Table Of ContentMilestones in Drug Therapy
MDT
Series Editors
Prof. Dr. Michael J. Parnham Prof. Dr. J. Bruinvels
PLIVA INFARM
Research Institute Sweelincklaan 75
Prilaz baruna Filipovica 25 NL-3723 JC Bilthoven
10000 Zagreb The Netherlands
Croatia
Macrolide Antibiotics
Edited by W. Schănfeld and H. A. Kirst
Springer Basel AG
Editors
Wolfgang SehOnfeld Herbert A. Kirst
PLIV A Researeh Elaneo Animal Health Researeh & Development
Antiinfeetive Research 2001 West Main Street
Prilaz baruna Filipovica 25 P.O. Box 708
l ()()()() Zagreb Greenfield, Indiana 46140
Croatia USA
Advisory Board
J. C. Buekingham (Imperial College School of Medicine, London, UK)
D. de Wied (Rudolf Magnus Institute for Neurosciences, Utrecht, The Netherlands)
F. K. Goodwin (Center on Neuroscience, WashingtonUSA)
G. Lambrecht (J. W. Goethe Universităt, Frankfurt, Germany)
Library of Congress Cataloging-in-Publication Data
Macrolide antibiotics / edited by W. Schonfeld and H.A. Kirst.
p. em. - (Milestones in drug therapy)
Includes bibliographical references and index.
ISBN 978-3-0348-9438-8 ISBN 978-3-0348-8105-0 (eBook)
DOI 10.1007/978-3-0348-8105-0
1. Macrolides antibiotics. 1. Schonfeld, W. (Wolfgang), 1956-II. Kirst, Herbert A. III.
Series.
Deutsche Bibliothek CataIoging-in-Publication Data
Macrolides antibiotics / ed. by W. Schonfeld and H.A. Kirst. - Basel ;
Boston ; Berlin : Birkhăuser, 2002
(Milestones in drug therapy)
ISBN 978-3-0348-9438-8
ISBN 978-3-0348-9438-8
The publisher and editor can give no guarantee for the information on drug dosage and administration
contained in this publication. The respective user must check its accuracy by consulting other sources
of reference in each individual case.
The use of registered names, trademarks etc. in this publication, even if not identified as such, does not
imply that they are exempt from the relevant protective laws and regulations or free for general use.
This work is subject to copyright. Ali rights are reserved, whether the whole or part of the material is
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permission of the copyright owner must be obtained.
© 2002 Springer Basel AG
Originally published by Birkhiiuser Verlag in 2002
Softeover reprint of the hardcover 1 st edition 2002
Cover IlIustration: Erythromycin - the macrolide core and its most important derivatives
Printed on acid-free paper produced from chlorine-free pulp. TeF ""
ISBN 3-7643-6186-7
987654321 www.birkhiiuser-science.com
v
Contents
List of Contributors ................................................................................ VII
Preface .................................................................................................. IX
Herbert A. Kirst
Introduction to the macrolide antibiotics................................................... 1
Vito R. Iacoviello and Stephen H. Zinner
Macrolides: a clinical overview ............................................................... 15
Holly M. Mattoes and Charles H. Nightingale
Pharmacokinetics/pharmacodynamics of macrolides .................................. 25
Marie-Therese Labro
Cellular accumulation of macrolide antibiotics. Intracellular bioactivity....... 37
Takashi Adachi and Shigeo Morimoto
Clarithromycin and new derivatives of erythromycin................................. 53
Wolfgang SchOnfeld and Stjepan Mutak
Azithromycin and novel azalides ............................................................. 73
Andre Bryskier and Alexis Denis
Ketolides: novel antibacterial agents designed to overcome
resistance to erythromycin A within gram-positive cocci... ......... ........... ..... 97
Ly T. Phan and Zhenkun Ma
Novel macrolide derivatives active against resistant pathogens ................... 141
Leonard Katz
Polyketide diversity ................................................................................ 157
Eric Cundliffe
Biosynthesis of the macrolide antibiotic, tylosin ........................................ 177
Adel Ben Ali, Fred W. Goldstein and Jacques F. Acar
In vitro activity of macrolides against traditional susceptible bacteria .......... 185
VI
Lowell S. Young and Luiz E. Bermudez
