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Pseudomonas aeruginosa as an Opportunistic Pathogen
INFECTIOUS AGENTS AND PATHOGENESIS
Series Editors: Mauro Bendinelli , University of Pisa
Herman Friedman, University of South Florida
C O X S A C K I E V I R U S E S A General Update
Edited by Mauro Bendinelli and Herman Friedman
F U N G A L I N F E C T I O N S A N D I M M U N E RESPONSES Edited by Juneann W. Murphy, Herman Friedman, and Mauro Bendinelli
MYCOBACTERIUM TUBERCULOSIS Interactions with the Immune System
Edited by Mauro Bendinelli and Herman Friedman
N E U R O P A T H O G E N I C V I R U S E S A N D I M M U N I T Y Edited by Steven Specter, Mauro Bendinelli , and Herman Friedman
PSEUDOMONAS AERUGINOSA A S A N O P P O R T U N I S T I C P A T H O G E N Edited by Mario Campa, Mauro Bendinelli , and Herman Friedman
V I R U S - I N D U C E D I M M U N O S U P P R E S S I O N Edited by Steven Specter, Mauro Bendinelli , and Herman Friedman
Pseudomonas aeruginosa as an Opportunistic Pathogen Edited by
Mario Campa University of Pisa Pisa, Italy
Mauro Bendinelli University of Pisa Pisa, Italy
and
Herman Friedman University of South Florida Tampa, Florida
Springer Science+Business Media, LLC
Library of Congress Cataloglng-ln-PublIcation Data
Pseudomonas a e r u g i n o s a as an o p p o r t u n i s t i c pathogen / e d i t e d by Mari o Campa, Mauro Bend i n e 1 1 i , and Herman Friedman.
p. cm. — ( I n f e c t i o u s agents and p a t h o g e n e s i s ) I n c l u d e s b i b l i o g r a p h i c a l r e f e r e n c e s and index. ISBN 978-1-4613-6324-8 ISBN 978-1-4615-3036-7 (eBook) DOI 10.1007/978-1-4615-3036-7 1. Pseudomonas a e r u g i n o s a i n f e c t i o n s . 2. O p p o r t u n i s t i c
i n f e c t i o n s . I . Campa, M a r i o . I I . B e n d i n e 1 1 i , Mauro. I I I . Friedman, Herman. I V . - S e r i e s .
[DNLM: 1. Pseudomonas A e r u g i n o s a . 2. Pseudomonas I n f e c t i o n s . QW 131 P9735] QR201.P74P7 1992 616' . 0 1 4 5 — d c 2 0 DNLM/DLC f o r L i b r a r y of Congress 92-48759
CIP
ISBN 9 7 8 - 1 - 4 6 1 3 - 6 3 2 4 - 8
©1993 Springer Science+Business Media New York
Originally published by Plenum Press in 1993
A l l rights reserved
No part o f this book may be reproduced, stored in a retrieval system, or transmitted
in any form or by any means, electronic, mechanical, photocopying, microfi lming,
recording, or otherwise, without written permission from the Publisher
Contributors
DALE R. ABRAHAMSON • Department of Cell Biology, University of Alabama at Birmingham, UAB Station, Birmingham, Alabama 35294
ANDREW W. ARTENSTEIN • Infectious Disease Service, Department of Medicine, Walter Reed Army Medical Center, and Department of Bacterial Diseases, Walter Reed Army Institute of Research, Washington, D.C. 20307-5001
ALI AZGHANI • Department of Biochemistry, University of Texas Health Science Center at Tyler, Tyler, Texas 75710
FRANCIS BELLI DO • Eli Lilly, 1214 Geneva, Switzerland
RICHARD S. BERK • Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, Michigan 48201
KONRAD BOTZENHART • Department of General Hygiene and Environmental Hygiene, H ygiene-Institut, University of Tiibingen, D-7400 Tiibingen, Germany
MARIO CAMPA • Department of Biomedicine, Clinical Microbiology Section, University of Pisa, 56127 Pisa, Italy
MICHAEL S. COLLINS • Miles Pharmaceutical Division, Miles Inc., West Haven, Connecticut 06516-4175
ALAN S. CROSS • Infectious Disease Service, Department of Medicine, Walter Reed Army Medical Center, and Department of Bacterial Diseases, Walter Reed Army Institute of Research, Washington, D.C. 20307 -5001
STANLEY J. CRYZ, JR. • Swiss Serum and Vaccine Institute, CH-3001 Berne, Switzerland
