Hugo and Russell’s

PharmaceuticalMicrobiologyEDITED BY

Stephen P DenyerB Pharm PhD FRPharmSWelsh School of PharmacyCardiff UniversityCardiff

Norman A HodgesB Pharm PhD MRPharmSSchool of Pharmacy and Biomolecular SciencesBrighton UniversityLewes RoadBrighton

Sean P GormanBSc PhD MPSSchool of PharmacyQueen’s University BelfastMedical Biology CentreUniversity RoadBelfast

SEVENTH EDITION

BlackwellScience

Hugo and Russell’sPharmaceuticalMicrobiology

Hugo and Russell’s

PharmaceuticalMicrobiologyEDITED BY

Stephen P DenyerB Pharm PhD FRPharmSWelsh School of PharmacyCardiff UniversityCardiff

Norman A HodgesB Pharm PhD MRPharmSSchool of Pharmacy and Biomolecular SciencesBrighton UniversityLewes RoadBrighton

Sean P GormanBSc PhD MPSSchool of PharmacyQueen’s University BelfastMedical Biology CentreUniversity RoadBelfast

SEVENTH EDITION

BlackwellScience

© 1977, 1980, 1983, 1987, 1992, 1998, 2004 by Blackwell Science Ltda Blackwell Publishing companyBlackwell Science, Inc., 350 Main Street, Malden, Massachusetts 02148-5020, USABlackwell Publishing Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UKBlackwell Science Asia Pty Ltd, 550 Swanston Street, Carlton, Victoria 3053, AustraliaThe right of the Author to be identified as the Author of this Work has been asserted inaccordance with the Copyright, Designs and Patents Act 1988.

All rights reserved. No part of this publication may be reproduced, stored in a retrievalsystem, or transmitted, in any form or by any means, electronic, mechanical,photocopying, recording or otherwise, except as permitted by the UK Copyright, Designsand Patents Act 1988, without the prior permission of the publisher.

First published 1977Second edition 1980Third edition 1983Reprinted 1986Fourth edition 1987Reprinted 1989, 1991

Italian edition 1991Fifth edition 1992Reprinted 1993, 1994, 1995Sixth edition 1998Reprinted 1999, 2000, 2002, 2003Seventh edition 2004

Library of Congress Cataloging-in-Publication DataHugo and Russell’s pharmaceutical microbiology / edited by Stephen Denyer, Norman A.Hodges, Sean P. Gorman. — 7th ed.

p. cm.Rev. ed. of: Pharmaceutical microbiology / edited by W.B. Hugo and A.D. Russell.Includes bibliographical references and index.

ISBN 0-632-06467-61. Pharmaceutical microbiology.

[DNLM: 1. Anti-Infective Agents. 2. Technology, Pharmaceutical. QV 250 H895 2004] I. Title: Pharmaceutical microbiology. II. Hugo, W. B. (William Barry) III. Denyer, S. P. IV. Hodges, Norman A.V,. Gorman, S. P. VI.Pharmaceutical microbiology.

QR46.5.P48 2004615¢.1¢01579 —dc22

2003024264

ISBN 0–632–06467–6

A catalogue record for this title is available from the British Library

Set in Sabon 9.5/12 pt by SNP Best-set Typesetter Ltd., Hong KongPrinted and bound in the United Kingdom by Ashford Colour Press, Gosport

