Antifungal combinations in Mucorales: A microbiological perspective

Abstract

Summary Mucormycosis mostly affects immunocompromised patients and is associated with a high morbidity and mortality despite currently available treatments. In that context, combination therapy might be the key to a better outcome for these patients. Purpose of this review is to summarise and to discuss the current combination data obtained in vitro, in vivo in animal models of mucormycosis, and in patients. In vitro combination studies showed that most of the interactions between antifungal drugs were indifferent, even though that some synergistic interactions were achieved for the combination of echinocandins with either azoles or amphotericin B. Importantly, antagonism was never observed. Animal models of mucormycosis focused on infections caused by Rhizopus arrhizus, neglecting most other species responsible for human disease. In these experimental animal models, no strong interactions have been demonstrated, although a certain degree of synergism has been reported in some instances. Combinations of antifungals with non‐antifungal drugs have also been largely explored in vitro and in animal models and yielded interesting results. In patients with ketoacidosis and rhino‐orbito‐cerebral infection, combination of polyene with caspofungin was effective. In contrast, despite promising experimental data, adjunctive therapy with the iron chelator deferasirox was unfavourable and was associated with a higher mortality than monotherapy with liposomal amphotericin B. More combinations have to be tested in vitro and a much larger panel of Mucorales species has to be tested in vivo to give a valuable statement if antifungal combination therapy could be an effective treatment strategy in patients with mucormycosis.

In vitro synergy of isavuconazole in combination with colistin against Candida auris

“…Already prior to the COVID-19 pandemic repurposing of drugs had become trendy. Repurposed drugs have shown activity against bacteria 29 , yeasts 29,30 , and filamentous fungi [31][32][33][34] . Colistin is a drug of last resort with activity against multidrug-resistant gram-negative bacteria such as Pseudomonas aeruginosa, Klebsiella pneumoniae, or Acinetobacter baumanii 35 ; but colistin has also shown to damage the cell membrane of C. albicans 17 , which could make it an interesting partner in combination therapy against multidrug-resistant C. auris infections.…”

Surgical-site mucormycosis infection in a solid-organ transplant recipient and a concise review of the literature

“…The combinations in these studies were isavuconazole with amphotericin and isavuconazole with micafungin. All other in vitro studies showed either synergy or indifference 26…”

In Vitro Interaction between Isavuconazole and Tacrolimus, Cyclosporin A, or Sirolimus against Aspergillus Species

“…In vitro synergy between antifungals and immune suppressive drugs has been found for yeasts [30][31][32][33][34][35][36], and filamentous fungi such as the Mucorales [24,25,37,38], and Aspergillus species [39,40]. Nevertheless, in vitro indifference [21,41] and even antagonism has been reported for the combinations of voriconazole with tacrolimus or cyclosporin A against four A. fumigatus isolates and one A. fumigatus isolate, respectively [41].…”