Bull Wld Hlth Org 2001;79:528–533. Dingle JH, Badger GF, Jordan WS Jr: Streptococcal infections, in: Illness in the Home: A Study of 25,000 Illnesses in a Group of Cleveland Families. Cleveland, Press of Western Reserve University, 1964, pp 97–117. El-Kholy A, Sorour AH, Houser HB, Wannamaker LW, Robins M, Poitras JM, Krause RM: A three-year prospective study of streptococcal infections in a population of rural Egyptian school children. J Med Microbiol 1973;6:101–110. Leon AP, Cano C, Argott EE: Bacteriologic and serologic aspects of streptococcal pharyngitis in Mexico City. Bol Oficina Sanit Panam 1985;99:53–61. Cornfeld D, Hubbard J: A four year study of the occurrence of beta-hemolytic streptococci in 64 school children. N Engl J Med 1961;264:211–215. Kaplan EL, Johnson DR, Rehder CD: Recent changes in group A streptococcal serotypes from uncomplicated pharyngitis: A reflection of the changing epidemiology of severe group A infections? J Infect Dis 1994;170:1346–1347. Walsh BT, Bookheim WW, Johnson RC, Tompkins RK: Recognition of streptococcal pharyngitis in adults. Arch Intern Med 1975;135:1493–1497. Majeed HA, Yousof AM, Rotta J, Havlickpva H, Bahar G, Bahbahani K: Group A streptococcal strains in Kuwait: A nine-year prospective study of prevalence and associations. Pediatr Infect Dis J 1992;11:295–300; discussion 300–303. Steinhoff MC, Abd el Khalek MK, Khallaf N, Hamza HS, el Ayadi A, Orabi A, Fouad H, Kamel M: Effectiveness of clinical guidelines for the presumptive treatment of streptococcal pharyngitis in Egyptian children. Lancet 1997;350:18–21. Ogunbi O, Fadahunsi HO, Ahmed I, Animashaun A, Daniel SO, Onuoha DU, and Ogunbi LQ: An epidemiological study of rheumatic fever and rheumatic heart disease in Lagos. J Epidemiol Community Hlth 1978;32:68–71. Koshi G, Benjamin V: Surveillance of streptococcal infections in children in a south Indian community: A pilot survey. Indian J Med Res 1977;66:379–388. Gubbay L, Ellis A, Lopez Holtmann G, Galanternik L: Streptococcal pharyngitis in Argentina: A four-year study. Adv Exp Med Biol 1997:418:49–52. Cohen R, Estrangin E, Lecompte MD, Bouhanna CA, Wollner A, Koskas M, Martin P, Deforche D, Geslin P: Bacterial epidemiology of pharyngitis in pediatric private practice. Presse Méd 1994;23:1753–1757. Kaplan EL, Top FH Jr, Dudding BA, Wannamaker LW: Diagnosis of streptococcal pharyngitis: Differentiation of active infection from the carrier state in the symptomatic child. J Infect Dis 1971;123:490–501. Carapetis JR, Currie BJ, Kaplan EL: Epidemiology and prevention of group A streptococcal infections: Acute respiratory tract infections, skin infections, and their sequelae at the close of the twentieth century. Clin Infect Dis 1999;28:205–210. El-Kholy A, Sorour A, Houser H, Wannamaker L, Robins M, Poitras J, Krause R: Clinical and epidemiological features of streptococcal infections in a rural Egyptian population: in Haverkorn M (ed): Streptococcal Disease and the Community. Amsterdam, Excerpta Medica, 1974, pp 275–281. Valkenburg H, Muller A, Wolters C, Steenhuis E: Streptococci in Liberia and Nigeria, West Africa; in Haverkorn M (ed): Streptococcal Disease and the Community. Amsterdam, Excerpta Medica, 1974, pp 209–214. Gupta R, Prakash K, Kapoor AK: Subclinical group A streptococcal throat infection in school children. Indian Pediatr 1992;29:1491–1494. Karoui R, Majeed HA, Yousof AM, Moussa MA, Iskander SD, Hussain K: Hemolytic streptococci and streptococcal antibodies in normal schoolchildren in Kuwait. Am J Epidemiol 1982;116: 709–721. Maekawa S, Fukuda K, Yamauchi T, Yamaguchi T, Takahashi K, Sugawa K: Follow-up study of pharyngeal carriers of beta-hemolytic streptococci among school children in Sapporo City during a period of 2 yeas and 5 months. Clin Microbiol 1981;13:1017–1022.

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Wallace MR, Leng R, Gordon H, Davies N: The throat carriage rate of group A beta-haemolytic streptococci among Waikato primary school children. NZ Med J 1978;87:207–208. Duben J, Neubauer M, Rotta J, Jelinkova J, Beranek M, Kubcova M: Occurrence of streptococcal infections and the prevalence of type A groups of hemolytic streptococci in an urban health district. Cesk Epidemiol Mikrobiol Imunol 1970;19:230–239. Hoffman S, Sorensen CH, Vimpel T: Influence of antibiotic treatment on the isolation rate of group A streptococci from peritonsillar abscesses. Acta Otolaryngol 1987;104:360–362. Markowitz M: Streptococcal disease in developing countries. Pediatr Infect Dis J 1991;10:11–14. Myers R, Koshy G: Beta-hemolytic streptococci in a survey of throat cultures in an Indian population. Am J Publ Hlth 1961;51:1872–1892. Pike R, Fashena G: Frequency of hemolytic streptococci in the throats of well children in Dallas. Am J Publ Hlth 1946;36:611–622. Kaplan EL, Johnson DR, Nanthapisud P, Sirilertpanrana S, Chumdermpadetsuk S: A comparison of group A streptococcal serotypes isolated from the upper respiratory tract in the USA and Thailand: Implications. Bull Wld Hlth Org 1992;70:433–437. Ameen AS, Nsanze H, Dawson KP, Othman S, Mustafa N, Johnson DR, Kaplan EL: Serotypes of group A streptococci isolated from healthy schoolchildren in the United Arab Emirates. Bull Wld Hlth Org 1997;75:355–359. Johnson DR, Stevens DL, Kaplan EL: Epidemiologic analysis of group A streptococcal serotypes associated with severe systemic infections, rheumatic fever, or uncomplicated pharyngitis. J Infect Dis 1992;166:374–382. Stevens D, Kaplan E: Streptococcal Infections: Clinical Aspects, Microbiology, and Molecular Pathogenesis. New York, Oxford University Press, 2000, pp 76–101. Ayoub E, Kotb M, and Cunningham M: Rheumatic Fever Pathogenesis, in Stevens D, Kaplan E (eds): Streptococcal Infections. New York, Oxford University Press, 2000, pp 102–132. Kaplan EL: Epidemiological approaches to understanding the pathogenesis of rheumatic fever. Int J Epidemiol 1985;14:499–501. Rotta J: Antistreptolysin O surveys in the populations of some Asian and African countries; in Haverkorn M (ed): Streptococcal Disease and the Community. Amsterdam, Excerpta Medica, 1972. Shulman S, Tanz R, Gerber M: Streptococcal pharyngitis; in Stevens D, Kaplan E (eds): Streptococcal Infections. New York, Oxford University Press, 2000, pp 76–101. Wannamaker L: The epidemiology of streptococcal infections; in McCarty M (ed): Streptococcal Infections. New York, Columbia University Press, 1954. Chun LT, Reddy DV, Yamamoto LG: Rheumatic fever in children and adolescents in Hawaii. Pediatrics 1987;79:549–552. Ayoub EM, Barrett DJ, Maclaren NK, et al: Association of class II human histocompatibility leukocyte antigens with rheumatic fever. J Clin Invest 1986;77:2019–2026. Sarkar S, Biswas R, Gaur SD, Sen PC, Reddy DC: A study on sore throat and beta haemolytic streptococcal pharyngitis among rural school children in Varanasi, with reference to age and season. Indian J Publ Hlth 1988;32:190–198. Carapetis JR, Currie BJ: Group A streptococcus, pyoderma, and rheumatic fever. Lancet 1996; 347:1271–1272. Michaud C, Treijo-Guiterrez J, Cruz C, Pearson TA: Rheumatic heart disease; in Jamison D, Mosley WH, Measham AR, Bobadilla JL (eds): Disease Control Priorties in Developing Countries. New York, Oxford University Press, 1993. WHO, Cardiovascular Disease Unit, WHO programme for the prevention of rheumatic fever/rheumatic heart disease in 16 developing countries: Report from phase I (1986–1990). Bull WHO 1992;70:213–218. Steer AC, Carapetis JR, Nolan TM, Shann F: Systematic review of rheumatic heart disease prevalence in children in developing countries: the role of environmental factors. J Paediatr Child Health 2002;38:229–234. Olivier C: Rheumatic fever – is it still a problem? J Antimicrob Chemother 2000;T1:13–21. Ebell MH, Smith MA, Barry HC, Ives K, Carey M: The rational clinical examination: Does this patient have strep throat? JAMA 2000;284:2912–2918.

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Breese BB: A simple scorecared for the tentative diagnosis of streptococcal pharyngitis. Am J Dis Child 1977;131:514–517. McIsaac WJ, White D, Tannenbaum D, Low DE: A clinical score to reduce unnecessary antibiotic use in patients with sore throat. Can Med Assoc J 1998;158:75–83. Wald ER, Green M, Schwartz B, Barbadora K: A streptococcal score card revisited. Pediatr Emerg Care 1998;14:109–111. Attia M, Zaoutis T, Eppes S, Klein J, Meier F: Multivariate predictive models for group A betahemolytic streptococcal pharyngitis in children. Academic Emerg Med 1999;6:8–13. Komaroff AL, Pass TM, Aronson MD, Ervin CT, Cretin S, Winickoff RN, Branch WT Jr: The prediction of streptococcal pharyngitis in adults. J Gen Intern Med 1986;1:7 Centor RM, Witherspoon JM, Dalton HP, Brody CE, Link K: The diagnosis of strep throat in adults in the emergency room. Med Decis Making 1981;1:239–246. Dippel DW, Touw-Otten F, Habbema JD: Management of children with acute pharyngitis: A decision analysis. J Fam Pract 1992;34:149–159. Pichichero ME: Group A streptococcal tonsillopharyngitis: Cost-effective diagnosis and treatment. Ann Emerg Med 1995;25:390–403. Breese BB, Disney FA: The accuracy of diagnosis of beta-streptococcal infections on clinical grounds. J Pediatr 1954;44:670–673. Stillerman M, Bernstein SH: Streptococcal pharyngitis: Evaluation of clinical syndromes in diagnosis. Am J Dis Child 1961;101:476–489. World Health Organization: The Management of Acute Respiratory Infections in Children: Practical Guidelines for Outpatient Care. Geneva, World Health Organization, 1995. Ulukol B, Gunlemez A, Aysev D, Cin Surkru: Alternative diagnostic method for pharyngitis: Breese scoring system. Turkish J Peds 2000;42:96–100. Gerber MA, Randolph MF, Mayo DR: The group A streptococcal carrier state: A reexamination. Am J Dis Child 2 1988;14:562–565. Gerber MA: Diagnosis of group A streptococcal pharyngitis. Pediatr Ann 1998;27:269–273. Gerber MA, Tanz RR, Kabat W, Bell GL, Kaplan EL, Shulman ST: Antigen detection test for group A beta-hemolytic streptococcal pharyngitis that is sufficiently sensitive for use without confirmatory cultures. Adv Exp Med Biol 1997;418:39–40. Gerber MA: Use of antigen detection tests in the diagnosis and management of patients with group A streptococcal pharyngitis. Pediatr Infect Dis J 1997;16:1187. Finger R, Ho SH, Ngo TT, Ritchie CD, Nguyen TN: Rapid streptococcal testing in Vietnamese children with pharyngitis. Asia Pac J Publ Hlth 1999;11:26–29. Morita JY, Kahn E, Thompson T, Laclaire L, Beall B, Gherardi G, O’Brien KL, Schwartz B: Impact of azithromycin on oropharyngeal carriage of group A streptococcus and nasopharyngeal carriage of macrolide-resistant Streptococcus pneumoniae. Pediatr Infect Dis J 2000;19:41–46.

M.C. Steinhoff, MD Johns Hopkins University 615 N.Wolfe St., Rm E7152, Baltimore, MD 21205 (USA) Tel. ⫹1 410 955 1623, Fax. ⫹1 603 806 6642, E-Mail. [email protected]

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The Group A Streptococcal Upper Respiratory Carrier Diagnosis and Management

Edward L. Kaplan World Health Organization Collaborating Center for Reference and Research on Streptococci, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minn., USA

There are many perplexing issues associated with group A streptococcal respiratory tract infections. These include diagnosis, management, epidemiology, and especially pathogenesis. But one of the most puzzling – and still unresolved – clinical issues associated with group A streptococcal pharyngitis is that of the group A streptococcal upper respiratory tract carrier state. Unresolved questions remain about the bacterial physiology, about the host’s apparent immunological tolerance for harboring the organism, and about the explanation for the usually feeble or – often times – even absent immune response to streptococcal antigens. Why the carrier state appears not to result in suppurative and non-suppurative sequelae of this infection with a potentially virulent organism remains an enigma [1]. Each of these factors has a direct implication for the management of patients, as well as for the public health. For example, although a decrease in the incidence of rheumatic fever has been described in industrialized countries, it remains unknown whether this has been influenced by the prevalence of group A streptococcal carriers or by changes in the virulence of the organism or by both. It is the purpose of this discussion to reconsider the carrier state and to offer practical suggestions for management to both the clinician and to public health authorities. Definitions

For the purposes of this discussion, the group A streptococcal upper respiratory tract carrier will be defined as an individual who harbors

Titer Rise No Rise

Fig. 1. Of patients presenting with acute pharyngitis and having group A streptococci recovered by throat culture, slightly less than half did not experience a convalescent period antibody rise in either ASO and/or anti-DNase B. These data suggest a large percentage of such children are group A streptococcal upper respiratory tract ‘carriers’ (see text). [Modified from reference 2 with permission.]

Streptococcus pyogenes in the upper respiratory tract and, yet, fails to immunologically respond to the presence of streptococcal antigens, either somatic or extracellular. Human group A streptococcal carriers harbor the organism and yet do not appear to experience an antibody response to the recognized extracellular or somatic antigens, such as streptolysin O or to streptococcal nuclease B. Conversely, true or bona fide group A streptococcal upper respiratory tract infection indicates not only the presence of the organism in the upper respiratory tract but also requires that there be host recognition – an immune response – as measured by detectable increases in antibody titer to group A streptococcal antigens. Documentation that the carrier state exists is illustrated in the figure 1. Of those individuals presenting for medical care with a sore throat and a positive upper respiratory tract culture for group A streptococci, only approximately half demonstrate an immune response and satisfy the definition of being a ‘carrier’ [2]. Furthermore, of individuals who even continue to harbor the organism in the upper respiratory tract, many fail to mount a continually rising antibody titer; in fact, in some instances, the antibody titers have actually decreased.

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Pathophysiology of the Upper Respiratory Tract Carrier State

With prolonged streptococcal carriage in the upper respiratory tract, changes appear to take place in the physiology of the organism. For example, Krause and Rammelkamp reported that group A streptococci do not express M protein after prolonged periods of residence in the upper respiratory tract [3]. The investigators observed that, at the time of the initial acquisition, the organism expressed M protein. When transferred from an acutely infected human to the pharynx of monkeys, the organism was able to cause pharyngitis. However, after residing for a period of 2 months in the upper respiratory tract of the human host, the same group A streptococcus no longer expressed M protein and, when inoculated into the pharynx of monkeys, the M negative strain failed to produce clinical pharyngitis. That the two variants of the organisms were the same was shown after mouse passage of the M negative strain; there was renewed ability of the organism to express M protein. Which other changes occur in the organisms to allow this resulting symbiotic relationship with the human have not been defined. Thus, it is not clear if it is only the lack of expression of M protein which influences the establishment of the carrier state. In an attempt to explain the apparent inability of some group A streptococci to cause true human respiratory tract infection, investigators have studied the interaction between epithelial cells and group A streptococci. For example, Cleary and colleagues have shown that serotype M-1 streptococci may invade epithelial cells, and be internalized [4]. Österlund and colleagues also have reported intracellular survival of Streptococcus pyogenes in human respiratory epithelial cells grown in an antibiotic-supplemented medium [5]. Other studies showing intracellular streptococci have been reported [6]. Although intracellular organisms have been demonstrated in vitro, there is no definitive explanation as to how the in vivo human cell can accept these living streptococci cells as residents. If this occurs in vivo perhaps ‘protection’ associated with living within pharyngeal epithelial cells is essential to the establishment of a carrier state. Important questions remain about this hypothesis. Very little is known about the metabolic status of intracellular group A streptococci; it would almost have to be altered from the normal state. For example, essentially all group A streptococci produce the potent cytolysin, streptolysin O, which should theoretically be lethal to the invaded host cell if the streptococci are metabolically active. The indirect evidence suggests that lethality is not present. The organisms can be seen within cells and do not appear to be dead [5]. How they can remain viable and not kill the host cell remains perplexing. The possibility of internalized group A streptococci has practical implications for care of the patient. It has been shown that penicillin (and theoretically other beta lactam antibiotics) are less effective in eradicating group A streptococci from the throat of ‘carriers’ [7]. Should group A streptococci

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unequivocally be shown to be in an inactive metabolic state when ‘captive’ inside the pharyngeal epithelial cell, it could partially explain the relative ineffectiveness of penicillin and other beta lactam antibiotics even if they were to cross the cell wall in small concentrations. They would not be able to effectively kill the intracellular streptococci because there would be decreased cell wall production. However, comprehensive metabolic studies of intracellular group A streptococci have not been carried out with other classes of antibiotics which rely upon other antimicrobial mechanisms (i.e. inhibit protein synthesis, as is the case with macrolides) for death of the bacterial cell. Thus, the clinical argument that other classes of antibiotics may be more effective in eradicating the organism from carriers requires additional clarification. Much remains to be learned about the physiology of the Streptococcus pyogenes in individuals who become and remain ‘carriers’. Similarly, the modified host response also requires elucidation. Epidemiology of the Group A Streptococcal Upper Respiratory Tract Carrier

The classical studies carried out by Wannamaker and colleagues among military recruits living in crowded barracks showed the importance of personto-person transmission and documented the fact that group A streptococci are highly transmissible. Yet, ‘carriers’ tend to be less ‘contagious’ than are individuals with bona fide infection [1]. Even these carriers, when infected with one of the many viruses causing upper respiratory tract infections, still do not appear to transmit streptococci to their close family or school contacts as readily as do patients with true infection. The apparently contradictory reports of transmission of streptococci by carriers to contacts appear to be the result of a lack of a strict and uniform definition of the carrier state by investigators. For example, individuals who have been referred to as ‘dangerous carriers’ [8], in fact, represent patients who were most likely truly infected. The epidemiologic significance of this mystery seems obvious. The many epidemiologic studies showing high prevalence of group A streptococci in specific populations (e.g. school children) – as high as 20% – do not reveal significant spread to contacts associated with clinical infection and sequelae appear to be even more unusual. Clinical Diagnosis of the Group A Streptococcal Upper Respiratory Tract Carrier

The clinical diagnosis of the group A streptococcal upper respiratory tract carrier is most often difficult, except in retrospect. Even if one accepts the

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definition indicating that carriers fail to demonstrate an immune response, streptococcal antibody titers can provide no clinical assistance in differentiating the carrier from the truly infected individual except in retrospect. Our own clinical and epidemiological studies indicate that most carriers are clinically asymptomatic [1, 9]. Thus, clinical findings are also not universally helpful in accurately identifying carriers. Attempts to provide guidelines and algorithms to assist in the diagnosis of group A streptococcal upper respiratory tract infection have not been very successful [9]. However, when someone who is a group A streptococcal upper respiratory tract carrier becomes infected with another microorganism (e.g. a respiratory tract virus) and becomes symptomatic, perhaps even with fever, the clinician is put in a difficult position by being confronted by an ill patient with a positive throat culture or rapid antigen test for group A streptococci. There are specific signs and symptoms which are not associated with the presence of true group A streptococcal infection [9, 10]. The presence of sneezing, cough, coryza and the lack of a sudden onset of very sore throat strongly indicates that even with a positive throat culture or a rapid antigen detection test true group A streptococcal infection likely is not present; symptoms are likely due to another etiology. Unfortunately, many clinicians, confronted by such patients, acquiesce and prescribe antibiotics. The clinical microbiology laboratory does not help prospectively in differentiating the carrier from the truly infected individual. It has been suggested by some that carriers tend to have smaller numbers of organisms detected by the semi-quantitative throat culture and that carriers are more likely to be represented among false-negative rapid antigen detection tests (because the amount of antigen is too small to be detected). There are data which indicate that patients with true infection tend to have more organisms present on throat culture agar plates, but in studies correlating antibody response with semi-quantitative throat cultures, the association is not always reliable [2]. Streptococcal antibody tests such as those for anti-streptolysin O (ASO) or for anti-deoxyribonuclease B (anti-DNase B) are of little or no assistance in acutely differentiating the carrier from a patient with acute infection [11]. It has been reported that carriers – as a group – tend to have higher antibody titers at the time of the acute visit than do those who later prove to have rises in titers (have true infection) [2], but this observation serves no useful clinical purpose when an individual patient is initially evaluated. Studies investigating the possibility that acute phase reactants such as the erythrocyte sedimentation rate (ESR) or the C reactive protein (CRP) might help to differentiate the carrier from the acutely infected individual have not been uniformly helpful either [12]; there are no available data to suggest that such laboratory tests are sufficiently useful in this clinical situation. A diagnosis – clinical

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or laboratory – of the group A streptococcal carrier state can be deceiving, making medical and public health decisions difficult either for the individual physician or for public health authorities faced with a possible outbreak.

Do Group A Streptococcal Carriers Require Therapy?

This is another controversial aspect since it is difficult to ascertain with certainty which patients are carriers and which have true group A streptococcal upper respiratory tract infection. Most authoritative guidelines suggest that individuals without classical signs and symptoms of streptococcal upper respiratory tract infection rarely require either throat culture or antibiotic therapy [13]. On the other hand, in individuals in whom the upper respiratory tract symptoms are not clearly helpful for differentiating acute infection from the carrier state, since the practitioner cannot clinically (or even with laboratory assistance) definitively differentiate these two conditions, antibiotic treatment is sometimes prescribed by the clinician rather than gamble. Essentially, all recommendations and guidelines formulated by professional societies currently suggest that the preferred initial therapy for group A streptococcal upper respiratory tract infection is penicillin [13–15]. Despite this, there is evidence to indicate that penicillin may not be the antibiotic of choice in those relatively rare instances when carriers are treated. In fact, the majority of individuals treated with penicillin with failure to eradicate the organism appear to be streptococcal carriers [7]. Since, in the group A streptococcal carrier, the organism is not rapidly dividing, beta lactam antibiotics, particularly penicillin, should be less effective as has been noted. Recently published guidelines offer precise recommendations for treating patients with persisting group A streptococci in their upper respiratory tract. In those unusual situations in which it is deemed important to eradicate the organism from the carrier, such as communities in which there is an outbreak of streptococcal sequelae or in families where there are individuals who previously have experienced attacks of rheumatic fever, several other possibilities exist for eradication of the organism. Clindamycin, penicillin along with rifampin and Augmentin have been successfully used [13].

Public Health Implications of the Group A Streptococcal Upper Respiratory Tract Carrier State

Because of the many incompletely explained epidemiologic and pathophysiologic issues related to the group A streptococcal upper respiratory tract

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carrier state, the public health implications of having carriers mixed in with the normal population remain problematic. This is especially true for the individual patient who harbors the organism in his or her upper respiratory tract. As has been previously pointed out it is difficult in most instances for the clinician prospectively to differentiate the carrier from the truly infected individual. Thus, symptomatic individuals usually must be considered as having true infection even if there are questions about the specificity of the presenting signs and symptoms. There are unique public health aspects of the group A upper respiratory tract carrier state which require special consideration. For example, particularly in temperate climates, it is well known that surveillance of entire populations of school children may reveal prevalence rates of group A streptococci in the upper respiratory tract ranging from five percent to almost twenty percent [16]. While some may offer the alternative explanation that since the ‘serotypes’ responsible for high prevalence rates often are not ‘rheumatogenic’ and, therefore, would not likely lead to rheumatic fever, in fact, a high prevalence rate may just as likely represent infected individuals with multiple different serotypes, and they should not be ignored. That asymptomatic individuals can develop rheumatic fever is well known [17]. Since active prospective surveillance of school populations is extraordinarily rare, this seldom presents a public health decision making problem for management of culture-positive school children. In those instances, however, where either there are clinically apparent outbreaks of typical upper respiratory tract infection with either a high incidence of new cases of pharyngitis or an unusually high prevalence of positive throat cultures, public intervention may be indicated. This is done with the realization that a proportion of these individuals are likely to be carriers. While the situations just described frequently are found among school children, other epidemiologic situations with a large percentage of culturepositive individuals probably are less likely to represent a high prevalence of carriers. For example, high prevalence rates associated with symptomatic disease in military populations and even moderately high prevalence rates among residents of group homes or nursing care facilities more frequently may dictate more aggressive culturing and treatment [18]. The same can be said for very young children in a daycare setting [19]. It is interesting to speculate what public health impact, if any, the future development and implementation of a group A streptococcal vaccine may have on the problem of streptococcal carriers. While it is possible that a streptococcal vaccine could reduce the group A streptococcal prevalence rates in susceptible populations, the fact that there are more than 130 distinct types [20] of group A streptococci recognized at the present time might have an adverse

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effect on vaccine efficacy, especially if the candidate vaccine is based upon host type specific immunity. There are no comprehensive data to allow one to predict the future efficacy or cost effectiveness of a group A streptococcal vaccine.

Conclusion

The 1980 review of the enigma of the group A streptococcal carrier state might as well have been written 20 years later. This rather unique and inadequately understood symbiotic relationship between the human host and the group A beta hemolytic streptococci remains a biologic and epidemiologic mystery. This particular relationship, however, has particular relevance to the everyday management of patients presenting with pharyngitis and other upper respiratory tract infections. Not only will further studies be required to shed light on the relationship of the organism to its human host during the carrier state, but there is little doubt that further elucidation of this relationship may even have important pathogenetic implications for understanding the pathogenesis of the very serious sequelae associated with the group A streptococcal infections.

References 1 2

3

4 5

6

7

8

9

Kaplan EL: The group A streptococcal upper respiratory tract carrier state: An enigma. J Pediatr 1980;97:337. Kaplan EL, Top F Jr, Dudding BA, Wannamaker LW: Diagnosis of streptococcal pharyngitis: The problem of differentiating active infection from the carrier state in the symptomatic child. J Infect Dis 1971;123:490. Krause RM, Rammelkamp CH Jr: Studies of the carrier state following infection with a group A streptococcus. II. Infectivity of streptococci isolated during acute pharyngitis and during the carrier state. J Clin Invest 1962;41:575–582. La Penta D, Rubens C, Chi E, Cleary PP: Group A streptococci invade human respiratory epithelial cells. Proc Natl Acad Sci USA 1994;91:12115–12119. Österlund A, Popa R, Nikkilä T, Scheynius A, Engstrand L: Intracellular reservoir of Streptococcus pyogenes in vivo: A possible explanation for recurrent pharyngotonsillitis. Laryngoscope 1997;107:640–647. Neeman R, Keller N, Barzilai A, Korenman Z, Sela S: Prevalence of internalisation-associated gene, prtF1, among persisting group-A streptococcus strains isolated from asymptomatic carriers. Lancet 1998;352:1974–1977. Kaplan EL, Gastanaduy AS, Huwe BB: The role of the carrier in treatment failures following antibiotic therapy for group A streptococci in the upper respiratory tract. J Lab Clin Med 1981;98:326. Hamburger M Jr, Green MJ, Hamburger VG: The problem of the ‘dangerous carrier’ of hemolytic streptococci. I. Number of hemolytic streptococci expelled by carriers with positive and negative nose cultures. J Infect Dis 1945;77:68–72. Wannamaker LW: Perplexity and precision in the diagnosis of streptococcal pharyngitis. Am J Dis Child 1972;124:352–358.

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10 11

12 13

14 15

16 17

18

19 20

Kaplan EL: Commentary: Clinical guidelines for group A streptococcal throat infections. Lancet 1997;350:899–900. Shet A, Kaplan EL: The clinical use and interpretation of group A streptococcal antibody tests: A practical approach for the pediatrician or primary care physician. Pediatr Infect Dis J 2002;21: 420–426. Kaplan EL, Wannamaker LW: The C-reactive protein in streptococcal pharyngitis. Pediatrics 1977;60:28–32. Bisno AL, Gerber MA, Gwaltney JM Jr, Kaplan EL, Schwartz RH: Practice guidelines for the diagnosis and management of group A streptococcal pharyngitis. (Infectious Diseases Society of America). Clin Infect Dis 2002;35:113–125. Report of the Committee on Infectious Disease of the American Academy of Pediatrics. Evanston, American Academy of Pediatrics, 2000. Drugs Used in the Treatment of Streptococcal Pharyngitis and Prevention of Rheumatic Fever. WHO Model Prescribing Information. WHO/EDM/PAR/99.1. Geneva, World Health Organization, 1999. Cornfeld D, Hubbard JP: A four year study of the occurrence of beta hemolytic streptococci in 64 school children. Am J Publ Health 1961;51:242–251. Gordis L, Lilienfeld A, Rodriguez R: Studies in the epidemiology and preventability of rheumatic fever. II. Socio-economic factors and the incidence of acute attacks. J Chron Dis 1969;21: 655–666. Crum NF, Hale BR, Bradshaw DA, Malone JD, Chun HM, Gill WM, Norton D, Lewis CT, Truett AA, Beadle C, Town JL, Wallace MR, Morris DJ, Yasumoto EK, Russell KL, Kaplan EL, Van Beneden C, Gorwitz R: Outbreak of group A streptococcal pneumonia among marine corps recruits – California, November 1–December 20, 2002. MMWR 2003;52:106–109. Smith TD, Wilkinson V, Kaplan EL: Group A Streptococcus-associated upper respiratory tract infections in a day care center. Pediatrics 1989;83:380–384. Facklam RF, Martin DR, Lovgren M, Johnson DR, Efstratiou A, Thompson TA, Gowan S, Kriz P, Tyrrell GJ, Kaplan EL, Beall B: Extension of the Lancefield classification for group A streptococci by addition of 22 new M protein gene sequence types from clinical isolates: emm 103 to emm 124. Clin Infect Dis 2002;34:28–38.

Edward L. Kaplan, MD Department of Pediatrics, MMC 296 University of Minnesota Medical School 420 Delaware St. SE; Minneapolis, MN 55455 (USA) Tel. ⫹1 612 624 1112, Fax ⫹1 612 624 8927, E-Mail [email protected]

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The Laboratory Diagnosis of Streptococcal Pharyngitis Throat Cultures, Rapid Tests and Streptococcal Antibodies

Diana R. Martin Institute of Environmental Science and Research, Porirua, New Zealand

Diagnosis of Streptococcal Pharyngitis

Streptococcus pyogenes (group A streptococcus) is the most common cause of bacterial pharyngitis. The principal reservoirs for the spread of this organism to susceptible hosts are infected persons and carriers. For the accurate diagnosis of pharyngitis reliable bacteriological methods are needed to establish if group A streptococcus is the cause and to enable appropriate antibiotic treatment. Prompt treatment is necessary to prevent rheumatic fever (RF) particularly in populations at high risk, to prevent suppurative complications, shorten duration of symptoms and to reduce the risk of transmission [1–4]. Cantanzaro et al. [4] showed that up until 9 days from onset of streptococcal pharyngitis, penicillin therapy could prevent RF. Classically, the streptococcal sore throat presents with an abrupt onset, pain on swallowing, fever, enlarged cervical lymph nodes and tonsillar exudate. Other less specific symptoms may occur but these are also associated with respiratory infections from other causes. There is no one symptom that can accurately be used to exclude or to diagnose a streptococcal sore throat [5]. As an example, Breese and Disney [6] using clinical signs and symptoms alone correctly predicted only 372 of 536 (69.6%) positive throat cultures. Although a number of clinical scoring algorithms exist, accurate diagnosis still depends on culture of a group A streptococcus or a positive rapid antigen detection test (RADT). Neither throat culture nor rapid testing can reliably distinguish between the acute streptococcal infection or the streptococcal carrier with a

concomitant viral infection [4]. In school-aged populations, at highest risk for RF, 70–80% sore throats are most likely to be of non-bacterial etiologies [7]. An informed decision as to which diagnostic tests should be used will take account of the high or low risk category for RF of the person under test, their age, the epidemiology of streptococcal infection in the local population, and the physical presenting symptoms.

Diagnostic Sensitivity of the Throat Swab

The optimal and traditional method for establishing the actual presence of a group A streptococcus in the throat is the throat swab. Diagnostic sensitivity is dependent on a number of variables including the adequacy of the swabbing technique, conditions operating for transportation of the swab, the methodology employed to detect a group A streptococcus and the interpretation of the results obtained including consideration of any recent antimicrobial exposure. The recommended procedure for a throat swab is direct visualization of the tonsillarpharyngeal area and vigorous swabbing of the tonsils or tonsillar crypts and of the posterior pharyngeal wall [4]. The type of swab (cotton or synthetic fiber) used for specimen collection is usually determined by the choice of swab available at the point of collection. Any delay between collection of a specimen and its examination in the laboratory increases the likelihood of false-negative results [8]. If transportation to the laboratory is prolonged, streptococci are more likely to remain viable when held in a dry state. Survival of streptococci has been shown to be less than optimal on swabs that remain moist for a long time during transit, particularly in higher temperatures [9, 10]. Transport media present in the tubes of commercial swabs provide holding environments suitable for retaining viable streptococci for at least 24 h [11]. Some commercial swab systems use a liquid medium, Modified Stuart’s transport medium, contained on a pad at the base of the tube. Systems that use an agarose butt of Amies semi-solid transport medium allow better recovery of streptococci as the agar plug surrounding the swab protects streptococci from changes in humidity within the tube. Swabs can be successfully transported by just replacing them in their tube but higher recovery rates may be obtained by placing the swab in contact with sterile desiccant (silica gel removes moisture from around the swab) [9] or by smearing on to sterile filter paper strips housed in foil [12]. When a dry method of transportation is used care has to be taken that swabs are not left exposed to ultraviolet light or extremes of temperature. Culturing of dried specimens can be postponed for up to 7 days without significant decrease in streptococcal counts.

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Laboratory Culture

The gold standard test for detection of a group A streptococcus in the throat is culture on blood agar. The agar medium used must be enriched to support growth as streptococci are fastidious organisms and must also contain blood to allow observation of ␤-hemolysis. Blood is used at a concentration of 5% most commonly in a base of columbia blood agar or trypticase soy agar. Two lysins, streptolysin O and streptolysin S are produced by group A streptococci. Streptolysin O is oxygen labile whereas streptolysin S is not and is mostly responsible for observed hemolysis on blood agar. To view hemolysis, swabs are either rolled over the complete plate or over half the plate and then further streaked to separate colonies. Hemolysis can vary with the animal source for the blood, or the type of basal medium used. In some parts of the world, particularly where there is difficulty with supply of sheep or horse blood, outdated human blood is often used. This is not recommended as there is a lack of consistency in the product and the blood may contain antibodies or antimicrobial agents which can prevent growth of streptococci. A broth-enhanced culture method whereby the swab is grown in a suitable broth either prior to, or additional to, plating on blood agar has been shown to be valuable for increasing the yield of streptococci [11], but is not often employed because of the added workload, material cost and time. Todd Hewitt broth cultures are incubated in a waterbath to ensure an even growth temperature. To improve recovery of group A streptococci from throat swabs media containing growth inhibitors or antibiotics have been advocated to selectively inhibit various organisms of the normal flora. Blood agar containing crystal violet (1 ␮g/ml) can be used to inhibit staphylococci, a method adapted from Pike’s broth [13]. Blood agar with colistin (10 ␮g/ml) and nalidixic acid (15 ␮g/ml) inhibits gram-negative organisms but not staphylococci nor corynebacteria [14]. The use of oxolinic acid (5 ␮g/ml) in place of nalidixic acid is inhibitive to staphylococci, corynebacterium and gram-negative organisms [15]. SBA-SXT, that is 5% sheep blood agar containing trimethoprim (1.25 ␮g/ml)-sulfamethoxazole (23.75 ␮g/ml), has been shown to inhibit ␣-hemolytic streptococci and pneumococci while supporting the growth of group A streptococci [16]. A number of studies have suggested better recovery rates for group A streptococci using SBA-SXT. However, Kellogg’s analysis of four independent studies concluded that when cultures were incubated for 48 h, recovery of group A streptococci on SBA-SXT was either equivalent, or superior, to that using the best of the SBA-atmosphere combinations [17]. Recently a new alkaline pH-adjusted medium was described to enhance isolation of group A streptococci by minimizing bacterial interference due to Streptococcus salivarius [18].

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Streptococci are aerobic or facultatively anaerobic. Growth is stimulated by an atmosphere of 5–10% CO2 or by anaerobic conditions. However, use of a CO2-supplemented atmosphere is also conducive to the growth of other facultative anaerobes reducing the likelihood of recovery of S. pyogenes from throat swabs [17]. Aerobic incubation reduces the numbers of ␤-hemolytic streptococci other than group A streptococci, resulting in a saving on costs for serological identification. Aerobic conditions are quite satisfactory and reduction in oxygen tension to facilitate recognition of subsurface hemolysis can be achieved if cuts are made in the surface of the agar at the time of streaking [17]. Anaerobic incubation is favored by many because it enhances hemolysis but is also more costly and time consuming. Anaerobic conditions are also favorable to many facultative anaerobes that then must be differentiated from group A streptococci. The optimum temperature of incubation is 35–37⬚C. Cultures negative for S. pyogenes following overnight incubation are incubated for another 24 h. Increases in the recovery of streptococci of up to 46% have been reported [17].

Rapid Streptococcal Detection Tests (RADTs)

Rapid streptococcal detection kits offer a faster although more costly method for identifying group A streptococci than plate culturing which takes 24–48 h to provide a result with the consequent delay in implementation of antibiotic therapy. While some of the rapid detection kits currently marketed, are moderately easy to perform and involve few steps others have more complex procedures. Their relative complexity means that tests are better performed in batches or in a laboratory setting. RADTs are mostly designed to provide near-patient testing and therefore are less skill dependent. This is an important issue in areas of the world where rheumatic heart disease is still a main cause of death and disability and there is a shortage of qualified technicians. Finger et al. [19], in a recent study, observed that rapid tests could have other benefits in their country. By providing a prompt testing result using a RADT, patients with pharyngitis who were positive received appropriate treatment, and others tested, who would otherwise have been treated empirically, were not prescribed unnecessary broad-spectrum antibiotics. Most RADTs are based on detection of the group A-specific carbohydrate and represent an extension from the extraction of isolated streptococci for grouping purposes. Either nitrous acid or enzymes are used to extract the group-specific carbohydrate antigen from streptococci collected on the throat swab. Detection of extracted antigen then relies on specific recognition by group-specific antibody and visualization of the reaction which may be assisted by a color change. In some systems group-specific antibody is coupled to

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particles and a reaction with specific antigen results in visible agglutination. Latex, liposomes or protein A function as the particles for antibody attachment [20–24]. The polysaccharide antigen can also be detected using a competitive inhibition enzyme immunosorbent assay [25] In the optical immunoassay (OIA), polysaccharide antigen extracted from a swab is bound to groupspecific antibody immobilized on a silicon wafer causing an observable change in the reflection of light [26]. Highly specific and sensitive nucleic acid detection methods using rapid-cycle real-time PCR have now been developed that can distinguish groups A, C, and G streptococci from throat swabs [27]. A single throat swab cultured correctly on blood agar has been shown to have a sensitivity of 90–95% in detecting group A streptococci. Compared to this gold standard culture method, most RADTs have specificities greater than 95%. As false-positive test results are unusual therapeutic decisions can be made with some confidence on the basis of a positive result [4]. False-positive results have been reported resulting from pharyngeal carriage of a serogroup A-producing Streptococcus intermedius [28]. Sensitivities vary considerably among RADTs with most less than 90%. Sensitivity measurements are affected both by the comparative method used to set the gold standard and by the location where testing occurs [4]. If the gold standard used for comparison is the combination of results from a direct plate culture and broth enhancement, then the rates of recovery of group A streptococci usually are higher than when plate culture alone is used as the standard. Gerber and co-workers showed that the positive rates recorded for plate culture were reader-dependent. Laboratory workers identified a higher number of positives among plate cultures than other workers [29]. For a patient with signs and symptoms consistent with a group A streptococcal pharyngitis, a positive RADT is considered diagnostic. However, to overcome the lack of sensitivity of RADTs the American Academy of Pediatrics recommended the all negative RADT tests be backed up with the results of a throat culture [30]. Kurtz et al. [31] showed that when two swabs were taken the combined result was significantly (p ⬍ 0.05) more sensitive than culture of either swab alone. Similarly, these workers showed that two swabs extracted and tested together was significantly more sensitive than two single swab extractions although the specificity decreased. Currently, the overall consensus is that RADTs are mostly of insufficient sensitivity to replace the standard culture for detection of group A streptococci, particularly in populations at risk for rheumatic fever. However, the decision is complicated by the fact that there is no universally accepted procedure for performing the blood agar culture. A PCRbased assay has been developed in association with optimal culturing, in an attempt to establish a reference standard [32].

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Identification of Group A Streptococci

Any colonies on blood agar plates showing ␤-hemolysis require to be identified as to their serogroup, or by using bacitracin discs presumptively identified as a group A streptococcus. Most ␤-hemolytic group A streptococci will be apparent on blood agar within 24 hours. Colonies vary in shape and size and may be mucoid. Under aerobic conditions some may appear ␣-hemolytic [33]. Non-hemolytic group A streptococci have also been reported [34]. Colonies of group A streptococci are often indistinguishable from other ␤-hemolytic streptococci, especially serogroups C and G. The number of colonies on a plate is not a good indicator for differentiating true infection from the carrier state. In sub-culture group A streptococci can be presumptively identified using a 0.04 unit bacitracin differential disc [35]. Inappropriate results will be achieved if the higher dose antibiotic sensitivity discs are used in error. Bacitracin is strongly inhibitory to S. pyogenes but not usually to other ␤-hemolytic streptococci, although it has been shown that streptococci of groups B, C, and G, can be as sensitive as group A’s [35]. Erroneous results may be obtained if bacitracin discs are placed on primary cultures, rather than pure cultures, and it has been suggested that up to 50% of S. pyogenes may be missed by this practice. An alternative screening test used is the PYR test which relies on the ability of organisms to hydrolyze L-pyrrolidonyl ␤-naphthylamide or L-pyroglutamic acid ␤-naphthylamide (PYR) [36]. Most group A streptococci are PYR-positive. A few group C and G isolates have also been found PYRpositive [37]. A number of different methods are available for extraction of the groupspecific carbohydrate including extraction with hydrochloric acid, formamide, nitrous acid, or enzymes [37]. Commercially available streptococcal grouping kits, equivalent to the RADTs, are marketed for laboratory use. Most use group-specific rabbit antibody bound either to protein A or to latex beads. Visual specific agglutination is the end point.

