Efficacy of voriconazole-liposomal amphotericin B combination against azole-resistant Aspergillus fumigatus in an in vitro pharmacokinetic-pharmacodynamic model

Maria Siopi


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.  



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Full conference title: 

European Congress of Clinical Microbiology and Infectious Diseases
    • ECCMID 26th (2016)