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Cited by 32Antifungal resistance and susceptibilityFungal Plant Pathogen ControlFungal Infections and Studies

Investigational Agents for the Treatment of Resistant Yeasts and Molds

Open access
Seiler, Garret T., Ostrosky-Zeichner, Luis·2021·Current Fungal Infection Reports
DOI 10.1007/s12281-021-00419-5PMC PMC8162489
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Abstract

Purpose of review This review summarizes the investigational antifungals in clinical development with the potential to address rising drug resistance patterns. The relevant pharmacodynamics, spectrum of activity, preclinical studies, and latest clinical trial data are described.Recent findings Agricultural and medicinal antifungal use has been selected for inherently drug-resistant fungi and acquired resistance mechanisms. The rates of fungal infections and immunocompromised populations continue to grow as few new antifungals have hit the market. Several agents with the potential to address the emergence of multidrug-resistant (MDR) molds and yeasts are in clinical development.Summary Evolved formulations of echinocandins, polyenes, and triazoles offer less toxicity, convenient dosing, and greater potency, potentially expanding these classes' indications. Ibrexafungerp, olorofim, oteseconazole, and fosmanogepix possess novel mechanisms of actions with potent activity against MDR fungi. Successful clinical development is neither easy nor guaranteed; thus, perpetual efforts to discover new antifungals are needed.

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Crossref · 10.1007/s12281-021-00419-5

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Claims the paper makes

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  • Premisecitation

    Ibrexafungerp maintains in vitro activity against fluconazole- and echinocandin-resistant Candida species, including pan-resistant C. auris.

    “IBX maintains in vitro activity against fluconazole and echinocandin-resistant Candida species including pan-resistant C. auris [24•, 25, 26•].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24•, 25, 26•]

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  • Interpretationnone given

    Several investigational antifungals in clinical development have the potential to address multidrug-resistant molds and yeasts.

    “Several agents with the potential to address the emergence of multidrug-resistant (MDR) molds and yeasts are in clinical development.”
    Quote in the paperSubstantial claim
  • Premisecitation

    In a phase II study of invasive candidiasis in non-neutropenic patients, oral ibrexafungerp had similar safety and efficacy to fluconazole as step-down therapy after echinocandin treatment.

    “In a phase II study of IC in non-neutropenic patients, oral IBX demonstrated similar safety and efficacy compared to fluconazole as step-down therapy following echinocandin treatment [27••].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27••]

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  • Premisecitation

    Ibrexafungerp's spectrum of activity includes highly resistant Candida, Cryptococcus species, Aspergillus species, and endemic fungi.

    “It is anticipated to advance the treatment of highly resistant Candida infections; however, its spectrum of activity also includes Cryptococcus species, Aspergillus species, and endemic fungi (Fig. 1) [20].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Davis MR, Donnelley MA, Thompson GR. Ibrexafungerp: a novel oral glucan synthase inhibitor. Medical Mycology. 2020;58(8):579–92. source

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  • Premisecitation

    Mucorales species have baseline resistance to echinocandins, itraconazole, and voriconazole via alterations in LDM.

    “Mucorales species possess baseline resistance to echinocandins, itraconazole, and voriconazole via alterations in LDM.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Schwarz P, Cornely OA, Dannaoui E. Antifungal combinations in Mucorales: a microbiological perspective. Mycoses. 2019;3:746–60. source

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  • May combine two claims. 36
  • Classified as probably not a substantial claim. 4

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    Premisecitation

    Widespread fluconazole use has promoted acquired resistance among all Candida species and shifted the epidemiology of invasive candidiasis.

    “Widespread fluconazole use has promoted acquired resistance amongst all Candida species and shifted the epidemiology of invasive candidiasis (IC).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Perlin DS, Rautemaa-Richardson R, Alastruey-Izquierdo A. The global problem of antifungal resistance: prevalence, mechanisms, and management. The Lancet Infectious Diseases. 2017;17:e383–92. source

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  • May combine two claims.

    Interpretationnone given

    Ibrexafungerp, olorofim, oteseconazole, and fosmanogepix have novel mechanisms of action and potent activity against multidrug-resistant fungi.

    “Ibrexafungerp, olorofim, oteseconazole, and fosmanogepix possess novel mechanisms of actions with potent activity against MDR fungi.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In C. auris, reported resistance rates are fluconazole 90-93%, amphotericin B 15-30%, and echinocandin 2-10%.

