Review of treatment options for a multidrug-resistant fungus: Candida auris.

Candida auris is a widely distributed, highly lethal, multidrug-resistant fungal pathogen. It was first identified in 2009 when it was isolated from fluid drained from the external ear canal of a patient in Japan. Since then, it has caused infectious outbreaks in over 45 countries, with mortality rates approaching 60%. Drug resistance is common in this species, with a large proportion of isolates displaying fluconazole resistance and nearly half are resistant to two or more antifungal drugs. In this review, we describe the drug resistance mechanism of C. auris and potential small-molecule drugs for treating C. auris infection. Among these antifungal agents, rezafungin was approved by the US Food and Drug Administration (FDA) for the treatment of candidemia and invasive candidiasis on March 22, 2023. Ibrexafungerp and fosmanogepix have entered phase III clinical trials.

Invasive Candida infection: epidemiology, clinical and therapeutic aspects of an evolving disease and the role of rezafungin.

INTRODUCTION: Invasive Candida Infections (ICIs) have undergone a series of significant epidemiological, pathophysiological, and clinical changes during the last decades, with a shift toward non-albicans species, an increase in the rate of exogenous infections and clinical manifestations ranging from candidemia to an array of highly invasive and life-threatening clinical syndromes. The long-acting echinocandin rezafungin exhibits potent in-vitro activity against most wild-type and azole-resistant Candida spp. including C.auris. AREAS COVERED: The following topics regarding candidemia only and ICIs were reviewed and addressed: i) pathogenesis; ii) epidemiology and temporal evolution of Candida species; iii) clinical approach; iv) potential role of the novel long-acting rezafungin in the treatment of ICIs. EXPERT OPINION: Authors' expert opinion focused on considering the potential role of rezafungin in the evolving context of ICIs. Rezafungin, which combines a potent in-vitro activity against Candida species, including azole-resistant strains and C.auris, with a low likelihood of drug-drug interactions and a good safety profile, may revolutionize the treatment of candidemia/ICI. Indeed, it may shorten the length of hospital stays when clinical conditions allow and extend outpatient access to treatment of invasive candidiasis, especially when prolonged treatment duration is expected.

Azole resistance in Candida auris: mechanisms and combinatorial therapy.

Multidrug resistance Candida auris is a dangerous fungal pathogen that is emerging at an alarming rate and posing serious threats to public health. C. auris is associated with nosocomial infections that cause invasive candidiasis in immunocompromised patients. Several antifungal drugs with distinct mechanisms of action are clinically approved for the treatment of fungal infections. The high rates of intrinsic and acquired drug resistance, particularly to azoles, reported in characterized clinical isolates of C. auris make treatment extremely problematic. In systemic infections, azoles are the first-line treatment for most Candida species; however, the increasing use of drugs results in the frequent emergence of drug resistance. More than 90% of the clinical isolates of C. auris is shown to be highly resistant to azole drugs especially fluconazole, with some strains (types) resistant to all three classes of commonly used antifungals. This presents a huge challenge for researchers in terms of completely understanding the molecular mechanism of azole resistance to develop more efficient drugs. Due to the scarcity of C. auris therapeutic alternatives, the development of successful drug combinations provides an alternative for clinical therapy. Taking advantage of various action mechanisms, such drugs in combination with azole are likely to have synergistic effects, improving treatment efficacy and overcoming C. auris azole drug resistance. In this review, we outline the current state of understanding about the mechanisms of azole resistance mainly fluconazole, and the current advancement in therapeutic approaches such as drug combinations toward C. auris infections.

Cellular apoptosis and cell cycle arrest as potential therapeutic targets for eugenol derivatives in Candida auris.

