Food and Drug Administration Public Workshop Summary-Development Considerations of Antifungal Drugs to Address Unmet Medical Need.

Pressing challenges in the treatment of invasive fungal infections (IFIs) include emerging and rare pathogens, resistant/refractory infections, and antifungal armamentarium limited by toxicity, drug-drug interactions, and lack of oral formulations. Development of new antifungal drugs is hampered by the limitations of the available diagnostics, clinical trial endpoints, prolonged trial duration, difficulties in patient recruitment, including subpopulations (eg, pediatrics), and heterogeneity of the IFIs. On 4 August 2020, the US Food and Drug Administration convened a workshop that included IFI experts from academia, industry, and other government agencies to discuss the IFI landscape, unmet need, and potential strategies to facilitate the development of antifungal drugs for treatment and prophylaxis. This article summarizes the key topics presented and discussed during the workshop, such as incentives and research support for drug developers, nonclinical development, clinical trial design challenges, lessons learned from industry, and potential collaborations to facilitate antifungal drug development.

Phase 2 Randomized Study of Oral Ibrexafungerp Versus Fluconazole in Vulvovaginal Candidiasis.

BACKGROUND: Vulvovaginal candidiasis affects approximately 75% of women in their lifetime. Approved treatment options are limited to oral or topical azoles. Ibrexafungerp, a novel, first-in-class oral triterpenoid glucan synthase inhibitor, has demonstrated broad fungicidal Candida activity and a favorable tolerability profile. The primary objective of this dose-finding study was to identify the optimal dose of oral ibrexafungerp in patients with acute vulvovaginal candidiasis. METHODS: Patients with vulvovaginal signs and symptoms score ≥7 were randomized equally to 6 treatments groups: 5 treatment doses of oral ibrexafungerp or oral fluconazole 150 mg. The primary endpoint was the percentage of patients with a clinical cure (complete resolution of vulvovaginal signs and symptoms) at the test-of-cure visit (day 10). RESULTS: Overall, 186 patients were randomized into the 6 treatment groups. Results, using the modified intent-to-treat population (baseline positive culture), are reported for ibrexafungerp 300 mg twice daily (BID) for 1 day (n = 27), which was the dose selected for phase 3 studies, and fluconazole 150 mg for 1 day (n = 24). At day 10, the clinical cure rates for ibrexafungerp and fluconazole were 51.9% and 58.3%, respectively; at day 25, patients with no signs or symptoms were 70.4% and 50.0%, respectively. During the study ibrexafungerp patients required less antifungal rescue medications compared with fluconazole (3.7% vs 29.2%, respectively). Ibrexafungerp was well tolerated, with the most common treatment-related adverse events being mild gastrointestinal events. CONCLUSIONS: Ibrexafungerp is a well-tolerated novel antifungal with comparable efficacy to fluconazole in the treatment of acute vulvovaginal candidiasis. CLINICAL TRIALS REGISTRATION: NCT03253094.

Ibrexafungerp Versus Placebo for Vulvovaginal Candidiasis Treatment: A Phase 3, Randomized, Controlled Superiority Trial (VANISH 303).

BACKGROUND: Current treatment of vulvovaginal candidiasis (VVC) is largely limited to azole therapy. Ibrexafungerp is a first-in-class triterpenoid antifungal with broad-spectrum anti-Candida fungicidal activity. The objective of this study was to evaluate the efficacy and safety of ibrexafungerp compared with placebo in patients with acute VVC. METHODS: Patients were randomly assigned 2:1 to receive ibrexafungerp (300 mg twice for 1 day) or placebo. The primary endpoint was the percentage of patients with a clinical cure (complete resolution of vulvovaginal signs and symptoms [VSS] = 0) at test-of-cure (day 11 ± 3). Secondary endpoints included the percentage of patients with mycological eradication, overall success (clinical cure and mycological eradication), clinical improvement (VSS ≤ 1) at test-of-cure, and symptom resolution at follow-up (day 25 ± 4). RESULTS: Patients receiving ibrexafungerp had significantly higher rates of clinical cure (50.5% [95/188] vs 28.6% [28/98]; P = .001), mycological eradication (49.5% [93/188] vs 19.4% [19/98]; P < .001), and overall success (36.0% [64/178] vs 12.6% [12/95]; P < .001) compared with placebo. Symptom resolution was sustained and further increased with ibrexafungerp compared with placebo (59.6% [112/188] vs 44.9% [44/98]; P = .009) at follow-up. Post hoc analysis showed similar rates of clinical cure and clinical improvement at test-of-cure for Black patients (54.8% [40/73] and 63.4% [47/73], respectively) and patients with a body mass index >35 (54.5% [24/44] and 68.2% [30/44], respectively) compared with overall rates. Ibrexafungerp was well tolerated. Adverse events were primarily gastrointestinal and mild in severity. CONCLUSIONS: Ibrexafungerp provides a promising safe and efficacious oral treatment that mechanistically differs from current azole treatment options for acute VVC.

