Antifungal Drug Resistance: Mechanisms, Epidemiology, and Consequences for Treatment

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Abstract

Antifungal resistance continues to grow and evolve and complicate patient management, despite the introduction of new antifungal agents. In vitro susceptibility testing is often used to select agents with likely activity for a given infection, but perhaps its most important use is in identifying agents that will not work, i.e., to detect resistance. Standardized methods for reliable in vitro antifungal susceptibility testing are now available from the Clinical and Laboratory Standards Institute (CLSI) in the United States and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) in Europe. Data gathered by these standardized tests are useful (in conjunction with other forms of data) for calculating clinical breakpoints and epidemiologic cutoff values (ECVs). Clinical breakpoints should be selected to optimize detection of non–wild-type (WT) strains of pathogens, and they should be species-specific and not divide WT distributions of important target species. ECVs are the most sensitive means of identifying strains with acquired resistance mechanisms. Various mechanisms can lead to acquired resistance of Candida species to azole drugs, the most common being induction of the efflux pumps encoded by the MDR or CDR genes, and acquisition of point mutations in the gene encoding for the target enzyme (ERG11). Acquired resistance of Candida species to echinocandins is typically mediated via acquisition of point mutations in the FKS genes encoding the major subunit of its target enzyme. Antifungal resistance is associated with elevated minimum inhibitory concentrations, poorer clinical outcomes, and breakthrough infections during antifungal treatment and prophylaxis. Candidemia due to Candida glabrata is becoming increasingly common, and C glabrata isolates are increasingly resistant to both azole and echinocandin antifungal agents. This situation requires continuing attention. Rates of azole-resistant Aspergillus fumigatus are currently low, but there are reports of emerging resistance, including multi-azole resistant isolates in parts of Europe.

Section snippets

Case Study: Multidrug Resistance (MDR) in Candida glabrata

The following is based on a case recently reported by Chapeland-Leclerc and coworkers3:

A 9-year-old girl with Fanconi anemia who underwent a hematopoietic stem cell transplant (HSCT) becomes fungemic with Candida glabrata. She is treated with antifungals from each of the major antifungal drug classes (sometimes in combination)—including flucytosine (5FC), fluconazole, voriconazole, liposomal amphotericin B, and caspofungin (CSF)—without success. Minimum inhibitory concentrations (MICs) of

Antifungal Resistance: Definitions

Antifungal resistance can be defined as microbiologic or clinical resistance, or as a composite of the two.4 Microbiologic resistance is said to occur when growth of the infecting organism or pathogen is inhibited by an antimicrobial agent concentration higher than the range seen for wild-type strains. Clinical resistance is defined by the situation in which the infecting organism is inhibited by a concentration of an antimicrobial agent that is associated with a high likelihood of therapeutic

Testing Methods for Antifungal Resistance

The need for reproducible, clinically relevant, antifungal susceptibility testing has been prompted by the increasing number of IFIs, the expanding use of new and established antifungal agents, and recognition of antifungal resistance as an important clinical problem.5, 6, 7 Currently, there are 2 independent standards for broth microdilution (BMD) susceptibility testing of Candida and filamentous fungi: the Clinical and Laboratory Standards Institute (CLSI) methods8, 9, 10, 11 and the European

Development of Breakpoints

Both CLSI and EUCAST have established clinical breakpoints for fluconazole and voriconazole versus Candida by taking into account the MIC distributions, pharmacokinetic (PK) and pharmacodynamic (PD) parameters, resistance mechanisms, and clinical outcomes as they relate to MIC values.10, 13, 14, 32 Initially with fluconazole, the CLSI did not allow for species-specific clinical breakpoints and assigned values of ≤8 μg/mL as susceptible (S), 16-32 μg/mL as susceptible dose-dependent (SDD), and

Mechanisms of Resistance

Each of the antifungal classes utilizes a different means to kill or inhibit the growth of fungal pathogens.41, 42, 43 Mechanisms of antifungal resistance are either primary or secondary, and are related to intrinsic or acquired characteristics of the fungal pathogen that interfere with the antifungal mechanism of the respective drug/drug class or that lower target drug levels. Resistance can also occur when environmental factors lead to colonization or replacement of a susceptible species with

Consequences of Antifungal Resistance

Antifungal resistance has consequences in terms of elevated MICs that are associated with poorer outcomes and breakthrough infections during antifungal treatment and prophylaxis. Antifungal resistance and its negative consequences can often be traced to acquisition of particular resistance mechanisms. The most obvious consequence of antifungal resistance may be seen in the results shown in Tables 2 and 3, where the clinical outcome was significantly poorer for those patients infected with

Epidemiology of Antifungal Resistance

Our understanding of the epidemiology of invasive fungal infections and associated resistance profiles has been enhanced considerably by data collected and published by various sentinel and population-based surveillance programs.1, 40, 50, 51, 52 Ever since the introduction of fluconazole in 1990 for the treatment of candidiasis, empirical antifungal therapy has been driven by fear of C glabrata.53, 54 Decreased susceptibility of C glabrata to fluconazole, and cross-resistance to other azoles,

Case Study: Azole-Resistant Central Nervous System (CNS) Aspergillosis

The following is based on a case recently reported in the Netherlands by van der Linden and coworkers69:

An 11-year-old girl with B cell lymphoma presented with cough and fever 7 months after beginning chemotherapy. She was admitted to the hospital and treated with antibiotics (vancomycin and ceftazidime). Her fever persisted, and a repeat chest x-ray showed a lobar infiltrate. Four days postadministration, the patient experienced a seizure that persisted for 2 hours despite antiepilepsy

Summary

In vitro antifungal susceptibility testing is now standardized internationally. The establishment of ECVs and new clinical breakpoints for azoles and echinocandins promises to provide a more sensitive means of detecting emerging resistance and to improve clinical utility of in vitro testing. Recent data regarding resistance mutations encompass both Candida and Aspergillus and document spread of antifungal resistance within hospitals and possibly the larger environment. Multidrug resistance in

Author Disclosures

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

Michael A. Pfaller, MD, has received consulting fees and grants for contracted research from Astellas, Merck & Co., Inc., Pfizer.

Acknowledgment

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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