Candida auris, the youngest Candida species, is known to cause candidiasis and candidemia in humans and has been related to several hospital outbreaks. Moreover, Candida auris infections are largely resistant to the antifungal drugs currently in clinical use, necessitating the development of novel medications and approaches to treat such infections. Following up on our previous studies that demonstrated eugenol tosylate congeners (ETCs) to have antifungal activity, several ETCs (C1-C6) were synthesized to find a lead molecule with the requisite antifungal activity against C. auris. Preliminary tests, including broth microdilution and the MUSE cell viability assay, identified C5 as the most active derivative, with a MIC value of 0.98 g/mL against all strains tested. Cell count and viability assays further validated the fungicidal activity of C5. Apoptotic indicators, such as phosphatidylserine externalization, DNA fragmentation, mitochondrial depolarization, decreased cytochrome c and oxidase activity and cell death confirmed that C5 caused apoptosis in C. auris isolates. The low cytotoxicity of C5 further confirmed the safety of using this derivative in future studies. To support the conclusions drawn in this investigation, additional in vivo experiments demonstrating the antifungal activity of this lead compound in animal models will be needed.

Discovery of a new chemical scaffold for the treatment of superbug Candida auris infections.

Candida auris has emerged as a serious threat of public health and caused global epidemic due to multi-drug resistance, remarkable transmissibility and high mortality. To tackle the challenging super fungus, novel benzoanilide antifungal agents were discovered by an integrated strategy of phenotypic screen, hit optimization, antifungal assays and mechanism exploration. The most promising compound A1 showed potent in vitro and in vivo efficacy against Candida auris infection. Mechanism investigation revealed that compound A1 blocked the biosynthesis of virulence factors and fungal cell walls through the inhibition of glycosylphosphatidylinositol (GPI) and GPI-anchored proteins. Thus, compound A1 represents a promising lead compound to combat drug-resistant candidiasis.

Emergence of Antifungal Resistant Subclades in the Global Predominant Phylogenetic Population of Candida albicans.

Candida albicans remains the most common species causing invasive candidiasis. In this study, we present the population structure of 551 global C. albicans strains. Of these, the antifungal susceptibilities of 370 strains were tested. Specifically, 66.6% of the azole-nonsusceptible (NS)/non-wild-type (NWT) strains that were tested belonged to Clade 1. A phylogenetic analysis, a principal components analysis, the population structure, and a loss of heterozygosity events revealed two nested subclades in Clade 1, namely, Clade 1-R and Clade 1-R-α, that exhibited higher azole-NS/NWT rates (75.0% and 100%, respectively). In contrast, 6.4% (21/326) of the non-Clade 1-R isolates were NS/NWT to at least 1 of 4 azoles. Notably, all of the Clade 1-R-α isolates were pan-azole-NS/NWT that carried unique A114S and Y257H double substitutions in Erg11p and had the overexpression of ABC-type efflux pumps introduced by the substitution A736V in transcript factor Tac1p. It is worth noting that the Clade 1-R and Clade 1-R-α isolates were from different cities that are distributed over a large geographic span. Our study demonstrated the presence of specific phylogenetic subclades that are associated with antifungal resistance among C. albicans Clade 1, which calls for public attention on the monitoring of the future spread of these clones. IMPORTANCE Invasive candidiasis is the most common human fungal disease among hospitalized patients, and Candida albicans is the predominant pathogen. Considering the large number of infected cases and the limited alternative therapies, the azole-resistance of C. albicans brings a huge clinical threat. Here, our study suggested that antifungal resistance in C. albicans could also be associated with phylogenetic lineages. Specifically, it was revealed that more than half of the azole-resistant C. albicans strains belonged to the same clade. Furthermore, two nested subclades of the clade exhibited extremely high azole-resistance. It is worth noting that the isolates of two subclades were from different cities that are distributed over a large geographic span in China. This indicates that the azole-resistant C. albicans subclades may develop into serious public health concerns.

Drug Resistance and Novel Therapeutic Approaches in Invasive Candidiasis.

