Invasive Mycoses: Strategies for Effective Management

https://doi.org/10.1016/j.amjmed.2011.10.009Get rights and content

Abstract

Effective management of invasive fungal infections (IFIs) depends on early individualized therapy that optimizes efficacy and safety. Considering the negative consequences of IFI, for some high-risk patients the potential benefits of prophylactic therapy may outweigh the risks. When using a prophylactic, empiric, or preemptive therapeutic approach, clinicians must take into account the local epidemiology, spectrum of activity, pharmacokinetic and pharmacodynamic parameters, and safety profile of different antifungal agents, together with unique host-related factors that may affect antifungal efficacy or safety. Therapeutic drug monitoring is increasingly recognized as important or necessary when employing lipophilic triazoles (itraconazole, voriconazole, posaconazole) or flucytosine. Because early diagnostics remain limited for uncommon, yet emerging opportunistic molds (e.g., Mucorales), and treatment delay is associated with increased mortality, early effective management often depends on a high index of suspicion, taking into account predisposing factors, host cues favoring mucormycosis, and local epidemiology. Antifungal options for mucormycosis are limited, and optimal management depends on a multimodal approach that includes early diagnosis/clinical suspicion, correction of underlying predisposing factors, radical debridement of affected tissues, and extended antifungal therapy. This article discusses strategies for the effective management of invasive mycoses, with a particular focus on antifungal hepatotoxicity.

Section snippets

General Approaches to the Management of Invasive Fungal Infections

Four general approaches are available for the management of IFIs: prophylaxis and empiric, preemptive, or targeted therapy.12, 13 A prophylactic approach may be warranted when a patient is at sufficient risk of IFI and its negative consequences to justify the cost and potential exposure of an uninfected individual to drug-related toxicity. In addition to increased costs and possible exposure to drug-related toxicities, prophylaxis also provides an environment for development of drug-resistant

Factors Influencing Selection of Antifungal Agent

Antifungal agents available for the management of IFIs include polyenes (amphotericin B deoxycholate and 3 lipid formulations of amphotericin B), triazoles (fluconazole, itraconazole, voriconazole, and posaconazole), echinocandins (caspofungin, micafungin, and anidulafungin), and flucytosine.31, 32 These agents differ in spectrum of activity, PK/PD properties, indications, safety, cost, and ease of use or convenience. All of these factors are important to consider when selecting an antifungal

Therapeutic Drug Monitoring

In a recent review, Lewis11 listed 3 general criteria useful for identifying pharmaceutical agents as suitable candidates for therapeutic drug monitoring: (1) unpredictable population PKs or an unpredictable dose-response relationship, (2) a narrow therapeutic window, and (3) a clinically defined therapeutic range. Of the currently available antifungal agents, only the lipophilic triazoles (itraconazole, voriconazole, and posaconazole) and flucytosine meet all 3 criteria well enough to be

Case 1

A 44-year-old man with myelodysplastic syndrome treated >90 days ago with a matched unrelated-donor, allogeneic HSCT, and a history of extensive graft-versus-host disease (GVHD) presented with new pleural-based nodular lesions, pleurisy, and GVHD of the skin. He was admitted to the hospital. A medical history revealed the patient had been receiving a prophylactic anti-infective regimen consisting of liposomal amphotericin B (3 times a week), valganciclovir, sulfamethoxazole-trimethoprim, and

Case 2

A 58-year-old woman with leukemia and presumed aspergillosis presented with progressing pneumonia despite what seemed to be appropriate antifungal therapy (voriconazole, 6 mg/kg IV every 12 hours for the first day, followed by 4 mg/kg IV every 12 hours thereafter).29

This is a patient type commonly seen in tertiary care hematology centers—i.e., a patient with documented or presumed pulmonary aspergillosis who exhibits infectious disease progression despite recommended first-line therapy. The

Mucormycosis

Mucormycosis is an important and increasing (although still relatively uncommon) cause of morbidity and mortality in immunocompromised patients. In the current environment, clinicians should consider possible mucormycosis in patients with signs and symptoms of infection, particularly in those with progressing disease despite antifungal treatment covering most other fungal pathogens.

Summary

When presented with a patient with or at risk for IFI, clinicians must weigh various factors when individualizing therapy to optimize outcomes. Antifungal drug options have increased over recent years, and the various agents differ in terms of spectrum of activity, PK/PDs, indications, safety, cost, and ease of use. These differences should be considered and an attempt made to match these drug-related characteristics with host-related factors to provide the best chance for IFI eradication with

Author Disclosures

The author of this article has disclosed the following industry relationships:

  • Dimitrios P. Kontoyiannis, MD, ScD, has received consulting fees and/or fees for non-CME services from Astellas, Enzon, Merck & Co., Inc., Pfizer and funds for contracted research from Astellas, Enzon, Merck & Co., Inc.

Acknowledgments

I thank Russell E. Lewis, PharmD, for useful comments. Editorial support for this publication was provided by Global Education Exchange, Inc., Freehold, New Jersey.

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    Statement of author disclosure: Please see the Author Disclosures section at the end of this article.

    This supplement is in part based on a closed roundtable meeting that was held June 7, 2011 in New York City and was jointly sponsored by Postgraduate Institute for Medicine and Global Education Exchange through an educational grant from Merck & Co., Inc. The webinar was peer-reviewed and accepted as a free multimedia activity of The American Journal of Medicine and is available at www.antifungaltherapy2.net.

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