v
VI CONTRIBUTORS
GERD DORING • Department of General Hygiene and Environmental Hygiene, Hygiene-Institut, University of Tiibingen, D-7400 Tiibingen, Germany
DARRELL R. GALLOWAY • Department of Microbiology, The Ohio State University, Columbus, Ohio 43210-1292
ROBERT E. W. HANCOCK • Department of Microbiology, University of British Columbia, Vancouver, British Columbia, Canada V6T lW5
LOUIS W. HECK • Department of Medicine, Veterans Administration Medical Center, University of Alabama at Birmingham, UAB Station, Birmingham, Alabama 35294
JANEL HECTOR • Department of Biochemistry, University of Texas Health Science Center at Tyler, Tyler, Texas 75710
IAN ALAN HOLDER • Shriners Burns Institute, Cincinnati, Ohio 45229-3095
RANDALL T. IRVIN • Department of Medical Microbiology and Infectious Diseases, University of Alberta, Edmonton, Alberta, Canada T6G 2H7
ALICE JOHNSON • Department of Biochemistry, University of Texas Health Science Center at Tyler, Tyler, Texas 75710
FRED JOSEPH, JR. • Department of Pediatrics, Louisiana State University Medical Center, New Orleans, Louisiana 70112
ANTONELLA LUPETTI • Department of Biomedicine, Clinical Microbiology Section, University of Pisa, 56127 Pisa, Italy
PAOLA MARELLI • Department of Biomedicine, Clinical Microbiology Section, University of Pisa, 56127 Pisa, Italy
RANDAL E. MORRIS • Department of Anatomy and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0521
GERALD B. PIER • Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115-5899
CATHARINE B. SAELINGER • Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0524
CHRISTINE M. SHUMARD • Diagnostics Division, Abbott Laboratories, Abbott Park, Illinois 60064
CONTRIBUTORS Vll
RICARDO U. SORENSEN • Department of Pediatrics, Louisiana State University Medical Center, New Orleans, Louisiana 70112
DAVID P. SPEERT • Departments of Pediatrics and Microbiology and the Canadian Bacterial Diseases Network, University of British Columbia, and Division of Infectious and Immunological Diseases, British Columbia's Children's Hospital, Research Centre, Vancouver, British Columbia, Canada V5Z 4H4
ROBERT STEADMAN • Institute of Nephrology, Cardiff Royal Infirmary, Cardiff, Wales CF2 ISZ
DONALD E. WOODS • Department of Microbiology and Infectious Diseases, University of Calgary Health Sciences Centre, Calgary, Alberta, Canada T2N 4Nl
DANIEL J. WOZNIAK • Department of Microbiology and Immunology, University of Tennessee, Memphis, Tennessee 38163
Preface
This volume is devoted to Pseudomonas aeruginosa as an "opportunistic" pathogen in humans. We have attempted to provide balanced coverage of epidemiology, pathogenesis, clinical features, and control measures. All the chapters have been contributed by outstanding authorities on specific aspects of P. aeruginosa research. This book should prove useful to physicians and surgeons who have in their care patients infected, or at risk of becoming infected, with P. aeruginosa and who want to gain a greater understanding of this elusive microorganism, the diseases it produces, and means of control. We also hope that the book will stimulate further studies on the mechanisms whereby P. aeruginosa establishes itself and causes disease in compromised patients.
The opportunistic behavior of this bacterium was recognized a long time ago. Since then, the extent of our knowledge about P. aeruginosa and microbes in general has burgeoned. Nevertheless, there are still few real clues as to why P. aeruginosa infection is much less common than one would expect considering the wide distribution of this bacterium in nature and why it mainly infects individuals whose local or systemic antibacterial defenses are compromised.
