Clinical breakpoints for the echinocandins and Candida revisited: Integration of molecular, clinical, and microbiological data to arrive at species-specific interpretive criteria

Rapid Detection of FKS -Associated Echinocandin Resistance in Candida glabrata

“…The goal of current echinocandin breakpoints is to distinguish C. glabrata isolates with a WT FKS from those containing FKS mutations that are unlikely to respond to echinocandin therapy (9). While mutations at almost every amino acid position within the FKS hot spot 1 and 2 regions confer some degree of resistance (20), recent studies have shown that the majority of mutations that affect C. glabrata susceptibility to the echinocandins are located within FKS1 and FKS2 HS1 regions.…”

“…Current echinocandin clinical breakpoints for C. glabrata were established by the CLSI for all echinocandins and by EUCAST for micafungin and anidulafungin. Breakpoints were specifically developed to identify C. glabrata harboring FKS mutations by considering multiple factors, such as ␤-1,3-D-glucan synthase enzyme kinetics and echinocandin pharmacokinetic and pharmacodynamic data (6,9). However, despite standardized methodologies, important limitations with the in vitro susceptibility testing cannot be ignored: first, the assay has a time-consuming setup and intrinsically slow turnaround time, requiring 24 to 48 h after isolate recovery; second, interlaboratory variability of caspofungin MICs has limited direct testing of this drug (10); and third, susceptible and resistant populations overlap (11).…”

Development of echinocandin resistance in Candida krusei isolates following exposure to micafungin and caspofungin in a BM transplant unit

“…For each patient, two later colonizing isolates recovered from digestive tract had two unknown missense mutation (S659P heterozygous and S659F homozygous, respectively) localized in the HS1 region. 9 These mutations were associated with increased caspofungin MICs in the corresponding isolates. Isolates of a given patient shared similar MLST profiles suggesting that they were genetically linked.…”

Treatment of Candida Glabrata With Micafungin: A Case Report and Brief Review of the Literature

“…For C. glabrata, the susceptible breakpoint for micafungin is lower (0.012 µg/mL) than for caspofungin or anidulafungin (0.06 mg/mL). Looking back at the susceptibilities retrospectively, the C. glabrata strain in this patient was resistant (0.5 µg/mL) to caspofungin but was susceptible (≤ 0.015 µg/mL) to micafungin [12]. Pharmacokinetic/ pharmacodynamic modeling techniques have provided more accurate information for current and future decision-support analysis.…”

“…Recently, the CLSI have reset the breakpoints for Candida based on pharmacokinetic and pharmacodynamic modeling. Echinocandin breakpoints for Candida are now species specific and in the case of C. glabrata, different for micafungin than to caspofungin [12]. Similarly, the European Committee on Antimicrobial Susceptibility Testing (EUCAST) have also set drug-specific breakpoints for Candida for each of the echinocandin drugs, although due to inter laboratory variation in MIC ranges, the breakpoints for caspofungin against C. glabrata have not yet been established by EUCAST [13].…”