Streptococcal Antibody Tests

Antibody tests have no value in the diagnosis of a streptococcal sore throat. However, they are very important in providing evidence for antecedent streptococcal infection in support of the major and minor manifestations described in the Jones criteria [38]. Streptococcal antibody titres take around 10–14 days to elevate. Thus, a sequential rise in titers will confirm recent streptococcal infection. The serological tests most commonly performed are

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the antistreptolyin O test (ASO), and anti-deoxyribonuclease B (anti-Dnase B). Kits for undertaking the anti-hyaluronidase test are no longer marketed. True group A streptococcal infections involve a specific immunologic response as measured by a significant increase in the titer of antibodies to at least one of the extracellular antigens, streptolysin O, deoxyribonuclease B, hyaluronidase, streptokinase and nicotinamide adenine dinucleotidase. The neutralization of enzyme by specific antibodies present in a patient’s serum is the basis of each streptococcal antibody test used. Antibody raised against extracellular enzyme antigens reaches a peak 2–3 weeks after acute infection. The level of antibody reached is generally governed by idiosyncratic differences within individuals and will be determined by the existing level of that antibody from previous infections. Antibody is maintained for 2–3 months before declining [39]. A number of studies have attempted to correlate the number of colonies obtained on a throat culture with the subsequent level of antibody detected. However, there seems to be little correlation between the degree of positivity and the changes in streptococcal antibody titres observed. Thus, the differentiation of patients with streptococcal infections (a positive throat culture and a rise in streptococcal antibodies) and those who are streptococcal carriers (positive throat culture but no elevation of antibody) cannot be made on the basis of the degree of positivity alone [40, 41]. It is unclear whether antibiotic therapy suppresses the formation of streptococcal antibodies but it is possible that antibiotics could modify antibody levels. Anti-Streptolysin O (ASO) ASO is the most widely used and the most easily standardized of the serological tests available. Streptolysin O (SLO) is antigenic. Neutralizing antibodies to SLO are found elevated after 3–5 weeks following infection with group A streptococci and may also be elevated following infection with groups C and G streptococci. Commercial kits are available and the test can be undertaken using micro- or macro-methods. The test uses the property that SLO in its reduced form will hemolyze red blood cells. Known dilutions of a patient’s serum are reacted with a standardized concentration of SLO. Residual SLO is detected using red blood cells as the indicator. The antibody end point is the highest dilution showing no hemolysis. False-positive results may be recorded if the SLO becomes oxidized or if the serum being tested is either contaminated or hyperlipemic [39]. Streptolysin O titers are often reported as Todd Units which represent the highest dilution of serum showing complete inhibition of hemolysis [42]. About 20% of infected individuals will not respond with an increase in anti-streptolysin O antibody [43]. Thus, a negative anti-streptolysin O titer alone cannot be used to rule out preceding streptococcal infection.

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Anti-Deoxyribonuclease B Group A streptococci produce four deoxyribonucleases (DNases) designated A, B, C and D. During infection greatest response is against DNase B. The presence of antibodies against DNase B provides evidence of recent infection with S. pyogenes [43] although some isolates of groups C and G streptococci also produce DNase B. The anti-DNase B test is usually used in parallel with the ASO test. Peak levels of anti-DNase B may be slower to occur, taking 6–8 weeks to peak, but may remain elevated for longer periods than ASO. In the test anti-DNase B antibodies neutralize the enzymatic activity of DNase B preventing it from depolymerizing DNA that has been coupled to an indicator dye. In the absence of antibodies depolymerization is detected through a color change. The anti-DNase B test has the advantage that the reagents are stable, purified antigen can be stored for long periods of time without losing potency, and false positive tests are not recorded. The test is available commercially and can be performed as a micro or macro test. Currently, no standard international reference serum for anti-DNase B is available. In countries with high rates of skin infection upper limits of normal for school-aged children may be as high as 600 units [44]. Other Streptococcal Antibody Tests Anti-Hyaluronidase Titer (AHT). Hyaluronidase is an enzyme expressed by group A streptococci which hydrolyses hyaluronic acid. The AHT test measures the level of antibody in a patient’s serum that will neutralize hyaluronidase, preventing hydrolysis of the substrate potassium hyaluronate [45]. Unfortunately, this test is no longer being marketed and will be discussed no further. Anti-nicotinamide adenine dinucleotidase (NADase) and anti-streptokinase (ASK) tests currently are uncommonly used for determination of streptococcal antibodies. References 1 2 3 4 5 6 7

Denny FW, Wannamaker LW, Brink WR, Rammelkamp CH, Custer EA: Prevention of rheumatic fever: Treatment of the preceding streptococcal infection. JAMA 1950;143:151–153. Dajani A, Taubert K, Ferrieri P, et al: Treatment of acute streptococcal pharyngitis and prevention of rheumatic fever: A statement for health professionals. Pediatrics 1995;96:758–764. Cantanzaro FJ, Stetson CA, Morris AJ, Chamovitz R, Rammelkamp CH, Stolzer BL, Perry WD: The role of streptococcus in the pathogenesis of rheumatic fever. Am J Med 1954;17:749–756. Bisno AL, Gerber MA, Gwaltney JM, Kaplan EL, Schwartz RH: Diagnosis and management of group A streptococcal pharyngitis: A practice guideline. Clin Infect Dis 1997;25:574–583. Ebell MH, Smith MA, Barry HC, Ives K, Carey M: Does this patient have strep throat? JAMA 2000;284:2912–2918. Breese BB, Disney FA: The accuracy of diagnosis of beta streptococcal infections on clinical grounds. J Pediatr 1954;44:670–673. Pichichero ME: Group A beta-hemolytic streptococcal infections. Pediatr Rev 1998;19:291–302.

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Johnston DR, Kaplan EL, Sramek J, Bicova R, Havlicek J, Havlickova, Motlova J, Kriz P (eds): Laboratory Diagnosis of Group A Streptococcal Infections. Geneva, World Health Organisation, 1996, pp 4–10. Redys JJ, Hibbard EW, Borman EK: Improved dry-swab transportation for streptococcal specimens. Publ Hlth Rep 1968;83:143–149. Rubbo SD, Benjamin M: Some observations on survival of pathogenic bacteria on cotton-wool swabs: Development of a new type of swab. Br Med J 1951;4713:983–987. Facklam RR: A review of the microbiological techniques for the isolation and identification of streptococci. CRC Crit Rev Clin Lab Sci 1976;6:287–317. Hollinger NF, Lindberg LH, Russell EL, Sizer HB, Cole RM, Browne AS, Updyke EL: Transport of streptococci on filter paper strips. Publ Hlth Rep 1960;75:251–259. Pike RM: The isolation of hemolytic streptococci from throat swabs: Experiments with sodium azide and crystal violet in enrichment broth. Am J Hyg 1945;41:211–220. Ellner PD, Stoessel CJ, Drakeford E, Vasi F: A new culture medium for medical bacteriology. Am J Clin Path 1966;36:502–504. Petts DN: Colistin-oxolinic acid-blood agar: A new selective medium for streptococci. J Clin Microbiol 1984;19:4–7. Gunn BA, Ohashi DK, Gaydos CA, Holt ES: Selective and enhanced recovery of group A and B streptococci from throat cultures with sheep blood agar containing sulfamethoxazole and trimethoprim. J Clin Microbiol 1977;5:650–655. Kellogg JA: Suitability of throat culture procedures for detection of group A streptococci and as reference standards for evaluation of streptococcal antigen detection kits. J Clin Microbiol 1990;28:165–169. Dierksen KP, Ragland NL, Tagg JR: A new alkaline pH-adjusted medium enhances detection of ␤-hemolytic streptococci by minimizing bacterial interference due to Streptococcus salivarius. J Clin Microbiol 2000;38:643–650. Finger R, Ha HS, Thi NT, Ritchie CD, Nhan NT: Rapid streptococcal testing in Vietnamese children with pharyngitis. Asia Pac J Publ Hlth 1999;11:26–29. Miller JM, Phillips HL, Graves RK, Facklam RR: Evaluation of the directigen group A strept test kit. J Clin Microbiol 1984;20:846–848. Slifkin M, Gil GM: Evaluation of the culturette brand ten-minute group A strep ID technique. J Clin Microbiol 1984;20:12–14. Hadfield SG, Petts DN, Kennedy P, Lane A, McIllmurray MB: Novel color test for rapid detection of group A streptococci. J Clin Microbiol 1987;25:1151–1154. Ogay K, Bille J: Rapid coagglutination test for the direct detection of group A streptococci from throat swabs. Eur J Clin Microbiol 1986;5:317–319. Dale JC, Vetter EA, Contezac JM, Iverson LK, Wollan PC, Cockerill FR: Evaluation of two rapid antigen assays, BioStar Strep A OIA and Pacific Biotech CARDS O⬎S⬎ and culture for detection of group A streptococci in throat swabs. J Clin Microbiol 1994;32:2698–2701. Knigge KM, Babb JL, Firca JR, Ancell K, Bloomster TG, Marchlewicz BA: Enzyme immunoassay for the detection of group A streptococcal antigen. J Clin Microbiol 1984;20:735–741. Harbeck RJ, Teague J, Crossen GR, Maul DM, Childers PL: Novel, rapid optical immunoassay technique for detection of group A streptococci from pharyngeal specimens: comparison with standard culture methods. J Clin Microbiol 1993;31:839–844. Uhl JR, Adamson SC, Vetter EA, Schleck CD, Harmsen WS, Iverson LK, Santrach PJ, Henry NK, Cockerill FR: Comparison of lightcycler PCR, rapid antigen immunoassay, and culture for detection of group A streptococci from throat swabs. J Clin Microbiol 2003;41:242–249. Rubin LG, Kahn RA, Vellozzi EM, Isenberg HD: False-positive detection of group A Streptococcus antigen resulting from colonization with cross-reacting Streptococcus intermedius (S. milleri group). Pediatr Infect Dis J 1996;15:715–717. Gerber MA, Tanz RR, Kabat W, Dennis E, Bell GL, Kaplan EL, Shulman ST: Optical immunoassay test for group A ␤-hemolytic streptococcal pharyngitis. JAMA 1997;277:899–903. American Academy of Pediatrics: Group A streptococcal infections; in Peter G (ed): 1994 Red Book: Report of the Committee on Infectious Diseases, ed 23. Elk Grove Village, American Academy of Pediatrics, 1994, p 433.

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Kurtz B, Kurtz M, Roe M, Todd J: Importance of inoculum size and sampling effect in rapid antigen detection for diagnosis of Streptococcus pyogenes pharyngitis. J Clin Microbiol 2000;38:279–281. Kaltwasser G, Diego J, Welby-Sellenriek PL, Ferrett R, Caparon M, Storch GA: Polymerase chain reaction for Streptococcus pyogenes used to evaluate an optical immunoassay for the detection of group A streptococci in children with pharyngitis. Pediatr Infect Dis J 1997;16:748–753. Pinney AM, Widdowson JP, Maxted WR: Inhibition of ␤-haemolysis by opacity factor in group A streptococci. J Hyg1977;78:355–362. James L, McFarland RB: An epidemic of pharyngitis due to a nonhemolytic group A streptococcus at Lowry Air Force Base. N Engl J Med 1971;284:750–752. Maxted WR: The use of bacitracin for identifying group A haemolytic streptococci. J Clin Pathol 1953;6:224–226. Facklam RR, Thacker LG, Fox B, Eriquez L: Presumptive identification of streptococci with a new test system. J Clin Microbiol 1982;15:987–990. Johnston DR, Kaplan EL, Sramek J, Bicova R, Havlicek J, Havlickova, Motlova J, Kriz P (eds): Laboratory Diagnosis of Group A Streptococcal Infections. Geneva, World Health Organisation, 1996, pp 23–32. Guidelines for the diagnosis of rheumatic fever: Jones criteria, 1992 update. Special writing group of the committee on rheumatic fever, endocarditis, and Kawasaki disease, American Heart Association. JAMA 1992;268:2069–2073. Ayoub EM: Streptococcal antibody tests in rheumatic fever. Clin Immunol Newslett 1982;3:107–111. Kaplan EL, Anthony BF, Chapman SS, Ayoub EM, Wannamaker LW: The influence of the site of infection on the immune response to group A streptococci. J Clin Invest 1970;49:1405–1414. Gerber MA, Randolph MF, Chanatry J, Wright LL, DeMeo KK, Anderson LR: Antigen detection test for streptococcal pharyngitis: Evaluation of sensitivity with respect to true infections. J Pediatr 1986;108:654–657. Todd E: Antigenic streptococcal hemolysis. J Exp Med 1932;55:267–280. Ayoub EM, Wannamaker LW: Evaluation of the streptococcal desoxyribonuclease B and di-phosphopyridine nucleotidase antibody tests in acute rheumatic fever and acute glomerulonephritis. Pediatrics 1962;29:527–538. Dawson KP, Martin DR: Streptococcal involvement in childhood acute glomerulonephritis: A review of 20 cases at admission. NZ Med J 1982;95:373–376. Murphy RA: Improved antihyaluronidase test applicable to the microtitration technique. Appl Microbiol 1972;23:1170–1171.

Diana R. Martin, PhD, FRSNZ Institute of Environmental Science and Research PO Box 50 248, Porirua (New Zealand) Tel. ⫹64 4 914 0778, Fax ⫹64 4 914 0770, E-Mail [email protected]

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Pechère JC, Kaplan EL (eds): Streptococcal Pharyngitis. Issues Infect Dis. Basel, Karger, 2004, vol 3, pp 85–94

Diagnosis of Non-Suppurative Complications of Group A Streptococcal Pharyngitis Patricia Ferrieri Departments of Laboratory Medicine and Pathology and Pediatrics, and Clinical Microbiology Laboratory, University of Minnesota Medical School, Minneapolis, Minn., USA

This review will focus on three major non-suppurative complications of group A streptococcal pharyngitis: acute post-streptococcal glomerulonephritis, acute rheumatic fever, and post-streptococcal reactive arthritis. Since these entities are present in many populations of the world, there is merit in discussing the clinical presentations, the epidemiology and the proposed pathogenesis of all three entities. Acute Post-Streptococcal Glomerulonephritis

The clinical presentation of edema, oliguria, and discolored urine following scarlet fever in patients was described more than 200 years ago [1]. This may have been the first published observation that associated renal disease with streptococcal infection. Later, in 1827, Bright [2] described the first studies on the pathologic changes in patients with glomerulonephritis. Further substantiating the thinking that the beta-hemolytic Streptococcus was the causative agent of scarlet fever, and, could also cause nephritis, were the descriptions of Dick and Dick [3]. This was followed in 1924 by the studies of Dochez and Sherman [4] that further established this association. In 1938, Lyttle et al. [5] described the serum anti-streptolysin titer rises in acute glomerulonephritis, with documentation of streptococcal infections in 94% of 116 patients with acute glomerulonephritis. It is now abundantly clear that acute glomerulonephritis, following streptococcal infections, has its own distinct epidemiology, specific serotypic distribution of group A streptococcal serotypes, and unique immunologic and

Table 1. Findings in post-streptococcal acute glomerulonephritis Clinical findings

Laboratory findings

Hematuria (smoky urine) Edema Decreased urine output Fever Hypertension Congestive heart failure

Hematuria, red cell casts Proteinuria Elevated sedimentation rate Elevation of BUN, Cr, K Decreased serum complement Recovery of GAS from throat or skin lesions Elevated streptococcal antibody titers

GAS ⫽ Group A streptococci.

Table 2. Comparison of key features of acute post-streptococcal glomerulonephritis following pharyngitis versus impetigo Feature

After pharyngitis

After impetigo

Clinical presentation Pathology Age Sex Latent period Attack rate GAS serotypes Streptococcal antibody response Occurrence in families Season Geographic distribution

same same young, school age 2M:1F 10 days variable 10–15% limited types1 generally good common winter and spring north and south

same same ⬍5 years equal distribution 18–21 days variable 10–15% or ⬎ limited types but different1 variable, depending on antigen common late summer and early fall north and south

GAS ⫽ Group A streptococci. 1 Following infection with a nephritogenic strain.

histologic findings. The frequency of the development of acute glomerulonephritis is very dependent on the serotype, varying from 0, or near 0, with the so-called non-nephritogenic serotypes to about 12% following infection with nephritogenic serotypes [6]. The clinical and laboratory findings in patients with poststreptococcal acute glomerulonephritis are shown in table 1. It is widely acknowledged that acute nephritis may follow infection of either the skin or the upper respiratory tract. Although there are several differences in the two groups (table 2), either following pharyngitis or impetigo, one of the most fascinating differences is the shorter latent period of 10 days between acute infection of the pharynx and development of acute nephritis,

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compared to 18–21 days following group A streptococcal skin infections or impetigo. It is important to note that the clinical presentations cannot be distinguished, nor the histopathologic findings in biopsies of the kidney. The predominance of males to females in a ratio of two to one in patients with nephritis following streptococcal pharyngitis is difficult to explain, since there are no discernible differences in the occurrence of streptococcal infection of the pharynx or the skin between the sexes [7]. In the presence of a nephritogenic serotype and the clinical findings of infection, the actual attack rates of acute nephritis are very similar, regardless of the site of infection. Infection of the throat with certain specific serotypes of group A streptococci is known to commonly result in acute nephritis, whereas pharyngeal infection with many other serotypes does not lead to this non-suppurative complication [7]. The association of M types 1, 3, 4, 12, 25 and 49 with postpharyngitis nephritis has been reasonably well documented [6, 7]. In contrast, M types 49 (more commonly seen with skin, rather than with pharyngitis-associated acute nephritis), 55, 57, 60, and 70 are usually associated with pyoderma-associated acute nephritis [7, 8]. However, there are some fascinating differences that should be emphasized from the studies of Anthony, Kaplan, and Wannamaker and colleagues, where it was observed that M-type 49 infection carried a 5% risk of nephritis when present in the throat and a 25% risk if the infection occurred in the skin [9]. There are differences in the immune response to various streptococcal antigens, according to the site of infection. In patients with acute nephritis following streptococcal pharyngitis or tonsillitis, there is a very good antibody response in the patients with elevated titers of ASO (anti-streptolysin O) antibody, and the anti-DNase B (anti-streptococcal deoxyribonuclease B) antibody, and an excellent response to anti-NADase (anti-nicotinamide-adeninedinucleotidase) antibody. In contrast, in patients with acute nephritis following streptococcal impetigo or pyoderma, the best immunologic response is to the DNase B protein antigen. The feeble response of the ASO antibody in patients with skin-associated nephritis is thought to be due to the diminished antigenicity of streptolysin O at cutaneous sites, possibly due to interference by streptolysin O binding to cholesterol and skin lipids [7, 10]. Other laboratory assays that are valuable in assessing patients with acute post-streptococcal nephritis include serum complement, measured sequentially. Both total hemolytic complement activity and C3 concentrations are depressed early in the course of the illness, and in most cases, return to the normal range in 6–8 weeks [11]. If the C3 level remains low over a period of several weeks or months after the presentation, this should suggest a different entity, rather than acute post-streptococcal glomerulonephritis; lupus nephritis and membranoproliferative glomerulonephritis should be considered. A differentiating feature

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of these latter entities includes absence of the responses to the streptococcal antigens, commonly seen in those patients with post-streptococcal nephritis. Pathogenesis of Acute Post-Streptococcal Glomerulonephritis Various pathogenic mechanisms may explain the evolution of acute glomerulonephritis. These include deposition of immune complexes, deposition of cross-reactive antibodies to streptococcal and glomerular antigens, molecular alteration of glomeruli by streptococcal enzymes, such as streptokinase or protease, and direct activation of complement by streptococcal antigens deposited in the renal glomerular tissue [12]. The presence of immunoglobulin G and C3 within glomeruli, using immunophorescent techniques, suggests an immune-complex process. However, it is unclear if the inflammation is medated by circulating immune complexes or complexes formed in situ (i.e. within the kidney) or both. A widely disseminated theory is that nephritogenic streptococci produce proteins that have antigenic determinants with an affinity for sites within the normal glomerulus [13]. Once they are released into the circulation, they may then reside within the glomerulus, binding to specific sites. This can be followed by the activation of complement directly by interaction with properdin, leading to activation of the alternative complement pathway. It is possible, then, that these proteins bound to the glomeruli may serve as a site for subsequent immune-complex formation with circulating anti-streptococcal antibodies. This may lead to additional complement binding via the classical complement pathway, followed by the generation of various inflammatory mediators and an influx of polymorphonuclear leukocytes. Some of the possible nephritogenic antigens are SPEB (streptococcal pyogenic exotoxin B or proteinase), also designated as NSAP (nephritic strainassociated protein) or NPBP (nephritis plasmin-binding protein). Cu, Mezzano and Zabriskie have demonstrated that 67% of acute post-streptococcal glomerulonephritis kidney biopsy specimens stain positive for SPEB, but only 16% of non-nephritis biopsies were positive for SPEB [14]. In addition, the presence of high antibody titers against SPEB in the acute nephritis patients, compared to normal controls, was supportive of the possible role of this protein in the pathogenesis of acute post-streptococcal nephritis [14]. SPEB is antigenically and biochemically similar to streptokinase from group C streptococci, but is thought not to be related to group A streptococcal streptokinase [12]. It is thought that the SPEB or NSAP protein is actually streptococcal pyrogenic exotoxin B, also known as the streptococcal proteinase zymogen [12]. Studies by Nordstrand et al. [15] of group A streptococcal streptokinase in an experimental mouse model revealed that streptokinase production was a prerequisite for the capacity of the organism to induce nephritis in mice. In this model, the findings support the hypothesis that the streptokinase initiated the nephritic

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process by deposition within the glomeruli, with local activation of a complement system. As part of this process, the streptokinase converted plasminogen to plasmin with the subsequent deposition of complement within the glomeruli. These authors believe that the potential for nephritogenicity is related to the streptokinase genotype (ska) and that streptokinase of the ska2 profile, in particular, has the highest affinity for kidney epitopes; there are several ska genotypes [12, 15]. Other antigens that have been implicated in the pathogenesis of acute poststreptococcal nephritis include endostreptosin, a 40 to 50- kD protein, most likely derived from the streptococcal cytoplasm [16]. Lange et al. [17] believed that elevated levels of antibody to endostreptosin are diagnostic of post-streptococcal glomerulonephritis. This particular protein is thought to be similar to the pre-absorbing antigen (PA-Ag) described by Yoshizawa et al. [18]. Another consideration is the potential role of nephritis-associated plasmin receptor (NAP1r) in the pathogenesis of acute post-streptococcal nephritis, supported by the deposition of this protein within glomeruli of patients with acute nephritis [18]. The precise mechanisms for the pathogenesis of acute nephritis remain a challenge and the process may likely be a multi-factorial one, rather than due to a single agent or process. The long-term outlook for patients with post-streptococcal nephritis has been controversial. Although most patients, particularly children, eventually have a complete recovery, hypertension, recurrent or persistent proteinuria, and chronic renal insufficiency develop in a small percentage, probably less than 10–15% [11]. Prevention of nephritis by penicillin treatment of preceding respiratory infections due to group A streptococci is only partially successful, and may be even more difficult in streptococcal impetigo. No comprehensive studies have demonstrated that antibiotic treatment of streptococcal skin infections will reduce the frequency of acute nephritis [7].

Acute Rheumatic Fever

The association of group A streptococcal infections of the pharynx with acute rheumatic fever has been well recognized, and it is generally accepted that acute rheumatic fever never follows infection of the skin with these bacteria [7, 8, 12]. This puzzling difference may be partially explained by the difference in the group A streptococcal M serotypes associated with pharyngeal infections, in contrast to those serotypes isolated from skin lesions [7, 12, 19]. A large number of group A streptococcal M types infecting the pharynx have been associated with acute rheumatic fever; examples of M types that have been studied particularly well are M types 1, 3, 5, 6 and 18 [12]. The emm gene

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sequences of over 95 known M protein serotypes have been identified by rapid PCR analysis [20]. In general, there is a very good correlation between the known serologic designation of M serotypes with emm gene sequencing using molecular techniques. It is thought that the majority of group A streptococcal serotypes have rheumatogenic potential [7, 21, 22]. This is why no distinction is made, on the basis of M type, on whom to treat with group A streptococcal infection of the throat, for the prevention of acute rheumatic fever. Although some of the so-called pyoderma serotypes are found frequently in the throat as a late finding in patients with impetigo, they rarely produce true clinical infection of the throat, and, therefore, they may lack some rheumatogenic factor. The latency period for the development of rheumatic fever after a group A streptococcal infection averages 18 days, with even longer latent periods of several months in patients presenting with Sydenham’s chorea and erythema marginatum [6, 7]. This long latency period has the advantage of preventing acute rheumatic fever by appropriate treatment of the infection. However, this relatively long latency period permits the host the opportunity to develop an immune response, which may initiate the pathophysiologic manifestations. Epidemiology and Clinical Manifestations of Rheumatic fever The epidemiology of rheumatic fever reveals that there are areas of the world with a very high incidence and these include Auckland, New Zealand, the northern region of Australia’s Northern Territory, and India [12]. Kaur, Ganguly, Kaplan, and colleagues have noted that the incidence of rheumatic heart disease worldwide ranges from 0.55 to 11 per 1,000 individuals [12, 23]. It is a curiosity of the past 17 years that outbreaks of rheumatic fever have been observed in the United States, beginning when Utah reported an outbreak associated with children from middle- to upper-income families [24]. This area of the United States has continued to have a high prevalence of acute rheumatic fever. Curiously, mucoid M type 18 group A streptococcal strains were associated with the original outbreak in Utah [24, 25]. The five major clinical manifestations that may be seen in rheumatic fever are involvement of the heart (carditis), inflammation of the joints (arthritis), the central nervous system (chorea), the skin rash (erythema marginatum), and/or subcutaneous nodules [12, 26]. These, as well as minor manifestations or criteria, were incorporated in a diagnostic scheme by Dr. T. Duckett Jones. The original publication by Jones in 1944 has been followed by several revisions of the guidelines, including the latest statement by the American Heart Association Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease [26]. The validity of the major and minor Jones Criteria, as applied to the diagnosis of rheumatic fever, has been reaffirmed by this American Heart

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Association Committee, which has reinforced that these criteria should continue to be the accepted standard for diagnosis of initial attacks of acute rheumatic fever [27]. The diagnosis of acute rheumatic fever using the Jones Criteria requires the presence of either two major manifestations or one major and two minor manifestations [26]. The major manifestations are as above, and the minor manifestations include fever, arthralgia, elevated sedimentation rate, elevated C-reactive protein, and elevated P-R interval. In addition, the diagnosis requires that supportive evidence of a preceding group A streptococcal infection be established, with either a positive throat culture for group A streptococci and/or an elevated or rising ASO titer, elevated anti-DNase B titer, or an elevated group A carbohydrate antibody titer [26]. Other streptococcal antibodies, such as anti-hyaluronidase or anti-streptokinase, have not been as well standardized as the ASO and anti-DNase B antibodies.

Pathogenesis of Rheumatic Fever It is intriguing that, although many people develop streptococcal pharyngitis, only a small percentage of individuals develop acute rheumatic fever. This suggested that there may be genetic factors that predispose the human host to rheumatic fever, in the face of a group A streptococcal infection with a ‘rheumatogenic’ strain [7, 12]. A recent review of the host susceptibility to acute rheumatic fever may be referred to for further details [12]. Among the studies defining individuals who may be susceptible to acute rheumatic fever are those of Patarroyo, Zabriskie and colleagues who identified a non-HLA B-cell marker, known as 883 or D8/17, which identified 100% of rheumatic fever patients evaluated by them in the United States [28, 29]. Monoclonal antibody to D8/17 reacted with 33–40% of these cells from patients with a history of acute rheumatic fever, whereas only minimal staining was observed in control groups (5–7% of these cells stained positively) [29]. However, studies by Kaur and colleagues revealed that the B-cell marker was elevated in only 66% of a north Indian study group; he and colleagues developed a new monoclonal antibody against the B cells of this population with rheumatic fever, and this monoclonal antibody, PGI/MNII, reacted with a larger number of north Indian rheumatic fever patients, supporting that the D8/17 B cell marker did not identify all ethnic groups [23]. The role of autoimmunity and molecular mimicry in rheumatic fever has been under study for many decades. Kaplan and Frengley [30] in 1969 demonstrated antibodies to heart tissue in acute rheumatic fever sera using immunofluorescent techniques. These findings were confirmed by other investigators and support the hypothesis that there is an autoimmune origin in acute rheumatic fever. It is not precisely clear what the role of cross-reactive and

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polyspecific autoantibodies are in the pathogenesis of rheumatic fever. However, Cunningham [12] reported two monoclonal antibodies, one a human and another a mouse, which were cytotoxic for heart cells in culture, and these cytotoxic antibodies recognized epitopes on the surface of heart cells. Extensive studies by her and her colleagues have revealed that antistreptococcalantimyosin antibodies can be potentially damaging to heart cells or tissues [12]. The sharing of antigenic epitopes by the host and the streptococci is known as molecular mimicry. The M protein antigen is the most thoroughly characterized of the streptococcal antigens involved in molecular mimicry. For a review of human anti-streptococcal monoclonal antibody specificities, and the specific antigens with which they cross-react, a recent publication may be consulted [12]. At this time, there is no simple, practical test based on these molecular techniques that can be applied at the bedside or in the clinic for a rapid diagnosis of acute rheumatic fever. The diagnosis is inextricably tied to clinical findings and evidence of a preceding group A streptococcal infection, detected by a positive culture for group A streptococci in the pharynx and/or elevated or rising streptococcal antibody titers.

Post-Streptococcal Reactive Arthritis

There are patients who develop arthritis that is atypical in its time of onset or duration, but they have no other major manifestations of acute rheumatic fever [26]. Typically, these patients fail to respond dramatically to salicylate therapy, in contrast to patients with polyarthritis of acute rheumatic fever. Some of these patients do fulfill the Jones Criteria, and, therefore, should be diagnosed as having acute rheumatic fever. Also, in contrast, patients with rheumatic fever have acute migratory polyarthritis that is self-limited, and rarely lasts more than a few days [31]. For those who do not fulfill the Jones Criteria, the diagnosis of post-streptococcal reactive arthritis (PSRA) should be made only after other rheumatologic conditions have been carefully eliminated [26, 31]. Patients with PSRA have prolonged clinical symptoms and protracted arthritis that is also unresponsive to nonsteroidal anti-inflammatory drugs. Further features of PSRA include the development of arthritis 3–14 days after streptococcal pharyngitis; fever and a scarlatiniform rash are often present during the acute phase of pharyngitis, but absent by the time arthritis appears [31]. The non-migratory arthritis in PSRA can affect both large and small joints, primarily the knees, ankles, wrists and proximal interphalangeal joints. In a small percentage of patients with PSRA, carditis has been reported to have developed at a later time, suggesting that the original diagnosis was likely acute rheumatic fever.

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Pathogenesis of PSRA. The pathogenesis of PSRA is incompletely delineated and some studies suggest that antibodies that develop against the group A streptococci cross-react with the joint synovial tissue or cartilage, similar to the findings with acute rheumatic fever [32]. Recent studies have suggested an increased frequency of the class II HLA DRB1 01 allele in PSRA compared to normal individuals or patients with rheumatic fever [32]. The laboratory confirmation of PSRA comprises essentially the presence of a positive throat culture for group A streptococci and/or to elevated or rising ASO and anti-DnaseB titers. The medical management of patients with PSRA is not universally agreed upon, but there may be merit in prescribing antibiotic prophylaxis to prevent recurrent streptococcal infections (as in patients with a history of acute rheumatic fever). One may continue the prophylaxis for one year and follow for any evidence of carditis; if none is observed during that period, it may be discontinued. Obviously, patients who develop carditis on follow-up should be classified as having acute rheumatic fever and should continue to receive antibiotic prophylaxis, according to recommendations by the American Heart Association [26]. References 1 2 3 4

5 6 7 8 9

10 11 12 13 14

Von Plenciz MA: Tractatus III de Scarlatina. Vienna, Trattner, 1762. Bright R: Report of Medical Cases Selected with a View of Illustrating Symptoms and Cure of Diseases by Reference to Morbid Anatomy, vol 1. London, Longmans, Green, 1827. Dick GF, Dick GH: Experimental scarlet fever. JAMA 1923;81:1166–1171. Dochez AR, Sherman L: The significance of Streptococcus hemolyticus in scarlet fever and the preparation of a specific antiscarlatinal serum by immunization of the horse to Streptococcus hemolyticus scarlatinae. JAMA 1924;82:542–544. Lyttle JD, Seegal D, Loeb EN, Jost EL: The serum anti-streptolysin titer in acute glomerulonephritis. J Clin Invest 1938;17:631–639. Wannamaker LW, Ferrieri P: Streptococcal Infections – Updated. Chicago, Year Book Medical Publishers, 1975. Wannamaker LW: Differences between streptococcal infections of the throat and of the skin. N Engl J Med 1970;282:23–31, 78–85. Ferrieri P, Dajani AS, Chapman SS, Jensen JB, Wannamaker LW: Appearance of nephritis associated with type 57 streptococcal impetigo in North America. N Engl J Med 1970;283: 832–836. Anthony BF, Kaplan EL, Wannamaker LW, Briese FW, Chapman SS: Attack rates of acute nephritis after type 49 streptococcal infection of the skin and of the respiratory tract. J Clin Invest 1969; 48:1697–1704. Kaplan EL, Wannamaker LW: Streptolysin O: Suppression of its antigenicity by lipids extracted from skin. Proc Soc Exp Biol Med 1974;146:205–208. Hricik DE, Chung-Park M, Sedor JR: Glomerulonephritis. N Engl J Med 1998;339:888–899. Cunningham MW: Pathogenesis of group A streptococcal infections. Clin Microbiol Rev 2000; 13:470–511. Nordstrand A, Norgren M, Holm SE: Pathogenic mechanism of acute post-streptococcal glomerulonephritis. Scand J Infect Dis 1999;31:523–537. Cu GA, Mezzano S, Bannan JD, Zabriskie JB: Immunohistochemical and serological evidence for the role of streptococcal proteinase in acute post-streptococcal glomerulonephritis. Kidney Int 1998;54:819–826.

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Nordstrand A, Norgren M, Ferretti JJ, Holm SE: Streptokinase as a mediator of acute post-streptococcal glomerulonephritis in an experimental mouse model. Infect Immun 1998;66:315–321. Lange K, Ahmed U, Kleinberger H, Treser G: A hitherto unknown streptococcal antigen and its probable relation to acute poststreptococcal glomerulonephritis. Clin Nephrol 1976;5:207–215. Lange K, Seligson G, Cronin W: Evidence for the in situ origin of poststreptococcal GN: Glomerular localization of endostreptosin and the clinical significance of the subsequent antibody response. Clin Nephrol 1983;19:3–10. Yoshizawa N: Acute glomerulonephritis. Intern Med 2000;39:687–694. Bessen D, Beall B, Hollingshead S: emm Genes and Tissue Tropisms of Group A Streptococci. ASM Conference on Streptococcal Genetics: Genetics of the Streptococci, Enterococci, and Lactococci. Washington, American Society for Microbiology, 1998, pp 19–20. Beall B, Facklam RR, Elliott A, Franklin AR, Hoenes T, Jackson D, LaClaire L, Thompson T, Viswanathan R: Streptococcal emm types associated with T-agglutination types and the use of conserved emm gene restriction fragment patterns for subtyping group A streptococci. J Med Microbiol 1998;47:893–898. Bisno AL:The concept of rheumatogenic and non-rheumatogenic group A streptococci; in Read SE, Zabriskie JB (eds): Streptococcal Diseases and the Immune Response. New York, Academic Press, 1980, pp 789–803. Martin DR: Rheumatogenic and nephritogenic group A streptococci; in Horaud T, Bouvet A, Leclerq R, de Montclos H, Sicard M (eds): Streptococci and the Host. New York, Plenum Press, 1997, pp 21–27. Kaur S, Kumar D, Grover A, Khanduja KL, Kaplan EL, Gray ED, Ganguly NK: Ethnic differences in expression of susceptibility marker(s) in rheumatic fever/rheumatic heart disease patients. Int J Cardiol 1998;64:9–14. Veasy LG, Wiedmeier SE, Orsmond GS: Resurgence of acute rheumatic fever in the intermountain area of the United States. N Engl J Med 1987;316:421–427. Veasy LG, Tani LY, Hill HR: Persistence of acute rheumatic fever in the intermountain area of the United States. J Pediatr 1994;124:9–16. Dajani AS, Ayoub E, Bierman FZ, Bisno AL, Denny FW, Durack DT, Ferrieri P, Freed M, Gerber M, Kaplan EL, Karchmer AW, Markowitz M, Rahimtoola SH, Shulman ST, Stollerman G, Takahashi M, Taranta A, Taubert KA, Wilson W: Guidelines for the diagnosis of rheumatic fever: Jones Criteria, updated 1992. JAMA 1992;268:2069–2073. Ferrieri P for the Jones Criteria Working Group: Proceedings of the Jones Criteria Workshop. Circulation 2002;106:2521–2523. Patarroyo ME, Winchester RJ, Vejerano A, Gibofsky A, Chalem F, Zabriskie JB, Kunkel HG: Association of a B-cell alloantigen with susceptibility to rheumatic fever. Nature 1979;278:173–174. Khanna AK, Buskirk DR, Williams Jr RC, Gibofsky A, Crow MK, Menon A, Fotino M, Reid HM, Poon-King T, Rubinstein P, Zabriskie JB: Presence of a non-HLA B cell antigen in rheumatic fever patients and their families as defined by a monoclonal antibody. J Clin Invest 1989;83:1710–1716. Kaplan MH, Frengley JD: Autoimmunity to the heart in cardiac disease: Current concepts of the relation of autoimmunity to rheumatic fever, postcardiotomy and post infarction syndromes and cardiomyopathies. AM J Cardiol 1969;24:459–473. Ahmed S, Ayoub EM: Poststreptococcal reactive arthritis. Pediatr Infect Dis J 2001;20:1081–1082. Ahmed S, Ayoub EM, Scornik JC, Wang C-Y, She J-X: Poststreptococcal reactive arthritis: Clinical characteristics and association with HLA-DR alleles. Arthritis Rheum 1998;41: 1096–1102.

P. Ferrieri, MD University of Minnesota Medical School 420 Delaware St. SE, MMC 134, Minneapolis, MN 55455 (USA) Tel. ⫹1 612 624 1112, Fax ⫹1 612 624 8927, E-Mail [email protected]

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Diagnosis and Management of Suppurative Complications of Streptococcal Pharyngitis P. Gehanno Hôpital Bichat, Paris, France

Pyogenic infections complicating streptococcal pharyngitis are usually confined to an anatomic space partly circumscribed by fascia and muscles. Deep extensive cellulitis can occur when the bacteria track along the natural passages connecting anatomic spaces or when the walls of these spaces are destroyed by necrosis. The spaces in which pus collects can be roughly described as follows. The peritonsillar space is located between the capsule surrounding the tonsil and the superior pharyngeal constrictor. Collection of pus in this endopharyngeal space is called peritonsillar abscess, or quinsy. The three other spaces are peripharyngeal, i.e. superficial to the muscle wall formed by the pharyngeal constrictors and their fasciae. The lateral peripharyngeal space, located lateral to the tonsillar region, is subdivided into two compartments by the muscles arising from the styloid process. The anterior compartment contains masticators (the pterygoid muscles), connective tissue, and lymph nodes, whereas the posterior compartment contains cranial nerves (IX, X, XI, XII), the internal carotid artery, and the sympathetic nerve. The retropharyngeal space is bounded anteriorly by the pharynx, posteriorly by the cervical vertebras, and laterally by the neurovascular bundle of the neck. It is subdivided into an anterior and a posterior compartment by two extremely thin fascial sheets located in the coronal plane anterior to the spine. The space between these two sheets extends from the skull base to the diaphragm. Neck infections can track along this space down into the mediastinum.

Collection of Pus

Peritonsillar Abscess Peritonsillar abscesses develop between the tonsillar capsule and the superior pharyngeal constrictor. This is the most common local suppurative complication of streptococcal pharyngeal infection and also the nearest to the primary focus of infection. Peritonsillar abscess typically occurs in a young adult, in spring or summer. In some patients, the abscess complicates an apparently unremarkable episode of tonsillitis. More often, the abscess is the first manifestation, presenting as unilateral pharyngitis with fever and pain, often in a patient with a history of recurrent tonsillitis or, more rarely, of similar episodes [1]. Diagnosis is readily established in a young patient with a 2- to 3- day history of severe unilateral pharyngeal pain. Drooling caused by severe odynophagia is common. The voice has a distinctive muffled sound (hot potato voice). The fever is often moderate, although high-grade fever (39⬚C) occurs in some patients [2, 3]. Another finding is trismus, which is a major obstacle to examination of the oropharynx, where a sign of considerable diagnostic value lies: on the side of the pain, a swelling above the anterior pillar displaces the tonsil downwards and toward the midline. The uvula is swollen and pushed across the midline. Finally, the only differential diagnosis is peritonsillar cellulitis at the precollection stage, a condition that resolves fully under antimicrobial therapy alone. Severe trismus may be in favour of cellulitis rather than of an abscess [4]. Needle aspiration distinguishes the two conditions by recovering pus if there is a collected abscess. Needle aspiration is as effective in establishing the diagnosis as computed tomography (CT) [5], which should be reserved for patients with severe trismus precluding examination of the oropharynx. Treatment rests on antimicrobial therapy and drainage of the abscess. • Antimicrobial therapy should be given for 7–10 days. The choice of antimicrobials should take into account the possibility of co-infection with anaerobic commensals inhabiting the tonsillar crypts. In patients who are treated repeatedly for recurrent tonsillitis, these anaerobes can acquire the ability to produce beta-lactamase. The drug of first choice is co-amoxicillin with clavulanic acid. Clindamycin should be used instead in patients who are allergic to penicillin. • Drainage of the pus is the mainstay of therapy. Three methods can be used: incision of the mucous membrane at the upper part of the anterior pillar followed by dissociation of the pillar muscle to gain access to the collection of pus, needle aspiration, and immediate tonsillectomy. – The first two methods are used under local anesthesia. However, incision causes considerable discomfort to the patient. Needle aspiration

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should be done using a large-gauge needle inserted at the site of maximum bulging and pushed no farther than 1.5 cm under the mucosal surface to avoid injuring the blood vessels. If there is no long-lasting improvement, the aspiration can be repeated. Immediate tonsillectomy is performed for practical reasons, usually 1 or 2 days after the outpatient visit, and has the advantage of both treating the abscess and preventing recurrences. This procedure requires general anaesthesia and does not provide the prompt pain relief afforded by needle aspiration. Nevertheless, the advocates of immediate tonsillectomy argue that the drainage is excellent and, consequently, the cure rate high. Tonsillectomy to prevent recurrences is particularly appropriate in young patients with a history of recurrent tonsillitis.