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v

Contributors, vii

Preface to Seventh Edition, ix

Preface to First Edition, x

Part 1: Biology of Microorganisms

1. Introduction to Pharmaceutical

Microbiology, 3

Stephen Denyer, Norman Hodges and

Sean Gorman

2. Fundamental Features of

Microbiology, 9

Norman Hodges

3. Bacteria, 23

David Allison and Peter Gilbert

4. Fungi, 44

Kevin Kavanagh and Derek Sullivan

5. Viruses, 59

Jean-Yves Maillard and David Stickler

6. Protozoa, 82

Tim Paget

7. Principles of Microbial Pathogenicity and

Epidemiology, 103

Peter Gilbert and David Allison

Part 2: Antimicrobial Agents

8. Basic Aspects of the Structure and Functioning

of the Immune System, 117

Mark Gumbleton and James Furr

9. Vaccination and Immunization, 138

Peter Gilbert and David Allison

10. Types of Antibiotics and Synthetic

Antimicrobial Agents, 152

A Denver Russell

11. Laboratory Evaluation of Antimicrobial

Agents, 187

JMB Smith

12. Mechanisms of Action of Antibiotics and

Synthetic Anti-infective Agents, 202

Peter Lambert

13. Bacterial Resistance to Antibiotics, 220

Anthony Smith

14. Clinical Uses of Antimicrobial Drugs, 233

Roger Finch

Part 3: Microbiological Aspects ofPharmaceutical Processing

15. Ecology of Microorganisms as it Affects the

Pharmaceutical Industry, 251

Elaine Underwood

16. Microbial Spoilage, Infection Risk and

Contamination Control, 263

Rosamund Baird

17. Chemical Disinfectants, Antiseptics and

Preservatives, 285

Sean Gorman and Eileen Scott

18. Non-Antibiotic Antibacterial Agents: Mode

of Action and Resistance, 306

Stephen Denyer and A Denver Russell

19. Sterile Pharmaceutical Products, 323

James Ford

20. Sterilization Procedures and Sterility

Assurance, 346

Stephen Denyer and Norman Hodges

21. Factory and Hospital Hygiene, 376

Robert Jones

22. Manufacture of Antibiotics, 387

Sally Varian

Contents

Contents

vi

23. The Manufacture and Quality Control of

Immunological Products, 398

Michael Corbel

24. Pharmaceutical Biotechnology, 416

Miguel Cámara

25. Additional Applications of Microorganisms in

the Pharmaceutical Sciences, 441

Denver Russell

Index, 459

vii

Contributors

Dr David AllisonSchool of Pharmacy and Pharmaceutical

SciencesUniversity of ManchesterOxford RoadManchester M13 9PLUK

Dr Rosamund BairdVisiting Senior LecturerSchool of Pharmacy and PharmacologyUniversity of BathClaverton DownBath BA2 7AYUK

Dr Miguel CámaraSenior Lecturer in Molecular MicrobiologyInstitute of Pharmaceutical SciencesSchool of Pharmaceutical SciencesUniversity of NottinghamNottingham NG7 2RDUK

Dr Michael CorbelNational Institute for Biological Standards

and ControlBlanche LaneSouth MimmsPotters BarHertfordshire EN6 3QGUK

Professor Stephen DenyerWelsh School of PharmacyCardiff UniversityCardiff CF10 3XFUK

Professor Roger FinchProfessor of Infectious DiseasesClinical Sciences BuildingUniversity of NottinghamThe City HospitalNottingham NG5 1PBUK

Dr Robert JonesSchool of Pharmacy and Biomedical SciencesUniversity of PortsmouthSt Michael’s BuildingWhite Swan RoadPortsmouth PO1 2DTUK

Dr Kevin KavanaghHead of Medical Mycology UnitDepartment of Biology National University of IrelandMaynoothCo. KildareIreland

Dr Peter LambertAston Pharmacy SchoolAston UniversityAston TriangleBirmingham B4 7ETUK

Dr Jean-Yves MaillardSchool of Pharmacy and Biomolecular

SciencesUniversity of BrightonLewes RdBrighton BN2 4GJUK

Dr Tim PagetDepartment of Biological SciencesUniversity of HullHull HU6 7RXUK

Professor A Denver RussellWelsh School of PharmacyCardiff UniversityKing Edward VII AvenueCardiff CF10 3XF Wales

Dr Eileen ScottSchool of PharmacyThe Queen’s University of BelfastBelfast BT9 7BLNorthern Ireland