    “Various studies have reported fluconazole resistance 90–93%, amphotericin B (AmB) resistance 15–30%, and echinocandin resistance 2–10% [11].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Forsberg K, Woodworth K, Walters M, Berkow EL, Jackson B, Chiller T, et al. Candida Auris : The recent emergence of a multidrug-resistant fungal pathogen. Medical Mycology. 2019;57(1):1–12. https://doi.org/10.1093/mmy/myy054. source

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    Premisecitation

    C. albicans remains the most common cause of invasive candidiasis, but non-albicans species are increasing.

    “While C. albicans remains the most common cause of IC, non-albicans species are on the rise (C. glabrata, C. parapsilosis, C. tropicalis, and C. krusei) [8].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Perlin DS, Rautemaa-Richardson R, Alastruey-Izquierdo A. The global problem of antifungal resistance: prevalence, mechanisms, and management. The Lancet Infectious Diseases. 2017;17:e383–92. source

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    Premisecitation

    Ibrexafungerp had average MIC50 0.5 μg/mL and MIC90 1 μg/mL against 100 C. auris isolates and increased survival and decreased fungal tissue burden in mouse and guinea pig models of C. auris infection.

    “It maintained an average MIC50 of 0.5 μg/mL and MIC90 of 1 μg/mL against 100 C. auris isolates and demonstrated increased survival and decreased fungal tissue burden in mouse and guinea pig models of C. auris infections [25].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Barat S, Borroto-Esoda K, Angulo D. SCY-078 Demonstrates significant tissue penetration in rats and mice following oral or IV administration. Open Forum Infectious Diseases. 2017;4:S471–1. source

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    Premisecitation

    Echinocandins are now the initial drug of choice for invasive candidiasis because of azole resistance and better clinical outcomes.

    “Due to azole resistance, and better clinical outcomes, echinocandins are now the initial drug of choice for IC.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Perlin DS, Rautemaa-Richardson R, Alastruey-Izquierdo A. The global problem of antifungal resistance: prevalence, mechanisms, and management. The Lancet Infectious Diseases. 2017;17:e383–92. source

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  • May combine two claims.

    Premisenone given

    Ibrexafungerp inhibits (1,3)β-d-glucan synthase via alternative binding sites, rendering it unaffected by FKS mutations.

    “Similar to echinocandins, IBX inhibits (1,3)β-d-glucan synthase but via alternative binding sites rendering it unaffected by FKS mutations.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Pan-azole-resistant A. fumigatus is increasingly reported in Europe and the USA, and intrinsic triazole resistance is higher among cryptic Aspergillus species.

    “While resistance rates remain generally favorable amongst common Aspergillus species (A. fumigatus, A. flavus, A. versicolor, etc.), pan-azole-resistant A. fumigatus is increasingly reported in Europe and the USA, and intrinsic triazole resistance is higher amongst cryptic species [12].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Walker TA, Lockhart SR, Beekmann SE, Polgreen PM, Santibanez S, Mody RK, et al. Recognition of azole-resistant aspergillosis by physicians specializing in infectious diseases, United States. Emerging Infectious Diseases. 2018;24. source

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    Premisecitation

    Among 195 C. auris isolates from a New York City outbreak, 194 were susceptible to ibrexafungerp with a mean MIC of 0.407 μg/mL, including five pan-resistant isolates.

    “Amongst 195 C. auris isolates from an outbreak in New York City, 194 were susceptible to IBX with a mean MIC of 0.407μg/mL, including five pan-resistant isolates [26•].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26•]

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Invasive fungal infections and the immunocompromised population have increased, carrying significant mortality and healthcare costs.

    “The incidence of invasive fungal infections (IFI) has since increased along with the immunocompromised population carrying significant mortality rates and costs to healthcare systems [3, 4].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [3] Vallabhaneni S, Mody R, Walker T, Chiller T. The global burden of fungal diseases. Infectious Disease Clinics of North America. 2016;30:1–11. source

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    • cites [4] Lum L, Lee A, Vu M, Strasser S, Davis R. Epidemiology and risk factors for invasive fungal disease in liver transplant recipients in a tertiary transplant center. Transpl Inf Dis. 2020:e13361. source

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    Premisecitation

    Scedosporium and Lomentospora species are rare opportunistic molds with broad and even pan-resistant tendencies and mortality rates exceeding 80%.

