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

Disclosures:

J. C. Bader, None

E. A. Lakota, None

S. Bhavnani, None

P. G. Ambrose, None

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