DK2996_half-series-title.qxd 6/24/05 12:04 PM Page 1 Fungal Infections in the Immunocompromised Patient DK2996_half-series-title.qxd 6/24/05 12:04 PM Page 2 INFECTIOUS DISEASE AND THERAPY Series Editor Burke A.Cunha Winthrop-University Hospital Mineola, and State University of New York School of Medicine Stony Brook, New York 1. Parasitic Infections in the Compromised Host, edited by Peter D. Walzer and Robert M. Genta 2. Nucleic Acid and Monoclonal Antibody Probes: Applications in Diagnostic Methodology, edited by Bala Swaminathan and Gyan Prakash 3. Opportunistic Infections in Patients with the Acquired Immunodeficiency Syndrome, edited by Gifford Leoung and John Mills 4. Acyclovir Therapy for Herpesvirus Infections, edited by David A. Baker 5. The New Generation of Quinolones, edited by Clifford Siporin, Carl L. Heifetz, and John M. Domagala 6. Methicillin-Resistant Staphylococcus aureus: Clinical Management and Laboratory Aspects, edited by Mary T. Cafferkey 7. Hepatitis B Vaccines in Clinical Practice, edited by Ronald W. Ellis 8. The New Macrolides, Azalides, and Streptogramins: Pharmacology and Clinical Applications, edited by Harold C. Neu, Lowell S. Young, and Stephen H. Zinner 9. Antimicrobial Therapy in the Elderly Patient, edited by Thomas T. Yoshikawa and Dean C. Norman 10. Viral Infections of the Gastrointestinal Tract: Second Edition, Revised and Expanded, edited by Albert Z. Kapikian 11. Development and Clinical Uses of Haemophilus bConjugate Vaccines, edited by Ronald W. Ellis and Dan M. Granoff 12. Pseudomonas aeruginosaInfections and Treatment, edited by Aldona L. Baltch and Raymond P. Smith 13. Herpesvirus Infections, edited by Ronald Glaser and James F. Jones 14. Chronic Fatigue Syndrome, edited by Stephen E. Straus 15. Immunotherapy of Infections, edited by K. Noel Masihi 16. Diagnosis and Management of Bone Infections, edited by Luis E. Jauregui 17. Drug Transport in Antimicrobial and Anticancer Chemotherapy, edited by Nafsika H. Georgopapadakou 18. New Macrolides, Azalides, and Streptogramins in Clinical Practice, edited by Harold C. Neu, Lowell S. Young, Stephen H. Zinner, and Jacques F. Acar DK2996_half-series-title.qxd 6/24/05 12:04 PM Page 3 19. Novel Therapeutic Strategies in the Treatment of Sepsis, edited by David C. Morrison and John L. Ryan 20. Catheter-Related Infections, edited by Harald Seifert, Bernd Jansen, and Barry M. Farr 21. Expanding Indications for the New Macrolides, Azalides, and Streptogramins, edited by Stephen H. Zinner, Lowell S. Young, Jacques F. Acar, and Harold C. Neu 22. Infectious Diseases in Critical Care Medicine, edited by Burke A. Cunha 23. New Considerations for Macrolides, Azalides, Streptogramins, and Ketolides, edited by Stephen H. Zinner, Lowell S. Young, Jacques F. Acar, and Carmen Ortiz-Neu 24. Tickborne Infectious Diseases: Diagnosis and Management, edited by Burke A. Cunha 25. Protease Inhibitors in AIDS Therapy, edited by Richard C. Ogden and Charles W. Flexner 26. Laboratory Diagnosis of Bacterial Infections, edited by Nevio Cimolai 27. Chemokine Receptors and AIDS, edited by Thomas R. O’Brien 28. Antimicrobial Pharmacodynamics in Theory and Clinical Practice, edited by Charles H. Nightingale, Takeo Murakawa, and Paul G. Ambrose 29. Pediatric Anaerobic Infections: Diagnosis and Management, Third Edition, Revised and Expanded, Itzhak Brook 30. Viral Infections and Treatment, edited by Helga Ruebsamen-Waigmann, Karl Deres, Guy Hewlett, and Reinhold Welker 31. Community-Aquired Respiratory Infections, edited by Charles H. Nightingale, Paul G. Ambrose, and Thomas M. File 32. Catheter-Related Infections: Second Edition, Harald Seifert, Bernd Jansen and Barry Farr 33. Antibiotic Optimization: Concepts and Strategies in Clinical Practice (PBK), edited by Robert C. Owens, Jr., Charles H. Nightingale and Paul G. Ambrose 34. Fungal Infections in the Immunocompromised Patient, edited by John R. Wingard and Elias J. Anaissie 35. Sinusitis: From Microbiology To Management, edited by Itzhak Brook 36. Herpes Simplex Viruses, edited by Marie Studahl, Paola Cinque and Tomas Bergstrom 37. Antiviral Agents, Vaccines, and Immunotherapies, Stephen K. Tyring DK2996_half-series-title.qxd 6/24/05 12:04 PM Page 4 Fungal Infections in the Immunocompromised Patient edited by John R. Wingard University of Florida College of Medicine Gainesville,Florida,U.S.A. Elias J. Anaissie The University of Arkansas for Medical Sciences Little Rock,Arkansas,U.S.A. Boca Raton London New York Singapore DK2996_Discl.fm Page 1 Wednesday, June 29, 2005 7:53 AM Published in 2005 by Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2005 by Taylor & Francis Group, LLC No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 0-8247-5428-X (Hardcover) International Standard Book Number-13: 978-0-8247-5428-0 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. 