FDA Public Workshop Summary-Coccidioidomycosis (Valley Fever): Considerations for Development of Antifungal Drugs.

Coccidioidomycosis is a fungal disease endemic to the southwestern United States, Mexico, and Central and South America. Prevalence rates are increasing steadily, and new endemic areas of Coccidioides are emerging. Standard treatment is often administered for months to decades, and intolerance to medications and treatment failures are common. No new treatments for coccidioidomycosis have been approved in the United States in nearly 40 years. On 5 August 2020, the US Food and Drug Administration convened experts in coccidioidomycosis from academia, industry, patient groups, and other government agencies to discuss the disease landscape and strategies to facilitate product development for treatment of coccidioidomycosis. This article summarizes the key topics concerning drug development for coccidioidomycosis presented by speakers and panelists during the workshop, such as unmet need, trial designs, endpoints, incentives, research and development support, and collaborations to facilitate antifungal drug development.

In Vitro pH Activity of Ibrexafungerp against Fluconazole-Susceptible and -Resistant Candida Isolates from Women with Vulvovaginal Candidiasis.

The vaginal environment with candidiasis has a pH of 3.8 to 4.5 and this has a negative effect on the activity of antifungals. Ibrexafungerp was evaluated against 187 Candida isolates, including fluconazole-sensitive and -resistant Candida albicans, Candida glabrata, Candida krusei, Candida parapsilosis, and Candida tropicalis with the media adjusted to pH 7.0 and pH 4.5. Ibrexafungerp MIC values were not adversely affected when tested at pH 4.5. Ibrexafungerp exhibited significant activity against all isolates at pH 4.5.

Endoscopic treatment of postoperative esophagogastric leaks with fully covered self-expanding metal stents.

BACKGROUND: the management of postoperative esophageal leaks is a huge therapeutic challenge. Thanks to the advances in endoscopy, treatment with esophageal stents has been proposed as a valid option. AIMS: the main objective of the study was to evaluate the effectiveness and safety of the use of fully covered esophageal metal stents in the treatment of postoperative esophageal leaks. METHODS: a retrospective observational study was performed in patients with postoperative esophageal leaks, treated with fully covered self-expandable metal stents between June 2011 and May 2018. RESULTS: twenty-five patients were evaluated and 34 stents were placed. The closure of the leak was observed in 21 patients after removal of the stent, with an overall technical success rate of 84 %. The mean time with a stent placed for closure of the fistula was 55.7 ± 27.11 days/patient (mean of 39 ± 24.30 days/stent). The most frequent complication was a partial distal stent migration (7/34 stents), followed by five cases of complete migration into the stomach. CONCLUSIONS: endoscopic treatment with fully covered self-expandable metal stents seems to be an effective and safe first-line treatment for postoperative esophageal leaks, according to the experience in our center.

[Influence of the lockdown due to COVID-19 on weight-loss results during the first year after sleeve gastrectomy]. / Influencia del confinamiento por COVID-19 en los resultados ponderales durante el primer año tras la gastrectomía vertical.

