lIPOSOMAl TARGETING OF ANTIMICROBIAL AGENTS TO BACTERIAL INFECTIONS

174 Pages·2011·3.8 MB·English

lIPOSOMAl TARGETING
OF ANTIMICROBIAL AGENTS
TO BACTERIAL INFECTIONS
RAYMOND MICHEL SCHIFFELERS
Liposomal targeting of antimicrobial agents to bacterial infections
by Raymond Michel Schiffelers.
Thesis Erasmus universllyMedical Center Rotterdam - With bibliography - With
references - With summary in Dutch
Ms. C.M. Luteijn is thanked for the technical realization of my cover design
ISBN 90-9014452-8
Subject headings: drug targeting! Iiposomes ! bacterial infections
© 2000 R.M. Schiffelers. No part of this publication may be reproduced, by any
means, without prior permission.
lIPOSOMAl TARGETING
OF ANTIMICROBIAL AGENTS
TO BACTERIAL INFECTIONS
HET DOELGERICHT AFLEVEREN VAN
ANTI-MICROBIELE MIDDELEN AAN BACTERIELE INFECTIES
MIDDELS LIPOSOMEN
PROEFSCHRIFT
TER VERKRDGING VAN DE GRAAD VAN DOCTOR
AAN DE ERASMUS UNIVERSITEIT ROTTERDAM
OP GEZAG VAN DE RECTOR MAGNIFICUS
PROF. DR. IR. J.H. VAN SEMMEL
EN VOLGENS BESLUIT VAN HET COLLEGE VOOR PROMOl1ES
DE OPENBARE VERDEDIGING ZAL PLAATSVINDEN OP
WOENSDAG 7 FEBRUARI 2001 OM 15.45 UUR
DOOR
RAYMOND MICHEL SCHIFFELERS
GEBOREN TE 'S-GRAVENHAGE
PROMOTIECOMMISSIE
Promotoren: Prof. dr. H.A. Verbrugh
Prof. dr. G. Storm
Overige leden: Prof. dr. A.M.M. Eggermont
Prof. dr. R. de Groot
Prof. dr. J.W.M. van der Meer
Copromotor: Dr. LAJ.M. Bakker-Woudenberg
The studies presented in this thesis were performed at the Department of Medical
Microbiology & Infectious Diseases, Erasmus university Medical Center Rotterdam,
Rotterdam, The Netherlands, and the Department of Pharmaceutics, Utrecht
Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
The research was supported by grant 902-21-161 from the Dutch Organization for
Scientific Research (N.W.O.).
The publication of this thesis was financially supported by:
Dr. Ir. Van de Laar Stichting, Heerlen; Dr. Saal van Zwanenbergstichting, Oss;
Nederlandse Organisatie voor Wetenschappelijk Onderzoek (N.w.O.), Den Haag
Ter herinnering aan mijn moeder

CONTENTS
1. General Introduction 9
2. Localization of sterically stabilized liposomes in
Klebsiella pneumoniae-infected rat lung tissue:
influence of liposome characteristics 31
3. Host factors influencing the preferential localization
of sterically stabilized liposomes in Klebsiella pneumoniae
infected rat lung tissue 47
4. Localization of sterically stabilized liposomes in experimental
rat Klebsiella pneumoniae pneumonia:
dependence on circulation kinetics and
presence of poly(ethylene) glycol-coating 67
5. Liposome-encapsulated aminoglycosides in
preclinical and clinical studies 81
6. Therapeutic efficacy of liposome-encapsulated gentamicin
in rat Klebsiella pneumoniae pneumonia in relation to
impaired host defense and low bacterial gentamicin-susceptibility 105
7. In vivo synergistc interaction of liposome-co-encapsulated
gentamicin and ceftazidime 125
8. Summary 143
9. Samenvatting voor niet-ingewijden 153
List of Publications 161
Curriculum vitae 165
Nawoord 167
Abbreviations 171
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1. General Introduction
Summary
Failure of antimicrobial treatment is observed frequently in hospitalized patients resulting in
morbidity and mortality, A possible way to improve antimicrobial treatment is the targeted
delivery of antimicrobial agents, This thesis describes a study on tihe use of long-Circulating
liposomes for the targeted delivery of antimicrobial agents to sites of bacterial infections, In
this chapter an introduction is given on the use of targeted drug delivery in infectious
diseases, which is followed by the aims and outline of this thesis,
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Chapter 1
1. Infectious diseases
Infectious diseases remain an important cause of morbidity and mortality in the Western
world, especially in hospitalized patients. The long, invasive, and intensive hospital
treatments lower the barriers to microbial invasion of host tissues and compromise the
development of an adequate inflammatory/immune response. In addition, the host response
may be weakened by administration of immunosuppressants or cytotoxic drugs or as a
result of a pathology that affects the host defense. Under these circumstances antimicrobial
treatment frequently fails. This thesis focuses on ways to increase the efficacy of
antimicrobial treatment against bacterial infections.
Bacteria are unicellular prokaryotic organisms with a circular double-stranded
deoxyribonucleic acid (DNA) molecule that bears the genetic information (Salyers, 1994).
Additional genetic information may be present in the form of plasmids, small
extrachromosomal, self-replicating, and transferable DNA molecules (Actis, 1999; Davison,
1999). Some components of the bacterial cell wall, like peptidoglycan, (Iipo)teichoic acid and
lipopolysaccharide (LPS), are toxic molecules known as endotoxins (Seydel, 2000; Wiese,
1999; Sriskandan, 1999). In addition, bacteria may also secrete soluble toxic proteins,
known as exotoxins (Guerrant, 1999; Middlebrook, 1984, Lesieurs, 1997). These toxins have
detrimental effects on the infected host, as they may destruct host cells or structures and
may affect host homeostasis. The effects of toxins on host cytokine profiles may lead to
disseminated intravascular coagulation, severe inflammatory response syndrome and
ultimately septic shock and multiple organ failure by distorting the balance between pro
inflammatory and anti-inflammatory stimuli (Bone, 1997; Deitch, 1999; van der Meer,
1999).
2. Antimicrobial treatment
Impediment of bacterial contamination and colonization, for example by sterilization,
disinfection, or isolation is a way to prevent the development of infectious diseases. Once
the bacteria have invaded the host, the aspecific and speCific host defense become activated
to control the infection. For prevention or treatment of bacterial infections antimicrobial
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