In Vitro Antifungal Activity of Ibrexafungerp (SCY-078) Against Contemporary Blood Isolates From Medically Relevant Species of Candida: A European Study.

Background: Ibrexafungerp (SCY-078) is the newest oral and intravenous antifungal drug with broad activity, currently undergoing clinical trials for invasive candidiasis. Objective: The aim of this study was to assess the in vitro activity of ibrexafungerp and comparators against a collection of 434 European blood isolates of Candida. Methods: Ibrexafungerp, caspofungin, fluconazole, and micafungin minimum inhibitory concentrations (MICs) were collected from 12 European laboratories for 434 blood isolates, including 163 Candida albicans, 108 Candida parapsilosis, 60 Candida glabrata, 40 Candida tropicalis, 29 Candida krusei, 20 Candida orthopsilosis, 6 Candida guilliermondii, 2 Candida famata, 2 Candida lusitaniae, and 1 isolate each of Candida bracarensis, Candida catenulata, Candida dubliniensis, and Candida kefyr. MICs were determined by the EUCAST broth microdilution method, and isolates were classified according to recommended clinical breakpoints and epidemiological cutoffs. Additionally, 22 Candida auris from different clinical specimens were evaluated. Results: Ibrexafungerp MICs ranged from 0.016 to ≥8 mg/L. The lowest ibrexafungerp MICs were observed for C. albicans (geometric MIC 0.062 mg/L, MIC range 0.016-0.5 mg/L) and the highest ibrexafungerp MICs were observed for C. tropicalis (geometric MIC 0.517 mg/L, MIC range 0.06-≥8 mg/L). Modal MICs/MIC50s (mg/L) against Candida spp. were 0.125/0.06 for C. albicans, 0.5/0.5 for C. parapsilosis, 0.25/0.25 for C. glabrata, 0.5/0.5 for C. tropicalis, 1/1 for C. krusei, 4/2 for C. orthopsilosis, and 0.5/0.5 for C. auris. Ibrexafungerp showed activity against fluconazole- and echinocandin-resistant isolates. If adopting wild-type upper limits, a non-wild-type phenotype for ibrexafungerp was only observed for 16/434 (3.7%) isolates: 11 (4.6%) C. parapsilosis, 4 (5%) C. glabrata, and 1 (2.5%) C. tropicalis. Conclusion: Ibrexafungerp showed a potent in vitro activity against Candida.

Outbreak of Candida auris in Spain: A comparison of antifungal activity by three methods with published data.

Candida auris is an emerging pathogen causing candidaemia outbreaks in several countries for which azole, amphotericin B (AmB) and echinocandin resistance has been reported. In this study, the antifungal susceptibilities of 73 Spanish C. auris isolates (56 bloodstream and 17 urine) to eight antifungal agents were determined using three methods. Isolates were identified by internal transcribed spacer (ITS) sequencing, and minimum inhibitory concentrations (MICs) of fluconazole, isavuconazole, itraconazole, posaconazole, voriconazole, anidulafungin, micafungin and AmB were determined by EUCAST methodology and Sensititre® YeastOne® (SYO) (bloodstream isolates) and Liofilchem® MIC Test Strip (all isolates). Agreement between the methods was analysed and the MICs (ours and published data) were categorised using recently proposed epidemiological cut-off values (ECVs). Fluconazole MICs were >64 mg/L, whilst >60% of voriconazole MICs were >1 mg/L by the three methods. Posaconazole was the most active azole (EUCAST geometric mean MIC, 0.053 mg/L), followed by isavuconazole (0.066 mg/L) and itraconazole (0.157 mg/L). Echinocandins MICs were ≤0.5 mg/L by SYO and EUCAST. The overall lowest AmB MICs (≤0.25 mg/L) were obtained by EUCAST. Essential agreement (±2 dilutions) between EUCAST and SYO was >93% for the eight antifungals. For this new C. auris clade, all isolates were resistant to fluconazole, and MICs for anidulafungin, micafungin and AmB were ≤1 mg/L using dilution methods. Voriconazole MICs were method-dependent. The number of non-wild-type (non-WT) isolates depended on the ECV applied; by the 97.5% ECV all isolates were WT except for isavuconazole (1.8% non-WT). Good essential agreement (>93%) was observed between EUCAST and SYO.

Activity of Amphotericin B and Anidulafungin Combined with Rifampicin, Clarithromycin, Ethylenediaminetetraacetic Acid, N-Acetylcysteine, and Farnesol against Candida tropicalis Biofilms.