INTRODUCTION: COVID-19 pandemic has lead to lockdown of population in many countries. In Spain, the state of alarm was established from March 15 to June 20, 2020. Usually this fact decreased people's mobility and physical activity, in addition to producing or exacerbating psychological disorders. Our aim was to determine the influence that this condition had over the short-term ponderal results of patients undergoing laparoscopic vertical gastrectomy from May 2019 to May 2020. METHODS: Case-control study for comparing the percentage of excess weight lost (%EWL) and the percentage of total weight lost (%TWL) of patients that underwent a VG during the last year, so they were affected by lockdown in April and part of March 2020 (group 1), to the %EWL and %TWL of a control group (group 2), obtained from our previous series. RESULTS: The mean %EWL in group 1 is 47,37 ± 18,59 and in group 2 is 51,13 ± 17,59, being p = 0,438. Meanwhile, the mean %TWL in group 1 is 21,14 ± 8,17 and in group 2 is 24,67 ± 8,01, with p = 0,115. CONCLUSIONS: Population lockdown by COVID-19 did not get worse short-term results of vertical gastrectomy. More studies with a larger number of patients are necessary to draw firm conclusions.

Penetration of Ibrexafungerp (Formerly SCY-078) at the Site of Infection in an Intra-abdominal Candidiasis Mouse Model.

Ibrexafungerp (IBX), formerly SCY-078, is a novel, oral and intravenous, semisynthetic triterpenoid glucan synthase inhibitor in clinical development for treating multiple fungal infections, including invasive candidiasis. Intra-abdominal candidiasis (IAC) is one of the most common types of invasive candidiasis associated with high mortality largely due to poor drug exposure in infected lesions. To better understand the potential of IBX to treat such infections, we investigated its penetration at the site of infection. Using matrix-assisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI) and laser capture microdissection (LCM)-directed high-pressure liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), we investigated tissue distribution and lesion-specific drug exposure of IBX in a clinically relevant IAC mouse model. After a single-dose treatment, IBX quickly distributed into tissues and efficiently accumulated within lesions. Drug concentrations of IBX within the liver abscesses were almost 100-fold higher than the serum concentration. In addition, drug penetration after repeated treatment of IBX was compared with micafungin. IBX exhibited robust and long-lasting lesion penetration after repeated treatment. These data indicate that IBX penetrates into intra-abdominal abscesses highly efficiently and holds promise as a potential therapeutic option for IAC patients.

Combination Therapy with Ibrexafungerp (Formerly SCY-078), a First-in-Class Triterpenoid Inhibitor of (1→3)-ß-d-Glucan Synthesis, and Isavuconazole for Treatment of Experimental Invasive Pulmonary Aspergillosis.

Ibrexafungerp (formerly SCY-078) is a semisynthetic triterpenoid and potent (1→3)-ß-d-glucan synthase inhibitor. We investigated the in vitro activity, pharmacokinetics, and in vivo efficacy of ibrexafungerp (SCY) alone and in combination with antimold triazole isavuconazole (ISA) against invasive pulmonary aspergillosis (IPA). The combination of ibrexafungerp and isavuconazole in in vitro studies resulted in additive and synergistic interactions against Aspergillus spp. Plasma concentration-time curves of ibrexafungerp were compatible with linear dose proportional profile. In vivo efficacy was studied in a well-established persistently neutropenic New Zealand White (NZW) rabbit model of experimental IPA. Treatment groups included untreated control (UC) rabbits and rabbits receiving ibrexafungerp at 2.5 (SCY2.5) and 7.5 (SCY7.5) mg/kg of body weight/day, isavuconazole at 40 (ISA40) mg/kg/day, or combinations of SCY2.5+ISA40 and SCY7.5+ISA40. The combination of SCY+ISA produced an in vitro synergistic interaction. There were significant in vivo reductions of residual fungal burden, lung weights, and pulmonary infarct scores in SCY2.5+ISA40, SCY7.5+ISA40, and ISA40 treatment groups versus those of the SCY2.5-treated, SCY7.5-treated, and UC (P < 0.01) groups. Rabbits treated with SCY2.5+ISA40 and SCY7.5+ISA40 had prolonged survival in comparison to that of the SCY2.5-, SCY7.5-, ISA40-treated, or UC (P < 0.05) groups. Serum galactomannan index (GMI) and (1→3)-ß-d-glucan levels significantly declined in animals treated with the combination of SCY7.5+ISA40 in comparison to those of animals treated with SCY7.5 or ISA40 (P < 0.05). Ibrexafungerp and isavuconazole combination demonstrated prolonged survival, decreased pulmonary injury, reduced residual fungal burden, and lower GMI and (1→3)-ß-d-glucan levels in comparison to those of single therapy for treatment of IPA. These findings provide an experimental foundation for clinical evaluation of the combination of ibrexafungerp and an antimold triazole for treatment of IPA.