Parapharyngeal Abscesses These spaces located outside the tonsillar region are, as mentioned above, divided into two compartments by the three muscles that arise from the styloid process and extend anteriorly toward the hyoid bone, forming a sling with superior concavity. Abscesses in the Prestyloid Space. The prestyloid space is the anterior compartment. Because the pterygoid muscles are located in this compartment, the trismus is as severe as in peritonsillar abscesses. Two subtle semiological characteristics suggest a prehyoid parapharyngeal collection rather than a peritonsillar abscess: there is no uvular oedema, and the swelling is not located at the upper part of the anterior pillar in the lateral portion of the soft palate but lower down, in the middle of the anterior pillar, where it pushes the tonsil toward the midline. Finally, there is a moderate amount of swelling behind the angle of the mandible. These clinical details should lead to CT, which shows the site of the collection. Abscesses in the Retrostyloid Space. These occur mainly in children aged 3–10 years but can arise in adults. Their distinctive manifestations make the diagnosis far easier than that of prestyloid abscesses: the unilateral pharyngeal pain is consistently associated with cervical symptoms, and the oropharyngeal signs are very different from those described above. – A swelling is visible high in the neck, under the mastoid process, beneath the canopy formed by the sternomastoid muscle. – There is no trismus, and inspection of the pharynx shows that the bulge is located neither in the anterior pillar nor in the soft palate but in the posterior pillar, pushing the tonsil forwards. Most patients have suppurative adenitis initially, rather than a collected abscess. Here also, CT is of considerable assistance for the diagnosis. The

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inflammation around the internal carotid artery, sensorimotor nerves, and XIIth nerve explain why deficits in the territories of several nerve trunks and/or Horner’s syndrome occur in some patients. Life-threatening vascular complications can occur, including suppurative thrombosis of the internal jugular vein and, above all, rupture of the internal carotid artery, of which we have seen 3 cases in children. Before the advent of antibiotics, rupture of the carotid artery was the most severe complication of deep neck space infections, including retrostyloid abscesses. In a landmark series published in 1933 [6] in the United States, of 227 cases, 62% of hemorrhage were caused by rupture of the internal carotid artery. The outcome was often fatal. Carotid artery rupture rarely occurs without warning: most patients (including the three in our experience) have premonitory manifestations related to fissuring of the artery and alerting to the dreaded possibility of arterial rupture. These premonitory manifestations consist of an increase in the size of the swelling in the upper neck, palsy of one or more of the above-listed cranial nerves, red blood coming from the posterior pillar through a fissure in the artery, and development of a pulsating haematoma at the posterior wall of the oropharynx. These manifestations should lead to emergency surgery consisting in ligation of the internal carotid artery above the bulb, or if the inflammation is too severe to allow this procedure, in ligation of the carotid artery. Both procedures are life saving and often well tolerated in young patients. Treatment rests both on antimicrobial therapy given according to the same rules as in peritonsillar abscesses and on surgery. However, the intra-oral approach does not provide adequate access to the lesion and carries a risk of vascular injury. Consequently, the lesion must be approached through the neck. In a patient with a prestyloid abscess, the incision should curve around the angle of the mandible to expose the abscess above and medial to the posterior belly of the digastric muscle and the stylohyoid muscle. If the abscess is in the restrostyloid space, the incision is made anterior to the sternomastoid muscle to provide easy and rapid access to the neurovascular bundle of the neck. The incision should be long enough to ensure good control of the common carotid artery and carotid bifurcation.

Extensive Cervical Cellulitis and Necrotising Fasciitis

These are currently the most severe regional complications of streptococcal pharyngitis. In some cases, a beta-haemolytic streptococcus is the only organism recovered, although anaerobes such as Peptococcus, Peptostreptococcus, or Bacteroides spp. are often present also. Failure to recover anaerobes does not

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mean that these organisms are absent. Cellulitis can be preceded by one of the peritonsillar or parapharyngeal infections described above but often seems to occur de novo, without a previous phase of collection. The cellulitis spreads to all the anatomic spaces in the neck, including the neurovascular compartment, parotid compartment, submandibular space, prevertebral and retrovisceral spaces, thyroid compartment, and supraclavicular space. The infection tracks along the prevertebral and retrovisceral space to the opposite side and to the posterior and anterior mediastinum. At surgery, a variable combination of purulent extensions filling all the anatomic spaces and disrupting the neck fascia is found. In addition, necrosis can occur in any tissue, including the striated muscles (such as the pharyngeal constrictors and oesophageal muscles), the salivary glands, the thyroid gland, and the laryngeal and tracheal cartilaginous structures. Venous thrombosis is common and can affect veins of any size. Rupture can occur in any of the segments of the carotid artery. In our experience, collections of gas (gas gangrene) form in one-fourth of cases as multiple small gas bubbles that puff up the muscle fascia and subcutaneous tissue. These gas collections produce crepitus upon palpation. They are readily seen on plain radiographs and on CT scans. Clinically, diagnosis is easy to suspect based on the combination of constitutional symptoms and of changes in the appearance of the neck. Constitutional Symptoms Fever is present in every case (38.5–39⬚C), and general health is severely deteriorated. Septic shock can be present on arrival at the hospital. Local and Regional Manifestations

They consist of symptoms including pharyngeal pain, cervical pain, a variable degree of trismus in some patients and, above all, laryngeal dyspnea reflecting spread of the oedema to the laryngeal vestibule. The dyspnea can be so severe as to require endotracheal intubation before transport to the hospital. The presence of polypnea or chest pain should prompt a search for thoracic complications (purulent pleural effusion, pericarditis). Physical Findings Changes in the appearance of the neck are not described in detail in articles on cervical cellulitis. Nevertheless, we have managed 59 cases [unpubl. data] that fell into two very different groups in terms of their clinical presentation and course. (1) Gas gangrene occurs in about one-fourth of cases and produces a very moderate swelling of the soft tissues in the neck, slightly blunting the bony and

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cartilaginous prominences. The skin shows no evidence of inflammation. Crepitus is heard upon palpation, denoting the existence of gas under the skin. The gas effusion spreads very quickly, reaching the other side of the neck and the upper chest within a few hours. Imaging studies and surgical findings confirm the diagnosis. In our experience, these forms with gas gangrene were more likely to cause mediastinitis and, consequently, carried a worse prognosis. (2) Lymph node phlegmon produces a very different picture. Development of the manifestations is slower, sometimes taking a few days rather than a few hours. A painful swelling is found at the side of the neck. The skin is tight, inflammatory, and painful to palpation. The swelling slowly spreads to the other side and can extend down to the anterior aspect of the clavicle. Some forms are intermediate between these two main categories. They are best diagnosed by imaging studies rather than by palpation of the neck. The diagnosis rests on the coexistence of severe constitutional manifestations, a variable combination of symptoms, and changes in the appearance of the neck suggesting either cellulitis with gas gangrene or a lymph node phlegmon with a painful inflammatory neck swelling, in a patient with a recent history of acute painful febrile pharyngitis.

Investigations

If the patient’s hemodynamic status is satisfactory and if CT is available, this investigation should be performed within 1 h after admission. The neck and chest should be scanned. Multiple collections of pus are found, confirming the diagnosis and providing a road map for the surgeon. Effusions of air are seen in some cases. On the chest images, the mediastinum, pericardium, pleural cavity, and pulmonary parenchyma should be examined. In patients with lymph node phlegmon, the course is slower, leaving a little more time to perform CT. A blood culture, renal function tests, and routine blood tests should be performed.

Treatment and Course

The patient is admitted to the intensive care unit and given the same antimicrobials as in other situations, i.e. drugs directed to streptococci and possible coexisting anaerobes. Again, the mainstay of treatment is surgical drainage of the collections of pus. However, necrotic tissues must be removed also. Surgery should be performed within the first few hours after admission in patients with gas formation. In lymph node phlegmon without evidence of

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hemodynamic instability, there is time to prepare the patient and to obtain a cervical and thoracic CT under good conditions. Type of Surgical Drainage If CT is feasible, the results serve as a road map to the surgeon during exploration of the neck. At the least, a curved incision should be made along the side of the neck, from the tip of the mastoid process to the suprasternal area. All collections visualised by CT should be drained. When CT cannot be performed, we use a bilateral U-shaped neck incision to explore all the anatomic spaces in the neck, including the retrovisceral and pretracheal spaces. All necrotic tissues, regardless of their anatomic nature, should be removed, as well as any veins that seem thrombotic. At the end of the procedure, irrigationlavage systems are implanted and the skin flap is put back into place over drapes soaked in antiseptics that isolate the flap from the deeper structures. The flap can be lifted daily to check the condition of the underlying tissues. The patient, ventilated through an endotracheal tube, is returned to the intensive care unit. Irrigation-lavage of the wound is performed several times a day. The appearance of the neck is checked by lifting the skin flap. If further necrosis occurs or if there is an abundant discharge of pus indicating inadequate drainage, surgery is repeated, as many times as necessary. Apart from monitoring the local condition, detection of intrathoracic complications is the main concern. Plain radiographs, an electrocardiogram, and an ultrasonogram ensure detection of pleural and pericardial effusions, which require simple conventional drainage. Conversely, spread of the infection to the upper anterior or posterior mediastinum occurs insidiously. Persistence or recurrence of the evidence of sepsis in a patient whose neck wound is adequately drained, or development of hemodynamic instability requiring vasopressor administration, should suggest the diagnosis. If the hemodynamic condition of the patient is adequate, CT should be considered indispensable to the diagnosis. In some cases, however, surgical exploration of the mediastinum through a thoracic incision is decided based on a clinical presumption.

Prognosis

Cellulitis of the neck, particularly with spread to the mediastinum [7–11], remains the most severe complication of streptococcal pharyngitis. The overall prognosis depends on the time to diagnosis and surgical drainage, on whether gas formation is present, and on whether the mediastinum is involved. Both gas formation and delayed diagnosis and drainage increase the risk of mediastinitis. When all stages in the course of the infection were

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combined, only 7 (12%) of our 59 patients died. Mortality rates seem considerably higher in other series. As mentioned above, the risk of death is closely dependent on whether the mediastinum is involved. In patients with established mediastinitis, the mortality rate is still about 16–37%. Early diagnosis and early surgical treatment improve the overall prognosis of these complications, which remain fatal in many patients despite adequate management.

References 1 2 3 4 5 6 7 8 9 10 11

Savolainen S. Jousimies-Somer HR, Makitie AA, et al: Peritonsillar abscess: Clinical and microbiologic aspects and treatment regimens. Arch Otolaryngol Head Neck Surg 1993;119:521–524. Ophir D, Bawnik J, Poria Y, et al: Peritonsillar abscess: A prospective evaluation of outpatient management by needle aspiration. Arch Otolaryngol Head Neck Surg 1988;114:661–663. Stringer SP, Schaefer SD, Close LG: A randomized trial for outpatient management of peritonsillar abscess. Arch Otolaryngol Head Neck Surg 1988;114:296–298. Shoemaker M, Lampe RM, Weir MR: Peritonsillitis: Abscess or cellulitis? Pediatr Infect Dis 1986;5:435–439. Patel KS, Ahmad S, O’Leary G, et al: Role of computed tomography in the management of peritonsillar abscess. Otolaryngol Head Neck Surg 1992;107:727–732. Salinger S, Pearlman S: Hemorrhage from pharyngeal and peritonsillar abscesses. Arch otolaryngol 1933;18:464–509. Marty-Ane CH, Alouzen M, Airic P, et al: Descending necrotizing mediastinites: Advantage of mediastinal drainage with thoracotomy. J Thorac Cardiovasc Surg 1994;107:55–61. Mathieu D, Neviere R, Teillon C, Chagnon JC, Lebleu N, Wattel F: Cervical necrotizing fascitis: Clinical manifestation and management. Clinical Infectious Diseases. 1995;21:51–56. Colmenero-Ruiz C, Labajo A, Diez R, Yanez Vilas I, Paniagua J: Thoracic complications of deeply situated serious neck infections. J Cranio-Maxillo-Facial Surg 1993;21:76–81. De Backert T, Bossuyt, Schoenaers J: Management of necrotizing fasciitis in the neck. J CranioMaxillo-Facial Surg 1997;24:366–371. Alessandro Brunelli MD, Armando Sabbatini MD, Gianbattista Catalini MD: Descending necrotizing mediastinitis. Arch Otolaryngol Head Neck Surg 1996;122:1326–1329.

P. Gehanno, Service ORL Hôpital Bichat 46 rue Henri Huchard 75018 Paris (France) Tel. ⫹33 1 40 257751, Fax ⫹33 1 42 286182

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Pechère JC, Kaplan EL (eds): Streptococcal Pharyngitis. Issues Infect Dis. Basel, Karger, 2004, vol 3, pp 103–114

Antibiotic Treatment for Streptococcal Pharyngitis Penicillin First?

Juan C. Salazar Division of Pediatric Infectious Diseases, University of Connecticut School of Medicine, Connecticut Children’s Medical Center, Hartford, Conn., USA

The main goals of therapy for group A ␤-hemolytic streptococcus (Streptococcus pyogenes) pharyngitis (GABHS) are to avoid suppurative complications (peritonsillar or retropharyngeal abscess, cervical lymphadenitis, mastoiditis, sinusitis and otitis media), prevent rheumatic fever, abort person to person transmission, and diminish the signs and symptoms associated with this disease. Oral and parenteral penicillins, first through third generation oral cephalosporins, macrolides, and clindamycin have all been studied and found to be effective in meeting the majority of these goals. Nevertheless, leading authorities continue to recommend penicillin as the drug of choice for GABHS pharyngitis [1]. This recommendation is based on penicillin’s efficacy, narrow spectrum of antimicrobial activity, the infrequency of associated adverse reactions, and its low cost. In addition penicillin remains the only antibiotic that has been shown to effectively prevent primary [2, 3] and secondary attacks of rheumatic fever [4]. In the following pages we will analyze the scientific and practical merits of this recommendation. Historical Perspective

In the midst of World War II came an achievement that would save the lives of millions and mark the dawn of modern medicine. Although penicillin had been discovered in 1928 by British bacteriologist Alexander Flemming in his London laboratory, the active substance was difficult to extract and preserve. Out of frustration Fleming shelved his discovery. A decade later, a pair of

British scientist (physiologist Ernest Chain and biochemist Howard Florey) revived Fleming’s work and managed to produce sufficient quantities of the compound to determine that penicillin injections killed numerous bacteria in laboratory animals. During this time England was under heavy aerial bombardment making research projects very difficult if not impossible to complete. Intuitively, the Oxford scientists sought help from colleagues in the United States. One of their collaborators was Dr. Martin Henry Dawson from Columbia University College of Physicians and Surgeons. Dr. Dawson and his associates successfully used crudely processed penicillin to treat infected patients. They presented their work at the 1941, 33rd annual meeting of the American Society for Clinical Investigation in Atlantic City, New Jersey. Convinced that this ‘wonder drug’ would save the lives of injured American soldiers in Europe, then United States President Franklin D. Roosevelt asked the pharmaceutical industry to start massive production of the compound. However, because of a multitude of technical difficulties considerable production of penicillin could not be established until the spring of 1942. When it finally became available penicillin’s clinical impact was astonishing. Bacterial pneumonia, meningitis and endocarditis, previously highly fatal, could in fact be treated. European and American investigators showed that penicillin was also effective in preventing the suppurative complications of GABHS and far superior to sulfonilamides in eradicating the bacterium from the throat of patients with pharyngitis [5]. Although a number of other antibiotics have been introduced for the treatment of GABHS since penicillin’s commercialization, it continues to be the drug of choice for treating pharyngitis and successfully preventing rheumatic fever. Moreover, studies of antibiotic sensitivity have not demonstrated a single GABHS penicillin resistant strain [6].

Pharmacology

Chemical Composition and Mode of Action Penicillin is a dipeptide, 6 amino penicillanic acid, which contains a ␤-lactam ring, a thiazolidone ring and a side chain. Acylation of the side chain with a benzyl radical produces penicillin G, and acylation with a phenoxymethyl radical produces penicillin V. In actively dividing bacteria, such as GABHS, penicillin inhibits certain enzymes that create the cross linkage between the peptide chains and thereby prevents development of the peptidoglycan containing cell wall. These enzymes are termed the penicillin-binding proteins. In addition penicillin activates the endogenous autolytic system of bacteria, a process that initiates cell lysis and death.

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Pharmacodynamics/Pharmacokinetics The natural penicillins were the first agents in the penicillin family to be introduced for clinical use. One such compound, benzylpenicillin (penicillin G) has been extensively utilized since its introduction. Penicillin G can be administered orally, intravenously, intrathecally, or intramuscularly. Intramuscular (im) penicillin G can be administered as a repository salt (procaine or benzathine) to achieve a longer duration of maximal levels. For instance benzathine penicillin G at a dose of 1.2 million U results in serum levels of 0.15 ␮g/ml on day 1, 0.03 ␮g/ml on day 14, and 0.003 ␮g/ml on day 32 [7]. These levels are usually effective, as they meet or surpass minimum inhibitory concentration (MIC) for most of the bacteria for which penicillin is currently used. Penicillin G can also be given orally but in its parenteral formulation it is rapidly degraded by gastric acid. Phenoxymethyl penicillin (penicillin VK) is an oral form of penicillin G that resists gastric acid. Penicillin VK is absorbed in the upper part of the small bowel and produces peak serum levels within one hour. For example, following a dose of 600 mg to adults, serum levels of over 4.0 ␮g/ml are achieved in less than an hour. Oral penicillin V, given as a single 500-mg dose, achieves serum levels of over 3.0 to 5.0 ␮g/ml in less than an hour [8]. Dosage and Route of Administration for GABHS Pharyngitis Penicillin can be given either orally or parenterally for the treatment of GABHS pharyngitis. Table 1 shows WHO recommended penicillin and erythromycin dosages for treatment of GABHS pharyngitis. The oral potassium salt of phenoxymethyl penicillin (penicillin VK) has largely replaced intramuscular benzathine penicillin G for treatment of acute streptococcal pharyngitis. Twice-daily dosing with oral penicillin V may be adequate therapy, but a once-daily dose is not [9]. A 10-day course of oral penicillin has been shown to be superior to a 5- or 7-day course of therapy [10, 11]. Benzathine penicillin G continues to be the preferred formulation for patients who are unlikely to complete a full 10-day course of oral therapy. This may be particularly relevant for many developing countries were rheumatic fever remains unchecked. Orally administered aminopenicillins (ampicillin and amoxicillin) are equivalent but not superior to penicillin for GABHS pharyngitis [12]. Amoxicillin is often used in place of oral penicillin V in young children; the efficacy appears equal. This choice is primarily related to acceptance of the taste of the suspension. In a well-designed study, Feder et al. [13] recently corroborated that once a day oral amoxicillin (750 mg once daily) for 10 days was equivalent to penicillin VK (250 mg three times a day) for the treatment of streptococcal pharyngitis. In both the penicillin and amoxicillin cohorts microbiologic failure rates were low.

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Table 1. Antimicrobial therapy for group A ␤-hemolytic streptococcal pharyngitis Drug

Dose

Duration

Penicillin V (oral)

250 mg 2 or 3 times daily for children 250 mg 3–4 times daily or 500 mg 2 times daily for adolescents and adults

10 days

Penicillin G benzathine (intramuscular)

600,000 units for ⬍27 kg 1,200,000 units for ⬎27 kg

1 dose

Amoxicillin (oral)*

125 mg three times daily for ⬍15 kg 250 mg three times daily for ⬎15 kg

10 days

20–40 mg/day, divided into 2–4 doses (maximum 1 g per day)

10 days

Erythromycin ethylsuccinate (oral)

40 mg/day, divided into 2–4 doses (maximum 1 g per day)

10 days

Clarithromycin (oral)

children: 7.5 mg/kg divided in 2 doses adults: 250 mg twice a day

10 days

Azithromycin (oral)

children: 12 mg/kg single dose adults: 500 mg first day, then 250 mg a day for 4 days

5 days

Clindamycin (oral)

20–30 mg/kg/day divided in three doses

10 days

Cephalosporins (oral)

varies with agent

10 days

Penicillin allergic patients Erythromycin estolate (oral)

*Amoxicillin is often used in place of oral penicillin V in young children; efficacy appears to be equal. This choice is primarily related to acceptance of the taste of the suspension.

Side Effects Allergic or hypersensitivity reactions are thought to be the most common side effects associated with penicillin. An estimated 3% of the population may be allergic to penicillin. The frequency is least when given orally, higher with intravenous administration, and much higher when combined with procaine. Patients allergic to one form of penicillin should be considered allergic to the other members of the family. Allergic patients should receive erythromycin or a similar compound. Fortunately, true anaphylactic reactions to penicillin are rare, occurring in 0.004% of the instances of penicillin use. A skin test should be used for predicting an immediate hypersensitivity reaction, including anaphylaxis, when a history of a possible severe penicillin adverse event is unclear.

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Clinical Efficacy of Penicillin for Treatment of GABHS

Researchers have known for over four decades that rheumatic fever is a sequel to group A streptococcal upper respiratory infection. It is well accepted that up to 3% of untreated individuals with bona fide, acute streptococcal pharyngitis will develop rheumatic fever unless they are treated [3]. It is also known that the first line of defense against rheumatic fever is treatment of acute GABHS upper respiratory tract infection. In spite of the more than 40-year role as the therapy of choice for acute streptococcal pharyngitis some have questioned whether penicillin should remain the drug of choice based on studies showing an apparent decreased effectiveness of penicillin therapy [14]. The more controversial features will be reviewed and critiqued here. Prevention of Rheumatic Fever Classic investigations carried out in the late 1940s at Fort Warren Air Force Base, Wyoming, demonstrated that treatment of acute streptococcal pharyngitis, with intramuscular procaine penicillin G in peanut or sesame oil containing 2% aluminum monostereate, effectively prevented acute rheumatic fever [2, 3]. Prevention of rheumatic fever was highest when post treatment GABHS isolation was lowest. These remain the only placebo-controlled studies that document the efficacy of an antimicrobial agent to prevent rheumatic fever. Benzathine penicillin G has also been shown to be effective in prevention of the initial attack of rheumatic fever following an episode of GABHS pharyngitis [4]. Benzathine penicillin G also prevents recurrent attacks of rheumatic fever in patients with a previous diagnosis of the disease [15]. These penicillin studies form the basis for the current assumption that other agents that reliably eradicate GABHS from the upper respiratory tract, including all oral regimens commonly used today, are effective primary prevention of rheumatic fever. Eradication of GABHS Several reports published in the latter part of the 1980s, suggested that bacteriologic failure rates following 10 days of oral penicillin treatment had increased. Not convinced with the evidence, Markowitz et al. [16] analyzed the bacteriologic failure rates associated with oral penicillin. The authors evaluated 51 penicillin studies that met criteria that would ensure comparability between the protocols. In their analysis no significant differences were observed between studies reported from 1953 to 1979 and those reported from 1980 to 1993 (table 2). They concluded that oral penicillin was as effective in the 1980s and early 1990s as it was 40 years earlier for the treatment of GABHS streptococcal pharyngitis.

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Table 2. Bacteriologic failure rates after oral penicillin treatment for GABHS pharyngitis Mean failure rates no studies

days 1–14

days 1–60

Including all studies 1953–1993 1953–1979 1980–1993

51 29 22

11.6 11.1 12.4

17.3 16.9 17.7

With serotyping 1953–1993 1953–1979 1980–1993

32 18 14

11.3 10.5 12.0

15.2 14.0 19.9

Adapted from Markowitz et al. [16]

Numerous studies comparing oral penicillin V to oral cephalosporins have been published [17, 18]. A 1991 meta-analysis by Pichichero and Margolis [19] summarized 19 of those trials. This meta-analysis was both controversial and provocative. Based on their findings, the authors concluded that cephalosporins were more effective than penicillin and could therefore replace penicillin as the treatment of choice. In their report, the overall bacteriologic cure rate for penicillin was 84% (95% CI, 91–94%) compared with 92% (95% CI, 91–94%) among patients treated with cephalosporins (P ⬍ 0.001). However, this study has been extensively critiqued and discounted for its methodological flaws by leading authorities in the field [20, 21]. Only 3 of 19 studies that were included fulfilled criteria necessary to truly measure eradication. Not all the studies were randomized, adherence was not always assessed and serotyping was not always done at the onset and completion of therapy. In the only three studies were these criteria were met cephalosporins were better than penicillin therapy in eradicating GABHS, but only by 4–6%. A recent well designed study where serious efforts were made to avoid including GABHS carriers, penicillin compared favorably to cephalosporin and amoxicillin-clavulanate [22]. The above findings to determine bring to light a very important issue that needs special attention when performing clinical trials to determine antibiotic efficacy for treatment of GABHS. That is to try not to include in the study streptococcal carriers experiencing intercurrent viral pharyngitis. Because it is difficult to always distinguish between these two kinds of patients, carriers may be inadvertently included in clinical studies. Since cephalosporins are more effective in eradicating the carrier state, comparative trials disservice

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penicillin [23]. This may occur because organisms present in the upper respiratory tracts of GABHS carriers are not rapidly dividing when compared with those in the throat of acutely infected individuals. Alternatively or in addition, the presence of intracellular streptococci in carriers may make eradication with penicillin more difficult because it does not effectively penetrate into cells [24]. Particularly for children in developing countries the unfeasibility of routinely utilizing expensive cephalosporins or macrolides for GABHS pharyngitis make this recommendation unworkable and not cost effective. Adherence A real important cause of true penicillin treatment failure in GABHS pharyngitis is poor adherence to the prescribed antibiotic [25]. Oral penicillin is generally administrated three to four times a day and the recommendation is usually made that the antibiotic be taken on an empty stomach. This regimen can be impractical for families where both parents work, for children who attend daycare and for children living in underserved areas of the world where proper storage facilities for the antibiotic may not be available. In addition, a complex regimen is simply difficult to remember. Not surprisingly, antibiotic regimens that require multiple daily doses, particularly with the avoidance of meals, may indeed lead to diminished adherence. Simplified regimens using penicillin twice a day have been shown to be effective and can therefore enhance adherence [9]. In developing countries a single dose of benzathine penicillin G may be the most effective manner to assure antibiotic levels in pharyngeal and tonsillar tissue that surpass streptococcal MICs for at least 10 days. Copathogenicity Some investigators have suggested that ␤-lactamase production by normal flora in the upper respiratory tract may be responsible for the greater occurrence of GABHS pharyngitis treatment failure with penicillin [26–28]. The proposed mechanism of action involves elaboration of ␤-lactamase by indigenous flora, including Staphylococcus aureus, Haemophilus influenza, Moraxella catarrhalis and a variety of anaerobic species, which thereby provide ‘protection’ of the GABHS from penicillin by inactivation of the antibiotic. However, findings from these studies have been inconclusive and inconsistent. A recent study [22] did not demonstrate that ␤-lactamase production was associated to bacteriologic treatment failure. The investigators conducted a prospective, randomized clinical trial in which 462 patients with acute pharyngitis and a positive culture for GABHS were randomly assigned to receive a first generation cephalosporin (cefadroxil) or penicillin. For patients

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classified as likely to have bona fide GABHS pharyngitis, there was no difference in bacteriologic treatment success rates between the two treatment groups (95 and 94%, respectively). Among patients classified clinically as likely to be streptococcal carriers, bacteriologic treatment success rates in cefadroxil and penicillin groups were 92 and 73%, respectively. The presence of ␤-lactamase producing ‘copathogenic’ pharyngeal flora had no consistent effect on bacteriologic eradication rates among patients in either penicillin or cefadroxil treatment groups or among patients having either GABHS pharyngitis or streptococcal carriage. Antibiotic-associated eradication of normal non-pathogenic flora may also lead to penicillin failure. Alpha-streptococci in particular may present colonization by GABHS. Much of this interference seems to occur through the action of bacteriocins, which are protein or protein-complex antibiotics produced by a variety of bacterial species. Penicillins such as oral ampicillin have been shown to potently suppress alpha-streptococci and thus may impair this protective mechanism. Crowe’s group showed in the early 1970s that children who did not become colonized with GABHS had significantly greater anti-GABHS inhibitory activity in their pharyngeal flora than either before or during colonization with GABHS. These observations led to the suggestion that bacterial interference by pharyngeal flora may influence the outcome of penicillin treatment of GABHS pharyngitis. However, the role of bacterial interference in treatment failures has not been clearly established [29–31]. In a recent study, Gerber et al. [22] found no evidence or bacterial interference in relation with treatment success or failure in GABHS pharyngitis. In their study, the presence of bacteriocin-producing pharyngeal flora had no consistent effect on bacteriologic eradication rates among patients treated with either penicillin or a first-generation oral cephalosporin. Antimicrobial Resistance Penicillin resistance has not been a significant problem in the treatment of GABHS [1, 6]. In fact, there has yet to be a single, well-documented report of a clinical isolate resistant to penicillin. Several investigators have searched for penicillin resistance in isolates of GABHS and in all these studies the isolates were extremely sensitive to penicillin G (MIC ⬍0.06 ␮g/ml). Coonan and Kaplan [32] examined GABHS pharyngeal isolates from 282 patients for antibiotic susceptibility; 276 were from patients with uncomplicated pharyngitis and 6 were associated with documented cases of acute rheumatic fever. An additional 43 isolates collected during the same period from patients with severe or invasive GABHS were also included. The MIC for penicillin G of 90% of the isolates was ⬍0.012 ␮g/ml; only one isolate had an MIC of 0.024 ␮g/ml. There were no differences in penicillin sensitivity of GABHS

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isolates from patients with severe or invasive disease compared with those isolated from patients with uncomplicated pharyngitis. Although resistance has not been documented, important questions about available intramuscular benzathine penicillin preparations remain to be answered. A number of published reports have demonstrated a reduced duration of adequate serum penicillin levels after injection of recommended doses of repository benzathine penicillin G when compared to early studies [33]. A recent report by Zaher et al. [34] indicates that variations in manufacture of the product can adversely influence both peak levels and duration of adequate serum levels. Properly manufactured benzathine penicillin is critical in both the therapy of GABHS and the prevention of rheumatic fever. Contrary to the lack of GABHS resistance to penicillin, decreased susceptibility to sulfa drugs and macrolides has been well documented [35, 36]. Inappropriate overuse of erythromycin in Japan during the 1960s and 1970s, resulted in more than half of GABHS developing resistance to erythromycin. More recently, documentation of erythromycin resistance in northern Europe has also been described. Fewer than 5% of GABHS isolated in the United States have been shown to be resistant to erythromycin [32]. Sulfonamides and tetracyclines are not recommended for treatment because of the higher rates of resistance to these agents and the frequent failure of these agents to eradicate even susceptible organisms from the pharynx. Penicillin Tolerance Penicillin tolerance, or diminished killing of bacteria by growth-inhibiting concentrations of penicillin has been suggested as another reason for penicillin failures. Penicillin tolerance is usually demonstrated in vitro by a significant (⬎32-fold) disparity seen between the minimum bactericidal concentration (MBC) and the MIC of the organism and by overall decreases in killing rates. Because many laboratory variables influence MBC values studies of penicillintolerant GABHS are difficult to compare and interpret. One study by Kim and Kaplan [37] reported 25% tolerant group A streptococcal strains from patients who had failed penicillin therapy. At the present time there is not sufficient evidence to support a correlation between in vitro penicillin tolerance and treatment failure. On the other hand, evidence to exclude penicillin tolerance is also lacking and therefore this phenomenon cannot be fully ruled out.

Conclusions

Periodic assessment of therapeutic options for GABHS pharyngitis appears appropriate. At the time of this writing, oral penicillin V administered

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two to three times daily for 10 days continues to be the treatment of choice and as the oral standard against which other proposed treatments must be measured [1]. The efficacy of intramuscular benzathine penicillin as a single dose for acute streptococcal pharyngitis has not been convincingly challenged [38, 39]. Other agents (cephalosporins and macrolides) may be associated with slightly higher bacteriologic eradication rates than penicillin. However, because of penicillin’s narrow spectrum of antimicrobial activity, the infrequency with which it produces adverse reactions, and its modest cost, it remains the first choice, particularly in the developing world were rheumatic fever remains rampant.

References 1 2 3

4

5 6

7 8 9 10 11

12

13 14 15

Bisno AL, Gerber MA, Gwaltney JM Jr., Kaplan EL, Schwartz RH: Practice guidelines for the diagnosis and management of group A streptococcal pharyngitis. Clin Infect Dis 2002;35:113–125. Denny FW, Wannamaker LW, Brink DN, Randall EL, Rammelkamp CH Jr, Custer EA: Prevention of rheumatic fever: Treatment of the preceding streptococcic infection. JAMA 1950;143:151–153. Wannamaker LW, Rammelkamp CH Jr, Denny FW, Brink WR, Houser HB, Hahn EO, et al: Prophylaxis of acute rheumatic fever by treatment of the preceding streptococcal infection with various amounts of depot penicillin. Am J Med 1951;10:673–695. Chamovitz R, Catanzarro FJ, Stetson CA, Rammelkamp CH Jr: Prevention of rheumatic fever by treatment of previous streptococcal infections. I. Evaluation of benzathine penicillin G. N Engl J Med 1951;251:466–471. Jersild T: Penicillin therapy in scarlet fever and complicating otitis. Lancet 1948;671–673. Kaplan EL, Johnson DR, Del Rosario MC, Horn DL: Susceptibility of group A beta-hemolytic streptococci to thirteen antibiotics: Examination of 301 strains isolated in the United States between 1994 and 1997. Pediatr Infect Dis J 1999;18:1069–1072. Wright AJ: The penicillins. Mayo Clin Proc 1999;74:290–307. Sabath LD: Phenoxymethylpenicillin (penicillin V) and phenthicillin. Med Clins N Am 1970;54:1101–1111. Gerber MA, Spadaccini LJ, Wright LL, Deutsch L, Kaplan EL: Twice-daily penicillin in the treatment of streptococcal pharyngitis. Am J Dis Child 1985;139:1145–1148. Gerber MA, Randolph MF, Chanatry J, Wright LL, De Meo K, Kaplan EL: Five vs ten days of penicillin V therapy for streptococcal pharyngitis. Am J Dis Child 1987;141:224–227. Schwartz RH, Wientzen RL Jr Pedreira F, Feroli EJ, Mella GW, Guandolo VL: Penicillin V for group A streptococcal pharyngotonsillitis: A randomized trial of seven vs ten days’ therapy. JAMA 1981;246:1790–1795. Stillerman M, Isenberg HD, Facklam R: Treatment of pharyngitis associated with group A streptococcus: Comparison of amoxicillin and potassium phenoxy methyl penicillin. J Infect Dis 1974;129:S169–S177. Feder HM Jr, Gerber MA, Randolph MF, Stelmach PS, Kaplan EL: Once-daily therapy for streptococcal pharyngitis with amoxicillin. Pediatrics 1999;103:47–51. Pichichero ME: Cephalosporins are superior to penicillin for treatment of streptococcal tonsillopharyngitis: Is the difference worth it? Pediatr Infect Dis J 1993;12:268–274. Wood HC, Feinstein AR, Taranta A, Epstein JA, Simpson R: Rheumatic fever in children and adolescents: A long-term epidemiologic study of subsequent prophylaxis, streptococcal infections, and clinical sequelae. III. Comparative effectiveness of three prophylaxis regimens in preventing streptococcal infections and rheumatic recurrences. Ann Intern Med 1964; 60(suppl 5):31–46.

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16 17

18

19

20 21 22 23

24 25 26 27

28

29

30

31

32 33

34

35 36 37

Markowitz M, Gerber MA, Kaplan EL: Treatment of streptococcal pharyngotonsillitis: Reports of penicillin’s demise are premature. J Pediatr 1993;123:679–685. Gooch WM III, Swenson E, Higbee MD, Cocchetto DM, Evans EC: Cefuroxime axetil and penicillin V compared in the treatment of group A beta-hemolytic streptococcal pharyngitis. Clin Ther 1987;9:670–677. McCarty JM: Comparative efficacy and safety of cefprozil versus penicillin, cefaclor and erythromycin in the treatment of streptococcal pharyngitis and tonsillitis. Eur J Clin Microbiol Infect Dis 1994;13:846–850. Pichichero ME, Margolis PA: A comparison of cephalosporins and penicillins in the treatment of group A beta-hemolytic streptococcal pharyngitis: A meta-analysis supporting the concept of microbial copathogenicity. Pediatr Infect Dis J 1991;10:275–281. Shulman ST, Gerber MA, Tanz RR, Markowitz M: Streptococcal pharyngitis: The case for penicillin therapy. Pediatr Infect Dis J 1994;13:1–7. Gerber MA: Treatment failures and carriers: Perception or problems? Pediatr Infect Dis J 1994;13:576–579. Gerber MA, Tanz RR, Kabat W, Bell GL, Siddiqui B, Lerer TJ, et al: Potential mechanisms for failure to eradicate group A streptococci from the pharynx. Pediatrics 1999;104:911–917. Tanz RR, Shulman ST, Sroka PA, Marubio S, Brook I, Yogev R: Lack of influence of betalactamase-producing flora on recovery of group A streptococci after treatment of acute pharyngitis. J Pediatr 1990;117:859–863. LaPenta D, Rubens C, Chi E, Cleary PP: Group A streptococci efficiently invade human respiratory epithelial cells. Proc Natl Acad Sci USA 1994;91:12115–12119. Dajani AS: Adherence to physicians’ instructions as a factor in managing streptococcal pharyngitis. Pediatrics 1996;97:976–980. Pichichero ME: Controversies in the treatment of streptococcal pharyngitis. Am Fam Physn 1990;42:1567–1576. Tack KJ, Hedrick JA, Rothstein E, Nemeth MA, Keyserling C, Pichichero ME: A study of 5-day cefdinir treatment for streptococcal pharyngitis in children. Cefdinir Pediatric Pharyngitis Study Group. Arch Pediatr Adolesc Med 1997;151:45–49. Pichichero ME, Mclinn SE, Gooch WM III, Rodriguez W, Goldfarb J, Reidenberg BE: Ceftibuten vs. penicillin V in group A beta-hemolytic streptococcal pharyngitis. Members of the Ceftibuten Pharyngitis International Study Group. Pediatr Infect Dis J 1995;14:S102–S107. Roos K, Grahn E, Holm SE, Johansson H, Lind L: Interfering alpha-streptococci as a protection against recurrent streptococcal tonsillitis in children. Int J Pediatr Otorhinolaryngol 1993;25:141–148. Brook I, Gober AE: Role of bacterial interference and beta-lactamase-producing bacteria in the failure of penicillin to eradicate group A streptococcal pharyngotonsillitis. Arch Otolaryngol Head Neck Surg 1995;121:1405–1409. Brook I, Gober AE: Persistence of group A beta-hemolytic streptococci in toothbrushes and removable orthodontic appliances following treatment of pharyngotonsillitis. Arch Otolaryngol Head Neck Surg 1998;124:993–995. Coonan KM, Kaplan EL: In vitro susceptibility of recent North American group A streptococcal isolates to eleven oral antibiotics. Pediatr Infect Dis J 1994;13:630–635. Kaplan EL, Berrios X, Speth J, Sieffereman T, Guzman B, Quesny F: Pharmacokinetics of benzathine penicillin G: Serum levels during the 28 days after intramuscular injection of 1,200,000 units. J Pediatr 1989;115:146–150. Zaher S, Kassem A, Abou-Shlieb H, Kholy AE, Kaplan EL: Differences in serum penicillin concentrations following intramuscular injection of benzathine penicillin G from different manufactures. J Pharm Med 1992;2:17–23. Seppala H, Nissinen A, Jarvinen H, Huovinen S, Henriksson T, Herva E, et al: Resistance to erythromycin in group A streptococci. N Engl J Med 1992;326:292–297. Bassetti M, Manno G, Collida A, Ferrando A, Gatti G, Ugolotti E, et al: Erythromycin resistance in Streptococcus pyogenes in Italy. Emerg Infect Dis 2000;6:180–183. Kim KS, Kaplan EL: Association of penicillin tolerance with failure to eradicate group A streptococci from patients with pharyngitis. J Pediatr 1985;107:681–684.

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Kaplan EL, Johnson DR: Unexplained reduced microbiologic efficacy of intramuscular penicillin G and of oral penicillin V in eradicating Group A Streptococci from children with acute pharyngitis. Pediatrics 2001;108:1180–1186. Stollerman GH, Kaplan EL, Johnson DR: Penicillin failures?! Pediatrics 2002;109:1190–1192.