Activity of macrolides against mycobacteria ............................................. 201
Margaret R. Hammerschlag
Chlamydia pneumoniae and asthma and atherosclerosis: role of macrolides .. 215
Geoffrey L Ridgway
Activity of macrolides in sexually transmitted diseases .............................. 229
Francis Megraud
Helicobacter pylori and macrolides .......................................................... 243
Norris E. Allen
Effects of macrolide antibiotics on ribosome function ................................ 261
Joyce A. Sutcliffe and Roland Leclercq
Mechanisms of resistance to macrolides, lincosamides, and ketolides .......... 281
Subject index ......................................................................................... 319
VII
List of contributors
Jacques F. Acar, Hopital Saint Joseph, Laboratoire de Microbiologie Medicale,
185 rue Raymond Losserand, 75674 Paris Cedex 14, France
Takashi Adachi, Medicinal Research Laboratories, Taisho Pharmaceutical Co.,
Ltd., 403 Yoshino-cho l-chome, Saitama-shi, Saitama 330-8530, Japan;
e-mail: [email protected]
Adel Ben Ali, Hopital Saint Joseph, Laboratoire de Microbiologie Medicale, 185
rue Raymond Losserand, 75674 Paris Cedex 14, France; e-mail:
[email protected]
Norris E. Allen, Animal Science Discovery and Development Research, Elanco
Animal Health, 2001 West Main Street, Greenfield, IN 46140, USA;
e-mail: [email protected]
Luiz E. Bermudez, Kuzell Institute for Arthritis and Infectious Diseases, Cali
fornia Pacific Medical Center Research Institute, 2200 Webster Street, Suite
305, San Francisco, CA 94115, USA; e-mail: [email protected]
Andre Bryskier, Aventis Pharma Research Center, 102, route de Noisy, 93230
Romainville, France; e-mail: [email protected]
Eric Cundliffe, Department of Biochemistry, University of Leicester, Adrian
Bldg., University Road, Leicester LEI 7RH, United Kingdom;
e-mail: [email protected]
Alexis Denis, Aventis Pharma Research Center, 102, route de Noisy, 93230
Romainville, France; e-mail: [email protected]
Fred W. Goldstein, Hopital Saint Joseph, Laboratoire de Microbiologie Medicale,
185 rue Raymond Losserand, 75674 Paris Cedex 14, France
Margaret R. Hammerschlag, Division of Infectious Diseases, Department of
Pediatrics, SUNY Health Science Center at Brooklyn, 450 Clarkson Ave.,
Brooklyn, NY 11203-2098, U.S.A.; [email protected]
Vito R. Iacoviello, Harvard Medical School, Mount Auburn Hospital, 330 Mount
Auburn Street, Cambridge, MA 02238, USA
Leonard Katz, Kosan Biosciences Inc., 3832 Bay Center Place, Hayward, CA
94611, USA; e-mail: [email protected]
Herbert A. Kirst, Elanco Animal Health Research & Development, 2001 West
Main Street, Greenfield, IN 46140-0708, USA;
e-mail: [email protected]
Marie-Therese Labro, INSERM U479, CHU X. Bichat-Cl. Bernard, 46 rue Henri
Huchard, 75018 Paris, France; e-mail: [email protected]
Roland Leclerq, Department of Microbiology, CHU, Cote de Nacre, Av. Cote de
Nacre, 14033 Caen, France; e-mail: [email protected]
VIII
Zhenkun Ma, Abbott Laboratories, 200 Abbott Park Road, Abbott Park, IL
60064-3537, USA; e-mail: [email protected]
Holly M. Mattoes, Department of Pharmacy Research, Hartford Hospital, Uni
versity of Connecticut, 80 Seymour Street, Hartford, CT 06102-5037, USA
Francis Megraud, Laboratoire de Bacteriologie, Hopital Pellegrin, Place Amelie
Raba-Leon, 33076 Bordeaux cedex, France;
e-mail: [email protected]
Shigeo Morimoto, Medicinal Research Laboratories, Taisho Pharmaceutical Co.,
Ltd., 403 Yoshino-cho l-chome, Saitama-shi, Saitama 330-8530, Japan;
e-mail: [email protected]
Stjepan Mutak, Antiinfective Research, PLIVA d.d., Prilaz Barona Filipovica 25,
10000 Zagreb, Croatia; e-mail: [email protected]
Charles H. Nightingale, Department of Pharmacy Research, Office of Research
Administration, Hartford Hospital, University of Connecticut, 80 Seymour
Street, Hartford, CT 06102-5037, USA; e-mail: [email protected]
Ly T. Phan, Enanta Pharmaceuticals, Inc., 500 Arsenal Street, Watertown, MA
02472, USA; e-mail: [email protected]
Geoffrey L. Ridgway, Department of Clinical Microbiology, University College
London Hospitals, Grafton Way, London WClE 6DB, UK,