Professor James FordSchool of Pharmacy and ChemistryLiverpool John Moores UniversityByrom StreetLiverpool L3 3AF UK

Dr James FurrWelsh School of PharmacyCardiff UniversityKing Edward VII AvenueCardiff CF10 3XFWales

Professor Peter GilbertSchool of Pharmacy and Pharmaceutical

SciencesUniversity of ManchesterOxford RdManchester M13 9PLUK

Professor Sean GormanProfessor of Pharmaceutical MicrobiologySchool of PharmacyThe Queen’s University of BelfastBelfast BT9 7BLNorthern Ireland

Dr Mark GumbletonWelsh School of PharmacyCardiff UniversityKing Edward VII AvenueCardiff CF10 3XFWales

Dr Norman HodgesPrincipal Lecturer in Pharmaceutical

MicrobiologySchool of Pharmacy and Biomolecular

SciencesUniversity of BrightonLewes RoadBrighton BN2 4GJUK

Contributors

viii

Dr Anthony SmithDepartment of Pharmacy and PharmacologyUniversity of Bath (5 West — 2.18)Claverton DownBath BA2 7AYUK

Professor JMB (Sandy) SmithHead of Department of MicrobiologyOtago School of Medical SciencesUniversity of OtagoDunedinNew Zealand

Dr Elaine UnderwoodSMA NutritionHuntercomb Lane SouthTaplowMaidenheadBerks SL6 0PHUK

Dr Sally VarianConsultantUlverstonCumbria LA12 8PTUK

Dr David Stickler School of BiosciencesCardiff UniversityMain BuildingMuseum AvenuePO Box 915Cardiff CF10 3TLWales

Dr Derek SullivanMicrobiology Research UnitSchool of Dental ScienceTrinity CollegeDublin 2Ireland

ix

Preface to the Seventh edition

We were much honoured to be recommended byProfessor A.D. Russell to act as editors for the 7thedition of Pharmaceutical Microbiology. All threeof us have used this textbook in its various editionsthroughout our careers as teachers and researchers,and we recognize the important role it fulfils.

As might be anticipated when a new editorialteam is in place, a substantial number of changeshave been made. Well over half the chapters havenew authors or co-authors. We also use Chapter 1to give a rationale for the scope and content of thebook, emphasizing the interrelated character of thediscipline of pharmaceutical microbiology. In addi-tion, by combining and reorganizing chapters, byintroducing new material and through a revised page format we have tried to provide readers with adistinctive 7th edition.

We must thank our contributors for their willing collaboration in this enterprise, especially Professor Russell for his continuing contri-butions, and our publishers for their support andexpertise.

Finally, this addition is a tribute to the farsighted-ness of A.D. Russell and W.B. Hugo who took upthe challenge in 1977 to produce a popular and con-cise read for pharmacy students required to studypharmaceutical microbiology. We are delightedthat this current edition recognizes these origins bycontinuing the association with Hugo and Russellin its revised title.

S.P. DenyerS.P. Gorman

N.A. Hodges

x

When we were first approached by the publishers towrite a textbook on pharmaceutical microbiologyto appear in the spring of 1977, it was felt that sucha task could not be accomplished satisfactorily inthe time available.

However, by a process of combined editorshipand by invitation to experts to contribute to the various chapters this task has been accomplishedthanks to the cooperation of our collaborators.

Pharmaceutical microbiology may be defined asthat part of microbiology which has a special bear-ing on pharmacy in all its aspects. This will rangefrom the manufacture and quality control of phar-maceutical products to an understanding of themode of action of antibiotics. The full extent of microbiology on the pharmaceutical area may bejudged from the chapter contents.

