1973. Emerging Candida glabrata Resistance and Echinocandin Dosing: A Call to Arms!
Session: Poster Abstract Session: Antimicrobial Pharmacokinetics and Pharmacodynamics
Saturday, October 29, 2016
Room: Poster Hall
Background: The rapid development of echinocandin resistance in C. glabrata is a growing concern for practitioners. This trend provides the impetus to question whether current dosing standards provide efficacious drug exposures. PK-PD target attainment analyses, evaluating FDA-approved anidulafungin, micafungin, and caspofungin dosing regimens for candidemia, were carried out to elucidate which were PK-PD-optimized for C. glabrata.

Methods: Published population PK models [J Clin Pharmacol 2004; 44:590-598, ICAAC 2008; Abstr A-011, Antimicrob Agents Chemother 2013; 57:1664-1671] were used to conduct Monte Carlo simulations (n=2000). The intravenous dosing regimens evaluated were anidulafungin 200 mg followed by 100 mg daily (q24h), micafungin 100 mg q24h, and caspofungin 70 mg followed by 50 mg q24h. Individual free-drug plasma AUC values from time zero to 24 h (AUC0-24) were calculated for each agent on Days 1 to 14. MIC values for each agent were assigned to simulated patients individually based on C. glabrata MIC distributions [ICAAC 2015; Abstr M-849]. Free-drug plasma AUC0­24:MIC targets associated with 1-log10 CFU reductions from baseline of C. glabrata for anidulafungin (32), micafungin (9.45), and caspofungin (13.5), derived from neutropenic murine disseminated candidiasis models, were used [Antimicrob Agents Chemother 2010; 54:2497-2506]. Percent probabilities of PK-PD target attainment were computed on each day of therapy for each dosing regimen. Additional regimens were assessed to identify PK-PD optimized dosing regimens.

Results: Across Days 1 to 14, percent probabilities of PK-PD target attainment were ≤5.40, ≥48.9, and ≥94.4% for the FDA-approved anidulafungin, micafungin, and caspofungin dosing regimens, respectively (Figure). Anidulafungin doses providing high probabilities of PK-PD target attainment were above the maximum dose studied in clinical trials. Percent probabilities ≥87.6% were achieved for micafungin 200 mg followed by 150 mg q24h.

Conclusion: These analyses revealed disparities among FDA-approved echinocandin dosing regimens for candidemia when examined from a PK-PD perspective in the context of C. glabrata. Anidulafungin and micafungin dosing regimens were found to be suboptimal while the caspofungin regimen yielded high percent probabilities of PK-PD target attainment.

Justin C. Bader, Pharm.D., MBA, Elizabeth A. Lakota, Pharm.D., M.S., Sujata Bhavnani, Pharm.D., M.S. and Paul G. Ambrose, Pharm.D., FIDSA, Institute for Clinical Pharmacodynamics, Schenectady, NY


J. C. Bader, None

E. A. Lakota, None

S. Bhavnani, None

P. G. Ambrose, None

Findings in the abstracts are embargoed until 12:01 a.m. CDT, Wednesday Oct. 26th with the exception of research findings presented at the IDWeek press conferences.