Candida species are the leading cause of invasive fungal infections worldwide and are associated with acute mortality rates of ~50%. Mortality rates are further augmented in the context of host immunosuppression and infection with drug-resistant Candida species. In this review, we outline antifungal drugs already in clinical use for invasive candidiasis and candidaemia, their targets and mechanisms of resistance in clinically relevant Candida species, encompassing not only classical resistance, but also heteroresistance and tolerance. We describe novel antifungal agents and targets in pre-clinical and clinical development, including their spectrum of activity, antifungal target, clinical trial data and potential in treatment of drug-resistant Candida. Lastly, we discuss the use of combination therapy between conventional and repurposed agents as a potential strategy to combat the threat of emerging resistance in Candida.

Activity of Compound Agrimony Enteritis Capsules against invasive candidiasis: Exploring the differences between traditional Chinese medicine prescriptions and its main components in the treatment of diseases.

ETHNOPHARMACOLOGICAL RELEVANCE: Compound Agrimony Enteritis Capsules (FFXHC) is an ethnomedicine derived from Yi Nationality Herbal Medicine for the treatment of enteritis. We found that compared to berberine hydrochloride (BBR), a component of this medicine, FFXHC was more efficacious in the mouse model of IC mice in significantly alleviating lung and intestinal lesions. " Our study provides a novel perspective into the pharmacological mechanism of action of the ethnic compound FFXHC. AIM OF THE STUDY: To determine the underlying mechanism of the superiority of FFXHC over BBR in IC. MATERIALS AND METHODS: The susceptibility of Candida albicans to FFXHC was evaluated in vitro. The mouse model of IC was established and the survival rate, weight change, the number of organ colonies, and immune organ coefficient of the mice were determined, the effect of FFXHC on the immune function of mice, including changes in the number of immune cells, levels of the related inflammatory cytokines (INF-γ, TNF-α, MCP-1, IL-6, and IL-17A), and the antimicrobial peptide, LL-37 (CRAMP in mice), were determined. Mice feces were collected and changes in the intestinal microecology were studied. RESULTS: Our findings indicated that FFXHC was not active against Candida albicans and did not restore the sensitivity of the resistant strain in vitro; however, it had a therapeutic effect that improve survival rate on mice with IC. The number of lymphocytes and neutrophils of mice with IC treated with FFXHC increased significantly. The intestinal microecology of mice was restored and the abundance of the probiotic Bacteroides was increased, which further stimulated the production of the antimicrobial peptide, LL-37, which is required for acquired immunity. Furthermore, the levels of Th cell-related cytokines, including INF-γ, TNF-α, and IL-17A were significantly increased, whereas those of the proinflammatory cytokines, IL-6 and MCP-1, decreased. With the activation of acquired immunity, the immune function of mice was restored, the body weight and survival rate of mice improved considerably, the coefficients of the thymus and spleen increased, and the number of fungal colonies in the lung and kidney decreased. CONCLUSIONS: FFXHC could eliminate fungi by increasing the relative abundance of probiotics in Bacteroides and the number of neutrophils, thereby promoting the production of CRAMP and resulting in a fungicidal effect, leading to acquired immunity. Although BBR has an antifungal effect, we found that it was not as effective as FFXHC.

Ibrexafungerp Demonstrates In Vitro Activity against Fluconazole-Resistant Candida auris and In Vivo Efficacy with Delayed Initiation of Therapy in an Experimental Model of Invasive Candidiasis.

Candida auris is an emerging pathogen that has rapidly spread to many countries on multiple continents. Invasive infections caused by this species are associated with significant mortality, and treatment options are limited due to antifungal resistance. Ibrexafungerp is the first-in-class member of the triterpenoids, which inhibit the production of (1,3)-ß-d-glucan and can be administered orally. We evaluated the in vitro activity and in vivo efficacy of ibrexafungerp against C. auris Antifungal susceptibility was tested by broth microdilution against 54 C. auris isolates. Neutropenic mice were intravenously infected with a clinical isolate, and a 7-day treatment course was begun 24 h postinoculation with vehicle control, ibrexafungerp (20, 30, and 40 mg/kg orally twice daily), fluconazole (20 mg/kg orally once daily), or caspofungin (10 mg/kg intraperitoneally once daily). Fungal burden was assessed by colony counts in the kidneys on day 8 and on day 21 or as mice became moribund in the survival arm. Ibrexafungerp demonstrated consistent activity, with MICs ranging between 0.25 and 2 µg/ml against all isolates. Marked improvements in survival were observed in mice treated with the higher doses of ibrexafungerp and caspofungin. Similarly, reductions in kidney fungal burden were also observed in these groups. No improvements in survival or reductions in fungal burden were observed with fluconazole, consistent with the in vitro resistance of the isolate used to establish infection to this azole. These results demonstrate that ibrexafungerp is effective in vivo against C. auris even when the start of therapy is delayed.

