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Kucer s the Use of Antibiotics Two Volume Set 6th
Edition M. Lindsay Grayson Digital Instant Download
Author(s): M. Lindsay Grayson
ISBN(s): 9781444128666, 1444128663
Edition: 6
File Details: PDF, 31.40 MB
Year: 2010
Language: english
KUCERS’
THE USE OF ANTIBIOTICS

A CLINICAL REVIEW OF ANTIBACTERIAL,

ANTIFUNGAL, ANTIPARASITIC AND
ANTIVIRAL DRUGS
This page intentionally left blank
KUCERS’ THE USE OF
ANTIBIOTICS
A CLINICAL REVIEW OF ANTIBACTERIAL,
ANTIFUNGAL, ANTIPARASITIC AND
ANTIVIRAL DRUGS

VOLUME 1
6TH EDITION

M Lindsay Grayson MB BS MD MSC FRACP FRCP FAFPHM

Professor of Medicine and Director, Infectious Disease and Microbiology Departments, Austin Health
Department of Epidemiology and Preventive Medicine, Monash University
Department of Medicine, University of Melbourne, Melbourne, Australia
Suzanne M Crowe MBBS FRACP MD
Head, Centre for Virology, Burnet Institute for Medical Research and Public Health
Consultant Physician in Infectious Diseases and General Medicine, The Alfred Hospital
Professor of Medicine, Monash University, Victoria, Australia
James S McCarthy MD FRACP
Queensland Institute for Medical Research, University of Queensland
Department of Infectious Diseases, Royal Brisbane and Womens Hospital
Brisbane, Australia
John Mills MD FACP FRACP
Professor of Medicine, Microbiology & Epidemiology, Monash University and Consultant Physician in
Infectious Diseases, The Alfred Hospital, Melbourne, Australia
Johan W Mouton MD PhD
Department of Medical Microbiology and Infectious Diseases, Canisius Wilhelmina Hospital, Nijmegen;
Department of Medical Microbiology, Radboud University Nijmegen Medical Center, The Netherlands
S Ragnar Norrby MD PhD FRCP
Professor Emeritus, Swedish Institute for Infectious Disease Control, Solna, Sweden
David L Paterson MBBS PhD FRACP FRCPA
Professor of Medicine, University of Queensland Centre for Clinical Research,
Consultant Physician, Infectious Diseases Unit, Royal Brisbane and Women’s Hospital,
Consultant Clinical Microbiologist, Pathology, Queensland,
Brisbane, Queensland, Australia
Michael A Pfaller MD
Professor Emeritus, Departments of Pathology and Epidemiology, University of Iowa College of Medicine
and College of Public Health, Iowa, USA
First published in Great Britain in 1972 by Butterworth-Heinemann
Second edition 1975
Reprinted 1977
Third edition 1979
Reprinted 1982
Fourth edition 1987
Reprinted 1988, 1989
Fifth edition 1997
This sixth edition published in 2010 by
Hodder Arnold, an imprint of Hodder Education, an Hachette UK Company,
338 Euston Road, London NW1 3BH

http://www.hoddereducation.com

r 2010 Edward Arnold (Publishers) Ltd

All rights reserved. Apart from any use permitted under UK copyright law, this publication may only be
reproduced, stored or transmitted, in any form, or by any means with prior permission in writing of the publishers
or in the case of reprographic production in accordance with the terms of licences issued by the Copyright
Licensing Agency. In the United Kingdom such licences are issued by the Copyright Licensing Agency:
Saffron House, 6-10 Kirby Street, London ECIN 8TS

Whilst the advice and information in this book are believed to be true and accurate at the date of going to press,
neither the author[s] nor the publisher can accept any legal responsibility or liability for any errors or omissions that
may be made. In particular (but without limiting the generality of the preceding disclaimer) every effort has been
made to check drug dosages; however it is still possible that errors have been missed. Furthermore, dosage
schedules are constantly being revised and new side-effects recognized. For these reasons the reader is strongly
urged to consult the drug companies’ printed instructions before administering any of the drugs recommended in
this book.

British Library Cataloguing in Publication Data

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

Library of Congress Cataloging-in-Publication Data

A catalog record for this book is available from the Library of Congress

ISBN 978 0 340 927 670

1 2 3 4 5 6 7 8 9 10

Commissioning Editor: Caroline Makepeace

Production Editor: Sarah Penny
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Contents
Contributors ix Cefotaxime 319
Foreword xix Ceftriaxone 351
Obituary xxi Ceftizoxime, Cefdinir, Cefditoren, Cefpodoxime,
Preface xxiii Ceftibuten, Cefsulodin, and Cefpiramide 390
Abbreviations xxv Cefixime 398
Ceftazidime 405
Volume I Cefpirome 422
Cefepime 427
Section I - ANTIBIOTICS Ceftaroline 442
Ceftobiprole 448
Part - 1 Penicillins and Related Drugs Aztreonam 458

Benzylpenicillin (Penicillin G) 5 Part - 3 Carbapenems

Phenoxypenicillins 59
Ampicillin, Amoxicillin and Other Ampicillin-Like Imipenem 471
Penicillins 65 Meropenem 500
Methicillin 93 Doripenem 514
Isoxazolyl Penicillins: Oxacillin, Cloxacillin, Dicloxacillin Ertapenem 526
and Flucloxacillin 100 Biapenem 542
Nafcillin 115 Faropenem 547
Carbenicillin, Carindacillin, Carfecillin and Panipenem 553
Ticarcillin 123 Ritipenem 558
Mezlocillin, Azlocillin, Apalcillin and Piperacillin 135 Sulopenem 562
Mecillinam (Amdinocillin) and Pivmecillinam 152
Temocillin 160 Part - 4 Glycopeptides and Lipopeptides

Vancomycin 569
Beta-Lactamase Inhibitors and Combinations Teicoplanin 601
Daptomycin 621
Clavulanic Acid 167 Oritavancin 638
Sulbactam 175 Dalbavancin 645
Tazobactam and Brobactam 180 Telavancin 654
Amoxicillin–Clavulanic Acid (Co-Amoxiclav) 187 Ramoplanin 661
Ampicillin–Sulbactam 204
Ticarcillin–Clavulanic Acid 221 Part - 5 Aminoglycosides
Piperacillin–Tazobactam 238
Kanamycin 667
Part - 2 Cephalosporins and Related Drugs Gentamicin 674
Tobramycin 699
Cephalothin and Cefazolin 257 Amikacin 712
Cephalexin 268 Sisomicin and Netilmicin 727
Cephadroxil, Cephaloridine, Cephacetrile, Cephapirin, Isepamicin 736
Cephradine, and Other Rarely Used First-Generation Neomycin 742
Cephalosporins 275
Cefaclor, Cefprozil, and Loracarbef 280 Part - 6 Macrolides and Ketolides
Cefuroxime 286
Cefotiam, Cefuzonam, Cefamandole, Cefonicid and Erythromycin 751
Ceforanide 295 Roxithromycin 770
Cefoxitin, Cefotetan and Other Cephamycins Clarithromycin 779
(Cefmetazole and Flomoxef) 301 Azithromycin 801
Cefoperazone and Cefoperazone–Sulbactam 311 Josamycin and Rosaramicin 819
vi Contents

Telithromycin 825 Gemifloxacin 1466

Cethromycin 834 Sitafloxacin 1475
Enoxacin 1482
Part - 7 Tetracyclines and Related Drugs Pefloxacin 1490
Sparfloxacin 1501
Tetracycline 843 Lomefloxacin 1509
Doxycycline 851 Rufloxacin 1517
Minocycline 870 Tosufloxacin 1521
Tigecycline 881 Fleroxacin 1526
Newer, Discontinued Fluoroquinolones: Temafloxacin,
Trovafloxacin, Grepafloxacin, and Clinafloxacin 1538
Part - 8 Other Antibiotics

Linezolid 895 Part - 12 Anti-Tuberculous Drugs

Quinupristin–Dalfopristin 920
Pristinamycin 930 Isoniazid 1549
Fosfomycin 935 Ethambutol 1570
Fusidic Acid (Fusidate Sodium) 945 Pyrazinamide 1581
Polymyxins 955 Rifampicin (Rifampin) 1587
Novobiocin 971 Rifabutin 1627
Bacitracin and Gramicidin 975 Rifaximin 1637
Mupirocin 980 Rifapentine 1645
Lincomycin and Clindamycin 987 Streptomycin 1650
Chloramphenicol and Thiamphenicol 1008 Para-Aminosalicylic Acid (PAS) 1662
Spectinomycin 1030 Ethionamide and Prothionamide 1666
Thiacetazone 1672
Part - 9 Anti-Folate Agents and Other Capreomycin 1677
Cycloserine 1681
Synthetic Antibacterials
Viomycin 1687
Sulfonamides 1037
Trimethoprim, Co-Trimoxazole (Co-T) and Related Volume 2
Agents 1076
Pyrimethamine 1150 Section II - ANTI-FUNGAL DRUGS
Dapsone 1164
Trimetrexate 1182 Part - 1 Polyenes
Iclaprim 1187
Nitrofurans: Nitrofurazone, Furazolidone and Amphotericin B (AMP): Deoxycholate and Lipid
Nitrofurantoin 1195 Formulations 1693
Methenamine Mandelate and Methenamine Nystatin 1728
Hippurate 1205 Natamycin (Pimaricin) 1733

Part - 10 Nitroimidazoles
Part - 2 Echinocandins, Allylamines and
Metronidazole 1211 Benzylamine Derivatives
Tinidazole 1238
Echinocandins – Caspofungin, Anidulafungin and
Part - 11 Quinolones and Fluoroquinolones Micafungin 1739
Terbinafine 1763
Nalidixic Acid and Other Older Quinolones 1249 Butenafine 1772
Ciprofloxacin 1265 Naftifine 1776
Norfloxacin 1347
Ofloxacin 1362 Part - 3 Systemic Azoles
Levofloxacin 1396
Moxifloxacin 1412 Ketoconazole 1781
Gatifloxacin 1429 Fluconazole 1806
Garenoxacin 1452 Itraconazole 1824
 Contents vii

Miconazole 1844 Mefloquine 2024

Voriconazole 1852 Halofantrine 2036
Posaconazole 1862 Lumefantrine 2042
Ravuconazole 1871 Primaquine 2049
Albaconazole 1877 Piperaquine 2059
Isavuconazole 1882 Tafenoquine 2068
Atovaquone 2073
Proguanil and Chloroproguanil 2082
Part - 4 Topical Azoles
Artemisinins 2090
Bifonazole 1889
Butoconazole 1893 Part - 2 Agents Active Against Intestinal and
Clotrimazole 1896 Intra-Abdominal Protozoa
Croconazole 1903
Eberconazole 1905 Iodoquinol and Quinacrine 2107
Econazole 1907 Fumagillin 2110
Enilconazole 1911 Furazolidone (Furazolidine) 2114
Fenticonazole 1912 Diloxanide Furoate 2121
Flutrimazole 1915 Spiramycin 2125
Isoconazole 1917 Nitazoxanide 2132
Lanoconazole 1919 Paromomycin 2140
Neticonazole 1921
Oxiconazole 1923 Part - 3 Agents Active Against American
Sertaconazole 1926 Trypanosomiasis
Sulconazole 1930
Terconazole 1933 Benznidazole 2151
Tioconazole 1936 Nifurtimox 2155
KP-103 1939
Part - 4 Agents Active Against African
Part - 5 Topical Agents - Thiocarbamates, Trypanosomiasis
Hydroxypridones and Morpholine
Suramin 2167
Tolnaftate 1943 Melarsoprol 2177
Amorolfine 1945 Eflornithine 2189
Ciclopirox 1949
Rilopirox 1953
Part - 5 Agents Active Against Leishmania
and Other Pathogens
Part - 6 Other Antifungal Agents and New
Agents in Development Pentamidine 2203
Antimonial Agents 2208
Flucytosine (5-Fluorocytosine; 5-FC) 1957 Miltefosine 2214
Griseofulvin 1964
Haloprogin 1970 Part - 6 Agents Active Against Helminths
New Agents in Development – Nikkomycin Z, CAY-1,
Sodarins, Butenolides, Enfungumab, Inositol Phosphocer- Albendazole 2227
amide Synthase Inhibitors 1972 Mebendazole 2240
Thiabendazole 2246
Triclabendazole 2250
Section III Anti - Parasitic Drugs Ivermectin 2254
Diethylcarbamazine (DEC) 2263
Part - 1 Anti-Malarial Agents Pyrantel Pamoate 2272
Praziquantel 2276
Chloroquine 1989 Oxamniquine 2285
Amodiaquine 2003 Metrifonate 2289
Quinine and Quinidine 2011 Niclosamide 2293
viii Contents

Part - 7 Agents Active Against Ectoparasites Delavirdine 2702

Etravirine 2711
Permethrin 2299 Rilpivirine 2723
Piperonyl Butoxide 2306
Lindane 2310 Inhibitors of HIV Protease
Malathion 2318
Crotamiton 2325 Saquinavir 2731
Ritonavir 2759
Section IV ANTI-VIRAL DRUGS Indinavir 2776
Nelfinavir 2788
Part - 1 Agents Active Against Herpesviruses Lopinavir 2797
Amprenavir and Fosamprenavir 2809
Aciclovir 2333 Darunavir 2824
Valaciclovir 2361 Atazanavir 2830
Famciclovir and Penciclovir 2370 Tipranavir 2842
Ganciclovir and Valganciclovir 2378
Cidofovir 2403 Other Anti-HIV Agents
Vidarabine 2429
Foscarnet 2433 Enfuvirtide 2861
Maribavir 2456 Maraviroc 2869
Trifluridine (Trifluorothymidine) 2461 Raltegravir and Other HIV Integrase Inhibitors 2877
Idoxuridine 2465
Fomivirsen 2470 Part - 3 Agents Active Against Hepatitis
Viruses
Part - 2 Agents Active Against the Human
Immunodeficiency Virus Entecavir 2891
Adefovir Dipivoxil 2899
Inhibitors of Reserve Transcriptase Telbivudine 2908
Torcitabine and Valtorcitabine 2915
Zidovudine 2479 Clevudine 2918
Didanosine 2512 Ribavirin and Viramidine 2923
Zalcitabine 2533 Pegylated Interferon Alfa 2959
Lamivudine 2545 Protease and Polymerase Inhibitors for the Treatment of
Stavudine (d4T) 2563 Hepatitis C Virus Infection 2976
Abacavir 2575
Emtricitabine 2595 Part - 4 Agents Active Against Respiratory
Tenofovir 2613
Viruses
Amdoxovir 2627
Apricitabine 2636
Amantadine and Rimantadine 2993
Zanamivir and Polymeric Zanamivir Conjugates 3013
Non-Nucleoside Reverse Transcriptase Inhibitors Oseltamivir 3029
(NNRTIs) Peramivir 3043
Nevirapine 2645 Index 3051
Efavirenz 2675
Contributors
Rahul Anand MBBS MD Mark A Boyd BA BMBS MD FRACP MHID DCTM&H
Division of Infectious Diseases, Thomas Jefferson University Therapeutic and Vaccine Research Program
Philadelphia, PA, USA National Centre in HIV Epidemiology and Clinical Research
University of New South Wales
David Andes MD Darlinghurst, NSW, Australia
Department of Medicine and Medical Microbiology and
Immunology, Section of Infectious Diseases Sumudu Britton MBBS BSc
University of Wisconsin Mater Adult Hospital
Madison, WI, USA Queensland, Australia

