Since its original isolation in 2009, has spread across the globe as a causative agent of invasive candidiasis. is typically intrinsically resistant to fluconazole and can also be resistant to echinocandins and even amphotericin B. Thus, there is an urgent need to find new treatment options against this emerging pathogen. To address this growing problem, we performed a screen of the Prestwick Chemical library, a repurposing library of 1,280 small molecules, consisting mostly of approved off-patent drugs, in search of those with activity against a multidrug-resistant isolate. Our initial screen, using standardized susceptibility testing methodologies, identified nine miscellaneous compounds with no previous clinical indication as antifungals or antiseptics that displayed activity against Confirmation and follow-up studies identified ebselen as the drug displaying the most potent activity, with 100% inhibition of growth detected at concentrations as low as 2.5 μM. We further evaluated the ability of ebselen to inhibit biofilm formation and examined the effects of combination therapies of ebselen with clinically used antifungals. We extended our studies to different strains with various susceptibility patterns and also confirmed its antifungal activity against and clinical isolates of multiple other species. Furthermore, ebselen displayed a broad spectrum of antifungal actions on the basis of its activity against a variety of medically important fungi, including yeasts and molds. Overall, our results indicate the promise of ebselen as a repositionable agent for the treatment of candidiasis and possibly other mycoses and, in particular, for the treatment of infections refractory to conventional treatment with current antifungals.
VT-1598 demonstrated in vitro activity against yeasts, moulds and endemic fungi, which was maintained against isolates that had reduced susceptibility to other antifungals. Further studies are warranted to evaluate the in vivo efficacy of VT-1598 against various fungal pathogens.
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.
Aspergillus
species are capable of causing both invasive disease and chronic infections in immunocompromised patients or those with preexisting lung conditions.
Aspergillus fumigatus
is the most commonly cultured species, and there is increasing concern regarding resistance to the azoles, which are the mainstays of antifungal therapy against aspergillosis. We evaluated the species distribution and susceptibility profiles of isolates within
Aspergillus
section
Fumigati
in the United States over a 52-month period.
The global incidence of mucormycosis has increased in recent years owing to higher numbers of individuals at risk for these infections. The diagnosis and treatment of this aggressive fungal infection are of clinical concern due to differences in species distribution in different geographic areas and susceptibility profiles between different species that are capable of causing highly aggressive infections. The purpose of this study was to evaluate the epidemiology and susceptibility profiles of Mucorales isolates in the U.S. over a 52-month period. Species identification was performed by combined phenotypic characteristics and DNA sequence analysis, and antifungal susceptibility testing was performed by CLSI M38 broth microdilution for amphotericin B, isavuconazole, itraconazole, and posaconazole. During this time-frame, 854 isolates were included, representing 11 different genera and over 26 species, of which
Rhizopus
(58.6%) was the predominant genus followed by
Mucor
(19.6%). The majority of isolates were cultured from the upper and lower respiratory tracts (55%). Amphotericin B demonstrated the most potent
in vitro
activity, with GM MICs of ≤0.25 μg/mL against all genera with the exception of
Cunninghamella
species (GM MIC 1.30 μg/mL). In head-to-head comparisons the most active azole was posaconazole followed by isavuconazole. Differences in azole and amphotericin B susceptibility patterns were observed between the genera with the greatest variability observed with isavuconazole. Awareness of the epidemiology of Mucorales isolates and differences in antifungal susceptibility patterns in the U.S. may aide clinicians in choosing antifungal treatment regimens. Further studies are warranted to correlate these findings with clinical outcomes.
The in vitro and in vivo activity of the arylamidine T-2307 against Candida auris was evaluated. T-2307 demonstrated in vitro activity (MIC ranges ≤ 0.008 to 0.015 μg/ml at 50% inhibition; 0.125 to >4 μg/ml at 100% inhibition). Treatment with T-2307 (3 mg/kg subcutaneous [SC] once daily) also significantly improved survival (70% at 21 days postinfection) and reduced kidney fungal burden (5.06 log10 CFU/g) compared to control (0% survival and 7.09 log10 CFU/g) (P < 0.01).
Background
Invasive fusariosis is associated with marked morbidity and mortality in immunocompromised hosts, and clinical outcomes are poor with conventional therapy. Olorofim (F901318) is an investigational antifungal in the orotomide class that selectively targets fungal dihydroorotate dehydrogenase (DHODH) causing inhibition of pyrimidine biosynthesis.
Objective
We evaluated the in vitro activity of olorofim against 61 clinical isolates of the Fusarium oxysporum and F solani species complexes (FOSC and FSSC, respectively), the most prevalent causes of invasive fusariosis.
Methods
Clinical isolates of FOSC (n = 45) and FSSC (n = 16) were identified using DNA sequence analysis of the translation elongation factor 1‐alpha (TEF1α) and RNA polymerase II second largest subunit (RPB2). Antifungal susceptibility testing was performed by CLSI M38 broth microdilution for olorofim, amphotericin B, isavuconazole, posaconazole, voriconazole and micafungin.
Results
Olorofim demonstrated good in vitro activity against both FOSC and FSSC. Against the 45 FOSC isolates, olorofim MICs ranged between 0.03‐0.5 mg/L and 0.06‐>4 mg/L at the 50% and 100% inhibition endpoints, respectively. Against FSSC isolates, olorofim MIC ranged between 0.25‐1 mg/L and 1‐>4 mg/L at 50% and 100% inhibition, respectively. While amphotericin B also demonstrated similar in vitro activity (MIC ranges 1‐4 and 0.25‐4 mg/L against FOSC and FSSC, respectively), neither the triazoles nor micafungin demonstrated consistent in vitro activity against Fusarium isolates at clinically relevant concentrations.
Conclusions
The investigational agent olorofim demonstrated good in vitro activity against FOSC and FSSC clinical isolates. Further studies are warranted to determine how well this in vitro activity translates into in vivo efficacy.
Dermatophytes are common causes of skin, hair, and nail infections in humans. The most common species causing infections in humans are
Trichophyton rubrum
,
Trichophyton mentagrophytes
, and
Trichophyton interdigitale
.
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