An evaluation of ibrexafungerp for the treatment of invasive candidiasis: the evidence to date.

INTRODUCTION: Invasive fungal infections, especially candidemia and invasive candidiasis, cause significant morbidity and mortality. The epidemiology of candida infections have changed dramatically due to an increase in risk factors associated with the development of infection and the emergence of resistant isolates such as C. glabrata and C. auris. This has prompted the search for novel and effective antifungals. AREAS COVERED: The results of in vitro studies evaluating the activity of ibrexafungerp against Candida species are reviewed and the pharmacokinetic/pharmacodynamic properties are highlighted. Available results and safety data from limited clinical studies are discussed. EXPERT OPINION: Ibrexafungerp demonstrates potent in vitro activity against susceptible and resistant Candida species, including echinocandin-resistant C. glabrata and multidrug-resistant C. auris. It also offers the flexibility of a parenteral and an oral preparation, minimal adverse effects, and low drug-drug interactions. In Phase 2/3 clinical trials, ibrexafungerp appears to have excellent clinical activity in patients with candidemia, invasive candidiasis, and mucosal candidiasis. Although there are several ongoing clinical trials, ibrexafungerp appears to be a promising agent and an important addition to the antifungal armamentarium necessary to treat emerging and resistant pathogens, including several of the Candida species.

Therapeutic Potential of Fosmanogepix (APX001) for Intra-abdominal Candidiasis: from Lesion Penetration to Efficacy in a Mouse Model.

Intra-abdominal candidiasis (IAC) is one of the most common yet underappreciated forms of invasive candidiasis. IAC is difficult to treat, and therapeutic failure and drug-resistant breakthrough infections are common in some institutions despite the use of echinocandins as first-line agents. Fosmanogepix (FMGX, formerly APX001) is a first-in-class antifungal prodrug that can be administered both intravenously and orally. FMGX is currently in phase 2 clinical development for the treatment of life-threatening invasive fungal infections. To explore the pharmacological properties and therapeutic potential of FMGX for IAC, we evaluated both drug penetration and efficacy of the active moiety manogepix (MGX, formerly APX001A) in liver tissues in a clinically relevant IAC mouse model infected with Candida albicans Matrix-assisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI) and laser capture microdissection (LCM)-directed absolute drug quantitation were employed to evaluate drug penetration into liver abscess lesions both spatially and quantitatively. The partitioning of MGX into lesions occurred slowly after a single dose; however, robust accumulation in the lesion was achieved after 3 days of repeated dosing. Associated with this drug penetration pattern, reduction in fungal burden and clearance in the liver were observed in mice receiving the multiday FMGX regimen. In comparison, administration of micafungin resulted in marginal reduction in fungal burden at the end of 4 days of treatment. These results suggest that FMGX is a promising candidate for the treatment of IAC.

Optimization of Fluconazole Dosing for the Prevention and Treatment of Invasive Candidiasis Based on the Pharmacokinetics of Fluconazole in Critically Ill Patients.

