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Disclaimer: CME certification for these activities has expired. All information is pertinent to the timeframe in which it was released.


New Developments in the Treatment of Invasive Fungal Disease


GOAL
To provide physicians with the most current information on new advances in the treatment of invasive fungal disease.

TARGET AUDIENCE
This activity is designed for infectious disease specialists, oncologists, hematologists, critical care specialists, transplant surgeons, and interventional cardiologists. No prerequisites required.

LEARNING OBJECTIVES
The Johns Hopkins University School of Medicine takes responsibility for the content, quality, and scientific integrity of this CME activity. At the conclusion of this activity, participants should be able to:

  • Identify fungal infection of the central nervous system.
  • Understand trends in invasive fungal infections, including trends in cryptococcosis and prevention of aspergillosis.
  • Monitor response to treatment and know how to decide early if a patient is failing therapy.
  • Understand when combinations of antifungals are beneficial.
  • Describe the effects of a genetically recombinant antibody against candidiasis.

ACCREDITATION STATEMENT
The Johns Hopkins University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to sponsor continuing medical education for physicians.

CREDIT DESIGNATION STATEMENT
The Johns Hopkins University School of Medicine designates this educational activity for a maximum of 2 category 1 credits toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the activity.

The estimated time to complete this educational activity: 2 hours.

Release date: January 15, 2003. Expiration date: January 15, 2005.

This continuing education activity was produced under the supervision of John G. Bartlett, MD, Chief, Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.

DISCLAIMER STATEMENT
The opinions and recommendations expressed by faculty and other experts whose input is included in this program are their own. This enduring material is produced for educational purposes only. Use of Johns Hopkins University School of Medicine name implies review of educational format design and approach. Please review the complete prescribing information of specific drugs or combinations of drugs, including indications, contraindications, warnings and adverse effects, before administering pharmacologic therapy to patients.

This program is supported by an unrestricted educational grant from Merck & Co, Inc.

Advanced Studies in Medicine (ISSN-1530-3004) is published by Galen Publishing, LLC, an HMG Company. P.O. Box 340, Somerville, NJ 08876. (908) 253-9001. Web site: www.galenpublishing.com. Copyright ©2001 by Galen Publishing, LLC. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, without first obtaining permission from the publisher. Bulk postage paid at Somerville, NJ Post Office and at additional mailing offices. Advanced Studies in Medicine is a registered trademark of The Healthcare Media Group, LLC. Printed on acid-free paper. BPA Membership applied for December 2000.

Full Disclosure Policy Affecting CME Activities:
As a sponsor accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of Johns Hopkins University School of Medicine to require the disclosure of the existence of any significant financial interest or any other relationship a faculty member or a sponsor has with the manufacturer(s) of any commercial product(s) discussed in an educational presentation. Faculty Advisors and Participating Faculty reported the following:

PROGRAM DIRECTORS

    John G. Bartlett, MD
    Professor
    Department of Medicine
    Chief
    Division of Infectious Diseases
    Johns Hopkins University School of Medicine
    Baltimore, Maryland
    • Dr Bartlett reports serving on the HIV advisory board for Abbott Laboratories and Merck & Co, Inc.

    John H. Rex, MD, FACP
    Professor
    Department of Medicine
    Section of Infectious Diseases
    University of Texas Medical School
    Houston, Texas
    • Dr Rex reports receiving grants and/or research support from, serving as a consultant to, or receiving honoraria from Bristol-Myers Squibb Company; Fujisawa Pharmaceutical Co, Ltd; Gilead Sciences, Inc; Janssen Pharmaceutica; Merck & Co, Inc; Ortho Biotech Products, LP; Pfizer Inc; Schering-Plough Corporation; Lipsome Company, Inc; and Versicor Inc.

PARTICIPATING FACULTY

    Manuel Cuenca-Estrella, MD, PhD
    Clinical Researcher
    Unidad de Micologia
    Instituto de Salud Carlos III
    Centro Nacional de Microbiologia
    Madrid, Spain
    • Dr Cuenca-Estrella reports no financial or advisory relationships with pharmaceutical companies related to this activity.

    Renée Grillot, PhD
    Professor
    Parasitologie-Mycologie Médicale
    Centre Hospitalier Universitaire et Université Joseph Fourier
    Grenoble, France
    • Prof Grillot reports no financial or advisory relationships with pharmaceutical companies related to this activity.

    Bart-Jan Kullberg, MD
    Associate Professor of Medicine
    Department of Internal Medicine
    University Hospital Nijmegen
    Nijmegen, The Netherlands
    • Dr Kullberg reports receiving grants and/or research support from Pfizer Inc, and receiving honoraria from Pfizer Inc; Schering-Plough Corporation; and Ortho Biotech Products, LP.

    Ruth Matthews, MD, PhD, FRCPath
    Research and Development Director
    NeuTec Pharma plc
    Manchester Royal Infirmary
    Manchester, United Kingdom
    • Prof Matthews is the Founding Director/Research and Development Director of NeuTec Pharma plc.

    John R. Perfect, MD
    Professor of Medicine
    Associate Professor of Microbiology
    Director, Mycology Research Unit
    Duke University Medical Center
    Durham, North Carolina
    • Dr Perfect reports receiving grants and/or research support from Elan Corporation; Fujisawa Pharmaceutical Co, Ltd; Merck & Co, Inc; Pfizer Inc; Pliva dd; and Schering-Plough Corporation.

Notice:
In accordance with the ACCME Standards for Commercial Support, the audience is advised that one or more articles in this continuing medical education activity contains reference(s) to unlabeled or unapproved uses of drugs or devices. The following faculty members have disclosed that their articles have referenced the following unlabeled/unapproved uses of drugs or products:

Posaconazole — Dr Kullberg
Mycograb® — Prof Matthews

All other faculty have indicated that they have not referenced unlabeled/unapproved uses of drugs or devices.

Advanced Studies in Medicine provides disclosure information from contributing authors, lead presenters, and participating faculty. Advanced Studies in Medicine does not provide disclosure information from authors of abstracts and poster presentations. The reader shall be advised that these contributors may or may not maintain financial relationships with pharmaceutical companies.

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. Laverdière 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–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.

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





Johns Hopkins Advanced Studies in Medicine (ISSN-1558-0334), is published by Galen Publishing, LLC, d/b/a ASiM, PO Box 340, Somerville, NJ 08876. (908) 253-9001. Copyright ©2012 by Galen Publishing. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, without first obtaining permission from the publisher. ASiM is a registered trademark of The Healthcare Media Group, LLC.