Voriconazole efficacy against Candida glabrata and Candida krusei: preclinical data using a validated in vitro pharmacokinetic/pharmacodynamic model

Abstract

Background Voriconazole exhibits in vitro activity against Candida glabrata and Candida krusei (EUCAST/CLSI epidemiological cut-off values 1/0.25 and 1/0.5 mg/L, respectively). Yet, EUCAST found insufficient evidence to set breakpoints for these species. We explored voriconazole pharmacodynamics (PD) in an in vitro dynamic model simulating human pharmacokinetics (PK). Methods Four C. glabrata and three C. krusei isolates (voriconazole EUCAST and CLSI MICs of 0.03–2 mg/L) were tested in the PK/PD model simulating voriconazole exposures (t½ ∼6 h q12h dosing for 3 days). PK/PD breakpoints were determined calculating the PTA for exposure indices fAUC0–24/MIC associated with half-maximal activity (EI50) using Monte Carlo simulation analysis. Results Fungal load increased from 3.60 ± 0.35 to 8.41 ± 0.24 log10 cfu/mL in the drug-free control, with a maximum effect of ∼1 log10 kill of C. glabrata and C. krusei isolates with MICs of 0.06 and 0.25 mg/L, respectively, at high drug exposures. The 72 h log10 cfu/mL change versus fAUC0–24/MIC relationship followed a sigmoid curve for C. glabrata (R2=0.85–0.87) and C. krusei (R2=0.56–0.76) with EI50 of 49 (32–76) and 52 (33–78) fAUC/MIC for EUCAST and 55 (31–96) and 80 (42–152) fAUC/MIC for CLSI, respectively. The PTAs for C. glabrata and C. krusei isolates with EUCAST/CLSI MICs ≤0.125/≤0.06 mg/L were >95%. Isolates with EUCAST/CLSI MICs of 0.25–1/0.125–0.5 would require trough levels 1–4 mg/L; isolates with higher MICs would not attain the corresponding PK/PD targets without reaching toxicity. Conclusions The in vitro PK/PD breakpoints for C. glabrata and C. krusei for EUCAST (0.125 mg/L) and CLSI (0.06 mg/L) bisected the WT populations. Trough levels of >4 mg/L, which are not clinically feasible, are necessary for efficacy against WT isolates.

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

“…On the contrary, voriconazole had no fungicidal effect against C. albicans (1 log increase from initial inoculum), yet the EI 50 which corresponded to an increase of approximately 2 log 10 CFU/mL from initial inoculum resulted in a PK/PD susceptibility breakpoint that was equal to the susceptibility breakpoint of EUCAST for voriconazole and C. albicans , validating the clinical relevance of EI 50 [26] . Although voriconazole had a fungicidal effect against C. glabrata and C. krusei isolates (0.5-1 log kill maximal effect), the corresponding EI 50 values indicated that these species are not a good target for voriconazole [27] . The present authors have shown previously that the in-vitro EI 50 in serum-free media corresponded to near stasis in animal neutropenic models [ 15 , 26 ].…”

Effectiveness of fluconazole as antifungal prophylaxis in cancer patients undergoing chemotherapy, radiotherapy, or immunotherapy: systematic review and meta‐analysis

“…In the study of Morgenstern et al., 1999 [42], for example, a double‐placebo method would have been required, but this approach was rejected because it was considered unreasonable to ask patients to take large volumes of liquid medicines, which many find unpalatable and because this would probably reduce compliance [42]. A series of powerful antifungals like voriconazole and posoconazole [58, 59] was not assessed due to the lack of studies within the eligibility criteria of this review. This aspect in conjunction with the low number of studies in the pooling by type of antifungal therapy limits the results regarding the choice of an antifungal as a prophylactic agent for the development of oral fungal diseases.…”

Voriconazole Admixed with PMMA—Impact on Mechanical Properties and Efficacy

“…The parameters are the composition of the cement, the porosity, and the preparation of the cement. The addition of radio opacifiers and antibiotics to bone cement slightly decreases its mechanical strength [26,[30][31][32], as do antifungals such as voriconazole.…”