Epidemiology and management of invasive fungal infections in immunocompromised hosts ...

200 Pages·2010·4.49 MB·English

Epidemiology and management
of invasive fungal infections
in immunocompromised hosts
Alexander C.A.P. Leenders
CIP-GEGEVENS KONINKLlJKE BIBLIOTHEEK, DEN HAAG
Leenders, Alexander Canisius Antonius Paulus
Epidemiology and management of invasive fungal infections in immunocompro
mised hosts I Alexander Canisius Antonius Paulus Leenders.
Thesis Erasmus University Medical Center Rotterdam. - With ref.- With summary
in Dutch.
ISBN 90-9012312-1
NUGI743
Subject headings: Invasive fungal infections lliposomal amphotericin B /epidemi
ology.
C 1998 ACAP Leenders
Aile rechten voorbehouden. Niets uit deze uitgave mag worden verveelvoudigd,
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All rights reserved. No part of this publication may be reproduced, stored in a re
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from the author.
Epidemiology and management
of invasive fungal infections
in immunocompromised hosts
Epidemiologie en management
van invasieve mycosen
in immuungecompromitteerde gastheren
PROEFSCHRIFT
ter verkrijging van de graad van doctor
aan de Erasmus Universiteit Rotterdam
op gezag van de Rector Magnificus
Prof.dr. P.W.C. Akkermans M.A.
en volgens besluit van het College voor Promo ties
in het openbaar te verdedigen op
woensdag 3 februari 1999 om 15.45 uur
door
ALEXANDER CANISIUS ANTONIUS PAULUS LEENDERS
GEBOREN TE EINDHOVEN
Promotiecommissie
Promotor: Prof.dr. H.A. Verbrugh
Overige Leden: Prof.dr. J.A.A. Hoogkamp-Korstanje
Prof.dr. B. Lowenberg
Prof.dr. A.D.M.E. Osterhaus
Copromotor: Dr. S. de Marie
Part of the studies presented in this thesis (chapter 6, 7 and 9) have been
financially supported by NeXstar Pharmaceuticals, Inc., San Dimas, CA, USA
and the Academic Hospital Rotterdam-Dijkzigt, Rotterdam, The Netherlands.
Printing: Veenman, Rotterdam.
The printing of this thesis was financially supported by NeXstar Pharmaceuticals,
Inc., San Dimas, CA, USA.
The grants from Janssen-Cilag B.V., Pfizer B.V., Abbott B.v., Bayer B.v.,
Hoechst Marion Roussel B.V., Eli Lilly Nederland B.V., Roche Nederland B.V.,
Merck Sharp & Dome B.V., Oxoid B.V. and Zeneca Farma are gratefully acknow
ledged.
Aan mijn ouders
Voor Marjan en Meilinde

CONTENTS
Chapter 1 General introduction and outline of the thesis. 9
Part 1: epidemiology
Chapter 2 Molecular epidemiology of apparent outbreak of invasive 27
aspergillosis in a hematology ward.
Chapter 3 Density and molecular epidemiology of Aspergillus in air 47
and it's relation to outbreaks of Aspergillus infection.
Chapter 4 Molecular typing of Cryptococcus neoformans: taxonomic 65
and epidemiological aspects.
Part 2: management
Chapter 5 The use of lipid formulations of amphotericin B for systemic 89
fungal infections.
Chapter 6 AmBisome reduces dissemination of infection as compared 107
to amphotericin B deoxycholate in a rat-model of pulmonary
aspergillosis.
Chapter 7 AmBisome compared with amphotericin B in the treatment of 121
neutropenia-associated invasive fungal infections.
Chapter 8 Cryptococcal meningitis in HIV-infected patients: CSF-opening 141
pressure as prognostic factor.
Chapter 9 AmBisome compared with amphotericin B both followed by 149
oral fluconazole in the treatment of AIDS-associated cryptococ-
cal meningitis.
Discussion
Chapter 10 General discussion 169
Summary en samenvatting 183
Nawoord 195
Curriculum vitae 197

Chapter 1
General introduction and outline of the thesis.
Alexander CAP Leenders
9
Chapter 1
BACKGROUND
Fungal infections in man usually are divided into three categories based upon
their major pathophysiological characteristics: superficial and cutaneous, subcuta
neous and, systemic infections. The last category consists of two separate enti
ties. First there are the so called "endemic mycoses" caused by dimorphic fungi
including Coccidioides immiiis, Paracoccidioides brasiliensis, Histoplasma
capsula tum and Blastomyces dermatitidis which occur in patients who live in, or
have travelled through geographical regions in which these pathogenic fungi have
1
their habitat. Although the consequences of endemic mycoses are sometimes
very severe, these infections were not viewed as a very major subject in the field
of infectious diseases, probably due to their relatively rare and geographically
restricted occurrence. The second entity consists of opportunistic infections
caused by fungi that are ubiquitously present around the globe. The number of
these infections has increased dramatically during the last three decades. For
example, in 1966 invasive aspergillosis was called a disease of medical progress,
and world literature on this subject was reviewed in a paper only six pages in
length.2 In contrast in 1990, Denning et al. used 55 pages only to review the
literature on the treatment of such infections.3 Several factors have been recogni
zed to be responsible for this rapid increase, all of which are the consequence of
advances in medicine. The use of antibacterial agents, the use of cytotoxic
chemotherapy, organ transplantation combined with the use of immunosup
pressive therapy, the use of indwelling catheters all one way or the other,
compromise the defence mechanisms of the human host (Table 1 ).4-7 Some of
these factors disrupt more than one line of defence; for example, longterm use of
steroids, influences cellular immunity, macrophage function and neutrophil
function, whereas the integrity of the skin and mucous membranes is little
affected.8
The number of patients which are immunocompromised due to one or a
combination of these factors, has been increasing steadily. In addition, the
pandemic caused by the human immunodeficiency virus (HIV) has dramatically
further increased the number of patients susceptible to opportunistic fungal
infections, especially infections caused by Candida, Cryptococcus and Pneumo
cystis car/nil (although this last species has only recently been recognized to be a
fungus).9-11 All these developments taken together have pushed opportunistic
fungal infections into the category of emerging infectious diseases that urgently
require more attention.
10