Because of its minimal growth requirements and nutritional flexibility, P. aeruginosa is particularly able to adapt to changing ecological conditions. It is also capable of surviving for long periods, especially in moist environments. In addition, the poor permeability of its outer membrane makes it intrinsically resistant to many disinfectants and antimicrobial agents, and it is therefore well adapted to compete with antibiotic-secreting microorganisms in its natural ecosystem, the soil, and to exploit the selective advantages provided by hospital environments.
Understanding why in healthy humans-in spite of the large variety of virulent factors produced by the microorganism-the carrier state is generally rare and unstable and, in contrast, infection of the immunocompromised
IX
x PREFACE
is common and severe is not only a challenge per se but may also help shed light on opportunistic microorganisms in general. The number of immunocompromised individuals has exploded worldwide as a consequence of progresses in modern medicine and, more recently, the epidemic of acquired immunodeficiency syndrome. There is a consensus that this population "class" will increase considerably in the next few decades. This will not only expand the number of potential victims of opportunistic infections but may also provide new opportunities for pseudomonads and other agents to gradually adapt better to the human host. New knowledge may help reduce such risks.
We are grateful to the excellent scientists who provided enthusiastic support for the preparation of this volume, and we are confident that their collective effort will be appreciated by the reader.
Mario Campa Mauro Bendinelli Herman Friedman
Contents
1. Ecology and Epidemiology of Pseudomonas aeruginosa
KONRAD BOTZENHART and GERD DORING
1. Introduction ............................................. 1 2. Ecology.................................................. 2
2.1. Adaptability ........................................ 2 2.2. Inanimate Environment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2.3. Healthy Humans .................................... 6
3. Epidemiology ............................................ 7 3.1. Incidence of Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 3.2. Routes of Transmission .............................. 7
4. Resume.................................................. 12 References ............................................... 13
2. Attachment and Colonization of Pseudomonas aeruginosa: Role of the Surface Structures
RANDALL T. IRVIN
1. Introduction ............................................. 19 2. Role of Adherence in Pathogenesis. . . . . . . . . . . . . . . . . . . . . . . . . . 20
2.1. Morphology of Adherence to Human Respiratory Cells. . 21 2.2. Effect of Epithelial Cell Type on Adherence. . .. . . . . . . . . 21
3. Adhesins................................................. 22 3.1. Structure and Function of the Capsule . . . . . . . . . . . . . . . . . 23 3.2. Exoenzyme S ....................................... 28 3.3. Structure of Pili ..................................... 29
Xl
Xli CONTENTS
3.4. Synthesis and Assembly of Pili ........................ 29 3.5. Structural Variability in Pilins . . . . . . . . . . . . . . . . . . . . . . . . . 30 3.6. Pilin-Pilin Interactions ............................... 30 3.7. Function of Pili. . . . . . . . . . . . . . .. . . . . .. . . . . . . . . . . . . . . . . 31 3.8. The Pilus and Exoenzyme S Receptor(s) ............... 32 3.9. Structural Organization of Pili ........................ 33
4. Summary and Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 References ............................................... 36
3. Phenazine Pigments in Pseudomonas aeruginosa Infection
RICARDO U. SORENSON and FRED JOSEPH, JR.
