Antifungal Activity of SCY-078 and Standard Antifungal Agents against 178 Clinical Isolates of Resistant and Susceptible Candida Species

Schell, Wiley A.; Jones, Alexander M.; Borroto–Esoda, Katyna; Alexander, Barbara D.

doi:10.1128/aac.01102-17

Cited by 54 publications

(52 citation statements)

References 21 publications

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“…Two of these agents are now in clinical trials. Ibrexafungerp (SCY078) is an oral glucan synthase inhibitor with activity versus most Candida species, including many echinocandinresistant isolates (17). APX001 (formerly E1210) is a novel agent that inhibits the Gwt1 enzyme responsible for cross-linking cell wall mannoproteins to ␤-1,6-glucan compromising the structural integrity.…”

Section: Commentarymentioning

confidence: 99%

Amphotericin B Induction with Voriconazole Consolidation as Salvage Therapy for FKS -Associated Echinocandin Resistance in Candida glabrata Septic Arthritis and Osteomyelitis

Wright

Bejou

Shields

et al. 2019

Antimicrob Agents Chemother

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We report the case of a 61-year-old female with Crohn’s disease dependent on total parenteral nutrition who developed a central venous catheter bloodstream infection and septic arthritis, complicated further by osteomyelitis and persistent Candida glabrata fungemia. Fluconazole treatment led to persistent infection, and micafungin therapy failed with development of FKS-associated resistance. Infection responded after initiation of amphotericin B plus voriconazole. Echinocandin resistance is increasingly recognized, suggesting a role for alternative antifungal therapies.

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Section: Commentarymentioning

confidence: 99%

Amphotericin B Induction with Voriconazole Consolidation as Salvage Therapy for FKS -Associated Echinocandin Resistance in Candida glabrata Septic Arthritis and Osteomyelitis

Wright

Bejou

Shields

et al. 2019

Antimicrob Agents Chemother

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“…unlike the echinocandins ibrexafungerp is administered orally and retains activity against some fks mutant Candida species isolates (1)(2)(3)(4).…”

mentioning

confidence: 99%

In Vitro Activity of Ibrexafungerp (SCY-078) against Candida auris Isolates as Determined by EUCAST Methodology and Comparison with Activity against C. albicans and C. glabrata and with the Activities of Six Comparator Agents

Arendrup

Jørgensen

Hare

et al. 2020

Antimicrob Agents Chemother

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Ibrexafungerp (SCY-078) is a novel first-in-class antifungal agent targeting glucan synthase. Candida auris is an emerging multidrug-resistant species that has caused outbreaks on five continents. We investigated the in vitro activity of ibrexafungerp against C. auris by applying EUCAST E.Def 7.3.1 methodology. C. albicans and C. glabrata, as well as anidulafungin, micafungin, amphotericin B, fluconazole, voriconazole, and isavuconazole, were included as comparators. Three C. auris reference strains (CBS12372, CBS12373, and CBS10913) and 122 C. auris, 16 C. albicans, and 16 C. glabrata isolates were evaluated. C. albicans ATCC 64548, C. parapsilosis ATCC 22019, and C. krusei ATCC 6258 served as quality control strains. Echinocandin-resistant isolates were fks sequenced. MIC ranges and modal MIC and MIC50 values were determined. Wild-type upper limits (the upper MIC value where the wild-type distribution ends) were determined according to EUCAST principles for setting ECOFFs. Nine repetitions of three QC strains and MICs for C. albicans and C. glabrata yielded narrow MIC ranges with modal MICs in agreement with established EUCAST modal MICs, confirming a robust test performance. The ibrexafungerp MICs against C. auris isolates displayed a Gaussian distribution with a modal MIC (range) of 0.5 mg/liter (0.06 to 2 mg/liter), suggesting uniform susceptibility. Of 122 isolates, 8 were echinocandin resistant and harbored the S639F Fks1 alteration. All but one were fluconazole resistant, and the MIC distributions for voriconazole and isavuconazole were multimodal confirming variable susceptibility. Ibrexafungerp demonstrated promising activity against C. auris, including isolates resistant to echinocandins and/or other agents. The MICs were similar to those reported for the Clinical and Laboratory Standards Institute method, suggesting that a common clinical breakpoint may be appropriate.

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“…However, few studies have evaluated the effect of these drugs in dermatophytes. In particular, VT-1161 is currently under phase I clinical trial for onychomycosis NCT02267356 ( Garvey et al, 2015 ; Schell et al, 2017a ). This drug inhibits the fungal cytochrome P-450 enzyme lanosterol 14-α-demethylase (Cyp51), being effective against several fungi including the dermatophytes Trichophyton rubrum, Trichophyton mentagrophytes , and Epidermophyton floccosum ( Garvey et al, 2015 ).…”

Section: Natural and Synthetic Compounds With Antifungal Activitymentioning

confidence: 99%

Dermatophyte Resistance to Antifungal Drugs: Mechanisms and Prospectus

et al. 2018

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Dermatophytes comprise pathogenic fungi that have a high affinity for the keratinized structures present in nails, skin, and hair, causing superficial infections known as dermatophytosis. A reasonable number of antifungal drugs currently exist on the pharmaceutical market to control mycoses; however, their cellular targets are restricted, and fungi may exhibit tolerance or resistance to these agents. For example, the stress caused by antifungal and cytotoxic drugs in sub-inhibitory concentrations promotes compensatory stress responses, with the over-expression of genes involved in cellular detoxification, drug efflux, and signaling pathways being among the various mechanisms that may contribute to drug tolerance. In addition, the ATP-binding cassette transporters in dermatophytes that are responsible for cellular efflux can act synergistically, allowing one to compensate for the absence of the other, revealing the complexity of drug tolerance phenomena. Moreover, mutations in genes coding for target enzymes could lead to substitutions in amino acids involved in the binding of antifungal agents, hindering their performance and leading to treatment failure. The relevance of each one of these mechanisms of resistance to fungal survival is hard to define, mainly because they can act simultaneously in the cell. However, an understanding of the molecular mechanisms involved in the resistance/tolerance processes, the identification of new antifungal targets, as well as the prospective of new antifungal compounds among natural or synthetic products, are expected to bring advances and new insights that facilitate the improvement or development of novel strategies for antifungal therapy.

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Antifungal Activity of SCY-078 and Standard Antifungal Agents against 178 Clinical Isolates of Resistant and Susceptible Candida Species

Cited by 54 publications

References 21 publications

Amphotericin B Induction with Voriconazole Consolidation as Salvage Therapy for FKS -Associated Echinocandin Resistance in Candida glabrata Septic Arthritis and Osteomyelitis

Amphotericin B Induction with Voriconazole Consolidation as Salvage Therapy for FKS -Associated Echinocandin Resistance in Candida glabrata Septic Arthritis and Osteomyelitis

In Vitro Activity of Ibrexafungerp (SCY-078) against Candida auris Isolates as Determined by EUCAST Methodology and Comparison with Activity against C. albicans and C. glabrata and with the Activities of Six Comparator Agents

Dermatophyte Resistance to Antifungal Drugs: Mechanisms and Prospectus

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