In Vitro and In Vivo Correlation of the Synergistic Interaction between Voriconazole (VRC) and Anidulafungin (AFG) against Aspergillus fumigatus Using the Bliss Independence Drug Interaction (BIDI) Analysis.

J. MELETIADIS, T. STERGIOPOULOU, V. PETRAITIS, R. PETRAITIENE, J. E. HUGHES, M. P. COTTON, T. SEIN, R. SCHAUFELE, J. BACHER, E. ROILIDES, T. J. WALSH;

Author address: 

NIH, Bethesda, MD.

Abstract: 

Background: In vitro combination studies with antifungal agents are seldom correlated with in vivo results. We therefore aimed by using BIDI analysis to study the combination of VRC+AFG in vitro and in vivo in experimental invasive pulmonary aspergillosis (IPA). Methods: In vitro susceptibility of Aspergillus fumigatus clinical isolate AF4215 to the combination of VRC+AFG was tested in triplicate with broth microdilution checkerboard technique based on the CLSI M-38A. Fungal growth was assessed spectrophotometrically at 405 nm after incubation at 37°C for 48h and % of growth was calculated for each drug concentration compared to the drug-free growth control. IPA due to AF4215 in persistently neutropenic rabbits was then treated with 10 mg/kg of VRC t.i.d. and 5 or 10 mg/kg of AFG q.d., alone and in combination. Outcome was assessed based on residual fungal burden and pulmonary infarct scores. In vitro and in vivo combinations were analyzed with the BIDI model, where the observed effect (fungal growth) EOBS of each drug combination was compared with the theoretical expected effect ETHE calculated as EVRC x EAFG (EVRC and EAFG are the observed effects of the drugs alone). If the mean difference ETHE-EOBS (916;E) and its 95% CI among the replicates/animals was higher or lower than 0, statistically significant synergy or antagonism, respectively was concluded. Results: In vitro the combination of VRC+AFG was synergistic (916;E=27±4%). In vivo the combination of VRC with 5 mg/kg of AFG was also found to be synergistic of the same magnitude based on residual fungal burden (916;E=30%, p
2007

abstract No: 

M-740

Full conference title: 

47th Interscience Conference on Antimicrobial agents and Chemotherapy
    • ICAAC 47th