1. Introduction ............................................. 43 2. Structure and Chemical Properties. . . . . . . . . . . . . . . . . . . . . . . . . . 44 3. Purification, Synthesis, and Methods of Detection ............ 46 4. Regulation of Phenazine Production and Possible Function .... 47 5. Biological Effects of Phenazine Pigments .................... 48
5.1. Effect on Bacteria ................................... 48 5.2. Effect on Mitochondrial Respiration ................... 49 5.3. Effect on Neutrophil Function ........................ 49 5.4. Effect on Cell Proliferation and Cytokine Secretion. . . . . . 50 5.5. Effect on Ciliary Beating ............................. 51 5.6. Intratracheal Instillation of Pyocyanine in Vivo ... . . . . . . . 52 5.7. Effect on Vascular Reactivity . . . . . . . . . . . . . . . . . . . . . . . . . . 52
6. Phenazine Pigments in Pseudomonas Infections ............... 52 6.1. Presence of Phenazine Pigments at Sites of Infection .... 52 6.2. Role of Phenazines in Chronic P aeruginosa Infections ... 53
7. Concluding Remarks ...................................... 53 References ............................................... 54
4. Regulation of Toxin A Synthesis in Pseudomonas aeruginosa
CHRISTINE M. SHUMARD, DANIEL J. WOZNIAK, and DARRELL R. GALLOWAY
1. Introduction ............................................. 59 1.1. Historical Perspectives Regarding the Regulation of
Toxin A Synthesis ................................... 60 2. Influence of Environmental Factors on Toxin A Synthesis ..... 61
2.1. Regulation of Toxin A Production by Iron ............. 62 3. Genetic Regulation of Toxin A Synthesis .................... 64
3.1. Evidence for an Activator ............................ 64
CONTENTS Xlll
3.2. Characterization of toxR: A Gene Involved in the Positive Regulation of Toxin A Synthesis ...................... 66
3.3. Transcriptional Analysis of the toxR Gene .............. 67 3.4. Report on a Second Gene Involved in Regulation of
Toxin A Production: regB ............................ 68 3.5. Mutational Analysis of Genes Involved in Toxin A
Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 3.6. The Role of toxR in the Regulation of Toxin A
Expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 3.7. Evidence for Additional Factors Regulating Toxin A
Synthesis ........................................... 72 4. Summary and Conclusions ................................. 73
References ............................................... 74
5. Susceptibility of Mammalian Cells to Pseudomonas Exotoxin A
RANDAL E. MORRIS and CATHARINE B. SAELINGER
1. Introduction ............................................. 79 2. Structure-Function Relationship ............................ 81 3. Receptor-Mediated Endocytosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
3.1. Role of Acidic Compartments. . . . . . . . . . . . . . . . . . . . . . . . . 86 3.2. Temperature Dependence. . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
4. Similarities with Viral Entry ............................... 87 5. Experimental Data. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
5.1. The Binding Event .................................. 88 5.2. Endocytic Uptake of Pseudomonas and Diphtheria Toxins
by Mouse LM Fibroblasts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 5.3. Activation and Escape of Pseudomonas Toxin in LM
Fibroblasts .......................................... 93 5.4. Isolation of the Receptor for Pseudomonas Exotoxin A
from Mouse LM Fibroblasts .......................... 97 6. A Cell Line Resistant to Pseudomonas Exotoxin A-Ovcar Cells 98 7. Chimeric Toxins .......................................... 98 8. Conclusions .............................................. 99
References ............................................... 100
6. Role of Exotoxins in the Pathogenesis of P aeruginosa Infections
DARRELL R. GALLOWAY
1. Introduction and Historical Perspectives. . . . . . . . . . . . . . . . . . . . . 107 1.1. Pseudomonas aeruginosa-The Opportunistic Pathogen ... 108
2. Exotoxin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
XIV CONTENTS
3. Exoenzyme S ............................................. 113 4. Elastase.................................................. 115 5. Phospholipases ........................................... 119 6. In Conclusion ............................................ 120
References ............................................... 121
7. The Role of Proteases in the Pathogenesis of Pseudomonas aeruginosa Infections
ROBERT STEADMAN, LOUIS W HECK, and DALE R. ABRAHAMSON
1. Introduction ............................................. 129 2. The Control of Protease Secretion .......................... 130 3. Protease Involvement in Pathogenicity. . . . . .. . . .. . . . . . . . . . . . . 131 4. Tissue Damage Induced by Proteases ....................... 132 5. Effects of Proteases on the Immune System ................. 135 6. Inhibition of Proteases .................................... 139 7. Summary ................................................ 139