    “Scedosporium and Lomentospora species are rare opportunistic molds demonstrating broad and even pan-resistant tendencies with mortality rates breaching 80%.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Ramirez-Garcia A, Pellon A, Rementeria A, Buldain I, Barreto-Bergter E, Rollin-Pinheiro R, et al. Scedosporium and Lomentospora: an updated overview of underrated opportunists. Medical Mycology. 2018;56(1):102–25. source

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    Premisecitation

    C. krusei is intrinsically resistant to fluconazole, and C. glabrata has a very high rate of resistance.

    “C. krusei is intrinsically resistant to fluconazole, and C. glabrata carries a very high rate of resistance.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Perlin DS, Rautemaa-Richardson R, Alastruey-Izquierdo A. The global problem of antifungal resistance: prevalence, mechanisms, and management. The Lancet Infectious Diseases. 2017;17:e383–92. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    C. auris is a major cause of multidrug-resistant, healthcare-associated candidiasis with mortality rates of 30-45%.

    “C. auris has burst onto the scene as a major cause of MDR, healthcare-associated candidiasis with mortality rates ranging from 30 to 45% [10, 11].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [10] Adams E, Quinn M, Tsay S, Poirot E, Chaturvedi S, Southwick K, et al. Candida auris in healthcare facilities, New York, USA, 2013–2017. Emerging Infectious Diseases. 2018;24(10):1816–24. https://doi.org/10.3201/eid2410.180649. source

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    • cites [11] Forsberg K, Woodworth K, Walters M, Berkow EL, Jackson B, Chiller T, et al. Candida Auris : The recent emergence of a multidrug-resistant fungal pathogen. Medical Mycology. 2019;57(1):1–12. https://doi.org/10.1093/mmy/myy054. source

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  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Evolved formulations of echinocandins, polyenes, and triazoles offer less toxicity, more convenient dosing, and greater potency, potentially expanding their indications.

    “Evolved formulations of echinocandins, polyenes, and triazoles offer less toxicity, convenient dosing, and greater potency, potentially expanding these classes’ indications.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Candida resistance is mediated by amplification of transcription factors such as UPC2, TAC1, MRR1, or CgPdr1, causing ERG11 overexpression or drug efflux transporter overexpression; ERG11 point mutations can alter LDM structure.

    “Resistance in Candida species is mediated by the amplification of zinc cluster transcription factors such as UPC2, TAC1, MRR1, or CgPdr1 (particularly in C. glabrata). UPC2 upregulation causes the overexpression of the LDM gene ERG11, while mutations in TAC1, MRR1, and CgPdr1 overexpress drug efflux transporters. Additionally, resistance can occur via altered LDM structure from point mutations in”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [8] Perlin DS, Rautemaa-Richardson R, Alastruey-Izquierdo A. The global problem of antifungal resistance: prevalence, mechanisms, and management. The Lancet Infectious Diseases. 2017;17:e383–92. source

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    • cites [9] Whaley SG, Berkow EL, Rybak JM, Nishimoto AT, Barker KS, Rogers PD. Azole antifungal resistance in Candida albicans and emerging non-albicans Candida species. Frontiers in Microbiology. 2017;7. https://doi.org/10.3389/fmicb.2016.02173. source

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    Premisecitation

    Rezafungin is the latest echinocandin, with structural modifications that enhance chemical stability and solubility, granting a long half-life that enables once-weekly intravenous dosing.

    “Structural modifications have enhanced its chemical stability and solubility granting a long half-life enabling once-weekly IV dosing [31].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Krishnan BR, James KD, Polowy K, Bryant BJ, Vaidya A, Smith S, et al. CD101, a novel echinocandin with exceptional stability properties and enhanced aqueous solubility. J Antibiot. 2017;70:130–5. source

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    Premisecitation

    Antifungal use in agriculture and medicine has driven acquired resistance and shifted fungal prevalence toward species with inherent resistance.

