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

Abstract

Antifungal combination therapy with voriconazole or amphotericin B and an echinocandin is often employed as primary or salvage therapy for management particularly of refractory aspergillosis. The pharmacodynamic interactions of amphotericin Band voriconazole-based combinations with the three echinocandins caspofungin, micafungin, and anidulafungin in the presence of serum were tested against 15 Aspergillus fumigatus complex, A. flavus complex, and A. terreus complex isolates to assess both their growth-inhibitory and fungicidal activities. The in vitro activity of each drug alone and in combination at a 1:1 fixed concentration ratio was tested with a broth microdilution colorimetric method, and interactions were assessed by isobolographic analysis. Synergy was found for all amphotericin B-and voriconazole-based combinations, with amphotericin B-based combinations showing strong inhibitory synergistic interactions (interaction indices of 0.20 to 0.52) and with voriconazole-based combinations demonstrating strong fungicidal synergistic interactions (interaction indices of 0.10 to 0.29) (P < 0.001). Drug-and species-specific differences were found, with caspofungin and the A. fumigatus complex exhibiting the weakest synergistic interactions. In the presence of serum, the synergistic interactions were reduced in the order (from largest to smallest decrease) micafungin > anidulafungin > caspofungin, and A. flavus complex > A. fumigatus complex > A. terreus complex, resulting in additive interactions, particularly for inhibitory activities of amphotericin B-echinocandin combinations and fungicidal activities of voriconazole-echinocandin combinations. Drug-and species-specific differences were found in the presence of serum for inhibitory activities of antifungal drugs, with the lowest interaction indices being observed for amphotericin B-caspofungin (median, 0.77) and for the A. terreus complex (median, 0.56). The present in vitro data showed that serum had a major impact on synergistic interactions of amphotericin B-echinocandin and voriconazole-echinocandin combinations, resulting in additive interactions and explaining the indifferent outcomes usually observed in vivo.

Echinocandins for the Treatment of Invasive Aspergillosis: from Laboratory to Bedside

“…have shown various results. Importantly, the type of growth medium was found to influence the in vitro interactions and serum attenuated the synergistic effect, suggesting that these observations may not necessarily have the same significance in vivo (66). Moreover, differences in drug exposure were found to influence these interactions (67).…”

Antifungal Therapy: New Advances in the Understanding and Treatment of Mycosis

“…There are numerous in vitro studies of antifungal combinations using triazole with echinocandin or triazole with AmB (Elefanti et al, 2013; Katragkou et al, 2014). Regardless, the clinical results of combinatory treatment remain unclear and are generally described for infections caused by fungi, which present difficulty in treatment, such as in aspergillosis and mucormycosis (Belanger et al, 2015).…”

Combination Antifungal Therapy: When, Where, and Why

“…The combinations of triazole with echinocandin or triazole with amphotericin B appear to be the most common combinations tested [11][12][13][14][15][16][17]. The problem with in vitro studies is determining the likely clinical efficacy as there are currently no current standards for testing combined antifungal agents [18].…”