e-mail: [email protected]
Wolfgang SchOnfeld, PLIVA Research, Antiinfective Research, Prilaz Barona
Filipovica 25,10000 Zagreb, Croatia; e-mail: [email protected]
Joyce A. Sutcliffe, Rib-X Pharmaceuticals, 25 Science Park, Room 561, New
Haven, CT 06511, USA; e-mail: [email protected]
Lowell S. Young, Kuzell Institute for Arthritis and Infectious Diseases, California
Pacific Medical Center Research Institute, 2200 Webster Street, Suite 305, San
Francisco, CA 94115, USA; e-mail: [email protected]
Stephen Zinner, Harvard Medical School, Mount Auburn Hospital, 330 Mount
Auburn Street, Cambridge, MA 02238, USA
IX
Preface
There are only very few chemical classes of antibiotics in medical use, and these
have originated over a span of more than 60 years of research. Almost half a
century ago, the first member of the macrolides, erythromycin, was introduced as
a treatment option for bacterial infections. Erythromycin is a very complex
fermentation product obtained from the soil bacterium Saccharopolyspora ery
thraea (originally named Streptomyces erythreus). The success of erythromycin,
based on its efficacy and tolerability, stimulated researchers throughout the world
to undertake intense efforts to understand the biology and chemistry of macrolides
and to use this experience to improve the properties of this compound class. The
second generation of macrolides, based on chemical modifications of erythromy
cin, is currently being in broad use, especially for treatment of respiratory tract
infections. We presently foresee the introduction of a new generation of macro
lides, i.e. the ketolides, which have the potential to overcome rising resistance
problems.
This monograph is intended to give the interested reader an overview on
"macrolide experience", covering important areas from basic research to clinical
use.
Starting from a historic overview, the essential basic parameters - efficacy,
pharmacokinetics, pharmacodynamics, and pharmacology - are highlighted in
order to introduce the reader to the rationale for clinical use of macrolides.
The following group of chapters cover the complex chemistry of the macro
lactone structures, giving historic background, basic structure-activity relation
ships of various derivatization strategies, and perspectives for future discovery of
new semisynthetic macrolide antibiotics.
Our current understanding of the biosynthesis of the natural macrolide scaf
folds is summarized in the following two chapters. This area rapidly emerged
during the last few years as a result of the enormous progress in understanding the
metabolic pathways by which macrolides are assembled in microorganisms and
developing new technologies to exploit this knowledge to create novel analogs.
In the next chapters, the authors give detailed overviews of the antibacterial
properties of macrolides, which are the basis for their clinical use. General profiles
allowing the physician to evaluate the potency and usefulness of individual
compounds for treatment of defined bacterial infections are combined with
epidemiological data indicating the status of resistance among important bacteria.
Finally, the molecular mode of action of macrolides and the molecular basis of
bacterial resistance mechanisms are thoroughly described in the last two chapters.
This book is intended to give the readers - whether they are professionals in the
pharmaceutical industry, physicians treating infections, or microbiologists at
x
hospitals, health institutes, or universities - a detailed and up-to-date knowledge
base about current research activities and also a sound, stimulating overview and
perspective about the class of macrolide antibiotics.
We are very grateful to all authors who took the additional effort on top oftheir
daily multiple obligations to prepare this book. Without their enthusiasm and
outstanding expertise, this monograph would not be available.
In addition, we highly appreciate the great help from the team of our publishing
team, Karin Neidhart and Detlef Kliiber, who gave us the professional support
needed to successfully publish this book.
Herbert Kirst
Wolfgang Schonfeld Summer 2001
