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J Antimicrob Chemother. 2019 Oct 29. pii: dkz425. doi: 10.1093/jac/dkz425. [Epub ahead of print]

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

Author information

1
Clinical Microbiology Laboratory, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
2
Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Center, Rotterdam, The Netherlands.
3
Unit of Mycology, Statens Serum Institut, Copenhagen, Denmark.
4
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
5
Department of Clinical Microbiology, University of Copenhagen, Copenhagen, Denmark.

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.

PMID:
31665417
DOI:
10.1093/jac/dkz425

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