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.
Fungal infections are being caused by a broadening spectrum of fungi, yet in many cases, identification to the species level is required for proper antifungal selection. We investigated the fungal intergenic spacer sequence (IGS) in combination with nanopore sequencing, for fungal identification. We sequenced isolates from two Cryptococcus species complexes, C. gattii and C. neoformans, which are the main pathogenic members of this genus, using the Oxford Nanopore Technologies MinION device and Sanger sequencing. There is enough variation within the two complexes to argue for further resolution into separate species, which we wanted to see if nanopore sequencing could detect. Using the R9.4.1 flow cell, IGS sequence identities averaged 99.57% compared to Sanger sequences of the same region. When the newer R10.3 flow cell was used, accuracy increased to 99.83% identity compared to the same Sanger sequences. Nanopore sequencing errors were predominantly in regions of homopolymers, with G homopolymers displaying the largest number of errors and C homopolymers displaying the least. Phylogenetic analysis of the nanopore and Sanger derived sequences resulted in indistinguishable trees. Comparison of average percent identities between the C. gattii and C. neoformans species complexes resulted in only a 74-77% identity between the two complexes. Sequencing using the nanopore platform could be completed in less than an hour and samples could be multiplexed in groups as large as twenty-four sequences in a single run. These results suggest that sequencing the IGS region using nanopore sequencing could be a potential new molecular diagnostic strategy.
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.
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