Impact of milbemycin oxime on fluconazole resistance in Candida auris.

Abstract

Background: Candida auris is a pathogenic yeast that can develop resistance to multiple antifungals, particularly to azoles (e.g. fluconazole). Milbemycin oxime potentiates the effect of fluconazole against Candida spp. by inhibiting ABC transporters, such as Cdr1, which is involved in azole drug efflux.

Objectives: This study aimed to assess the interaction of milbemycin oxime and fluconazole against clinical (n = 4) and laboratory-generated (n = 4) C. auris isolates with different mechanisms of azole resistance.

Methods: Interactions of milbemycin oxime and fluconazole were assessed by chequerboard assays and defined as synergistic, indifferent or antagonistic according to the FIC index (FICI) values. The fluorescent substrate rhodamine 6 g (R6G) was used to measure ABC transporter activity in the absence or presence of milbemycin oxime.

Results: A synergistic interaction between milbemycin oxime and fluconazole was observed against most isolates, including those harbouring Cdr1-independent mechanisms of azole resistance (e.g. ERG11 mutations). The highest synergism was observed in a laboratory-generated strain overexpressing CDR1, while the interaction was indifferent in a strain lacking CDR1. R6G experiments confirmed the inhibitory effect of milbemycin oxime on ABC transporters.

Conclusions: Milbemycin oxime could represent an interesting adjunctive therapy against azole-resistant C. auris, particularly those with CDR1 overexpression.