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Library of Congress Cataloging-in-Publication Data Catalog record is available from the Library of Congress Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com Taylor & Francis Group is the Academic Division of T&F Informa plc. Preface Opportunistic infections have always been accompaniments of medical conditions that compromise host defenses. Because of the severe morbidity and mortality that result from such infectious complications, these pose substantial challenges for the clinician who cares for such individuals. With medical progress, the number of immunocompromised patients is steadily climbing. Moreover the types of host defense compromises are changing. As transplant practices evolve, as critical care procedures advance, and as HIV management strategies change, the spectrum of opportunistic pathogens shifts. Initially, bacterial infections were most problematic. As strategies to control bacterialinfectionsimproved,theherpesvirusescametoincreasingattentionofclin- icians. Herpes simplex and varicella zoster virus cause considerable morbidity and occasional mortality. Cytomegalovirus (CMV) became recognized as a major killer oftransplantrecipients,butmorbiditydeclinedduetoadvancesinrapiddiagnostics and the introduction of effective antiviral agents such as acyclovir and ganciclovir. Today, the invasive fungal pathogens have seized center stage from the above historicallyimportantopportunisticpathogens.Duringthe1980stherateofnosoco- mialinvasivefungaldiseaseinU.S.hospitalsdoubledwithnosignofslowingduring the 1990s. Candida has become the fourth leading bloodstream isolate in U.S. hos- pitals, surpassing many historically important bacterial pathogens. Estimates are thattheUnitedStatesspendsapproximatelyonebilliondollarsannuallyforCandida infections, and more than $650 million annually for Aspergillus disease. However, accurate diagnostics and effective therapies have lagged for this emerging group of opportunists. As survival from bacteria and the herpesviruses has improved, more immunocompromised patients are now living to develop infection from fungi. Candida is the most common genus of fungal pathogens. C. albicans long was recognized as a cause of mucosal disease of the mouth, esophagus, and vagina in patients with T-cell deficiency, as seen in patients with HIV infection, those treated with corticosteroids or other potent immunosuppressive drugs, and patients with lymphoreticular neoplasms. Fungemia is especially problematic in cancer patients withchemotherapy-inducedmyelosuppression,bloodandmarrowtransplantrecipi- ents, and patients in critical care units on multiple antibiotics with venous, bladder, or endotracheal catheters. With the increasing use of potent immunosuppressive iii iv Preface purine analogues, such as fludarabine, pentostatin, and cladribine, and anti-T and anti-B cell antibodies (e.g., rituximab, alemtuzumab, and anti-thymocyte globulin) in the management of hematolymphoreticular malignancies, increasing emphasis onchemotherapydoseintensityinoncologicpractice,andthegrowthincriticalcare, the number of patients at risk for fungal diseases is growing. In recent years, the non-albicans Candida species have become increasingly recognizedasfungalpathogensinimmunocompromisedpatients.Incancerpatients, C. tropicalis and C. glabrata are especially problematic. In critical care patients, the rates of C. glabrata infections are climbing. A variety of risk factors for different Candidaspecieshasbeen identified. Aspergillus species have been the chief non-Candida fungal opportunistic pathogens. The major portals of entry for these airborne organisms are the nasal passages, sinuses, and respiratory tract, in contrast to the gastrointestinal tract for Candidaorganisms.Inbonemarrowtransplantrecipientsandinpatientswithacute leukemia, the mortality is in excess of 75%. Mold pathogens other than Aspergillus are increasing. The agents of mucor- mycosis are quite difficult to culture and the syndromes caused by these infections are indistinguishable from those caused by Aspergillus species; response to therapy is poor. Fusarium, a soil fungus, has been historically impervious to most therapeu- tics. Scedosporium, another emerging pathogen, is being increasingly reported in blood and marrow transplant recipients. Difficulty in accurate diagnosis has been a tremendous impediment hindering therapeutic advances. Noninvasive techniques have been limited for most opportu- nistic fungal pathogens. Blood culture techniques have improved for detection of Candida, but still are not foolproof. Aspergillus is poorly diagnosed by broncho- scopy, and reliable diagnosis requires a thoracotomy, an invasive procedure which is quite dangerous in many of the patients that are suspected to be infected. There is an urgent need for noninvasive, rapid, accurate diagnostics. Antigen detection