    “Agricultural and medicinal antifungal use has been selected for inherently drug-resistant fungi and acquired resistance mechanisms.”
    • Also stated in: § Epidemiology and Mechanisms of Antifungal Resistance · plain
      “Antifungal pesticides in agricultural systems and widespread healthcare use have fueled acquired resistance as well as shifted fungal prevalence toward species with inherent antifungal resistance [6].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Verweij PE, Snelders E, Kema GH, Mellado E, Melchers WJ. Azole resistance in Aspergillus fumigatus: a side-effect of environmental fungicide use? The Lancet Infectious Diseases. 2009;9:789–95. source

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    Premisecitation

    Rezafungin has shown activity against Pneumocystis, reducing biofilm mass and inhibiting its production, and preventing Pneumocystis pneumonia in immunocompromised mice.

    “However, RZF has shown activity against Pneumocystis, reducing biofilm mass and inhibiting its production as well as preventing pneumocystis pneumonia (PJP) in immunocompromised mice [38•].”
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    • cites [38•]

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    Premisecitation

    PC945 is a potent inhaled topical triazole with little systemic absorption.

    “PC945 is a potent inhaled topical triazole with minimal systemic absorption.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [81] Colley T, Alanio A, Kelly SL, Sehra G, Kizawa Y, Warrilow AGS, et al. In vitro and in vivo antifungal profile of a novel and long-acting inhaled azole, PC945, on aspergillus fumigatus infection. Antimicrob Agents Chemother. 2017;61(5):e02280–16. https://doi.org/10.1128/aac.02280-16. source

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    Premisecitation

    Fosmanogepix possesses broad in vitro activity against Candida (excluding C. krusei), Trichosporon, Coccidioides, Cryptococcus, Aspergillus (A. fumigatus, A. flavus, A. niger), and amphotericin B-resistant strains of Fusarium and Scedosporium.

    “Fosmanogepix possesses broad in vitro activity against many genera of fungi: Candida (excluding C. krusei), Trichosporon, Coccidioides, Cryptococcus, Aspergillus (A. fumigatus, A. flavus, A. niger), as well as AmB-resistant strains of Fusarium and Scedosporium (Fig. 1) [51, 53–55].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [51] Miyazaki M, Horii T, Hata K, Watanabe NA, Nakamoto K, Tanaka K, et al. In vitro activity of E1210, a novel antifungal, against clinically important yeasts and molds. Antimicrob Agents Chemother. 2011;55:4652–8. source

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    • cites [53] Castanheira M, Duncanson FP, Diekema DJ, Guarro J, Jones RN, Pfaller MA. Activities of E1210 and comparator agents tested by CLSI and EUCAST broth microdilution methods against Fusarium and Scedosporium species identified using molecular methods. Antimicrob Agents Chemother. 2012;56:352–7. source

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    • cites [54] Hager CL, Larkin EL, Long L, et al. In vitro and in vivo evaluation of the antifungal activity of APX001A/APX001 against Candida auris. Antimicrob Agents Chemother. 2018;62:e02319–7. source

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    • cites [55] Jørgensen KM, Astvad KMT, Arendrup MC. In vitro activity of manogepix (APX001A) and comparators against contemporary molds: MEC comparison and preliminary experience with colorimetric MIC determination. Antimicrob Agents Chemother. 2020;64(8):e00730–20. https://doi.org/10.1128/AAC.00730-20. source

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    Premisecitation

    Olorofim has in vitro activity against triazole-resistant A. fumigatus (MIC ≤ 0.008-0.03 mg/L), L. prolificans (MIC 0.03-0.5 mg/L), Scedosporium species (MIC 0.03-0.5 mg/L), Rasamsonia argillacea (MIC ≤0.008-0.03 mg/L), and certain Fusarium species (F. oxysporum complex but not F. solani).

    “In vitro activity has been demonstrated against triazole-resistant A. fumigatus (MIC ≤ 0.008–0.03 mg/L), L. prolificans (MIC 0.03–0.5mg/L), Scedosporium species (MIC 0.03–0.5mg/L), Rasamsonia argillacea (MIC ≤0.008 – 0.03 mg/L), and certain Fusarium species (F. oxysporum complex but not F. solani) [66•, 67].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [66•, 67]

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    Premisecitation

    Olorofim is a first-in-class orotomide that affects pyrimidine synthesis via reversible inhibition of dihydroorotate dehydrogenase.

