Breaking New Ground: An Evaluation of Susceptibility Breakpoints for Echinocandins against Candida Species

Abstract

Abstract Background The increasing prevalence of resistant Candida species has led to renewed interest in evaluating the utility of echinocandins. PK-PD target attainment analyses are increasingly used to inform decisions about susceptibility breakpoints. We carried out such analyses to evaluate anidulafungin, micafungin, and caspofungin Clinical and Laboratory Standards Institute (CLSI) susceptibility breakpoints for C. Albicans, C. glabrata, and C. parapsilosis. Methods Monte Carlo simulations (n = 2000) were conducted using published population PK models [J Clin Pharmacol 2004; 44:590–598, ICAAC 2008; Abstr A-011, AAC 2013; 57:1664–1671]. The following labeled intravenous dosing regimens for the treatment of candidemia were evaluated: anidulafungin 200 mg followed by 100 mg daily, micafungin 100 mg daily, and caspofungin 70 mg followed by 50 mg daily. Day 1 free-drug plasma AUC values were calculated for simulated patients after administration of each agent. Free-drug plasma AUC:MIC ratio targets associated with 1-log10 CFU reductions from baseline of C. Albicans and C. glabrata for anidulafungin, micafungin, and caspofungin, derived from neutropenic murine disseminated candidiasis models, were used [AAC 2007; 52:539–550, AAC 2010; 54:2497–2506]. Similar such targets for C. parapsilosis were utilized to evaluate caspofungin and micafungin. Percent probabilities of PK-PD target attainment were computed by MIC. The results were evaluated in the context of MIC distributions for each pathogen from a collection of isolates obtained worldwide from 2014 to 2015 [ECCMID 2017; Abstr P1748]. Results Among the CLSI susceptibility breakpoints evaluated, only one was supported by the analysis results shown in Figure 1 (caspofungin vs. C. glabrata), and only one other susceptibility breakpoint was within one dilution of the highest MIC at which the percent probability of PK-PD target attainment was ≥90% (anidulafungin vs. C. glabrata). All other susceptibility breakpoints were ≥2 dilutions above this MIC. Conclusion These results demonstrate the need to re-evaluate the echinocandin susceptibility breakpoints for Candida spp. Establishing appropriate susceptibility breakpoints will ensure appropriate prescribing and optimal patient outcomes. Disclosures All authors: No reported disclosures.