Alternation of echinocandins with liposomal amphotericin B for treatment of Nakaseomyces glabratus candidemia: an effective strategy to reduce echinocandin tolerant pool and to minimize echinocandin resistance

Echinocandins are frontline antifungal drugs and the emergence of echinocandin resistant (ECR) species, such as Nakaseomyces glabratus, complicates patient outcomes. Intriguingly, under laboratory conditions, we previously showed that echinocandin alternation with metabolic-independent antifungals, such as amphotericin B, more effectively kills and minimizes the ECR in N. glabratus. Building upon our previous observations, we examined the efficacy of echinocandin alternation to amphotericin B (EAMB) over echinocandin monotherapy using a systemic candidiasis mouse model to assess if EAMB warrants investigation with potential for clinical evaluation. Interestingly, we show that regardless of the mice immune status (immunocompromised and immunocompetent) and the N. glabratus isolates (high and low echinocandin tolerance (ECT)) tested, EAMB more rapidly cleared the infection the minimized ECR in all organs tested compared to caspofungin monotherapy. Pharmacokinetic data suggested that the superiority of EAMB is due to concentration-independent killing activity of liposomal AMB. Although biomarkers suggested higher kidney and liver damage in the EAMB group, histological analysis showed similar damage among both groups. Collectively, using comprehensive ex vivo and in-vitro/vivo experimental conditions, we introduce a novel antifungal therapeutic regimen, which effectively minimizes the ECT and ECR rate in N. glabratus and lays the foundation for inhuman studies and clinical trials.