As this book is aimed at undergraduate pharmacy students (as well as microbiologists en-tering the pharmaceutical industry) we were underconstraint to limit the length of the book to retain itin a defined price range. The result is to be found in

the following pages. The editors must bear respon-sibility for any omissions, a point which has mostconcerned us. Length and depth of treatment weredetermined by the dictate of our publishers. It ishoped that the book will provide a concise readingfor pharmacy students (who, at the moment, lack atextbook in this subject) and help to highlight thoseparts of a general microbiological training whichimpinge on the pharmaceutical industry.

In conclusion, the editors thank most sincerelythe contributors to this book, both for complyingwith our strictures as to the length of their contribu-tion and for providing their material on time, andour publishers for their friendly courtesy and effi-ciency during the production of this book. We alsowish to thank Dr H.J. Smith for his advice on vari-ous chemical aspects, Dr M.I. Barnett for usefulcomments on reverse osmosis, and Mr A. Keall who helped with the table on sterilization methods.

W.B. HugoA.D. Russell

Preface to the First Edition

Part 1

Biology of Microorganisms

3

1 Microorganisms and medicines

Despite continuing poverty in many parts of theworld and the devastating effects of HIV and AIDSinfection on the African continent and elsewhere,the health of the world’s population is progressivelyimproving. This is reflected in the increase in life expectancy that has been recorded for the great majority of the countries reporting statistics to theWorld Health Organization over the last 40 years.In Central America, for example, the life expectancyhas increased from 55 years in 1960 to 71 years in2000, and the increase in North (but not sub-Saharan) Africa is even greater, from 47 to 68 years.Much of this improvement is due to better nutritionand sanitation, but improved health care and thegreater availability of effective medicines withwhich to treat common diseases are also major contributing factors. Substantial inroads have beenmade in the prevention and treatment of cancer,cardiovascular disease and other major causes ofdeath in Western society, and of infections and diar-rhoeal disease that remain the big killers in develop-ing countries. Several infectious diseases have beeneradicated completely, and others from substantialparts of the world. The global eradication of small-pox in 1977 is well documented, but 2002 saw threeof the world’s continents declared free of polio, andthe prospects are good for the total elimination ofpolio, measles and Chagas disease.

The development of the many vaccines and othermedicines that have been so crucial to the improve-ment in world heath has been the result of the largeinvestment in research by the major internationalpharmaceutical companies. This has led to the manufacture of pharmaceuticals becoming one of

the most consistently successful and important in-dustries in many countries, not only in the tradi-tional strongholds of North America, WesternEurope and Japan but, increasingly, in Eastern Eu-rope, the Indian subcontinent and the Far East.Worldwide sales of medicines and medical devicesare estimated to have exceeded $US 401 billion (ap-proximately £250 billion) in 2002, and this figure isrising by 8% per annum. In the UK alone, the valueof pharmaceutical exports is currently £10.03 bil-lion each year, a figure that translates to more than£150 000 for each employee in the industry.

The growth of the pharmaceutical industry in re-cent decades has been paralleled by rising standardsfor product quality and more rigorous regulation ofmanufacturing procedures. In order to receive amanufacturing licence, a modern medicine must beshown to be effective, safe and of good quality.Most medicines consist of an active ingredient thatis formulated with a variety of other materials (ex-cipients) that are necessary to ensure that the medi-cine is effective, and remains stable, palatable andsafe during storage and use. While the efficacy andsafety aspects of the active ingredient are within thedomain of the pharmacologist and toxicologist, respectively, many other disciplines contribute tothe efficacy, safety and quality of the manufacturedproduct as a whole. Analytical chemists and phar-macists take lead responsibility for ensuring thatthe components of the medicine are present in the correct physical form and concentration, butquality is not judged solely on the physicochemicalproperties of the product: microorganisms alsohave the potential to influence efficacy and safety.

It is obvious that medicines contaminated withpotentially pathogenic (disease-causing) micro-

Chapter 1

Introduction to pharmaceutical microbiology

Stephen Denyer, Norman Hodges and Sean Gorman

1 Microorganisms and medicines 2 The scope and content of the book