J.C. Salazar, MD, MPH Division of Pediatric Infectious Diseases University of Connecticut School of Medicine, Connecticut Children’s Medical Center 282 Washington Street, Hartford, CT 06033 (USA) Tel: ⫹1 860 545-9490, Fax: ⫹1 860 545-9371, E-Mail [email protected]

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Antibiotic Treatment for Streptococcal Pharyngitis What is the Role of Oral Cephalosporins

Dieter Adama, Manfred Helmerkingb a

Department of Antimicrobial Therapy, Dr. V. Haunersches Children’s Hospital, University of Munich, and bAlgora Clinical Research, Munich, Germany

Antibiotic treatment of tonsillopharyngitis caused by group A betahemolytic streptococcus (GABHS) can have several different aims: prevention of acute rheumatic fever (ARF) and acute glomerulonephritis, faster resolution of acute clinical signs and symptoms, prevention of suppurative complications (e.g. peritonsillar abscess, cervical lymphadenitis, or mastoiditis), and eradication of GABHS to reduce transmission to family members, classmates and other close contacts [1, 2]. Results from first studies in the treatment of GABHS tonsillopharyngitis with various long-acting formulations of parenteral penicillins have shown a dramatic reduction of acute rheumatic fever among military recruits compared to an untreated control group [3, 4]. Subsequent studies showed that the eradication rates of GABHS after treatment with oral penicillin were nearly identical compared with parenteral penicillin G [5]. However, it has never been shown that oral penicillin can prevent rheumatic fever [6]. The highest rates of ARF in the world have been reported for the Aboriginal population of the Northern Territory of Australia. In this population, throat carriage rates of group A streptococcus are extremely low and symptomatic group A streptococcal pharyngitis is uncommon. In contrast, carriage rates of group C and G streptococci are very high. These findings suggest that group C and group G pharyngeal carriage may be capable of causing rheumatic fever [7]. However, severe consequences of group A streptococcal infections have become relatively uncommon in industrialized countries: the incidence of

ARF has declined in North America and Western Europe. By the late 1970s, reports from many US centers documented very low annual incidence rates, ranging from 0.23 to 1.88/100,000 in school-age children [8]. In the late 1990s results from a large-scale randomized multicenter study in the treatment of group A streptococcal tonsillopharyngitis in Germany have shown that the incidence of ARF and acute glomerulonephritis remains very rare [9]. Nevertheless, undiagnosed and untreated group A streptococcal infections of the pharynx and tonsils may lead, in susceptible individuals, to rheumatic fever [10].

Antimicrobial Therapy

Antimicrobial therapy of group A streptococcal pharyngitis is indicated for patients with acute clinical symptoms (e.g. fever ⱖ38⬚C and ⱖ1 of the following: exudate or erythema of pharynx or tonsils, cervical lymphadenopathy) and with a positive reaction from a swab specimen by a rapid antigen test for group A beta-hemolytic streptococcus. A number of oral antibiotics have been shown to be effective in the treatment of group A streptococcal pharyngitis. Oral penicillin V, aminopenicillins, including the combination with ␤-lactamase inhibitors, several cephalosporins and macrolides are frequently used in different proportions of prescriptions in some countries. Penicillin was the best antibacterial agent for the treatment of group A streptococcal infections in the 1950s and 1960s and penicillin V 3 times daily for 10 days has been called the gold standard of therapy [11]. The increasing incidence of penicillin failures and the availability of new effective oral antibiotics are cause for reevaluation of the role of penicillin in the treatment of group A streptococcal pharyngitis [6, 12, 13]. The lack of compliance due to the frequent daily dosing or the prolonged treatment course of penicillin is well known to be a primary cause of treatment failure in streptococcal pharyngitis but shorter penicillin therapy results in significantly poorer eradication rates [14, 15]. A second accepted explanation for penicillin treatment failure is the copathogenicity that may occur when various ␤-lactamase-producing organisms such as staphylococci, Haemophilus spp., Moraxella catarrhalis or Fusobacterium spp. are present in the pharynx and their enzymes inactivate the penicillin [6, 12, 16]. In addition, the intracellular niche as well as the tonsillar crypts may protect the bacterium from penicillin [16, 17]. Another cause of penicillin treatment failures is the disturbed ecological balance of the normal flora; for example, eradication of alpha-streptococci that may protect the pharynx from colonization by group A beta-hemolytic streptococcus [12, 16].

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Other Explanations for Treatment Failure with Penicillin The efficacy of ␤-lactam antibiotics depends on maintenance of serum concentrations of antibiotic in excess of the MIC at the site of infection for periods of 20–40% of the dosage interval to achieve a bacteriostatic effect and for longer to achieve a cidal effect [18]. For penicillins, Craig et al. [19] proposed that the important pharmacodynamic criteria are that serum concentrations need to be above the MIC for 30–40% of the dosage interval. Penicillin V, although exquisitely active against group A streptococci (MIC ⱕ 0.06 ␮g/ml), is not a particularly well-absorbed agent and peak serum levels reach only 1.0 ␮g/ml after administration of 240 mg penicillin V orally [19], falling below the detection limit in 8 h. Penicillin levels in tonsillar tissue may therefore be borderline in terms of antibacterial cover, particularly if ␤-lactamase-producing, commensal strains are also present [20–23].

The Role of Oral Cephalosporins

Cephalosporins are a milestone in the development of oral ␤-lactam antibiotics because they are stable in the environment of ␤-lactamase production from colonizing bacteria of the normal flora in the pharynx and group A betahemolytic streptococci have remained highly susceptible to all ␤-lactam antibiotics. Thus, they are a suitable candidate for treatment of GABHS tonsillopharyngitis and a number of studies have been carried out to investigate the efficacy and safety in this indication. Pichichero and Margolis [13] conducted a meta-analysis of 19 clinical studies published between 1970 and 1990 comparing the efficacy of penicillin and various cephalosporins in the treatment of group A streptococcal pharyngitis. The results have shown that orally administered cephalosporins for 10 days are superior to 10 days’ treatment with penicillin in the eradication of group A streptococci and clinical cure of pharyngitis. In a second analysis of 22 studies published between 1991 and 1999 Pichichero et al. [12] confirmed the results of this meta-analysis. Effectiveness of Short Course Therapy Antibiotics with less frequent dosing and efficacy with short duration of treatment are beneficial for patients and parents. A once or twice a day regimen is a best choice if efficacy and safety are comparable. Penicillin V must be administered for 10 days to achieve maximal eradication of group A streptococci, but certain new antibiotics have been administered in shorter courses. Cephalosporins have superior pharmacokinetic and pharmacodynamic features that allow a less frequent dosing and a shorter duration of treatment (tables 1, 2). Physicians are aware that tissue penetration, antibiotic half-life and

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Table 1. Pharmacokinetic parameters of oral cephalosporins Antibiotic

Single dose g

Mean peak serum level mg/l

Half-life h

Protein binding %

Urinary recovery %, unchanged

Cefalexin Cefadroxil Cefaclor Cefuroxime axetil Cefpodoxime proxetil Cefetamet pivoxil Cefixime Ceftibuten Cefprozil Loracarbef

1 1 1 0.25 0.2 0.5 0.2 0.4 0.5 0.4

24.7 28 27 4.2 2.4 4.5 2.7 17 10 14

1 1.5 1 1.2 2.3 3 2.5 2.5 1.3 1

12 20 50 20 40 20 63 63 35 25

90 85 60 35 35 50 20 65 65 90

Table 2. Dosage regimens for oral cephalosporins Oral cephalosporins

Age

Oral dose (24 h)

Dose frequency/day

Cephalexin

infants 3–12 months children 1–12 years adolescents, adults infants 3–12 months children 1–12 years adolescents, adults infants 3–12 months children 1–12 years adolescents, adults infants 3–12 months children 1–12 years adolescents, adults infants 3–12 months children 1–12 years adolescents, adults infants 3–12 months children 1–12 years adolescents, adults infants 3–12 months children 1–12 years adolescents, adults infants 3–12 months children 1–12 years adolescents, adults infants 6–12 months children 1–12 years adolescents, adults

50–100 mg/kg 50–100 mg/kg 1.5–3.0 g 50–100 mg/kg 50–100 mg/kg 2–4 g 50–100 mg/kg 50–100 mg/kg 1.5–4 g 20–30 mg/kg 20–30 mg/kg 0.5–1 g 8–10 mg/kg 8–10 mg/kg 0.4 g no data 20 mg/kg 1–2 g 8 mg/kg 8 mg/kg 0.4 g 9 mg/kg 9 mg/kg 0.4 g 15–30 mg/kg 15–30 mg/kg 0.4–0.8 g

3 3 3 2 2 2 2–3 2–3 3 2 2 2 2 2 2

Cefadroxil

Cefaclor

Cefuroxime axetil

Cefpodoxime proxetil

Cefetamet pivoxil

Cefixime

Ceftibuten

Loracarbef

Adam/Helmerking

2 1–2 1–2 1–2 1–2 1–2 1–2 1–2 2 2 2

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achievable levels of antibiotic in the tonsils are the most important factors for the dosing frequency and the duration of therapy. Results of several studies with a 4- to 5-day course of oral cephalosporins have consistently shown that they are as effective as a 10-day course of oral penicillin in eradicating group A streptococci in patients with pharyngitis [24–28]. Unfortunately, it is difficult to compare eradication rates of group A beta-hemolytic streptococcus or clinical cure rates in patients with streptococcal pharyngitis from various clinical studies because of differences in the study design, e.g. study population, number of patients and age, dosing regimens, timing for assessment and other evaluation criteria. Therefore, Adam et al. [9] conducted a large-scale prospective randomized multi-center study (4,782 patients) to compare the efficacy and safety of 3 oral cephalosporins, 2 macrolides and amoxicillin-clavulanate as short course therapy for 5 days (3,214 patients) and penicillin V for 10 days (1,568 patients) under almost identical conditions. The treatment groups were comparable with regard to demographic data, environmental factors, and clinical presentations. The sample size was calculated to establish equivalence in efficacy for tonsillopharyngitis treatment between the 5-day treatment groups and the 10-day penicillin V group. Clinical Efficacy. The overall clinical success rate (cure and improvement) in this study was 94.1% after completion of therapy (days 2–4 post-treatment) and 87.7% at the second visit (days 7–9 post-treatment). The 2 treatment groups had equivalent rates of clinical success: 94.5% for the 5-day group and 93.4% for the 10-day group, at the first visit (p ⬍ 0.001, equivalence test), and 87.3% versus 88.6% at the second visit (p ⫽ 0.13, equivalence test). Resolution of Clinical Symptoms. The resolution of acute clinical symptoms was faster in the 5-day than in the 10-day treatment group. This difference is statistically significant (p ⫽ 0.022, Fisher’s exact test 2-sided). Recurrence of Tonsillopharyngitis. In 53% of recurrent infections, a new serotype was identified. The results were similar in the 2 treatment groups. The most frequently isolated serotypes were M 1, M 4, and M 12. Recurrences occurred more frequently in patients treated with 10 days penicillin V (24.4%) than with the short-course therapy (21.9%). This difference is statistically significant (p ⫽ 0.03, Fisher’s exact test 2-sided) and is in agreement with results of a study published by Pichichero et al. [29] in 1998. Eradication of GABHS. The eradication rate of group A streptococci at the first visit after completion of treatment was 83.7% and has been equivalent in the 2 treatment groups (p ⫽ 0.022): 83.3% in the 5-day group versus 84.4% in the 10-day group. 6–7 weeks after the end of treatment the eradication rates remained equivalent (p ⫽ 0.141) in both groups, i.e. 85.0% in the 5-day group and 86.8% in the 10-day group.

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The issue of GABHS carriage remains a confounding factor in studies of tonsillopharyngitis. Clearly, whatever treatment is used, there is a possibility of carriage which may not always be detected if numbers of organisms are very low or if Streptococcus pyogenes is able to survive in the intracellular niche or tonsillar crypts [16, 17]. Oral Antibiotics for Short Course Therapy The 2 macrolides (clarithromycin and erythromycin) used in the multicenter study [9] for a short course therapy of 5 days showed comparable clinical efficacy to 10 days’ penicillin V at the 2–4 days post-treatment visit. However, in this study only 88.6% of the 4,162 group A streptococcal isolates tested were susceptible to macrolides [30]. In addition, there were defined geographic areas with a dramatically decreased susceptibility of 81.6 and 77.1%, respectively, which may be a result of excessive use of macrolides. For example, the eradication rate in this study was 82.6% for clarithromycin compared to amoxicillin/ clavulanate and cefuroxime axetil with 92.9 and 89.9%, respectively [31]. These differences are statistically significant (p ⬍ 0.001, Fisher’s exact test 2-sided). The decreased susceptibility of macrolides and the lower eradication rate of clarithromycin had impact on clinical efficacy and resulted in a lower cure rate. Both amoxicillin/clavulanate and cefuroxime axetil were significantly more effective compared to clarithromycin (91.6 and 89.8% vs. 84.0%, p ⬍ 0.001 and p ⫽ 0.0077 Fisher’s exact test 2-sided). Similar experience on development of resistance of GABHS has been reported for Italy [32]. Cefuroxime axetil bid for 5 days was statistically equivalent to penicillin V t.i.d. for 10 days in clinical efficacy assessed 2–4 days after end of treatment using the one-sided equivalence test as per protocol. In a two-sided test, cefuroxime axetil was shown to be superior to penicillin clinically (p ⬍ 0.001). This finding was similar to results obtained by Aujard et al. [27]. The same superiority of cefuroxime axetil was shown in eradication of GABHS (90%) compared to penicillin (84.1%). This difference was statistically significant (p ⬍ 0.001) using Fisher’s exact test 2-sided [34]. The response rates for ceftibuten once a day and loracarbef b.i.d., both in a short course treatment for 5 days, were comparable to a 10-day penicillin V treatment and the data are submitted for publication. Despite the fact that oral penicillin given for 10 days has never been shown to prevent acute rheumatic fever prevention of post-streptococcal sequelae remains an important issue for a short course treatment of 5 days even though equivalence in eradication and clinical cure rates have been established. In this large scale multi-center study post-streptococcal sequelae have been documented in a 12-month follow-up period. Evaluating more than 4,000 patients only 3 cases of rheumatic diseases according to the revised Jones criteria and

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2 cases of glomerulonephritis have been observed [9]. As seen in this study as well as reported for the United States [8] the incidence of rheumatic fever remains extremely low that no reasonably sized study would be expected to have enough cases to draw any conclusions about effectiveness of different antibiotic regimens to prevent acute rheumatic fever. Therefore, prevention of post-streptococcal sequelae should be no longer an influencing factor to choose penicillin V for the treatment of group A streptococcal pharyngitis. Antibiotic Prescription for Patients with Sore Throat Recently a national survey in the United States (1989–1999) has been published by Linder and Stafford [35]. 76% of adults and 71% of children diagnosed with pharyngitis in 1992 were treated with an antibiotic. Over the 11-year period antibiotics for sore throat in adults were prescribed in 73% of the visits. Recommended antibiotic use (penicillin, oral or intramuscular or erythromycin) decreased from 32% of visits in 1989 to 11% in 1999 (p for trend, ⬍0.001). Penicillin use decreased from 17% of visits in 1989 to 6% in 1999 and erythromycin from 15% of visits in 1989 to 6% in 1999. In addition, aminopenicillins decreased from 27% in 1989 to 16% in 1999. In contrast, oral cephalosporins increased from 12% in 1989 to 19% in 1999. This prescription data confirm the trend of a change from penicillins and macrolides to cephalosporins recommended as result of many studies published and reviewed since the 1970s. In summary, the antibiotics used for the treatment of pharyngitis may differ between countries depending on the physicians own treatment aims, their perceived risk of serious complications and local epidemiological information. Oral cephalosporins have been demonstrated to be superior or equivalent in clinical and microbiological efficacy when administered once a day or bid for 4–5 days. A short course therapy with oral cephalosporins offers a therapeutic advantage. References 1 2

3 4

5

Bisno AL, Gerber MA, Gwaltney JM, Kaplan EL, Schwartz RH: Diagnosis and management of group A streptococcal pharyngitis: A practice guideline. Clin Infec Dis 1997;25:574–583. Dajani A, Taubert K, Ferrieri P, Peter G, Shulman S, et al: Treatment of acute streptococcal pharyngitis and prevention of rheumatic fever: A statement for health professionals. Pediatrics 1995;96:758–764. Denny FW, Wannamaker LW, Brink WR, Rammelkamp CH Jr, Custer EA: Prevention of rheumatic fever: Treatment of the preceding streptococcal infection. JAMA 1950;143:151–153. Wannamaker LW, Rammelkamp CH Jr, Denny FW, Brink WR, Houser HB, Hahn EO, Dingle JH: Prophylaxis of acute rheumatic fever by treatment of the preceding streptococcal infection with various amounts of depot penicillin. Am J Med 1951:673–695. Wannamaker LW, Denny FW, Perry WD, Rammelkamp CH Jr, Eckhardt GC, Houser HB, Hahn, EO: The effect of penicillin prophylaxis on streptococcal disease rates and the carrier state. N Engl J Med 1953;249:1–7.

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Pichichero ME: Evaluating the need, timing and best choice of antibiotic therapy for acute otitis media and tonsillopharyngitis in children. Pediatr Infect Dis J 2000;19:131–140. Haidan A, Talay SR, Rohde M, Sriprakash KS, Currie BJ, Chhatwal GS: Pharyngeal carriage of group C and group G streptococci and acute rheumatic fever in an Aboriginal population. Lancet 2000;356:1167–1169. Bisno AL: Group A streptococcal infections: The changing scene. Curr Opin Infec Dis 1995;8: 117–122. Adam D, Scholz H, Helmerking M: Short-course antibiotic treatment of 4782 culture-proven cases of group A streptococcal tonsillopharyngitis and incidence of poststreptococcal sequelae. J Infect Dis 2000;182:509–516. Snitcowsky R: Rheumatic fever prevention in industrializing countries: Problems and approaches. Pediatrics 1996;(suppl):996–998. Markowitz M, Gerber MA, Kaplan EL: Treatment of streptococcal pharyngotonsillitis: Report of penicillin’s demise are premature. J Pediatr 1993;123:679–685. Pichichero ME, Casey JR, Mayes Th, Francis AB, Marsocci SM, Murphy M, Hoeger W: Penicillin failure in streptococcal tonsillopharyngitis: Causes and remedies. Pediatr Infect Dis J 2000;19: 917–923. Pichichero ME, Margolis PA: A comparison of cephalosporins and penicillins in the treatment of group A beta-hemolytic streptococcal pharyngitis: A meta-analysis supporting the concept of microbial copathogenicity. Pediatr Infect Dis J 1991;10:275–281. Schwartz RH, Wientzen RL, Pedreira F, Feroli EJ, Mella GW, Guandolo VL: Penicillin V for group A streptococcal pharyngotonsillitis: A randomized trial of seven vs. ten days’ therapy. JAMA 1981;246:1790–1795. Gerber MA, Randolph MF, Chanatry J, Wright LL, De Meo K, Kaplan EL: Five vs. ten days of penicillin V therapy for streptococcal pharyngitis. AJDC 1987;141:224–227. Sela S, Barzilai A: Why do we fail with penicillin in the treatment of group A streptococcus infections? Ann Med 1999;31:303–307. Holm SE: Treatment of recurrent tonsillopharyngitis. JAC 2000;45:topic T1, 31–35. Holm, SE, Henning, C, Grahn, E, Lomberg, H, Staley H: Is penicillin the appropriate treatment for recurrent tonsillopharyngitis? Results from a comparative randomized blind study of cefuroxime axetil and phenoxymethylpenicillin in children. Scand J Infect Dis 1995;27:221–228. Craig WA: Interrelationship between pharmacokinetics and pharmacodynamics in determining dosage regimens for broad-spectrum cephalosporins. Diagn Micr Infec Dis 1995;22:89–96. Quay JF, Bergstrom RF: Pharmacology and pharmacokinetics of penicillins; in Queener SF, Webber JA ,Queener, SW (eds): ␤-Lactam Antibiotics for Clinical Use. New York, Dekker, 1986, pp 163–224. Simon HJ: Sukai Staphylococcal antagonism to penicillin G therapy of haemolytic streptococcal pharyngeal infection: Effect of oxacillin. Paediatrics 1968;31:463–469. Brook I, Yocum P: Quantitative measurement of beta-lactamase in tonsils of children with recurrent tonsillitis. Acta Oto-Laryngol 1984;98:556–559. Brook I: The role of ␤-lactamase-producing bacteria in the persistence of streptococcal tonsillar infection. Rev Infect Dis 1984;6:601–607. Portier H, Chavanet P, Gouyon JB, Guetat F: Five day treatment of pharyngotonsillitis with cefpodoxime proxetil. J Antimicrob Chemother 1990;26(suppl E):79–85. Peyramond D, Tigaud S, Bremard-Oury C, Scheimberg A: Multicenter comparative trial of cefixime and phenoxymethylpenicillin for group A beta-hemolytic streptococcal tonsillitis. Curr Ther Res 1994;55(suppl A):14–21. Pichichero ME, Gooch WM, Rodriguez WR, Blumer JL, Aronoff SC, Jacobs RF, Musser JM: Effective short-course treatment of acute group A ␤-hemolytic streptococcal tonsillopharyngitis. Arch Pediatr Adolesc Med 1994;148:1053–1060. Aujard Y, Boucot I, Brahimi N, Chiche D, Bingen E: Comparative efficacy and safety of four-day cefuroxime axetil and ten-day penicillin treatment of group A beta-hemolytic streptococcal pharyngitis in children. Pediatr Infect Dis J 1995;14:295–300. Tack KJ, Henry DC, Gooch WM, Brink DN, Keyserling CH, the Cefdinir Pharyngitis Study Group: Five-day cefdinir treatment for streptococcal pharyngitis. Antimicrob Agents Chemother 1998;43:1073–1075.

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Pichichero ME, Green JL, Francis AB, Marsocci SM, Murphy AL, Hoeger W, Noriega C, Sorrento A, Gootnick J: Recurrent group A streptococcal tonsillopharyngitis. Pediatr Infect Dis J 1998;17: 809–815. Scholz H, Adam D, Helmerking M: Antimicrobial resistance of group A beta-hemolytic streptococci (GABHS) in 4,782 patients and serotyping in treatment failures. Abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy (Toronto). Washington, American Society for Microbiology, 2000, abstr 1557. Adam D, Scholz H, Helmerking M: Short course antibiotic therapy of streptococcal pharyngitis: Comparison of clarithromycin with amoxicillin/clavulanate and cefuroxime axetil [abstract 1826]. Abstracts of the 41th Interscience Conference on Antimicrobial Agents and Chemotherapy (Chicago). Washington, American Society for Microbiology, 2001, abstr 1826. Varaldo PE, Debbia EA, Nicoletti G, Pavesio D, Ripa S, Schito GC, Tempera G, and the ArtemisItaly Study Group: Nationwide survey in Italy of treatment of Streptococcus pyogenes pharyngitis in children: Influence of macrolide resistance on clinical and microbiological outcomes. Clin Infect Dis 1999;29:869–873. Adam D, Scholz H, Helmerking M, Esch K, Machka K: Acute A-streptococcal tonsillopharyngitis: 5-day amoxicillin/clavulanate versus 10-day penicillin V treatment – clinical and bacteriological efficacy and incidence of poststreptococcal sequelae. Abstracts of the 22nd International Congress of Chemotherapy, Amsterdam, 2001, abstr P17.049. Adam D, Scholz H, Helmerking M: Comparison of short-course (5 day) cefuroxime axetil with a standard 10 day oral penicillin V regimen in the treatment of tonsillopharyngitis. JAC 2000; 45(topic T1):23–30. Linder JA, Stafford RS: Antibiotic treatment of adults with sore throat by community primary care physicians. JAMA 2001;286:1181–1186.

D. Adam, MD PhD Department of Antimicrobial Therapy Dr. V. Haunersches Children’s Hospital, University of Munich Lindwurmstrasse 4, DE–80337 Munich (Germany) Tel. ⫹49 89 6424 9595, Fax ⫹49 89 6424 9597, E-Mail [email protected]

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What is the Current Role of Macrolides and Ketolides in the Treatment of Group A Streptococcal Pharyngitis? André Bryskiera, Giuseppe Cornagliab a

Infectious Diseases Group, Clinical Pharmacology, Aventis Pharma, Romainville, France; bDipartimento di Patologia, Università di Verona, Verona, Italy

Most bacterial pharyngitis is caused by ␤-hemolytic streptococci, mainly Streptococcus pyogenes (GABHS), which represent about 15% of the etiological agents of pharyngitis. Phenoxypenicillin namely penicillin V (oral drug) has been the drug of choice since the mid-1950s [1]. Oral penicillin V is given in the dose of 250 mg 2–3 times daily for 10 days. Completion of the full treatment is essential to prevent rheumatic fever [2]. In recent years, the rate of bacteriological failures in patients with GABHS pharyngitis treated with penicillin V increased to 30%, which compares to rates of 2–10% reported in the 1960s and 1970s [3, 4]. Bacterial failures are complex phenomena. ␤-Lactamase-producing bacteria in the oropharynx, inactivating penicillin V, noncompliance, inadequate concentrations of penicillin in the tonsillar tissue, and localization of S. pyogenes in tonsillar epithelium [5, 6] have been suggested to explain the sustained recovery of GABHS in these patients. Macrolide antibiotics are an alternative therapy in the treatment of GABHS pharyngitis, especially in patients allergic to ␤-lactams, when penicillin V fails, or in multiple recurrences. Macrolide Antibiotics

Macrolides belong to a complex family of antibiotics, mainly divided in 2 groups according to the size of the lactone ring: 14- and 16-membered ring macrolides [7].

Table 1. Macrolides and ketolides licensed for the treatment of GABHS pharyngitis Erythromycin A Erythromycin A Other 14-membered 16-membered Ketolides derivatives semisynthetic ring macrolides ring macrolides derivatives Base Ethylsuccinate Propionate Stearate Acistrate Estolate RV-11

Roxithromycin Clarithromycin Flurithromycin Davercin Azithromycin

Oleandomycin

Josamycin Spiramycin Midecamycin Miocamycin Rokitamycin

Telithromycin Cefthromycin

*Under clinical investigation.

Within the 14-membered ring macrolides, erythromycin A is the reference compound, which is also a good substrate for chemical alterations. According to the nature of the chemical modifications, three subgroups of erythromycin A semisynthetic derivatives have been described: substitution of lactone ring (roxithromycin, clarithromycin, flurithromycin, davercin), extension of the lactone ring yielding a new chemical family: azalides (azithromycin) [8], and removal of the L-cladinose moiety resulting in a new class of antibacterial agents [9]. At least 19 drugs have reached the clinical practice since 1952, and all of them (with some variation by countries) are licensed for the treatment of GABHS pharyngitis (table 1).

Microbiology

In vitro Activities Against Susceptible S. pyogenes The most active compounds are those having a 14-membered ring lactone derived from erythromycin A, in particular telithromycin with an MIC50 of 0.015 mg/l [10], followed by clarithromycin (MIC50 of 0.03 mg/l). The least active compound is spiramycin (MIC50 of 0.25 mg/l) (table 2). Impact on Oral Flora The presence of normal throat flora has been suggested to be important as a protective mechanism against invading GABHS. It was found that the lack of viridans group streptococci with growth-inhibiting capacity on the invading GABHS correlated well with an increased incidence of recurrences [13, 14].

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Table 2. In vitro activity of macrolides against S. pyogenes isolates susceptible to erythromycin A Compounds

n

MIC50mg/l

Ref.

Erythromycin A Clarithromycin Roxithromycin Azithromycin Josamycin Miocamycin Spiramycin Rokitamycin Telithromycin

1,152 1,152 1,152 1,152 1,152 486 486 486 1,152

0.06 0.03 0.12 0.12 0.25 ⱕ0.06 0.25 ⱕ0.06 0.015

[11] [11] [11] [11] [11] [12] [12] [12] [11]

Table 3. Percentage of streptococci resistant to macrolides after therapy up to 6 weeks Compounds

n

After 1 week

After 2 weeks

After 3 weeks

After 4 weeks

After 6 weeks

Clarithromycin Azithromycin Erythromycin Roxithromycin Josamycin

60 60 12 12 12

28.5 45.1 40 45.5 37.5

22.5 35.7 40 45.5 50

9.4 31.7 8.3 30 50

14.2 21 0 9 12.5

5 29 – 9 12.5

In a prospective, open-label, randomized study five macrolides were investigated for their likelihood to promote resistance in the oral flora of children with respiratory tract infections. Children were randomly assigned to receive azithromycin, clarithromycin, erythromycin, roxithromycin, and josamycin. Throat swab cultures were obtained prior to treatment and weekly for 6 weeks. The percentage of patients harboring a streptococcal isolate resistant to erythromycin A decreased significantly at week 6, but remained at a high level for azithromycin (table 3) [15].

Pharmacokinetics

Distribution in Tonsillar Tissue Antibiotic concentrations have been measured in tonsillar tissues in patients undergoing tonsillectomies. For both macrolides and ketolides the

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levels reached in tonsils are higher than those assayed in serum and remain for a longer period of time. A review of available data are summarized in table 4. The degree of hydrolysis in plasma and tonsils have been investigated with erythromycin acistrate. At 3.6 h after administration of the 2’ester the degrees of hydrolysis were 34.4 ⫾ 11.8% and 51.5 ⫾ 13.0% in serum and tonsils, respectively [23].

Concentrations in Saliva Therapeutic concentrations of antibiotics maintained throughout the day would be considered beneficial for the treatment of pharyngitis. However, as noted for penicillin V eliminated in saliva (well in excess of the MIC of viridans group streptococci) could contribute to the disturbance of the oral flora, being a potential factor of selection of resistant mutants (table 5). In volunteers receiving telithromycin, the mean peaks plasma and saliva concentration (Cmax) were 2.35 mg/l in plasma (range 1.46–3.74) and 3.05 mg/l (range 1.49–5.39), 24 h after the first administration. The residual concentration at 24 h was 0.01 and 0.07 mg/l in plasma and saliva, respectively. The area under the curve at 24 h (AUC0→24 h) were 9.27 and 15.6 mg⭈h/l in plasma and saliva, respectively. The ratio between AUCsaliva and AUCplasma was 1.7. On day 10 the ratio was 1.6 [32]. In volunteers receiving clarithromycin, the mean peaks plasma and saliva concentration (Cmax) were 2.98 mg/l in plasma (range 1.74–4.94) and 2.38 mg/l (range 0.78–4.58), 24 h after the first administration. At 24 h, clarithromycin was not detected in plasma and saliva. The area under the curve at 10 h (AUC0→10 h) were 18.1 and 13.3 mg⭈h/l in plasma and saliva, respectively. The ratio between AUCsaliva and AUCplasma was 0.7. On day 10 the ratio was 1.0. In the clarithromycin group, the plasma and saliva concentrations were similar at days 1 and 10 [32]. After administration of 500 mg once daily of azithromycin for 3 consecutive days, important concentrations of azithromycin could be detected up to 6.5 days in saliva [34]. The plasma/saliva concentration ratio ranged from 0.21 to 0.30 after erythromycin acistrate (400 mg t.i.d). The degree of hydrolysis of 2’acetyl erythromycin was higher in saliva (61–78%) than in plasma (27–41%). In plasma, the percentage of hydrolysis was inversely correlated with the concentration of acid ␣1-glycoprotein. The antibiotic concentration was clearly higher in plasma than in saliva [39]. For dirithromycin, the concentrations achieved after repeated doses of 500 mg are low and individual variations are important: 0–1.4 and 0–0.088 mg/l in plasma and saliva, respectively [33].

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Table 4. Macrolides and ketolides concentrations in tonsils [16–26] Compounds

Erythromycin Estolate Ethylsuccinate

Stearate Base Acistrate Oleandomycin triacetylate Roxithromycin

Doses

125 mg SD 125 mg MD 100 mg MD

500 mg t.i.d. MD 30 mg/kg MD 500 mg t.i.d. MD 500 mg MD, EA 500 mg MD, E 1,000 mg MD 50 mg/kg 5 mg/kg ⫹ 2.5 mg/kg MD 5 mg/kg SD

Roxithromycin

5 mg/kg SD

Clarithromycin

5 mg/kg MD 250 mg MD

Flurithromycin

500 mg MD

Dirithromycin

500 mg MD

Azithromycin

500 mg MD, D5 500 mg MD, D10 10 mg/kg MD 20 mg/kg MD 250 mg ⫻ 2

Bryskier/Cornaglia

n

Sampling time h

Concentrations, mg/kg or mg/l plasma

tissues

12 35

4–6 4–6 2 3 4 3.5 3 4 3–8 3–8 2.5–3.5 2–3

0.28–5.10 0.48–3.8 2.8 ⫾ 0.13 2.4 ⫾ 0.12 1.44 ⫾ 0.13 1.32 ⫾ 0.95 2.46–7.9 1.78 ⫾ 1.41 5.79 ⫾ 2.08 2.16 ⫾ 0.89 1.41 2.27

0.16–2.6 0.34–1.2 3.39 ⫾ 0.28 2.72 ⫾ 0.23 1.98 ⫾ 0.12 0.72 ⫾ 0.58 0.91–7.10 0.86 ⫾ 1.06 2.87 ⫾ 2.11 1.36 ⫾ 0.91 4.09 12.2

17

6

2.23 ⫾ 0.32

R 2.91 ⫾ 0.29

17 18 18 18 18 18 10 60

6 1 2 4 6 12 4 1 2 4 6 8 12 4 4 4 15 24 13 14 12–204 12–204 13 23 59

2.23 ⫾ 0.32 4.9 ⫾ 1.1 6.6 ⫾ 1.55 4.71 ⫾ 1.36 2.71 ⫾ 0.41 1.60 ⫾ 0.22 5.6 ⫾ 1.9 1.36 ⫾ 0.48 1.82 ⫾ 0.46 1.14 ⫾ 0.32 0.70 ⫾ 0.21 0.26 ⫾ 0.11 0.12 ⫾ 0.04 0.67 ⫾ 0.13 0.67 ⫾ 0.13 0.18 0.08 NS 0.20 ⫾ 0.07 0.17 ⫾ 0.10 0.13 ⫾ 0.027 0.13 ⫾ 0.027 0.03 0.01 0.01

L 2.87 ⫾ 0.64 6.0 ⫾ 1.0 6.0 ⫾ 1.0 6.0 ⫾ 1.0 6.0 ⫾ 1.0 6.0 ⫾ 1.0 4.63 ⫾ 0.97 1.88 ⫾ 0.35 3.76 ⫾ 1.98 6.74 ⫾ 3.83 5.48 ⫾ 2.5 4.16 ⫾ 1.51 2.6 ⫾ 0.65 L 1.32 ⫾ 0.21 R 1.43 ⫾ 0.20 3.6 1.8 1.37 ⫾ 0.55 4.62 ⫾ 0.97 3.47 ⫾ 2.84 12.1 ⫾ 4.5 12.1 ⫾ 4.5 4.5 3.9 4.3

5 5 20 20 20 12 10 12 14

11 11 11 11 15 8 4

5 5 8

128

Table 4 (continued) Compounds

Doses

250 mg ⫻ 2 10 mg/kg SD

Spiramycin

50, 75, 100 mg/kg MD 3,000 mg MD

Josamycin

500 mg SD

Miocamycin

600 mg SD 600 mg MD

Rokitamycin

600 mg SD

Telithromycin

800 mg SD

n

3 3 4 5 6 5 9 4 30 20 10 23 36 20

2 2 2 2 2 1 6 8 8

Sampling time h

Concentrations, mg/kg or mg/l plasma

tissues

83 178 24 48 96 192 12–84

0.006 0.006 0.047 ⫾ 0.001 0.014 ⫾ 0.0008 0.008 ⫾ 0.002 0.004 NS

2.5 0.93 10.33 ⫾ 3.9 7.21 ⫾ 4.04 9.3 ⫾ 3.74 1.49 ⫾ 0.48 8–78

12

NS

21.5–40

4 4 3 1 1–6 2 4 6 8 12 0.5 0.75 1.0 1.5 2 4 3 12 24

0.76 ⫾ 0.22 1.81 ⫾ 0.06 0.4 ⫾ 0.1 2.8 ⫾ 0.29 NS 1.3 ⫾ 0.33 0.5 ⫾ 0.14 0.35 ⫾ 0.13 0.13 ⫾ 0.06 ND 0.5 0.5 1.24 0.71 0.67 0.14 1.24 ⫾ 0.29 0.23 ⫾ 0.32 0.06 ⫾ 0.01

21.24 ⫾ 6.5 13.62 ⫾ 2.7 3.1 ⫾ 0.7 14.7 ⫾ 5.05 3.9 ⫾ 0.8 3.2 ⫾ 0.82 1.75 ⫾ 0.31 0.52 ⫾ 0.19 0.3 ⫾ 0.08 0.12 ⫾ 0.05 ⱕ0.04 ⱕ0.04 0.86 0.55 0.43 0.13 3.95 ⫾ 0.5 0.88 ⫾ 0.5 0.72 ⫾ 0.29

NS ⫽ Nonspecified; SD ⫽ single dose; MD ⫽ multiple doses; ND ⫽ nondetected; EA ⫽ erythromycin acistrate; E ⫽ erythromycin; D ⫽ day.

Clinical Efficacy

Different American scientific societies recommend using penicillin or erythromycin (for those who were allergic to penicillin) as first-line drug for patient with sore throat due to GABHS [40–42]. In the United States, 6.7 million adult patients visit annually office-based community physicians for sore throats,

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Table 5. Concentrations of macrolides and ketolides in saliva Compounds

Doses

Erythromycin Estolate Ethylsuccinate Propionate Stearate Base

Roxithromycin Clarithromycin

Dirithromycin

Azithromycin Josamycin Spiramycin

Rokitamycin Telithromycin

n

Sampling time h

Concentrations, mg/l plasma

tissues

4.7 ⫾ 2.0 4.8 ⫾ 2.5 0.82 ⫾ 0.66 1.4 ⫾ 0.64 4.07 ⫾ 0.29 2.15 ⫾ 0.14 1.11 1.19 0.96 6.12 ⫾ 1.94 1.49 2.98 3.87 0.10 ⫾ 0.20 0.14 ⫾ 0.07 0.20 ⫾ 0.30 0.27 ⫾ 0.32 0.27 ⫾ 0.34 NS

ⱖ0.1 ⱖ0.1 0.1–1.0 0.1–1.0 0.84 ⫾ 0.09 0.57 ⫾ 0.08 1.11 1.01 1.29 0.67 ⫾ 0.12 1.93 2.38 4.29 0.09 ⫾ 0.16 0.16 ⫾ 0.13 0.23 ⫾ 0.25 0.18 ⫾ 0.20 0.26 ⫾ 0.26 2.14 ⫾ 0.3

2.61 1.6 ⫾ 0.5 2.4–4.3 2.1–4.0 2.3–4.0 3.14 ⫾ 1.04 2.35 2.03

1.03 ⫾ 0.43 1.4 ⫾ 0.5 3.1–6.9 5.1–13 9.6–14 0.3 3.04 3.06

10 mg/kg fed NS 10 mg/kg fast NS 15 mg/kg fed NS 15 mg/kg fast NS 7.5 mg/kg SD 7.5 mg/kg SD 200 mg SD, i.m.

18 20 18 11 8 8 20

300 ⫹ 150 ⫻ 3 300 mg SD 500 mg b.i.d., D1 500 mg b.i.d., D10 500 mg o.d., D2 500 mg o.d., D3 500 mg o.d., D4 500 mg o.d., D5 500 mg o.d., D7 500 mg MD

24 3 10 10 20

28

2–4 2–4 2–4 2–4 2 2 1 2 3 1–12 2.5 24 24 24 24 24 24 24 12

1,500 ⫹ 500 MD 1,000 mg ⫻ 2 MD 1,500 mg MD 2,000 mg MD 3,000 mg MD 400 mg NS 800 mg D1 800 mg D10

4 6 3 3 3 5 10 10

NS 3 NS NS NS 1 24 24

Ref.

[27] [27] [28] [28] [29]

[30] [31] [32] [33]

[34] [35] [36, 37]

[38] [32]

D ⫽ days; SD ⫽ single dose; MD ⫽ multiple dose; NS ⫽ nonspecified IM ⫽ intramuscular.

without significant changes during the last 11 years. Overall 12% of the adult patients received erythromycin as a treatment of their sore throat [43]. Erythromycin Erythromycin A is the support of the drug erythromycin. Erythromycin is the recommended alternative therapy for penicillin V, especially in patients who

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are allergic to ␤-lactams. One of the weaknesses of erythromycin A is the erratic pharmacokinetics after oral absorption and inactivation in an acidic environment [7]. To overcome this inconvenience, many approaches have been made: film-coated gastroresistant tablets, esterification of the 2’hydroxyl group of the D-desosamine, the amino sugar (propionate, ethylsuccinate of erythromycin A) or a stoichiometric mixture with a salt (stearate) or a mixture of a salt and the 2’ester of erythromycin A (estolate, acistrate of erythromycin). None of them are fully satisfactory, despite improved formulations. Erythromycins in different formulations have been tested for efficacy and safety in the treatment of GABHS pharyngitis in comparison with ␤-lactam antibiotics and semisynthetic macrolides. Since the introduction of erythromycin in clinical practice in the 1950s [44], its efficacy had been studied extensively in the treatment of GABHS pharyngitis. Studies carried out with erythromycin base in 1957 and 1958 found this formulation less effective than penicillin V, probably due to the erratic absorption and acid instability [45]. In 1958, the clinical introduction of erythromycin estolate (lauryl sulfate salt of 2’OH propionate erythromycin A) and ethylsuccinate presenting a better oral absorption have resulted in a wide use of both formulations in the treatment of streptococcal infections. In a metaanalysis of 13 publications [46], the clinical cure rates range from 78 to 96% in the estolate group (1,177 patients, doses from 20 to 40 mg/kg/daily in 2–4 divided doses) and from 67 to 87% in the ethylsuccinate group (326 patients, 20–60 mg/kg/day in 2–4 divided doses). A daily dose of 30 mg/kg of erythromycin estolate seems to be more efficient than erythromycin ethylsuccinate when considering the bacteriological outcome at the follow-up visit, with bacteriological failure rates of 24.7 and 5.1% for estolate and ethylsuccinate, respectively [47]. The appropriate daily dose for erythromycin estolate is 20–30 mg/kg/daily in 2, 3 or 4 divided doses. At the daily dose of 40 mg/kg in 3–4 divided doses, erythromycin ethylsuccinate is equally active as penicillin V. Erythromycin has been used as an alternative to penicillin V in the treatment of GABHS pharyngitis, with a failure rate as high as 15%. However, a study comparing cefprozil, 20 mg/kg q.d. to erythromycin ethylsuccinate, 30 mg/kg in 4 divided doses in pediatric patients, clinical and bacteriological responses for both groups were 95% at the end of therapy. Recurrence rates after the second throat culture ranged from 6 to 14% in the cefprozil group versus 11% in the ethylsuccinate group [48]. Whatever the formulation, the acid degradation of the erythromycin lactone ring results in bacteriologically inactive products mimicking the motilin, causing poor gastrointestinal tolerance and consequently inadequate compliance. A daily dose of 20 mg/kg of erythromycin ethylsuccinate,

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Table 6. Clinical and bacteriological efficacy of clarithromycin versus penicillin V Treatments

n

Daily doses mg

Outcome at end of therapy, % clinical cure

bacteriological eradication

Follow-up visit %

Ref.

