Table Of ContentDK2996_half-series-title.qxd 6/24/05 12:04 PM Page 1
Fungal Infections
in the
Immunocompromised
Patient
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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
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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
