Antifungal Agents: Advances and Problems

252 Pages·2003·5.26 MB·English

by  Johannes Müller

Antifungal
Agents
Advances and Problems
Special Topic
Progress in
Drug Research
Edited by Ernst Jucker, Basel
Advisor
Annemarie Polak
Authors
Johannes MOller and Annemarie Polak
Reinhard Kappe and Dagmar Rimek
Annemarie Polak
Michael Seibold and Kathrin Tintelnot
Springer Basel AC
Editor
Dr. E. Jucker
Steinweg 28
C H-41 07 Ettingen
Switzerland
e-mail: [email protected]
A CIP catalogue record for this book is available from the Library of Congress, Washington D.C., USA
Bibliographic information published by Die Deutsche Bibliothek.
Die Deutsche Bibliothek lists this publication in the Deutsche Nationalbibliografie; detailed biblio
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ISBN 978-3-7643-6926-2 ISBN 978-3-0348-7974-3 (eBook)
DOI 10.1007/978-3-0348-7974-3
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© 2003 Springer Basel AC
Originally published by Birkhăuser Verlag in 2003
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Cover design and layout: Graflin Graphic Design, Basel
ISBN 978-3-7643-6926-2
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Contents
Classification and taxonomy of fungi pathogenic for
warm-blooded hosts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
By Johannes Muller and Annemarie Polak
Fungal diseases ................................................................ 1 3
By Reinhard Kappe and Dagmar Rimek
Diagnosis of fungal diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
By Reinhard Kappe and Dagmar Rimek
Antifungal therapy - state of the art at the beginning of
the 21 st century. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
By Annemarie Polak
Susceptibility testing of fungi - current status and
open questions................................................................ 191
By Michael Seibold and Kathrin Tintelnot
Index ........................................................................... 243
Foreword by the Editor
In the early 1990s Annemarie Polak and P.G. Hartmann expressed some hope
that the battle for an effective therapy in dermatology as well as in deep
mycoses could be won (PDR 37, 181 (1991». Five years later (PDR 49, 219
(1996», in an update of the above review and in summarising the then pre
vailing situation, A. Polak came to the conclusion that the search for new
antifungals was an everlasting battle: despite the fact that important new
antifungals were discovered and introduced into therapy, the breakthrough
was still far away. This battle is still going on, and this volume Antifungal
Agents - Advances and Problems aims at providing the reader with a concise
overview of the situation, but might also give an impulse to further research
in this important field of human disorders.
Antifungal Agents - Advances and Problems contains five chapters, each rep
resenting an up-to-date review covering the major problems of medical
mycology. Physicians confronted with the various forms and problems of
fungal diseases will welcome this monograph as a useful tool in their daily
work and as a source of relevant original literature. Advanced students will
benefit from the concise form of the presentation covering all major aspects
of antifungals and their therapeutic application.
The main emphasis of the book is on antifungal therapy (chapter 4), cov
ering the present state of art of chemotherapy for dermatomycoses, subcu
taneous and invasive mycoses and also thoroughly dealing with open ques
tions and unsolved problems.
In addition to this status quo review, an outlook into the future, to new
biochemical and/or genetic targets, as well as to the new approaches inter
fering with the host defence or the virulence of fungi, which will become
more important in the future, is provided. The author of this chapter,
Annemarie Polak, not only shared her extended knowledge and experience
but she also acted as Advisor for the entire monograph. The Editor is espe
cially indebted to her.
The first chapter deals with various growth forms of the pathogenic fungi
and classifies these fungi based on characteristics of their sexual life cycle and
on their RNA/DNA pattern.
The second chapter describes the clinical manifestations of the complete
set of human fungal infections known today. In addition to the clinical symp-
vii
toms, on which the main emphasis lies, data on prevalence, overall impor
tance and epidemiology are provided.
The third chapter deals with the various laboratory methods in the field
of diagnosis of fungal infections which are necessary and suitable for a timely
and accurate diagnosis. The identification techniques are described accord
ing to the fungal group involved, i.e. techniques for yeast and filamentous
fungi are separate.
The last chapter deals with the field of susceptibility testing. On one hand
the most relevant standard methods and their intrinsic problems related to
media, fungi or drugs are presented; on the other hand, the usefulness of sus
ceptibility data in connection with epidemiology and guidance of therapy is
discussed. A special part of this last chapter is dedicated to the question
whether a correlation exists between in vitro and in vivo data.
The Editor is grateful to the authors for their comprehensively written arti
cles which in a very concise form cover all aspects of the current situation in
the field of fungal diseases and therapeutic possibilities. My sincere thanks
also go the members of Birkhauser Publishing who participated in the pro
duction of this monograph. Thus, I am indebted to Beatrice Menz and
Gabriele Fertoszogi for their great help as members of the Editorial Depart
ment. H.-P. Ebneter, Eduard Mazenauer and Gregor Messmer did contribute
- as in the past decades - their vast knowledge, experience and innovative
skill in the production of this book: for all their efforts and, especially, for the
harmonious cooperation, I cannot thank all of them enough.
My very special thanks go to Hans-Peter Thur, Birkhauser Publishing CEO.
