Abstract
Invasive fungal infections (IFIs) are associated with high mortality rates and timely appropriate antifungal therapy is essential for good outcomes. Emerging antifungal resistance among Candida and Aspergillus spp., the major causes of IFI, is concerning and has led to the increasing incorporation of in vitro antifungal susceptibility testing (AST) to guide clinical decisions. However, the interpretation of AST results and their contribution to management of IFIs remains a matter of debate. Specifically, the utility of AST is limited by the delay in obtaining results and the lack of pharmacodynamic correlation between minimal inhibitory concentration (MIC) values and clinical outcome, particularly for molds. Clinical breakpoints for Candida spp. have been substantially revised over time and appear to be reliable for the detection of azole and echinocandin resistance and for outcome prediction, especially for non-neutropenic patients with candidemia. However, data are lacking for neutropenic patients with invasive candidiasis and some non-albicans Candida spp. (notably emerging Candida auris). For Aspergillus spp., AST is not routinely performed, but may be indicated according to the epidemiological context in the setting of emerging azole resistance among A. fumigatus. For non-Aspergillus molds (e.g., Mucorales, Fusarium or Scedosporium spp.), AST is not routinely recommended as interpretive criteria are lacking and many confounders, mainly host factors, seem to play a predominant role in responses to antifungal therapy. This review provides an overview of the pre-clinical and clinical pharmacodynamic data, which constitute the rationale for the use and interpretation of AST testing of yeasts and molds in clinical practice.
Highlights
Appropriate antifungal therapy is a key determinant for the outcome of invasive fungal infections (IFIs)
IC: invasive candidiasis, AST: antifungal susceptibility testing, MIC: minimal inhibitory concentration, NAC: non-albicans Candida spp., NCCLS: National Committee for Clinical Laboratory Standards, CLSI: Clinical and Laboratory Standards Institute, European Committee on Antimicrobial Susceptibility Testing (EUCAST): European Committee on Antimicrobial Susceptibility testing, SYO: Sensititre YeastOneTM, AUC = area under the time-concentration curve, Dosewn = dose normalized to weight, NS: not specified
Studies correlating MIC/outcome and limited to invasive aspergillosis (IA) are scarce, but are needed with the raising concern of emerging azole resistance. Their results are controversial (Table 4), which is mainly due to the low proportion of cyp51A mutant isolates and the confounding factor of non-azole drugs
Summary
Appropriate antifungal therapy is a key determinant for the outcome of invasive fungal infections (IFIs). The artificial in vitro conditions of testing by microbroth dilution method may differ considerably from the actual pathophysiological environment of IFIs. For example, invasive infections by molds affect mainly solid tissues (rather than biological fluids), have relatively low fungal inoculum (compared to the very high spore concentrations used in AST), and are often accompanied by tissue infarction and necrosis that might preclude appropriate drug penetration at the site of infection. Sessing the correlation between drug exposure/MIC and therapeutic response These data addition, the chemical composition of AST growth media differs from real pathogenic conditions regarding important elements for fungal growth Because of the delay in culture results, initial antifungal therapy is usually empirical and switched to targeted treatment
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