In Vivo Efficacy of Amphotericin B against Four Candida auris Clades

Forgács, Lajos; Borman, Andrew M.; Kovács, Renátó; Balázsi, Dávid; Tóth, Zoltán; Balázs, Bence; Chun-Ju, Chiu; Kardos, Gábor; Kovács, Ilona; Majoros, László

doi:10.3390/jof8050499

Cited by 3 publications

(5 citation statements)

References 37 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Hernando-Ortiz,

Eraso,

Jauregizar

et al. 2024

Microbiol Spectr

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The multidrug-resistant Candida auris is a global health emergency, being responsible for outbreaks of invasive candidiasis worldwide. Limited effective therapeutic options make it difficult to treat this emerging pathogen. In this context, combinations of different antifungal drugs are considered a promising therapeutic alternative. The aim of this work was to analyze the antifungal activity of combinations of amphotericin B and echinocandins against five clinical blood isolates of C. auris . One of these isolates showed an aggregative phenotype already described in C. auris species, forming large aggregates of cells that are very difficult to disintegrate. First, the in vitro activity of these drugs was evaluated both in monotherapy and in combination, and results showed synergistic interactions between amphotericin B and echinocandins in most cases, although higher minimum inhibitory concentration (MIC) values were observed against the aggregative isolate compared to non-aggregative counterparts. The most promising drug combinations were then selected for in vivo activity evaluation using a Caenorhabditis elegans model of candidiasis and by determination of survival rates. The combination of amphotericin B and caspofungin showed the strongest protective effect during C. elegans infection with C. auris blood isolates, achieving up to 99% C . elegans survival. Although the MIC values for micafungin were low in vitro , these drug concentrations had no effect in vivo , and the combination of amphotericin B and micafungin was the least effective. The results of this study showed that the combination amphotericin B and echinocandins might be a promising therapeutic approach for the treatment of invasive candidiasis caused by C. auris . Moreover, the nematode C. elegans is a suitable alternative model for screening of new therapeutic agents capable of overcoming multidrug-resistant C. auris infections. IMPORTANCE Multidrug resistance is a rising problem among non- Candida albicans species, such as Candida auris . This therapeutic problem has been very important during the COVID-19 pandemic. The World Health Organization has included C. auris in its global priority list of health-threatening fungi, to study this emerging multidrug-resistant species and to develop effective alternative therapies. In the present study, the synergistic effect of the combination of amphotericin B and echinocandins has been demonstrated against blood isolates of C. auris . Different susceptibility responses were also observed between aggregative and non-aggregative phenotypes. The antifungal activity of these drug combinations against C. auris was also demonstrated in the Caenorhabditis elegans host model of candidiasis, confirming the suitability and usefulness of this model in the search for solutions to antimicrobial resistance.

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Section: Discussionmentioning

confidence: 99%

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

Hernando-Ortiz,

Eraso,

Jauregizar

et al. 2024

Microbiol Spectr

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“…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.…”

Section: Host Colonizationmentioning

confidence: 98%

“…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.…”

Section: Topical Focusmentioning

confidence: 99%

“…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].…”

Section: Virulencementioning

confidence: 99%

“…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.…”

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confidence: 99%

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

Santana,

Zhao,

O’Meara

2024

PLoS Pathog

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Candida auris is an emerging fungal pathogen with unusual evolutionary history—there are multiple distinct phylogeographic clades showing a near simultaneous transition from a currently unknown reservoir to nosocomial pathogen. Each of these clades has experienced different selective pressures over time, likely resulting in selection for genotypes with differential fitness or phenotypic consequences when introduced to new environments. We also observe diversification within clades, providing additional opportunities for phenotypic differences. These differences can have large impacts on pathogenic potential, drug resistance profile, evolutionary trajectory, and transmissibility. In recent years, there have been significant advances in our understanding of strain-specific behavior in other microbes, including bacterial and fungal pathogens, and we have an opportunity to take this strain variation into account when describing aspects of C. auris biology. Here, we critically review the literature to gain insight into differences at both the strain and clade levels in C. auris, focusing on phenotypes associated with clinical disease or transmission. Our goal is to integrate clinical and epidemiological perspectives with molecular perspectives in a way that would be valuable for both audiences. Identifying differences between strains and understanding which phenotypes are strain specific will be crucial for understanding this emerging pathogen, and an important caveat when describing the analysis of a singular isolate.

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In Vivo Efficacy of Rezafungin, Anidulafungin, Caspofungin, and Micafungin against Four Candida auris Clades in a Neutropenic Mouse Bloodstream Infection Model

Balázsi,

Tóth,

Locke

et al. 2024

JoF

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Objectives: Rezafungin is the first new drug approved to treat candidaemia and invasive candidiasis in more than 10 years. However, data are scant on the in vivo efficacy of rezafungin and the other three approved echinocandins against different Candida auris clades. Methods: This study involved 10 isolates representing 4 C. auris clades: South Asian (n = 2), East Asian (n = 2), South African (n = 2), and South American (n = 4, including 2 environmental isolates). In the lethality experiment and fungal tissue burden experiment (kidney, heart, and brain), cyclophosphamide-treated BALB/c male mice were intravenously infected (107 and 8 × 106 colony-forming units [CFU]/mouse, respectively). A 20 mg/kg dose of rezafungin was administered on days 1, 3, and 6. Alternatively, beginning 24 h post-infection, mice received 3 mg/kg of caspofungin, 5 mg/kg of micafungin, or 5 mg/kg of anidulafungin once daily for 6 days. Results: Regardless of isolate and clade, all echinocandin regimens improved survival after 21 days (p = 0.0041 to p < 0.0001). All echinocandins frequently produced >3-log mean CFU/g decreases in the fungal kidney and heart burdens, although some of these decreases were not statistically significant. Rezafungin, regardless of clade, produced 3–5 and 2–4 log CFU/g decreases in the kidney and heart burdens, respectively. Echinocandins did not inhibit fungal growth in the brain. Histopathological examination performed on day 7 showed no fungal cells in the heart and kidneys of rezafungin-treated mice and to a lesser extent, caspofungin-treated mice, regardless of the clinical isolate. All echinocandin-treated mice showed medium and/or large foci of fungal cells in their cerebrum or cerebellum. Conclusions: Regardless of the C. auris clade, rezafungin activity in vivo was comparable to or improved over that of the three previously approved echinocandins.

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In Vivo Efficacy of Amphotericin B against Four Candida auris Clades

Cited by 3 publications

References 37 publications

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

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

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

In Vivo Efficacy of Rezafungin, Anidulafungin, Caspofungin, and Micafungin against Four Candida auris Clades in a Neutropenic Mouse Bloodstream Infection Model

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