Graciela Andrei PhD Kirsty Buising MB BS MD MPH FRACP

Laboratory of Virology and Chemotherapy St Vincent Hospital, Melbourne and Victorian Infectious
Department of Microbiology and Immunology Diseases Service, Royal Melbourne Hospital, Parkville
Rega Institute for Medical Research Victoria, Australia
Leuven, Belgium
Paul U Cameron MBBS PhD FRACP FRCPA
Fred Y Aoki MD
Infectious Diseases Unit, Alfred Hospital;
Departments of Medical Microbiology, and Pharmacology and
Department of Medicine, Monash University,
Therapeutics, University of Manitoba
Melbourne, Australia
Winnipeg, Canada
Deon V Canyon PScF PhD MPH
Jennifer Audsley BApp Sci PhD
Anton Breinl Centre for Public Health and Tropical Medicine
Infectious Diseases Unit, The Alfred Hospital and the Burnet
James Cook University
Institute,
Townsville, Australia
Melbourne, Australia
Christina C Chang MB BS FRACP
Hisashi Baba MD PhD
Infectious Disease Unit, Alfred Hospital, and the Burnet
Department of Infectious Diseases
Institute, Melbourne, Australia
Nagoya University Hospital
Nagoya, Japan
Patrick GP Charles MB BS PhD FRACP
Bridget E Barber MBBS DTM&H Infectious Diseases Department, Austin Health
Victorian Infectious Diseases Service, Royal Melbourne Hospital Heidelberg, Victoria, Australia
Victoria, Australia
Sharon CA Chen PhD MBBS FRACP FRCPA
Brenda L Bartlett MD Centre for Infectious Diseases and Microbiology and the
Center for Clinical Studies University of Sydney, Westmead Hospital
Houston, Texas, USA Westmead, NSW, Australia

Paul B Bartley BMedSc MBBS FRACP FRCPA PhD Allen C Cheng MB BS FRACP MPH PhD
Griffith University School of Medicine; University of Queensland Infectious Diseases Unit, Alfred Hospital
School of Medicine; Department of Epidemiology and Preventive Medicine,
Wesley Private Hospital Monash Univeristy
Auchenflower, Queensland, Australia Melbourne, Australia

Miles H Beaman MBBS FRACP FRCPA FACTM Catherine L Cherry MBBS PhD FRACP Grad Dip (Clin Epi)
University of Notre Dame, Western Diagnostic Pathology Infectious Disease Unit, Alfred Hospital, and The Burnet
Myaree, Western Australia, Australia Institute, Melbourne, Australia

Francesco Blasi MD Ruth Chin MBBS PhD

Institute of Respiratory Diseases, University of Milan, IRCCS Department of Medicine, Austin Health
Ospedale Maggiore Milano The University of Melbourne
Milan, Italy Heidelberg, Victoria, Australia
x Contributors

Sunwen Chou MD Robert N Davidson MD FRCP DTM&H

Infectious Disease Division, Department of Medicine, Department of Infection and Tropical Medicine, Lister Unit,
Oregon Health and Science University Northwick Park Hospital
Portland, OR, USA Harrow, UK

Keryn Christiansen MB BS FRCPA Timothy ME Davis BSc Med MBBS D Phil (Oxon) FRACP FRCP
School of Pathology and Laboratory Medicine University of Western Australia
University of Western Australia School of Medicine and Pharmacology, Fremantle Hospital
Microbiology and Infectious Diseases Department, Royal Perth Fremantle, Western Australia, Australia
Hospital Sabine De Silva MB BS FRACP
Perth, Australia Infectious Diseases Department, Austin Health
Heidelberg, Victoria, Australia
Kyra Chua MB BS FRACP
Infectious Diseases Department Margriet L den Boer MSc PharmD
Austin Health, Heidelberg Médecins Sans Frontières Holland
Victoria, Australia Amsterdam, The Netherlands

David A Cooper MD DSc Justin T Denholm MBBS

National Centre in HIV Epidemiology and Clinical Research Infectious Diseases Unit
University of New South Wales The Alfred Hospital
Sydney, Australia Melbourne, Australia
Daryl DePestel PharmD
William Couet PharmD PhD University of Michigan Health System
INSERM ERI-23, University of Poitiers University, School of Ann Arbor, MI, USA
Medicine and Pharmacy
Pôle Biologie Santé, Poitiers, France Yohei Doi MD PhD
University of Pittsburgh School of Medicine
William A Craig MD Pittsburgh, USA
University of Wisconsin-Madison, William S. Middleton
Greg Dore BSc MBBS MPH FRACP PhD
Memorial VA Hospital
National Centre in HIV Epidemiology and Clinical Research,
Madison, WI, USA
University of New South Wales
Sydney, Australia
Jared Crandon PharmD
Center for Anti-Infective Research and Development, Hartford Geoffrey S Dow PhD
Hospital Division of Experimental Therapeutics,
Hartford, CT, USA Walter Reed Army Institute of Research
Silver Spring, MD, USA
Suzanne M Crowe MBBS FRACP MD
Alison Duncan
Centre for Virology,
Pharmacy Department,
Macfarlane Burnet Institute for Medical Research and Public
Alfred Hospital
Health
Melbourne, Australia
Infectious Disease Unit, Alfred Hospital,
Department of Medicine, Michael D Edstein MSc PhD
Professor of Medicine Australian Army Malaria Institute, Enoggera
Monash University Queensland, Australia
Alfred Hospital
Damon P Eisen MBBS MD FRACP
Melbourne, Australia
Victorian Infectious Diseases Service and University of
Melbourne, Royal Melbourne Hospital
Jonathan Darby MBBS FRACP
Parkville, Victoria, Australia
St Vincent’s Hospital
Melbourne, Australia George M Eliopoulos MD
Division of Infectious Diseases,
Kathryn Daveson MB BS Beth Israel Deaconess Medical Center,
Infectious Diseases Department Professor of Medicine
Royal Brisbane and Women’s Hospital Harvard Medical School
Brisbane, Australia Boston, MA, USA
 Contributors xi

Anne Ellett Aron J Gewirtzman MD

Macfarlane Burnet Institute for Medical Research and Public Center for Clinical Studies
Health Houston, Texas, USA
Melbourne, Victoria, Australia
Mahmoud Ghannoum MSc PhD EMBA
Sean Emery MD Center for Medical Mycology, Department of Dermatology,
Therapeutic and Vaccine and Research Programme National University Hospitals of Cleveland and Case Western Reserve
Centre in HIV Epidemiology and Clinical Research University
Darlinghurst, Australia Cleveland, OH, USA
Andrea Endimiani MD PhD
Louis Stokes Veterans Affairs Medical Center Michelle Giles MB BS FRACP PhD
Case Western Reserve University School of Medicine Infectious Disease Unit, Alfred Hospital,
Cleveland, Ohio, USA Burnet Institute
Melbourne, Australia
Teresa Hope Evering MD
The Aaron Diamond AIDS Research Center/Rockefeller Marta U Gomez Pharm D
University University of Queensland Centre for Clinical Research
New York Brisbane, Australia
NY, USA
Claire Gordon MBBS BMedSci
Matthew E Falagas MD MSc DSc Infectious Diseases Department, Austin Health
Alfa Institute of Biomedical Sciences (AIBS) Melbourne, Victoria, Australia
Athens, Greece
Department of Medicine, Henry Dunant Hospital David Gordon MBBS FRACP FRCPA PhD
Athens, Greece Microbiology and Infectious Diseases Department,
Department of Medicine, Tufts University School of Medicine Flinders Medical Centre and Flinders University
Boston, MA, USA Adelaide, Australia

Denis Frasca MD Paul R Gorry PhD

INSERM ERI-23, University of Poitiers University, School of Macfarlane Burnet Institute for Medical Research and Public
Medicine and Pharmacy Health;
Pôle Biologie Santé, Poitiers, France Department of Medicine, Monash University and
Department of Microbiology and Immunology,
Martyn A French MD FRACP
University of Melbourne
Department of Clinical Immunology and Immunogenetics, Royal
Melbourne, Victoria, Australia
Perth Hospital and PathWest Laboratory Medicine and School
of Pathology and Laboratory Medicine, University of Western Ian M Gould BSC PhD MBChB FRCPEdin FRCPath
Australia Medical Microbiology, Aberdeen Royal Infirmary
Perth, Australia Aberdeen
UK
Niels Frimodt-Møller MD DMSc
National Center for Antimicrobials and Infection Control
M Lindsay Grayson MBBS MD MSc FRACP FAFPHM FRCP
Statens Serum Institut
Infectious Diseases and Microbiology Departments, Austin
Copenhagen, Denmark
Health
Marco Tulio A Garcı́a-Zapata MD PhD Department of Epidemiology and Preventive Medicine, Monash
Instituto de Patologia Tropical e Saúde Pública, Universidade University
Federal de Goiás, Setor Leste Universitário Department of Medicine, University of Melbourne
Goiânia, Brazil Melbourne, Australia

Jose M Gatell MD PhD Jason Grebely BSc PhD

Infectious Diseases and AIDS Units, Hospital Clinic National Centre in HIV Epidemiology and Clinical Research,
University of Barcelona University of New South Wales
Barcelona, Spain Sydney, Australia

Alasdair M Geddes CBE MBChB FRCP FRCPath FMedsci Paul M Griffin BSc MBBS
Emeritus Professor of Infection Infectious Diseases Unit
School of Medicine, University of Birmingham Royal Brisbane and Women’s Hospital
Birmingham, UK Herston, Queensland, Australia
xii Contributors

Lisa Grillone John Horton MA MB BChir MRCGP FFPM

PharmaQuest Associates Tropical Projects
Carlsbad, CA, USA Hertfordshire, UK

David Guay Pharm D Benjamin P Howden MBBS FRACP FRCPA PhD

Department of Experimental and Clinical Pharmacology Infectious Diseases Department, Austin Health
College of Pharmacy, University of Minnesota University of Melbourne,
Minneapolis, Minnesota, USA Melbourne, Victoria, Australia
Inge C Gyssens MD PhD
Nijmegen Institute for Infection, Inflammation and Immunity Jennifer Hoy MBBS FRACP
(N4i), Radboud University Nijmegen Medical Centre, Infectious Diseases Unit, Alfred Hospital
Canisius Wilhelmina Hospital Department of Medicine, Monash University
Nijmegen, The Netherlands Melbourne, Australia

Krispin M Hajkowicz MBBS FRACP Mark A Jacobson MD

Royal Darwin Hospital Positive Health Program, Department of Medicine,
Darwin, Australia University of California, San Francisco,
UCSF CTSI Clinical Research Center at SFGH,
Abdulla Fatimah Haslina MB BS San Francisco General Hospital, San Francisco, USA
Infectious Diseases Unit
Royal Brisbane and Women’s Hospital Grant Jenkin MB BS FRACP PhD
Brisbane, Australia and Infectious Diseases Department, Monash Medical Centre
Kuala Terengganu General Hospital Clayton, Victoria, Australia
Kuala Terengganu, Malaysia
Soren Jensen-Fangel MD PhD DMSc
Yoshiro Hayashi MD PhD
Aarhus University Hospital
University of Queensland Centre for Clinical Research
Aarhus, Denmark
Brisbane, Australia
Douglas Johnson MB BS FRACP
Margaret Hellard MBBS FRACP FAPHM PhD
Infectious Diseases Department, Austin Health
Centre for Population Health, Burnet Institute, Infectious
Melbourne, Australia
Disease Unit, Alfred Hospital,
Melbourne, Australia
Paul DR Johnson MBBS PhD FRACP
Jorg Heukelbach MD PhD DTMPH MScIH Infectious Diseases Department, Austin Health
Departamento de Saúde Comunitária, Faculdade de Medicina – Department of Medicine, University of Melbourne,
Universidade Federal do Ceará Victoria, Australia
Fortaleza, Brazil
Ralph Junckerstorff MBBS DTM&H
Natasha E Holmes MBBS FRACP Sir Charles Gairdner Hospital
Infectious Diseases Department, Austin Health, Melbourne, Perth, Australia
Victoria, Australia
Harin Karunajeewa MBBS FRACP PhD
David C Hooper MD University of Western Australia
Division of Infectious Diseases, Massachusetts General Hospital Nedlands, Western Australia, Australia
Harvard Medical School
Boston, USA Christine Katlama MD
Hôpital Pitié-Salpêtrière, Service des Maladies Infectieuses et
William Hope MBBS FRACP FRCPA PhD
Tropicales
University of Manchester
Paris, France
Manchester, UK

David Horn MD FACP Harold A Kessler MD

Division of Infectious Diseases, Thomas Jefferson University Rush University Medical Center
Philadelphia, PA, USA Chicago, USA

Alphons M Horrevorts MD PhD Baek-Nam Kim MD

Department of Medical Microbiology and Infectious Diseases, Department of Internal Medicine,
Canisius Wilhelmina Hospital Inje University Sanggye-Paik Hospital, Nowon-gu
Nijmegen, The Netherlands Seoul, Republic of Korea
 Contributors xiii

Aryun Kim Pharm D Sharon R Lewin MBBS PhD FRACP

Center for Anti-Infective Research and Development Department of Medicine, Monash University
Hartford Hospital and Infectious Diseases Unit, Alfred Hospital
Connecticut, USA Melbourne, Victoria, Australia
Jan AJW Kluytmans MD PhD Russell E Lewis Pharm D
Amphia Ziekenhuis, Laboratory for Microbiology and Infection University of Houston College of Pharmacy and University of
Control Texas MD Anderson Cancer Center
Breda, The Netherlands and Houston, Texas
Department of Medical Microbiology and Infection Control, VU
Medical Center Jian Li PhD
Amsterdam, The Netherlands Facility for Anti-infective Drug Development and Innovation,
Drug Delivery, Disposition and Dynamics
Dimitrios P Kontoyiannis MD ScD
Monash Institute of Pharmaceutical Sciences
Mycology Research Program, University of Houston College of
Monash University, Melbourne, Australia
Pharmacy and
University of Texas MD Anderson Cancer Center Ronni Lieberman MD
Houston, Texas Ophthalmology Department
Mount Sinai Hospital
Steven Kopp BVSc PhD
New York, NY, USA
School of Veterinary Science, University of Queensland
Brisbane, Australia
Jeffrey Lipman MBBCh DA FFA FFA (Crit Care) FCICM MD
Tony M Korman MB BS FRACP FRCPA Burns Trauma and Critical Care Research Centre,
Department of Infectious Diseases, Monash Medical Centre University of Queensland
Melbourne, Australia Brisbane, Australia
Department of Medicine, Monash University
Stephen Locarnini MBBS PhD
Melbourne, Australia
Molecular Research and Development, Victorian Infectious
Ed J Kuijper MD PhD Diseases Reference Laboratory
Department of Medical Microbiology, North Melbourne, Victoria, Australia
Leiden University Medical Center
Leiden, The Netherlands David Looke MBBS FRACP FRCPA M Med Sci
Department of Medicine
Manish Kumar PhD University of Queensland
Department of Ophthalmology, College of Medicine, Louisiana Infection Management Services,
State University Health Science Center Princess Alexandra Hospital
New Orleans, LA, USA Woollongabba Queensland, Australia

Joseph L Kuti Pharm D Graeme MacLaren MBBS FJFICM FRACP FCCP

Center for Anti-Infective Research and Development National University Hospital, Singapore and
Hartford Hospital The Royal Children’s Hospital
Connecticut, USA Melbourne, Australia
Luxshimi Lal BPharm BAppSci
James McCarthy MBBS MD DTM&H FRACP
Burnet Institute
Infectious Diseases Department, Mater Health Services,
Melbourne, Victoria, Australia
Infectious Diseases Department, Royal Brisbane Hospital
Harry W Lampiris MD and Queensland Institute of Medical Research
San Francisco VA Medical Center University of Queensland
San Francisco, CA, USA Queensland, Australia

Katherine Langan BMBS BBioMedSci Joe McCormack MB BCh FRCP MD FRACP

Infectious Diseases Department, Austin Health Department of Medicine, Mater Hospital
Melbourne, Australia University of Queensland and Mater Hospitals, Brisbane
Queensland, Australia
Joep Lange MD
Academic Medical Center, University of Amsterdam, Faculteit Lachlan McDowell MBBS
der Geneeskunde Royal Brisbane and Women’s Hospital, Brisbane
Amsterdam, The Netherlands Queensland, Australia
xiv Contributors

