Course: New Developments in the Treatment of Invasive Fungal Disease
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New Developments in the Treatment of Invasive Fungal Disease

     John G. Bartlett, MD,* and John H. Rex, MD, FACP

Invasive fungal infections represent a major clinical challenge for physicians. In terms of patient population and epidemiology, these infections usually develop in patients who are immunocompromised and/or very ill. Moreover, the incidence of these infections continues to rise, largely because of the growing number of patients with human immunodeficiency virus and acquired immune deficiency syndrome (AIDS) and the more frequent use of immunosuppressive agents, antibiotics, and stem-cell, bone marrow, and solid-organ transplants.

Currently available therapies are often limited by lack of efficacy, suboptimal efficacy, and toxicity. The emergence of resistant fungi further limits the utility of current treatment strategies. Together, these factors explain why invasive fungal infections are associated with considerable morbidity and mortality and why new therapeutic strategies are needed.

The articles appearing in this issue of Advanced Studies in Medicine are based on presentations at the 12th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) held in Milan, Italy, April 24-27, 2002. The authors address the identification, assessment, and management of patients who are at risk; new therapies; and other issues of importance to infectious disease specialists, oncologists, hematologists, and specialists in intensive care and critical care.

In his presentation during an ECCMID symposium on infections of the central nervous system, Dr Bart-Jan Kullberg focused on 3 opportunistic cerebral mycoses: zygomycosis, candidiasis, and aspergillosis. In his article, he reviews risk factors, presenting signs and symptoms, and treatment options for each of these mycoses, with special attention to 3 forms of Candida meningitis: chronic Candida meningitis, and Candida meningitis in patients with AIDS and in neurosurgery patients.

Prof Renée Grillot describes the population at highest risk for invasive aspergillosis, reviews how the infection is acquired, addresses the need for prevention, and suggests several measures for preventing nosocomial aspergillosis. Prof Grillot acknowledges the recent efforts of several working groups in Europe that have drafted or are currently drafting recommendations for preventing or reducing the risk of Aspergillus infections.

In his article on concurrent combination therapy with antifungal agents, Dr Manuel Cuenca-Estrella explores several combinations that have been used or proposed for the treatment of invasive fungal infections. These include amphotericin B plus flucytosine, amphotericin B plus azoles, azoles plus flucytosine, amphotericin B or azoles plus terbinafine, and amphotericin B or azoles plus caspofungin. Clinical trial data, which are available only for the first 3 combinations at this time, show that concurrent combination therapy is clearly superior to monotherapy in the treatment of cryptococcal meningitis and similar to monotherapy in the treatment of infections with other fungi. However, clinical trial data and clinical experience suggest that combination therapy could be an alternative to monotherapy for invasive infections caused by multiresistant fungi, as well as an alternative in patients who do not respond to monotherapy.

In reviewing the development of a genetically recombinant antibody for the treatment of candidiasis, Prof Ruth Matthews describes its in vitro effects on Candida species, as well as its effects in animal models and in small, open-label dose-ranging and safety studies involving humans. She also emphasizes that the antibody was specifically designed to work with other antifungal agents in combination regimens to increase efficacy and reduce mortality, risk of toxicity from amphotericin B, and risk of resistance.

The clinical update on invasive candidiasis includes a reprint of a groundbreaking randomized, double-blind study by Mora-Duarte and colleagues, comparing caspofungin with amphotericin B in the treatment of neutropenic and nonneutropenic patients with invasive candidiasis. In the modified intention-to-treat analysis, caspofungin was equivalent to amphotericin B in resolving symptoms of infection and eradicating Candida organisms after 14 days of intravenous therapy. In the analysis of evaluable patients, caspofungin was more effective than amphotericin B. In both analyses, caspofungin was associated with better tolerability, fewer drug-related and infusion-related adverse events, and a markedly lower incidence of hypokalemia and nephrotoxicity. In the accompanying commentary to the original article, Thomas J. Walsh, MD discusses the implications of this study. The last part of this clinical update section includes an interview with study investigator John R. Perfect, MD. Dr Perfect answers questions regarding the study results as they relate to the current available armamentarium against invasive candidiasis.

Also included in this publication are highlights of selected ECCMID poster presentations. Given the emergence of non-Candida albicans infections and the increasing resistance of azoles that have changed the pattern of invasive fungal infections usually seen in cancer patients, Dr M. Laverdi&Mac182;re and colleagues note the need to develop other antifungal agents. To this end, they compared the in vitro activity of caspofungin, fluconazole, itraconazole, and amphotericin B in fungemic yeasts recovered from cancer patients, using both the E test and the broth dilution M27A reference method of the National Committee for Clinical Laboratory Standards. Their results demonstrate that caspofungin, an echinocandin, is very active against Candida in cancer patients.

Dr Philippe M. Hauser and colleagues describe a rapid method they developed (polymerase chain reaction&Mac220;single-strand conformation polymorphism [PCR-SSCP]) to discriminate between dihydropteroate synthase (DHPS) gene mutations of Pneumocystis carinii associated with in vitro resistance to the sulfa drugs used to treat P carinii pneumonia. Dr Hauser and colleagues found 4 DHPS genotypes when applying PCR-SSCP to bronchoalveolar lavage specimens from 397 patients, with the mutant genotype M2 associated with sulfadoxine therapy and the M3 genotype associated with sulfamethoxazole therapy.

Drs Amar Safdar and T.W. Bannister report in their poster presentation that hematogenous candidiasis, which is common in immunocompromised patients, is a serious and often fatal complication, even in immunocompetent individuals. This was a major finding from their study of 81 consecutive episodes of fungemia in 75 hospitalized patients who were evaluated retrospectively for the presence of concurrent infections and medical conditions including cancer, coronary artery disease, diabetes, and renal failure.

Dr Hande Arslan and her associates report clinical and laboratory findings in 8 patients who developed invasive aspergillosis after receiving kidney (n = 4) or liver (n = 4) transplants. Definitive diagnosis of aspergillosis was made at autopsy in 5 patients, 2 of whom had received no antifungal therapy. Of the 3 living patients in whom aspergillosis was diagnosed, 1 died and 2 survived, prompting the investigators to recommend that antifungal therapy be initiated as soon as specimens have been obtained for microbiologic testing.

The continuing medical education test concludes this issue, which highlights new developments and provides new insights into the treatment of invasive fungal disease.

*Chief, Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; †Professor, Department of Medicine, Section of Infectious Diseases, University of Texas Medical School, Houston, Texas.

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Volume 3, Number 1A - January 2003
This CME Expires on January 31, 2005; no tests will be accepted after this date.

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