title: Clinical breakpoints for the echinocandins and Candida revisited: integration of molecular, clinical, and microbiological data to arrive at species-specific interpretive criteria.
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.
authors.affiliation: University of Iowa, Iowa City, United States. michael-pfaller@uiowa.edu
authors.forename: M A
authors.initials: MA
authors.lastname: Pfaller
authors.forename: D J
authors.initials: DJ
authors.lastname: Diekema
authors.forename: D
authors.initials: D
authors.lastname: Andes
authors.forename: M C
authors.initials: MC
authors.lastname: Arendrup
authors.forename: S D
authors.initials: SD
authors.lastname: Brown
authors.forename: S R
authors.initials: SR
authors.lastname: Lockhart
authors.forename: M
authors.initials: M
authors.lastname: Motyl
authors.forename: D S
authors.initials: DS
authors.lastname: Perlin
mesh_terms: D000077612:Anidulafungin; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D002175:Candida / Q000187:drug effects* / Q000235:genetics; D002177:Candidiasis / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D000077336:Caspofungin; D025141:Drug Resistance, Fungal / Q000187:drug effects* / Q000235:genetics; D054714:Echinocandins / Q000008:administration & dosage / Q000627:therapeutic use; D015725:Fluconazole / Q000494:pharmacology; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D055666:Lipopeptides / Q000008:administration & dosage / Q000627:therapeutic use; D000077551:Micafungin; D008826:Microbial Sensitivity Tests; D009154:Mutation; D011509:Proteoglycans; D016032:Randomized Controlled Trials as Topic; D013045:Species Specificity; D016896:Treatment Outcome; D047071:beta-Glucans / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D011509:Proteoglycans; D047071:beta-Glucans; C010770:polysaccharide-K; D015725:Fluconazole; D000077612:Anidulafungin; D005964:Glucosyltransferases; C559403:beta-1,3-D-glucan synthetase, Candida albicans; D000077336:Caspofungin; D000077551:Micafungin