In-vitro pharmacokinetic/pharmacodynamic model data suggest a potential role of new formulations of posaconazole against Candida krusei but not Candida glabrata infections

Posaconazole exhibits in-vitro activity against Candida glabrata and Candida krusei. Epidemiological cut-off values set by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the Clinical and Laboratory Standards Institute (CLSI) are 1/1 and 0.5/0.5 mg/L, respectively, but clinical breakpoints have not been established to date. This study explored the pharmacodynamics (PD) of posaconazole in a validated one-compartment in-vitro pharmacokinetic (PK)/PD model, and determined the probability of PK/PD target attainment (PTA) for the available formulations. Five C. glabrata and three C. krusei isolates with posaconazole minimum inhibitory concentrations (MICs) of 0.06–2 and 0.03–0.25 mg/L, respectively, were tested in the PK/PD model simulating different time–concentration profiles of posaconazole. The exposure–effect relationship fAUC0–24/MIC was described for EUCAST/CLSI methods, and PTA was calculated in order to determine PK/PD susceptibility breakpoints for oral solution (400 mg q12h), and intravenous (i.v.)/tablet formulations (300 mg q24h). Fungicidal activity (~2log kill) was found against the most susceptible C. glabrata isolate alone, and against all three C. krusei isolates. The corresponding EUCAST/CLSI PK/PD targets (fAUC0–24/MIC) were 102/79 for C. glabrata and 12/8 for C. krusei. Mean PTA was high (>95%) for C. glabrata isolates with EUCAST/CLSI MICs ≤0.03/≤0.03 mg/L for oral solution and ≤0.125/≤0.125 mg/L for i.v. and tablet formulations for the wild-type population. For C. krusei isolates, mean PTA was high (>95%) for EUCAST/CLSI MICs ≤0.25/≤0.5 mg/L for oral solution and ≤1/≤2 mg/L for i.v. and tablet formulations for the wild-type population. The use of posaconazole to treat C. glabrata infections is questionable. Intravenous and tablet formulations may be therapeutic options for the treatment of C. krusei infections, and oral exposure can be optimized with therapeutic drug monitoring (trough levels >0.6–0.9 mg/L).

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