References ............................................... 140
8. Genetic Regulation and Expression of Elastase in Pseudomonas aerugtnosa
JANEL HECTOR, ALI AZGHANI, and ALICE JOHNSON
1. Introduction ............................................. 145 1.1. Pseudomonas Elastase ................................. 146 1.2. Chemistry .......................................... 146 1.3. Biological Effects .................................... 147 1.4. Bacterial Adherence ................................. 149
2. Environmental Effects on Elastase Production. . . . . . . . . . . . . . . . 149 2.1. Source ............................................. 150 2.2. Antibiotics.......................................... 150 2.3. Culture Conditions .................................. 150 2.4. Media Composition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150 2.5. Duration of Culture ................................. 151
3. Molecular Biology Studies ................................. 152 3.1. Elastase-Deficient Mutants. ... . . . . . .. . .. . . .. . . .. . . .. . . 152 3.2. Elastase Genes ...................................... 154 3.3. Processing of Elastase. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155 3.4. Secretion ........................................... 157
CONTENTS xv
4. Conclusions .............................................. 159 References ............................................... 159
9. Pseudomonas aeruginosa-Phagocytic Cell Interactions
DAVID P. SPEERT
1. Introduction ............................................. 163 2. Mechanisms of Phagocytosis ............................... 164
2.1. Professional Phagocytic Cells: In Defense against Infection ........................................... 164
2.2. The Process of Phagocytosis .......................... 164 2.3. Opsonic and Nonopsonic Phagocytosis. . . . . . . .. . . . . . . . . 165
3. Phagocytosis of Pseudomonas aeruginosa . . . . . . .. . . . . . . . . . . . . . . 166 3.1. Opsonic Phagocytosis...... . .... ................... . . 166 3.2. Nonopsonic Phagocytosis ............................. 167
4. Phagocytic Killing of Pseudomonas aeruginosa . . . . . . . . . . . . . . . . . 168 4.1. Bactericidal Mechanisms of Phagocytic Cells ........... 168 4.2. Mechanism of Pseudomonas aeruginosa Killing. . . . . . . . . . . 169
5. Pseudomonas aeruginosa Products with Effects on Phagocytosis 169 5.1. Cytotoxins.......................................... 170 5.2. Elastase ............................................ 171 5.3. ExotoxinA ......................................... 171 5.4. Mucoid Exopolysaccharide ........................... 172 5.5. Slime Glycolipoprotein ............................... 172 5.6. Pyocyanine.......................................... 173
6. Disease States in which Phagocytic Dysfunction May Predispose to Infections with Pseudomonas aeruginosa .............. . . . . . . 173 6.1. Neutropenia ........................................ 173 6.2. Thermal Burns ..................................... 174 6.3. Cystic Fibrosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174 References ............................................... 176
10. Genetic Regulation of the Murine Corneal and Non-Corneal Response to Pseudomonas aeruginosa
RICHARD S. BERK
1. Introduction ............................................ 183 2. Non-Ocular Studies. . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . 185
2.1. Systemic Infections-Genetic Studies ................. 185 2.2 T-cell Immunity-Genetic Studies .................... 185
3. Corneal Infections ....................................... 188
XVI CONTENTS
3.1. Genetic Studies .................................... 188 3.2. Humoral Response of Resistant and Susceptible Mice .. 197 3.3. Role of Complement in Corneal Resistance ............ 199 3.4. Role of Age in Resistance ........................... 199 3.5. Immunization Studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
4. Discussion .............................................. 200 References .............................................. 202
11. Effects of Pseudomonas aeruginosa on Immune Functions
MARIO CAMPA, PAOLA MARELLI, and ANTON ELLA LUPETTI
1. Introduction ............................................ 207 2. Interference with Nonspecific Immune Defense Mechanisms 208 3. Interference with Specific Immune Defense Mechanisms. . . . . 212 4. Concluding Remarks .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
References .............................................. 216
12. Local and Disseminated Diseases Caused by Pseudomonas aerugmosa
ANDREW W ARTENSTEIN and ALAN S. CROSS
1. Introduction ............................................ 223 2. Bacteremia.............................................. 224
2.1. Epidemiology...................................... 224 2.2. Clinical Presentation ................................ 225 2.3. Dermatologic Features .............................. 225 2.4. Therapy........................................... 225 2.5. Prognosis.......................................... 226
