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Antimicrobial Chemotherapy Antimicrobial Chemotherapy SEVENTH EDITION Professor Peter Davey Lead for Clinical Quality Improvement Medical Education Institute University of Dundee Professor Mark Wilcox Consultant / Head of Microbiology Leeds Teaching Hospitals NHS Trust Professor of Medical Microbiology & Sir Edward Brotherton Chair of Bacteriology University of Leeds Lead on C. difficile infection Public Health England Professor William Irving Professor and Honorary Consultant in Virology University of Nottingham and Nottingham University Hospitals NHS Trust Professor Guy Thwaites Director of the Oxford University Clinical Research Unit and the Wellcome Trust Major Overseas Research Programme, Viet Nam Senior Research Fellow Nuffield Department of Medicine University of Oxford Honorary Consultant in Infectious Diseases and Clinical Microbiology Guy’s and St Thomas’ NHS Foundation, London 1 1 Great Clarendon Street, Oxford, OX2 6DP, United Kingdom Oxford University Press is a department of the University of Oxford. It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide. Oxford is a registered trade mark of Oxford University Press in the UK and in certain other countries © Oxford University Press 2015 The moral rights of the authors have been asserted First Edition published by Ballière Tindall in 1983 Second Edition published in 1989 Third Edition published in 1995 Fourth Edition published in 2000 Reprinted in 2001, 2003 (twice), 2004, 2005 Fifth Edition published in 2007 Sixth Edition published in 2012 Seventh Edition published in 2015 Impression: 1 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Oxford University Press, or as expressly permitted by law, by licence or under terms agreed with the appropriate reprographics rights organization. Enquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above You must not circulate this work in any other form and you must impose this same condition on any acquirer Published in the United States of America by Oxford University Press 198 Madison Avenue, New York, NY 10016, United States of America British Library Cataloguing in Publication Data Data available Library of Congress Control Number: 2014958214 ISBN 978–0–19–968977–4 Printed in Great Britain by Clays Ltd, St Ives plc Oxford University Press makes no representation, express or implied, that the drug dosages in this book are correct. Readers must therefore always check the product information and clinical procedures with the most up-to-date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulations. The authors and the publishers do not accept responsibility or legal liability for any errors in the text or for the misuse or misapplication of material in this work. Except where otherwise stated, drug dosages and recommendations are for the non-pregnant adult who is not breast-feeding Links to third party websites are provided by Oxford in good faith and for information only. Oxford disclaims any responsibility for the materials contained in any third party website referenced in this work. Preface Almost everyone in the developed world will receive several antibiotic courses during their lifetime. It is therefore not surprising that most clinicians and dentists will prescribe these drugs on a regular basis throughout their professional career. Indeed, several antibiotics figure among the most frequent of all prescribed drugs. Antibiotics are not only life-saving with regard to severe infections, such as pneumonia, menin- gitis, and endocarditis, but are also responsible for controlling much of the morbidity associated with non-life-threatening infectious disease; illness is abbreviated, return to normal activities is hastened, risk of infection transmission may be reduced and there is often economic benefit to the individual, as well as society, by reducing the number of working days lost. In addition, infectious complications of many commonly conducted surgical procedures are now preventable by the use of peri-operative antibiotic prophylaxis. Likewise procedures such as bone marrow and organ transplantation are also possible because of the effective control of complicating infections. These benefits are well known to healthcare professionals and to the public who no longer fear infection in the way earlier generations did. The very success of antimicrobial chemotherapy has led to a perception that such agents are generally safe and that industry will continue to generate new agents to ensure the effective control of most infectious problems. Antibiotics have largely been derived from natural sources, mainly from environmental bacteria and fungi. Their use in clinical medicine has been one of the major successes of the past century. The term ‘antibiotic’ was coined by Selman A Waksman, who recognized that these ‘naturally derived substances were antagonistic to the growth of other micro-organisms in high dilution.’ Over the years, other agents have been developed by chemical synthesis. More recently much effort has been applied to identifying genomic research based products. The term ‘antimicrobial agents’ captures all such compounds which in turn have been subdivided into antibacterial, antifungal, antiparasitic (anthelminthic and antiprotozoal) and antiviral agents according to the target pathogen. However, this purist approach is often ignored in practice and the term antibiotic is somewhat loosely applied to all these agents. The reader will find all such terms in use in this book. Antibiotics are unique among therapeutic agents in that they target invading micro-organisms rather than any pathological process arising from host cells or tissues. Furthermore, unlike other classes of drug, micro-organisms have the inherent or acquired ability to evade or inactivate antimicrobial activity of these drugs. Such resistance presents a major threat to sustaining effective treatment and prevention of infectious disease. In addition, there is increasing recognition of the importance of the normal bacterial flora of the human body and of the consequences of collateral damage from the use of antibacterials, such as the risk of Clostridium difficile infection. Indeed, controlling antibiotic resistance is one of the greatest challenges facing healthcare professionals and the public and is likely to remain so. While new drugs, vaccines and better diag- nostic methods are still a requirement, the fundamental issue is to ensure that existing agents are used effectively. This can only be achieved by ensuring those doctors, dentists, and, increasingly, other healthcare professionals who use these agents in the care of their patients, pursue good prescribing practice. vi PREFACE Good prescribing practice is the product of sound education, with particular emphasis on the acquisition of appropriate knowledge, skills, and professional behaviour. Good science informs good practice and since the knowledge base for prescribing practice is continuously expanding, the need for life-long learning is self-evident. Patient safety remains paramount in medicine. This is of particular importance since antibiotics are often used in the management of mild to moderate community infections and the prophylaxis of infections. The safety of antibiotics is monitored closely during drug development, at licensing and in clinical use. Since no drug is free from side effects, it is essential that the balance of risks and benefits of prescribing is understood by the prescribing practitioner. With more than 100 antimicrobial compounds currently available in the UK, this remains a particular challenge. Setting forth the principles of rational antimicrobial chemotherapy is the whole purpose of this book. In revisiting the contents, we welcome Dr Guy Thwaites among the editors. All chapters have been revised, several rewritten and a new chapter introduced on Antimicrobial Stewardship, Surveillance of Antimicrobial Consumption and Its Consequences to reflect the changes that have taken place in guiding prescribing practices. However, the basic plan of the book remains unchanged and much of the material provided by former authors has been retained attesting to its durability. As such, it reflects the vision of Pro- fessor David Greenwood, who was the inspiration for this book and Professor Roger Finch, who guided the first six editions so successfully. We sincerely hope that this 7th edition of Antimicrobial Chemotherapy will continue to furnish students and all healthcare professionals throughout the world with the necessary framework for understanding what antimicrobial agents will and will not do, and provide a firm basis for their informed use in the treatment and control of infection. March 2015 P.D. M.W. W.I. G.T. Contents List of Abbreviations ix Part 1 General properties of antimicrobial agents 1 Mechanisms of action and resistance to modern antibacterials, with a history of their development 3 2 Inhibitors of bacterial cell wall synthesis 10 3 Inhibitors of bacterial protein synthesis 24 4 Synthetic antibacterial agents and miscellaneous antibiotics 36 5 Antiviral agents 44 6 Antiretroviral agents 58 7 Drugs used in the treatment of viral hepatitis 66 8 Antifungal agents 75 9 Antiprotozoal and anthelminthic agents 81 Part 2 Resistance to antimicrobial agents 10 The problem of resistance 91 11 The genetics and mechanisms of acquired resistance 101 Part 3 General principles of usage of antimicrobial agents 12 Laboratory investigations and the treatment of infection 121 13 General principles of the treatment of infection 133 14 Pharmacokinetic and pharmacodynamic principles 140 15 Prescribing in special groups: effects of age, pregnancy, body weight, and hepatic and renal impairment 148 16 OPAT: outpatient parenteral antimicrobial therapy 159 17 Adverse drug reactions, and patient safety 168 18 Chemoprophylaxis and immunization 178 19 Guidelines, formularies, and antimicrobial policies 191 20 Antimicrobial stewardship, surveillance of antimicrobial consumption, and its consequences 206 Part 4 Therapeutic use of antimicrobial agents 21 Respiratory tract infections 227 22 Topical use of antimicrobial agents 240 viii CONTENTS 23 Urinary tract infections 248 24 Sexually transmitted infections 257 25 Gastrointestinal infections 267 26 Serious bacterial bloodstream infections 279 27 Bone and joint infections 297 28 Infections of the central nervous system 303 29 Skin and soft-tissue infections 317 30 Tuberculosis and other mycobacterial diseases 326 31 Infections in immunocompromised