Gastrointestinal bleeding in a pancreatic arteriovenous malformation successfully treated by transarterial embolization.

Pancreatic arteriovenous malformation (PAVM) is a rare case of upper gastrointestinal bleeding (UGIB), but it must be recognized in clinical practice, as it may be a potentially lethal condition in case of rupture and haemorrhage. This anatomic alteration is extremely rare as less than a hundred cases are reported in the scientific literature. The aim of this work is to report a case of PAVM presented as upper gastrointestinal bleeding (UGIB) and successfully treated by transarterial embolization.

SCY-078, a Novel Fungicidal Agent, Demonstrates Distribution to Tissues Associated with Fungal Infections during Mass Balance Studies with Intravenous and Oral [14C]SCY-078 in Albino and Pigmented Rats.

SCY-078, a fungicidal ß-1,3-glucan synthesis inhibitor administered as intravenous or oral [14C]SCY-078 to rats, was distributed primarily into tissues associated with invasive fungal disease (kidney, lung, liver, spleen, bone marrow, muscle, vaginal tissue, and skin) to levels exceeding those in plasma. Oral fraction absorbed was ∼40%. Elimination was primarily via bile and feces (∼90%) and urine (∼1.5%). Mean half-time was ∼8 h. Quantitative whole-body autoradiography showed a rapid distribution at 8 h and elimination by 168 h postdose.

In Vitro Activity of Ibrexafungerp, a Novel Glucan Synthase Inhibitor against Candida glabrata Isolates with FKS Mutations.

Ibrexafungerp is a first-in-class glucan synthase inhibitor. In vitro activity was determined for 89 Candida glabrata isolates with molecularly identified FKS1 or FKS2 mutations conferring resistance to the echinocandins. All isolates were resistant to at least one echinocandin (i.e., anidulafungin, caspofungin, or micafungin) by broth microdilution. Results for ibrexafungerp were compared with those for each echinocandin. Ibrexafungerp had good activity against all echinocandin-resistant C. glabrata isolates.

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.

Barrett's esophagus: "All diseases are divine and all are human".

Barrett's esophagus (BE) is a controversial condition. The significance of this condition lies in its premalignant potential, so it is important that clinically applicable biomarkers be identified for early detection and targeted prevention. Dysplasia is currently used as main biomarker, but others most recently surveyed in cancer also include microRNAs. Classically, BE was considered to be an acquired disease related to pathological gastroesophageal acid and bile reflux. However, some cases are associated with genetic predisposition, representing an inherited, familial form of BE. The actual gene, or genes, involved in this condition have not yet been identified. Main therapeutic options include medical treatment and antireflux surgery. Both types of treatment are equally efficient in controlling symptoms and neither is able to cause the metaplastic segment to disappear, which is why the risk of malignancy remains. However, we may use endoscopic radiofrequency to eradicate BE and replace it by the typical squamous epithelium of the esophagus. The currently accepted indications of radiofrequency in BE include low- and high-grade dysplasia, but not Barrett's esophagus without dysplasia. In conclusion, BE may have two different presentations: environmental ("human", reflux) or sporadic BE, which is the most common form, and genetic ("divine", inherited) or familiar BE, less common but with a greater risk for malignancy. As they might be two different diseases, surveillance programs and treatments should also be different.

Is prophylactic gastrectomy indicated for healthy carriers of CDH1 gene mutations associated with hereditary diffuse gastric cancer?

INTRODUCTION: hereditary diffuse gastric cancer (HDGC) is a recently reported hereditary cancer syndrome. Patients with suspected HDGC must be under surveillance via endoscopy and multiple biopsies. As an alternative, some studies suggest prophylactic gastrectomy (PG) for disease carriers. The goal of this article was to report our experience with a CDH1 mutation positive family who underwent PG. PATIENTS AND METHODS: the index case was a 34-year-old female diagnosed with diffuse gastric adenocarcinoma and massive carcinomatosis. There was a family history of gastric adenocarcinoma in seven family members. A genetic study identified the c.1577G>A mutation, in exon 11 of the CDH1 gene via sequencing analysis. RESULTS: this mutation was also present in other six family members, who subsequently underwent prophylactic gastrectomy. The pathology study of resected gastric segments revealed multiple microscopic foci of adenocarcinoma in five of these individuals. These foci were not detected in the multiple endoscopies performed before surgery. CONCLUSIONS: we recommend prophylactic gastrectomy for CDH1 mutation carriers even in the absence of lesions during endoscopic screening.

