Background: A recent randomized clinical trial showed that voriconazole-anidulafungin combinationtherapy may improve outcome of voriconazole monotherapy against invasive aspergillosis when drugswere combined at standard dosages (Marr e al Ann Intern Med. 2015). Whether alternative dosagescan maximize efficacy of combination therapy particularly against azole-resistant isolates is unknown.We therefore investigated the activity of voriconazole-anidulafungin combination against voriconazole-susceptible and -resistant Aspergillus fumigatususing different doses of anidulafungin in anin vitropharmacokinetic pharmacokinetic-pharmacodynamic model.
Material/Methods: Four clinical A. fumigatus isolates with anidulafungin CLSI MEC 0.008 mg/L and voriconazole CLSI MICs 0.12-2 mg/L were tested in a pharmacokinetic-pharmacodynamic model (Siopi AAC2015). Free human serum drug concentration-time profiles were simulated for nine combination regimens of voriconazole (fCmax3/1.5/0.3 mg/L, t1/26h dosed q12) and anidulafungin(fCmax0.16/0.08/0.01 mg/L, t1/2 24h dosed q24) (Liu AAC2014). Drug levels were determined by microbiological diffusion assays and fungal growth by measuring galactomannan production using a commercially available sandwich-ELISA. In vitrointeractions were assessed with Bliss independence model and response surface was modeled using the canonical-mixture nonlinear global response-surface Emax-based model (MeletiadisAAC2007). The % of patients attained the pharmacodynamic target associated with 50% of maximal efficacy (EI50) was calculated for 10.000 simulated patientstreated with 4 mg/kg of voriconazole alone and together with 100, 50 and 25 mg of anidulafungin as a combination therapy and for isolates with different voriconazole MICs. The optimal total target serumlevels were determined taking into account the protein binding of each drug.
Results: The combination was mostly independent against voriconazole-susceptible isolates at intermediate and high drug exposures, whereas synergistic interactions (8-16%) were found at lowdrug concentrations. Stronger synergy (20-80%) was observed for isolates with high voriconazole MICs at intermediate and low drug exposures, while at higher drug concentrations independence was found. At the highest anidulafungin exposure (fCmax=0.16 mg/L), antagonistic effects (-5−-12%)were observed. The EI50attainment rates for isolates with voriconazole MICs 0.5, 1, 2 and 4 mg/L were 97%, 72%, 9% and 0% for voriconazole monotherapy and increased to 100%, 86%, 34% and 2% for combination therapy with 100mg anidulafungin, respectively. The highest EI50attainment rates werefound for combination therapy with 25 mg of anidulafungin (100%, 99%, 79% and 16%, respectively).The serum target levels required to attain the EI50were two-fold reduced from 3 tCmin/MIC in voriconazole monotherapy to 1.5 tCmin/MIC in combination therapy providing that anidulafungin tCmaxwill be between 6 and 10 mg/L.
Conclusions: The combination of voriconazole-anidulafungin is beneficial particularly for patients with sub-therapeutic serum concentrations infected with voriconazole-resistant A. fumigatus isolates. The lower dose of 25 mg of anidulafungin may increase efficacy of combination therapy.
Full conference title:
- ECCMID 26th (2016)