Dose optimization of voriconazole-anidulafungin combination against invasive aspergillosis - preclinical data

Maria Siopi, Nikolaos Siafakas, Sophia Vourli, Johan Willem Mouton, Loukia Zerva, Joseph Meletiadis


Background: A recent randomized clinical trial showed that voriconazole-anidulafungin combination
therapy may improve outcome of voriconazole monotherapy against invasive aspergillosis when drugs
were combined at standard dosages (Marr e al Ann Intern Med. 2015). Whether alternative dosages
can maximize efficacy of combination therapy particularly against azole-resistant isolates is unknown.
We therefore investigated the activity of voriconazole-anidulafungin combination against voriconazolesusceptible
and -resistant Aspergillus fumigatus using different doses of anidulafungin in an in vitro
pharmacokinetic 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 AAC 2015). Free human serum drug concentration-time profiles were simulated for nine
combination regimens of voriconazole (fCmax 3/1.5/0.3 mg/L, t1/2 6h dosed q12) and anidulafungin
(fCmax 0.16/0.08/0.01 mg/L, t1/2 24h dosed q24) (Liu AAC 2014). Drug levels were determined by
microbiological diffusion assays and fungal growth by measuring galactomannan production using a
commercially available sandwich-ELISA. In vitro interactions were assessed with Bliss independence
model and response surface was modeled using the canonical-mixture nonlinear global responsesurface
Emax-based model (Meletiadis AAC 2007). The % of patients attained the pharmacodynamic
target associated with 50% of maximal efficacy (EI50) was calculated for 10.000 simulated patients
treated 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 serum
levels 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 low
drug 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 EI50 attainment 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 EI50 attainment rates were
found for combination therapy with 25 mg of anidulafungin (100%, 99%, 79% and 16%, respectively).
The serum target levels required to attain the EI50 were two-fold reduced from 3 tCmin/MIC in
voriconazole monotherapy to 1.5 tCmin/MIC in combination therapy providing that anidulafungin tCmax
will 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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abstract No: 


Full conference title: 

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