We evaluated the activity of (1) amphotericin-B (AMB), combined with rifampicin (RIF), clarithromycin (CLA), N-acetylcysteine (NAC), ethylenediaminetetraacetic acid (EDTA), and farnesol (FAR) (1000, 1000, 1000, 4000, and 30,000 mg/L, and 300 µM, respectively), against Candida tropicalis biofilms formed on polytetrafluoroethylene (PTFE) and (2) anidulafungin (ANF) combined with the same compounds at 8, 10, 5, 40, and 30 mg/L, and 30 µM, respectively, against biofilms formed on titanium. Biofilm growth kinetics were performed in a CDC Biofilm Reactor (CBR). PTFE or titanium disks were removed from the CBR at 24, 48, 72, and 96 h to determine the Log10CFU/cm². Killing kinetics were performed by adding the drugs to 24-h-mature biofilms (time 0). Disks were removed after 24, 48, and 72 h of drug exposure to determine Log10CFU/cm². Viable cells in biofilms were 4.73 and 4.29 Log10CFU/cm² on PTFE and titanium, respectively. Maximum Log10 decreases in CFU/cm² depend on the combination and were: 3.53 (AMB + EDTA), 2.65 (AMB + RIF), 3.07 (AMB + NAC), 2.52 (AMB + CLA), 1.49 (AMB + FAR), 2.26 (ANF + EDTA), 2.45 (ANF + RIF), 2.47 (ANF + NAC), 1.52 (ANF + CLA), and 0.44 (ANF + FAR). In conclusion, EDTA, NAC, RIF, and CLA improve the activity of AMB and ANF against biofilms developed on both surfaces, which could be an effective strategy against C. tropicalis biofilm-related infections.

Time-kill assays of amphotericin B plus anidulafungin against Candida tropicalis biofilms formed on two different biomaterials.

PURPOSE: To determine the fungicidal activity by time-killing assays of amphotericin B (AMB) combined with anidulafungin (ANF) against biofilms of 2 clinical isolates of Candida tropicalis and the reference strain ATCC® 750, developed on polytetrafluoroethylene (PTFE) and titanium, using the CDC Biofilm Reactor (CBR) as an in vitro model. METHODS: Biofilms were developed for 24 hours on the disk surfaces and then exposed to AMB (40 mg/L), ANF (8 mg/L), alone and combined. At predetermined time points after drug exposure, biofilms were removed from the disk surface by vortexing-sonication to quantify viable biofilm cells. RESULTS: Drug activity was dependent on strain and time. After exposure to AMB, the mean decrease in viable cells attached to PTFE was 2.23 ± 0.89 Log10 cfu/cm2 (range 0.6-3.56 Log10), and on titanium 2.91 ± 1.04 (range 1.49-4.51 Log10). The reduction with ANF was 0.78 ± 0.5 (0.03-1.58 Log10) on PTFE and 0.8 ± 2.26 (0.42-1.16 Log10) on titanium. The reduction obtained with the combination of AMB + ANF was 1.8 ± 1.07 (0.22-3.54 Log10) on PTFE and 1.97 ± 0.49 (1.36-2.84 Log10) on titanium. The interaction was classified as indifferent with a tendency to antagonism. CONCLUSIONS: The activity of antifungal agents depends on the biomaterial surfaces the biofilm forming capacity of the isolate. AMB + ANF is less effective than AMB alone on both surfaces. Thus, the combination of these antifungals does not seem to add additional benefits to the treatment of C. tropicalis biofilm-related infections.

[Activity of amphotericin B and anidulafungin, alone and combined, against Candida tropicalis biofilms developed on Teflon® and titanium]. / Actividad de la anfotericina B y la anidulafungina, solas y combinadas, frente a biopelículas de Candida tropicalis formadas sobre Teflon® y titanio.

BACKGROUND: Current therapeutic strategies have a limited efficacy against Candida biofilms that form on the surfaces of biomedical devices. Few studies have evaluated the activity of antifungal agents against Candida tropicalis biofilms. OBJECTIVES: To evaluate the activity of amphotericin B (AMB) and anidulafungin (AND), alone and in combination, against C. tropicalis biofilms developed on polytetrafluoroethylene (teflon -PTFE) and titanium surfaces using time-kill assays. METHODS: Assays were performed using the CDC Biofilm Reactor equipped with PTFE and titanium disks with C. tropicalis biofilms after 24h of maturation. The concentrations assayed were 40mg/l for AMB and 8mg/l for AND, both alone and combined. After 24, 48 and 72h of exposure to the antifungals, the cfu/cm2 was determined by a vortexing-sonication procedure. RESULTS: AMB reduced biofilm viable cells attached to PTFE and titanium by ≥99% and AND by 89.3% on PTFE and 96.8% on titanium. The AMB+AND combination was less active than AMB alone, both on PTFE (decrease of cfu/cm2 3.09 Log10vs. 1.08 when combined) and titanium (4.51 vs. 1.53 when combined), being the interaction irrelevant on both surfaces. CONCLUSIONS: AMB is more active than AND against C. tropicalis biofilms. Yeast killing rates are higher on titanium than on PTFE surfaces. The combination of AMB plus AND is less effective than AMB alone on both surfaces.