3. Endocarditis ............................................ 226 3.1. Epidemiology...................................... 226 3.2. Clinical Presentation ................................ 227 3.3. Therapy........................................... 227
4. Respiratory Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227 4.1. Epidemiology...................................... 227 4.2. Clinical Presentation ................................ 228 4.3. Radiology ......................................... 228 4.4. Therapy........................................... 228 4.5. Cystic Fibrosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
5. Urinary Tract Infections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229 5.1. Epidemiology...................................... 229
CONTENTS XVll
5.2. Clinical Presentation ................................ 229 5.3. Therapy........................................... 229
6. Bone and Joint Infections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 6.1. Epidemiology...................................... 230 6.2. Addict-associated Infection .......................... 230 6.3. Osteochondritis .................................... 230
7. Central Nervous System Infections. .. . . . . .. . . .. . . . . . . . . . . . . 231 7.1. Meningitis......................................... 231 7.2. Brain Abscess. . . . . . . . . . . . . . . . . . .. . . .. . . . . . . . . . . . . . . 231
8. Wound Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 9. Skin Infections .......................................... 232
9.1. General Considerations ............................. 232 9.2. Clinical Syndromes ................................. 232
10. Ocular Infections ........................................ 233 10.1. General Considerations ............................ 233 10.2. Keratitis.......................................... 234 10.3. Endophthalmitis .................................. 234
11. Otolaryngologic Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235 11.1. General Considerations ............................ 235 11.2. ExternaIOtitis.................................... 235 11.3. Malignant External Otitis .......................... 235 11.4. Other Syndromes ................................. 236
12. Dialysis Infections ....................................... 237 12.1. General Considerations ............................ 237 12.2. Clinical Features .................................. 237
13. Gastrointestinal Infections ................................ 237 13.1. General Considerations ............................ 237 13.2. Typhlitis.......................................... 238 13.3. Perirectal Disease ................................. 238
14. Miscellaneous Infections ........... . . . . . . . . . . . . . . . . . . . . . . . 239 References .............................................. 239
13. Chronic Pseudomonas aeruginosa Lung Infection in Cystic Fibrosis Patients
GERD DORING
1. Introduction ............................................ 245 2. Acquisition.............................................. 246
2.1. In Hospitals ....................................... 246 2.2. Outside of Hospitals. .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247 2.3. Intestinal Colonization .............................. 248
3. Virulence and Host Defense .............................. 248
XVlll CONTENTS
3.1. Adhesion.......................................... 248 3.2. Virulence Determinants. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250 3.3. Persistence: The Surface Enlargement Strategy. . . . . . . . 256 3.4. Tissue Damage: A Neutrophil Enzyme Effect ......... 257
4. New Strategies for Therapy and Prevention. . . . . . . . . . . . . . . . . 258 4.1. Antibiotics......................................... 258 4.2. Anti-Inflammatory Therapy ......................... 258 4.3. Immunoprophylaxis and Immunotherapy . . . . . . . . . . . . . 259 4.4. Disinfection and Hygiene ........................... 260 References .............................................. 260
14. P. aeruginosa Burn Infections: Pathogenesis and Treatment
IAN ALAN HOLDER
1. Introduction and Brief History. . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 2. Antimicrobial Treatment: Parenteral and Topical. . . . . . . . . . . . 276 3. Immunotherapy......................................... 277 4. Pseudomonas Virulence-associated Factors: Their Role in
Pathogenesis in Burned Hosts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277 4.1. Exotoxin A ........................................ 279 4.2. Proteolytic Enzymes ................................ 281 4.3. Pili ............................................... 283 4.4. Flagella, Motility, and Chemotaxis .................... 284
5. Speculations on the Role(s) of Pseudomonas Virulenceassociated Factors on the Pathogenic Process of Burn Wound Infections and Novel Treatment Approaches ................ 285 References .............................................. 290
15. Acquired Resistance to P. aeruginosa
GERALD B. PIER
