Dose optimization of the combination of voriconazole-anidulafungin against Aspergillus fumigatus: Clinical implications for azole-resistant aspergillosis

OBJECTIVE Combination therapy of voriconazole with an echinocandin is often administered to increase the efficacy of voriconazole monotherapy, particularly against azole-resistant Aspergillus fumigatus isolates and in patients with subtherapeutic serum levels. The aim of this study was to investigate the pharmacodynamic effects of the combination of voriconazole-anidulafungin against A. fumigatus, including azole-resistant strains, using a validated in vitro pharmacokinetic/pharmacodynamic (PK/PD) model for determining target serum levels of combination regimens. METHOD Four clinical A. fumigatus isolates with different in vitro susceptibility to voriconazole (MIC 0.125-2 mg/L) and anidulafungin (MEC 0.008-0.015 mg/L) were tested in an in vitro PK/PD model simulating human serum free concentrations of standard dosages of antifungals. Fungal growth was assessed using galactomannan production and drug concentrations were determined by bioassay. Pharmacodynamic interactions were assessed using the Bliss independence analysis (BI) and the Loewe additivity-based canonical mixture response-surface non-linear regression analysis (LA). Target attainment rates (TAR) were estimated with Monte Carlo analysis for different doses of anidulafungin (25 mg, 50 mg and 100 mg) and for centers with increasing azole-resistance rates (5-25%). RESULTS Synergy [BI 51 (8-80%), LA 0.63 (0.38-0.79)] was found at low anidulafungin and voriconazole exposures (fC(max)/MIC <10), while antagonism [BI 12 (5-18%), LA 1.12 (1.04-4.6)] was found at higher exposures. The largest increase in TAR was found with 25 mg of anidulafungin and voriconazole MIC distributions with high (>10%) resistant rates. The TAR for isolates with voriconazole MICs <= 1, 2 and >= 4 mg/L were >= 78%, 12% and 0% with voriconazole monotherapy and 96-100%, 68-82%, 9-20% with combination therapy, respectively. Optimal activity was associated a tC(min)/MIC ratio of 3 for voriconazole monotherapy and 1.5 for combination therapy. CONCLUSIONS A low dose of anidulafungin may increase efficacy and reduce the costs of combination therapy.