Pharmacodynamic Optimization for the Treatment of Invasive Candida auris Infection

Abstract

Background Candida auris is an emerging, nosocomial multidrug-resistant threat with high treatment failure rate and mortality. The optimal antifungal agent to use and susceptibility breakpoints are based on limited clinical data.Methods Nine clinical C. auris strains were used. MICs were determined by CLSI standards. Drug treatment studies consisted of: fluconazole (FLC) dose range 0.78–200 mg/kg/12 h, micafungin (MFG) dose range 0.3125–80 mg/kg/24 h, or amphotericin B deoxycholate (AMB) dose range 0.0.78–20 mg/kg/24 hours. Plasma PK was previously determined in the murine model for all three drugs. A 96 h neutropenic murine model of invasive candidiasis (IC) was used for all studies. The Emax Hill equation was used to model the dose–response data to PK/PD index AUC/MIC (FLC and MFG) and Cmax/MIC (AMB). The static and 1 log kill doses (when achieved) and the associated PK/PD targets (AUC/MIC or Cmax/MIC) were determined and compared with previous murine IC studies with C. albicans, C. glabrata, and C. parapsilosis.ResultsMIC range: FLC 2–256 mg/l, MFG 0.125–4 mg/l, and AMB 0.38–6 mg/l. Dose-dependent activity was observed with all three drugs. Net stasis was achieved against seven strains for FLC, eight strains for MFG, and eight strains for AMB. However, MFG performed significantly better than comparators for cidal endpoints. A 1 log kill endpoint was achieved in eight strains for MFG, whereas this endpoint was only achieved in one strain for FLC and three strains for AMB. PK/PD analyses demonstrated a strong relationship between AUC/MIC and treatment outcome for FLC (R2 0.61) and MFG (R2 0.77); and Cmax/MIC and treatment outcome for AMB (R2 0.64). The median static dose and 1 log kill dose (MFG only) and associated AUC/MIC or Cmax/MIC values are shown (Table).Stasis1 log killDrugDose (mg/kg/24 hours)AUC/MIC or [Cmax/MIC]Dose (mg/kg/24 hours)AUC/MICFLC10726.3MFG1.2553.73.36130AMB3.86[0.87]ConclusionMFG was the most potent drug over the dose range achieving up to 2 log kill against eight of nine strains. PK/PD targets for C. auris against FLC and AMB were similar to other Candida species; however, MFG targets were ≥20-fold lower than C. albicans, C. glabrata, and C. parapsilosis. Using the median stasis targets and human PK for each drug, resistance thresholds could be 16 mg/l for FLC, 2–4 mg/l for MFG, and 1–2 mg/l for AMB.Disclosures All authors: No reported disclosures.