The efficacy of fluconazole is related to the area under the plasma concentration-time curve (AUC) over the MIC of the microorganism. Physiological changes in critically ill patients may affect the exposure of fluconazole, and therefore dosing adjustments might be needed. The aim of this study was to evaluate variability in fluconazole drug concentration in intensive care unit (ICU) patients and to develop a pharmacokinetic model to support personalized fluconazole dosing. A prospective observational pharmacokinetic study was performed in critically ill patients receiving fluconazole either as prophylaxis or as treatment. The association between fluconazole exposure and patient variables was studied. Pharmacokinetic modeling was performed with a nonparametric adaptive grid (NPAG) algorithm using R package Pmetrics. Data from 33 patients were available for pharmacokinetic analysis. Patients on dialysis and solid organ transplant patients had a significantly lower exposure to fluconazole. The population was best described with a one-compartment model, where the mean volume of distribution was 51.52 liters (standard deviation [SD], 19.81) and the mean clearance was 0.767 liters/h (SD, 0.46). Creatinine clearance was tested as a potential covariate in the model, but was not included in the final population model. A significant positive correlation was found between the fluconazole exposure (AUC) and the trough concentration (Cmin). Substantial variability in fluconazole plasma concentrations in critically ill adults was observed, where the majority of patients were underexposed. Fluconazole Cmin therapeutic drug monitoring (TDM)-guided dosing can be used to optimize therapy in critically ill patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02491151.).

Selection and evaluation of appropriate reference genes for RT-qPCR based expression analysis in Candida tropicalis following azole treatment.

Candida tropicalis arises as one of the predominant non-Candida albicans Candida (NCAC) species causing invasive candidiasis in Asian countries. A rise in reports of C. tropicalis with a parallel increase in fluconazole resistance has also been observed. The genes and underlying pathways associated with azole antifungal resistance in C. tropicalis is still not properly understood. The RT-qPCR is the most promising approach for expression analysis of target genes to understand the mechanisms of resistance. The reliability and reproducibility of this technique depend on the selection of suitable reference genes for the normalization in expression study. The present study investigated the expression stability levels of ten genes including ACT1, EF1, GAPDH, PGK1, RDN5.8, RDN18, RDN28, SDHA, TUB1, and UBC13 for their suitability in fluconazole treated/untreated C. tropicalis. The stability levels of these genes were examined by the ∆∆CT, ΔCT, Pfaffl methods and five independent software including hkgFinder, geNorm, NormFinder, BestKeeper, and RefFinder software. We report, the EF1 and ACT1 were the most stable reference genes for normalization and can be used for the gene expression analysis in C. tropicalis. To the best of our knowledge, our study is the first to select and validate the reference genes in C. tropicalis for RT-qPCR based expression analysis.

Invasive Candidiasis.

Invasive candidiasis (IC) is the most frequent health care associated invasive fungal infection. It is also associated with high morbidity, mortality, and cost. The most frequent etiologic agent is Candida albicans, but non-albicans species are increasing and associated with reduced antifungal susceptibility and outbreaks. Candida auris is an emerging multidrug-resistant species recently described. IC presents as a spectrum of disease, going from fungemia to deep-seated candidiasis, and to septic shock with multiorgan failure. Diagnosis of IC is challenging. Several biomarkers and molecular methods are available for improving diagnosis. Early initial treatment with echinocandins is the treatment of choice. Step-down therapy when antifungal susceptibility is available is possible. Several new antifungal agents for the treatment of IC are in clinical development.

Rezafungin treatment in mouse models of invasive candidiasis and aspergillosis: Insights on the PK/PD pharmacometrics of rezafungin efficacy.

Rezafungin acetate is a novel echinocandin in clinical development for prevention and treatment of invasive fungal infections. Rezafungin is differentiated by a pharmacokinetic/pharmacodynamic (PK/PD) profile that includes a long half-life allowing once-weekly administration, front-loaded plasma drug exposures associated with antifungal efficacy, and penetration into deep-seated infections, such as intra-abdominal abscesses. In this series of in vivo studies, rezafungin demonstrated efficacy in the treatment of neutropenic mouse models of disseminated candidiasis, including infection caused by azole-resistant Candida albicans, and aspergillosis. These results contribute to a growing body of evidence demonstrating the antifungal efficacy and potential utility of rezafungin in the treatment of invasive fungal infections.