assays have been helpful aids to diagnosis for only a few fungal pathogens, such as Cryptococcus and Histoplasma. Recent studies suggest that antigen detection assays (such as galactomannan and glucan) and PCR methods for detecting fungal antigens may finally yield promising tools for a broader array of fungal pathogens and these will be discussed in the book. Antifungal therapy had been quite limited in the past. The gold standard of therapyhasbeenamphotericinB,apolyeneantifungalagentwithconsiderabletoxi- city. This concern was somewhat eased by the development of lipid formulations of amphotericin B, permitting delivery of high doses of amphotericin B with sub- stantially less toxicity. The introduction of antifungal azoles offered considerable promise, but because of limited spectrum of activity and poor or erratic bioavailability,littleprogresswasrealizeduntilfluconazolewasintroducedadecade ago.Withexcellentbioavailability,littletoxicity,andbothoralandintravenousfor- mulations,fluconazolewasquicklyembracedbyclinicianstreatingimmunocompro- mised patients with suspected or proven Candida infection. The only blemish of fluconazole is a limited spectrum of activity: excellent activity against many yeast pathogens, but none against mold pathogens. Selection of fluconazole resistant yeasts was also a concern, especially in patients with advanced HIV disease failing anti-retroviral therapy. Newantifungalagentshavebeenintroducedintotheclinicalarenaandmoreare arriving.Caspofungin,amemberofauniqueclassofagents,theechinocandins,was licensedseveralyearsago.Thisclassofagentsactsonthefungalcellwall,interfering Preface v with the biosynthesis of beta glucan, the main constituent of the fungal cell wall, whereas both polyenes and azoles act on a constituent of the fungal cell membrane, namely ergosterol. With excellent activity against the two most frequent invasive fungalpathogens,CandidaandAspergillus,andanoutstandingsafetyprofile,caspo- fungin has rapidly become widely used. Anidulafungin and micafungin are also on the horizon. New extended spectrum azoles have been introduced and others are in development.One,voriconazole,hasbeenshowntobemoreeffectivethanamphoter- icinBasfirst-linetherapyofinvasiveaspergillosis,inarandomizedtrial.Thedrugis nowavailableworldwide.Neworalandintravenousformulationsofitraconazolewere approved to expand that agent’s utility in clinical practice. Other broad spectrum azoles,suchasposaconazole,areinclinicaltrials. Even with effective and safe therapeutics, treatment is frequently started late during the course of infection, when the burden of organisms is high and the likeli- hoodoftherapeuticsuccesslow.Thisaccountsformuchoftheextraordinarilyhigh mortality. Accordingly, considerable attention has been paid to different antifungal strategies.Prophylaxisandempirictherapyhavebeenevaluatedingroupsofimmu- nocompromisedpatientsathighriskforfungalinfection.Today,therearegoodevi- dence-baseddatatosupportuseofabroadarrayofantifungalagentsandstrategies for different patient settings. Considerable progress has been achieved during the pastdecade. The cumula- tive mortality from Candida infections is finally beginning to recede. However, the collective mortality from aspergillosis continues to climb. Moreover, infection rates fromfungi also areincreasing.Moreworkisneeded. Yet,withnewdiagnosticsand the expanding array of antifungals, the future looks bright. The goal of this book is to provide an up-to-date overview of the fungal syn- dromesinimmunocompromisedpatients,describetheshiftsinfungalpathogensand thereasonsbehindthem,indicatethesettinginwhichtheycauseillnessandtherisk factors for infection, cover the pros and cons of current and emerging diagnostic measures, and discuss treatment modalities and strategies. The book is divided into five sections to cover the above topics, with individual chapters devoted to specific syndromes, infections, and settings. Thisbookistargetedtotheclinician caringforimmunocompromisedpatients atriskforinvasivefungalinfections.Thisincludestransplantclinicians,criticalcare specialists, oncologists, stem cell transplant specialists, and infectious disease physi- cians. Both academic physicians and practitioners will find this book informative. Clinical microbiologists, mycologists, and individuals with research interests in developing new antimicrobial agents will also find very useful information related to their respective fields. Aninternationalgroupofexpertclinicianswhohavedefinedmanyoftheper- tinent issues in fungal epidemiologic studies and clinical trials have contributed to this effort. The authors review the published data, offer critical insights as to the interpretation of the literature, and provide timely summaries of the current state of knowledge. We are truly grateful for their hard work in making this project happen. John R. Wingard Elias J. Anaissie