In Vitro and In Vivo Evaluation of Voriconazole-Containing Antifungal Combinations against Mucorales Using a Galleria mellonella Model of Mucormycosis.

Daiana Macedo,Gustavo Giusiano,Soledad Gamarra,Roxana G Vitale,Guillermo Garcia-Effron,Catiana Dudiuk,Florencia Leonardelli,Eleodoro Del Valle

doi:10.3390/jof5010005

Abstract

Mucorales are resistant to most antifungals. Mucormycosis associated mortality is unacceptable and new treatment approaches are needed. The objectives of this work were (i) to evaluate the nature and intensity of the in vitro effect of three drugs combinations which included voriconazole (plus amphotericin B, posaconazole and caspofungin) against 25 strains of six different Mucorales species; (ii) to evaluate a Galleria mellonella mucormycosis model; and (iii) to establish if any in vitro–in vivo correlation exists. As expected, amphotericin B and posaconazole were the most active drugs when tested alone. However, species-specific differences were found. The ΣFICs varied according to the used combination. Only five strains showed synergism when voriconazole was combined with posaconazole and three strains when combined with amphotericin B. Microscopic hyphae alteration were observed for some isolates when confronted against drugs combinations. Using a Galleria mellonella mucormycosis model, better survival was seen in voriconazole plus amphotericin B and plus caspofungin combined treatments when compared with AMB alone for R. microsporus. These survival improvements were obtained using a 32-fold lower amphotericin B doses when combined with VRC than when treated with the polyene alone. These lower antifungal doses emulate the antifungal concentrations where the microscopic hyphae alterations were seen.

Highlights

Mucormycosis is a rapidly progressing fungal infection with high morbidity and mortality rates
Spellberg et al described the reasons for studying a particular combination therapy for Mucormycosis [4], including agents already approved for use in humans, which improve survival in animal models and known to be effective and safe
Species-specific differences were found for amphotericin B (AMB) but not for PSC

Summary

Introduction

Mucormycosis is a rapidly progressing fungal infection with high morbidity and mortality rates. Posaconazole (PSC) and more recently isavuconazole were added to the antifungal armamentarium as step-down and salvage therapy [1,2] Despite these advances, mortality is still unacceptable and, clearly, new approaches are needed [3]. Most of them, describing the effectiveness of different combinations assessed empirically (tested in vivo without a previous in vitro evaluation) using murine models of infection These studies included combinations of AMB with different echinocandins and/or iron chelators and the combination of azole (in vitro active against Mucorales as isavuconazole and PSC) with echinocandins and calcineurin inhibitors [5,6,7,8,9,10,11]

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Conclusion