Steve McGloughlin BSc BMed MPHTM Li Min Ling MBBS MRCP

Infectious Diseases Department, Royal Brisbane Hospital Department of Infectious Diseases
Queensland, Australia Tan Tock Seng Hospital, Singapore

Ian R McNicholl Pharm D BCPS AAHIVE Jean-Michel Molina MD

University of California, San Francisco School of Pharmacy, and Department of Infectious Diseases, Saint-Louis Hospital
UCSF Positive Health Program, Department of Medicine at San Paris, France
Francisco General Hospital Medical Center, San Francisco
Thomas A Moore MD FACP
General Hospital
University of Kansas School of Medicine – Wichita Campus
San Francisco, USA
Wichita, KS, USA
Alan J Magill MD Johan W Mouton MD PhD
Division of Communicable Diseases and Immunology, Department of Microbiology, Radboud University Nijmegen
Walter Reed Army Institute of Research, Silver Spring Medical Centre and
MD, USA Department Medical Microbiology and Infectious Diseases,
Canisius Wilhelmina Hospital
Martin Markowitz MD
Nijmegen, The Netherlands
Aaron Diamond AIDS Research Center;
Rockefeller University Wendy Munckhof MB BS FRACP FRCPA PhD
New York, NY, USA Infection Management Services, Princess Alexandra Hospital
University of Queensland
Valérie Martinez MD PhD
Brisbane, Queensland, Australia
Department of Internal Medicine, Antoine Béclère Hospital
Clamart Cedex, France Jean-Luc Murk MD PhD
Department of Medical Microbiology and Infection Control,
Gail Matthews MBChB MRCP FRACP
VU Medical Center
National Centre in HIV Epidemiology and Clinical Research,
Amsterdam, The Netherlands
University of New South Wales
Sydney, Australia Mary Murphy MD
Section of Infectious Diseases, Department of Medicine,
Natalie Mendoza MD MSc Louisiana State University Health Sciences Center
Center for Clinical Studies New Orleans, LA, USA
Houston, Texas, USA
Robert Murphy MD
Renee-Claude Mercier Pharm D Hôpital Pitié-Salpêtrière, Service des Maladies Infectieuses et
University of New Mexico – Health Sciences Center, Tropicales, Paris, France
College of Pharmacy Northwestern University Feinberg School of Medicine, Division
Albuquerque, NM, USA of Infectious Diseases
Chicago, IL, USA
Gregory Mertz MD
Division of Infectious Diseases, Ronan J Murray MBBS DTM&H MRCPI FRACP FRCPA FACTM
University of New Mexico School of Medicine Division of Microbiology and Infectious Diseases, PathWest
Albuquerque, NM, USA Laboratory
Medicine WA, Queen Elizabeth II Medical Centre
Anne M Mijch MBBS FRACP Grad Dip Epi Biostat OAM Perth, Australia
Department of Medicine,
Monash University and Victorian HIV/AIDS Service, Alfred Marrigje H Nabuurs-Franssen MD PhD
Hospital Department of Medical Microbiology and Infectious Diseases,
Canisius Wilhelmina Hospital and Department of Medical
John Mills MD FACP FRACP ARCPA Microbiology, Radboud University Nijmegen Medical Center
Infectious Disease Unit, Alfred Hospital, Nijmegen, The Netherlands
Departments of Medicine, Epidemiology and Microbiology,
Roger L Nation PhD
Monash University
Facility for Anti-infective Drug Development and Innovation,
Melbourne, Australia
Drug Delivery, Disposition and Dynamics
Olivier Mimoz MD PhD Monash Institute of Pharmaceutical Sciences
INSERM ERI-23, University of Poitiers University Monash University
School of Medicine and Pharmacy Melbourne
Pôle Biologie Santé, Poitiers, France Australia
 Contributors xv

Dionissis Neofytos MD MPH Marien Pluim

Johns Hopkins University School of Medicine Department of Clinical Pharmacy, Canisius Wilhelmina Hospital
Division of Infectious Diseases Nijmegen, The Netherlands
Baltimore, MD, USA
James Pollard MBBS
Jeniel Nett MD Division of Medicine and Department of Infectious Diseases,
Section of Infectious Diseases Mater Adult Hospital
Department of Medicine, University of Wisconsin South Brisbane, Australia
Madison, WI, USA Ric N Price MD FRACP FRCP FRCPath
Anthony M Nicasio PharmD Menzies School of Health Research
Center for Anti-Infective Research and Development, Darwin, Australia
Hartford Hospital Petros I Rafailidis MD MRCP (UK) MSc
Hartford, CT, USA Alfa Institute of Biomedical Sciences (AIBS)
David P Nicolau Pharm D FCCP Athens, Greece
Center for Anti-Infective Research and Development, Division Department of Medicine, Henry Dunant Hospital
of Infectious Diseases, Hartford Hospital Athens, Greece
Hartford, Connecticut, USA Ahmad K ab Rahman MB BS
S Ragnar Norrby Infectious Diseases Unit
Swedish Institute for Infectious Disease Control Royal Brisbane and Women’s Hospital
Solna, Sweden Brisbane, Australia and
University of Queensland Centre for Clinical Research
Samar Ojaimi MBBS Brisbane, Australia
Department of Infectious Diseases, Monash Medical Centre
Clayton, Victoria, Australia Reena Rajasuriar BPharm MPharm
Infectious Diseases Unit, Alfred Hospital
Lars Ostergaard MD PhD DMSc Department of Medicine
Department of Infectious Diseases, Aarhus University Hospital Monash University
Aarhus, Denmark Melbourne, Australia
Birte Pantenburg MD Matthew Rawlins
Infectious Diseases Division, Department of Internal Medicine Pharmacy Department, Royal Perth Hospital
University of Texas Medical Branch Perth, WA, Australia
Galveston, TX, USA
Pilar Retamar MD
Maria Pappalettera MD Hospital Universitario Virgen Macarena
Institute of Respiratory Diseases, University of Milan, IRCCS Seville, Spain
Ospedale Maggiore Milan
Milan, Italy Jason A Roberts B Pharm PhD
Pharmacy Department, Burns Trauma and Critical Care
David L Paterson MB BS FRACP FRCPA PhD Research Centre
University of Queensland Centre for Clinical Research, Brisbane, Australia
Infectious Diseases Unit, Royal Brisbane and Women’s Hospital Department of Intensive Care Medicine, Royal Brisbane and
and Pathology, Queensland, Women’s Hospital
Brisbane, Australia Brisbane, Australia
Anton Y Peleg MBBS FRACP James Owen Robinson MD ID FMH
Division of Infectious Diseases, Beth Israel Deaconess Medical Microbiology and Infectious Diseases Department, Royal Perth
Center and Harvard Medical School Hospital
Boston, MA, USA Perth, Western Australia, Australia
Sarah L Pett MD Sutthichai Sae-Tia MD
Therapeutic and Vaccine and Research Programme, National University Pittsburgh Medical Center Shadyside
Centre in HIV Epidemiology and Clinical Research Pittsburgh, PA
Darlinghurst, Australia USA
Michael A Pfaller MD Margaret Salmon MD MPM
Departments of Pathology and Epidemiology, University of Iowa Department of Emergency Medicine, University of California San
College of Medicine and College of Public Health, Iowa City Francisco and San Francisco General Hospital
Iowa, USA San Francisco, CA, USA
xvi Contributors

Matilde Sánchez Conde Alan C Street MBBS FRACP

Infectious Diseases and HIV-1 Units, Gregorio Marañon Hospital Infectious Disease Units, Royal Melbourne and Alfred Hospitals,
Madrid, Spain and the Department of Medicine, University of Melbourne,
Melbourne, Australia
Joe Sasadeusz MBBS PhD FRACP
Infectious Disease Units, Alfred and Royal Melbourne Hospitals; Rhonda L Stuart MB BS FRACP PhD
and the Burnet Institute for Medical Research Infectious Diseases Department, Monash Medical Centre,
Melbourne, Australia Southern Health
Clayton, Victoria, Australia
Thomas R Schulz MBBS BSc
Victorian Infectious Diseases Service, Royal Melbourne Hospital Ashwin Swaminathan MB BS MPH FRACP
Victoria, Australia Australian National University and Infectious Diseases
Department, The Canberra Hospital
Essam S Shaalan PhD
Canberra, ACT, Australia
Zoology Department
Aswan Faculty of Science
Babafemi Taiwo MD
South Valley University
Northwestern University Feinberg School of Medicine, Division
Aswan, Egypt
of Infectious Diseases
Dennis Shanks MD MPH-TP Chicago, IL, USA
Australian Army Malaria Institute
Enoggera, Australia Paolo Tarsia MD
Institute of Respiratory Diseases, University of Milan, IRCCS
Frank Shann MBBS MD FRACP FJFICM Ospedale Maggiore Milan
The Royal Children’s Hospital, and Milan, Italy
The University of Melbourne
Melbourne, Australia Karin Thursky MBBS BSc FRACP MD
Department of Infectious Diseases, Peter MacCallum Cancer
Julie A Simpson PhD Centre,
Centre for Molecular, Environmental Victorian Infectious Diseases Service, Royal Melbourne Hospital
Genetic and Analytic Epidemiology Melbourne, Australia
School of Population Health
University of Melbourne Joseph Torresi MBBS PhD FRACP
Victoria, Australia Hepatitis Molecular Virology Laboratory
Department of Medicine,
Monica A Slavin MB BS MD FRACP University of Melbourne;
Department of Infectious Diseases and Department of Infectious Diseases, Austin Hospital,
Peter MacCallum Cancer Centre Victoria, Australia
East Melbourne, Australia
Rana Traboulsi MD
Robert Snoeck MD PhD
Center for Medical Mycology, Department of Dermatology,
Laboratory of Virology and Chemotherapy
University Hospitals of Cleveland Case Medical Center and
Department of Microbiology and Immunology
Case Western Reserve University
Rega Institute for Medical Research
Cleveland, USA
Leuven, Belgium
Adrian Tramontana MBBS FRACP
Tania C Sorrell MD MBBS FRACP
Department of Infectious Diseases,
Centre for Infectious Diseases and Microbiology and the
Peter MacCallum Cancer Centre
University of Sydney, Westmead Hospital
Melbourne, Australia
Westmead, NSW, Australia

Richard Speare BVSc MB BS PhD Anne Marie Tremaine MD

Anton Breinl Centre for Public Health and Tropical Medicine Center for Clinical Studies
James Cook University Houston, Texas, USA
Townsville, Australia
John Turnidge MB BS FRACP FRCPA MASM
Andrew Stewardson MB BS FRACP Division of Laboratory Medicine, Women’s and Children’s
Infectious Diseases Department, Austin Health Hospital
Melbourne, Australia North Adelaide, Australia
 Contributors xvii

Stephen K Tyring MD PhD MBA A Clinton White Jr MD

Dermatology Department Infectious Diseases Division, Department of Internal Medicine,
University of Texas Health Science Center University of Texas Medical Branch
and Center for Clinical Studies Galveston, TX, USA
Houston, Texas, USA
Michael Whitby MBBS MPH DTM&H FRACP FRACGP FRCPA FAFPHM
Franc- oise Van Bambeke PharmD PhD Infection Management Services, Princess Alexandra Hospital
Pharmacologie Cellulaire et Moléculaire, University of Queensland
Catholic University of Louvain Herston, Queensland 4029
Brussels, Belgium Australia
Emily D Varnell MS John R Wingard MD
Department of Ophthalmology, College of Medicine, Louisiana Bone Marrow Transplant Program, Division of Hematology/
State University Health Science Center Oncology,
New Orleans, LA, USA University of Florida Shands Cancer Center, Gainsville,
Florida, USA
Paschalis Vergidis MD
Alfa Institute of Biomedical Sciences (AIBS) Sarah Y Won MD
Athens, Greece and Fellow Rush University Medical Center
Section of Infectious Diseases, Department of Medicine, Boston Chicago, USA
Medical Center
Marion L Woods MD MPH FRACP FAFPHM FACP
Boston, MA, USA
Infectious Diseases, Royal Brisbane and Women’s Hospital
Joost Vermeulen MD University of Queensland
Academic Medical Center, University of Amsterdam Herston, Queensland, Australia
Amsterdam, The Netherlands
Edwina Wright MBBS FRACP
Mai P Vu Pharm D Alfred Hospital Infectious Diseases Unit
San Francisco VA Medical Center Melbourne, Victoria, Australia
San Francisco, CA, USA
Kunikazu Yamane MD PhD
Amanda Wade MBBS FRACP Laboratory of Antimicrobial Agents and Resistance
Barwon Health Department of Bacterial Pathogenesis and Infection Control
Geelong, VIC National Institute of Infectious Diseases
Australia Tokyo, Japan
Mark A Wainberg OC OQ FRSC Mesut Yilmaz MD
McGill University AIDS Center, Infectious Diseases and Clinical Microbiology,
Lady Davis Institute-Jewish General Hospital Cerrahpasa Medical Faculty,
Montreal, Canada University of Istanbul
Istanbul, Turkey
Steven Wesselingh MBBS PhD FRACP
Infectious Disease Unit, Alfred Hospital; Fabian Yuh Shiong Kong BPharm MEpi
Faculty of Medicine, Nursing and Health Sciences, Centre for Population Health, Burnet Institute
Monash University, Melbourne, Victoria, Australia
Victoria, Australia
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Foreword to Kucers’ ‘‘The Use of Antibiotics’’
Robert C Moellering Jr

