In Vivo Efficacy of Amphotericin B against Four Candida auris Clades

Abstract

Candida auris is a multidrug-resistant fungus against which in some clinical situations amphotericin B (AMB) remains the alternative or first line drug. We compared daily 1 mg/kg of AMB efficacy in a neutropenic murine bloodstream infection model against 10 isolates representing four C. auris clades (South Asian n = 2; East Asian n = 2; South African n = 2; South American n = 4; two of which were of environmental origin). Five days of AMB treatment significantly increased the survival rates in mice infected with isolates of the East Asian clade, and 1 isolate each from the South African and South American clades (originated from bloodstream), but not in mice infected with the South Asian and 2 environmental isolates from the South American clades. AMB treatment decreased the fungal burden in mice infected with the 2 isolates each from East Asian and South African, and 1 out of 2 bloodstream isolates from South American clades in the hearts (p < 0.01), kidneys (p < 0.01) and brain (p < 0.05). AMB treatment, regardless of clades, significantly decreased colony forming units in the urine at day 3. However, histopathological examination in AMB-treated mice revealed large aggregates of yeast cells in the kidneys and hearts, and focal lesions in the cerebra and cerebelli, regardless of precise C. auris clade. Our clade-specific data confirm that the efficacy of AMB against C. auris is weak, explaining the therapeutic failures in clinical situations. Our results draw attention to the necessity to maximize the killing at the start of treatment to avoid later complications in the heart and central nervous system.

Efficacy of the combination of amphotericin B and echinocandins against Candida auris in vitro and in the Caenorhabditis elegans host model

“…The isolate with the aggregative phenotype showed higher in vitro MIC values compared to the non-aggregative isolates both in monotherapy and in combination assays. Interestingly, it has been suggested that the formation of aggregates may be a survival strategy of C. auris ( 20 ), which has also been observed in vivo ( 59 ). Based on our findings, when MIC values of antifungal susceptibility testing are high in monotherapy for a C. auris isolate, combination therapy has been shown to be a good alternative to reduce drug concentrations.…”

The many faces of Candida auris: Phenotypic and strain variation in an emerging pathogen

“…In an in vitro model using an artificial human axillary sweat medium and ex vivo porcine skin as a substrate, C. auris was able to produce dense, multilayered accumulation [98]. Interestingly, C. auris exhibited a fungal burden 10-fold greater than that of C. albicans in the artificial sweat medium but not RPMI-MOPS, along with an apparent persistence of C. auris in concentrated [24,25,28,[77][78][79][80][81][82][83][84] directly comparing virulence between isolates of different clades (A) or body site origins (B) in animal infection models. For each study, the virulence of each isolate was ranked by mortality and median survival.…”

“…For experimental virulence models, 11 reports of invertebrate or murine infection models [24,25,28,[77][78][79][80][81][82][83][84] were identified that met the acceptance criteria of having (1) Multiple isolates with clade or body site origin indicated; (2) Identical infection protocol between isolates; and (3) Survival data available. Because of the small number of studies available, an acceptance criteria including any study that compared more than 1 isolate from different groups was established, with the anticipated limitation that studies with small sample sizes might exhibit greater variation from a true effect.…”

“…Multiple mammalian and invertebrate infection models have been employed to characterize C. auris virulence, with some reports directly comparing isolates of distinct genetic lineages or origins [24,25,27,28,[77][78][79][80][81][82][83][84]. Independently, 2 separate reports concluded that isolates from clade IV showed the highest virulence of the 4 major clades in either murine or silkworm infection models [27,28].…”

“…Experimental infection models suggest C. auris exhibits clade-specific but not body site specific virulence. Survival data were extracted from studies[24,25,28,[77][78][79][80][81][82][83][84] directly comparing virulence between isolates of different clades (A) or body site origins (B) in animal infection models. For each study, the virulence of each isolate was ranked by mortality and median survival.…”