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

Drug Resist Updat. 2011 Jun;14(3):164-76. doi: 10.1016/j.drup.2011.01.004. Epub 2011 Feb 24.

Abstract

The CLSI established clinical breakpoints (CBPs) for caspofungin (CSF), micafungin (MCF) and anidulafungin (ANF) versus Candida. The same CBP (susceptible (S): MIC ≤ 2 mcg/ml; non-S: MIC > 2 mcg/ml) was applied to all echinocandins and species. More data now allow reassessment of these CBPs. We examined cases of echinocandin failure where both MICs and fks mutations were assessed; wild type (WT) MICs and epidemiological cutoff values (ECVs) for a large Candida collection; molecular analysis of fks hotspots for Candida with known MICs; and pharmacokinetic and pharmacodynamic (PK/PD) data. We applied these findings to propose new species-specific CBPs for echinocandins and Candida. Of 18 candidiasis cases refractory to echinocandins and with fks mutations, 28% (CSF), 58% (ANF) and 66% (MCF) had MICs in the S category using CBP of ≤ 2 mcg/ml, while 0-8% would be S using CBP of ≤ 0.25 mcg/ml. WT MIC distributions revealed ECV ranges of 0.03-0.25 mcg/ml for all major species except C. parapsilosis (1-4 mcg/ml) and C. guilliermondii (4-16 mcg/ml). Among Candida tested for fks mutations, only 15.7-45.1% of 51 mutants were detected using the CBP for NS of >2 mcg/ml. In contrast, a cutoff of >0.25 mcg/ml for C. albicans, C. tropicalis, C. krusei, and C. dubliniensis detected 85.6% (MCF) to 95.2% (CSF) of 21 mutant strains. Likewise, a cutoff of >0.12 mcg/ml for ANF and CSF and of >0.06 mcg/ml for MCF detected 93% (ANF) to 97% (CSF, MCF) of 30 mutant strains of C. glabrata. These data, combined with PK/PD considerations, support CBPs of ≤ 0.25 mcg/ml (S), 0.5 mcg/ml (I), ≥ 1 (R) for CSF/MCF/ANF and C. albicans, C. tropicalis and C. krusei and ≤ 2 mcg/ml (S), 4 mcg/ml (I), and ≥ 8 mcg/ml (R) for these agents and C. parapsilosis. The CBPs for ANF and CSF and C. glabrata are ≤ 0.12 mcg/ml (S), 0.25 mcg/ml (I), and ≥ 0.5 mcg/ml (R), whereas those for MCF are ≤ 0.06 mcg/ml (S), 0.12 mcg/ml (I), and ≥ 0.25 mcg/ml (R). New, species-specific CBPs for Candida and the echinocandins are more sensitive to detect emerging resistance associated with fks mutations, and better able to predict risk for clinical failure.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Anidulafungin
  • Antifungal Agents / administration & dosage*
  • Antifungal Agents / therapeutic use
  • Candida / drug effects*
  • Candida / genetics
  • Candidiasis / drug therapy*
  • Candidiasis / metabolism
  • Candidiasis / microbiology
  • Caspofungin
  • Drug Resistance, Fungal / drug effects*
  • Drug Resistance, Fungal / genetics
  • Echinocandins / administration & dosage
  • Echinocandins / therapeutic use
  • Fluconazole / pharmacology
  • Glucosyltransferases / antagonists & inhibitors*
  • Glucosyltransferases / metabolism
  • Humans
  • Inhibitory Concentration 50
  • Lipopeptides / administration & dosage
  • Lipopeptides / therapeutic use
  • Micafungin
  • Microbial Sensitivity Tests
  • Mutation
  • Randomized Controlled Trials as Topic
  • Species Specificity
  • Treatment Outcome
  • beta-Glucans / metabolism

Substances

  • Antifungal Agents
  • Echinocandins
  • Lipopeptides
  • beta-1,3-D-glucan
  • beta-Glucans
  • Fluconazole
  • Anidulafungin
  • Glucosyltransferases
  • beta-1,3-D-glucan synthetase, Candida albicans
  • Caspofungin
  • Micafungin