Clonality of Fluconazole-Nonsusceptible Candida tropicalis in Bloodstream Infections, Taiwan, 2011-2017.

Candida tropicalis is the leading cause of non-C. albicans candidemia in tropical Asia and Latin America. We evaluated isolates from 344 patients with an initial episode of C. tropicalis candidemia. We found that 58 (16.9%) patients were infected by fluconazole-nonsusceptible (FNS) C. tropicalis with cross resistance to itraconazole, voriconazole, and posaconazole; 55.2% (32/58) of patients were azole-naive. Multilocus sequence typing analysis revealed FNS isolates were genetically closely related, but we did not see time- or place-clustering. Among the diploid sequence types (DSTs), we noted DST225, which has been reported from fruit in Taiwan and hospitals in Beijing, China, as well as DST376 and DST505-7, which also were reported from hospitals in Shanghai, China. Our findings suggest cross-boundary expansion of FNS C. tropicalis and highlight the importance of active surveillance of clinical isolates to detect dissemination of this pathogen and explore potential sources in the community.

Efficacy of Delayed Therapy with Fosmanogepix (APX001) in a Murine Model of Candida auris Invasive Candidiasis.

The emerging pathogenic yeast Candida auris is associated with antifungal resistance and high mortality. The novel antifungal agent manogepix (APX001A) inhibits glycosylphosphatidylinositol-anchored protein maturation and has demonstrated activity against numerous pathogenic fungi, including C. auris Our objective was to evaluate the in vivo efficacy of fosmanogepix, the N-phosphonooxymethyl prodrug (APX001), following delayed initiation of therapy in a murine model of C. auris invasive candidiasis. Neutropenic mice were intravenously infected with a fluconazole-resistant clinical isolate of C. auris Twenty-four hours postinoculation, treatment began with vehicle control, fosmanogepix (104 and 130 mg/kg of body weight by intraperitoneal injection three times daily, or intraperitoneal 260 mg/kg twice daily), fluconazole (20 mg/kg by oral gavage once daily), or caspofungin (intraperitoneal 10 mg/kg once daily) and continued for 7 days. Fungal burden was assessed via colony count in the kidneys and brains on day 8 in the fungal burden arm and on day 21 as the mice became moribund in the survival arm. Significant improvements in survival were observed in each group administered fosmanogepix and caspofungin. Similarly, reductions in fungal burden were also observed in both the kidneys and brains of mice treated with the highest dose of fosmanogepix in the fungal burden arm and in each fosmanogepix group and with caspofungin in the survival arm. In contrast, no improvements in survival or reductions in fungal burden were observed in mice treated with fluconazole. These results demonstrate that fosmanogepix is effective in vivo against fluconazole-resistant C. auris even when therapy is delayed.

MSG-10: a Phase 2 study of oral ibrexafungerp (SCY-078) following initial echinocandin therapy in non-neutropenic patients with invasive candidiasis.

OBJECTIVES: To evaluate the safety and efficacy of two dosing regimens of oral ibrexafungerp (formerly SCY-078), a novel orally bioavailable ß-glucan synthase inhibitor, in subjects with invasive candidiasis versus the standard of care (SOC) and to identify the dose to achieve target exposure (15.4 µM·h) in >80% of the intended population. METHODS: In a multinational, open-label study, patients with documented invasive candidiasis were randomized to receive step-down therapy to one of three treatment arms: two dosing regimens of novel oral ibrexafungerp or the SOC treatment following initial echinocandin therapy. Plasma samples were collected to evaluate exposure by population pharmacokinetic (PK) modelling. Safety was assessed throughout the study and global response at the end of treatment. RESULTS: Out of 27 subjects enrolled, 7 received ibrexafungerp 500 mg, 7 received ibrexafungerp 750 mg and 8 received the SOC. Five did not meet criteria for randomization. Population PK analysis indicated that an ibrexafungerp 750 mg regimen is predicted to achieve the target exposure in ∼85% of the population. The rate of adverse events was similar among patients receiving ibrexafungerp or fluconazole. Similar favourable response rates were reported among all groups: 86% (n = 6) in the ibrexafungerp 750 mg versus 71% (n = 5) in both the fluconazole and ibrexafungerp 500 mg treatment arms. The one subject treated with continued micafungin had a favourable global response. CONCLUSIONS: The oral ibrexafungerp dose estimated to achieve the target exposure in subjects with invasive candidiasis is 750 mg daily. This dose was well tolerated and achieved a favourable global response rate, similar to the SOC.