Clarithromycin Penicillin V

47 43

250 b.i.d. 250 t.i.d.

96 89

100 100

11 15

[53]

Clarithromycin Penicillin V

179 177

250 b.i.d. 250 t.i.d.

94 86

95 87

NS NS

[55]

Clarithromycin Penicillin V

252 253

250 b.i.d. 250 t.i.d.

97 94

94 78

17.6 17.4

[54]

Clarithromycin Penicillin V

65 63

250 b.i.d. 250 t.i.d.

95 91

88 91

NS NS

[56]

Clarithromycin Penicillin V

67 58

250 b.i.d. 250 t.i.d.

96 98

100 97

NS NS

[57]

250 b.i.d. 250 t.i.d.

96 94

92 91

NS NS

[58]

Clarithromycin Penicillin V

given twice daily, produced 89% bacteriological eradication in patients with 90% compliance, 76% in patients with 75% compliance and only 60% in patients with 50% compliance [49]. However, semi-synthetic derivatives of erythromycin with higher acid stability, and improved gastrointestinal tolerance [50] now tend to replace progressively the older erythromycin formulations. Clarithromycin Clarithromycin is a semisynthetic derivative of erythromycin A which bears a 6-methoxy group on the erythronolide A ring [51], which is thought to prevent the internal ketalisation between the 9-keto group and the 6-hydroxyl group. Clarithromycin is the most active compound within the 14- and 15-membered ring macrolides against S. pyogenes. Many comparative studies have been published comparing clarithromycin with other macrolides, ketolides, penicillin V (table 6) and other ␤-lactam antibiotics. A modified slow release formulation of clarithromycin had been recently introduced in clinical practice to reduce the length of therapy to 5 days and to be administered once daily, with equivalent clinical and bacteriological efficacy [52]. In five published studies, clarithromycin 500 mg administered in two daily doses, compared to penicillin V, 250 mg three times a day, clinical cure rates and eradication were similar at the end of therapy. More recurrence occurred after

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penicillin V (15%) than after clarithromycin (11%) [53]. In another study, the bacteriological eradication rate was significantly higher with clarithromycin (94%) than with penicillin V (78%) at 48 h post-treatment visit, but a similar number of relapses and reinfection occurred at the follow-up visit [54]. Azithromycin Azithromycin is a semisynthetic derivative of erythromycin A obtained through a Beckmann rearrangement. The endogenous nitrogen at position 9a gives new class of antibacterial agents: azalides which are composed of a 15-membered ring lactone [8]. Azithromycin is characterized by a long apparent elimination half-life, allowing short-term therapy (3–5 days) with one administration per day. One of the advantages of a short-term therapy is to improve patient compliance. Results with azithromycin therapy are controversial (table 7). Some studies concluded to results similar to those obtained with penicillin V, after 3 [63] of 5 days [60] of azithromycin therapy. Other studies raised concerns about the rate of bacterial eradication, shown to be inferior with azithromycin 3 days than with penicillin V 10 days at the late post-treatment visit [59, 61, 68]. The same concern was expressed in a study comparing 10 days of clarithromycin and 5 days of azithromycin [69]. Roxithromycin Roxithromycin is a semisynthetic derivative of erythromycin A, having a 9-oxime substituted side chain [70]. Few studies have been carried out on the treatment of GABHS pharyngitis with roxithromycin. In 227 adult patients, two regimens of roxithromycin (150 mg b.i.d. and 300 mg o.d.) were compared to erythromycin ethylsuccinate (400 mg four times daily). No statistical significant differences were found between treatment groups, either for clinical outcome or for bacteriological response (rates between 84 and 92%) [71]. In an open randomized trial, overall clinical efficacy was 96% (27/28) for roxithromycin 300 mg o.d. against 77% (27/35) with clarithromycin 250 mg b.i.d. in an open randomized trial. The average treatment duration was 9 days [72]. Dirithromycin Dirithromycin is a 9-ester of erythromycylamine, a semisynthetic derivative of erythromycin A [73]. In a double-blind randomized study, dirithromycin, 500 mg once daily for 10 days was compared to penicillin V, 250 mg four times a day for 10 days.

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Table 7. Comparative studies with azithromycin Treatments

n

Daily doses

Duration Favourable days outcome, % clinical

microbiological

Follow-up days

Ref.

Azithromycin Penicillin V

160 10 mg/kg o.d. 3 160 100,000 IU/kg t.i.d. 10

93 89

65 82

45 20

[59]

Azithromycin Penicillin V

152 500/250 ⫻ 4 90 250 q.i.d.

1⫹4 10

99 99

90.8 95.6

9.6 11.9

[60]

Azithromycin Penicillin V

41 10 mg/kg o.d. 44 125–250 q.i.d.

3 10

98 100

95 95

14 8.0

[61]

Azithromycin Penicillin V

76 10 mg/kg o.d. 78 50,000 IU/kg b.i.d.

3 10

75 91

53.9 85.8

21.6 5.6

[62]

3 3 10

87 98 99

85 84 87

6.0 5.0 1.0

[63]

Azithromycin Azithromycin Penicillin V

123 10 mg/kg o.d. 103 20 mg/kg o.d. 132 125–250 q.i.d.

Azithromycin Clarithromycin

71 500 o.d. 73 250 b.i.d.

3 10

86 97

91.6 91.6

8.3 8.3

[64]

Azithromycin Clarithromycin

63 10 mg/kg o.d. 63 7.5 mg/kg b.i.d.

3 10

95.9 96.8

94.6 95.2

NS NS

[65]

Azithromycin EES

46 10 mg/kg o.d. 47 30–50 mg/kg t.i.d.

3 10

95 98

91 98

14 13

[66]

Azithromycin Cefaclor

51 10 mg/kg o.d. 51 30 mg/kg t.i.d.

3 10

94.1 94.1

36.5 73.9

42.4 12.8

[67]

EES ⫽ Erythromycin ethylsuccinate.

Favorable clinical outcomes were 96.7% and 94.2%, respectively, with bacterial eradication of 85.3 and 82.5% in the dirithromycin and penicillin V group, respectively [74]. A double blind double dummy multicenter study compared the safety and the efficacy of dirithromycin (500 mg o.d.) to erythromycin base (1 g four times a day) for 10 days. At post-therapy (3–5 days after completion of therapy) favorable clinical outcome were reported in 94.1% (159/169) and 94.6% (158/167) in the dirithromycin and erythromycin group respectively. Posttherapy throat cultures were negative for GABHS in 79.3% (134/169) and 86.2% (144/177) in the dirithromycin and erythromycin group, respectively. At the last visit post-therapy, pathogens were absent in 69.9% (107/153) and 86.1% (130/151) in the dirithromycin and erythromycin group, respectively [75].

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Table 8. Comparative studies with spiramycin Compounds

Daily dose

Duration days

n

Outcome at the end of therapy, % clinical

Spiramycin Penicillin V Spiramycin Amoxicillin Spiramycin Penicillin V Spiramycin Erythromycin Spiramycin Erythromycin

100,000 IU/kg b.i.d. 25,000 IU/kg t.i.d. 1,000 mg b.i.d. 500 mg t.i.d. 1,000 mg b.i.d. 1,000 mg t.i.d. 500 mg t.i.d. 500 mg t.i.d. 1,000 mg b.i.d. 500 mg q.i.d.

5 7 7 7 8 8 3 5 7 7

102 96 108 98 49 89 50 83.3 28 100 27 97.3 50 94 50 76 53 100 67 100

Comments

Ref.

3 failures 3 failures 5 failures 8 failures – 1 failures 2 failures 8 failures – –

[79]

microbiological 79.4 89.8 ND ND ND ND ND ND 100 100

In a single-blind randomized, parallel group study dirithromycin (500 mg o.d.) was compared to miocamycin (600 mg b.i.d.) for 10 days. Each group was composed of 30 patients. The overall clinical efficacy was 100% in both groups. The bacteriological eradication of GABHS was 96.7 and 92.9% in the dirithromycin and miocamycin group, respectively [76]. Flurithromycin Flurithromycin is a semisynthetic derivative of erythromycin A, having a 8 fluorine atom [77]. The comparative efficacy and tolerance of flurithromycin (375 mg b.i.d.) and clarithromycin (250 mg b.i.d.) for 10 days was assessed in a multicenter parallel groups, in a double-blind double dummy study of 151 patients (73 and 79 patients in each group). The clinical cure rate was 95.2% (69/73) and 92.4% (73/79) in the flurithromycin and clarithromycin group respectively. The bacteriological eradication rate for both groups was 91% [78]. Spiramycin Spiramycin is a 16-membered ring macrolide composed of 3 components, named I, II and III. The results of several comparative studies are summarized in table 8. Josamycin Josamycin is a 16-membered ring macrolide extracted from the fermentation of Streptomyces josamiceticus spp narbonensis. Josamycin belong to the leucomycin A3 group [77].

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[80] [81] [82] [83]

Two comparative studies have shown that the release of symptoms in josamycin group occurred later than ␤-lactam antibiotics or erythromycin ethylsuccinate [83, 84]. Two hundred and sixty-five patients were enrolled in a multicenter open study comparing josamycin (2 g or 50 mg/kg b.i.d. for 5 days) and penicillin V (3 millions units t.i.d. for 10 days). The clinical cure rates were similar in both groups: 95.2% and 96.6% in the josamycin and penicillin V groups, respectively. Bacteriological eradication at the late post-treatment visit in the josamycin group was 98.7% when the isolate was susceptible to the drug and 87.6% in the case of josamycin resistance. In the penicillin V group of patients, the eradication rate at the end of therapy was 88.1% (89/101) and 95.1% (78/82) at the follow-up visit [86]. In an open clinical trial comparing penicillin V (1 million units three times daily) for 10 days and josamycin (1 g ⫻ 12 h) for 5 days, authors investigated the kinetic of eradication of S. pyogenes by throat cultures everyday and at follow-up (48 h, 30 days, 3 or 4 months). Twenty-four hours after the beginning of therapy, S. pyogenes was eradicated in 76.2% (16 of 21 patients) and 66.7% (18 of 27 patients) in the penicillin V and josamycin groups, respectively. At 48 h, 90.5% (19 of 21) and 100%, respectively. For the remaining 2 patients in the penicillin V group, eradication of S. pyogenes was achieved at day 5. In 1 patient eradication of S. pyogenes was not achieved. At day 30, 33% (9 of 27) and 9.5% (2 of 21) patients have a positive throat culture of S. pyogenes in the josamycin and penicillin V groups, respectively. At day 90 or day 120, 3 of 9 patients in the josamycin group have a negative throat culture for S. pyogenes, and 3 other patients were carriers of S. pyogenes harboring another serotype than those found at entrance into the study. Those new serotypes were found in the patient surroundings [87]. Telithromycin Erythromycin A resistance within S. pyogenes was initially reported in the 1950s with the first report of widespread and frequent resistance coming from Japan in the early 1970s [89]. A correlation between in vitro erythromycin A resistance in S. pyogenes infections and clinical failures with macrolide therapy has been reported [90]. Ketolides are semisynthetic derivatives of erythromycin A which were designed to overcome erythromycin A resistance within gram-positive cocci including S. pyogenes [9, 50, 91]. Two comparative, randomized and double-blind studies have been carried out to investigate the clinical and the bacteriological outcomes of telithromycin given 800 mg once daily for 5 days with either penicillin V (500 mg t.i.d.) or clarithromycin (250 mg b.i.d.) for 10 days. At post-therapy (day 16–20) clinical

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cure was achieved in 94.8 and 94.1% in the telithromycin and penicillin V groups, respectively. GABHS eradication rates for telithromycin and penicillin at post-therapy were 85.2 and 89.1% , respectively, and 86.1 and 86.5%, respectively, at the late post-therapy visit (days 38–45) [92]. In a multicenter study comparing telithromycin and clarithromycin, bacteriological eradication was achieved for 92.8% (116/125) and 93% (107/115) in the telithromycin and clarithromycin groups, respectively. When a S. pyogenes isolate resistant to erythromycin A (MIC ⱖ 1.0 mg/l) was cultured, no eradication of GABHS was obtained in the clarithromycin group, whereas a 40% eradication was achieved in the telithromycin group [93]. Conclusion

Since the erection of ‘Saint Anthony Chapel’ in Edinburgh for sufferers of ‘Saint Anthony Fire’ (erysipelas), a major cause of mortality at the end of the XVth century, to the discovery of S. pyogenes and its pathogenicity, huge progress has been achieved in the management of streptococcal infections. The clinical introduction of penicillin after the end of the second world war and the discovery of the relationship of GABHS pharyngitis with rheumatic fever and the establishment of penicillin V in the treatment of GABHS pharyngitis to prevent rheumatic fever and the sequelae by Breese et al. [1] was a milestone in the therapy of chronic diseases. The main objective of therapy for GABHS pharyngitis is to prevent suppurative complications, rheumatic fever and its sequelae and to decrease infectivity so that patients can return at school or to work rapidly. Penicillin V remains the ‘gold standard’ for GABHS pharyngitis therapy [94], and no resistant S. pyogenes strains to penicillin G have been isolated [95]. However, 5–30% of patients harbor GABHS in the pharynx after completion of penicillin oral therapy. In addition, patients can be allergic to ␤-lactam antibiotics. Macrolides represent an alternative therapy deserving consideration. Newer macrolide compounds offer improved gastro-intestinal tolerance than the initial erythromycin derivatives. Telithromycin is active against most macrolide-resistant S. pyogenes isolates. Macrolide resistance in some geographic areas obliges to take into account the epidemiological situation when using macrolides. References 1 2

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Bryskier A: Ketolides telithromycin, an example of a new class of antibacterial agents. Clin Microbiol Infect 2000;6:661–669. Norrby SR, Rabie WJ, Bacart P, Mueller O, Leroy B, Rangaraju M, Butticaz-Iroudayassamy E: Efficacy of short-course therapy with the ketolide telithromycin compared with 10 days of penicillin V for the treatment of pharyngitis/tonsillitis. Scand J Infect Dist 2002;33:883–890. Quinn J, Ziter P, Leroy B, Sidarous E, Belker M: Oral telithromycin (HMR 3647) 800 mg once daily for 5 days is well tolerated and as effective as clarithromycin 250 mg twice daily for 10 days in group A-hemolytic streptococcal (GABHS) pharyngitis/tonsillitis (poster). 40th Int Conf Antimicrob Agents Chemother (ICCAC), Toronto, 2000, abstr 2229, p 472. Bisno AL: Acute pharyngitis. N Engl J Med 2001;344:205–211. Macris MH, Hartmen N, Murray B, et al: Studies on the continuing susceptibility of group A streptococcal strain to penicillin during eight decades. Pediatr Infect Dis J 1998;17:377–381.

A. Bryskier, MD Infectious Diseases Group, Clinical Pharmacology Aventis Pharma, F–93230 Romainville (France) Tel. ⫹33 149915121, Fax ⫹33 149915020 E-Mail [email protected]

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Pechère JC, Kaplan EL (eds): Streptococcal Pharyngitis. Issues Infect Dis. Basel, Karger, 2004, vol 3, pp 143–149

Mechanisms of Antibiotic Resistance in Streptococcus pyogenes Noboru Yamanaka Department of Otolaryngology-Head and Neck Surgery, Wakayama Medical University, Wakayama, Japan

Oral Antimicrobial Susceptibilities of Streptococcus pyogenes

The choice of antibiotic for the treatment of streptococcal pharyngitis is penicillin, due to its proven efficacy, safety, and low cost and for patients allergic to this antibiotic, erythromycin or other macrolides are the drugs of choice. Lately, however, an increase in macrolide resistance has been observed in different countries. Bandak et al. [1] reported that clinical isolates of S. pyogenes were susceptible in vitro to penicillin and other ␤-lactams by testing antimicrobial susceptibilities of 1,050 isolates collected from 11 study centers in five countries, i.e. Italy, Spain, France, Sweden and Turkey, for a year between 1998 and 1999. All isolates of S. pyogenes tested were susceptible to penicillin (MIC ⬎ 0.12 ␮g/ml) and cefaclor (MIC ⬎ 0.25 ␮g/ml). Azithromycin, clarithromycin and erythromycin resistance rates were 15.9, 15.4 and 15.8%, respectively. MIC90s for penicillin, cefaclor, azithromycin, clarithromycin, erythromycin, and roxithromycin were 0.015, 0.12, ⬎4, 8, ⬎1 and 16 ␮g/ml, respectively. Macrolide (erythromycin) resistance rates were highest in study centers in Italy (31.0%) and Spain (26.6%). Lower macrolide resistance rates were identified in study centers in Turkey (4.8%), France (3.8%), and Sweden (3.7%). Thus, clinical isolates of S. pyogenes remain exquisitely susceptible in vitro to penicillin and other ␤-lactams including cefaclor, however, increased macrolide usage following the introduction of the second-generation macrolides has been directly associated with the recent increase of resistance to these agents in S. pyogenes. In 1992, Seppälä et al. [2] reported a high rate of erythromycin resistance (44%) in Finland, linked to an increased rate of erythromycin

consumption in outpatients. The same researchers subsequently demonstrated that reduced erythromycin use in Finland was associated with a significant decrease in erythromycin resistance [3]. High frequencies of erythromycin resistance have also been reported from the USA (32%) [4]. On the other hand, resistance rates as low as 0.5 and 1.6% have been found in The Netherlands [5] and in southwestern Germany [6]. Arvand et al. [7] tested 212 clinical S. pyogenes isolates in Berlin for susceptibility to various antibiotics by agar dilution. The overall frequency of erythromycin resistance was 12.7%, being higher in isolates from children (18.9%) than in those from adult patients (10.7%). Similar results were found for clarithromycin, while 2.8% of the isolates were resistant to ciprofloxacin. All strains were susceptible to penicillin and cefotaxime. Of the erythromycin-resistant isolates subjected to the double-disc diffusion test for erythromycin and clindamycin, 35% expressed constitutive and 55% inducible resistance to clindamycin. In Japan, the frequency of erythromycin resistance among S. pyogenes increased to approximately 80% during the 1970s [8] and the resistance rate of isolates showed a marked decline during the 1980s [9]. In the late 1990s, the surveillance in the western part of Japan revealed that the frequencies of erythromycin resistance were between 2.8 and 6.5% [10].

Mechanisms of Macrolides Resistance in Streptococcus pyogenes

There are presently three recognized mechanisms of resistance of macrolide antibiotics: target modification, efflux and inactivation. A target site modification by an rRNA-methylating enzyme encoded by the ermAM and ermTR. The second mechanism of resistance, named the M phenotype, is mediated by an efflux pump encoded by the mefA gene, rendering the bacteria resistant to 14- and 15-membered macrolides, with retained susceptibility to clindamycin and streptogramin B. Resistance to MLS antibiotics due to inactivation has been described for a number of clinically important organisms including Staphylococcus aureus, Staphylococcus haemolyticus, and Escherichia coli. To our knowledge, no form of macrolide inactivation has been described for streptococci.

rRNA Methylases

A large number of different rRNA methylase genes (erm) have been isolated from a variety of bacteria that range from E. coli to Haemophilus influenzae in gram-negative species and from Streptococcus pneumoniae to Corynebacterium spp. in gram-positive species. There are currently at least eight classes of

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Macrolide binding NH2

O

23S rRNA erm gene

Ribosome methylase S-adenosyl -L-methionine

Macrolide CH3

N

CH3

O

No binding Methylated 23S rRNA

Fig. 1. erm-dependent methylation of 23S rRNA.

erm genes distinguishable by hybridization criteria [11, 12]. Erm methylases add either one or two methyl residues to a highly conserved adenine residue in domain V, the peptidyl transferase center, of 23S rRNA [12, 13]. This modification renders the strain resistant to most macrolides, lincosamides and streptogramin B compounds: phenotypically, this resistance pattern is known as MLSB resistance [13, 14] (fig. 1). Expression of MLSB resistance can be inducible or constitutive and is unrelated to the class of an erm determinant. Regulation of the methylase depends upon the sequence of the regulatory domain upstream of the structural gene and is accounted for by a translational attenuation mechanism [11, 16, 17]. Some of the enzymes are inducibly regulated by translational attenuation of a mRNA leader sequence; in the absence of erythromycin, the mRNA is in an inactive conformation due to a sequestered Shine-Dalgarno sequence, preventing efficient initiation of translation of the erm transcripts. Mutational analyses of the ermC leader peptide suggested that the peptide, (FS)IFVI, is critical for induction [17]. However, when the erm peptides from the erm genes are compared, little sequence similarity is apparent [17]. Recently, a second mechanism of regulation has been described in which the lack of erythromycin prevents the complete synthesis of the mRNA due to rho factor-independent termination. This type of regulation has been described for the ermK system [18]. In either system, inducible isolates, when tested, may appear to be susceptible or intermediately resistant to macrolides and susceptible to lincosamides. Erythromycin is generally a good inducer in most species; in animal or human streptococcal isolates, lincosamides and/or streptogramin B may be good

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inducers. Inducible stains predominated in the 1960s to 1970s. However, today it is more common in many geographical areas to find isolates that constitutively produce the rRNA methylase without preexposure to antibiotics. Constitutive erm gene expression is usually associated with structural alternations in the erm translational attenuator, including deletions, duplications, and point mutations in ermC [19]. They can be distinguished from inducible isolates by the stable MICs for them regardless of whether they are pregrown with or without an inducer [16]. In streptococci MLSB resistance has commonly been due to genes belonging to the ermAM (ermB) gene class. The ermAM gene was first sequenced from plasmid pAM77 of Streptococcus sanguis [20]. Thereafter, genes of the same class have been sequenced from S. pneumoniae, S. pyogenes, and Streptococcus agalactiae. Seppälä et al. [21] have recently characterized a novel erm gene, ermTR, from an erythromycin-resistant clinical strain of S. pyogenes (A200) isolated in Finland. The ermTR gene shares only a 58% homology with the sequence of the ermB (ermAM) gene, but an 82% homology with the sequence of ermA of Staphylococcus aureus. Hence, it has been proposed that the ermTR and the ermA genes may share a common origin, and they have been assigned to the same ermA class of genes (ermA ⫽ ermTR) [22].

Efflux System

In early years, most macrolide resistance was mediated by the presence of erm genes. However, more recently, other mechanisms of macrolide resistance, efflux system, have been found in increasing frequency in certain gram-positive pathogens. Active drug efflux is mediated in S. pyogenes by the mefA (macrolide efflux) gene [23]. It causes resistance to 14- and 15-membered macrolide compounds only; this phenotype is called the M-phenotype [23, 24]. The efflux genes do not modify either the antibiotic or the antibiotic target, but instead pump the antibiotic out of the cell or the cellular membrane, keeping intracellular concentrations low and ribosomes free from antibiotic. Many of these proteins (mefA, mefE, and lmrA) have homology to the major facilitator superfamily (MFS) of efflux proteins. If an isolate carries a mef gene, clindamycin can be considered, whereas the presence of an ermB gene would preclude consideration of a lincosamide. Recently, Streptococcus pneumoniae strains which carry both mef and ermB genes and have the MLSB phenotype have been identified [25, 26]. The mefA gene was described in S. pyogenes, while the mefE genes was found in S. pneumoniae. Since the two genes share 90% DNA and 91% amino acid homology, Roberts et al. [22] recommended that these two genes be considered a single class, A: mefA gene and MefA protein.

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Molecular Epidemiology of Erythromycin Resistance Genes in Streptococcus pyogenes

A total of 238 erythromycin-resistant S. pyogenes isolates collected in 1986–1997 from eight different countries in Europe and North and South America were studied their clonal origin [27]. The mefA gene was detected in all 54 isolates with the M-phenotype and was widely distributed and was found in every country. The ermTR gene was found in five European countries: Sweden, England, Bulgaria, Italy and Greece, and also outside Europe in Argentina and the USA. The ermB gene was found in four countries: Italy, England, Sweden and the USA. Thus, in addition to the mefA gene, the recently sequenced ermTR gene was also widely distributed among isolates of different clonal origin. Regarding the prevalence of macrolide resistance in group A streptococci, Bessen et al. [28] hypothesized that horizontal transfer of erm genes between group A streptococci might occur and cause the emergence of new clones with unique pathogenic qualities. Avanzini et al. [29] typed some S. pyogenes strains by analyzing the bacterial genome by random amplification of polymorphic DNA (RAPD) to evidentiate a possible clonal distribution of the circulating microorganisms. Characterization of the phenotype of resistant isolates revealed the prevalence of constitutive resistance in 1996, whereas the M phenotype, characterized by resistance to 14- and 15-membered macrolides with susceptibility to clindamycin and streptogramin B, prevailed in 1998. The RAPD revealed that four main DNA profiles were demonstrated in the genomic profile of 32 S. pyogenes strains, generally related to the macrolideresistance phenotype and for the major part to the T serotype. Similarly, Savoia et al. [30] analyzed the resistant and some of the susceptible strains by pulsedfield gel electrophoresis (PFGE) and genomic patterns were defined on the basis of band size and number. Five DNA profiles were found among erythromycin-resistant strains: three patterns characterized the new resistance phenotype and one each the inducible resistance and constitutive resistance phenotypes. The distribution of resistant strains according to their genomic patterns appeared to be related to the resistance phenotype and only in some cases to the T serotype of bacteria. They concluded that the S. pyogenes strains analyzed were genetically heterogeneous and therefore the high rate of erythromycin resistance observed was not caused by the spread of a single clone nor was it related to a particular serotype. On the other hand, Murase et al. [31] analyzed 17 erythromycin resistance genes in S. pyogenes isolated in the central part of Japan from 1982 to 1985 by PFGE and reported 14 of them harbored ermB gene with an identical PFGE pattern, indicating the spread of a single clone.

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Conclusion

The introduction in recent years of newer macrolides with enhanced pharmacokinetic properties and their recommended use both as first-line therapy to treat upper respiratory infections and for prophylactic purposes has led to an excessive use of these drugs in many countries [3, 32]. In Spain, a report by Baquero [33] and the Task Force studying the development of antibiotic resistance and its relation to antibiotic use and consumption indicates that the drugs prescribed by general practitioners were inadequate in the majority of cases. It is clear that the most efficient control of the clinical problem of macrolide resistance is to reduce the use of macrolides accompanied by ongoing surveillance analysis. It should be stressed that a concerted effort of all social and scientific agencies involved in health care is prerequisite to control the emergence of antibiotic resistance. References 1 2 3

4

5

6 7 8

9 10 11 12 13 14

Bandak SI, Turnak MR, Allen BS, et al: Oral antimicrobial susceptibilities of Streptococcus pyogenes recently isolated in five countries. Int J Clin Pract 2000;54:585–588. Seppälä H, Nissinen A, Jarvinen H, et al: Resistance to erythromycin in group A streptococci. N Engl J Med 1992;326:292–297. Seppälä H, Klaukka T, Vuopio-Varikila J, et al: The effect of changes in the consumption of macrolide antibiotics on erythromycin resistance in group A streptococci in Finland. N Engl J Med 1997;337:441–446. York MK, Gibbs L, Perdreau-Remington F, Brooks GF: Characterization of antimicrobial resistance in Streptococcus pyogenes isolates from the San Francisco Bay area of Northern California. J Clin Microbiol 1999;37:1727–1731. Van Asselt GJ, Sloos JH, Mouton RP, Van Boven CP, Van de Klundert JA: Susceptibility of Streptococcus pyogenes to azithromycin, clarithromycin, erythromycin and roxithromycin in vitro. J Med Microbiol 1995;43:386–391. Traub WH, Leonhard B: Comparative susceptibility of clinical group A, B, C, F, and G betahemolytic streptococcus isolates to 24 microbial drugs. Chemotherapy 1997;43:10–20. Arvand M, Hoeck M, Hahn H, Wagner J: Antimicrobial resistance in Streptococcus pyogenes isolates in Berlin. J Antimicrob Chemother 2000;46:621–623. Mitsuhashi S, Inoue K, Saito K, Nakane M: Drug resistance in Streptococcus pyogenes strains isolated in Japan; in Schlessinger D (ed): Microbiology. Washington, American Society for Microbiology, 1982, pp 151–154. Fujita K, Murono K, Yoshikawa M, Murai T: Decline of erythromycin resistance of group A betastreptococci in Japan. Pediatr Infect Dis J 1994;13:1075–1078. Kano S, Kimura T: Prevalence of hemolytic streptococcal infection in Kitakyushu: Incidence and characteristics of isolates (1994–1997) (in Japanese). Kansenshougaku-Zasshi 2000;74:511–517. Leclercq R, Courvalin P: Bacterial resistance to macrolide, lincosamide, and streptogramin antibiotics by target modification. Antimicrob Agents Chemother 1991;35:1267–1272. Weisblum B: Erythromycin resistance by ribosome modification. Antimicrob Agents Chemother 1995;39:577–585. Lai CJ, Weisblum B: Altered methylation of ribosomal RNA in an erythromycin-resistant strain of Staphylococcus aureus. Proc Natl Acad Sci USA 1971;68:856–860. Fernandez-Munoz R, Monro RE, Torres-Pinedo R, Vasquez D: Substrate- and antibiotic-binding sites at the peptidyl-transferase center of Escherichia coli ribosomes: Studies on the chloramphenicol, lincomycin and erythromycin sites. Eur J Biochem 1971;23:185–193.

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15 16 17 18 19 20

21 22

23 24 25

26 27

28 29

30 31 32

33

Dubnau D: Translational attenuation: the regulation of bacterial resistance to the macrolidelincosamide-streptogramin B antibiotics. Crit Rev Biochem 1990;16:103–132. Weisblum B: Insights into erythromycin action from studies of its activity as inducer of resistance. Antimicrob Agents Chemother 1995;39:797–805. Weisblum B: Macrolide resistance. Drug Resist Update 1998;1:29–41. Choi SS, Kim SK, Oh TG, Choi EC: Role of mRNA termination in regulation of erm K. J Bacteriol 1997;179:2065–2067. Werckenthin C, Schwarz S, Westh H: Structural alterations in the translational attenuator of constitutively expressed ermC genes. Antimicrob Agents Chemother 1999;43:1813–1814. Horinouchi S, Byeon WH, Weisblum B: A complex attenuator regulates inducible resistance to macrolides, lincosamides, and streptogramin type B antibiotics in Streptococcus sanguis. J Bacteriol 1983;154:1252–1262. Seppälä H, Skurnik M, Soini H, Roberts MC, Huovinen P: A novel erythromycin resistance methylase gene (erm TR) in Streptococcus pyogenes. Antimicrob Agents Chemother 1998;42:257–262. Roberts MC, Sutcliffe J, Courvalin P, Jensen LB, Rood J, Seppälä H: Nomenclature for macrolide and macrolide-lincosamide-streptogramin B resistance determinants. Antimicrob Agents Chemother 1999;43:2823–2830. Clancy J, Petitpas J, Dib-Hajj F, et al: Molecular cloning and functional analysis of a novel macrolideresistance determinant, mefA, from Streptococcus pyogenes. Mol Microbiol 1996;22:867–879. Kataja J, Huovinen P, Skurnik M, Seppälä H: Erythromycin resistance genes in group A streptococci in Finland. Antimicrob Agents Chemother 1999;43:48–52. Johnston NJ, de Azavedo JC, Kellner JD, Low DE: Prevalence and characterization of the mechanisms of macrolide, lincosamide, and streptogramin resistance in isolates of Streptococcus pneumoniae. Antimicrob Agents Chemother 1998;42:2425–2426. Luna VA, Coates P, Eady EA, Cove J, Nguyen TTH, Roberts MC: A variety of gram–positive bacteria carry mobile mef genes. J Antimicrob Chemother 1999;44:19–25. Kataja J, Huovinen P, The Macrolide Resistance Study Group, Seppälä H: Erythromycin resistance in group A streptococci of different geographical origins. J Antimicrob Chemother 2000;46: 789–792. Bessen DE, Sotir CM, Readdy TL, Hollingshead SK: Genetic correlates of throat and skin isolates of group A streptococci. J Infect Dis 1996;173:896–900. Avanzini C, Bosio K, Volpe G, Dotti G, Savoia D: Streptococcus Pyogenes collected in Torino (Northern Italy) between 1983 and 1998: Survey of macrolide resistance and trend of genotype by RAPD. Microb Drug Resist 2000;6:289–295. Savoia D, Avanzini C, Bosio K, Volpe G, Carpi D, Dotti G, Zucca M: Macrolide resistance in group A streptococci. J Antimicrob Chemother 2000;45:41–47. Murase T, Suzuki R, Watanabe Y, Yamai S: Erythromycin resistance genes in Streptococcus pyogenes isolates in Kanagawa, Japan. Microbiol Immunol 2000;44:863–865. Granizo J, Aguilar L, Dal-Re R: Ten Years Streptococcus pyogenes resistance to macrolides in Spain, in relation to macrolide consumption. Proceeding of the Second International Meeting on the Therapy of the Infections, Florence, 1998, p 99. Baquero F: Antibiotic resistance in Spain: What can be done? Task Force of the General Direction for Health of the Spanish Ministry of Health. Clin Infect Dis 1996;23:819–823.

N. Yamanaka, MD, PhD Department of Otolaryngology-Head and Neck Surgery Wakayama Medical University, 811–1, Kimiidera, Wakayama, 641-0012, Japan Tel. ⫹81 73 441 0651, Fax ⫹81 73 448 2434, E-Mail [email protected]

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Pechère JC, Kaplan EL (eds): Streptococcal Pharyngitis. Issues Infect Dis. Basel, Karger, 2004, vol 3, pp 150–165

Macrolide Resistance of Streptococcus pyogenes Giuseppe Cornagliaa, André Bryskierb a b

Dipartimento di Patologia, Università di Verona, Verona, Italy; Direction des Recherches Anti-Infectieux Aventis, Romainville, France

Although benzylpenicillin (penicillin G) or the oral phenoxypenicillin (penicillin V) are reported by American and European textbooks as the first-choice drugs in the management of pharyngitis caused by Streptococcus pyogenes (group A ␤-hemolytic streptococcus) [1, 2], the use of erythromycin A and its derivatives or analogues is of great importance if one considers that macrolides become first-choice drugs in all those instances in which ␤-lactams cannot be used in clinical practice, for example, when the patient suffers from ␤-lactam hypersensitivity. Moreover, high rate of bacteriological failures have been reported in the last decade for treatments with penicillin V [3, 4], thus prompting for alternative therapeutic regimens. Multiple causes can account for what looks like a complex phenomenon, and among them one can include the localization of S. pyogenes in tonsillar intraepithelium [5, 6]. Group A streptococci, although typical extracellular pathogens, can in fact be efficiently internalized by and survive within human cells of respiratory tract origin. The invading ability varies from one S. pyogenes strain to another, and a streptococcal adhesin, fibronectin-binding F-1 (encoded by gene prtF1) is required for efficient entry in epithelial cell [7]. It has been shown that prtF1-positive strains were significantly more abundant among erythromycin A resistant isolates than among erythromycin-susceptible isolates (89% versus 21%). The gene was present in all isolates of the MLSB type (inducible and constitutive) and in 73% of the M-phenotype strains [8]. Thus, the invading ability of some S. pyogenes strains and its greater diffusion among erythromycin A resistant isolates may well contribute to the failures of many therapies with ␤-lactam antibiotics – which notoriously

(and contrary to macrolides) have no intracellular activity – and it may facilitate as well the widespread diffusion of erythromycin A-resistant isolates. However, few reports of S. pyogenes resistant to erythromycin A were available until recently, all isolates being considered basically susceptible to erythromycin A and its derivatives, but over the past few years increased resistance rates have frequently been reported, somehow paralleling the increased clinical use of old and new macrolides in upper respiratory tract infections. Consumption of macrolides in upper respiratory tract infections is indeed widespread, and has been held responsible for the upsurge in macrolide resistance in all major outbreaks so far described [9–12], as discussed later in this chapter.

Mode of Action of 14- and 15-Membered Ring Macrolides and Ketolides

Macrolide antibiotics are composed of a large (macro) lactone ring (olide) and one or two sugars (neutral and amino), and are divided, according to the size of the lactone ring, in 14-, 15-, 16-membered ring macrolides. Erythromycin A and its semisynthetic derivatives prevent bacterial protein synthesis by binding to the bacterial ribosome and inhibiting elongation of the nascent polypeptide chain. The site and mode of action on the ribosome of erythromycin A, a 14-membered ring macrolide, roughly overlaps that of other 14- and 15-membered ring macrolides, as well as the site of action of the chemically distinct lincosamides and streptogramin type B antibiotics. Hence, streptococci are also cross-resistant to the semisynthetic derivatives of erythromycin A (clarithromycin, roxithromycin and flurithromycin) and to the 15-membered ring azalide azithromycin. The target of erythromycin A and derivatives is the blockage of the peptidyltransferase site but not of the enzymatic activity (inhibition by the 16-membered ring macrolides). The peptidyltransferase site is located in the 23S rRNA of the 50S ribosomal subunit. The 23S rRNA is composed of six domains. Two of them belongs to the peptidyltransferase site: domain V and II which are linked by the 5S rRNA. Erythromycin A binds specifically on adenine 2058 located on domain V. The ketolides in addition to their fixation on domain V are linked to domain II through their C11-C12 side chain (telithromycin) or the C-6 side chain (cefthromycin). Erythromycin A is able to blocks the synthesis of the nascent 50S ribosomal subunit leading to a strong intracellular depression of ribosomal content of the bacterial cell as described for Staphylococcus aureus and Bacillus subtilis. However, no data are available for S. pyogenes.

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Molecular Basis of Macrolide Resistance

Macrolide resistance in streptococci can be related to either target site modification or active efflux. The third resistance mechanism, namely enzymatic inactivation or hydrolysis of the lactone ring, has not be reported to date for streptococci. Modification of the Target Site The target modifications are located at the level of the 50S ribosomal subunit either by mutation occurring on domain V of the 23S rRNA (peptidyltransferase site) or by methylation at this level. Mutations in ribosomal protein L4 and in 23S rRNA have been reported originally in macrolide-resistant pneumococci, but a recent report shows that similar mutations can be found in macrolide-resistant S. pyogenes too [13]. Differently to that found in pneumococci, no mutation in ribosomal protein L22 has been so far reported in macrolide-resistant S. pyogenes. Post-transcriptional modification of a highly conserved adenine residue (termed A2058 on the basis of its position in Escherichia coli) by an N-methyltransferase (‘methylase’) causes a structural modification of the ribosome, which confers high level resistance to all macrolide, lincosamide, and streptogramin B antibiotics and has been named ‘MLSB’ resistance. MLSB resistance can be divided into constitutive, when the methylase is produced continuously, and inducible, when the presence of an inducing antibiotic is required for production of the enzyme. The family of enzymes which catalyse this modication are designated by the acronym Erm, which stands for erythromycin resistance methylase. In S. pyogenes, MLSB resistance has commonly been ascribed to the erm(AM) gene until a few years ago, when a novel erm gene, originally designated erm(TR), was characterized from a clinical strain isolated in Finland [14]. According to a recently proposed nomenclature [15], the erm genes are now designated as erm(A) [formerly erm(TR)] and erm(B) [formerly erm(AM)]. Many recent reports suggests that erm(A) is not only the most common erm gene detected in S. pyogenes from various geographic areas [9, 16], but also circulates among species of several bacterial genera, including anaerobic cocci of the oropharyngeal flora [17, 18]. Plasmids carrying the erm(B) gene have been isolated from S. pyogenes [19], though, in general, antibiotic resistance genes in streptococci are chromosomal and often associated with conjugative transposons [20]. Conjugative transfer of the erm(A) gene from Peptostreptococcus magnus to S. pyogenes [18] and from S. pyogenes to S. pyogenes, Enterococcus faecalis and Listeria innocua [21] have been recently demonstrated.

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Table 1. In vitro activities of macrolides and ketolides for S. pyogenes MLSB isolates classified by erm gene Genotype

Number of isolates

Antibacterials

erm(B)

52

erm(A)

18

MIC, ␮g/ml range

MIC50

MIC90

Erythromycin A Clindamycin Josamycin Spiramycin Miocamycin Rokitamycin Telithromycin

256–⬎256 0.032–1 ⱕ0.06–⬎256 0.12–⬎256 ⱕ0.06–⬎256 ⱕ0.06–⬎256 0.006–⬎32

⬎256 0.125 ⬎256 ⬎256 256 256 0.094

⬎256 0.38 ⬎256 ⬎256 ⬎256 ⬎256 8

Erythromycin A Clindamycin Josamycin Spiramycin Miocamycin Rokitamycin Telithromycin

256–⬎256 0.064–0.19 ⱕ0.06–⬎256 ⱕ0.06–⬎256 ⱕ0.06–256 ⱕ0.06–0.5 0.006–0.125

⬎256 0.094 ⱕ0.06 0.5 ⱕ0.06 ⱕ0.06 0.016

⬎256 0.125 2 8 32 ⱕ0.06 0.125

The presence of an erm(B) gene impairs in vitro activities of 14-, 15-, and 16-membered ring macrolides with MICs ⱖ256 ␮g/ml. Telithromycin activity is bimodal, with more than 95% of isolates remaining susceptible (MIC ⱕ2 ␮g/ml). This fact is probably due to the degree of methylation of N6 amino group of adenine 2058. When this amino group is monomethylated, only telithromycin retains activity and macrolides are inactive. If this amino group is dimethylated, both macrolides and ketolides are inactive [22]. For S. pyogenes isolates harboring the erm(A) gene, which encodes for an inducible mechanism of resistance, in vitro activity of 16-membered ring macrolides is retained as well as those of telithromycin. In vitro activities of 14-and 15-membered ring macrolides are invariably affected (table 1).

Erythromycin A Efflux The efflux-based resistance was defined in studies conducted by Sutcliffe et al. [23], who reported that the vast majority of erythromycin A-resistant S. pyogenes and S. pneumoniae strains collected between 1993 and 1995 in the United States had the ‘M phenotype’, which they characterized as resistance to 14-membered and 15-membered ring macrolides, but not to clindamycin and streptogramin type B antibiotics.