While one generally thinks of antibacterial agents as unique and literal deconstruction and reconstruction of the HIV virus allowed the
important contributions to the battle against infectious diseases in the discovery of numerous potential points of attack and provided the
20th Century, our modern antimicrobial agents are not the first basis for the discovery of a panoply of new agents, many studied in
effective drugs to be discovered and used to treat human infections. well-designed publicly funded trials that have demonstrated their
Quinine (as an extract from the bark of the cinchona tree initially efficacy in HIV infections. Indeed, the present edition of this textbook
found in the Andes) was discovered and utilized as an effective details 27 chapters on new antiviral agents directed at HIV. The use of
antimalarial agent by Europeans since the 17th Century (Snowden, these drugs has now converted AIDS from a universally fatal disease to
2006). It played a major role in the colonial expansion of the European a chronic disease controlled for years by effective antiviral agents and
powers thereafter and it, not Salvarsan, was really the first ‘‘magic allowing a normal or near normal lifespan for many of its victims.
bullet’’ of antimicrobial chemotherapy. Moreover, when one tracks Similar if somewhat less dramatic progress is being made in the
back through history one finds that agents with antibacterial activity discovery and development of other antiviral agents as well as new
such as copper salts, honey grease, and myrrh were used for topical antifungal and antiparasitic agents which are well documented in this
wound therapy (with no understanding of the basis for wound sepsis, of textbook.
course) dating back to the time of the ancient Egyptians in 2500 BC In an era when large textbooks are in danger of becoming dinosaurs,
and the Greeks and Romans thereafter (Majno, 1975). The ancient Kucers’ ‘‘The Use of Antibiotics’’ stands out. It brings together in 258
Chinese employed mouldy soybean curd which likely contained chapters and two large volumes a compendium of information on
antimicrobial activity against wound pathogens as well (Majno, antimicrobial agents which is unmatched. A book which began as a
1975). Nonetheless the bulk of the effort to discover antimicrobials single-authored tour de force by Alvis Kucers has evolved into a multi-
and to learn the mechanisms by which they produce selective activity authored therapeutic encyclopedia. The addition of antiparasitic
against microbes without harming their human hosts is a unique agents in this edition means that it now covers the whole of
contribution of the 20th Century, beginning with Paul Ehrlich’s antimicrobial therapy. It maintains the clinical bent which made the
discovery and clinical application of Salvarsan in the first decade of original Kucers texts so valuable for the physician dealing with
this century (Moellering, 1995). The flowering of research in infections, and incorporates enough basic science to be useful to
antibacterials reached its zenith in the 1980’s when many new agents microbiologists and researchers in the field as well. I am unaware of
were brought to clinical use and some ‘‘experts’’ including yours truly any textbook which provides such comprehensive coverage of the field
raised the possibility that the plethora of such agents might overwhelm and doubt that this work will be surpassed in the foreseeable future, if
the clinicians trying to discover their appropriate use (Murray and ever! My congratulations to Lindsay Grayson, his co-editors, and all of
Moellering, 1981). However, these concerns have proven to be short the authors of chapters in this remarkable contribution to the field of
lived and totally incorrect. Since then there has been a steady decline antimicrobial therapy. It is a monumental achievement!
in the discovery and licensing of new antibacterial agents. The reasons
for this are legion, but among them are the fact that most of the References
obvious bacterial targets for antimicrobials have been discovered and
exploited; the fact that the cost of bringing new drugs to the market Majno G (1975). The Healing Hand. Cambridge, Massachusetts: Harvard
has skyrocketed; and the fact that there are increasing regulatory University Press.
hurdles in certain countries including the United States (Talbot et al., Moellering Jr RC (1995). Past, present and future of antimicrobial agents. Am J
2006). Add to this the fact that worldwide there is increasing Med 99 (Suppl 6A): 6S–15S.
resistance to antimicrobial agents among key bacterial pathogens and Murray BE, Moellering Jr RC (1981). Cephalosporins. Ann Rev Med 32:
one has the basis for a looming crisis. 359–81.
But all is far from bleak. The discovery and successful application of Snowden FM (2006). The Conquest of Malaria. New Haven CT, USA: Yale
antiviral chemotherapy is a particularly bright spot. Fifty years ago it University Press.
was thought that it would be virtually impossible to develop antiviral Talbot GH, Bradley J, Edwards Jr JE et al. (2006). Bad bugs need drugs: an
agents with selective toxicity because of the unique ability of viruses to update on the development pipeline from the Antimicrobial Availability
invade and take over replication of molecular processes in mammalian Task Force of the Infectious Diseases Society of America. Clin Infect Dis 42:
cells. When the AIDS era began in the early 1980’s, this diagnosis was 657–68.
a virtual death sentence. The remarkable basic virology which led to a
This page intentionally left blank
Obituary
Dr. Alvis Kucers was an incredible taskmaster for himself and others who worked with
4/10/1933–15/2/2007 him. For those of us who had the great honor of co-writing the fifth
edition with him, he was tremendously supportive and encouraging,
Dr Alvis Kucers, one of Australia’s leading infectious diseases while being totally dogged, self-disciplined and single-minded in his
physicians, whose seminal textbook on the use of antibiotics became insistence on consistency of style, format and meeting chapter
the cornerstone of clinicians’ libraries for more than 30 years, has died deadlines.
of disseminated melanoma. He was 73. The worldwide recognition achieved by Use of Antibiotics is a total
Born in Latvia, Kucers arrived in Melbourne from war-torn Europe credit to Kucers.
in 1950, aged 16 and unable to speak English. When introduced by the In 1981, he took over as director of medical services at Fairfield
headmaster to his new year 11 class at University High School, he was Hospital following the mass resignation of senior medical staff due to
mistakenly announced to the other students as planning to do administration problems. His appointment calmed the many political
medicine (in fact, he meant to say ‘‘law’’, but got the English words tensions and the following 10 years under his leadership became a key
muddled). Two years later he graduated with honours and a sporting time for the hospital as it took on a leading national role in managing
award for soccer. the emerging HIV-AIDS epidemic, assessing new anti-HIV drugs and
Despite the initial confusion in his career choices, he decided to caring for the many infected patients who were often suffering
study medicine after all and graduated second in his year from discrimination in other hospitals.
Melbourne University in 1957. He completed his residency at Royal For Victorian public health, those were the glory years, with the
Melbourne Hospital, then trained as a specialist physician while then chief health officer, Dr Graham Rouch, and Kucers providing an
working at Fairfield Hospital. Soon after he was appointed as a junior impressive media tag-team; the public was calmly informed of the
clinician at Fairfield. important facts, and the steps being put in place to manage the issue.
In 1968, the director, Dr John Forbes, encouraged Kucers to Many Victorian health ministers slept soundly at night because of the
undertake a three-month hospital-funded trip to the US; both men skill, honesty and authority of these two men.
believed the US approach of training infectious diseases physicians, The early 1990s, however, were a more difficult period, with the
rather than the European focus on training clinical microbiologists, concerted and ultimately successful government attempt to close
was likely to become important. Fairfield Hospital. To Kucers, Fairfield’s closure highlighted the lack of
Kucers was impressed with the US approach but recognised some understanding about the hospital’s importance to infectious diseases
confusion regarding how best to use the new antibiotics that were training and the public health of Victorians. Generations of Melbourne
being rapidly developed at that time. When he returned from his study and Monash university medical students benefited from the infectious
tour in 1969, he wrote an antibiotic booklet to assist trainee doctors in diseases training they received from Kucers and other key staff at
understanding how best to use these agents. Fairfield.
Forbes recognised the value of Kucers’ clear, practical writing style Kucers was a tremendous mentor for trainee infectious diseases
for practising clinicians and encouraged him to publish the first edition registrars, encouraging them to look beyond Australia’s shores to
of Use of Antibiotics in 1972. widen their experience.
Kucers regularly attended key international meetings, where he was In recognition of his contribution to Australasian infectious diseases,
highly respected for his authoritative comments on practical issues in 2002 he was made a life member of the Australasian Society for
relating to the use of antibiotics. He was appointed to a number of Infectious Diseases.
World Health Organization committees to advise on antibiotic use in He is survived by his longtime partner, Anne Smith, who nursed
developing countries, and he helped develop the current ‘‘Essential him tirelessly in his difficult last months, his brother, son and daughter.
Drug List’’ – a key guide for national health departments.
Kucers updated his Use of Antibiotics through five editions (the last The Age, Wednesday March 7, 2007
in 1997) and made sure that all the contracts and details were signed By Professor M. Lindsay Grayson, President, Australasian
off for the forthcoming sixth edition. In writing Use of Antibiotics, he Society for Infectious Diseases
This page intentionally left blank
Preface
This 6th Edition starts with an inaccuracy since it no longer simply Many have argued that textbooks are no longer necessary, given the
describes ‘‘the use of antibiotics’’, but instead aims to outline the growth of the internet and search capabilities via PubMed or Medline.
clinical use of all antimicrobials-antibiotics, antifungals, antiparasitic However, it is our view that there is now simply so much information
and antiviral agents. As clinicians this seemed a logical next step from available, that reference texts such as this are important to help collate
the previous editions where although there had been some evolution these data and to make sense of it all – we hope we have achieved this.
into antivirals and antifungals, the majority of the text was related to For those of us who had the good fortune and honour to train with
antibiotics. This expansion has mirrored the massive growth in Dr Alvis Kucers and to become his colleague and friend, we hope we
knowledge and number of active agents for various infections since the have been able to live up to the high standards he always demanded–
last edition, but has come at the price of a hugely expanded text – to focus on the important clinical issues that relate to patient care, to
increasing from 146 chapters in the 5th edition to 258 chapters; from balance the important anecdote with the randomized double-blind
1950 pages to more than 3000 pages and from one volume into two. trial and to describe the data in a way that is interesting and useful to
Where appropriate we have either deleted chapters on older, little- health professionals who treat patients.
used agents, or more often amalgamated them into single chapters that Of course, the 6th Edition would not be possible without the hard
provide an overview, and then directed the reader to previous editions work and commitment of the international cast of distinguished
for more information. The dilemma we faced in electing to expand the authors, the eight section editors and the patience of staff at Hodder,
book was the sheer number of drugs and time needed to adequately including Sarah Penny, Caroline Makepeace and many others.
research these. It was for this reason we decided to expand the Alvis Kucers was a very special person – we hope he would be happy
authorship and establish eight section editors – but to maintain the with the 6th Edition, which we have named in his honour.
system where all chapters were written under strictly defined sub-
headings. New features include a diagram of the chemical structure for M. Lindsay Grayson, MD
each compound, many more tables to better summarise susceptibility Editor-in-Chief
data, drug dosing and to collate important clinical trials, and new Infectious Diseases Department, Austin Health
sections regarding clinically important pharmacokinetic/pharmacody- Department of Medicine, University of Melbourne,
namic data and drug interactions. Melbourne, Australia
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Abbreviations
5-FU 5-fluorouracil EBA early bactericidal activity
AAC aminoglycoside acetyltransferase EBV Epstein-Barr virus
ACT artemisinin-based combination therapies EC effective concentration
AE adverse event ECG electrocardiogram
AECB acute exacerbations of chronic bronchitis EF elongation factor
AECOPD acute exacerbation of chronic obstructive EFV efavirenz
pulmonary disease ELF epithelial lining fluid
AIDS acquired immune deficiency syndrome ESBL extended-spectrum beta-lactamase
ALT alanine aminotransferase ESR erythrocyte sedimentation rate
AOM acute otitis media EUCAST European Commitee on Antimicrobial
ART antiretroviral Susceptibility Testing
AST aspartate aminotransferase F/M Fetal/maternal
ATV atazanavir FDA Food and Drug Administration
AUC area-under-the-concentration-time curve INR international normalized ratio
BAL Bronchial alveolar lavage FTC emtrictiabine
BHIVA British HIV Association G6PD glucose-6-phosphate dehydrogenase
BMD bone mineral density GABA Gamma-aminobutyric acid
BMI body mass index GFR glomerular filtration rate
BSAC British Society for Antimicrobial GI gastrointestinal
Chemotherapy GIQ genotypic inhibitory quotient
CA-MRSA Community-acquired MRSA GISA Glycopeptide-intermediate resistant
CAP community-acquired pneumonia Staphylococcus aureus
CAPD continuous ambulatory peritoneal dialysis GLUT1 glucose transporter type 1
CAT chloramphenicol acetyltransferase GVHD graft-versus-host-disease
CDAD Clostridium difficile-associated diarrhea HA-MRSA hospital-acquired MRSA
CDC Centers for Disease Control and Prevention HAP hospital-acquired pneumonia
CFU colony forming units HBV hepatitis B virus
CHB chronic hepatitis B HCAP healthcare-associated pneumonia
CHSS chlorhexidine-silver sulfadiazine HD high-dose
CI confidence interval HDL high-density lipoprotein
CL clearance HIV human immunodeficiency virus
CLSI Clinical and Laboratory Standards Institute HLA human leukocyte antigen
CMS colistin methanesulfonate HLAR high-level aminoglycoside-resistant
CNS central nervous system HPLC-MS high-pressure liquid chromatography and mass
CPK creatine phosphokinase spectrometry
CRBSI catheter-related bloodstream infection HPLC high-performance liquid chromatography
CRP C-reactive protein IC invasive candidiasis
CRRT continuous renal replacement therapy ICU Intensive Care Unit
CSF cerebrospinal fluid INH isoniazid
cSSI complicated skin and skin structure infections INR International Normalized Ratio
CVVH continuous venovenous hemofiltration IPC inositol phosphoceramide
CVVHD continuous venovenous hemodialysis IPTi intermittent preventive therapy of malaria in
CYP cytochrome P-450 infants
ClCr creatinine clearance IPTp intermittent preventive therapy of malaria
CoNS coagulase-negative staphylococci during pregnancy
DEXA dual-energy X-ray absorptiometry ITT intent-to-treat
DHBV duck hepatitis B virus IU international unit
DHFR dihydrofolate reductase IgG immunoglobulin G
DHHS Department of Health and Human Services LDH lactate dehydrogenase
DHPS dihydropteroate synthetase LDL low-density lipoprotein
DRV darunavir LPS lipopolysaccharide
EAP Expanded Access Program LPV lopinavir
xxvi Abbreviations

MAC Mycobacterium avium complex SBA Serum bactericidal activity

MAX maximal concentration SBP spontaneous bacterial peritonitis
MBC minimal bactericidal concentrations SCC staphylococcal cassette cartridge
MDR multidrug resistant SDD selective decontamination of the digestive
MEF middle ear fluid tract
MICs minimum inhibitory concentrations SIV simian immunodeficiency virus
MLC minimum lethal concentration SJS Stevens-Johnson syndrome
MPC mutant prevention concentration SME sub-MIC effect
MRI magnetic resonance imaging SNPs Single nucleotide polymorphisms
MRSA methicillin-resistant Staphylococcus aureus SSD silver sulfadiazine
MS mass spectrometry SSSI skin and skin structure infections
MSSA methicillin-susceptible Staphylococcus aureus TAMS thymidine analog mutations
MSW mutant selection window TB tuberculosis
NADPH nicotinamide adenine dinucleotide phosphate TBW total bodyweight
NAG N-acetyl-glucosaminidase TDF tenofovir disoproxil fumarate
NAT2 N-acetyltransferase 2 TDM therapeutic drug monitoring
NCEP National Cholesterol Education Program TEN toxic epidermal necrolysis
NDA New Drug Application THF tetrahydrofolic
NNRTI non-nucleoside reverse transcriptase inhibitor TNF tumor necrosis factor
NRTI nucleoside reverse transcriptase inhibitor TOC test of cure
OAI osteoarticular infections TPV tipranavir
OI opportunistic infection TSH thyroid stimulating hormone
OP-MRSA other-phenotype MRSA TdP torsades de pointes
OR odds ratio ULN upper limit of normal
OTC over-the-counter UTI urinary tract infection
PA-SME post-antibiotic sub-MIC effect UV ultraviolet
PABA p-aminobenzoate VAP ventilator-associated pneumonia
PAE post-antibiotic effect VISA vancomycin-intermediate-resistant
PBMC peripheral blood mononuclear cells Staphylococcus aureus
PBP penicillin-binding protein VRE vancomycin-resistant enterococci
PCR polymerase chain reaction VREF vancomycin-resistant E. faecium
PD peritoneal dialysis VRSA vancomycin-resistant Staphylococcus aureus
PD pharmacodynamic VVC vulvovaginal candidiasis
PEP post-exposure prophylaxis Vdss volume of distribution at steady state
PFGE Pulsed-field gel electrophoresis Vss volume of distribution at steady state
PFOR pyruvate:ferredoxin oxidoreductase WHO World Health Organization
PI protease inhibitor WHV woodchuck hepatitis virus
PID pelvic inflammatory disease cART combined antiretroviral treatment
PK-PD pharmacokinetic-pharmacodynamic cSSSI complicated skin and skin structure infections
PK pharmacokinetic cccDNA covalently closed circular DNA
PMN human polymorphonuclear leukocyte dGTP dideoxyadenosine triphosphate
PNP purine nucleoside phosphorylase ddI 2u,3u-dideoxyinosine
POR pyruvate oxidoreductase fAUC/MIC Ratio of the free area under the
PPI proton pump inhibitor concentration-time curve ( f ) over the MIC
PRSP penicillin-resistant Streptococcus pneumoniae fAUC free area under the concentration-time curve
PSI pneumonia severity index hGISA heterogenous glycopeptide-intermediate
PSSP penicillin-susceptible S. pneumoniae Staphylococcus aureus
PT prothrombin time hVISA heterogeneous vancomycin-intermediate
PTA probability of target attainment Staphylococcus aureus
PVL Panton-Valentine leukocidin i.m. intramuscular
PrEP pre-exposure prophylaxis i.v. intravenous
QRDR quinolone resistance-determining region mITT modified intention to treat
RD recommended dose microITT microbiological intent-to-treat
RNA ribonucleic acid s.c. subcutaneously
SAE serious adverse event uSSSI uncomplicated skin and skin structure infection
 Section I
ANTIBIOTICS
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Part 1 Penicillins and Related Drugs
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1 Benzylpenicillin (Penicillin G)
Alasdair M Geddes
Ian M Gould