Repurposing of Ribavirin as an Adjunct Therapy against Invasive Candida Strains in an In Vitro Study.

The use of antifungal agents in clinical settings is limited by the appearance of drug resistance and adverse side effects. There is, therefore, an urgent need to develop new drugs to strengthen the treatment of invasive fungal diseases. The aim of this study is to describe the potential repurposing of ribavirin as an adjunct therapy against Candida spp. Primary screening of a Prestwick Chemical library against Candida albicans ATCC 90028 and fluconazole-resistant Candida albicans strains was performed. Subsequently, we evaluated the responses of 100 Candida sp. strains to ribavirin, an antiviral agent, using the broth microdilution method as recommended by CLSI. We checked the involvement of efflux pump activity in the development of ribavirin resistance. We studied time-kill curves and performed a checkerboard assay for a ribavirin-antifungal combination study. Twenty-one nonstandard antifungal compounds were identified, including ribavirin. Ribavirin had antifungal activity in vitro against 63 Candida strains, including strains of C. albicans, C. parapsilosis, and C. tropicalis, with MICs ranging from 0.37 to 3.02 µg/ml, while MICs for C. krusei, C. glabrata, C. lusitaniae, and some C. albicans strains remained high (≥24.16 µg/ml). No relation was observed between efflux pump activity and ribavirin resistance. Ribavirin exhibited fungistatic activity against multidrug-resistant (MDR) C. albicans and fungicidal activity against a C. parapsilosis strain. In addition, ribavirin acted synergistically with azoles against Candida strains for which ribavirin MICs were <24.4 µg/ml. This study highlights the potential clinical application of ribavirin, alone or in association with other antifungal agents, as an adjunct anti-Candida drug.

The Fungal Cyp51-Specific Inhibitor VT-1598 Demonstrates In Vitro and In Vivo Activity against Candida auris.

Candida auris is an emerging pathogen associated with significant mortality and often multidrug resistance. VT-1598, a tetrazole-based fungal CYP51-specific inhibitor, was evaluated in vitro and in vivo against C. auris Susceptibility testing was performed against 100 clinical isolates of C. auris by broth microdilution. Neutropenic mice were infected intravenously with C. auris, and treatment began 24 h postinoculation with a vehicle control, oral VT-1598 (5, 15, and 50 mg/kg of body weight once daily), oral fluconazole (20 mg/kg once daily), or intraperitoneal caspofungin (10 mg/kg once daily), which continued for 7 days. Fungal burden was assessed in the kidneys and brains on day 8 in the fungal burden arm and on the days the mice succumbed to infection or on day 21 in the survival arm. VT-1598 plasma trough concentrations were also assessed on day 8. VT-1598 demonstrated in vitro activity against C. auris, with a mode MIC of 0.25 µg/ml and MICs ranging from 0.03 to 8 µg/ml. Treatment with VT-1598 resulted in significant and dose-dependent improvements in survival (median survival, 15 and >21 days for VT-1598 at 15 and 50 mg/kg, respectively) and reductions in kidney and brain fungal burden (reductions of 1.88 to 3.61 log10 CFU/g) compared to the control (5 days). The reductions in fungal burden correlated with plasma trough concentrations. Treatment with caspofungin, but not fluconazole, also resulted in significant improvements in survival and reductions in fungal burden compared to those with the control. These results suggest that VT-1598 may be a future option for the treatment of invasive infections caused by C. auris.