Evolution of gastroesophageal reflux after laparoscopic vertical gastrectomy. A radiographic, manometric and pH-metric study.

INTRODUCTION: the relationship between laparoscopic vertical gastrectomy (LVG) and gastroesophageal reflux (GER) is still controversial. Therefore, its study is of great interest in order to obtain definitive conclusions. The goal of the study was to establish whether LVG modifies pH-metric GER in obese patients and to analyze the associated factors. PATIENTS AND METHODS: the first 26 patients who underwent LVG in our institution were enrolled in the study. A barium swallow, 24-hour ambulatory pH-metry and four-channel intraluminal esophageal manometry (IEM) were all performed before and one year after surgery. RESULTS: among the pH-metric data, there was a significant increase in the DeMeester index after the procedure (p = 0.028), while other parameters remained unchanged. Furthermore, 50% of patients with preoperative pH-metric GER had normal values at one year after surgery. IEM showed a decrease in lower esophageal sphincter (LES) pressure and in the mean wave amplitude at the distal third of the esophagus (p = 0.007 and p = 0.025, respectively). The rate of newly-developed hiatal hernias in the radiographic study was 36.4%. CONCLUSION: LVG mildly increases GER, which is likely related to the development of hiatal hernias and a decrease in LES pressure and esophageal sweep. However, LVG should not be contraindicated for patients with preoperative pH-metric GER, as this may clear after the procedure.

The Hyperhidrosis Disease Severity Measure-Axillary: Conceptualization and Development of Item Content.

INTRODUCTION: Patients with primary axillary hyperhidrosis (AHH) suffer from a variety of symptoms. Improved patient-reported outcome (PRO) measures are needed to better assess and categorize the severity of AHH symptoms experienced by patients because the widely used Hyperhidrosis Disease Severity Scale (HDSS) is a single-item measure that cannot capture the broad scope of disease impact. METHODS: The Hyperhidrosis Disease Severity Measure-Axillary (HDSM-Ax) was developed for determining the severity of excessive sweating in patients with primary focal AHH based on face-to-face concept elicitation interviews with 58 AHH patients, a literature review, and expert clinical input. Two waves of face-to-face cognitive interviews (n=26 and n=27) were conducted to evaluate HDSM-Ax clarity and relevance. Additional interviews (n=5) were conducted to confirm content. Adding Rasch Measurement Theory (RMT) analyses allowed for an iterative streamlined approach to documenting content validity and other cross-sectional measurement properties of the new HDSM-Ax measurement. RESULTS: The 11-item HDSM-Ax PRO scale (0-4 scale per item; 0-44 total scale) represents an AHH symptom range of 0 (no sweating) to 44 (worst possible sweating). Content validity of the HDSM-Ax was documented by showing that chronologically-grouped interviews demonstrated saturation in AHH symptom severity concepts. Cognitive debriefing interviews provided evidence that item content is complete, comprehensible, meaningful, and relevant. RMT-based exploration indicated that targeting of the HDSM-Ax was adequate, suggesting good matching between items and persons; item fit was adequate, suggesting a clinically cohesive scale; and items appeared to be stable between subgroups, thereby supporting a summary score. CONCLUSIONS: The HDSM-Ax is a well-developed measure of AHH severity based on patient-reported signs and symptoms. It is a superior measure to the HDSS and can be used in clinical research and clinical practice to quantify changes in symptom severity in response to treatment. J Drugs Dermatol. 2018;17(7):707-714.

SCY-078 Is Fungicidal against Candida Species in Time-Kill Studies.