1. DESCRIPTION
In spite of the availability of many new antibiotics, and the progressive to all penicillins and cephalosporins, is a beta-lactam antibiotic. Such
development of resistance in bacterial species, penicillin G (Pen G) compounds possess a beta-lactam ring which incorporates a beta-lactam
remains a very effective agent, although its usefulness is limited by the bond. The penicillin nucleus, 6-aminopenicillanic acid (6-APA),
necessity for parenteral administration (see Table 1.1). consists of three components – a thiazolidine ring, the beta-lactam
Penicillin was isolated from Penicillium notatum by Fleming in 1928 ring, and a side chain. The cephalosporin nucleus, 7-aminocephalos-
and introduced into clinical medicine in 1941 by Florey, Chain, and poranic acid (7-ACA), is similar, but the five-member thiazolidine ring
associates (Fleming, 1929; Chain et al., 1940; Abraham, 1980). The characteristic of the penicillins is replaced by a six-member dihy-
history of penicillin is recorded in a number of monographs (Hare, drothiazide ring (Waldvogel, 1982). Both 6-APA and 7-ACA were
1970; Bickel, 1972; Bud, 2007). isolated some 50 years ago and they have provided convenient starting
The penicillin used initially was an amorphous compound containing points for the synthesis of other penicillins and cephalosporins which
impurities, which were introduced during the fermentative process; its are described elsewhere in this book.
activity and dosage were expressed in units. Early penicillin was also a The terms ‘‘crystalline penicillin G’’ and ‘‘crystalline penicillin’’ are often
mixture of several penicillin compounds, designated F, G, X, and K. Pen used as synonyms for either of two highly soluble Pen G salts, sodium Pen
G (benzylpenicillin) was the most satisfactory, and this is now used in a G (sodium benzylpenicillin) and potassium Pen G, But all other penicillins
purified and crystalline form for clinical purposes. Pen G, similar in use are also crystalline, unlike the early impure amorphous compound.
The chemical structure of Pen G is shown in Figure 1.1.
Pen G is a rather unstable acid and the following relatively stable
salts are used clinically:
Table 1.1 Infections caused by the following organisms are still usually
readily treatable with penicillin
Infections caused 1a. Sodium Pen G or sodium
benzylpenicillin
Actinobacillus actinomycetemcomitans
Actinomyces This is a highly soluble salt, and a dose can be dissolved completely in
Arachnia
Bacteroides melaninogenicus a few milliliters of water prior to administration. The dosages of this
Bacteroides oralis and other Pen G preparations were previously expressed in units. One
Bacillus anthracis and most other Bacillus spp. (not B. cereus) unit of activity is equivalent to 0.6 mg of pure sodium Pen G.
Bifidobacteria
Bordetella pertussis
Borrelia burgdorferi
Borrelia hermsii 1b. Potassium Pen G
Capnocytophaga canimorsus
Cardiobacterium hominis One unit of activity of this very soluble salt is equivalent to 0.625 mg of
Clostridia except some strains of C. perfringens, tertium, and butyricum pure potassium Pen G.
Corynebacterium diphtheriae and many other coryneforms (not JK)
Eikenella corrodens
Erysipelothrix rhusiopathiae
Eubacteria 1c. Procaine Pen G (procaine
Fusobacterium necrophorum
Fusobacterium nucleatum benzylpenicillin or procaine penicillin)
Haemophilus influenzae (beta-lactamase-negative strains)
Kingella kingae/indologenes This is a much less soluble salt. It is administered intramuscularly
Lactobacilli (i.m.) as a suspension of crystal particles which dissolve slowly, so that
Leptospira
Leuconostoc absorption of liberated Pen G takes place over a prolonged period. One
Listeria monocytogenes unit of activity is equivalent to 1.0 mg of pure procaine penicillin.
Moraxella spp. (not catarrhalis) Availability of procaine penicillin varies in some regions; for instance,
Neisseria lactamica
Neisseria meningitidis (but reduced susceptibility in some countries)
Pasteurella multocida
Peptococci and anaerobic streptococci H
Prevotella melaninogenica N S
Propionibacterium spp.
Spirillum minus
Streptobacillus moniliformis O N
Streptococcus agalactiae
Streptococcus pneumoniae O
Streptococcus pyogenes (group A)
Streptococcus spp. (a- and b-haemolytic streptococci) OH
Trepomerna pallidum O
Veillonella spp.
Figure 1.1 Chemical structure of penicillin G.
6 Penicillins and Related Drugs

in the UK it is only available from two manufacturers on a named serum levels of Pen G. One unit of activity is equivalent to 0.75 mg of
patient basis for the treatment of syphilis. the pure substance. Availability of benzathine penicillin varies in some
regions; for instance, in the UK it is not available, whereas in Australia
1d. Benzathine Pen G (di-benzyl-ethylene- and many countries it is freely available.
Procaine and benzathine salts of Pen G are known as ‘‘long-acting’’,
diamine penicillin or DBED penicillin) ‘‘depot’’, or ‘‘repository’’ forms.
An even less soluble salt than procaine penicillin, benzathine Pen G is
more slowly absorbed from an i.m. injection site, producing prolonged

2. ANTIMICROBIAL ACTIVITY
2a. Routine susceptibility b-lactamase may be toxic to the organism; low-affinity PBPs cannot
be expressed or render the organism nonviable; or inefficient
Since the introduction of Pen G into clinical use, many organisms mechanisms for, or barriers to, transfer of genetic material from
which were originally highly susceptible have now developed resistant organisms exist in the oropharyngeal cavity (Horn et al.,
resistance. Tables 1.2 and 1.3 show the wild-type distribution of 1998).
MICs for some common bacterial species and their suggested Penicillin-tolerant strains of S. pyogenes with MBC/MIC ratios
EUCAST in vitro breakpoints. greater than 32 can be produced experimentally. These organisms have
also been isolated from clinical specimens (Gutmann and Tomasz,
1982; Dagan et al. 1987; Grahn et al., 1987). Their clinical significance
Aerobic Gram-positive cocci remains uncertain (Woolfrey et al., 1988; de Melo et al., 2003).
Streptococcus pyogenes (group A beta-hemolytic streptococcus) Pen G induces significant post-antibiotic effect (PAE) in S. pyogenes
This has remained very sensitive, and routine sensitivity testing is in vitro and in vivo. This means that there is a persisting suppression of
generally not required (Garrod, 1960a; Garrod 1960b; Barber and bacterial growth after short exposure to Pen G (Odenholt et al., 1989;
Waterworth, 1962; Burkert and Watanakunakorn, 1992; Chow and Odenholt et al., 1990; Winstanley, 1990). In serious infections such as
Muder, 1992; Betriu et al., 1993). There has been no shift toward necrotizing fasciitis, penicillin may be combined with a protein
higher MIC levels of Pen G for natural isolates, but less sensitive synthesis inhibitor such as clindamycin in an attempt to suppress toxin
mutants (MIC 0.2 mg/ml compared with 0.006 mg/ml for susceptible production (Stevens et al., 1988).
strains) can be produced in the laboratory (Gutmann and Tomasz,
1982; Coonan and Kaplan, 1994). Penicillin-binding proteins (PBPs) Group B beta-hemolytic streptococcus (Streptococcus agalactiae)
2 and 3 of such mutants have a decreased affinity for Pen G. This organism is usually carried in the lower intestinal tract by both
It is interesting to speculate on possible reasons for this sustained males and females; its common carriage in the urethral orifice,
susceptibility (Horn et al., 1998). Suggested reasons include: periurethral area, and vagina, by both pregnant and nonpregnant

Table 1.2 Wild type distributions and breakpoint MICs of benzylpenicillin for common bacterial pathogens (from EUCAST database).
Organism MIC (lg/ml) Wild-type breakpoint
rlg/ml
0.002 0.004 0.008 0.016 0.032 0.064 0.125 0.25 0.5 1 2 4

Gram-positive bacteria
Streptococcus agalactiae 0 0 8 145 1378 1302 83 0 0 0 0 0 0.125
Streptococcus anginosus 0 0 0 33 136 92 22 11 0 0 0 0 0.25
Streptococcus bovis 0 0 0 0 36 31 12 3 0 0 0 0 0.25
Streptococcus constellatus 0 0 0 39 263 97 38 3 0 0 0 0 0.25
Streptococcus group C 0 0 0 159 38 17 0 0 0 0 0 0 0.064
Streptococcus group G 1 17 66 672 85 19 0 0 0 0 0 0 0.064
Streptococcus intermedius 0 0 0 11 31 18 7 5 0 0 0 0 0.25
Streptococcus milleri 0 0 0 28 55 27 16 0 0 0 0 0 0.125
Streptococcus mitis 0 0 0 94 190 92 106 69 0 0 0 0 0.25
Streptococcus mutans 0 0 0 13 21 2 3 3 0 0 0 0 0.25
Streptococcus oralis 0 0 2 58 196 74 66 25 0 0 0 0 0.25
Streptococcus parasanguis 0 0 0 0 19 7 13 13 0 0 0 0 0.25
Streptococcus pneumoniae 107 884 4791 13,311 5900 1900 0 0 0 0 0 0 0.064
Streptococcus pyogenes 4 88 1416 1882 58 6 0 0 0 0 0 0 0.064
Streptococcus salivarius 0 0 0 10 50 47 45 15 0 0 0 0 0.25
Streptococcus sanguis 0 0 0 30 38 35 40 25 0 0 0 0 0.25
Streptococcus vestibularis 0 0 0 0 2 5 2 1 0 0 0 0 0.25
Streptococcus viridans 0 0 1 9 41 84 39 25 0 0 0 0 0.25
Staphylococcus aureus 0 0 85 553 547 223 199 308 0 0 0 0 0.25a
Staphylococcus lugdunensis 0 0 0 7 4 8 26 7 0 0 0 0 0.25
Enterococcus faecalis 0 0 0 7 3 3 7 17 66 448 4763 403 16.0
Enterococcus faecium 0 0 0 2 5 7 9 17 27 45 83 153 16.0
Enterococcus gallinarum 0 0 0 0 0 1 0 0 9 32 29 5 8.0
Listeria monocytogenes 0 0 0 7 1 5 13 82 136 28 0 0 1.0
Propionibacterium acne 0 0 1 118 92 62 30 0 0 0 0 0 0.125
Clostridium perfringens 0 0 0 11 22 20 7 0 0 0 0 0 0.125
Gram-negative bacteria
Neisseria meningitidis 0 0 8 135 513 674 155 73 0 0 0 0 0.25
Haemophilus influenzae 0 0 0 0 66 106 1199 6552 3528 1359 1195 0 2.0

a
Methicillin-susceptible and methicillin-resistant S. aureus (MSSA and MRSA).
Table 1.3 Breakpoints for sensitivity and resistance to penicillin and aminopenicillin with various bacterial species (from EUCAST).
Penicillins Entero- Staphylo- Entero- Streptococcus Viridans- S. H. M. N. N. Gram- Gram- Nonspecific
bacteriaceae coccus coccus A, B, C, G streptococcie pneu- influ- catarrhalish gonorrhoeae mening- negative positive related break
moniae enzaeg itidis anaerobesj anaerobes points
Sr/RW

c
Benzylpenicillin 0.12/0.12 0.25/0.25 0.25/2 0.06/2 IEk 0.06/1 0.06/0.25 0.25/0.5 0.25/0.5 0.25/2
Ampicillinl a
/8 b
4/8 d
0.5/2 0.5/2 1/1 1/1 i
(0.12/1) 0.5/2 4/8 2/8
a b d i
Amoxicillin /8 4/8 0.5/2 0.5/2 1/1 1/1 (0.12/1) 0.5/2 4/8 2/8
Phenoxy- 0.12b 0.25d 0.06f
methylpenicillin

a
Enterobacteriaceae and aminopenicillin breakpoints: The resistant breakpoint of RW8 mg/l ensures that all isolates with resistance mechanisms are reported resistant. The wide range of dosages and intravenous
versus oral administration significantly affect therapeutic efficacy. The unspecified S breakpoint enables the user to categorize wild-type Escherichia coli and Proteus mirabilis S or I to the aminopenicillins. This will
depend on dosing, route of administration, and on whether the infection is systemic or affects the urinary tract only. Irrespective of susceptibility testing results, Klebsiella spp. and Citrobacter diversus are poor targets
for penicillins with or without beta-lactamase inhibitors.
b
Staphylococci: Most staphylococci are penicillinase producers. Penicillinase producing strains are resistant to benzylpenicillin, phenoxymethylpenicillin, amino-, carboxy- and ureidopenicillins. The benzylpenicillin
breakpoint will mostly, but not unequivocally, separate beta-lactamase producers from nonproducers.
c
Enterococci: Refer to national or international endocarditis guidelines for breakpoints for Enterococcus spp. in endocarditis. Ampicillin and amoxicillin are considered active against wild-type enterococci. Enterococcus
faecium resistant to penicillins can be considered resistant to all other beta-lactam drugs including carbapenems.
d
Streptococci: The beta-lactam susceptibility of beta-hemolytic streptococci groups A, B, C and G is inferred from the penicillin susceptibility. Strains with MIC values above the S/I breakpoint are very rare or not yet
reported. The identification and antimicrobial susceptibility tests on any such isolate must be repeated and if the result is confirmed the isolate sent to a reference laboratory. Until there is evidence regarding clinical
response for confirmed isolates with MIC above the current resistant breakpoint (in italics) they should be reported resistant. Streptococci groups A, B, C and G do not produce beta-lactamase. The addition of a
beta-lactamase inhibitor does not add clinical benefit.
e
Viridans streptococci: Refer to national or international endocarditis guidelines for breakpoints for viridans streptococci in endocarditis. Use benzylpenicillin to categorize the susceptibility of ampicillin and
amoxicillin.
f
Streptococcus pneumoniae: Most MIC values for penicillin, ampicillin and amoxicillin differ by no more than one dilution step and isolates susceptible to benzylpenicillin can be reported susceptible to these and other
relevant beta-lactam antibiotics. In pneumonia, strains with with MIC r0.5 mg/l should be regarded as susceptible to penicillin at doses of at least 1.2 g  4, with MIC r1 mg/l at doses of 2.4 g  4 or 1.2 g  6 and
strains with MIC r2.0 mg/l susceptible at doses of 2.4 g  6. In meningitis, isolates with MICs above 0.06 mg/l should be categorized resistant to penicillin. For other indications breakpoints of 0.06/2 mg/l are valid.
Report S. pneumoniae with benzylpenicillin MICs above 0.06 mg/l resistant to phenoxymethylpenicillin.
g
Haemophilus influenzae: Always test for beta-lactamase and report positive strains resistant to penicillins without beta-lactamase inhibitors. Breakpoints relate only to beta-lactamase-negative strains. Strains may be
resistant to penicillins, aminopenicillins, and/or cefalosporins due to changes in PBPs (BLNAR: beta-lactamase negative, ampicillin resistant) and a few strains have both resistance mechanisms (BLPACR: beta-lactamase
positive, ampicillinclavulanate resistant).
h
Moraxella catarrhalis: Can be reported resistant to penicillins and aminopenicillins without inhibitors since W85% of the isolates produce beta-lactamase.
i
Neisseria gonorrhoeae: Should always be tested for beta-lactamase. If positive, report resistant to benzylpenicillin, ampicillin, and amoxicillin. The susceptibility of beta-lactamase negative isolates to ampicillin and
amoxicillin can be inferred from the susceptibility to benzylpenicillin.
j
Gram-negative anaerobes: Susceptibility to ampicillin and amoxicillin can be inferred from their susceptibility to benzylpenicillin.
k
Non-species-related breakpoints have been determined mainly on the basis of pharamcokinetic/pharmacodynamic data and are independent of MIC distributions of specific species. They are to be used only for
aerobic organisms that do not have specific breakpoints.
IE = There is insufficient evidence that the species in question is a good target for therapy with the drug.
8 Penicillins and Related Drugs

