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Fungal Infections in the Immunocompromised Patient

2005 Edition, August 5, 2005

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Active, Most Current

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ISBN: 978-0-8247-5428-0
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Product Details:

  • Revision: 2005 Edition, August 5, 2005
  • Published Date: August 5, 2005
  • Status: Active, Most Current
  • Document Language: English
  • Published By: CRC Press (CRC)
  • Page Count: 700
  • ANSI Approved: No
  • DoD Adopted: No

Description / Abstract:

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 bacterial infections improved, the herpesviruses came to increasing attention of clinicians. Herpes simplex and varicella zoster virus cause considerable morbidity and occasional mortality. Cytomegalovirus (CMV) became recognized as a major killer of transplant recipients, but morbidity declined due to advances in rapid diagnostics and the introduction of effective antiviral agents such as acyclovir and ganciclovir.

Today, the invasive fungal pathogens have seized center stage from the above historically important opportunistic pathogens. During the 1980s the rate of nosocomial invasive fungal disease in U.S. hospitals doubled with no sign of slowing during the 1990s. Candida has become the fourth leading bloodstream isolate in U.S. hospitals, surpassing many historically important bacterial pathogens. Estimates are that the United States spends approximately one billion dollars annually for Candida 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 with chemotherapy-induced myelosuppression, blood and marrow transplant recipients, and patients in critical care units on multiple antibiotics with venous, bladder, or endotracheal catheters. With the increasing use of potent immunosuppressive 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 on chemotherapy dose intensity in oncologic practice, and the growth in critical care, the number of patients at risk for fungal diseases is growing.

In recent years, the non-albicans Candida species have become increasingly recognized as fungal pathogens in immunocompromised patients. In cancer patients, 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 Candida species has been 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 Candida organisms. In bone marrow transplant recipients and in patients with acute leukemia, the mortality is in excess of 75%.

Mold pathogens other than Aspergillus are increasing. The agents of mucormycosis 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 therapeutics. 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 opportunistic fungal pathogens. Blood culture techniques have improved for detection of Candida, but still are not foolproof. Aspergillus is poorly diagnosed by bronchoscopy, 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 therapy has been amphotericin B, a polyene antifungal agent with considerable toxicity. This concern was somewhat eased by the development of lipid formulations of amphotericin B, permitting delivery of high doses of amphotericin B with substantially less toxicity. The introduction of antifungal azoles offered considerable promise, but because of limited spectrum of activity and poor or erratic bioavailability, little progress was realized until fluconazole was introduced a decade ago. With excellent bioavailability, little toxicity, and both oral and intravenous formulations, fluconazole was quickly embraced by clinicians treating immunocompromised 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.

New antifungal agents have been introduced into the clinical arena and more are arriving. Caspofungin, a member of a unique class of agents, the echinocandins, was licensed several years ago. This class of agents acts on the fungal cell wall, interfering 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 fungal pathogens, Candida and Aspergillus, and an outstanding safety profile, caspofungin 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, has been shown to be more effective than amphotericin B as first-line therapy of invasive aspergillosis, in a randomized trial. The drug is now available worldwide. New oral and intravenous formulations of itraconazole were approved to expand that agent's utility in clinical practice. Other broad spectrum azoles, such as posaconazole, are in clinical trials.

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 likelihood of therapeutic success low. This accounts for much of the extraordinarily high mortality. Accordingly, considerable attention has been paid to different antifungal strategies. Prophylaxis and empiric therapy have been evaluated in groups of immunocompromised patients at high risk for fungal infection. Today, there are good evidence- based data to support use of a broad array of antifungal agents and strategies for different patient settings.

Considerable progress has been achieved during the past decade. The cumulative mortality from Candida infections is finally beginning to recede. However, the collective mortality from aspergillosis continues to climb. Moreover, infection rates from fungi also are increasing. More work is needed. Yet, with new diagnostics and 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 syndromes in immunocompromised patients, describe the shifts in fungal pathogens and the reasons behind them, indicate the setting in which they cause illness and the risk 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.

This book is targeted to the clinician caring for immunocompromised patients at risk for invasive fungal infections. This includes transplant clinicians, critical care specialists, oncologists, stem cell transplant specialists, and infectious disease physicians. 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.

An international group of expert clinicians who have defined many of the pertinent 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.