1. Introduction ............................................ 297 2. Immunity to Infection ................................... 298 3. Acquired Resistance to Infection in Non-CF Humans. . . . . . . . 299
3.1. Naturally Acquired Active Immunity to Non-CF-Associated P. aeruginosa Infections . . . . . . . . . . . . . . . . . . . . 299
3.2. Vaccine-Induced Immunity to Non-CF-Associated P. aeruginosa Isolates ................................ 300
3.3. Antibody Isotype, Complement, and Phagocytes in Acquired Resistance to Non-CF-Associated P. aeruginosa Infection .......................................... 303
CONTENTS XIX
3.4. T-cell Immunity to Non-CF-Associated Isolates of P aeruginosa ....................................... 304
4. Acquired Resistance to Infection in CF Patients ............. 305 4.1. Naturally Acquired Resistance Among CF Patients to
P aeruginosa Infection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306 4.2. Vaccine-Induced Immunity and Prospective
Immunotherapeutic Strategies ....................... 306 4.3. Antibody Isotype, Complement, and Phagocytes in
Acquired Resistance to Infection in CF Patients . . . . . . . . 308 5. Summary............................................... 311
References .............................................. 311
16. Susceptibility and Resistance of Pseudomonas aeruginosa to Antimicrobial Agents
FRANCIS BELLI DO and ROBERT E. W HANCOCK
l. Introduction ............................................ 321 2. [3-Lactams .............................................. 322
2.l. Antipseudomonal[3-Lactams ........................ 322 2.2. Determinants of Efficacy .................... . . . . . . . . 324 2.3. Resistance ......................................... 330
3. Aminoglycosides......................................... 331 3.l. Determinants of Efficacy ............. . . . . . . . . . . . . . . . 331 3.2. Outer Membrane Permeation. . . . .. . . . . . . . . . . .. . . . . . . 334 3.3. Cytoplasmic Membrane Penetration .................. 335 3.4. Plasmid-Mediated Resistance ........................ 336 3.5. Clinical Resistance Development ..................... 336
4. Quinolones.............................................. 338 4.1. Determinants of Efficacy ............................ 338 4.2. Uptake Across the Outer Membrane ................. 338 4.3. Assays of Quinolone Uptake. . . . . . . . . . . . . . . . . . . . . . . . . 341 4.4. Mechanisms of Resistance ........................... 341 References .............................................. 342
17. Immunochemical Prophylaxis against Pseudomonas aeruginosa
MICHAEL S. COLLINS
l. Introduction ............................................ 349 2. Active Immunotherapy ................................... 350
2.l. Complex Vaccines, LPS-based ........................ 351 2.2. Defined Vaccines, LPS-based ........................ 351 2.3. Defined LPS-based Vaccines of Low Toxicity .......... 352
xx CONTENTS
2.4. Cross-protective Vaccines ............................ 352 3. Passive Immunotherapy .................................. 353
3.1. Immune Serum Globulin ........................... 354 3.2. Immune Serum Globulin for Intravenous Infusion. . . . . 354 3.3. Hyperimmune Immunoglobulin ..................... 356
4. Monoclonal Antibodies ................................... 363 4.1. Core Glycolipid Immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . 363 4.2. Immunotherapy with P. aeruginosa-Specific Monoclonal
Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365 4.3. Safety and Efficacy Considerations for Monoclonal
Antibody Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369 References .............................................. 369
18. The State of the Art in the Development of Pseudomonas aeruginosa Vaccines
STANLEY J. CRYZ, JR.
1. Clinical Significance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383 2. Human Immunity to P. aeruginosa ......................... 384 3. Development and Clinical Evaluation of Immunological Agents
against P. aeruginosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387 3.1. Background ....................................... 387 3.2. P. aeruginosa Vaccines ............................... 387
4. Passive Immunotherapy .................................. 390 4.1. Human Monoclonal Antibodies against P. aeruginosa ... 391 References .............................................. 392
19. Perspectives for the Control of Chronic Pseudomonas aeruginosa Lung Infections of Cystic Fibrosis Patients
DONALD E. WOODS
1. Introduction ............................................ 397 2. Animal Studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398 3. Regulation of Virulence .................................. 400 4. Direct versus Indirect Lung Injury ........................ 400 5. Effects of Antibiotics on Virulence. . . . . . . . . . . . . . . . . . . . . . . . . 401 6. Patient Studies .......................................... 403 7. Role of P. aeruginosa in Exacerbations of Lung Disease ...... 406 8. Conclusion.............................................. 407
References 409
Index ....................................................... 411