For a number of decades, Hans-Peter Thur participated directly in the efforts
linked with the PDR series, and it was he who initiated this new series of
monographs dealing with specific topics of drug research. My gratitude to
Hans-Peter is linked with sadness that due to my advanced age and my wish
for fewer responsibilities, this harmonious cooperation and our team-work
come to an end with this PDR Special Topic volume.
Basel, February 2003 Dr. E. Jucker
Antifungal Agents -Advances and Problems (E. lucker, Ed.)
©2003 Birkhauser Verlag, Basel (Switzerland)
Classification and
taxonomy of fungi
pathogenic
for warm-blooded
hosts
By Johannes MUlierl and
Annemarie Polak2
IBrandelweg 24, D-79312
Emmendingen-Maleck, Germany
2Spitzenrainweg 45, CH-4147 Aesch,
Switzerland
Johannes MOiler
received the Doctor rerum naturalium from the University of
Munich in 1956. In 1960, he joined the Institute ofH ygiene
and Microbiology at Freiburg i. Br. At this time there was a
department for extensive medical and microbiological diagnos
tics in bacteriology, virology, parasitology, and serology.
Johannes Muller created a diagnostic and research unit for med
ical mycology. His main interest was electron microscopy. In
1973, Johannes Muller was awarded the title "Medizinischer
Fachmikrobiologe DHGM"; in 1978, he received the "Habilita
tion" for medical microbiology and hygiene at the medical fac
ulty of the University Freiburg and became professor in 1984.
From 1975 to 1986 he was head of the division ofp arasitology
and mycology at the institute of hygiene, and from 1986-1992
he was head of the mycology unit. Johannes Muller was mainly
interested in host-parasite relationships in mycology, ultra
structure, pathogenesis, and immunology and development of
new diagnostic methods. He was active member of various
international research societies and later became an honorary
member of several of these societies.
Annemarie Polak
received her Ph.D. in microbiology from the Eidgenossische
Technische Hochschule (ETH), Zurich, Switzerland, in 1969. In
the same year, she joined Hoffmann LaRoche as a microbiolo
gist in the tropical medicine group. Her research interest
included mode of action studies and detecting new antifungals.
She became a specialist in the field of research on antifungals
and was later promoted to Scientific Expert, a cadre position at
Roche. In 1989, A. Polak did her "Habilitation" at the Institute
of Microbiology and Hygiene in the Medical Faculty of the Uni
versity Freiburg i. Br. (Germany) and received a professorship
for medical mycology in 1995.
Summary
The kingdom of fungi is described with emphasis on fungi pathogenic for
warm-blooded hosts. The various growth forms of the most frequent
causative agents of fungal infections are described and their classification
based on characteristics of their sexual life cycle and on their DNA/RNA pat
tern is summarized in various tables.
Classification and taxonomy of fungi pathogenic for warm-blooded hosts
Contents
1 Introduction ............ 3
2 Morphology 3
3 Classification 6
4 Nomenclature ....... 7
5 Taxonomy .... 8
5.1 Zygomycota ......... , .......... 9
5.2 Ascomycota ...... 10
5.3 Basidiomycota 12
References 12
Keywords
Taxonomy, pathogenic fungi, Zygomycota, Ascomycota, Basidiomycota.
1 Introduction
Fungi are regarded as a separate kingdom of eukariotic organisms apart from
plants and animals. They are heterotrophic, Le., lacking chlorophyll, and
are dependent on organiC carbon compounds for their nutrition. They feed
by excretion of enzymes into the colonized substrate and subsequent
uptake of digested compounds through the cell wall and cytoplasmic mem
brane.
2 Morphology
Like human cells, fungi are eukariotic cells, in contrast to bacteria. The
genome is organized in a nucleus surrounded by a membrane, which is con
tinuous with the endoplasmatic reticulum. Cellular division is accompanied
by meiosis or mitosis. Cell organelles such as mitochondria, ribosomes, vac
uoles, lipid bodies, and other storage inclusions are also present. The only
fungus-specific target for antifungal chemotherapy is the cell wall, which
3
Johannes Muller and Annemarie Polak
Table 1.
Causative agents of zygomycosis; Division: Zygomycota
Order Family Genus Species
Mucorales Mucoraceae Absidia A. corymbifera
Apophysomyces A. elegans
Mucor M. circinelloides
M. racemosus
Rhizomucor R. miehei
R. pusi/lus
R. variabilis
Rhizopus R. microsporus
R.oryzae
Cunninghamellaceae Cunninghamella C. bertholletiae
Syncephalastraceae Syncephalastrum S. racemosum
Saksenaeaceae 5aksenaea S. vasiformis
Mortierellales Mortierellaceae Mortierella M. wolfii
Entomophthorales Basidiobolaceae Basidiobolus B. ranarum
Ancylistaceae Conidiobolus C. coronatus
C. incongruus
consists mainly (90%) of the carbohydrates glucan, mannan, and chitin, the
latter two being absent in mammalian cells.
Pathogenic fungi grow in two different morphologic shapes. The main
elements are apically growing hyphae. These filamentous fungi invade the
substrate by single hyphae. The entire thallus is called mycelium. Unicellu
lar fungi grow in the yeast form characterized by propagating in forming
buds.
Suppression of hyphal growth due to environmental factors, e.g., nutri
tional conditions, temperature, host defense etc., often leads to deformation
of the fungal thallus. This phenomenon is called dimorphism and must be
regarded in diagnostic procedures. Dimorphism is conspicuous for Histo
plasma capsula tum, Blastomyces dermatitidis, Paracoccidioides brasiliensis, and
Penicillium marneffei, the hyphal form being saprophytic and the parasitic
one being yeast-like in shape. Candida albicans also shows dimorphism;
however, both phases of this species are responsible for pathogenicity.
The majority of fungi pass sexual life cycles (teleomorph) with formation
of sexual propagules. The sexual life cycle is the basis of ranging the fungi in
a natural classification system with regard to biological relationship. The
teleomorph life cycle of fungi pathogenic for warm-blooded hosts, however,
4