Background. Posaconazole is more in vitro active against Candida albicans than fluconazole and approved for the treatment of oropharyngeal candidiasis but not invasive candidiasis (IC). We explored the efficacy of posaconazole against C. albicans in an in vitro pharmacokinetic-pharmacodynamic (PK-PD) model of IC and determined the probability of pharmacodynamic target attainment for the oral solution (o.s.) and i.v./tablet formulations. Methods. Three clinical C. albicans isolates (posaconazole MICs 0.008-0.25 mg/liter) were studied in the in vitro PK-PD dilution model simulating steady state posaconazole PK. The in vitro exposure-effect relationship fAUC0-24/MIC was described and compared with in vivo outcome in animals with IC. PK-PD susceptibility breakpoints and trough levels required for optimal treatment were determined for EUCAST and CLSI24h/48h methods, using the fAUC0-24/MIC associated with half-maximal activity (EI50) and Monte Carlo simulation analysis for o.s. (400 mg q12h) and i.v./tablet formulations (300 mg q24h). Results. The in vitro mean (95%CI) EI50 was 330 (183-597) fAUC0-24/MIC for CLSI24h and 169 (92-310) for EUCAST/CLSI48h methods, which are close to the near-stasis in vivo effect. The probability of target attainment for EI50 was estimated and for the wild-type isolates (MIC ≤ 0.06 mg/liter) it was low for the o.s. and higher than 95% for the i.v./tablet formulations for the EUCAST/CLSI48h but not for CLSI24h method. Non-wild-type isolates with EUCAST/CLSI48h MICs 0.125 and 0.25 mg/liter would require trough levels >1.2 and >2.4 mg/liter, respectively. Conclusion. Posaconazole i.v./tablet formulations may have a role in the therapy of invasive infections by wild-type C. albicans isolates provided a steady state is reached fast. A PK-PD susceptibility breakpoint at the ECOFF of 0.06 mg/liter was determined.

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CLSI and EUCAST susceptibility breakpoints for voriconazole and Candida albicans differ by one dilution (≤0.125 and ≤0.06 mg/liter, respectively) whereas the epidemiological cutoff values for EUCAST (ECOFF) and CLSI (ECV) are the same (0.03 mg/liter). We therefore determined the pharmacokinetic/pharmacodynamic (PK/PD) breakpoints of voriconazole against C. albicans for both methodologies with an in vitro PK/PD model, which was validated using existing animal PK/PD data. Four clinical wild-type and non-wild-type C. albicans isolates (voriconazole MICs, 0.008 to 0.125 mg/liter) were tested in an in vitro PK/PD model. For validation purposes, mouse PK were simulated and in vitro PD were compared with in vivo outcomes. Human PK were simulated, and the exposure-effect relationship area under the concentration-time curve for the free, unbound fraction of a drug from 0 to 24 h (fAUC0–24)/MIC was described for EUCAST and CLSI 24/48-h methods. PK/PD breakpoints were determined using the fAUC0–24/MIC associated with half-maximal activity (EI50) and Monte Carlo simulation analysis. The in vitro 24-h PD EI50 values of voriconazole against C. albicans were 2.5 to 5 (1.5 to 17) fAUC/MIC. However, the 72-h PD were higher at 133 (51 to 347) fAUC/MIC for EUCAST and 94 (35 to 252) fAUC/MIC for CLSI. The mean (95% confidence interval) probability of target attainment (PTA) was 100% (95 to 100%), 97% (72 to 100%), 83% (35 to 99%), and 49% (8 to 91%) for EUCAST and 100% (97 to 100%), 99% (85 to 100%), 91% (52 to 100%), and 68% (17 to 96%) for CLSI for MICs of 0.03, 0.06, 0.125, and 0.25 mg/liter, respectively. Significantly, >95% PTA values were found for EUCAST/CLSI MICs of ≤0.03 mg/liter. For MICs of 0.06 to 0.125 mg/liter, trough levels 1 to 4 mg/liter would be required to attain the PK/PD target. A PK/PD breakpoint of C. albicans voriconazole at the ECOFF/ECV of 0.03 mg/liter was determined for both the EUCAST and CLSI methods, indicating the need for breakpoint harmonization for the reference methodologies.

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.

Background The CLSI breakpoint for micafungin and Candida albicans is 0.25 mg/L, higher than the CLSI epidemiological cut-off value (0.03 mg/L) whereas the EUCAST values are identical (0.016 mg/L). We developed a novel in vitro dialysis-diffusion pharmacokinetic/pharmacodynamic (PK/PD) model, confirmed correlation to in vivo outcome and studied micafungin pharmacodynamics against Canida albicans. Methods Four C. albicans isolates, including a weak (F641L) and a strong (R647G) fks1 mutants, were studied using a 104 cfu/mL inoculum and RPMI medium with and without 10% pooled human serum. The exposure-effect relationship fAUC0–24/MIC was described for CLSI and EUCAST methodology. Monte Carlo simulation analysis included standard (100 mg i.v.) and higher (150–300 mg) doses q24h to determine the corresponding probability of target attainment (PTA). Results The in vitro PK/PD targets for stasis/1-log kill were 36/57 fAUC0–24/MIC in absence and 2.8/9.2 fAUC0–24/MIC in the presence of serum, and similar for wild-type and fks mutant isolates. The PTAs for both PK/PD targets were high (>95%) for EUCAST susceptible isolates but not for CLSI susceptible non-wild-type isolates (CLSI MICs 0.06–0.25 mg/L). 300 mg q24h was needed to attain PK/PD targets for non-wild-type isolates with CLSI MICs 0.06–0.125 mg/L and EUCAST MICs 0.03–0.06 mg/L. Conclusion The in vitro 1-log kill effect corresponded to stasis in animal model and mycological response in patients with invasive candidiasis, thereby validating the model for studying pharmacodynamics of echinocandins in vitro. EUCAST breakpoints were well supported by our findings but our data questions whether the current CLSI breakpoint, which is higher than the epidemiological cut-off values, is appropriate.