SCY-078 is an orally bioavailable ß-1,3-glucan synthesis inhibitor (GSI) and the first-in-class of structurally novel triterpene antifungals in clinical development for treating candidemia and invasive candidiasis. In vitro susceptibilities by broth microdilution, antifungal carryover, and time-kill dynamics were determined for three reference (ATCC) strains (Candida albicans 90028, Candida parapsilosis 90018, and Candida tropicalis 750), a quality-control (QC) strain (Candida krusei 6258), and four other strains (C. albicans MYA-2732, 64124, and 76485 and Candida glabrata 90030). Caspofungin (CASP), fluconazole (FLC), and voriconazole (VRC) were comparators. For time-kill experiments, SCY-078 and CASP were evaluated at 0.25, 1, 2, 4, 8, and 16 times the MIC80, and FLU and VRC were evaluated at 4× MIC80 The time to reach 50%, 90%, and 99.9% reduction in the number of CFUs from the starting inoculum was determined. Net change in the number of CFU per milliliter was used to determine 50% and 90% effective concentrations and maximum effect (EC50, EC90, and Emax, respectively). The SCY-078 MIC range was between 0.0625 and 1 µg/ml and generally similar to that of CASP. Antifungal carryover was not observed for SCY-078. SCY-078 was fungicidal against seven isolates at ≥4× MIC (kill of ≥3 log10) and achieved a 1.7-log10 reduction in CFU count/milliliter against C. albicans 90028. CASP behaved similarly against each isolate and achieved a 1.5-log10 reduction in the number of CFU/milliliter against C. albicans 90028. Reductions of 50% in CFU count/milliliter were achieved rapidly (1 to 2.8 h); fungicidal endpoints were reached at 12.1 to 21.8 h at ≥4× MIC. EC90 was reached at ∼5× MIC at each time point to 24 h. The EC50 and EC90 values were generally similar (8 to 24 h). Time-kill behavior of CASP was similar to that of SCY-078. FLC and VRC were fungistatic. Overall, SCY-078 has primarily fungicidal activity against Candida spp. and behaved comparably to CASP.

De Novo Acquisition of Resistance to SCY-078 in Candida glabrata Involves FKS Mutations That both Overlap and Are Distinct from Those Conferring Echinocandin Resistance.

SCY-078 is an orally active antifungal whose target is the ß-(1,3)-d-glucan synthase (GS). We evaluated the spontaneous emergence of SCY-078-resistant Candida glabrata isolates following drug exposure in vitro Resistant isolates were analyzed using broth microdilution methodology and FKS sequencing. The kinetic inhibition parameter IC50 (50% inhibitory concentration) was also determined from GS complexes. The spectrum of resistance mutations found suggested a partially overlapping but independent binding site for SCY-078 relative to echinocandins on GS.

The Emerging Pathogen Candida auris: Growth Phenotype, Virulence Factors, Activity of Antifungals, and Effect of SCY-078, a Novel Glucan Synthesis Inhibitor, on Growth Morphology and Biofilm Formation.

Candidaauris, a new multidrug-resistant Candida spp. which is associated with invasive infection and high rates of mortality, has recently emerged. Here, we determined the virulence factors (germination, adherence, biofilm formation, phospholipase and proteinase production) of 16 C. auris isolates and their susceptibilities to 11 drugs belonging to different antifungal classes, including a novel orally bioavailable 1,3-ß-d-glucan synthesis inhibitor (SCY-078). We also examined the effect of SCY-078 on the growth, ultrastructure, and biofilm-forming abilities of C. auris Our data showed that while the tested strains did not germinate, they did produce phospholipase and proteinase in a strain-dependent manner and had a significantly reduced ability to adhere and form biofilms compared to that of Candida albicans (P = 0.01). C. auris isolates demonstrated reduced susceptibility to fluconazole and amphotericin B, while, in general, they were susceptible to the remaining drugs tested. SCY-078 had an MIC90 of 1 mg/liter against C. auris and caused complete inhibition of the growth of C. auris and C. albicans Scanning electron microscopy analysis showed that SCY-078 interrupted C. auris cell division, with the organism forming abnormal fused fungal cells. Additionally, SCY-078 possessed potent antibiofilm activity, wherein treated biofilms demonstrated significantly reduced metabolic activity and a significantly reduced thickness compared to the untreated control (P < 0.05 for both comparisons). Our study shows that C. auris expresses several virulence determinants (albeit to a lesser extent than C. albicans) and is resistant to fluconazole and amphotericin B. SCY-078, the new orally bioavailable antifungal, had potent antifungal/antibiofilm activity against C. auris, indicating that further evaluation of this antifungal is warranted.