Combination of Voriconazole and Anidulafungin for Treatment of Triazole-Resistant Aspergillus fumigatus in an In Vitro Model of Invasive Pulmonary Aspergillosis

Abstract

Voriconazole is a first-line agent for the treatment of invasive pulmonary aspergillosis. Isolates with elevated voriconazole MICs are increasingly being seen, and the optimal treatment regimen is not defined. We investigated whether the combination of voriconazole with anidulafungin may be beneficial for the treatment of A. fumigatus strains with elevated voriconazole MICs. We used an in vitro model of the human alveolus to define the exposure-response relationships for a wild-type strain (voriconazole MIC, 0.5 mg/liter) and strains with defined molecular mechanisms of triazole resistance (MICs, 4 to 16 mg/liter). All strains had anidulafungin minimum effective concentrations (MECs) of 0.0078 mg/liter. Exposure-response relationships were estimated using galactomannan as a biomarker. Concentrations of voriconazole and anidulafungin were measured using high-performance liquid chromatography (HPLC). The interaction of voriconazole and anidulafungin was described using the Greco model. Fungal growth was progressively inhibited with higher drug exposures of voriconazole. Strains with elevated voriconazole MICs required proportionally greater voriconazole exposures to achieve a comparable antifungal effect. Galactomannan concentrations were only marginally reduced by anidulafungin monotherapy. An additive effect between voriconazole and anidulafungin was apparent. In conclusion, the addition of anidulafungin does not markedly alter the exposure-response relationship of voriconazole. A rise in serum galactomannan during combination therapy with voriconazole and anidulafungin should be interpreted as treatment failure and not attributed to a paradoxical reaction related to echinocandin treatment.

Impact of In Vivo Triazole and Echinocandin Combination Therapy for Invasive Pulmonary Aspergillosis: Enhanced Efficacy against Cyp51 Mutant Isolates

“…Finally, we did not evaluate other triazole-echinocandin combinations. While one might expect similar results for drugs with similar mechanisms of action, a previous in vitro pharmacodynamic study against Cyp51 mutants did not demonstrate significant enhancement with combination voriconazole and anidulafungin (58).…”

Antifungal Pharmacokinetics and Pharmacodynamics

“…Azoles in combination with echinocandins in theory may provide the most promising combination strategy given that they act at completely distinct sites (the cell membrane and cell wall, respectively). An in vitro PD study of combination therapy with these two classes supports this tenet (Jeans et al 2012b). In vivo animal model experiments are also common, but few have been designed to analyze the combination effects from a pharmacodynamic perspective.…”

Amphotericin B- and Voriconazole-Echinocandin Combinations against Aspergillus spp.: Effect of Serum on Inhibitory and Fungicidal Interactions

“…However, pharmacodynamic interactions in clinical trials may be obscured by confounding factors such as underlying disease, concomitant therapy, and toxicity and because combination regimens were compared with one of the two monotherapy regimens without taking into account the effect of the second drug. Most of the available information concerning the efficacy of antifungal combinational therapy comes from preclinical studies, with in vitro studies demonstrating mostly synergistic-to-additive/indifferent interactions (10)(11)(12)(13)(14)(15) and in vivo studies showing mostly no significant improvement compared to monotherapy (16)(17)(18)(19)(20)(21)(22)(23)(24)(25).…”