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Table 2. In vitro activities of macrolides and ketolides for S. pyogenes isolates with or without the mefA efflux gene [63] Genotype

mef(A)⫺ (Ery S)

mef(A)⫹

Number of isolates

Antibacterials

334

45

MIC, ␮g/ml range

MIC50

MIC90

Erythromycin A Clindamycin Spiramycin Miocamycin Rokitamycin Josamycin Telithromycin

ⱕ0.016–0.19 0.016–0.125 ⱕ0.06–1 ⱕ0.06–1 ⱕ0.06– 0.5 ⱕ0.06–0.5 0.003–0.064

0.032 0.047 0.25 ⱕ0.06 ⱕ0.06 ⱕ0.06–0.5 0.012

0.064 0.094 0.5 ⱕ0.06 ⱕ0.06 ⱕ0.06 0.016

Erythromycin A Clindamycin Spiramycin Miocamycin Rokitamycin Josamycin Telithromycin

2–16 0.023–05 ⱕ0.06–0.5 ⱕ0.06–2 ⱕ0.06 ⱕ0.06–1 0.012–0.5

4 0.047 0.12 ⱕ0.06 ⱕ0.06 ⱕ0.06 0.38

8 0.094 0.5 0.12 ⱕ0.06 0.12 0.5

The efflux pumps are driven by an active proton motive force, and they belong to the efflux superfamily named ‘major facilitators’ [24]. The respective genes, mef(A) from S. pyogenes, and mef(E) from S. pneumoniae, encoding for membrane-associated proteins, were cloned, functionally expressed, and sequenced [25, 26]. They are 90% identical and were assigned to the same mef(A) class in the recently proposed nomenclature for macrolide resistance determinants [15]. However, the recent report that mef(A) and mef(E) genes are carried by different genetic elements, at least in S. pneumoniae, would suggest that the distinction between the two genes be maintained [27]. Transfer of mef(A) by conjugation from M-phenotype isolates to S. pyogenes and/or Enterococcus faecalis has recently been reported [9, 28]. Some mef-containing S. pneumoniae strains were able to transfer mef(A) (but not mef(E)) by conjugation, being possibly endowed with an element similar to the complete conjugative transposon described recently in S. pyogenes [27–29]. Table 2 reports the in vitro activities of macrolides and ketolides for S. pyogenes isolates with or without the mef(A) efflux gene. Laboratory Detection of Resistance The resistance phenotype of S. pyogenes isolates is determined in vitro by the double disk test with erythromycin A and clindamycin disks [30]. The disks

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are placed 15–20 mm apart on the surface of Mueller-Hinton agar, supplemented with 5% defibrinated sheep blood and inoculated by a direct colony suspension procedure (turbidity equivalent to 0.5 McFarland). After 18–42 h of incubation at 35⬚C, 5% CO2, the clindamycin inhibition zone may deviate from the expected circular shape and assume a distorted ‘D’ shape instead, indicating inducible MLSB resistance (IR), whilst resistance to clindamycin with no blunting of the clindamycin inhibition zone indicates constitutive MLSB resistance (CR). The M phenotype is characterized by resistance to erythromycin A and by susceptibility to clindamycin (as in MLSB-IR) without blunting of the inhibition zone around the clindamycin disk. All erythromycin A-resistant S. pyogenes isolates, irrespective of their phenotypes, are uniformly resistant to the 14- and 15-membered ring macrolides, such as erythromycin, clarithromycin, roxithromycin, and flurithromycin, and to the related 15-membered azalide azithromycin. The resistance levels are variable, since the MIC90 values for all these compounds are roughly 16 ␮g/ml in the IR and M phenotypes (low-level resistance) and ⬎64 ␮g/ml in the CR phenotypes (high-level resistance). On the other hand, the different phenotypes are endowed with different patterns of resistance to the 16-membered ring macrolides, such as spiramycin, josamycin, miocamycin and rokitamycin, and to the related compounds clindamycin and streptogramin B. All CR isolates are highly resistant to 16-membered ring macrolides and to clindamycin and streptogramin B, whereas all M isolates and variable percentages of IR isolates are susceptible to these antibiotics (‘dissociated resistance’). The dissociated resistance in IR streptococci is due to large differences in the inducing abilities of MLSB antibiotics, and is much less clear-cut than observed in staphylococci, accounting for the diversity of the resistance phenotypes observed in the double disk test when different 16-membered ring macrolides are tested on streptococci.

Epidemiology of Erythromycin A Resistance

Early Reports Erythromycin A-resistant S. pyogenes were first reported in 1959 in the United Kingdom [31], but the occurrence of such strains has been considered exceptional until the past decade. Throughout the 1970s, the frequency of isolation of S. pyogenes resistant to erythromycin A and lincomycin showed a dramatic nation-wide increase in Japan, up to 83.1% in 1977 [10, 32]. Resistance was often confined to the T12 type, known to be nephritogenic, but glomerulonephritis was rarely reported.

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The prevalence of erythromycin A-resistant S. pyogenes isolates decreased dramatically when the use of erythromycin was reduced [33]. The Last Decade and the Spread of Macrolide Resistance in Europe Over the period 1984–1996, 2,561 S. pyogenes isolates were studied in Spain [34]. Up until 1990, only 1.2% of isolates were resistant to erythromycin A. Thereafter, the prevalence increased every year up to 1995, when 34.8% of isolates were resistant to erythromycin A. After 1995, paralleling a significant reduction in erythromycin use for S. pyogenes infections, the resistance rate for erythromycin A decreased. A nationwide survey carried out in six Finnish centers in the early1990s showed that the resistance rate of erythromycin A for S. pyogenes collected from pharyngeal and pus samples had increased from approximately 5% in 1988–1989 to 13% in 1990. The plurality of PFGE profiles and serotypes suggested a multiclonal origin of this outbreak [35, 36]. A previously unrecognized phenotype, named NR standing for ‘novel resistance’ (later phenotype M), was exhibited by 38% of the S. pyogenes isolates [30]. The level of prescription of erythromycin, which had almost tripled in Finland during the 1980s, correlated significantly with the resistance rates in the different geographic areas of Finland, and then declined after a nation-wide reduction of the use of macrolides for outpatients for S. pyogenes infections [37]. Time trends in S. pyogenes resistance to erythromycin A and clindamycin, systematically assessed on the basis of data collected from 13 laboratories over the period from 1993 to 1995 [38, 39], showed a dramatic increase in the incidence of erythromycin A-resistant strains in Italy, with a clear parallelism between the increase in macrolide consumption and the upsurge in resistance [11]. The incidence of resistant strains increased up to 20 times, with a mean value of 26.8% in 1995 and roughly 40% in 1997–1998. The resistance most often than not affected the 16-membered ring macrolides and the lincosamides, too (MLSB phenotype). In another survey carried in Italy over a 6 year period in Siena, resistance rate to erythromycin A increased from 9% (in 1992) to 53% (in 1997). In 1992 and 1993, only erm(B) genes were detected but the incidence of erm(TR) gene increased steadily over the 4 following years (8, 5, 26 and 37%, respectively) [40]. A European network for the study of resistance in group A streptococci collected data from different areas in Europe in 1998–1999, drafting a rough map of erythromycin A resistance [41]. Such a map varied with astonishing rapidity according to the spread of resistance: no erythromycin A-resistant S. pyogenes had been detected in Iceland until the second quarter of 1998, but the incidence of such strains in that country rose up to 40–50% in the first months of 1999 [42]. Erythromycin A resistance seemed to be very limited in other countries of

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Northern Europe – except Finland – and in Ireland. No resistant S. pyogenes had been reported in Romania, and rates lower than 5% were reported from Russia, but ranged from 5 to 15% in most other Eastern and Central European countries with even higher prevalence in the Baltic Republics and Ukraine. Percentages ranging from 5 to 15% were also reported in Western Europe, with slightly higher resistance rates in Austria. As regards the countries of the former Yugoslavia for which data could be obtained, resistance rates were below 5% in Macedonia, whilst they exceeded 5% in Slovenia and 10% in Croatia. In the Southern Europe, Italy and Portugal led the field with the highest percentages (roughly 40%), and values over 25% were reported from Greece and Spain, too. The scarce available information about the resistance phenotypes and genotypes were in favor of a substantial prevalence of the M phenotype in Europe, with the partial exception of Italy [9, 12, 43–45]. Susceptibility Reports from Asia and Australia In Taiwan, erythromycin A and azithromycin showed poor activities against S. pyogenes strains isolated from January 1992 to December 1993, most isolates being not inhibited by a concentration of 128 ␮g/ml. Erythromycin was reported to have been prescribed frequently as a first-line antibiotic for patients with upper respiratory tract infections in hospital, in addition to being readily available over the counter in chemists’ shops, without a doctor’s prescription 4 [46]. In a survey carried out in Hong Kong in 1999, the prevalence of S. pyogenes isolates resistant to erythromycin A was 28%, half of which contained the erm(B) gene and the other half containing the erm(TR) gene. In the same surveillance study, the prevalence of S. pyogenes resistant to erythromycin A was 19.3% in Korea (73% erm(B) and 27% mef(A)), 15.8% in Japan (75% mef(A) and 20% erm(TR) and 5% erm(B) strains); in Indonesia, out of a relative small number of isolates, none proved resistant to erythromycin A [47]. Since January 1985, a dramatic increase in the prevalence of erythromycin-A resistant S. pyogenes infections occurred in outpatients presenting to the Fremantle Hospital in Western Australia, coinciding with the arrival of large numbers of visitors from elsewhere in Australia and from overseas to attend the America’s Cup competition. The prevalence of erythromycin A strains rose to 9.1% in 1986 and to 17.6% in 1987. Several M- and T-types of S. pyogenes were involved [48]. In a recent survey (1999–2000), the resistance rate for erythromycin A was 4.7% (erm(B) 57.1%, mef(A) 42.9%) [47]. Susceptibility Reports from North America and Latin America Reports from the United States indicated erythromycin A-resistance rates of 0.5% in 1978 [49] and 5% in 1981 [50]. Strains collected from 31 states over the period 1989 to 1992 demonstrated an erythromycin A MIC of 0.5 ␮g/ml or

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greater in approximately 4% of cases [51]. Of the respiratory tract isolates collected during the winter of 1993–1994 in 12 different outpatient clinics throughout continental USA, roughly 2% proved erythromycin A-resistant [52]. In 3,205 clinical isolates recently collected in Southern Ontario, Canada, resistance to erythromycin A was found in 2.1%; of the S. pyogenes isolates, 70% of them were fully susceptible to clindamycin and were found to harbor the mef(A) gene by PCR [16]. As far as South America is concerned, a survey on the prevalence of erythromycin A susceptibility of S. pyogenes was carried out between May and October 1994 in Argentina; 4 of 1,072 isolates were found to be resistant to erythromycin A [53]. In a recent survey between 1999 and 2000 in one center in Buenos Aires, the resistance rate was 12.1% and all the erythromycin A isolates harbored a mef(A) gene [37]. In the same survey it was found that the resistance rate for erythromycin A in Brazil was 5.5% (all mef(A)) and 11.1% in Mexico (73% mef(A) and 27% erm(TR)) [47]. Multiple clones of erythromycin A resistance in S. pyogenes were isolated in 1996 in Santiago, Chile; the M phenotype was the most prevalent, but all three phenotypes of erythromycin A resistance were found [54]. Present Trends In very recent years, the map of erythromycin A resistance in Europe, United States, Canada and Australia has been updated, and more light has been shed on the different phenotypes and molecular mechanisms involved. Most data stem from investigations on the activity of the new ketolide telithromycin, performed on clinical isolates recovered between 1999 and 2000, and provide us with information about this compound, too. In Western Europe (table 3), the incidence of erythromycin A resistance was lower than 5% in Norway, Sweden, Denmark, the Netherlands, Switzerland and Ireland, ranged between 5 and 10% in Austria, Finland, France and The United Kingdom, between 10 and 15% in Germany, Belgium and Luxembourg, and was above 20% in Italy, Spain, Greece, Iceland and Portugal; the latter country led the rank with 27.3% of resistant isolates [Aventis, data on file]. The erm and mef genes were evenly represented in the countries with less than 5% of resistant strains. The mef genes prevailed in Austria, Greece (roughly 65% in both countries) and mostly in Spain (83%, but 100% if the erm/mef combinations are included). The erm(B) gene could be found mostly in Portugal (68%), Belgium (being the only erm gene and accounting for almost 60% of all resistance determinants), France (50%, again the only erm gene) and Italy (34%, as for mef(A), versus 8% of erm(A)-bearing isolate), whilst erm(A) prevailed in the United Kingdom (53%), Greece (36%), and Austria (25%). As far as Eastern Europe is concerned (table 4), the incidence of erythromycin A resistance ranged between 5 and 10% in Romania, Hungary, Turkey,

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Table 3. S. pyogenes resistant to erythromycin A: prevalence of different genotypes in the different countries of Western Europe, 1999–2000

Austria Belgium Denmark Finland France Germany Greece Iceland Ireland (Eire) Italy Luxembourg The Netherlands Norway Portugal Spain Sweden Switzerland United Kingdom

Resistant strains

Genes, %

n

n

%

mef(A) erm(B)

erm(A)

erm(B)+mef

206 599 377 133 441 381 161 150 158 269 86 383 199 300 202 199 ? 994

20 82 11 10 38 55 36 32 3 64 9 5 2 82 48 0 ? 53

9.7 13.7 2.9 7.5 8.6 14.4 22.4 21.4 1.9 23.8 10.5 1.3 1.0 27.3 23.8 0.0 2.6 5.3

13 33 – 3 17 12 23 NT 1 22 1 – – 16 40 – ? 16

5 – 2 4 – 4 13 NT – 5 2 1 – 2 – – ? 28

– – 7 – – – – NT – 2 3 2 – – 8 – ? 1

2 49 2 3 19 1 – NT 2 22 3 2 – 64 – – ? 5

Czech Republic and Latvia, between 10 and 15% in Lithuania, Russia, Estonia and Slovenia, and between 15 and 20% in Bulgaria, Poland, Croatia and Slovak Republic [Aventis, data on file]. Genes of the mef class represented 80% of all resistance determinants in Romania and approached 70% in the Slovak Republic. Otherwise, the erm genes were largely prevalent in Russia, Hungary, Bulgaria and Croatia (roughly 65–80% of all resistance determinants in these countries) and represented almost 90% of all resistance determinants in Turkey and the only resistance determinant in Lithuania, Slovenia, Czech Republic, Latvia and Poland. the erm(A) gene was usually the most frequent or the only erm gene found in these countries [55], with the only exceptions of Hungary (40% erm(A) and 40% erm(B)) and Slovakia (where erm(B) was the only erm gene, accounting for 30.8% of all resistant strains). According to the breakpoints that have been official in Europe since July 2001, namely S (ⱕ0.5 ␮g/ml), I (1–2 ␮g/ml) and R (⬎2 ␮g/ml), telithromycin was active against 99.4% of the strains tested in Western Europe and against 98.5% of the strains tested in Eastern and Central Europe.

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Table 4. S. pyogenes resistant to erythromycin A: prevalence of different genotypes in Central and Eastern Europe (including Turkey), 1999–2000

Bulgaria Croatia Czech Republic Estonia Hungary Latvia Lithuania Poland Romania Slovakia Slovenia Russia Turkey

Resistant strains

Genes, %

n

n

%

erm(B)

erm(A)

mef(A)

106 99 104 100 97 100 99 98 103 102 102 600 100 92

18 17 8 13 5 9 10 16 10 16 13 0 14 8

17.0 17.2 7.7 13.0 5.2 9.0 10.1 16.3 9.7 15.7 12.7 0.0 14.0 7.0

– 28.6 – ND 40 – – 35.7 10 30.8 – – ND 11.1

66.7 35.7 100 ND 40 100 100 64.3 10 – 100 – ND 77.8

33.3 35.7 – ND 20 – – – 80 69.2 – – ND 11.1

ND ⫽ Not determined.

Until very recently, susceptibility reports on S. pyogenes from the United States have constantly shown low levels of erythromycin A resistance. In a recent survey carried out in the US in 1999, it was shown that the prevalence of S. pyogenes in the 9 US Bureau of the census regions ranged from 3.08% (New England) to 7.7% (Pacific) [56]. In previous reports, resistance rate was 2.6% between 1994 and 1997 [57]. In January 2001, during a longitudinal study of schoolchildren in Pittsburgh, PA, M-type erythromycin resistance was indeed detected in 48% of pharyngeal isolates of group A streptococci. Molecular typing indicated that the outbreak was due to a single strain of group A streptococci. This clonal outbreak also affected the wider community, since of 100 randomly selected isolates of group A streptococci obtained from the community, 38 were resistant to erythromycin [58]. Role of Low-Level Resistance and Clinical Importance of the Different Macrolides

Doubts about the clinical importance of in vitro resistance undoubtedly arise as a result of the high prevalence of the M phenotype, characterized by

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low-level resistance. The possibility of curing low-level-resistant strains with higher doses of erythromycin should be viewed with extreme caution from a clinical point of view, and it would appear to be hazardous at the very least to apply the same considerations regarding S. pneumoniae and penicillin G to another species, albeit in the same bacterial genus, and to a completely different class of antibiotic. The semisynthetic derivatives of erythromycin A show the same cross resistance as erythromycin A. Attempts at using ‘newer’, semisynthetic macrolides to overcome erythromycin A resistance, on the grounds of presumed clinical differences between low- and high-level resistance, are by no means a novel development in the use of these compounds. Basic knowledge of the history of macrolide resistance should remind us that whenever the so-called ‘dissociated resistance’ has been adduced in order to substitute newer – and supposedly more active – macrolides for those which the resistance has rendered ineffective, high-level constitutive resistance to all the compounds in this group has been selected. All the macrolides, including 16-membered ring macrolides, are ineffective against MLSB constitutive type of resistance. Inducible MLSB-resistant isolates of S. aureus apparently remained susceptible to 16-membered ring macrolides, such as spiramycin, josamycin or semisynthetic derivatives such as miocamycin and rokitamycin, and were described as showing ‘dissociated resistance’. Unexpectedly, however, the erythromycininducible (‘dissociated’) strains proved rapidly capable of developing an MLSBtype constitutive resistance, arising as a consequence of nucleotide sequence alterations (constitutive expression can be obtained in vitro from inducible strains at frequencies of 10–7 to 10–8) [59–62]. A practical consequence of a clinically important difference in resistance phenotypes would be that clinical microbiology laboratories should test and report on several MLSB antibiotics, and not only on erythromycin A, for a complete assessment of macrolide resistance in S. pyogenes. To this end, and for the purposes of administering the appropriate treatment, the precise implications of different resistance phenotypes for clinical and bacteriological outcomes need to be fully understood, mainly with a view to the possibility of using 16-membered ring macrolides in dissociated resistance and to the possible emergence of constitutively resistant mutants. Perhaps, there is no harm in recalling once again that all these clinical discussions make sense only when macrolides become first-choice antibiotics, owing to the extensive availability of first-line therapeutic alternatives. The rationale for the alleged possibility of using 16-membered ring macrolides when S. pyogenes isolates prove resistant to 14-membered and 15-membered ring macrolides is that these compounds proved somehow effective against the IR and M phenotypes. All of the M strains and 65% of the IR strains

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(but none of the CR strains) were susceptible to miocamycin in the Finnish outbreak [30]. Similarly, all of the M strains and less than 50% of the IR strains (but again none of the CR strains) were susceptible to josamycin in a survey carried out in Northern Italy [44]. In vitro activity of the different 16-membered ring macrolides varied against erythromycin A-resistant S. pyogenes isolated from different Italian geographic areas [63]. Such differences clearly related with the different phenotypes of erythromycin A resistance; resistance rate to the 16-membered ring macrolides was high among all the MLSB CR isolates, whilst the MLSB IR isolates showed different pattern of susceptibility. On the latter isolates, spiramycin and josamycin showed the lowest activity, whilst midecamycin and rokitamycin were more effective. In this study, all the M isolates proved susceptibility to all 16-membered ring macrolides. In spite of the in vitro results, the use of 16-membered ring macrolides against IR strains should be regarded with caution, on the basis of previous experience with the other cases of ‘dissociated’ resistance. It is worth reminding that the susceptibility of IR staphylococcal strains to non-inducing MLSB antibiotics in the clinical setting proved to be of limited value because of the rapidity with which constitutively resistant mutants were selected from these strains, resulting in clinical and bacteriological relapse [59–62]. Owing to the totally different mechanism of resistance, the use of 16-membered ring macrolides would seem safer against those S. pyogenes isolates endowed with an M phenotype, but this use has not been implemented by clinical evidences. Removal of L-cladinose at position 3 in the erythronolide A ring and oxidation of the resulting 3-hydroxyl to a 3-keto group has given rise to a new class of compounds designed to overcome erythromycin A resistance: the ketolides; only one compound, namely telithromycin, is currently introduced in clinical practice. Telithromycin does not share cross resistance with erythromycin A and post-marketing surveillance will be essential to detect how this compound will behave as far as resistance is concerned.

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Giuseppe Cornaglia, MD, PhD Department of Pathology, University of Verona Verona (Italy) Tel. ⫹39 045 802 7196, Fax ⫹39 045 584 4606, E-Mail [email protected]

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Pechère JC, Kaplan EL (eds): Streptococcal Pharyngitis. Issues Infect Dis. Basel, Karger, 2004, vol 3, pp 166–172

Cost Issues in Streptococcal Pharyngitis Jean Claude Pechère University of Geneva, Geneva, Switzerland

Several hundred millions of humans suffer from streptococcal pharyngitis every year and everybody realizes that the economical impact of the disease is considerable. However, beyond this very general statement, the actual cost of pharyngitis at the world level remains unknown. No large economical studies are available. In particular, cost data from developing countries, which pay large tributes to the disease, are almost nonexistent. Only a few economical evaluations have been published, which were carried out in developed areas at a local level. These studies considered essentially the direct costs, predominant in poor areas, but representing only a portion of the total bill in developed countries, where the impact of pharyngitis on the patient activities is by far the major cost driving force (table 1). Direct costs include physician visits, acquisition of drugs, laboratory tests, treatment of toxic and allergic reactions associated to therapy, and the cost of complications, considerable in areas of high prevalence of acute rheumatic fever (ARF). Indirect costs are much more difficult to evaluate. They include loss of earnings incurred by patients with pharyngitis, the time taken off work for carrers in case of children, plus the indirect costs associated with the complications such as the limitation of working capacities after rheumatic cardiac disease. Usually overlooked, although probably significant both money wise and for the environment, are the cost of bacterial resistance induced by antibiotic therapy, and the cost of epidemiological spread of Streptococcus pyogenes in untreated patients. Many basic and practical issues remain unclear in streptococcal pharyngitis, including those for the daily management. However, due to the considerable number of patients and billions of dollars involved, one may suggest that when different attitudes are available, based upon equivalent scientific evidence, the cost issue should be considered as a decisional tool. This is the purpose of this chapter. Two main questions will be examined, the first dealing with diagnostic procedures, and the second with cost-effectiveness of antibiotics for sore throat.

Table 1. Cost of pharyngitis in France before and after use of streptococcal rapid antigen test for the diagnosis of acute pharyngitis in adults of 25 years or more Structure of cost

Cost without rapid antigen test (‘before’) Euros

Cost with rapid antigen test (‘after’) Euros

Physician visits Antibiotic acquisition cost Symptomatic treatment Lab test Rapid antigen test Absenteeism Total

19.07 13.17 6.68 0.47 0 114.84 154.23

18.6 6.16 7.78 1.66 2.84 100 137.04

From Portier et al.

Is Microbiological Diagnosis of Streptococcal Pharyngitis Cost Effective?

First Approaches It is difficult to ensure the diagnosis of streptococcal pharyngitis on clinical grounds, when viruses cause most pharyngitis. So, a microbiological confirmation is often recommended, aiming at reducing antibiotic use in patients with pharyngitis. A simple (simplistic?) approach compares the acquisition cost of antibiotics plus that of the microbiology for two different strategies. (1) Treat all patients with pharyngitis without testing. (2) Sample the throat when a pharyngitis is diagnosed clinically and treat only with those positive for S. pyogenes. The calculation is easy, but obviously provides only a rough idea of the costbenefit of the microbiological diagnosis. Only the antibiotic treatment in 100% of the patients is considered in the ‘treat all’ strategy, when the cost of the ‘treat only the positives’ strategy includes throat sampling in all patients plus antibiotic treatment in patients with proven streptococcal pharyngitis. It becomes immediately apparent that, beside the cost of microbiology and antibiotics, the relative frequency of S. pyogenes is a key feature, as soon as the microbiology in cheaper than the treatment, which is usually the case in developed countries. More streptococci provide an advantage to the ‘treat all’ strategy. In Geneva in 1995, where during the study period 15% of acute pharyngitis were streptococcal, it appeared that, whatever the antibiotics prescribed by the physician for treating the pharyngitis, the ‘treat only the positives’ strategy was saving from 1.9 to 93 Swiss francs per patient [1]. The study was based on community medicine practice, where rapid streptococcal techniques, when negative, were

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Table 2. Cost of four management strategies [from ref. 2] Management strategy

Total cost per patient USD1

Cost of ARF prevented USD

Cost per suppurative complication prevented USD

Treat all Optical immunoassay (OIA) Culture OIA ⫹ culture

31.73 37.92 38.83 40.93

371,795 494,143 571,017 497,273

11,111 14,909 17,102 15,016

1

US dollars, value 1997.

eventually confirmed by a culture. Using the same simple evaluation system, but this time without validation, we have also calculated an estimated economical advantage to the ‘treat only the positives’ strategy all over Western Europe, Malaysia and Singapore [unpubl. pers. results]. However, in areas of higher prevalence of streptococcal pharyngitis, the ‘treat everybody’ strategy becomes more advantageous money wise, the break even for the streptococcal prevalence being around 25–35% (the cost of antibiotic therapy in each area accounts for this rather large range). For instance in Morocco, were more than one of three pharyngitis is streptococcal, sampling the throat would be economically non profitable, especially when a single injection of benzathine penicillin is used as treatment. Treating everybody is also likely to somewhat limit the spread of the disease, a highly desirable goal in poor areas. Hypothetical Cohorts and Meta-Analysis The cost effectiveness of four strategies for the management of pharyngitis was determined in Springfield, USA, using an hypothetical cohort of 100,000 children with pharyngitis: treat all, high-sensitivity antigen test, culture, and high-sensitivity antigen test with culture confirmation (table 2) [2]. The total costs included the costs of an office visit, the cost of the tests and subsequent follow up, and the cost of complications, but the indirect costs were not considered. The calculations were based upon several assumptions: 29% prevalence of S. pyogenes in the pharynx of those cultured (which is probably high for a standard practice in USA out of an epidemic context), 90% efficacy of compliant antibiotic therapy in preventing adverse sequelae, 1% peritonsillar abscess and 0.03% ARF in untreated patients. The ‘treat all’ strategy remained the most cost-effective strategy under all conditions studied except one: when the cost of antibiotics exceeded USD 10.76. Although most cost-effective, the ‘treat all’ strategy was not recommended because of the concerns about antibiotic resistance and risks of allergic reactions (mild reactions: 0.525%, severe

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Table 3. Cost of seven strategies for the management of pharyngitis in children older than 3 years, calculated from published literature [3] Management strategy

Cost (converted to 1995 USD)

No antibiotics, no testing EIA test; if ⫹ penicillin, if ⫺ do nothing EIA test; if ⫺ throat culture; if either test ⫹ penicillin OIA test; if ⫹ penicillin; if ⫺ do nothing OIA test; if ⫺ throat culture; if either test ⫹ penicillin Throat culture; if ⫹ penicillin, if ⫺ do nothing Empiric penicillin therapy, no test

9.57 8.91 10.45 12.18 13.35 6.85 11.62

EIA ⫽ Enzyme immunoassay; OIA ⫽ optical immunoassay.

reactions: 0.025%). Also, as discussed above, a lower than 29% figure for the prevalence of S. pyogenes in acute pharyngitis would have tipped the balance on the other side. A meta-analysis investigated seven management alternatives from the published literature with the cost-benefit perspective for children older than 3 years with pharyngitis [3]. Different outcomes were considered: prevalence of streptococcal pharyngitis, sensitivity/specificity of rapid tests, probability of penicillin allergy and anaphylaxis, probability of ARF and peritonsillar/ retropharyngeal abscess, expected effectiveness of the penicillin therapy in reducing the risk of ARF and abscesses. Results indicated that the cheapest strategy uses a throat culture and a penicillin therapy to the patients with positive culture (table 3). Also, strategies using an enzyme immunoassay were more effective than the ‘treat all’ strategy. Prospective Study in France A detailed prospective study on the economical impact of a rapid antigen test for S. pyogenes for the management of pharyngitis in adults older than 25 years has recently been conducted in France [4]. After just one training course, 100 participant physicians performed the test in 93% of cases (0% before the intervention), with a positive rate of 20.2%. The comparison ‘before-after’ (about 900 pharyngitis in each arm) (table 1) showed that the overall use of antibiotics was reduced by 48.4%. More surprisingly, some benefit was obtained in the cost of absenteeism. The total saving per patient was more than 17 €. Extrapolation to the whole country suggested a potential saving of more than

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27 millions € per year for adults only [5]. No significant complications were reported during the survey.

Cost-Effectiveness of Antibiotic Therapy for Sore Throat

The Western World The benefits of antibiotics in the management of sore throat has been recently assessed from 25 published studies where trials of antibiotics against control were carried out with either measures of the symptoms, or complications of sore throat. More than 11,000 cases of pharyngitis were included in this meta-analysis [6]. Impact on Symptoms. Antibiotic therapy reduced symptoms of headache, sore throat and fever to about one half. Evidence of this benefit was the greatest at about three and a half day, when the symptoms of about 50% of untreated patients had settled. The results of the throat swab influenced the results, antibiotics being more effective in case of positive results (OR reduced to 0.16, 95% CI 0.09–0.26) than when it was negative (OR 0.65, 95% CI 0.38–1.12). Antibiotics shortened the duration of symptoms by about 16 h overall, i.e. a quite modest effect. However, if we assume that absenteeism (which represents a substantial cost in developed countries) is of the same duration, the treatment would be economically beneficial, especially when the throat swab is positive. The time to resolution of symptoms is product-dependant, and was for instance found to be faster for a 3- and 5-day course of azithromycin (4.1 and 5 days, respectively) than a 10-day course of roxithromycin (7.5 days, p ⬍ 0.05) [7]. Impact on Complications. Prevention against suppurative and non-suppurative complications by antibiotics appeared to be of limited impact in modern developed societies. Altogether complications are becoming rarer in the Western world, hypothetically as a result of the large use of antibiotics in the management of sore throat. Table 4 summarizes the results of antibiotic effectiveness on complications. Compared to untreated groups, antibiotics reduced the incidence of acute otitis media by more than 75%, and that of peritonsillar/ retropharyngeal abscesses by more than 80%. Effect on sinusitis appeared less clear, and effect on ARF and acute glomerulonephritis was not estimable. In developed countries, the risk of ARF is now minimal, with a mean annual incidence of 0.5/100,000 children of school age [8], but some local outbreaks are possible as documented in the USA in the 1980s [9]. Side Effects of Antibiotics. Antibiotics are generally well tolerated, but side effects exist which can cause additional cost in the management of pharyngitis. For instance, the probability of a patient developing a drug allergy from penicillin therapy has been estimated at 0.015 (range: 0–0.1) and the risk of developing an

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Table 4. Impact of antibiotic therapy on the incidence of complications in patients with acute streptococcal pharyngitis [from ref. 6] Complication

n/N treated patients

n/N untreated patients

Odd ratio (95% CI)

NNT

Otitis media

11/2,325

28/1,435

0.22 (0.11, 0.43)

Sinusitis Abscesses ARF Pre-1975 Post-1975 AGN

4/1,545 2/1,438

4/842 23/995

0.46 (0.10, 2.05) 0.16 (0.07, 0.35)

33 (children) 130 (adults) 150 124

37/4,208 0/1,079 0/2,558

74/3,409 0/650 2/1,834

0.30 (0.20, 0.45) not estimatable 0.07 (0.07, 0.35)

55 not estimatable not estimatable

N ⫽ Number total of patients; n ⫽ number of patients with the complication; NNT ⫽ number of patients to be treated for avoiding one case with complication. Complications are defined by clinical criteria. Time of observation for each complication: otitis within 14 days, sinusitis within 14 days, AGN within 1 month, ARF and quinsy within 2 months.

anaphylactic penicillin reaction at 1 in 10,000 (range: 0–5 in 10,000) with a 0.1 chance of death (range: 0–1) [3]. Other common side effects include rashes and gastrointestinal disorders with cephalosporins and macrolides. Third World The situation is quite different in developing countries where the benefits of antibiotics for acute pharyngitis are more visible. More pharyngitis are caused by S. pyogenes, and more complications can be expected. Altogether the effectiveness of antibiotics is more visible. The main aim of antibiotic therapy for acute pharyngitis in poor areas remains the primary prevention of ARF. Even today, ARF is prevalent in many parts of the world, with an incidence 100–200 times higher than that of the developing countries. Especially harmful and costly is the rheumatic heart disease for which the prevalence per 1,000 children is as follows: Egypt: 10; Thailand: 1.2–2.1; India, 6–12; Pakistan: 1.8–11; Sri Lanka: 100–150 [10]. Rheumatic heart disease is a cruel condition, hitting millions of children, adolescents and young adults. Those who survive often suffer from severe valvulopathies requiring expensive surgical corrections. Classic studies in the 1950s showed that penicillin reduced the risk of ARF to about one third compared to the placebo group (table 3) and we may assume that a similar benefit can be found today. In areas of high ARF prevalence, antibiotic treatment of acute pharyngitis is mandatory, and not only for economical reasons.

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General Conclusion

In the developing world, with high prevalence of streptococcal pharyngitis and acute rheumatic fever, the benefit of antibiotics cannot be challenged. Sampling the throat for a microbiological confirmation is impractical and not economically profitable, so that the ‘treat all’ strategy can be recommended as is well illustrated by the successful Costa Rican experience [see this book, p. 192]. In the modern Western world, the practice of microbiological confirmation is an economically sound procedure, especially when one considers the selection of bacterial resistance. The ‘treat only the positives’ strategy reduces considerably the use of antibiotics for one of the commonest human infection, affecting annually hundreds of millions patients. Cost effectiveness of antibiotics is not so obvious in developed societies, but different studies seems to favor the use of antibiotics in confirmed cases of streptococcal pharyngitis. The use of algorithms, as presented in pp 36–48, may help to focus on reduced subpopulations of patients for both the throat swab and the use of antibiotics, and to contribute to decreased costs. References 1 2 3 4

5

6 7

8 9 10

Pechère JC: Pourquoi doit-on faire des prélèvements de gorge pour la recherche du streptocoque du groupe A au cours des pharyngites? Med Hyg 1996;54:1901–1905. Webb KH: Does culture confirmation of high-sensitivity rapid streptococcal tests make sense: A medical decision analysis. Pediatrics 1998;101:E21–E210. Tsevat J, Kotugal UR: Management of sore throats in children: A cost-effectiveness analysis. Arch Pediatr, Adolesc 1999;153:681–688. Portier H, Peyramond D, Boucot I, Grappin M, Boibieux A, Pribil C, groupe GRAPH: Assessing applicability of guidelines on management of pharyngitis in adults in general practice. Med Mal Inf 2001;31:396–402. Portier H, Peyramond D, Boucot I, Pribil C, Grappin M, Chicoye A, groupe GRAPH: Evaluation pharmaco-économique de l’usage des tests de diagnostic rapide dans l’angine de l’adulte. Med Mal Inf 2001;31:506–507. Del Mar CB, Glasziou PP, Spinks AB: The Cochrane Library, Issue 3. Oxford, Update Software, 2001. Carbon C, Hotton JM, Pépin LF, Wohlhuter C, Souetre E, Hardens M, Lozet H, Riviera M: Economic analysis of antibiotic regimens used in the treatment pharyngitis: A prospective comparison of azithromycin versus roxithromycin. J Antimicrob Chemother 1996;37(suppl C):151–161. Olivier C: Rheumatic fever – is it still a problem? J Antimicrob Chemother 2000;45:13–21. Kavey REW, Kaplan EL: Resurgence of acute rheumatic fever. Pediatrics 1989;84:485–486. Stollerman GH: Rheumatic group A streptococci and the return of rheumatic fever. Adv Intern Med 1990;35:1–25.

Prof. Jean Claude Pechère Universities of Geneva and Marrakesh 19 Krieg 1208 Geneva (Switzerland) Tel:⫹41 22 789 5815, Fax:⫹41 22 789 5815, E-mail: [email protected]

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Pechère JC, Kaplan EL (eds): Streptococcal Pharyngitis. Issues Infect Dis. Basel, Karger, 2004, vol 3, pp 173–183

Practical Problems Associated with the Prevention of Initial and Recurrent Attacks of Acute Rheumatic Fever in Developing Countries S.R. Zahera, A. Mandilb a

Department of Pediatrics, University of Alexandria, and bDepartment of Epidemiology, High Institute of Public Health, Alexandria, Egypt

The importance of preventive measures in reducing the incidence, morbidity, and mortality of rheumatic fever and rheumatic heart disease is undisputed [1–3]. The basic approaches for primary and secondary prevention are well defined, adaptable, and mostly affordable to the health and medical authorities in most of the developing countries. National and international prevention programs are operant in many of these countries, several of them being organized with the cooperation of the World Health Organization and other international organizations [4, 5]. Despite this, the incidence and morbidity of both diseases have not changed very much [5, 6]. Many problems in these countries clearly hamper the different aspects of prevention of rheumatic fever and rheumatic heart disease (table 1).

Governmental Involvement

Involvement of governments is required in order to achieve successful prevention programs, and their role is crucial and complementary in prevention (table 2). However, in developing countries, this role is not fulfilled effectively. Despite all governmental efforts, improvement of living conditions does not seem to be possible in the foreseeable future. This is mainly because of the observed rapid increase in populations, continuous internal migration, and increase in squatter establishments in these countries. However, in addition, there seems to be reluctance on the part of the governments to undertake serious

Table 1. Sources of problems related to prevention of rheumatic fever in developing countries 1 2 3 4 5 6 7 8

Governmental involvement Economic constraints Physicians’ attitudes in management Social and cultural constraints Patients’ compliance with prevention protocols Health education and public involvement Pharmacokinetics of benzathine penicillin G Technique of benzathine penicillin G injections Table 2. Role of governments in prevention approaches

1

2 3 4 5 6 7 8

To ameliorate the standard of living regarding Housing conditions Squatter settlements Overcrowding of schools To implement national guidelines for management To plan, implement, and audit national control programs To establish primary health care centers concerned with control of rheumatic fever To establish peripheral laboratories for streptococcal diagnosis To organize health education and professional training programs To assure quality control of antibiotics used for prevention To provide necessary antibiotics at low costs

approaches towards disease prevention. The reasons are diverse: First there is no real appreciation of the magnitude of rheumatic fever and rheumatic heart disease as public health problems, with other health priorities being at the top of the list. Secondly, as a result, there is also a lack of motivation on the part of the health administrators to undertake serious preventive approaches. A third important reason is the requirement of large resources, which are not available by any means in the poorer developing countries. All of the above form an obstacle to the international efforts, by the World Health Organization for example, in controlling rheumatic fever and its sequelae in these areas. Both international and local medical authorities have an important role in the motivation of the concerned governments to work actively in prevention [6, 7]. Economic Constraints

It has been shown clearly that primary and secondary prevention are cost effective [8, 9]. Accordingly, it is not unbeneficial for governments to allocate

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Table 3. Cost requirements for prevention programs 1 2 3 4

For establishment of laboratories for streptococcal diagnosis For establishment of health care facilities for management and control (rheumatic fever centers) For provision of necessary antibiotics, including benzathine penicillin For implementation of health education and professional training seminars

Table 4. Role of physicians in primary and secondary prevention 1

2 3

4

Cooperation in health education and orientation of the community about related issues Importance of reporting sore throats Benefits of diagnostic tests Importance of antibiotics Importance of compliance with prescribed treatments Measures to decrease contagiousness of streptococcal pharyngitis Adequate identification of group A streptococcal pharyngitis by appropriate diagnostic methods Adequate antibiotic therapy of group A streptococcal pharyngitis Appropriate choice of antibiotic Appropriate dosage schedule Appropriate duration Monitoring and ensuring compliance with prescribed antibiotic regimens

the necessary funds for preventive approaches (table 3). If adequate funding is not made available, preventive approaches would be practically difficult and of little effectiveness. Since most concerned countries have little resources and other financial health- and non-health-related problems, it is imperative that prevention programs be supported by local and international non-governmental organizations. Physicians’ Attitudes in Management

Primary health care physicians should make all efforts to ensure that primary or secondary prevention is implemented adequately (table 4). Essentially, they are the first to encounter children with streptococcal throat infections or rheumatic fever. Many of the problems of prevention are related to the unacceptable attitudes of the physicians in the management of these illnesses (table 5).

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Table 5. Physicians’ attitudes in management and prevention: potential problems 1 2 3 4

Negligence of health education during the medical visits Reluctance or inconsistency in the laboratory diagnosis of group A streptococcal pharyngitis Inappropriate antibiotic therapy of group A streptococcal pharyngitis Premature discontinuation of penicillin prophylaxis

Table 6. Prophylaxis-related problems and concerns of patients that may affect the success of secondary prevention 1 2 3 4 5 6 7 8

Experiencing pain during or after the injection Occurrence of local injection at injection site Occurrence of allergic reactions Occurrence of technical problems related to the injection (needle obstruction, incomplete injection) Cost of injection Difficulty in transport or accessibility to the clinic Loss of school/work days Fear of fatal penicillin allergy

Negligence of Health Education During the medical visit, physicians often underestimate their role in educating patients and their families about issues related to prevention. For children with pharyngitis, the physician should talk with the parents about the benefits and importance of diagnostic tests, antibiotic therapy, treatment compliance, and return visits. For children with rheumatic fever/rheumatic heart disease in a secondary prophylaxis program, physicians are required to always emphasize the importance of compliance with long-term prophylaxis and to respond to each individual patient’s concerns related to prophylaxis (table 6). Reluctance in the Laboratory Diagnosis of Group A Streptococcal Pharyngitis Although it is recommended that documentation of group A streptococcal pharyngitis should be done by appropriate diagnostic tests guided by an initial clinical diagnosis [10], physicians in developing countries are usually reluctant to obtain throat swabs from children with pharyngitis. The reasons are mainly the time delay and the added costs. This attitude is supported by strategies adopted by the World Health Organization, which, for practical and economical reasons, and in order to limit antibiotic overuse, recommends the reliance on clinical diagnosis only as a basis for prescription of an antibiotic [11]. However,

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Table 7. Hazards of the indiscriminate use of penicillin for treatment of presumed streptococcal pharyngitis 1 2 3 4

Increased risk of penicillin side effects including anaphylaxis Unnecessary pressure on the indigenous flora resulting in the production of tolerant or resistant bacteria Emergence of beta-lactamase producing co-pathogenic strains Eradication of alpha streptococci, providing an enhanced opportunity for colonization with pathogenic group B streptococci

this approach would result in many cases of group A streptococcal pharyngitis that are undiagnosed and untreated [12]. In view of such conflicting guidelines, physicians in developing countries tend to treat any upper respiratory tract infection with an antibiotic as preventive measure. As a matter of fact, broadbased community prophylaxis proved to be successful in reducing the incidence of rheumatic fever in some areas [13], whereby in high-risk areas all children with pharyngitis are given a single benzathine penicillin injection. Given the hazards of the indiscriminate use of penicillin in the treatment of presumed streptococcal pharyngitis (table 7), this approach has not gained much popularity and cannot yet be recommended [8]. Inappropriate Reliance on the Anti-Streptolysin O Antibody Titer as a Diagnostic/Prognostic Test Due to the prevalence of subacute low-grade forms of rheumatic fever in developing countries and also the frequent occurrence of non-specific polyarthralgias in schoolchildren, whether associated with pharyngitis or not, physicians will very often perform the anti-streptolysin O test in such children to rule out a diagnosis of rheumatic fever. It is then common to wrongly interpret a high titer as a rheumatic fever marker or predictor, resulting in overdiagnosis of rheumatic fever and subsequently unjustified penicillin prophylaxis for long durations. Inappropriate Antibiotic Therapy for Group A Streptococcal Pharyngitis Once Diagnosed This is an important cause of treatment failure in group A streptococcal pharyngitis. Physicians may prescribe antibiotics known to be ineffective in the eradication of group A streptococci or to which the organism is resistant in a particular region. Inadequate treatment dosage and duration are also common mistakes. Another economically related problem is the unjustifiable prescription of costly ‘new’ antibiotics, thus enhancing the potential of patient noncompliance.