women, appears to reflect secondary contamination (Anthony, 1982; isolates of group G streptococci also often show tolerance to Pen G
Dillon et al., 1982; Easmon, 1986; Persson et al., 1987). Since about and other antibiotics which act on the bacterial cell wall (Finch and
1960, group B streptococci have been increasingly recognized as an Aveline, 1984; Ashkenazi et al., 1988). Pen G plus gentamicin usually
important cause of neonatal infections (McCracken, 1973; Berg et al., exhibits in vitro synergism against group G streptococci (Lam and
1977; Cowen, 1979; Hamoudi and Hamoudi, 1981). High quantities Bayer, 1984).
of these organisms in the genital tract of the mothers at delivery results
in more frequent and heavier colonization of the babies, which may Streptococcus pneumoniae
constitute an increased risk for a neonatal infection (Persson et al., This organism remained Pen G sensitive until 1967, after which strains
1986). Group B streptococci have been also implicated in certain adult with intermediate resistance or resistance were isolated with increasing
infections, such as septicemia and meningitis (Anthony and Concep- frequency from patients with pneumococcal infections or carriers of
cion, 1975; Gallagher and Watanakunakorn, 1986; Verghese et al., the organism (see Table 1.4). In 1977 highly resistant pneumococcal
1986; Aharoni et al., 1990; Back et al., 1990; Dunne and Quagliarello, strains appeared in South Africa; initially their spread to other parts of
1993; Sarmiento et al., 1993). In adults there is some 30-fold increased the world was minimal, but they have now been detected in many
risk of infection by this organism in patients with diabetes mellitus, other countries. Pneumococcal strains with MICs of 0.06 mg/ml or less
cancer, or HIV infection (Farley et al., 1993; Wessels and Kasper, are traditionally regarded as susceptible, those with MICs of 0.1–
1993). Occasional cases have been reported with classical toxic shock- 1.0 mg/ml as intermediately resistant, or of reduced susceptibility, and
like syndrome, in which the patient is not bacteremic, but urine and those with MICs of higher than 1.0 mg/ml have in the past been
vaginal cultures grow group B streptococci which elaborate a pyrogenic designated as highly resistant or simply resistant (Jacobs, 1992).
toxin (Schlievert et al., 1993). Breakpoints have recently been revised (see below under 2b. Emerging
Group B streptococci are quite susceptible to Pen G, but their resistance and cross-resistance): CLSI has changed the in vitro
sensitivity is about 10-fold less than that of group A streptococci (see breakpoints for penicillin for nonmeningeal infections – strains of
Table 1.2). This sensitivity to Pen G has remained unchanged over the S. pneumoniae with MICs r2 mg/ml are now considered susceptible,
years and resistant strains have only occasionally been isolated from with ‘‘resistant’’ defined as an MIC Z8 mg/ml (Performance Standards
humans (Bayer et al., 1982; Berkowitz et al., 1990; Betriu et al., 1994; for Antimicrobial Susceptibility Testing; Eighteenth Informational
de Azavedo et al., 2001; Morikawa et al., 2003; Kimura et al., 2008). Supplement, 2008). A summary of key reports regarding the
Group B streptococci displaying resistance to penicillins, cephalospor- emergence of penicillin resistance among strains of S. pneumoniae is
ins, and several other antibiotics have also been isolated from the given in Table 1.4.
udders of dairy cattle which had received antibiotic chemoprophylaxis.
Resistance appeared to be due to alteration of PBPs, specifically Streptococcus viridans (alpha-hemolytic streptococci)
PBP2X (see below under 2b. Emerging resistance and cross-resistance) These streptococci may be further subdivided into species, such as
(Berghash and Dunny, 1985; Kimura et al., 2008), raising pencillin S. sanguis, S. mitior (mitis), S. mutans, S. salivarius, S. milleri, and
MICs to 1 mg/ml and ceftizoxime MICs to 128 mg/ml. S. constellatus. Streptococcus viridans is a common cause of bacterial
Some strains of group B streptococci may be penicillin tolerant, with endocarditis (Rapeport et al., 1986; Stein and Nelson, 1987), but the
their MBCs greatly exceeding their MICs (Kim and Anthony, 1981). S. milleri constellation group (often group F) is also implicated in
This phenomenon can be more marked at a lower pH, which could be serious suppurative infections in various parts of the body (Gossling,
of clinical significance (Horne and Tomasz, 1981). In vitro and animal 1988; Gelfand et al., 1991).
studies indicate that combinations of Pen G with an aminoglycoside, Streptococcus viridans is usually Pen G sensitive (Bourgault et al.,
such as gentamicin, are usually synergistic against group B streptococci 1979; Little et al., 1979). Resistant variants may be found in the
(Deveikis et al., 1977; Baker et al., 1981). In vitro, even the addition of pharynx and teeth cavities of patients who have been treated with a
low concentrations of gentamicin (0.1 or 0.5 mg/ml) to Pen G penicillin, or who have received oral penicillin V for prolonged periods
accelerates killing of group B streptococci. This provides a rationale to prevent rheumatic fever (Phillips et al., 1976). By contrast, patients
for the initial use of a combination of Pen G plus gentamicin in the treated with monthly i.m. benzathine penicillin have had little, if any,
treatment of group B streptococcal meningitis (see below under increase in resistant S. viridans strains. Concerns that continuous low-
7. Clinical uses of the drug) or endocarditis (Swingle et al., 1985; dose oral penicillin prophylaxis would result in a high prevalence of
Gallagher and Watanakunakorn, 1986). In vitro studies have shown endocarditis due to Pen G-resistant S. viridans have lessened, although
that killing of group B streptococci is enhanced if an opsonic it is well documented (Parrillo et al., 1979; Levin et al., 1982). Pen G-
intravenous (i.v.) immunoglobulin mixture is combined with Pen G, resistant viridans streptococci have also been isolated from the oral
suggesting that this combination has potential for use in the treatment flora (Hess et al., 1983) and from the blood (Rahman, 1982), from
of neonatal group B streptococcal infections (Miller et al., 1990). patients who have not received prior penicillin therapy. Venditti et al.
(1989) studied 63 streptococcal isolates (most S. viridans) obtained
Groups C, G, F, and R (Streptococcus suis) beta-hemolytic streptococci from blood cultures of neutropenic patients; 80% were Pen G sensitive
These are less common human pathogens. Group C (Arditi et al., and the others showed varying degrees of resistance. Wilcox et al.
1989; Bradley et al., 1991), group G (Craven et al., 1986; Venezio et al., (1993) tested 44 S. viridans strains collected from patients with
1986), group F (Libertin et al., 1985), and group R streptococci endocarditis; 20% of them were Pen G resistant. Highly resistant
(Arends and Zanen, 1988) are consistently sensitive to Pen G. A case viridans streptococci were detected initially in South Africa in
of penicillin-resistant group C streptococcus has been reported (MIC association with Pen G-resistant pneumococci. Later they appeared
2 mg/ml) although the mechanism of resistance was not clarified also in other countries. These strains are resistant to Pen G,
(Hutchinson and Eltringham, 1995). Strains of group C streptococci penicillinase-resistant penicillins, cephalosporins, piperacillin, azlocil-
can exhibit penicillin tolerance (Arditi et al., 1989); this was lin, and mezlocillin, but susceptible to vancomycin. They have altered
demonstrated in 16 of 17 clinical isolates tested by Portnoy et al. PBPs, similar to the Pen G-resistant pneumococci (Farber et al., 1983a;
(1981). Pen G and gentamicin synergism occurred against all of the 17 Quinn et al., 1988).
strains. Group F streptococci, otherwise known as S. milleri group or Westling et al. (2004) reported that 25% of 48 patients with acute
S. anginosus group, are usually fully susceptible to penicillin although leukemia had penicillin-resistant viridans group streptococci (VGS) in
there are several reports of increasing resistance due to altered PBPs their oral cavity (MIC W2 mg/ml). These 12 patients had a higher
(Bantar et al., 1996; Doern et al., 1996; Tracy et al., 2001). It is most frequency of septicemia (due to all organisms) (p = 0.04) and more
common among the S. anginosus and S. intermedius isolates. days of treatment with co-trimoxazole (p = 0.04) than patients with
Vancomycin or cefotaxime–ceftriaxone are alternatives. Clinical penicillin-susceptible or-intermediate strains. Eleven of the 12
Table 1.4 Summary of reports describing emerging penicillin resistance among strains of S. pneumoniae.
Reference No. of isolates Source Country %R (MIC Z2 lg/ %I (0.12–1 lg/ml) Period of study
ml)

Scott et al., 1998 71 Adult lung aspirate or blood Kenya coast 27 1994–1996
108 Pediatric invasive 29
90 NPI from sick children 47 (serotypes 13, 14, 19
and 23 strongly
associated with MIC
Z0.1)
Aldridge et al., 1998 481 Blood, URTb , LRT Louisiana 7 23 1995–1996
Araj et al., 1999 50 ‘‘Consecutive clinical isolates’’ (one Lebanon 18 38 1996–1998
per patient) blood (20) LRT (17)
Nagai et al., 2000 218 Children (mainly NPI from patients) Japan 9.6 (ST 19F [44 37.2 1993–1995
strains] associated
with I and R)
Sahin et al., 2006 37 Adult pneumonia sputum Turkey 0 24.3 1997–2000
Esel et al., 2001 193 49 sputum, 34 CSF, 33 ear, 26 Turkey 0 23 (ST 19, 23, 14,1) 1997–2000
blood, 22 eye, 10 pleural
Watson et al., 2003 1355 Non-indigenous children – invasive Australia 13–14 2001–2002
1504 Non-indigenous adults – invasive
Yee et al., 2004 377 CML SE Michigan 16 19 1997–1999
Melander et al., 2004 34,745 Pre-school CART Skane, Sweden 2.6 (MICZ0.5)  7.4 (W0.12) 1995–2001
Porat et al., 2004 ST 11A 8 MEF Israel 100 1998–2003
ST ISB/C 19 Israel 100 1998–2003
ST 19F 49 Costa Rica 80 1998–2001
Schrag et al., 2004 87 Invasive USA 1a 8 2000–2001
Decousser et al., 2004 222 Invasive France 16 31.5 2000–2002
Brown and Rybak, 2004 10,012 CARTI USA 21.2 14.2 2001–2002
Oteo et al., 2004 1968 Invasive Spain 9.2 to 26.4 2001–2003
(overall 39.5–33%
2001–2003 and
60.4–41.2% 2001–
2003 in o14y
[p = 0.002])
Castanheira et al., 2006 829 RTI/invasive Brazil 7.5 14.7 1998–2004
Farrell et al., 2007 557 Children USA 29.4 11.1 2000–2001
277 13.4 20.6 2003–2004
Messina et al., 2007 71 Invasive Dallas, USA 10 (estimate) 50.7 described as 1999
nonsusceptible
50 Children 2005
Sahm et al., 2007 847 Sinus USA 29.8 18.4 2001–2005
Critchley et al., 2007 1543 CARTI USA 8.7–22.5 by region 2005–2006
Felmingham et al., 2007 40 country survey of 20, CARTI South Africa 54 (approximate) 20 2001–2004
142 isolates Far East 43 (approximate) 20
Southern Europe 25.7 12.7
Northern Europe 6.1 7.3
France 15.9 40.4
Greece 15.9 42.0
Spain 13.1 29.4
Sener et al., 2007 301 CARTI Turkey 7.6 24.6 2004–2005

a
Tennessee,o5y, Z65y, resistance to at least three drug classes associated with very high resistance (MIC Z8 mg/l).
Increased in o10y (p o 0.02).
b
CART(I): community acquired respiratory tract (infection); CML: Clinical Microbiology Lab; MEF: middle ear fluid; NPI: nasopharyngeal isolates; ST: serotype.
 327 MIC Z2 mg/l with 305 of these isolated 1995–1998.
10 Penicillins and Related Drugs