patients, including HIV/AIDS 338 32 Viral infections 347 33 Management of HIV infection 357 34 Treatment of chronic viral hepatitis 364 35 Parasitic disease 373 36 The development and marketing of antimicrobial drugs 384 Appendix: Recommendations for Further Reading 397 Index 403 List of abbreviations 5FC flucytosine EMA European Medicines Agency AASLD American Association for the Study of EoT end of treatment Liver Disease EoTR end of treatment response ACT artemisinin combination treatment ESAC European Surveillance of Antibiotic ADR adverse drug reaction Consumption AIDS acquired immune deficiency syndrome ESBL extended spectrum β-lactamases ALT, alanine aminotransferase EVR early virological response ASA American Society of Anesthesiologists FDA Food and Drug Administration ATC anatomical therapeutic chemical G6PD glucose-6-phosphate AZT azidothymidine (Zidovudine) dehydrogenase BAN British Approved Name GABA gamma-amino butyric acid BARDA Biomedical Advanced Research and GAIN Generating Antibiotic Incentives Development Authority Now BNF British National Formulary GRE glycopeptide-resistant enterococci BNFC children’s version of the British HAART highly active antiretroviral National Formulary therapy cART combination antiretroviral therapy HBsAg hepatitis B surface antigen CDC Centers for Disease Control HBV hepatitis B virus CDI Clostridium difficile infection HCV hepatitis C virus cEVR complete early virological response HHV-6 human herpesvirus 6 CMV cytomegalovirus HIV human immunodeficiency virus COPD chronic obstructive pulmonary disease HLA human leukocyte antigen CRB carbapenem-resistant bacteria HPV human papillomavirus CRP C-reactive protein HSE herpes simplex virus encephalitis CSF cerebrospinal fluid IDU idoxuridine CSM Committee on Safety of Medicines IE infective endocarditis DAA directly acting antivirals IFN interferon DDD defined daily dose IGRA interferon-γ release assay DEET diethyltoluamide IL interleukin DHPG dihydroxypropoxymethylguanine IL-28B interleukin-28B DNA pol DNA polymerase IMI Innovative Medicines Initiative DRM drug resistance mutation INN International Non-Proprietary Name (specified)IRES internal EASL European Association for the Study of ribosomal entry site the Liver IRIS immune reconstitution EBV Epstein–Barr virus inflammatory syndrome ECDC European Centre for Disease IV intravenous Prevention and Control IVOST intravenous to oral switch therapy EDTA ethylenediaminetetraacetic acid LRTI lower respiratory tract infections eGFR estimated glomerular filtration rate LVM lamivudine EIA enzyme immunoassay x LIST OF ABBREVIATIONS MALDI-TOF matrix-assisted laser desorption/ pEVR partial early virological response ionization time of flight PJI prosthetic joint infection MDR-TB multidrug-resistant tuberculosis PI protease inhibitor MERS-CoV Middle East respiratory syndrome PICC p eripherally inserted central coronavirus catheters MIC minimum inhibitory concentration PPD purified protein derivative MHRA Medicines and Healthcare Products PVL Panton–Vallentine leukocidin (toxin) Regulatory Agency QIDP qualified infectious disease product MIR magnetic resonance imaging rINN r ecommended International Non- miR-122 microRNA-122 Proprietary Name MMR measles, mumps, and rubella RR relapser-responder (vaccination) rRNA ribosomal RNA mRNA messenger RNA RSV respiratory syncytial virus MRSA methicillin-resistant Staphylococcus RT reverse transcriptase aureus RTI reverse transcriptase inhibitors MSM men who have sex with men RV ribavirin MSQ mental state questionnaire RVR rapid virological response NA neuraminidase SAB Staphylococcus aureus bacteraemia NANBH non-A non-B hepatitis SARS-CoV severe acute respiratory syndrome NCR non-coding region ScRAP S cottish Reduction in Antimicrobial NICE National Institute for Health and Prescribing Clinical Excellence SIRS s ystemic inflammatory response NNIS National Nosocomial Infections syndrome Surveillance SNP single nucleotide polymorphism NNRTI non-nucleoside analogue reverse transcriptase inhibitor SVR sustained virological response NR non-response SVR12 s ustained virological response determined at 12 weeks after the end NRTI nucleos(t)ide analogue reverse of treatment transcriptase inhibitor SVR24 s ustained virological response NSAID non-steroidal anti-inflammatory determined at 24 weeks after the end drug of treatment OPAT outpatient parenteral antimicrobial TB tuberculosis therapy TESSy The European Surveillance System ORF open reading frame TK thymidine kinase ORION O utbreak Reports and Intervention studies Of Nosocomial (infection) USAN U nited States Adopted NameVRE vancomycin-resistant enterococcal PAS para-aminosalicylic acid VZV varicella-zoster virus PBP penicillin-binding protein WHO World Health Organization PCR polymerase chain reaction XDR extensively drug resistant PEG pegylated interferon XDR-TB extensively drug-resistant tuberculosis PEP post-exposure prophylaxis

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Antimicrobial agents are essential for the treatment of life-threatening infections and for managing the burden of minor infections in the community. In addition, they play a key role in organ and bone marrow transplantation, cancer chemotherapy, artificial joint and heart valve surgery. Unlike othe