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Table 8. Results of inappropriate social and cultural behaviors on the efficacy of prevention programs 1 2 3

Facilitated transmission of the streptococcus within the community Inadequate reporting and inadequate treatment for sore throat Poor compliance with treatment regimens

Premature Discontinuation of Penicillin Prophylaxis Physicians sometimes decide to discontinue penicillin prophylaxis in some patients on the assumption that there is no clear history of rheumatic fever or that a previously existing cardiac lesion has recovered. Although it is stated that the duration of penicillin prophylaxis may be individualized according to the patient and the community [8, 14], this should be very carefully evaluated, and the benefits versus disadvantages well weighed up. Every effort should be made to adhere to the guidelines recommended in relation to the duration of prophylaxis [14]. In view of the above-mentioned problems, it is required, and generally possible, to modify unacceptable physicians’ attitudes as regards preventive strategies. This requires the implementation of specific national guidelines and the organization of awareness seminars and programs to educate and update primary health care physicians.

Social and Cultural Constraints

The social and cultural structure of the community greatly hampers the efforts of primary and secondary prevention in several ways (table 8). The low socioeconomic status and the lack of adequate health information play an important role in favoring the transmission of the streptococcus in closed and semi-closed communities. Both factors, as well as the frequent reliance on home remedies in all social classes, enhance the likelihood that children with sore throats are not seen by a physician and hence remain untreated. This is also true for children living in remote suburban areas with difficult access to primary health care units. The social and cultural background also determines the patient compliance in antibiotic therapy for primary prevention and is closely related to the low compliance in penicillin prophylaxis programs. It is thus evident that the social and cultural background of the target populations should be taken into consideration whenever prevention programs are planned.

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Table 9. Causes of patient noncompliance with therapy for primary prevention

1 2 3 4 5

6 7

Rapid recovery Long duration of therapy Frequent dosing schedule Occurrence of adverse reaction Unjustified fear of penicillin allergy Past encounter with allergy Past experience with allergy Incorrect information from media Underestimating benefits of antibiotics High cost of antibiotics

Patient Compliance with Treatment Protocols

Primary Prevention Treatment failures are also caused by non-compliance of patients with antibiotic therapy. Often patients may refuse to initiate antibiotic therapy, be non-adherent to a prescribed regimen, or stop taking the prescribed antibiotic prematurely. The reasons are the same for all communities (table 9); however, certain features in developing countries such as lack of adequate public health information, low social standards, and unfavorable economy favor non-compliance. Improving compliance with antibiotic therapy can be achieved by the use of short duration regimens and the use of antibiotics with the least dosing frequency. In this context, the use of a single penicillin injection is a good therapeutic choice. Compliance can also be improved by parental and patient education about the importance of adherence, home visits or phone calls during therapy, and dispensing antibiotics free of charge. Secondary Prevention It is estimated that in the developing countries, up to 30% patients are noncompliant with penicillin prophylaxis [2, 5]. In general, the causes of noncompliance are ignorance of its importance (due to lack of information), inaccessibility to the prevention centers (due to financial or social restraints), negligence (due to lack of motivation or improper medical services), or refusal of prophylaxis (due to occurrence of side effects, depression, or assumption of cure). Several factors affect compliance rates and influence the method and outcome of interference to improve compliance (table 10). The different approaches suggested to improve compliance in secondary prevention are: – Health education using appropriate educational material and educational sessions. – Patient and family support including personal and group meetings, home visits, patient support groups, and financial support.

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Table 10. Factors affecting patient compliance in penicillin prophylaxis 1

Doctor

2

Patient

3

Medication

4

Clinical setting

5

Illness

Competence Communication skills Cooperation in treatment Age Gender Educational status Social status Knowledge of disease Experience with disease (presence of symptoms) Mode Frequency Duration (prospective) Pain of injection Side effects Costs Transportation Cost of visit Adequacy and time of service Moral support Presence of heart disease Chronicity of heart disease Severity of heart disease Threat of death vs. hope in cure

– Provision of optimal medical services including personnel, medications, and clinical equipment. – Monitoring compliance using follow-up cards, clinic registries, home visits, and urine tests for penicillin.

Health Education and Public Involvement

Health education should be directed equally to the public, the patients with rheumatic heart disease and their families, and to the health workers. Health education can be easily accomplished through the media, primary health care systems and children in schools. Health fairs in school and health education community campaigns are also effective methods of communication of the health messages. In many developing countries, it may be difficult to implement public health programs, except perhaps as a part of the primary health care

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system. This affects mainly the success and effectiveness of primary preventive measures. Pharmacokinetics of Benzathine Penicillin G

Benzathine penicillin G was initially used for prophylaxis at a dose of 1.2 million IU every 4 weeks [15, 16]. However, recurrences were still reported among patients who follow such controlled programs with a fair compliance especially in developing countries [17–19]. Such recurrences may be explained by the decreased activity of penicillin at the site of infection due to an insufficiently low serum concentration of penicillin. Data have shown that a significant proportion of patients do not have therapeutically effective concentrations 4 weeks after the injection [20–23]. The reasons of the observed low penicillin levels are diverse; some may be related to the product and its bioavailability and others to the technique and site of injection. Different brands of benzathine penicillin G are available on the market worldwide, some are produced by international pharmaceutical companies and some by local companies. Such locally manufactured preparations may be distributed worldwide. The activity of penicillin is expected to vary in some such brands in the absence of quality control measures. Many factors may be responsible for such variability; manufacturing, storage, and the physical properties of the solution [14, 23, 24]. Technique of Injection

Several technical factors related to the injection of benzathine penicillin can affect its bioavailability and hence reduce the efficacy of rheumatic fever prevention programs. When a small amount of diluent is used, the powder is not completely dissolved and the thick suspension frequently causes obstruction of the injection needle. With the use of small-sized needles the problem is more obvious. Obstruction of the needle during injection will lead to repeated injection trials, sometimes up to four injections, with subsequent loss of material during such trials. It has therefore been recommended that the vial should be diluted in about 4 or 5 ml of diluent. Larger needles are also preferred for the injection, usually of size 18 or 19 [14]. Moreover, it has been common practice in some rheumatic fever clinics that one needle is used for aspirating the solution into the syringe and another is used for the injection. Care should be taken, particularly in adults, that the whole content of the vial is fully removed and injected. It the responsible nurse is not well trained,

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she will not aspirate the froth resulting from the vigorous shaking of the vial that is required to allow complete dissolution of the powder. The amount of froth left in the vial may reach 0.5 ml, which means that 10–15% of the vial content would not be injected. In order to avoid this waste, the nurse should allow the solution to settle for few minutes, reshake lightly, and then aspirate the whole content of the vial. The injection should go deep into the gluteal muscle, as is generally recommended. More superficial injections allow the benzathine penicillin G to remain in the subcutaneous tissue leading to decreased absorption and lower serum levels. It is thus important that health workers responsible for administering the injections are well trained in the technique for giving injections adequately to allow for optimum results. Standardization of the injection technique, implementation of a national policy and health education and training programs for health workers are all required to ensure effective injections. Because of the variation of serum concentration and duration of effective penicillin blood levels with different brands of benzathine penicillin G, it is also recommended that continuous quality assurance be an integral part of prevention programs to optimize not only its chemical activity but also its biological activity and to reduce variations between different brands. In conclusion, the problems associated with prevention of rheumatic fever and rheumatic heart disease in developing countries are diverse but interrelated. Many can be successfully resolved without the need for major monetary funds. This requires sincere and effective governmental motivation and involvement, organization of training and education programs for primary care physicians and other health workers in the field, implementation of well-designed health education programs to the public, and finally, organization of primary health care centers (rheumatic fever clinics) for management and control of streptococcal infections and rheumatic fever.

References 1

2 3 4

5

Feinstein AR, Wood HF, Spagnuolo M, Taranta A, et al: Rheumatic fever in children and adolescents: A long-term epidemiologic study of subsequent prophylaxis, streptococcal infections, and clinical sequelae. VII. Cardiac changes and sequelae. Ann Intern Med 1964;60(suppl 5):87–123. Strasser T, et al: The community control of RF and RHD: Report of a WHO International Cooperative Project. Bull Wld Hlth Org 1981;59:85–94. Gordis L: The virtual disappearance of rheumatic fever in the United States: Lessons in the rise and fall of the disease. T. Duckett Jones Memorial Lecture. Circulation 1985;72:1155. World Health Organization: Joint WHO/ISFC Meeting on Rheumatic Fever/Rheumatic Heart Disease Control, with Emphasis on Primary Prevention. Report of a consultation, Geneva, 7–9 September 1994. WHO Document WHO/C VD/94.1. Geneva, World Health Organization, 1994. WHO/CVD Unit and Principal Investigators. WHO programme for the prevention of RH/RHD in 16 developing countries: Report from phase I (1986–1990). Bull Wld Hlth Org 1992;70:13–18.

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6

7 8 9 10 11 12

13 14

15

16 17 18

19

20

21

22 23

24

World Health Organization: The WHO Global Programme for the Prevention of Rheumatic Fever and Rheumatic Heart Disease. Report of a Consultation to Review Progress and Develop Future Activities. Geneva, 29 November–1 December 1999. WHO Document WHO/CVD/00.1. Geneva, World Health Organization, 1999. Zaher SR, Mandil AM: Rheumatic heart disease in Egypt: Situation analysis and prospects for prevention. Egyptian Heart J 1999;51:416–424. World Health Organization: Rheumatic fever and rheumatic heart disease: Report of a WHO study group. Wld Hlth Org Tech Rep Series 1988;764:19–21. World Health Organization: Community control of rheumatic heart disease in the developing countries. 2. Strategies for prevention and control. WHO Chron 1980;34:89–95. Bisno AL, Berber MA, Gwaltney JM, Kaplan EL, Schwartz RH: Diagnosis and management of group A streptococcal pharyngitis: A practice guideline. Clin Infect Dis 1997;25:574–583. Anonymous: Integrated Management of Childhood Illnesses (IMCI). Module No. 2: Assess and Classify the Sick Child – Age 2 Months up to 5 Years. Geneva, World Health Organization, 2000. Steinhoff MC, Abdel Khalek MK, Khallaf N, Hamza HS, El-Ayadi A, Orabi A, Fouad H, Kamel M: Effectiveness of clinical guidelines for the presumptive treatment of streptococcal pharyngitis in Egyptian children. Lancet 1997;350:918–921. Arguedas A, Mohs E: Prevention of rheumatic fever in Costa Rica. J Pediatr 1992;121:569–572. Anonymous: WHO Model Prescribing Information: Drugs Used in the Treatment of Streptococcal Pharyngitis and Prevention of Rheumatic Fever. WHO/EDM/PAR/99.1. Geneva, World Health Organization, 1999. American Heart Association: Committee on prevention of rheumatic fever and bacterial endocarditis. Prevention of rheumatic fever and bacterial endocarditis through control of streptococcal infections. Circulation 1955;11:317. Stollerrnan GH, Rusoff JH: Prophylaxis against group A streptococcal infections in rheumatic fever patients: Use of new repository penicillin preparation. JAMA 1952;150:1571–1575. Tompkins DG, Boxerbaum B, Liebman J: Long-term prognosis of rheumatic fever patients receiving regular intramuscular benzathine penicillin. Circulation 1972;45:543–551. Padmavati S, Sharma KB, Jayaram O: Epidemiology and prophylaxis of rheumatic fever in Delhi: A five-year follow-up. Singapore Med J 1973;14:457–461. Cited in Padmavati S, Gupta V, Prakash K, Sharma KB: Penicillin for rheumatic fever prophylaxis: 3-weekly or 4-weekly schedule? J Assoc Phys India 1987;35:753–755. Lue HC, Wu MH, Hsieh KH, Lin GJ, Hsieh RP, Chiou JF: Rheumatic fever recurrences: Controlled study of 3-week versus 4-week benzathine penicillin prevention programs. J Pediatr 1986;108:299–304. Kaplan EL, Berrios X, Speth J, Siefferman T, Guzman B, Quesny F: Pharmacokinetics of benzathine penicillin G: Serum levels during the 28 days after intramuscular injection of 1,200,000 units. J Pediatr 1989;115:146–150. Lamas MCP, Hilario MOE, Francisco Goldenberg J, Naspitz CK: Serum penicillin concentration after intramuscular administration of benzathine penicillin G in children with rheumatic fever and controls. J Invest Allergol Clin Immunol 1992;2:268–273. Ginsburg CM, McCracken GH, Zweighaft TC: Serum penicillin concentrations after intramuscular administration of benzathine penicillin G in children. Pediatrics 1982;69:452–454. Zaher SR, Kassem AS, Abou-Shleib H, El-Kholy AG, Madkour A, Kaplan EL: Differences in serum penicillin concentration following intramuscular injection of benzathine penicillin G from different manufacturers. J Pharm Med 1992;2:17–23. Pichichero ME: Group A beta-hemolytic streptococcal infections. Pediatr Rev 1998;19:291–303.

S.R. Zaher 21 Amin Fikry Street, Alexandria (Egypt) Tel. ⫹20 634860080, Fax ⫹20 34869562, E-Mail [email protected]

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Streptococcal Pharyngitis: A Continuing Important Public Health Issue Worldwide Thelma E. Tupasi Tropical Disease Foundation, Makati Medical Center, Makati, Philippines

Group A streptococcus (GAS) is a significant and common human pathogen worldwide. GAS causes a spectrum of diseases from uncomplicated pharyngitis and pyoderma to invasive life-threatening infections as well as nonsuppurative sequelae of acute rheumatic fever and post-streptococcal glomerulonephritis. Humans are the only reservoirs and transmission is dependent upon the density and magnitude of the close contact. GAS is transmitted through close contact between individuals via large droplet nuclei. Transmission in a susceptible individual who lacks type-specific immunity occurs following an exposure to a person with acute infection. Socioeconomic and environmental factors such as crowding, access to health care, environmental sanitation have been considered as important determinants of GAS transmission and resulting infections. Despite a general improvement in these socioeconomic factors in industrialized countries, however, GAS pharyngitis occurs just as frequently as in developing countries and the multifocal outbreaks of acute rheumatic fever in suburban communities with middle income families with access to health care in the Unites States in the 1980s and the increased frequency of invasive disease suggest that other factors such as the host and pathogen are significant determinants of disease causation [1]. Interfamilial transmission is significant and accounts for a high rate of recurrences and early treatment failure [2, 3]. Transmission in closed or semi-closed communities has resulted in sporadic or epidemic outbreaks of GAS pharyngitis [2, 4]. Epidemic outbreaks of GAS pharyngitis have also been linked to direct inoculation of food from infected food handlers who either have pharyngeal or skin infection [5].

Risk Groups for GAS

Schoolchildren between the ages of 5 and 15 years are at highest risk for GAS pharyngitis while streptococcal pyoderma is more commonly seen in children younger than 5 years. The incidence of GAS pharyngitis in this age group is estimated to range from 3,000 to 6,000 per 100,000 children per year although its true incidence is difficult to estimate because GAS pharyngitis is not uniformly considered as a reportable disease in all countries. This estimate is based on the incidence of symptomatic pharyngitis in this age group, which ranges from 18,000 per 100,000 to twice as much, 33% of whom would yield a positive pharyngeal culture for GAS with approximately half of these patients representing pharyngeal carriage with no etiologic significance [6]. In temperate countries, GAS pharyngitis usually is highly prevalent during the cold months of the year. Among school children in Fukuoka, Japan, outbreaks of GAS pharyngitis occur from fall to early spring [7]. The cumulative prevalence of isolation of GAS among students and their teachers in a third grade class in Minneapolis, with clinical symptoms of sore throat, rose from 26% to more than 80% in the five months from September to January [2]. In Belgium, sore throat is one of the most frequent causes of consultation seen by general practitioners, and GAS has been isolated in 20.3% of cases [8]. In tropical and developing countries, a similar prevalence of GAS pharyngitis has been reported in 24.3% in Egyptian children [9]. Outbreaks of GAS disease, either pharyngitis or invasive disease, have been associated with a high carriage rate in schoolchildren. In an outbreak of GAS invasive disease, 32% of schoolchildren studied in the outbreak area were colonized and this was significantly higher compared to other schools studied outside the area. Furthermore, the invasive clone identified by pulsed-field gel electrophoresis was circulating widely among schoolchildren in that county and identified in 78% of isolates in carriers and in 26.5% of patients with GAS pharyngitis also in the area [10] (fig. 1). Although younger children are at less risk of GAS pharyngitis, epidemic outbreaks of GAS pharyngitis have been reported in child day-care centers that accept both preschool aged children as well as school-aged children. In an outbreak investigation of GAS upper respiratory infection confirmed by pharyngeal culture in a child day-care center, pharyngeal culture was positive for GAS in 61% of children indicating a wide bacterial spread among the attendees and staff. This study suggests that GAS has the potential of being a significant respiratory pathogen in day-care centers catering to infants and pre-schoolers as well as school-aged children, with the latter possibly introducing the organism to this population. Contaminated damp material has been incriminated as another possible source of infection owing to heavy

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GAS

80

PFGE-1

70

Prevalence

60 50 40 30 20 10 0 X

A

B

C

GAS in schoolchildren and % PFGE-1 in isolates from 4 schools

Fig. 1. Prevalence of group A streptococcal carriage (solid bars) from March 23 through April 3, 1995 and the prevalence of PFGE-1 strain among isolated GAS (open bars) among pupils from kindergarten to grade 6 at a Minnesota elementary school (X) in a community associated with an outbreak of group A streptococcal invasive disease compared to other schools (A, B, C) in the neighbouring counties. Adapted from Cockevill et al. [10].

environmental contamination in the day-care center following the outbreak of GAS pharyngitis requiring a thorough cleaning of the environment [11].

Health and Economic Impact of GAS

GAS pharyngitis is a significant public health problem not only due to the high burden of infection in the community but more importantly, because of the substantial morbidity and mortality due to its suppurative and non-suppurative sequelae. These complications are life threatening and pose a significant clinical impact and economic burden in the community. Rheumatic fever occurs at a rate of 0.3% in sporadic cases of GAS pharyngitis and in 3% of epidemic outbreaks. The higher incidence of this non-suppurative complication in developing countries is clearly shown in table 1 where the yearly incidence of acute rheumatic fever in schoolchildren has been reported to range from a low of 0.2 per 100,000 in the Americas to a high of 300 per 100,000 in Africa [12]. Until the recent multifocal outbreaks of acute rheumatic fever in civilian and military populations in the mid 1980s, the problem of rheumatic fever was considered to have significantly declined in the United States [1]. These

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Table 1. Incidence of acute rheumatic fever in schoolchildren WHO regions

Rate per 100,000 per year

Africa Americas Eastern Mediterranean South-East Asia Western Pacific

300.0 0.2–50.5 51.0–100.0 30.0–50.0 93.0–150.0

Adapted from ref. 12, with permission.

Table 2. Prevalence of rheumatic fever/rheumatic heart disease by WHO region WHO region

Surveys n

Screened n

Cases of RF/RHD detected n

Prevalence per 1,000 (range)

Africa Americas Eastern Mediterranean South-East Asia Western Pacific All regions

11 5 19 6 17 58

173,408 23,328 409,933 195,142 631,899 1,433,710

818 35 1,807 26 449 3,135

4.7 (3.4–12.6) 1.5 (0.1–7.0) 4.4 (0.9–10.2) 0.12 (0.1–1.3) 0.7 (0.6–1.4) 2.2 (0.7–4.7)

Adapted from ref. 15, with permission.

outbreaks were considered to be the consequence of a shift in the prevalent GAS serotype to the M types 1, 3, 18 which are the most frequently isolated serotypes associated with serious GAS disease and rheumatic fever [13, 14]. Therefore, as long as GAS continues to circulate in the population and cause disease, the risk of rheumatic fever will continue. Despite the lack of reports on outbreaks in developing countries, it is generally accepted that GAS pharyngitis occurs just as frequently and its nonsuppurative sequelae of rheumatic fever and rheumatic heart disease are by far more prevalent in these countries where resources are limited. Baseline data involving the screening of 1,433,710 school children from 16 developing countries participating in a WHO programme showed that the prevalence rate of RF/RHD was 2.2 per thousand and ranged from 0.1 and 12.6 per thousand (table 2) [15]. The age of onset of these sequelae, as reported in the registry in seven centers from developing countries of the world, showed a median age of onset of 10 years for males and 11 years for females [16] (fig. 2). The enormous load on the limited health services and resources by these patients as well as the

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200 180 160

Number of cases

140 120 100 80 60 40 20 0 ⬍1 1

2

3

4

5

6

7

8

9 10 11 12 13 14 15 16 17 18 19 20 21⬎22 Age (years)

Fig. 2. Age at onset of rheumatic fever in patients registered in 7 centers from developing countries of the world: Cairo, Cyprus, Kingston, Lagos, New Delhi, Tehran, and Ulan Bator. Adapted from Strasser et al. [16].

loss of educational opportunity and productivity due to ill health underscore the adverse economic impact of such a high burden of illness in the developing countries. Mortality due to RHD has been reported to be 7% and is approximately 5 times the crude death rate for this age group in the general population [17]. Data from Thailand, as provided by Dr. M. Panamonta, indicate that RHD continues to constitute a sizable number of admissions to the hospital [14].

Public Health Approaches in the Control of Group A Streptococcal Infections

Approaches in the control of GAS infection focus on the individual patient and in the prevention of disease transmission in populations. In the management of an individual patient, early diagnosis and appropriate treatment is essential. Patients should return to work or school only after 24 h of treatment has been given to prevent further transmission of the infection among their contacts. Case management of GAS upper respiratory tract infection or primary prevention would reduce the incidence of suppurative and non-suppurative

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sequelae, reduce the incidence of symptomatic streptococcal sore throat and its corresponding contagion rate, break the chain of transmission thereby diminishing the possibility of its increased virulence, and finally reduce the inappropriate use of antibiotics [18]. On a clinical basis, laboratory confirmation of GAS by pharyngeal culture isolation is the gold standard. There are, however, sufficiently discriminating clinical signs and symptoms, which could be used as basis for deciding which patient with sore throat should have a pharyngeal culture. Alternatively, rapid antigen detection could be utilized for a more timely therapeutic decision. However, in the field setting in developing countries, these are not cost-effective. For this purpose, the World Health Organization ARI guidelines have been used for the training of doctors and field health workers in developing countries. Antibiotic treatment is recommended in patients with pharyngeal exudates plus enlarged and tender cervical node [19]. This guideline has been validated in Egyptian children and was found to be useful in identifying patients who are unlikely to have GAS pharyngitis, thereby diminishing inappropriate antibiotic use. However, it lacked the sensitivity to identify 70% of children who had GAS pharyngitis [9]. There are a number of antimicrobial agents that are effective in the management of GAS pharyngitis. Penicillin is the standard therapy for GAS as no resistance has yet been demonstrated worldwide. A single intramuscular dose of benzathine penicillin G is the most cost-effective antibiotic regimen and ensures compliance as well. For a successful community implementation, primary prevention should be integrated into the national primary health care system in developing countries. Adequate public health infrastructure and human resources are essential in carrying out this program. Although the integration of primary prevention in the primary health care program in developing countries may be difficult for these reasons, the impressive decline of rheumatic fever in Costa Rica following the nationwide implementation of primary prevention indicates the benefits of such a program when applied in similar developing countries [20]. Secondary prevention among patients with rheumatic fever to prevent recurrences and thereby prevent the development of rheumatic heart disease has been the strategy that has been more widely accepted. The implementation of this strategy includes the establishment of rheumatic fever registries, screening of high-risk populations to detect rheumatic heart disease, education of physicians in the promotion of the rheumatic fever prevention and control, and health education of the general public. Secondary prophylaxis with the use of benzathine penicillin has been implemented in a number of developing countries participating in the WHO programme [15, 16]. This programme has been found to be feasible and cost effective in a number of developing countries [16]. Approaches that focus on populations particularly following epidemic outbreaks in closed or semi-closed population, utilize mass penicillin prophylaxis. In

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the United States military training centers, penicillin prophylaxis is recommended if the incidence of GAS disease exceeds 10 cases per 1,000 trainees per week. This is an old practice, which has been terminated but has since been revived due to the outbreaks of GAS disease or acute rheumatic fever in the recent past [4]. In day-care center outbreaks, the intervention that has been applied includes repeated pharyngeal cultures of all attendees and staff and the antibiotic treatment of culture-positive individuals including patients with pharyngitis and asymptomatic carriers [11]. There are as yet no clear public health guidelines for the prevention of invasive GAS disease particularly in the case of communitywide outbreaks [21]. Treatment of carriers and prophylaxis of household contacts of patients with invasive GAS disease are considered appropriate in view of a risk of secondary disease in these populations [10, 22]. The most definitive method for the prevention of GAS transmission and infection would be through vaccination. However, differences in the serotypes isolated from country to country indicate the need for more studies to determine the optimal serotype composition of the vaccine [14]. Furthermore, molecular studies to identify antigenic moieties that may trigger an abnormal immune response have yet to be done to develop a safe GAS vaccine. Until that is accomplished, primary and secondary prophylaxis with penicillin remain to be the most practical public health measures to prevent the life threatening sequelae of GAS pharyngitis.

References 1 2

3 4 5 6 7

8 9

Markowitz M: Changing epidemiology of group A streptococcal infections. Pediatr Infect Dis J 1994;13:557–560. Mazon A, Gil-Setas A, Sota De La Grandara LJ, Vindel A, Saez-Nieto JA: Transmission of streptococcus pyogenes causing successive infection in a family. Clin Microbiol. Infect 2003; 9:554–559. Falck G, Holm SE, Kjellander J, Norgren M, Schwan A: The role of household contacts in transmission of group A streptococci. Scand J Infect Dis 1997;28:239–244. CDC: Group A beta-hemolytic streptococcal pharyngitis among US Air Force Trainees – Texas, 1988–89. MMWR 1990;39:11–13. Farley Ta, Wilson SA, Mahoney F, Kelso KY, Johnson DR, Kaplan EL: Direct inoculation of food as the cause of an outbreak of group A streptococcal pharyngitis. JID 1993;167:1223–1225. Murray CJL, Lopez AD: Global health statistics, World Health Organization, Harvard School of Public Health, World Bank. Geneva, WHO, 1996. Ohga S, Okada K, Mitsui K, Aoki T, Ueda K: Outbreaks of group A beta-hemolytic streptococcal pharyngitis in children: Correlation of serotype T4 with scarlet fever. Scand J Infect Dis 1992; 24:599–605. Vandepitte J: Streptococcal pharyngitis: A Belgian perspective. Pediatr Infect Dis J 1991;10: S64–S67. Steinhoff MC, El Khalil MKA, Khallaf N, Hamza HS, Ayadi AE, Orabi A, Fouad H, Kamel M: Effectiveness of clinical guidelines for the presumptive treatment of streptococcal pharyngitis in Egyptian children. Lancet 1997;350:918–921.

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10

11 12

13

14 15 16

17

18 19

20 21

22

Cockerill FR III, MacDonald KL, Thompson RL, Roberson F, Kohner PC, Besser-Wiek JB, Manahan JM, Musser JM, Schlievert PM, Talbot J, Frankfort B, Stechelberg JM, Wilson WR, Osterholm MT, and the Investigation Team: An outbreak of invasive group A streptococcal disease associated with high carriage rates of the invasive clone among school-aged children. JAMA 1997;277:38–43. Falck G and Kjellander J: Outbreak of group A streptococcal infection in a day-care center. Pediatr Infect Dis J 1992;11:914–919. Guzman SV: Epidemiology of rheumatic fever and rheumatic heart disease; in Calleja HB, Guzman SV (eds): Rheumatic Fever and Rheumatic Heart Disease. Epidemiology, Clinical Aspects, Management and Prevention and Control Programs. Manila, Philippine Foundation for the Prevention and Control of Rheumatic Fever/Rheumatic Heart Disease, 2001, pp 1–12. Kaplan EL, Johnson DR, Rehder CD: Recent changes in group A streptococcal serotypes from uncomplicated pharyngitis: A reflection of the changing epidemiology of severe group A infections? JID 1994;170:1346–1347. Kaplan EL: T. Duckett Jones Memorial Lecture. Global assessment of rheumatic fever and rheumatic heart disease at the close of the century. Circulation 1993;88:1964–1972. WHO Programme for the prevention of rheumatic fever/rheumatic heart disease in 16 developing countries: Report from phase I (1986–90). Bull Wld Hlth Org 1992;70:213–218. Strasser T, Dondog N, El Kholy A, Gharagozloo R, Kalbian VV, Ogunbi O, Padmavati S, Stuart K, Dowd E, Bekessy A: The community control of rheumatic fever and rheumatic heart disease: Report of a WHO international cooperative project. Bull Wld Hlth Org 1981;59:285–294. Grover A, Dhawan A, Iyengar SD, Anad IS, Wahi PL, Ganguly NK: Epidemiology of rheumatic fever and rheumatic heart disease in a rural community of north India. Bull Wld Hlth Org 1993;71:59–66. Strategy for Controlling Rheumatic Fever Rheumatic Heart Disease, with Emphasis on Primary Prevention: Memorandum from a joint WHO/ISFC meeting. Bull Wld Hlth Org 1995;73:583–587. Acute Respiratory Infections in Children: Case Management in Small Hospitals in Developing Countries, a Manual for Doctors and Other Senior Health Workers. WHO ARI.90.5. Geneva, WHO, 1991. Arguedas A, Mohs E: Prevention of rheumatic fever in Costa Rica. J Pediatr 1992;121:569–572. Robinson KA, Rothrock G, Phan Q, Sayler B, Stefonek K, van Benedin C, Levine OS: Active Bacterial Core Surveillance/Emerging Infections Program Network. Risk of severe group A streptococcal disease among patients’ household contacts. Emerg. Infect Dis 2003;9:443–447. Anonymous. Outbreak of group A streptococcal pneumonia among Marine Corps recruits— California November 1–December 20, 2002. MMWR 2003;52:106–109.

Thelma E. Tupasi, MD Tropical Disease Foundation, Makati Medical Center 2 Amorsolo St., Makati City 1200, Philippines Tel. ⫹63 2 893 6066, Fax ⫹63 2 810 2874, E-Mail [email protected], [email protected]

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Practical Management of Pharyngitis: The Costa Rica Experience and Its Impacts on Public Health Adriano Arguedasa, Edgar Mohsb a b

Instituto de Atención Pediátrica, and Universidad de Costa Rica, San José, Costa Rica

Acute pharyngitis is one of the most common diseases in childhood where group A beta-hemolytic streptococci (GABHS) is the most frequent bacterial isolate. There are more than 80 distinct M-protein types of GABHS and disease results from contact of the index person with an individual who has streptococcal pharyngitis [1, 2]. Streptococcal pharyngitis may occur at any age, but school-age children is the more vulnerable group; therefore, a special target group for any prevention/ intervention program [1]. Although after an incubation period of between 2 and 5 days, the course of the disease may be brief and self-limited, complications during the acute phase of the illness may occur due to local spread of the infection or to an erythrogenic toxin [1, 3]. In addition, non-purulent complications such as rheumatic fever and, less frequently, glomerulonephritis, may follow acute infection [4, 5]. While the initial diagnosis of pharyngitis is based on clinical grounds, a throat culture or one of the approved rapid diagnostic test for GABHS, is usually recommended in developing countries to differentiate between GABHS and viral pharyngitis [1, 6]. If the diagnosis of GABHS pharyngitis is confirmed using one of these techniques, a 10-day course of oral penicillin V is considered, by many, the drug of choice except in penicillin allergic patients in whom a macrolide is suggested [1, 7]. Antimicrobial treatment is recommended to eliminate nasopharyngeal colonization and secondary spread of the organism, decrease duration of signs and symptoms of disease, and prevent purulent and non-purulent complications.

The diagnostic and therapeutic approaches outlined above have proven to be efficacious in the treatment of the acute phase of GABHS pharyngitis, in the prevention of the acute complications and is also considered responsible for the decrease in the incidence rates of rheumatic fever in many developed countries including the United States [1, 7–10]. Special concern has been generated from reports indicating regional outbreaks of rheumatic fever [7, 11–15]. Although a specific cause for these outbreaks has not been established, problems with the 10 course of oral penicillin compliance have been suggested. In spite of the above recommendations, many developing countries, such as Costa Rica, consider this approach impractical because of economic and logistic issues derived from the cost of the rapid diagnostic test or a culture, the need, in some instances, for parents to return for a follow up visit, 24 or 48 h later, to obtain the results of a throat culture increasing significantly direct costs (microbiological confirmation) and indirect costs related to work absence and transportation expenses plus the difficulties imposed to working families by having them being compliant with a 10-day regimen of oral penicillin despite multiple daily doses of a suspension with proven poor acceptance [16, 17].

The Costa Rican Experience

During the beginning of the 1970s, an intense national health plan was undertaken in Costa Rica with the main objective of reducing the morbidity and mortality from infectious diseases [18, 19]. To accomplish this goal, four major steps were undertaken: (1) the original sanitary code from 1950 was transformed into a new general health law and the Ministry of Health was reorganized; (2) a program for health delivery to the rural areas was established as a way to assure primary care programs to the entire population; (3) all the hospitals of the country were transferred to a single institution named ‘Caja Costarricense de Seguro Social’ under the administration of the Costa Rican Social Security System, and (4) the academic curriculum of the health-related schools of the University of Costa Rica were reviewed in order to develop an academic program according to the new national health program [18, 19]. At the time the new health program was initiated, acute rheumatic fever and associated mitral valve disease represented approximately 25% of all deaths in children 5–15 years of age [18]. Because of this situation, the program included specific actions to diminish the national incidence of rheumatic fever. Although at that time, giving supportive therapy to the population that already had heart disease was important, a significant effort was placed to established feasible programs for the treatment of GABHS pharyngitis [16, 18].

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Table 1. Comparative incidence of rheumatic fever cases in various countries before the implementation of the benzathine penicillin treatment for suspected GABHS pharyngitis in Costa Rica Region

Year

Per 100,000 habitants

Developing countries Kuwait Iran Sri Lanka Costa Rica

1985 1972 1978 1970

31 58–100 140 90

Developed countries Norway Denmark England

1964 1970 1963

14 11 5

For many decades the incidence of rheumatic fever in Costa Rica was similar to the rates reported by many developing countries (1–22 per 1,000 schoolchildren) and much higher than the rates from developed countries (0.1 per 1,000 schoolchildren). In 1950, the attack rate was 120/100,000 inhabitants and no major changes were observed until the beginning of the 1970s (90/100,000) (table 1) [4, 18, 20]. In the specific case of GABHS throat infections, three important and carefully selected actions were taken: first, nationwide the diagnosis of a possible GABHS pharyngitis was based on clinical grounds; second, the avoidance of throat cultures or rapid diagnostic testing as a requirement to prescribe antimicrobials for these patients, and third, the selection of benzathine penicillin as the standard treatment. At the time this plan was released, multiple educational programs around the country were organized to inform health workers (physicians, nurses, health technicians, medical students, etc.) of this new campaign and all health centers were provided with sufficient amounts of benzathine penicillin to cover their needs. Since then, the national health authorities recommend treatment with benzathine penicillin to every patient that consults because of fever, throat pain and a physical examination showing bad breath, redness of the pharynx and hypertrophy of the tonsils with a white exudate. The main reason to include in the health program a statement that the diagnosis of GABHS pharyngitis should be established only on clinical grounds is to diminish direct and indirect costs associated with the cost of bacteriological confirmation. By doing this, the national health system has reduced the direct cost of rapid diagnostic test and throat cultures (USD 15.5–18.18 per patient) and indirect cost related to the follow-up visits required in those patients in whom a culture is obtained.

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The decision to recommend a single dose of benzathine penicillin over a 10-day course of oral penicillin for the treatment of patients with GABHS pharyngitis is based on the well-known pharmacodynamics of this compound [21], the previous experience in the treatment of GABHS pharyngitis [22–26] and its role in the prevention of rheumatic fever [27–30]. Other very important considerations in the selection of this agent, were the need to assure antimicrobial compliance (100% with benzathine penicillin) [31] and the treatment costs of a single course of benzathine penicillin versus 10 days of oral penicillin. It is known that all GABHS strains are sensitive to 0.005 mg/l of penicillin and that benzathine penicillin is a slowly absorbable compound that produces relatively low blood levels of penicillin G but that bactericidal levels for all GABHS strains are extended for up to 1 month [9, 32]. Clinical trials performed with Air Force trainees also demonstrated a 96% reduction in the attack rate of rheumatic fever when benzathine penicillin was used instead of no specific treatment for patients with exudative pharyngitis [27]. Information analyzed from other clinical trials [33–35] clearly demonstrates poor patient compliance with oral agents prescribed for 10 days, particularly if, like in the case of penicillin suspension, the taste is unpleasant. In a clinical trial performed in Costa Rica during the 1970s designed to monitor antimicrobial compliance, a 10-day course of oral erythromycin was prescribed for children with GABHS pharyngitis. Patients were closely followed up; at the end of therapy it was noted that more than 90% of patients had ended therapy by day 5 and less than 5% had completed the 10-day course [31]. In terms of antimicrobial expenses, in Costa Rica and, predominantly within the social security drug formulary, therapy for a patient with GABHS pharyngitis using a single dose of intramuscular benzathine penicillin is less costly than a 10-day course of oral penicillin or any other oral antimicrobial. As a standard example the cost of treating a 7-year-old (weight 24 kg) patient with GABHS pharyngitis, within the Social Security System, with a single dose of 1,200,000 units of benzathine penicillin is USD 0.19 (cost of a 1,200,000 units vial of benzathine penicillin is USD 0.16 plus one syringe for the skin test USD 0.03) whereas the cost of treatment for the same patient with a 10-day course of oral penicillin (50 mg/kg/day) is USD 0.84 (600 mg tablet of penicillin V cost USD 0.042). Furthermore, in the case of benzathine penicillin, a vial is stable under standard refrigeration for 24 h and therefore, if needed, one vial of 1,200,000 units may be used for two 3- to 5-year-old patients the same day reducing the parenteral cost to USD 0.11 per patient. Because of the nationwide condition of the antimicrobial programs, significant reductions in the price of the different medications, are obtained every year through the purchase of large amounts of agents, such as oral and parenteral penicillin, in some instances to local pharmaceutical companies. Although, for

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Number of deaths per 1,000 live births

180

160.2

160 132.4

140 120

90.2

100

74.3

80

61.5

60 40

19.1

15.3

10.8

1980

1990

2000

20 0 1930

1940

1950

1960

1970 Years

Fig. 1. Infant mortality rate in Costa Rica between 1970 and 2000.

a single patient, the differences in the antimicrobial costs (USD 0.68) observed in the above example of a 7-year-old patient may not be significant, it does represent a major budgetary issue in a nationwide program particularly, when in addition, there are also other savings derived from not performing, rapid diagnostic techniques or cultures (USD 15.5–18.18/patient). This provides the opportunity to health institutions to relocate some of these resources into other areas in need. Overall, the new health program has been extremely successful; the infant mortality rate and life expectancy (75.6 years in year 2000) in Costa Rica have reached rates similar to other developed countries (fig. 1). In the specific case of the GABHS pharyngitis plan, this approach has also been effectively implemented for over 30 years. After a significant increase in the number of benzathine penicillin vials used throughout the nation during the first decade (1970–1980) a sharp decrease in the incidence of new cases of rheumatic fever was observed (fig. 2). Since 1995, a reduction in the usage of benzathine penicillin has been detected at the National Children’s Hospital (fig. 3). Although not completely clear why the usage of benzathine penicillin has decreased, this situation may be related to three factors; first, a more active participation of other outpatient clinics, located in the metropolitan area, where patients with upper respiratory diseases are seen instead of receiving care at the National Children’s Hospital; second, a consequence of local epidemiological studies performed during the beginning of the 1990s in which the seasonality of respiratory viral infections (influenza and respiratory syncytial virus) in Costa Rica was analyzed, resulting in a more selective usage of antimicrobials during the viral months and third, the introduction of amoxicillin suspension into the drug formulary of the

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Fig. 3. Correlation between new cases of rheumatic fever at the National Children’s Hospital and an estimate in the number of vials of benzathine penicillin used in all the Health Care Centers in San Jose, Costa Rica.

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Table 2. Principal causes of death in children above 5 years of age at the National Children’s Hospital, San José, Costa Rica 1968

2000

Diarrhea Mitral valve disorder secondary to rheumatic fever Tetanus Central nervous system infection

Malignant tumors Trauma and poisoning Infectious diseases1 Congenital malformations

Source: Department of Census and Statistics, Hospital Nacional de Niños ‘Dr. Carlos Sáenz Herrera’, San José, Costa Rica. 1 Three cases of central nervous system infections; 2 cases of varicella; 2 cases of diarrhea; 1 case of an acquired immunodeficiency and 1 disseminated angioestrongiloidiasis.