    “Olorofim, developed by F2G, is a first-in-class orotomide which affects pyrimidine synthesis via reversible inhibition of dihydroorotate dehydrogenase (DHODH) [63].”
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    • cites [63] Oliver JD, Sibley GE, Beckmann N, et al. F901318 represents a novel class of antifungal drug that inhibits dihydroorotate dehydrogenase. Proc Natl Acad Sci USA. 2016;113:12809–14. source

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    Premisecitation

    Nikkomycin Z is a first-in-class chitin-synthase inhibitor developed as a targeted approach against endemic fungi, including Coccidioides species.

    “Nikkomycin Z is a first-in-class chitin-synthase inhibitor developed by Valley Fever Solutions as a targeted approach against endemic fungi, including Coccidioides species [101].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [101] Hector RF, Zimmer BL, Pappagianis D. Evaluation of nikkomycins X and Z in murine models of coccidioidomycosis, histoplasmosis, and blastomycosis. Antimicrob Agents Chemother. 1990;34:587–93. source

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    Premisecitation

    In a phase II trial of fosmanogepix for invasive candidiasis in non-neutropenic patients, treatment success was 80% without serious side effects, and the drug showed in vitro activity against all Candida isolates recovered in the study.

    “Data from a phase II clinical trial of fosmanogepix for the treatment of invasive candidiasis in non-neutropenic patients reported an 80% treatment success rate without serious side effects. Additionally, the drug exhibited in vitro activity against all Candida isolates recovered in the study [62••].”
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    • cites [62••]

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    Premisecitation

    Fosmanogepix and olorofim are the first drugs in their respective classes.

    “Perhaps the brightest future for the future of invasive mold infections lie in stage II and I agents fosmanogepix and olorofim, both first agents in their respective classes.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [51] Miyazaki M, Horii T, Hata K, Watanabe NA, Nakamoto K, Tanaka K, et al. In vitro activity of E1210, a novel antifungal, against clinically important yeasts and molds. Antimicrob Agents Chemother. 2011;55:4652–8. source

      Not checked in the free run.

    • cites [63] Oliver JD, Sibley GE, Beckmann N, et al. F901318 represents a novel class of antifungal drug that inhibits dihydroorotate dehydrogenase. Proc Natl Acad Sci USA. 2016;113:12809–14. source

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    Premisecitation

    IBX can be given orally with a favorable safety profile.

    “IBX introduces a novel mechanism, potent broad spectrum of activity and a safe oral formulation”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Davis MR, Donnelley MA, Thompson GR. Ibrexafungerp: a novel oral glucan synthase inhibitor. Medical Mycology. 2020;58(8):579–92. source

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  • May combine two claims.

    Premisecitation

    ATI-2307 is a first-in-class arylamidine that disrupts yeast cellular respiration by inhibiting mitochondrial respiratory chain complexes III and IV.

    “It is a first-in-class arylamidine with a novel antifungal mechanism: the disruption of yeast cellular respiration via inhibition of mitochondrial respiratory chain complexes III and IV.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [85] Yamashita K, Miyazaki T, Fukuda Y, et al. The novel arylamidine T-2307 selectively disrupts yeast mitochondrial function by inhibiting respiratory chain complexes. Antimicrob Agents Chemother. 2019;63:e00374–19. source

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    Premisecitation

    Encochleated amphotericin B was equally efficacious as amphotericin B and superior to oral fluconazole in cryptococcal meningoencephalitis.

    “CAmB was found to be equally efficacious as AmB with superiority over oral fluconazole in cryptococcal meningoencephalitis [77].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] Lu R, Hollingsworth C, Qiu J, Wang A, Hughes E, Xin X, et al. Efficacy of oral encochleated amphotericin B in a mouse model of cryptococcal meningoencephalitis. mBio. 2019;10:3. https://doi.org/10.1128/mBio.00724-19. source

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    Premisecitation

    Oteseconazole exhibited potent in vitro activity against most fluconazole-resistant C. albicans and C. krusei isolates (mean MIC ≤ 0.15 μg/mL) and echinocandin-resistant C. glabrata.

