Status of combination therapy for refractory mycoses

Invasive fungal infections remain a leading cause of infectious morbidity and mortality in heavily immunosuppressed patients. As the efficacy of current antifungal agents is suboptimal, combinations of antifungal agents, administered concomitantly or sequentially, are increasingly used (mostly empirically) as a strategy to improve the treatment outcomes for refractory mycoses. Here we review recent developments in the area of antifungal combinations based on both laboratory (in vitro and in animal models) and clinical studies.

With the exception of cryptococcal meningitis, the benefits of combination antifungal therapy have been more difficult to prove for other life-threatening mycoses such as invasive candidiasis or invasive aspergillosis. The recent introduction of a new class of antifungal agents (the echinocandins) and of extended spectrum triazoles has renewed interest in studying antifungal combinations that may result in additive or synergistic effects in difficult-to-treat mycoses. The combination of an echinocandin plus amphotericin B or a newer triazole seems to be the most promising in vitro and in animal model studies, whereas reliable clinical information especially for invasive mould infections is still lacking.

Antifungal combinations are conceptually appealing as a strategy to overcome the frequent failures of antifungal monotherapy in immunosuppressed patients with invasive mycoses. Results of in-vitro studies cannot yet be translated into measurable clinical results because of methodological problems and the complexity of designing relevant prospective clinical trials, but important findings are expected in the near future in this rapidly expanding investigational area.