National Children’s Hospital (not into the formulary of other clinics) and the subsequent use of this antibiotic in some patients. Despite the new findings mentioned above, a reduction in the number of new cases of rheumatic fever has been maintained for the last 30 years and opposed to the national statistics from 1968, rheumatic fever with associated mitral valve disease is currently not included in the list of common causes of morbidity and mortality in Costa Rican children (table 2). Although we recognize that the decision to treat a suspected case of GABHS pharyngitis based only on clinical grounds may result in an overuse of benzathine penicillin, including some patients with purulent tonsils due to a viral agent (adenovirus, Coxsackie, Epstein-Barr or others), the use of rapid agglutination tests or throat cultures is not recommended because they are still expensive. Besides, visits for microbiological confirmation in a subgroup of patients, cannot be assured in a massive national program. Another concern with the Costa Rican national policy has been the possibility of selection of bacterial resistance to penicillin. Similar to other reports [36, 37], 100% of GABHS strains isolated from throat, middle ear fluid or other sterile corporal fluids (blood, cerebral spinal fluid, etc.) in Costa Rican patients, remain susceptible to penicillin [38–40]. The susceptibility pattern of other common nasopharyngeal bacterial isolates (Streptococcus pneumoniae, Haemophillus influenzae) obtained in recent years from Costa Rican pediatric patients also shows similar or lower resistance rates compared with data published from other countries where the approach for the diagnosis and treatment of patients with GABHS pharyngitis follows the recommendation of antimicrobial treatment only for patients with microbiological confirmation. The dosage of penicillin used in Costa Rica is 300,000 units for patients less than 3 years old; 600,000 units for patients between 3 and 5 years old and

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1,200,000 units for patients older than 5 years. A penicillin skin test is placed in every patient older than 3 years of age. Other than a transitory painful sensation at the site of the injection or a transient rash, major penicillin-related side effects (anaphylactic reactions or local site abscesses) have been reported only sporadically through the National Registry Program for Drug Related Adverse Events. Nationwide, there have been no deaths in the pediatric population due to penicillin anaphylaxis. In patients with history of allergy to penicillin or with a positive skin test, the use of oral erythromycin at 30–40 mg/kg/day divided into 4 doses for 10 days is suggested. Currently, the new macrolide/azalide agents are not available within the National Drug Formulary and their current local price prevents them to be incorporated in the formulary. The GABHS antimicrobial treatment recommendation used in Costa Rica for the past 30 years has been extremely successful in the reduction, nationwide, of new cases of rheumatic fever. This program is less expensive than other treatment modalities allowing healthy institutions to relocate resources into other important programs; is easily implemented by health workers in outpatient clinics and in the field; has not been associated with major adverse events; guarantees 100% compliance and has not resulted in bacterial selection of resistance. Unlike other places where standard practice for the treatment of GABHS patients is to treat with a 10-day course of oral penicillin only those patients with microbiological confirmation [11–15], outbreaks of rheumatic fever have not been reported in Costa Rica since the current approach for GABHS pharyngitis patients was implemented 31 years ago. Consideration to adopt a similar program should be considered in other countries with still a high incidence of new cases of rheumatic fever and budgetary limitations.

References 1 2

3 4 5 6 7

Peter G (ed): Group A Streptococcal Infections. 1997 Red Book: Report of the Committee on Infectious Diseases, edn 24, Elk Grove Village, American Academy of Pediatrics, 1997, pp 483–494. Bisno AL, Berrios X, Quesney F, Monroe DM Jr, Dale JB, Beachey EH: Type-specific antibodies to structurally defined fragments of streptococcal M proteins in patients with acute rheumatic fever. Infect Immun 1982;38:573–579. Shulman ST: Invasive and toxin-related diseases caused by group A streptococci. Pediatr Infect Dis J 1991;10:S28–S31. Dajani AS: Current status of nonsuppurative complications of group A streptococci. Pediatr Infect Dis J 1991;10:S25–S27. Ayoub EM: Immune response to group A streptococcal infections. Pediatr Infect Dis J 1991;10:S15–S19. Fragoso MA, Manning L, Frenkel LD: Can parents do a throat cultures? Pediatr Infect Dis J 1989;8:845–847. Markowitz M, Gerber MA, Kaplan EL: Treatment of streptococcal phayngotonsillitis: Report of penicillin’s demise are premature. J Pediatr 1993;123:679–684.

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8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

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Markowitz M: The decline of rheumatic fever: Role of medical intervention. J Pediatr 1985; 106:545–550. Gordis L: Changing risk of rheumatic fever; in Shulman S (ed): Pharyngitis: Management in an Era of Declining Rheumatic Fever. Philadelphia, Praeger Scientific, 1984, pp 13–22. Land MA, Bisno AL: Acute rheumatic fever: A vanishing disease in suburbia. JAMA 1983; 249:895. Land MA, Bisno AL: Acute rheumatic fever: A vanishing disease in suburbia. JAMA 1983;249:895. Wallace MR, Garst PD, Papadimos TJ, Oldfield EC: The return of acute rheumatic fever in young adults. JAMA 1989;262:2557–2561. Griffith SP, Gersony WM: Acute rheumatic fever in New York City (1969 to 1998): A comparative study of two decades. J Pediatr 1990;116:882–887. Wald ER, Dashefsky B, Feidt C, Chiponis D, Byers C: Acute rheumatic fever in western Pennsylvania and the tristate area. Pediatrics 1987;80:371–374. Sreenivasan VV, Congen J, Rizzo C, Congeni B: Outbreak of acute rheumatic fever in northeast Ohio. J Pediatr 1987;111:176–179. Londino AV, Wald ER, Zanwill KM: Acute rheumatic fever in western Pennsylvania: A persistant problem into the 1980s. J Pediatr 1991;118:561–563. Arguedas A, Mohs E: Prevention of rheumatic fever in Costa Rica. J Pediatr 1992;121:569–572. Ruff ME, Schotik DA, Bass JW, Vincent JM: Antimicrobial drug suspensions: A blind comparison of taste of fourteen common pediatric drugs. Pediatr Infect Dis 1991;10:30–33. Mohs E: Infectious diseases and health in Costa Rica: The development of a new paradigm. Pediatr Infect Dis 1982;1:212–216. Mohs E: General theory of paradigms in health. Pediatr Infect Dis J 1991;10:428–433. Markowitz M: Streptococcal disease in developing countries. Pediatr Infect Dis J 1991;10:S11–S14. Mohler DN, Wallin DG, Dreyfus EG, et al: Studies in the home treatment of streptococcal disease: II. A comparison of the efficacy of oral administration of penicillin and intramuscular injection of benzathine penicillin in the treatment of streptococcal pharyngitis. N Engl J Med 1956;254:45–50. Bass JW: Antibiotic management of group A streptococcal phayngotonsillitis. Pediatr Infect Dis J 1991;10:S43–S49. Mohler DN, Wallin DG, Dreyfus EG, et al: Studies in the home treatment of streptococcal disease. II. A comparison of the efficacy of oral administration of penicillin and intramuscular injection of benzathine penicillin in the treatment of streptococcal pharyngitis. N Engl J Med 1956;254:45–50. Breese BB, Disney FA: A comparison of intramuscular and oral benzathine penicillin G in the treatment of streptococcal infections in children. J Pediatr 1957;51:157–163. Breese BB, Disney FA: Penicillin in the treatment of streptococcal infections: A comparison of effectiveness of five different oral and one parenteral form. N Engl J Med 1957;259:57–62. Chamovits R, Catanzaro FJ, Stetson CA, Rammelkamp CH Jr: Prevention of rheumatic fever by treatment of previous streptococcal infections. I. Evaluation of benzathine penicillin G. N Engl J Med 1954;251:466–471. Breese BB, Disney FA: The successful treatment of beta hemolytic streptococcal infections in children with a single injection of repository penicillin (benzathine penicillin G). Pediatrics 1955;15:516–521. Denny FW, Wannamaker LW, Brink WR, Rammelkamp CH Jr, Custe EA: Prevention of rheumatic fever: Treatment of preceding streptococci infection. JAMA 1950;141:151–153. Wannamaker LW, Rammelkemp CR Jr, Denny FW, Brink WR: Prophylaxis of acute rheumatic fever by treatment of the preceding streptococcal infection with various amounts of depot penicillin. Am J Med 1951;10:673–695. Rheumatic Fever Committee of the Council on Rheumatic Fever and Congenital Heart Disease of the American Heart Association: Statement. American Heart Association Circular, 1972. Bass JW, Crast FW, Kwoles CR, Onufer CN: Streptococcal pharyngitis in children: A comparison of four treatment schedules with intramuscular penicillin G benzathine. JAMA 1976;235:1112–1116. Mohs E: La fiebre reumática en Costa Rica. Rev Med Hosp Nal Niños Costa Rica 1985;20:77–85. Istre GR, Welch DF, Marks MI, Moyer N: Susceptibility of group A beta-hemolytic streptococcus isolates to penicillin and erythromycin. Antimicrob Agents Chemother 1981;20:244–246.

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Ayd FJ: Rational pharmacotherapy: Once-a-day drug dosage. Dis Nerv Syst 1971;34:371–378. Markello JR: Factor influencing pediatric compliance. Pediatr Infect Dis 1985;4:579–583. Shapera RM, Hable KA, Matsen JM: Erythromycin therapy twice daily for streptococcal pharyngitis: Controlled comparison with erythromycin or penicillin phenoxymethyl four times daily or penicillin G benzathine. JAMA 1973;226:531–535. Macris MH, Hartman N, Murray B, Klein RF, Roberts RB, Kaplan E, Horn D, Zabriskie JB: Studies of the continuing susceptibility of group A streptococcal strains to penicillin during eight decades. Pediatr Infect Dis J 1998;17:377–381. Horn DL, Zabriskie JB, Austrian R, Cleary PP, Ferretti JJ, Fischetti VA, Gotschlich E, Kaplan E, McCarty M, Opal SM, Roberts RB, Tomasz A, Wachtfoel Y: Why have group A streptococci remained susceptible to penicillin? Report on a Symposium. Clin Infect Dis 1998;26:1341–1345.

Adriano G. Arguedas MD Instituto de Atención Pediátrica PO Box 607–1150, San José (Costa Rica) Tel. ⫹506 222 9234, Fax ⫹506 222 9234, E-Mail [email protected]

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Pechère JC, Kaplan EL (eds): Streptococcal Pharyngitis. Issues Infect Dis. Basel, Karger, 2004, vol 3, pp 202–214

Vaccine Control Strategies against Group A Streptococcal Infections Expectations, Hopes and Possible Impact

Michael F. Good, K.S. Sriprakash, David J. Kemp Queensland Institute of Medical Research, The Bancroft Centre, Herston, Australia

Streptococcal pathology is diverse, not well understood, and experienced by all sectors of society in all countries of the world. Streptococcal pharyngitis is the most recognized manifestation of pathology and possibly the most common. Streptococcal pyoderma is also very common, particularly amongst certain disadvantaged groups [1]. These two disease categories, while very common, are relatively benign in terms of direct morbidity. However, poststreptococcal pathology (rheumatic fever (RF) and glomerulonephritis) can be severe. The WHO estimates that up to 500,000 lives are lost prematurely every year as a consequence of rheumatic heart disease (RHD). Most of these lives are taken in developing countries and from indigenous groups living in developed countries. While it has generally been thought for many years that streptococcal pharyngitis is a prerequisite for RF, this ‘dogma’ has recently been challenged by data from the Northern Territory of Australia which shows that amongst the Aboriginal population (who suffer the highest reported incidence for RF in the world) the incidence of streptococcal pharyngitis is low (and comparable to Australia’s Caucasian population) but the prevalence of pyoderma in school-aged children is approximately 70% [1]. Possibly streptococcal pyoderma directly leads to RF or may seed throat strains which lead to RF. In either case, prevention of streptococcal pyoderma may have a significant impact on the incidence of RF in certain populations. A diagnosis of RF necessitates regular antibiotic prophylaxis for many years. Compliance is often poor (e.g. approximately 50% amongst Aborigines) and consequently other modalities of prophylaxis are being sought – principally a vaccine to prevent infection with group A streptococcus (GAS). The purpose

of this review is to highlight some of the strategies being undertaken and discuss expectations of success. The complete genome sequence of type 1 Streptococcus pyogenes [2] revealed that more than 2.5% of its genetic endowment encodes genes for virulence factors. This may partly account for the wide range of diseases and sequelae that GAS can inflict upon humans and for its ability to affect diverse tissues. Although the M protein, one of the major virulence factors, is the beststudied streptococcal molecule and has a great potential to be a successful vaccine candidate, the search for candidate antigens for GAS vaccine strategies has always covered many possible choices. Obviously, an organism such as GAS that is exquisitely adapted to infecting two different tissues with drastically diverse environmental exposure, to escape host defenses and to persist may have capabilities to acquire (horizontally) genes for virulence factors to compensate for its low genetic endowment (1.8 Mbp). A consequence of this is divergence in the distribution for some virulence genes among GAS isolates. In line with this, even within the isolates belonging to a defined geographical locality, not only is the per capita diversity of the mga (chromosomal region containing the gene for M protein) high [3], but also differences in genetic endowment for various virulence factors are often observed [4]. The combinatorial effect of these may also determine differences in pathogenic potential. Thus, for an effective vaccine all these considerations should be addressed. Two approaches to control strategies will be discussed. Firstly, the challenges to developing a vaccine that can either prevent GAS infection or clear infection will be described. The leading vaccine candidates will be discussed. A second general strategy will then be discussed – the possibility of significantly reducing streptococcal skin disease by vaccinating to prevent infestation with the scabies mite – an organism thought responsible for up to 50% of all cases of streptococcal pyoderma in some populations.

GAS Vaccine Approaches

The M Protein The pioneering work of Rebecca Lancefield and her colleagues indicated a variable determinant on the surface of the organism that was the target of opsonic antibodies and the factor responsible for the very significant delay in acquisition of immunity to GAS [5]. The M protein is an ␣-helical coiled-coil protein extending from the plasma membrane of GAS through the capsule to the periphery [6]. It has different domains made up of repetitive sequence blocks. It is variable at the amino-terminus but becomes highly conserved near

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the carboxyl-terminus. The serotype of the organism is determined by variable segments within the M protein. Each organism expresses a single M protein although there are ‘M-like’ proteins, the function(s) of which are less well defined. Although up to 80 different serotypes have been described based on antibody-defined differences between organisms, many strains of GAS are ‘non-typable’, particularly strains from developing countries. Sequence analysis and PCR-based ‘vir regulon’ typing suggest that the diversity of strains is far greater than 80. The widespread diversity of GAS strains may explain, at least in part, the slow acquisition of immunity to GAS. Many believe that immunity to GAS requires prior exposure to all the common strains. While this explanation may prove to be incomplete, there are elegant studies showing that vaccination of laboratory animals with multiple serotypic determinants can protect against each of the represented strains. Thus, if all the common strains for a region or a country were defined, and if that number was not excessive, it might be possible to develop a multi-determinant vaccine. This is the approach being pursued by Jim Dale and colleagues from Memphis [7, 8] who have combined serotypic determinants representing the common north-American strains. This vaccine is currently in clinical trials. Such an approach, however, is unlikely to be efficacious for a vaccine targeting common strains found worldwide. Most serotypic determinants have not been defined and even if they were the limitations of modern vaccine technology would likely preclude such an approach given the very large number of serotypes likely to exist. A different approach has been to define conserved epitopes on the M protein. Groups working with Fischetti [9] and Dale [10] defined a mixture of peptides from the conserved C-repeat region, which when administered to mice could prevent subsequent pharyngeal colonization with different GAS strains. The mechanism of immunity was not defined. A related approach is to use the entire C-repeat region engineered in a bacterial vector [11]. We mapped a 20-mer peptide (p145) within the conserved region which could induce antibodies in mice capable of opsonizing multiple strains [12]. Antibodies specific for p145 were found in 90% of sera taken from adult Aborigines living in a streptococcal-endemic region of northern Australia. However, the peptide was recognized by ⬍50% of children under the age of 10 [13]. The acquisition of antibodies to this peptide parallelled the acquisition of immunity to GAS and provided an alternative or additional hypothesis for the slow acquisition of GAS immunity. p145 is poorly immunogenic and it takes several episodes of GAS exposure to develop antibodies naturally; nevertheless, antibodies, once induced, are protective or contribute to protection. Such epitopes have been defined in other systems and are referred to as ‘cryptic’.

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p145 was shown, however, to contain a segment capable of stimulating potentially heart-reactive T cells [14]. Evidence suggests that T cells might be largely responsible for the pathogenesis of RHD [15], although cross-reactive antibodies have also been nominated [16]. A minimal epitope within p145 that was recognized by antibodies but not heart-reactive T cells was subsequently defined and folded as an ␣-helix to enhance its immunogenicity [17]. Mice vaccinated with this minimal epitope, called J8, when conjugated to a carrier protein or as part of a multipeptide vaccine [18] developed antibodies capable of opsonizing GAS in vitro in the presence of neutrophils and complement. Vaccinated mice were protected from GAS. The degree of protection correlated with the titer of antibodies to the conserved epitope measured either in ELISA or in an opsonization assay [Batzolff et al., submitted]. Fibronectin-Binding Proteins (FBPs) FBPs are major streptococcal adhesins which mediate attachment of the pathogen to human epithelial cells. There are different FBPs of which four, namely SfbI, SfbII, FBP54 and PrtF2, are the major ones. Not all GAS strains express all of them. About 60–70% of GAS strains express SfbI [4]. In addition to its role in adherence to the host cells, this protein mediates invasion of the pathogen into the host cells [19]. Interestingly, a study from Israel showed that strains persisting after antibiotic treatment are more often SfbI-positive than those that are successfully cleared [20]. An interpretation of the observation is that SfbI-mediated internalization of host cells may promote persistence by avoiding the effect of penicillin [21]. If this interpretation holds, a vaccine based on SfbI may reduce colonization and interfere with internalization process. SfbI is highly immunogenic, and in a GAS-endemic population even 3-yearold children can seroconvert to this protein [4]. This population-based study from the Northern Territory of Australia suggests that the serum IgG response resulting from natural infection is, in itself, not protective against GAS infection. However, in a murine model intranasal immunization with SfbI offered 80% protection [22]. Furthermore, in another study SfbI was reported to have a profound adjuvanticity [23], and this property may be exploited to present other useful streptococcal candidate antigens by conjugating them to SfbI or parts thereof. SfbI has two fibronectin-binding domains, and a co-operative interaction between the domains is necessary to promote internalization of the host cells [24]. This suggests conformational changes may occur in SfbI upon binding to fibronectin via the primary site of interaction. Would this mean that there might be some hidden epitopes that could become accessible upon the primary interaction? Further dissection of SfbI to determine useful ‘hidden’ epitopes is underway.

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SfbII is responsible for causing opacity of serum and has been referred to as opacity factor. It is a highly divergent protein and is expressed in about a third of M serotypes. Knockout mutants show a marked decrease in virulence for mice [25]. Given that the fibronectin-binding repeat domain in SfbI elicits a protective immune response [26], the corresponding domain from SfbII may also prove to be a useful target for a vaccine. However, the variable region proximal to the aminoterminus is highly immunogenic and appears to mask immunogenicity of SfbII’s fibronectin-binding repeat domain in natural infection [Gillen et al, unpubl. obs.]. FBP54 is present in all GAS isolates [27; Del Vecchio et al., unpubl.]. Sequence data also suggest that the gene is only moderately variable [unpubl.]. Kawabata et al. [27] showed that mice immunized intranasally with FBP54 were significantly protected from a subsequent GAS challenge. Like SfbI, PrtF2 [28] also can promote GAS internalization of the host cells [29]. This latter report, and observations that SfbI-mediated internalization may be important in persistence (see above) prompted us to screen for the distribution of genes for SfbI and PrtF2 among isolates from severe invasive disease cases and from uncomplicated infections from patients of the Northern Territory, where GAS infection is endemic. We found that a significant proportion of strains isolated from normally sterile sites were more likely to possess the gene for PrtF2 than strains isolated from uncomplicated cases from the same population [Del Vecchio et al., unpubl.]. No such association was observed for the SfbI gene. This observation suggests that there may be a role for PrtF2 in causing invasive diseases in this population. Thus, a PrtF2 based vaccine may be useful against severe infections. Recently, Rocha and Fischetti [30] described yet another FBP called PFBP. Its potential as a vaccine antigen was not reported. However, this protein and PrtF2 share considerable sequence similarity at their C-proximal halves and hence they may be variants of the same protein. C5a Peptidase All GAS strains express C5a peptidase, which specifically cleaves the chemotactic signal, C5a. Consistent with this enzymatic activity, a C5a peptidase-negative mutant was cleared more efficiently than the parental wild-type organism in a mouse model [31]. Mice immunized with C5a peptidase intranasally produced secretory IgA and serum IgG responses, and showed reduced pharyngeal colonization by heterologous strains upon challenge [32]. These results and the conserved nature of the protein among diverse strains make this antigen an attractive vaccine candidate. Spa18, Another Coiled-Coil Protein Streptococcal protective antigen (Spa) was recently described and characterized from type 18 strains [33]. This antigen elicits opsonic antibodies, and

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inactivation of the gene resulted in an increase in LD50 in a murine model. The carboxyl-proximal half of Spa18 is highly similar to M protein from group C streptococcus (GCS) and lacks certain signature characteristics of the same region of GAS M protein. Examination of the Spa18 sequence revealed no homology to p145. For vaccine development it is important to determine the degree of diversity of Spa among various strains and its distribution in GAS isolates. Answers to these questions are not available at present. However, limited serological data [34] using sera collected in the 1980s from Saudi Arabian rheumatic fever patients revealed that 50% of the sera reacted with a peptide corresponding to the N-terminal region of Spa18. In contrast, only 15% of the same sera reacted with the peptide corresponding to M18. One possible interpretation is that the Spa-like gene may be distributed in other M types as well. Our recent study [35] analyzing serological response among the Australian Aboriginal population to group A, C and G streptococci suggested a possible role for GCS in the pathogenesis of ARF. Thus, a vaccine based on Spa might extend the cover to GCS as well.

Toxins Many GAS strains produce streptococcal pyrogenic exotoxins (Spe). Among these SpeA, B and C are well studied. All strains encode the gene for SpeB, which is a cysteine proteinase. Numerous observations have pointed to its role in pathogenesis. Inactivation of the gene for SpeB caused reduced resistance to phagocytosis and mice challenged with such a mutant lost the ability to cause lethality [36, 37]. Also, an inverse correlation was found between antibody titers to SpeB and severity of invasive diseases in humans [38]. Immunization of mice with this toxin protected them from challenge with Spe-positive GAS [39]. Together these observations are indeed encouraging. SpeA in particular, and SpeC were reported to be associated with streptococcal toxic shock syndrome. Mutations were introduced in the residues that are necessary for the mitogenic activity of these superantigens. The resulting non-superantigenic toxoids were found to elicit protective immune response against wild-type toxin-producing strains in experimental models [40, 41]. A recent more exciting development is the identification of a peptide antagonist that inhibited expression of cytokines responsible for shock [42]. This peptide protected mice against GAS challenge. The peptide also reversed toxic shock in animals in which this syndrome was established. In a separate study, Visvanathan et al. [43] showed that immunization with peptides corresponding to conserved domains of various superantigens provided protection against GAS challenge. These studies provide novel approaches to control GAS invasive disease.

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Is a Vaccine Against Scabies Possible?

The Need for a Scabies Vaccine Scabies (‘itch mite’, or Sarcoptes scabiei) is a common infestation in the developing world [44–47] with about 300 million people being afflicted. Although it can be treated [48], it is endemic in remote northern and central Australian Aborigine communities [50], in which up to 50% of children may be infested with S. scabiei. These infestations decrease the quality of life by causing intense itching and often lead to bacterial skin infections followed by serious complications, including septicemia and renal damage [50]. Scabies is also a problem in other overcrowded situations such as nursing homes. Scabies contributes heavily to GAS skin disease in children [51]. Control of scabies has been shown to reduce pyoderma and signs of renal damage in children. A vaccine against scabies would greatly improve the quality of life of many poor people, mostly children, worldwide. The common name of S. scabiei, itch mite, gives an impression of its debilitating and depressing effects. A vaccine is clearly the most desirable long-term solution because of limitations of drug delivery and compliance and there is a considerable body of evidence that infestation with the mite can lead to subsequent protective immunity. Evidence for a Role of Immunity in Self-Limiting Normal Scabies In most cases scabies is self-limiting in humans. Mellanby [52] determined that in experimental infestations the average number of mites on adults was 11–13. Reinfection was more difficult and the parasite rate was even lower. A minority of people develop the serious alternative form, crusted scabies. It was originally called Norwegian scabies as it was observed in leprosy patients in Norway. Outbreaks of scabies in hospitals after admission of such patients demonstrate that this is caused sby the same variety of mite that causes normal scabies, but is characterized by an extremely high burden of mites [53]. Crusted scabies more commonly occurs in patients with AIDS and other immunosuppressive conditions, but it also occurs in people with no known immune deficiency. It has been postulated that there is a specific immune deficit that results in a minority of individuals developing this hyperinfestation, with its nature yet to be defined [Kemp et al., in press]. It is clear that mites ingest human antibodies during feeding as human IgG can be demonstrated by immunological staining of sections of Psoroptes ovis and Psoroptes cuniculi [54] and proteins from S. scabiei mites contain significant amounts of antibody. Immunity following primary infestations has been clearly demonstrated in an animal model [55]. Taken together these observations suggest that antibodies may play a role in the development of protective immunity, but this has not been conclusively demonstrated. Mechanical

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removal of mites by scratching clearly can also play an important role in control of mite numbers. It would very likely be possible to control scabies in children using a vaccine. The epidemiology of scabies in populations suggests partial immunity is acquired with age and exposure. Scabies is a major veterinary problem internationally and this could provide an economically viable commercial framework for developmental stages of a human vaccine program. The pig industry in the USA and Europe are major potential consumers of a commercial vaccine. In Indiana, one of the top 5 pork-producing states in the USA, 25% of all pigs and 41% of all herds examined were infested with scabies while in Minnesota 14% of all pigs and 56% of all herds examined were infested [47, 56]. Proof of principle of a vaccine in such a setting could accelerate the development of a human vaccine. Tick Vaccine Studies: ‘Concealed Antigens’ Evidence from other ectoparasite systems suggests that a vaccine against scabies may be realistic. Immunological control of ectoparasites such as the cattle tick Boophilus microplus was first attempted over 60 years ago [57]. Willadsen and colleagues [58] have discussed the two major approaches to the development of vaccines against this organism. The first of these takes an approach typical in immunoparasitology and aims to identify antigens that elicit protective responses during natural infection. The major responses observed are typically to antigens of the salivary gland or mouthparts. The second approach is directed against antigens which do not play a role as a result of natural infestation. The term ‘concealed antigens’ has been used to describe these [59]. Concealed antigens are best exemplified by the molecule Bm86 [60] a membrane-bound glycoprotein on the surface of gut cells of B. microplus. This was shown to be an effective antigen when tested as a native protein in cattle [60]. Vaccination with a number of different recombinant forms expressed in a variety of systems has resulted in substantial protection, as measured by reductions in the number of engorging female ticks and their weight and fecundity [61]. The effect of antibodies on the tick gut could readily be observed as the ticks became red from leakage of blood through the gut wall [62]. Some sequence variation has been observed, as has strain susceptibility to the vaccine, although it is not clear whether these are related. Bm86 has been the sole antigen component of the commercial vaccines TickGARD™ and GAVAC™ which have been shown to be effective in field use [58]. A high level of crossprotection against Boophilus annulatus has been observed. The major problem with this vaccine is that as it is a ‘concealed’ antigen; antibody titers to Bm86 are not boosted by tick infestation and sustained tick control demands booster vaccinations.

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House Dust Mite Allergens House dust mites are a major source of allergens which are important in asthma and therefore have been extensively studied. At least 15 allergens have been identified to date [63]. Dominant among these are digestive enzymes secreted into the gut, such as the cysteine protease Derp1. Mite bodies are not the major source of allergens in the environment; almost all environmental Derp1 is of fecal origin. Homologues of Derp1 show about 30% identity to arthropod and helminth homologues. Other house dust mite allergens include amylase and trypsin, chymotrypsin and another serine protease [63]. Antibody studies demonstrated that scabies has a homologue of Derp1 [Walton, PhD thesis, 1999] and homologues of another allergen have been identified [Harumal et al., in preparation]. Presumably, most others will also have counterparts. As the sequences of these are all available, searching for their homologues among a large number of scabies gene sequences could provide a rapid way of obtaining a much larger library of antigens than is available for the tick. A Vaccine Strategy for Scabies It has been hypothesized [Kemp et al., in press] that immunization with a cocktail of the scabies homologues of house dust mite gut allergens would inhibit digestion and hence be protective. Further, we hypothesized that a scabies homologue of Bm86 exists and would be protective. In the case of B. microplus all of the equivalent set of homologues would fall into the class of concealed antigens. However in the case of scabies, mites dying in burrows could well release these molecules including a Bm86 homologue in a form accessible to the immune system. Certainly, antibodies to scabies antigens are detectable in patients and crossreactions between scabies and house dust mite antigens have been demonstrated. Hence, it seems reasonable to propose that such a vaccine would not require revaccination to the extent that the Bm86 anti-tick vaccine does. Currently, high throughput sequencing of a scabies cDNA library is in progress and it is expected to sequence about 50,000 clones [Harumal et al., in preparation]. It is to be expected that relevant homologues of Bm86 and house dust mite gut allergens will soon emerge from this. As an animal model exists it may be possible to directly test these for vaccine efficacy. The commercial applicability of such a veterinary vaccine should greatly facilitate proof-ofprinciple, allowing development of a vaccine for humans contributing to the control of GAS skin infection among socioeconomically deprived population. Conclusion

Finally, in formulating vaccine antigens to control GAS infection and diseases, it is important to consider the local needs and situations. Are we

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controlling diseases such as ARF, PSGN and invasive diseases? Or infection? Is throat or skin the primary site of infection? What is the genetic diversity of the GAS strains in the geographical location concerned? Should the vaccine be targeting children or adults? Should the vaccine cover other Lancefield streptococcal groups important for the communities? These and many other issues provide a compelling argument against the idea that a single vaccine formulation will suffice to control GAS diseases worldwide. The dynamics of strain structure resulting from antigenic variation, lateral genetic transfers, herd immunity, community-wide antibiotic treatments, opportunities for minor strains not covered by the vaccine for clonal expansion at the expense of other strains, etc., may dictate the need for continuous monitoring of these parameters and to vary the formulations suitably. Thus, a thorough knowledge of a bank of useful antigens and their protective mechanisms is mandatory for a ‘long-lasting’ efficacious vaccine strategy.

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M.F. Good Queensland Institute of Medical Research The Bancroft Centre, 300 Herston Road, Herston, QLD 4006 (Australia) Tel ⫹61 7 3362 0203, Fax ⫹61 7 3362 0110, E-Mail [email protected]

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Author Index

Adam, D. 115 Arguedas, A. 192

Kaplan, E.L. 66 Kemp, D.J. 202

Steinhoff, M.C. 49 Stevens, D.L. 3

Bisno, A.L. 22 Bryskier, A. 124, 150

Mandil, S. 173 Martin, D.R. 75 McIsaac, W.J. 36 Mohs, E. 192

Tanz, R.R. 16 Tupasi, T.E. 184

Pechère, J.C. 166 Peter, G.S. 22 Rimoin, A.W. 49

Zaher, S.R. 173

Cornaglia, G. 124, 150 Ferrieri, P. 85 Gehanno, P. 95 Good, M.F. 202 Helmerking, M. 115

Yamanaka, N. 143

Salazar, J.C. 103 Sriprakash, K.S. 202

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Subject Index

Adult streptococcal pharyngitis clinical features 23 diagnostic criteria 24, 26, 27 incidence 22–24 laboratory testing 28, 29 predictive rules 25, 26–28 treatment 30–32 Amoxicillin adult streptococcal pharyngitis management 31 dosing 106 Antibiotic overprescription, see Sore throat Arthritis, poststreptococcal clinical features 92 diagnosis 92 pathogenesis 93 Azithromycin, see also Macrolide antibiotics adult streptococcal pharyngitis management 31 clinical efficacy, streptococcal pharyngitis 133, 134 dosing 106 resistance, see Macrolide resistance Benzathine penicillin G, rheumatic fever prophylaxis Costa Rican experience, cost-effectiveness 195, 196 injection technique 181, 182 pharmacokinetics 181, 195

C5a peptidase, vaccine targeting 206 Carriers, group A streptococcus definition 66, 67 diagnosis, upper respiratory tract carriers 69–71 epidemiology 69 immune response 67 pathophysiology, upper respiratory tract carrier state 68, 69 public health implications 71–73 treatment recommendations 71 Cefthromycin 151 Cephalosporins dosing 106, 118 group A streptococcus treatment, short-course therapy clinical efficacy 119 comparison with other antibiotics 120, 121 eradication 119, 120 rationale 117, 119 recurrence rates 119 symptom resolution 119 mechanism of action 117 pharmacokinetics 118 prescription patterns 121 Cervical cellulitis and necrotizing fasciitis clinical features 99, 100 computed tomography 99–101 diagnosis 99, 100 pathogens 98, 99 prognosis 101, 102

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treatment 100, 101 Clarithromycin, see also Macrolide resistance clinical efficacy, streptococcal pharyngitis 132, 133 resistance, see Macrolide resistance short-course therapy 120 Computed tomography (CT) abscesses 96, 97 cervical cellulitis and necrotizing fasciitis 99–101 Cost analysis streptococcal pharyngitis burden 166, 167, 187, 188 streptococcal pharyngitis diagnosis, cost-effectiveness cohorts and meta-analysis 168, 169 management strategies and costs 167, 168, 172 prospective study 169, 170 streptococcal pharyngitis treatment, cost-effectiveness benzathine penicillin 195, 196 developed countries complication impact 170 side effects, antibiotics 170, 171 symptom impact 170 developing countries 171, 195, 196 Costa Rica, streptococcal pharyngitis management benzathine penicillin treatment, cost-effectiveness 195, 196 child mortality statistics 196, 198 diagnosis 192, 194 national health program 193, 194, 198 penicillin regimens 192, 193, 198, 199 rheumatic fever incidence 194, 199 Deoxyribonucleases antibody testing 82 virulence factors 7 Dirithromycin, see also Macrolide antibiotics clinical efficacy, streptococcal pharyngitis 133–135 resistance, see Macrolide resistance

Subject Index

Epidemiology, group A streptococcus developed countries 49, 50 developing countries, see also Costa Rica, streptococcal pharyngitis management carriage rates 53 non-group A streptococcus 53, 54 pharyngitis age and sex distribution 56 incidence 50, 51 prevalence 51, 52 risk factors 56 seasonality 56, 57 rheumatic fever pharyngitis relationship 58 pyoderma relationship 57, 58, 202 serologic surveys 55 serotype distribution 53–55 rheumatic fever, see Rheumatic fever risk groups 185, 186 transmission 184 Erythromycin, see also Macrolide antibiotics adult streptococcal pharyngitis management 31 classification of macrolide antibiotics 124, 125 clinical efficacy in streptococcal pharyngitis 130–132 dosing 106 resistance, see Macrolide resistance short-course therapy 120 Fibronectin-binding proteins, vaccine targeting 205, 206 Flurithromycin, see also Macrolide antibiotics clinical efficacy, streptococcal pharyngitis 135 resistance, see Macrolide resistance Glomerulonephritis, poststreptococcal clinical presentation 85, 86 immune response 87 laboratory findings 85–87 pathogenesis 12, 88, 89

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Glomerulonephritis, poststreptococcal (continued) post-impetigo glomerulonephritis, comparison 86, 87 prognosis 89 Group A streptococcus (GAS) adult infection, see Adult streptococcal pharyngitis carriers, see Carriers, group A streptococcus classification 4 epidemiology, see Epidemiology, group A streptococcus pediatric infection, see Pediatric streptococcal pharyngitis public health approaches, infection control 188–190 reservoirs 3 vaccination, see Vaccination, group A streptococcus virulence factors, see Virulence factors, Streptococcus pyogenes Hyaluronidase antibody testing 82 virulence factor 7 Josamycin, see also Macrolide antibiotics clinical efficacy, streptococcal pharyngitis 135, 136 resistance, see Macrolide resistance Ketolide antibiotics, see Cefthromycin; Telithromycin Macrolide antibiotics, see also specific antibiotics classification and structure 124, 125 mechanism of action 151 oral flora impact 125, 126 pharmacokinetics saliva concentrations 127, 130 tonsillar tissue distribution 126–129 streptococcal susceptibility 125, 126, 143 Macrolide resistance assays 154, 155 epidemiology

Subject Index

Australia 157 China 157 Europe 156–159 incidence 32, 144 Japan 111, 144 South America 158 trends 155, 156, 158–160 United States 157–159 low-level resistance and macrolide type differences 160–162 mechanisms efflux pump mediation of M phenotype 146, 153, 154 molecular epidemiology of resistance genes, Streptococcus pyogenes 147 overview 144 rRNA methylase genes 144–146, 152, 153 prospects for study 148 M phenotype, efflux pump mediation 146, 153, 154 M protein vaccine targeting 203–205 virulence factors 5 NADase antibody testing 82 virulence factor 7 Necrotizing fasciitis, see Cervical cellulitis and necrotizing fasciitis Opacity factor, virulence factor 6 Parapharyngeal abscesses prestyloid space abscess 97 retrostyloid space abscess 97, 98 treatment 98 Pediatric streptococcal pharyngitis clinical presentation in developed countries fever 16, 17 headache 17 lymph node swelling 18 nausea 17 scarlet fever 18, 19 sore throat 16, 17, 75, 76 tonsillar exudate 18 diagnosis in developing countries

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prediction rules 59, 60 rapid antigen tests 61, 62 throat cultures 60, 61 respiratory tract infection in young children 19, 20 seasonality 16 Penicillin adult streptococcal pharyngitis management 30–32 benzathine penicillin G, see Benzathine penicillin G group A streptococcus treatment administration routes 105 advantages 103, 110–112, 137 compliance 109, 116, 179, 180, 202 copathogenicity in failure 109, 110, 116 dosing 105, 106, 124 eradication efficacy 107–109 failure causes 116, 117 historical perspective 103, 104 rheumatic fever prevention 107, 115, 120, 121 sensitivity 31, 110, 111, 143 mechanism of action 104 pharmacodynamics 105 side effects 106 structure 104 tolerance 111 Peritonsillar abscess diagnosis 96 manifestations 96 treatment 96, 97 Polymerase chain reaction (PCR), streptococcal pharyngitis diagnosis 79 Protein F, virulence factor 6, 150 Pyoderma, rheumatic fever relationship 57, 58, 202 Pyogenic infection abscesses, see Parapharyngeal abscesses; Peritonsillar abscess pus collection sites 95 Pyrogenic exotoxins scabies streptococcal skin disease role 208 vaccination 208–210 vaccine targeting 207 virulence factors 8, 9

Subject Index

Rapid antigen detection test (RADT) adult streptococcal pharyngitis diagnosis 27, 29 cost-effectiveness, prospective study 169, 170 principles 78, 79 sensitivity 79 streptococcal pharyngitis diagnosis in developing countries 61, 62 Reservoirs carriers, see Carriers, group A streptococcus group A streptococcus 3 Rheumatic fever clinical manifestations 18, 19, 90, 91 developing countries benzathine penicillin G in prophylaxis 181, 182 economic constraints 174, 175 governmental intervention 173, 174 health education and public involvement 180, 181 health impact 186, 187 pharyngitis relationship 58 physician roles in prevention antibiotic therapy 177, 178 health education 176 laboratory diagnosis 176, 177 primary and secondary management 175 pyoderma relationship 57, 58 social and cultural constraints in prevention 178 treatment compliance 179, 180, 202 epidemiology 90, 115, 116, 186–188, 194 group A streptococcal M serotypes 89, 90 heart disease mortality 202 pathogenesis 11, 12, 91, 92 penicillin in prevention 107, 115, 120, 121 staphylococcal serotypes 115 Roxithromycin, see also Macrolide antibiotics clinical efficacy in streptococcal pharyngitis 133 resistance, see Macrolide resistance rRNA methylase, macrolide resistance role 144–146, 152, 153

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Scabies streptococcal skin disease role 208 vaccination concealed antigens in tick vaccine studies 209 house dust mite allergens 210 immunity in self-limiting normal scabies 208, 209 rationale 208 strategy for development 210 Sore throat antibiotic overprescription clinical error role 38, 39 overview 36 prevention 39, 40 cephalosporin prescription patterns 121 management practices of primary care physicians developed countries 36–38, 121 developing countries 177, 178 sore throat score management approach advantages 46, 47 impact on antibiotic overprescription 44, 45 limitations 45, 46 principles 40–42 reliability in different clinical settings 42–44 Spa18, vaccine targeting 206, 207 Spiramycin, see also Macrolide antibiotics clinical efficacy in streptococcal pharyngitis 135 resistance, see Macrolide resistance Streptokinase antibody testing 82 virulence factor 8 Streptolysin O antibody testing 81, 177 virulence factor 6, 7 Streptolysin S, virulence factor 7 Telithromycin clinical efficacy in streptococcal pharyngitis 136, 137

Subject Index

mechanism of action 151 pharmacokinetics saliva concentrations 127 tonsillar tissue distribution 126, 127 Throat culture conditions 77, 78 diagnostic sensitivity 76, 79 group A streptococci identification 80 media 77 pediatric streptococcal pharyngitis diagnosis 60, 61 swab collection 76 Vaccination, group A streptococcus prospects 190, 210, 211 rationale 203 targets C5a peptidase 206 fibronectin-binding proteins 205, 206 M protein 203–205 pyrogenic exotoxins 207 Spa18 206, 207 Virulence factors, Streptococcus pyogenes capsule 4 cell wall 4, 5 deoxyribonucleases 7 hyaluronidase 7 immunoglobulin-binding proteins 5, 6 M proteins 5 NADase 7 opacity factor 6 pathogenic mechanisms arthritis 93 cytokine induction 9, 10 glomerulonephritis 12, 88, 89 phagocyte inhibition 9 pharyngitis 10, 11 rheumatic fever 11, 12, 91, 92 protein F 6, 150 pyrogenic exotoxins 8, 9 SIC 6 streptokinase 8 streptolysin O 6, 7 streptolysin S 7

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