In vitro pharmacokinetic/pharmacodynamic model data suggest a potential role of new formulations of posaconazole against C. krusei but not C. glabrata infections.
Int J Antimicrob Agents. 2021 Jan 25;:106291
Authors: Beredaki MI, Arendrup MC, Mouton JW, Meletiadis J
Posaconazole exhibits in vitro activity against Candida glabrata and Candida krusei. EUCAST/CLSI epidemiological cut off values are 1/1 and 0.5/0.5 mg/L, respectively, but clinical breakpoints are not yet established. We explored posaconazole pharmacodynamics in a validated one compartment in vitro pharmacokinetic/pharmacodynamic (PK/PD) model and determined the probability of pharmacodynamic target attainment for the available formulations. Five C. glabrata and three C. krusei isolates with posaconazole MICs (mg/L) 0.06-2 and 0.03-0.25, respectively were tested in the PK/PD model simulating different time-concentration profile of posaconazole. The exposure-effect relationship fAUC0-24/MIC was described for EUCAST/CLSI methods and the probability of target attainment (PTA) calculated in order to determine PK/PD susceptibility breakpoints for oral solution (o.s.): 400 mg q12h, and i.v./tablet formulations: 300 mg q24h. Fungicidal activity (∼2log kill) was found only against the most susceptible C. glabrata isolate but 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 and C. krusei. Mean PTAs were high (>95%) for C. glabrata isolates with EUCAST/CLSI MICs ≤0.03/≤0.03 for simulated o.s. and ≤0.125/≤0.125 for simulated i.v./tablet formulations bisecting wild-type population. For C. krusei isolates, mean PTAs were high (>95%) for EUCAST/CLSI MICs ≤0.25/≤0.5 for simulated o.s. and ≤1/2 for the simulated i.v. and tablet formulations which cover the wild-type population. Posaconazole use for the treatment of C. glabrata infections is questionable. The i.v./tablet formulation may be a therapeutic option for the treatment of C. krusei infections whereas o.s. exposure can be optimized with therapeutic drug monitoring (trough levels >0.6-0.9 mg/L).
PMID: 33508404 [PubMed - as supplied by publisher]