Sample Cover

Contents

Registered office

John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, United Kingdom

For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at .

The right of the author to be identified as the author of this work has been asserted in accordance with the Copyright, Designs and Patents Act 1988.

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, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher.

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books.

Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is sold on the understanding that the publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought.

The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for every situation. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of experimental reagents, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each chemical, piece of equipment, reagent, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom.

Library of Congress Cataloging-in-Publication Data

Antibacterial agents: chemistry, mode of action, mechanisms of resistance, and clinical applications / Rosaleen Anderson .... [et al.].

p.; cm.

Includes bibliographical references and index.

ISBN 978-0-470-97244-1 (cloth) – ISBN 978-0-470-97245-8 (pbk.)

I. Anderson, Rosaleen J.

[DNLM: 1. Anti-Bacterial Agents. QV 350]

615.7′922–dc23

2012006648

A catalogue record for this book is available from the British Library.

HB ISBN: 9780470972441

PB ISBN: 9780470972458

Preface

Since the introduction of benzylpenicillin (penicillin G) in the 1940s, it is estimated that over 150 antibacterials have been developed for use in humans, and many more for veterinary use. It is the use of antibacterials in the treatment of infections caused by pathogenic bacteria that led to them being labelled as ‘miracle drugs’, and, considering their often simple pharmacology, the effect that they have had upon infectious diseases and population health is remarkable. We are lucky enough to have been one of the generations for whom antibiotics have been commonly available to treat a wide variety of infections. In comparison, our grandparents were from an era where bacterial infection was often fatal and where chemotherapeutic agents were limited to the sulfonamides and antiseptic agents. This golden age of antibacterial agents may, however, soon come to an end as more and more bacteria develop resistance to the classes of antibacterial agents available to the clinician.

The timescale of antibacterial development occupies the latter half of the 20th century, with the introduction of the sulfonamides into clinical use in the 1930s, shortly followed by the more successful penicillin group of antibiotics. The discovery of penicillin by Sir Alexander Fleming in 1928, for which he received the Nobel Prize jointly with Howard Florey and Ernst Boris Chain, represents one of the major events in drug discovery and medicine. The subsequent development and wartime production of penicillin was a feat of monumental proportions and established antibiotic production as a viable process. This discovery prompted research which was aimed at discovering other antibiotic agents, and streptomycin (the first aminoglycoside identified) was the next to be isolated, by Albert Schatz and Selman Waksman in 1943, and produced on a large scale. Streptomycin became the first antibiotic to be used to successfully treat tuberculosis, for which every city in the developed world had had to have its own specialised sanatorium for the isolation and rudimentary treatment of the ‘consumptive’ infected patients. It was estimated at the time that over 50% of the patients with tuberculosis entering a sanatorium would be dead within 5 years, so the introduction of streptomycin again proved a significant step in the treatment of infectious disease.

The development of antibacterials continued throughout the latter part of the 20th century, with the introduction into the clinic of the cephalosporins, chloramphenicol, tetracyclines, macrolides, rifamycins, quinolones, and others. All of these agents have contributed to the arsenal of antibacterial chemotherapy and all have a specific action on the bacterial cell and thus selective activity against specific bacteria. We hope that this book will serve to highlight the development of the major antibacterial agents and the synthesis (where plausible) of these drugs. In addition, as health care professionals, we hope that students of medicinal chemistry, pharmacy, pharmaceutical sciences, medicine, and other allied sciences will find this textbook invaluable in explaining the known mechanisms of action of these drugs. We believe that knowledge of the mode of action and pharmacology of antibacterial agents is essential to our understanding of the multidrug approach to the treatment of bacterial infections. Several administered antibiotics acting upon different bacterial cell functions, organelles, or structures simultaneously can potentiate the successful eradication of infection. In addition, by understanding the action of the antibacterial agents at a cellular level, we are able to envisage those mechanisms involved in drug toxicity and drug interactions. As is demonstrated with the majority of the available therapeutic agents, antibacterial toxicities are observed with increased doses, as well as idiosyncratically in some patients and in combination with other therapeutic agents in the form of a drug interaction.

We have endeavoured to provide the major clinical uses of each class of antibiotic at the time of writing. As bacterial resistance may develop towards these therapeutic agents, and as other antibiotics are developed, the prescribed indications of these agents may change. Antibacterial prescribing worldwide is a dynamic process due to the emergence of resistance, and consequently some drugs have remained in clinical use, while others have ‘limited’ use.

In most developed countries in the world, the use of antibiotics is second to analgesic use, and with such extensive use, antibacterial resistance has inevitably become a major global concern. Rational prescribing of antibiotics is a key target for the World Health Organization, which endeavours to limit the use of antibiotics in an attempt to reduce the incidence of drug resistance. Despite these attempts, it is the nature of bacteria that resistance will inevitably occur to some agents, and this should prompt the further development of new antibiotics by the pharmaceutical industry. If we revisited the topic of antibiotic use, development, and mechanisms of action in 10–20 years (this is not to be taken as a hint as to when we might revise this book), we would hopefully find that several new drugs had been developed, while some of the classes with which we are familiar would have disappeared. Perhaps the clinical picture would appear to be similar, but drug treatments would probably have changed.