    “It exhibited potent in vitro activity against most fluconazole-resistant C. albicans and C. krusei isolates (mean MIC ≤ 0.15 μg/mL) as well as echinocandin-resistant C. glabrata [44, 49].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [44] Schell WA, Jones AM, Garvey EP, et al. Fungal CYP51 inhibitors VT-1161 and VT-1129 exhibit strong in vitro activity against Candida glabrata and C. krusei isolates clinically resistant to azole and echinocandin antifungal compounds. Antimicrob Agents Chemother. 2017;61:e01817–6. source

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    • cites [49] Nishimoto AT, Wiederhold NP, Flowers SA, Zhang Q, Kelly SL, Morschhäuser J, et al. In vitro activities of the novel investigational tetrazoles vt-1161 and vt-1598 compared to the triazole antifungals against azole-resistant strains and clinical isolates of Candida albicans. Antimicrob Agents Chemother. 2019;63:1–11. source

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    Premisecitation

    PC945 is the first topical, inhaled triazole, designed primarily for invasive pulmonary aspergillosis, with prolonged lung tissue retention without significant systemic absorption and activity against posaconazole- and pan-azole-resistant A. fumigatus and C. auris.

    “PC945 is the first topical, inhaled triazole. Developed by Pulmocide, this drug is designed primarily for the treatment of IPA, boasting prolonged lung tissue retention without significant systemic absorption. Its antifungal spectrum is analogous to systemic triazoles but with significantly greater potency maintaining activity against posaconazole and pan-azole-resistant A. fumigatus, as well as C”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [81] Colley T, Alanio A, Kelly SL, Sehra G, Kizawa Y, Warrilow AGS, et al. In vitro and in vivo antifungal profile of a novel and long-acting inhaled azole, PC945, on aspergillus fumigatus infection. Antimicrob Agents Chemother. 2017;61(5):e02280–16. https://doi.org/10.1128/aac.02280-16. source

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    • cites [82] Rudramurth S, et al. In vitro antifungal activity of a novel topical triazole PC945 against emerging yeast Candida auris. J Antimicrob Chemother. 2019;74(10):2943–9. https://doi.org/10.1093/jac/dkz280. source

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    Premisecitation

    In a phase II randomized, blinded, placebo-controlled trial of adults with moderate-to-severe onychomycosis, oteseconazole treatment produced a 42% cure rate without hepatotoxicity or cardiac toxicity.

    “In a phase II randomized, blinded, placebo-controlled trial of adults with moderate-to-severe onychomycosis, treatment with VT-1161 saw a 42% cure rate without hepatotoxicity or cardiac toxicity [47••].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47••]

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    Premisecitation

    VT-1129 is an oral tetrazole with robust in vitro and in vivo efficacy against C. neoformans and C. gattii, maintaining activity (mean MIC 0.027 μg/mL) against fluconazole-resistant or dose-dependent C. neoformans isolates.

    “Preclinical studies have demonstrated robust in vitro and in vivo efficacy against C. neoformans and C. gattii, notably maintaining activity (mean MIC 0.027 μg/mL) against fluconazole-resistant or dose-dependent C. neoformans isolates (Fig. 1) [92–94].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [92] Lockhart SR, Fothergill AW, Iqbal N, Bolden CB, Grossman NT, Garvey EP, et al. The investigational fungal Cyp51 inhibitor VT-1129 demonstrates potent in vitro activity against Cryptococcus neoformans and Cryptococcus gattii. Antimicrob Agents Chemother. 2016;60:2528–31. source

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    • cites [93] Nielsen K, Vedula P, Smith KD, Meya DB, Garvey EP, Hoekstra WJ, et al. Activity of VT-1129 against Cryptococcus neoformans clinical isolates with high fluconazole MICs. Med Mycol J. 2017;55(4):453–6. https://doi.org/10.1093/mmy/myw089. source

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    • cites [94] Wiederhold NP, Najvar LK, Garvey EP, Brand SR, Xu X, Ottinger EA, et al. The fungal Cyp51 inhibitor VT-1129 is efficacious in an experimental model of cryptococcal meningitis. Antimicrob Agents Chemother. 2018;62. source

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  • May combine two claims.

    Interpretationcitation

    VT-1161 is expected to be used for recurrent vulvovaginal candidiasis and onychomycosis.