penicillin-resistant VGS were S. mitis, and one was S. sanguis. Four been as effective as a Pen G–streptomycin regimen for S. viridans
were also resistant to erythromycin. The literature on VGS infections endocarditis. If a patient is responsive both clinically and bacter-
in children with cancer was recently reviewed (Bruckner and Gigliotti, iologically, despite a demonstration of Pen G tolerance for the infecting
2006). Their incidence and severity have increased in the past 15 organism, it is unnecessary to alter antimicrobial therapy on the basis
years and account for up to one-third of bacteremias in this group of of this in vitro observation (Kim, 1988). The MBCs determined by
patients. Up to 37% were high-level penicillin resistant (W4 mg/ml). conventional methods are often inaccurate and so a nontolerant
Children appear to be more frequently colonized with penicillin- S. viridans strain may be labeled incorrectly as tolerant (James, 1990).
resistant strains of VGS than adults, possibly due to both more In vitro synergy between Pen G (or other penicillins, cephalosporins,
intensive antibiotic use in a healthy children with acute otitis media and vancomycin) and any of the aminoglycosides usually occurs with
and otherwise prophylactic use of fluoroquinolones and co-trimoxazole virtually all S. viridans strains, unlike Enterococcus faecalis (see below
(Elting et al., 1992; Razonable et al., 2002) in children with cancer. under Enterococci) (Sande and Scheld, 1980). Some S. viridans
Quinolone-resistant VGS have also been found in this context clinical isolates have exhibited high-level streptomycin resistance
(Razonable et al., 2002). (MICs W2000 mg/ml); Pen G and streptomycin are not synergistic
Streptococcus mitis is the species of VGS most commonly associated against these strains, but a combination of Pen G and gentamicin may
with reduced susceptibility to antibiotics. Penicillin resistance is usually be, so long as the isolate does not also exhibit high-level resistance to
associated with resistance to other b-lactams, owing to the modified gentamicin (MICs W500 mg/ml) (Farber et al., 1983b). In fact, given
PBPs, and frequently to other classes of antibiotics, especially the prevalence of penicillin-resistant VGS there are remarkably few
quinolones and macrolides. Vancomycin resistance is rarely encoun- cases of infective endocarditis (IE) due to these strains reported in the
tered however (Han et al., 2006). literature, possibly because species more associated with IE are less
In a recent review of community-acquired bacteremia in the UK associated with resistance. A retrospective analysis of a cohort of 29
(Tan et al., 2008), VGS caused 50/723 (6.9%) adult and 13/106 such cases over a 40-year period, including ten patients with prosthetic
(12.3%) pediatric episodes; 47.3% were of definite or probable clinical valve endocarditis, demonstrated that therapy with a b-lactam–
significance. No patients were neutropenic and overall penicillin aminoglycoside combination gave a good outcome (Knoll et al., 2007).
resistance was 20%; 25.5% of strains were erythromycin resistant and
10.9% resistant to both. Enterococci
Smith et al. (2004) analyzed 155 consective blood culture isolates of Although enterococci were once classified as streptococci, they have
VGS from febrile infected patients (adults and children) in Glasgow for some time now been known to be separate species (Herman and
during 1993–2000, the majority being hematology/oncology patients. Gerding, 1991). Enterococcus faecalis and E. faecium are the two most
These included 67 S. oralis and 66 S. mitis isolates. Eleven percent were common clinical pathogens; but less commonly encountered members
penicillin resistant, 40% resistant to erythromycin, and 3% to of the enterococci include E. durans, E. raffinosus, and E. avium
clindamycin. High-level resistance to ceftriaxone was found in 12 (Grayson et al., 1991b). Compared with streptococci, E. faecalis is much
isolates (S. oralis and S. mitis). less sensitive to Pen G and E. faecium is even less so (see Table 1.2)
In Taiwan, Teng et al. (1998) found that 35% of isolates of S. oralis (Moellering et al., 1979; Murray, 1991). Enterococci were considered to
were high-level penicillin resistant MIC Z4 mg/ml) compared with be naturally occurring tolerant organisms; penicillins and other drugs
20% of S. mitis isolates and 8% of S. salivarius isolates, but only 50% of which act on the cell wall (e.g. vancomycin, cycloserine, and
S. salivarius isolates were fully susceptible to penicillin (r0.125 mg/ml). bacitracin) have an MBC/MIC ratio of W32 for enterococci (Krogstad
A recent study of healthy children from Poland reported penicillin and Parquette, 1980). However, it has now been shown that tolerance
resistance in 16.7% of 425 VGS strains, of which 33 were S. mitis; is an acquired characteristic and not necessarily intrinsic. The MICs of
23.5% of VGS were also resistant to erythromycin, 23.1% to Pen G for enterococci from an antibiotic-virgin area of the Solomon
clindamycin, 52% to tetracycline, 16% to doxycycline, and 55.2% to Islands were similar to those of strains isolated in the USA. However,
ciprofloxacin (Rozkiewicz et al., 2006). the organisms from the Solomon Islands rapidly lysed and were killed by
In a Slovakian study of 127 episodes of VGS bacteremia (Mrazova concentrations of Pen G just above the MIC. After short exposure to
et al., 2005), mainly in cancer and infective endocarditis patients, Pen G in vitro, these organisms, like strains in the USA, rapidly became
penicillin resistance (14.5%) was associated with a mortality of 71% tolerant to beta-lactams (Moellering, 1991). Clinical isolates of
compared with 22.5% for penicillin-susceptible strains (po0.0002). enterococci often exhibit a peculiar type of tolerance to beta-lactams,
On the other hand, erythromycin resistance (13%) was not associated in that these bacteria may be killed by relatively low antibiotic
with increased mortality. concentrations (2–4  MIC), but the percentage of survivors increases
Streptococcus viridans strains are not infrequently Pen G tolerant at increasing antibiotic concentrations (Shah, 1982; Fontana et al.,
(Dankert and Hess, 1982; James, 1990). Streptococcus sanguis, in 1990a). When studying 50 clinical isolates of E. faecalis, Fontana et al.
particular, appears to be an inherently Pen G-tolerant organism; (1990b) found that this paradoxical response and tolerance were not
although its cell growth is inhibited by very low concentrations, Pen G exhibited by all strains. Some 22% of the strains were paradoxically
is not bactericidal. Streptococcus sanguis is defective in autolysins, responding but not tolerant, 65% were paradoxically responding and
which are essential for the irreversible bactericidal effect of Pen G tolerant, 12% were neither paradoxically responding nor tolerant, and
(Horne and Tomasz, 1977). ‘‘Nutritionally variant’’ streptococci have only 2% were tolerant, but not paradoxically responding.
been isolated from 5–10% of patients with viridans streptococcal The reason why enterococci have relatively high MICs to Pen G and
endocarditis (Gephart and Washington, 1982). These require supple- several other penicillins such as ampicillin (see Chapter 3, Ampicillin,
mental media for isolation and sensitivity testing, and may be Pen G Amoxicillin and Other Ampicillin-Like Penicillins) and are completely
sensitive, resistant, or tolerant (Feder et al., 1980; Stein and Nelson, resistant to other penicillins such as methicillin, and to all
1987). Eleven such strains tested by Holloway and Dankert (1982) cephalosporins (except new agents such as ceftobiprole; see Chapter
were all tolerant to Pen G. 34, Ceftobiprole) is diminished affinity of their PBPs for these drugs;
Tolerant S. viridans strains may possibly be responsible for failures of PBP5 is of special importance. This PBP has low affinity for penicillins
Pen G to protect against bacterial endocarditis (Holloway et al., 1980; and is responsible for the relatively high MICs of E. faecalis and
Anderson and Cruickshank, 1982; Brennan and Durack, 1983; Lowy E. faecium to Pen G. If enterococcal cells manufacture more PBP5, they
et al., 1983; Wilson et al., 1985). It is not known whether a synergistic develop intrinsic resistance to Pen G and ampicillin. This indicates that
Pen G–aminoglycoside combination would be more effective in this PBP5 has the potential capacity to take over the functions of all other
situation, although some authors have suggested this to be the case PBPs and therefore can fully compensate for their activity in cells
(Hess et al., 1983a; Hess et al., 1983b). In general, Pen G alone has overproducing PBP5 (Al-Obeid et al., 1990a; Al-Obeid et al., 1990b;
 Benzylpenicillin (Penicillin G) 11

Moellering, 1991; Fontana et al., 1992; Fontana et al., 1994). In one Similar to S. aureus beta-lactamase, the enzyme produced by
experiment in vitro it was possible to derive an E. faecium strain which E. faecalis can be inhibited by beta-lactamase inhibitors such as
had no PBP5. This strain could function normally and was very clavulanic acid (see Chapter 11, Clavulanic Acid) (Murray, 1991).
sensitive to all penicillins and cephalosporins (Fontana et al., 1985). This can be utilized in treatment. Patterson et al. (1988b) reported two
Enterococci with this intrinsic Pen G resistance have caused strains of E. faecalis which produced beta-lactamase. One also had
outbreaks in hospitals (Oster et al., 1990). In one hospital the Pen G high-level gentamicin resistance, but the other did not. With the latter
susceptibility of E. faecium was studied from strains isolated for 22 years it was possible to demonstrate synergistic killing with a combination of
starting in 1968. From 1969 to 1988 the geometric mean MIC was Pen G, clavulanic acid, and gentamicin, but not with the former.
14 mg/ml, whereas this was 123 mg/ml from 1989 to 1990. In the more Unfortunately, the majority of beta-lactamase-producing strains of
recently isolated resistant strains, the penicillin-binding affinity of PBP5 E. faecalis also show high-level gentamicin resistance (Patterson et al.,
was notably lower (Grayson et al., 1991a). Two E. faecium isolates were 1988a; Murray, 1989; Rice et al., 1991a; Chow et al., 1993).
described which had high-level resistance to Pen G due to altered At least one E. faecalis strain has been reported which produced
PBP5, and these strains were also resistant to vancomycin (Handwerger beta-lactamase and was also resistant to vancomycin (Handwerger
et al., 1992). Nosocomial outbreaks due to E. faecium have been et al., 1992). Beta-lactamase production has been largely reported in
reported where the strains had a high intrinsic resistance to Pen G, and E. faecalis and not with other enterococcal species. Coudron et al.
they were also resistant to gentamicin and vancomycin (Handwerger (1992) reported one isolate of E. faecium which produced beta-
et al., 1993; Landman et al., 1993). Experimental endocarditis in lactamase. This was plasmid mediated and transferable into other
animals due to such strains partially responded to a ciprofloxacin, plasmid-free E. faecium strains. The strain also showed high-level
rifampicin, and gentamicin combination, but the infection was not aminoglycoside resistance.
eradicated in 5 days (Whitman et al., 1993). If the strain of E. faecium is
not high-level gentamicin resistant (MIC W250–500 mg/ml), then if the Non-enterococcal group D streptococci
Pen G MIC is lower than 200 mg/ml, Pen G and gentamicin Unlike the enterococci, these organisms, such as S. bovis, which may
combination is synergistic. It may be possible to treat infections by cause endocarditis, are nearly always highly sensitive to Pen G (Tuazon
such strains with high-dose Pen G plus gentamicin (Torres et al., 1993). et al., 1986). Similar to S. viridans, Pen G acts synergistically with any
However, if high-level gentamicin resistance is present, then synergism of the aminoglycosides against nonenterococcal group D streptococci
is not observed (Mederski-Samoraj and Murray, 1983). (Moellering et al., 1974).
In vitro experiments have shown that increase in Pen G resistance of Leuconostoc and Micrococcus spp.
E. faecalis with changes in PBPs can be obtained by exposure of the Leuconostoc species are members of the family Streptococcaceae, and
strain to stepwise increasing concentrations of Pen G or, to a lesser they only rarely cause infections, mainly in compromised hosts. These
extent, by exposure to unchanging concentrations for a prolonged bacteria are moderately susceptible to Pen G, MICs ranging from 0.25
time. Pulsed administration of Pen G did not select intrinsic resistance to 1.0 mg/ml (Handwerger et al., 1990), but frequently vancomycin
(Hodges et al., 1992). resistant. Micrococcus is usually Pen G sensitive (Von Eiff et al., 1995).
The uncommon enterococcal species, E. avium and E. raffinosus, Stomatococcus mucilaginosus (Micrococcus mucilaginosus) rarely causes
have different Pen G susceptibilities. The MIC range for the former is septicemia in neutropenic patients. Its sensitivity to Pen G is variable,
0.5–2 mg/ml, and for the latter 4–64 mg/ml. Enterococcus raffinosus but this organism is always susceptible to vancomycin (McWhinney
appears to have a PBP7, which is a low-affinity PBP, and this may play et al., 1992; Henwick et al., 1993; Tan et al., 1994).
a role in the relative Pen G resistance of this species (Grayson et al.,
1991b; Patel et al., 1993). Staphylococcus aureus
Klare et al. (1992) considered that the overproduction of PBP5 is Originally this bacterium was very sensitive to Pen G, but the
not the only intrinsic resistance mechanism for enterococci. These prevalence of Pen G-resistant S. aureus strains in hospitals increased
authors found that overproduction of PBP5 occurred in E. faecium during the period 1942–1958, reaching a value of W70% of all isolates.
strains which were moderately Pen G resistant, but when MICs were Resistance was due to the production of beta-lactamases (penicilli-
128 mg/ml this was no longer so, and other so far unknown nases) which rapidly hydrolyze Pen G (Richmond, 1979), and this was
mechanisms were presumably involved. mediated by conjugative plasmids (Kaplan and Tenenbaum, 1982).
Another mechanism of Pen G resistance in the enterococci is beta- A variety of beta-lactamase plasmids have now been found in naturally
lactamase production. This was first described by Murray and occurring strains of Pen G-resistant S. aureus. Although most often
Mederski-Samoraj (1983) for one strain of E. faecalis. Soon such found are class II plasmids, an increasing number of strains have been
strains were found in other areas in the USA and also elsewhere in the described in which the genes for beta-lactamase production are located
world (George and Uttley, 1989; Murray, 1989; Murray, 1991; on the chromosome. A beta-lactamase transposon may also be present
Moellering, 1992). There was one large outbreak of colonization in some strains (Lyon and Skurray, 1987; Weber and Goering, 1988).
with beta-lactamase-producing enterococci in a children’s hospital in S. aureus produces four types of beta-lactamase (A, B, C, and D). Types
Boston (Rhinehart et al., 1990). Another study found evidence for A, B, and C exhibit similar activity against Pen G, but type D
clonal spread of a single strain of beta-lactamase-producing E. faecalis hydrolyzes the drug less rapidly. These four beta-lactamases vary as to
to six hospitals in five states in the USA (Murray, 1991). how rapidly they hydrolyze other beta-lactams, for example the
The beta-lactamase produced by some E. faecalis strains is similar to cephalosporins (Zygmunt et al., 1992).
that produced by S. aureus and it is encoded on plasmids, which can be Over the years, the majority of S. aureus strains, even outside
transferred by conjugation (Murray et al., 1986; Zscheck et al., 1988; hospitals, became beta-lactamase producers and resistant to Pen G
Patterson et al., 1990; Murray, 1992). One E. faecalis strain was found (Bengtsson et al., 1977; Helling et al., 1980). One survey in Denmark
to contain three conjugative plasmids and a conjugative transposon. found that 87% of isolates were Pen G resistant, and this percentage
These encoded beta-lactamase production, gentamicin resistance, was the same among strains isolated in the community as among those
and also resistance to other antibiotics (Murray et al., 1988). All such isolated in hospitals (Rosdahl et al., 1990). Another Danish survey
E. faecalis strains have not arisen from a single strain, as there is showed that during the period 1977–1990 the frequency of Pen G
significant variation in the plasmids which encode beta-lactamase resistance increased from 78.7% to 87.5% among a total of 278, 193
(Smith and Murray, 1992). By contrast, other authors have found that, S. aureus strains isolated from hospitalized patients (Renneberg and
in E. faecalis strains producing beta-lactamase, the beta-lactamase Rosdahl, 1992).
gene was integrated into the bacterial chromosome (Rice et al., 1991b; Resistance of S. aureus can also be intrinsic owing to PBP2 changes
Chow et al., 1993; Rice and Marshall, 1994). which render them resistant to Pen G and to all other penicillins,
12 Penicillins and Related Drugs