    “while VT-1161 is poised to treat recurrent VVC and onychomycosis with potential to garner other indications as clinical development progress.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [47] • Elewski B, Brand S, Degenhardt T, Curelop S, Pollak R, Schotzinger R, et al. A phase II, randomized double-blinded, placebo controlled, dose-ranging study to evaluate the efficacy and safety of VT-1161 oral tablets in the treatment of patients with distal and lateral subungual onychomycosis of the toenail. Br J Dermatol. 2020. https://doi.org/10.1111/bjd.19224Phase II data showing efficacy for moderate to severe onychomycosis. Current antifungals for onychomycosis have low success rate, systemic toxicities and are primarily indicated for mild–moderate disease. source

      Not checked in the free run.

    • cites [48] • Brand SR, Degenhart TP, Person KL, et al. Oral VT-1161 is highly effective and safe in patients with recurrent vulvovaginal candidiasis - results of REVIVE, a multicenter phase 2b study. ASM Microbe. New Orleans: Viamet Pharmaceuticals. 2017; Phase II data supporting its use for recurrent vaginal candidiasis.

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Fosmanogepix is a prodrug of manogepix and a first-in-class Gwt1 inhibitor.

    “Fosmanogepix, a prodrug of manogepix, is a first-in-class Gwt1 inhibitor developed by Amplyx Pharmaceuticals.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    VT-1598 is an oral tetrazole with a wide antifungal spectrum including yeast, molds, and dimorphic fungi.

    “VT-1598, another oral tetrazole, boasts a wide antifungal spectrum including yeast, molds, and dimorphic fungi.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Oteseconazole belongs to the tetrazole class, a new generation of oral lanosterol 14α-demethylase inhibitors with higher specificity for fungal CYP51 and theoretically less cross-inhibition of mammalian CYP enzymes, leading to fewer drug-drug interactions and adverse effects.

    “Oteseconazole (VT-1161), developed by Mycovia Pharmaceuticals, belongs to the tetrazole class, a new generation of oral lanosterol 14⍺-demethylase inhibitors which boast higher specificity for fungal CYP51 and therefore theoretically less cross-inhibition of mammalian CYP enzymes leading to fewer drug–drug interactions and adverse effects [42].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Warrilow AG, et al. The clinical candidate VT-1161 is a highly potent inhibitor of Candida albicans CYP51 but fails to bind the human enzyme. Antimicrob Agents Chemother. 2014;58(12):7121–7. https://doi.org/10.1128/aac.03707-14. source

      Not checked in the free run.

36 of 36

  • The paper relies on this without support.

    Only five antifungal classes are currently on the market.

    “Only five antifungal classes exist on the market.”

  • The paper relies on this without support.

    Nearly 20 years have passed since the newest antifungal class was introduced to the market.

    “Nearly 20 years have passed since the introduction of the newest antifungal class to the market.”

  • The paper relies on this without support.

    Current treatment options for onychomycosis have a low success rate.

    “Current treatment options for onychomycosis carry a low success rate.”

  • The paper relies on this without support.

    The number of immunocompromised patients is increasing.

    “with the rising immunocompromised population”

  • The paper relies on this without support.

    Antifungal resistance continues to evolve indefinitely.

    “perpetual evolution of antifungal resistance”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Multi-drug resistant Candida infections are on the rise due to a variety of mechanisms, particularly C. auris, with widespread azole resistance and the potential for development of resistance to all classes of antifungals during therapy.

    “Multi-drug resistant Candida infections are on the rise due to a variety of mechanisms (Table 2), particularly C. auris, with widespread azole resistance and the potential for development of resistance to all classes of antifungals during therapy, highlighting the need for new agents to keep up with changes in epidemiology.133,145–153”

    From Epidemiology of Invasive Candidiasis (2024) · cites this paper as [149]

    The “Epidemiology and Mechanisms of Antifungal Resistance > Yeast” section describes rising non-albicans Candida, multiple resistance mechanisms, and C. auris as a major cause of multidrug-resistant candidiasis with 90–93% fluconazole resistance. It also says echinocandin resistance can develop with prolonged drug exposure, but does not establish that C. auris can develop resistance to all antifungal classes during therapy. Page numbers were not available in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Rezafungin is similar in structure to anidulafungin but with an extended half-life allowing weekly administration.

    “It is similar in structure to anidulafungin but with an extended half-life allowing weekly administration which will improve its suitability for outpatient therapy.149”

    From Epidemiology of Invasive Candidiasis (2024) · cites this paper as [149]

    In ‘Agents in Phase III Clinical Trials’ (page unavailable), the rezafungin subsection says structural modifications give it a long half-life enabling once-weekly IV dosing. It does not establish structural similarity specifically to anidulafungin or say that weekly dosing will improve suitability for outpatient therapy. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Ibrexafungerp is currently only FDA approved as oral therapy for vulvovaginal candidiasis.

    “Ibrexafungerp is currently only FDA approved as oral therapy for vulvovaginal candidiasis, although clinical trials for invasive candidiasis step-down therapy, refractory candidiasis, and C. auris are ongoing.149,156–159”

    From Epidemiology of Invasive Candidiasis (2024) · cites this paper as [149]

    The Ibrexafungerp section (Agents in Phase III Clinical Trials; page unavailable) describes oral ibrexafungerp in ongoing trials, and the References list a phase III study for vulvovaginal candidiasis. Our copy does not state that ibrexafungerp is FDA approved, or that vulvovaginal candidiasis is its only approved indication. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Ibrexafungerp retains solubility and activity in acidic environments, making it suitable for use in abscesses.

    “Importantly, it retains solubility and activity in acidic environments, making it suitable for use in abscesses.149,157”

    From Epidemiology of Invasive Candidiasis (2024) · cites this paper as [149]

    The Ibrexafungerp subsection (Agents in Phase III Clinical Trials; page not provided) says the drug is soluble at lower pH, enhancing penetration into acidic environments such as abscesses. It reports antifungal activity elsewhere, but does not say that activity is retained under acidic conditions. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Ibrexafungerp has oral bioavailability of 35-50% and good systemic distribution except for the CNS.

    “It has oral bioavailability of 35–50% and good systemic distribution except for the CNS.”

    From Epidemiology of Invasive Candidiasis (2024) · cites this paper as [149]

    The Ibrexafungerp section (Agents in Phase III Clinical Trials; page unavailable) describes oral use and enhanced penetration into acidic environments such as abscesses or vaginal tissue. It does not give 35–50% oral bioavailability or establish good systemic distribution with the CNS as an exception. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Olorofim's QIDP designation is missing from the designation table

    Minor

    The text says olorofim has both QIDP and orphan-drug status, whereas the table's FDA-designations entry lists only orphan-drug status.

  • Oteseconazole is described as having a novel mechanism despite sharing an existing drug target

    Minor

    The abstract attributes a novel mechanism of action to oteseconazole, but the paper identifies it as a lanosterol demethylase inhibitor-the same mechanism it describes for existing azoles.

2 of 2

The citation lists haven’t been fetched yet

References 100 · Cited by 32

Research works printed but not linked: 2

  1. •• Synexis.com (2019) SCYNEXIS announces positive interim results from Phase 3 open-label FURI study. https://www.scynexis.com/news-media/press-releases/detail/169/scynexis-announces-positive-interim-results-from-phase-3. Accessed 11 Aug 2020. Early data from phase III study show ibrexafungerp is efficacious in invasive fungal infections resistant or refractory to other antifungals.
  2. Wiederhold NP, Patterson HP, Birch M, Law D. Evaluation of the in vitro activity of olorofim against Fusarium species. In Proceedings of the 9th Trends in Medical Mycology, Nice, France, 11–19 October 2019.

Authors
Seiler, G. T., & Ostrosky-Zeichner, L.
Affiliations
The University of Texas MD Anderson Cancer Center (US)
Corresponding author
Seiler, Garret T.
ORCID
Seiler, Garret T.
Venue
Current Fungal Infection Reports
Publisher
Springer Science and Business Media LLC
Published
2021-05-28
Volume
15
Issue
3
Pages
104-115
ISSN
  • 1936-3761 (ISSN-L)
  • 1936-377X
DOI
10.1007/s12281-021-00419-5
PMC
PMC8162489
OpenAlex
W3164199071
Cited by
32
References
100
Citations by year
2026: 2 · 2025: 7 · 2024: 4 · 2023: 5 · 2022: 10 · 2021: 4
FWCI
0.70
Type
journal article
Language
en
Open access
Licence
Locations
  • Current Fungal Infection Reports (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
  • Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
Keywords
antifungal agents, drug-resistant fungi, echinocandins, polyenes, triazoles, ibrexafungerp, olorofim, oteseconazole, fosmanogepix, acquired drug resistance, fungal infection, immunocompromised patients

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-04.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-04.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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