including the penicillinase-resistant penicillins (see Chapter 6, Australian survey of oral anaerobes, 74.5% of 106 Prevotella spp.
Nafcillin, and Chapter 5, Isoxazolyl Penicillins: Oxacillin, Cloxacillin, isolates were penicillin susceptible. Overall 77.6% of 201 oral
Dicloxacillin and Flucloxacillin) and cephalosporins – so-called anaerobes were penicillin susceptible (Warnke et al., 2008).
methicillin-resistant S. aureus (MRSA). This involves the insertion
of one of several scc Mec genes, and these strains have now become Gram-positive bacilli
dominant in many parts of the world.
S. aureus may also be Pen G tolerant. Staphylococci exhibiting this Corynebacterium diphtheriae is consistently sensitive to Pen G. Other
phenomenon have deficient cell wall autolytic enzyme activity. This corynebacteria vary in sensitivity, and 17 of 24 strains were found to be
enzyme augments bacterial cell wall damage initiated by Pen G and the tolerant (Maple et al., 1994; Hoban and Felmingham, 2002). This may
combined action produces a lethal effect on bacteria (Sabath et al., be an explanation for the well-described failure of penicillin to
1977). Although the penicillins inhibit these organisms in usual eradicate the carriage state. An amoxicillin-tolerant strain causing
concentrations, they are not bactericidal. Further aspects of tolerance endocarditis has also been described (Dupont et al., 1995).
of S. aureus to the penicillin group of drugs are discussed below under Arcanobacterium (formerly Corynebacterium) haemolyticum, which
2b. Emerging resistance and cross-resistance. causes pharyngitis, is Pen G sensitive (Carlson et al., 1995).
Corynebacterium pseudodiphthericum, which may cause endocarditis, is
Coagulase-negative staphylococci usually susceptible (Colt et al., 1991; Morris and Guild, 1991; Manzella
These constitute a heterogeneous group of organisms among which et al., 1995). Corynebacterium kerosis may also be Pen G sensitive
over 15 different species are recognized (Parisi, 1985). Three, (Booth et al., 1991). Corynebacterium striatum is usually Pen G sensitive
S. epidermidis (S. albus), S. haemolyticus, and S. saprophyticus, are (Watkins et al., 1993). Corynebacterium bovis varies in its sensitivity,
common pathogens particularly associated with the use of indwelling whereas the corynebacteria of group J.K. (C. jaikeium) are always
foreign devices and urinary tract infections. Staphylococcus epidermidis Pen G resistant (Lipsky et al., 1982).
may be Pen G sensitive, but the majority of strains are resistant Although most strains of Bacillus anthracis are susceptible to Pen G
(W80% of isolates in the UK) because, similar to S. aureus, they in vitro (Doganay and Aydin, 1991), they appear to have an inducible
produce plasmid-mediated beta-lactamases (Price and Flournoy, 1982; low-level penicillinase (class A) and a cephalosporinase (class B)
Richardson and Marples, 1982). Exchange of R plasmids may occur which is more obviously expressed, leading to in vitro cephalosporin
in vivo between S. epidermidis and S. aureus (Totten et al., 1981). resistance (Bell et al., 2002; Coker et al., 2002). Two b-lactamases,
Staphylococcus epidermidis usually also possess intrinsic resistance to the which are related to those found in B. cereus, are described in detail by
penicillins, rendering them methicillin resistant by insertion of the Chen et al. (2003). Penicillin has therefore fallen out of favor as first-
same SCC Mec genes as in S. aureus, S. saprophyticus was originally line monotherapy for serious disease due to B. anthracis. Athama et al.
regarded as being always Pen G sensitive (Wallmark et al., 1978). (2004) found that resistance to many different antibiotics was easily
Subsequently, an intermediate level of resistance for these organisms selected in vitro, and in another study the same group showed
was described, but the distinction of sensitive and resistant strains by ceftriaxone to be the least active agent against two standard strains.
the usual laboratory tests is difficult. Resistance seems to be due to a Moxifloxacin, quinupristin–dafopristin (Synercids), and rifampicin
beta-lactamase, but its activity and quantity appears to be much less were the most rapidly cidal (Athamna et al., 2004a; Athamna et al.,
than that produced by S. epidermidis. The clinical significance of this 2004b). Cavallo et al. (2002) recently reported 11.5% resistance to
resistance in S. saprophyticus is uncertain (Richardson and Marples, penicillin and amoxicillin in 96 French strains isolated between 1994
1980; Price and Flournoy, 1982). Cristino et al. (1989) described 100% and 2000, and Mohammed et al. (2002) found 2 of 65 strains resistant
susceptibility of 150 strains to penicillin in 1989. Methicillin resistance to Pen G. One of 50 historical isolates was b-lactamase-positive
due to carnage of SCC Mec has also been described (Higashide et al., (penicillin MIC 128 mg/ml). Seventy-eight percent of isolates showed
2008). Staphylococcus haemolyticus is usually Pen G resistant; many reduced susceptibility to ceftriaxone (MIC Z16 mg/ml). All 15 recent
strains are also methicillin resistant and some are now also vancomycin isolates from the USA were penicillin, doxycycline, and ciprofloxacin
and teicoplanin resistant (Isaac et al., 1993). susceptible although Coker et al. (2002) found 3 of 25 diverse isolates
to be penicillin resistant. All were b-lactamase negative. All 28 strains
Staphylococcus lugdunensis from cutaneous lesions from an endemic area were susceptible to
This is an uncommon pathogen which has caused endocarditis, penicillin (MIC r0.03 mg/ml) (Mustafa et al., 2002).
septicemia, deep tissue infections, and osteomyelitis. Of 59 strains Other Bacillus spp. can also cause serious infections in humans, such as
tested by Herchline et al. (1990), 76% were beta-lactamase negative endocarditis, meningitis, and surgical wound infections. Weber et al.
and Pen G sensitive, but 24% produced beta-lactamase and were Pen (1988) studied 89 strains, all isolated from blood cultures of patients.
G resistant. All strains were susceptible to oxacillin and to Bacillus cereus (54 strains) was the most common species and was Pen G
vancomycin. resistant, but it was susceptible to imipenem, vancomycin, chloramphe-
nicol, gentamicin, and ciprofloxacin. The rarer species, such as
Anaerobic Gram-positive cocci B. megaterium, B. polymyxa, B. pumilus, and B. subtililis, were generally
Pen G sensitive, but there was variability among the species. Erysipelothrix
These organisms, which include Peptococcus and Peptostreptococcus spp. rhusiopathiae seems to remain fully susceptible to pencillin (Gransden and
and anaerobic streptococci, were nearly always highly susceptible to Eykyn, 1988; Venditti et al., 1990; Yamamoto et al., 2000).
Pen G (Tally et al., 1975; Sutter and Finegold, 1976) but more recently Listeria monocytogenes is usually Pen G sensitive (Prichard et al.,
resistance rates of 10–24% have been reported (Greenwood and 1983; Larsson et al., 1985). This organism has five PBPs and PBP3 is
Palfreyman, 1987; Panichi et al., 1990). Others have also reported an essential protein in the sense that it is able to support normal
significant penicillin resistance in Finegoldia magna (16%), Micromonas growth of L. monocytogenes by itself and therefore becomes the lethal
micros (8%), and Peptostreptococcus anaerobius (Reig and Baquero, target for beta-lactams. Cephalosporins, unlike Pen G, interact poorly
1994; Wren, 1996). No beta-lactamase has been described in with PBP3, so L. monocytogenes is resistant to cephalosporins. The
anaerobic Gram-positive cocci, suggesting altered PBPs as the main organism is sensitive to imipenem and meropenem. In a laboratory an
mechanisms of resistance. A ten-country European survey of 299 imipenem-resistant mutant of L. monocytogenes was produced and this
isolates mainly described F. magna and Parvimonas micra (formerly mutant had altered PBP3, which also had reduced affinity for Pen G
Peptostreptococcus micros) (Brazier et al., 2008). All were susceptible to (Vicente et al., 1990).
metronidazole and vancomycin, but 7% (n = 21) were resistant to Listeria monocytogenes may show tolerance to Pen G and sometimes
penicillin (n = 13) and/or clindamicin (n = 12). From a recent this may be to a very high degree (Stamm et al., 1982), but if
 Benzylpenicillin (Penicillin G) 13

subcultures are performed after 48 hours’ rather than 24 hours’ with antibiotic-associated diarrhea or colitis are nearly always sensitive
incubation, Pen G is bactericidal to most strains of L. monocytogenes. to Pen G (Dzink and Bartlett, 1980; Levett, 1988; Jamal et al., 2002).
In this respect, L. monocytogenes is similar to S. aureus. The detection Pen G is active against nearly all strains of anaerobic Gram-positive
of tolerance depends on the laboratory test used and may be of asporogenous bacilli, such as Actinomyces, Eubacterium, Arachnia,
marginal clinical significance (Winslow et al., 1983). Pen G and Propionibacterium, Bifidobacterium, and Lactobacillus spp. (Sutter and
gentamicin act synergistically against L. monocytogenes both in vitro and Finegold, 1976; Holmberg et al., 1977; Denys et al., 1983; Brook and
in experimental animal infections (Edmiston and Gordon, 1979; Frazier, 1991; Fife et al., 1991; Brook and Frazier, 1993). Lactobacilli
Scheld et al., 1979). However, the clinical importance of this has been are being recognized increasingly as important pathogens causing
debated. infections such as bacterial endocarditis and neonatal meningitis
Nocardia spp. are Pen G resistant (Gutmann et al., 1983). (Broughton et al., 1983; Griffiths et al., 1992). Their MICs for Pen G
Rhodococcus equi is a Gram-positive aerobic cocco-bacillus. It was are quite low (0.3–1.0 mg/ml), but MBCs for about 75% of strains are
previously known only as an animal pathogen, but is now well high (Bayer et al., 1978), indicating tolerance. Pen G (or ampicillin)
described as a cause of infections, especially among the immunocom- combinations with either streptomycin or gentamicin are synergistic
promised, including patients with AIDS, in whom it usually causes a in vitro against tolerant Lactobacillus spp. strains (Bayer et al., 1980;
necrotizing pneumonia. Rhodococcus equi is Pen G resistant, but it is Griffiths et al., 1992).
generally susceptible to vancomycin, erythromycin, aminoglycosides,
and chloramphenicol (Emmons et al., 1991). The rare human
pathogen Rothia dentocariosa is usually Pen G sensitive (Pape et al., Gram-negative cocci
1979; Schafer et al., 1979; Anderson et al., 1993; Sudduth et al., 1993).
Anaerobic Gram-positive spore-forming bacilli, such as Clostridium Neisseria spp.
tetani, C. perfringens (welchii), C. septicum, C. botulinum, C. innocuum, Neisseria meningitidis was fully susceptible to Pen G for many years but,
and C. ramosum, are nearly always Pen G sensitive (Swenson et al., increasingly, reports of low-level resistant strains are now appearing
1980; Gabay et al., 1981; Dylewski et al., 1989; Finegold, 1989; Nord (see Table 1.5 and below under 2b. Emerging resistance and cross-
and Hedberg, 1990). Resistant strains of C. perfringens and other resistance). Neisseria meningitidis is occasionally isolated from the
Clostridium spp. have been detected (Silpa et al., 1982; Finegold, genitourinary tract and/or anal canal of patients tested for gonorrhoea
1989); relatively resistant strains of C. perfringens have also been (William et al., 1979), so it is possible that plasmids can be transferred
reported. Brown and Waatti (1980) tested 44 C. perfringens strains. from gonococci to meningococci in vivo. A strain of N. meningitidis
Only 68% were inhibited by o0.25 mg/ml Pen G, the remainder was isolated in Canada which harbored the 4.5 megadalton
requiring either 0.5, 1.0, or even 4.0 mg/ml for inhibition. The MICs of beta-lactamase-producing plasmid and the transfer factor, which are
45 C. perfringens strains tested by Marrie et al. (1981) were in the range present in beta-lactamase-producing gonococci (Dillon et al., 1983).
0.15–9.0 mg/ml; half were inhibited by 0.15 mg/ml and 90% by It was then demonstrated by Roberts and Knapp (1988) in vitro that
5.0 mg/ml. Therefore, routine sensitivity testing of clinical isolates of beta-lactamase-producing N. gonorrhoeae could easily transfer resis-
C. perfringens is advisable. Clostridium perfringens contains six PBPs. tance plasmids to N. meningitidis. Subsequently, Botha (1988) from
Resistance to Pen G in C. perfringens is mediated by a decreased South Africa described three patients with clinical meningococcal
affinity of the largest PBP, PBP1, for the antibiotic (Nord and Hedberg, meningitis. Two had organisms with MICs to Pen G W256 mg/ml and
1990). Clostridium butyricum may be Pen G resistant owing to beta- these produced beta-lactamase. The third organism had an MIC of
lactamase production (Finegold, 1989). Clostridium tertium is only 0.25 mg/ml and this had intrinsic relative resistance. A further report of
moderately Pen G susceptible, the MICs ranging from 0.25 to 8 mg/ml beta-lactamase-producing N. meningitidis came from Spain (Fontanals
(Speirs et al., 1988). Clostridium sordellii is nearly always Pen G et al., 1989), but other reports mainly describe isolates relatively
sensitive (Spera et al., 1992). Clostridium difficile isolates from patients resistant to Pen G due to intrinsic resistance.

Table 1.5 Summary of reports of penicillin resistance among strains of N. meningitidis.

Reference Country No. of % resistant Period of Comment
isolates (low level)a study

Guibourdenche et al., France 82 4 1994 52 invasive (blood/CSF)

1997 11 1995 30 miscellaneous
18 1996
Latorre et al., 2000 Barcelona, 498 9.1 in 1986 1986–1997 Invasive sero-group B – 22.1%
Spain 71.4 in 1997 of resistant strains; sero-group C – 52% of
resistant strains
Arreaza et al., 2000 Spain 901 55.3 invasive 1994–1997 Resistance most common in sero-group C
39.0 carriers 1996–1997
Richter et al., 2001 North America 53 30.2 1998–1999 Invasive
Kyaw et al., 2002 Scotland 557 8.3 1994–1999 Invasive isolates: 52.2% sero-group B; 39.2%
sero-group C; 7.8% sero-group W135
Punar et al., 2002 Turkey 30 43 1997 Invasive: 17% resistant
Nasopharyngeal carriage: 61% resistant
Antignac et al., 2003 France 2167 31.2 1999–2002 Invasive isolates: 20.1% intermediate to amoxicillin.
Most resistance in sero-groups C or W135
Gazi et al., 2004 Turkey 71 22.5 Uncertain
Ferreira et al., 2006 Portugal 118 24.6 2001–2002 Isolates all invasive. Predominant resistant strains
were sero-groups C:26:P1.5, ST-8 C/C A4
Australian Australia 214 ‘‘two-thirds’’ 2005 Invasive
Meningococcal
Surveillance
Programme (2005)

a
No high-level resistance (Z2 mg/ml or beta-lactamase positive).
Exploring the Variety of Random
Documents with Different Content
 Lahja: Nyt sinä liiottelet.

Pekka: En liiottele. Minulla on kaikki, sellaistakin, jota en muinoin

luullut koskaan voivani omistaa. — Kun olen saattanut teidät kotia,
arvaappas mitä senjälkeen ensiksi teen?

Lahja: Rupeat pohtimaan sitä iänikuista höyrykattilaasi,

Pekka: Kas veitikkaa! — Ei, ei niin. Mutta kaikkein ensiksi, vaikka

nyt onkin kelirikon aika, pistäyn Jyrkänkoskella — viemässä kukkia
äitini haudalle. Ja sitte minä otan sinut, ymmärrätkös? Ja sitte
tulkoot vasta työt.
XIX

Pekka makaa hangella, valkoisella hangella, jolle aurinko paistaa.

Hänellä on valkea hiihtopusero päällään, mutta se on veressä. Hänen
suksensa ovat eri tahoilla, toinen pitkänään toinen pystyssä. Toinen
sompasauva riippuu aidalla, toista ei näy. Aidan takana kohoaa
sylenkorkuinen kallioseinä. Sieltä onnellinen Pekka on laskenut
mäkeä, ja pudonnut aidanseipääseen, joka on puhkaissut hänen
vatsansa.

Heloittavalla keväthangella hän makaa. — Lumi voi olla haurasta

kiteinä, mutta haukena se on väkevää ja juhlallista, etenkin silloin
kun se auringossa säihkyy, valontäyteisen taivaankuvun sitä
vartioidessa. Hanki patjana ja taivaankansi peittona on Pekalla. Pari
mäntyä värähtelee sivumpana heikossa tuulen hengessä. Aidan
vierellä yksinäinen riippakoivu heiluttelee alastomia ritvojaan,
odottaen kesää. Hangen alla kaikki niityn ruohot nukkuvat, odottaen
nekin kesää.

Hangella nukkuja ei liiku, eikä nuku sellaista unta, josta herätään.

Ei hän kysy enään koskaan: miksi? Eikä hän enään odotakkaan
mitään. Mutta hänen vierellään seisoo valkea olento, joka näyttää
odottavan.
 Pekka: Kuka sinä olet, joka vielä tulet minun luokseni? Minä
pelkäsin että tähän voisi tulla surullisia ihmisiä ja minut voitaisi viedä
kuulemaan voivotuksia. Mutta sinun vaatteesi ovat valkeat, ja sinun
kasvosi näyttävät iloisilta. Kuka olet sinä?

Valkea: Etkö tunne minua?

Pekka: En tunne. Mutta sinä olet niinkuin se pouta, joka kerran

nauroi minulle kun minä luulin olevani minä. Ja samalla sinä olet
kuitenkin niinkuin Lahja, ja sinun hymysi on niinkuin minun lapseni,
joka jäi aamulla nukkumaan. Sinussa on kaikkea sitä, mitä minä olen
rakastanut. Signeäkin sinussa on, ja Elinaa. Vaaditko sinä minua
tilille?

Valkea: Näytänkö minä tuomarilta?

Pekka: Et näytä. Mutta minusta tuntuu että koko minun elämäni

on sinussa.

Valkea: Minä olen sinun elämäsi.

Pekka: Noin valkea! Mihin ovat tahrat jääneet?

Valkea: Ne olet sinä itse pessyt pois.

Pekka: Sehän on mahdotonta. Miten minä siihen olisin kyennyt?

Valkea: Näytpä kuitenkin kyenneen. — Nyt me lähdemme. Tule!

Pekka: Mihin minut viet?

Valkea: Elämään.

Pekka: Tuonnekko, josta vastikään pääsin pois?

 Valkea: Sinne juuri, vaikka se, mitä sinä tarkotat, oli vain pieni
hiihtoretki. Minä vien sinut sinne, missä sinä et omista mitään, mutta
jossa kaikkeus omistaa sinut. Vien sinut vapauteen. — Katso, minä
puhallan sinut tomuksi.
 *** END OF THE PROJECT GUTENBERG EBOOK SULJETTUJEN
OVIEN TAKANA ***

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