Thomas F. Patterson

Treatment of symptomatic patients with coccidioidomycosis often involves the use of triazole antifungals. There is concern for reduced susceptibility of Coccidioides to fluconazole, as a high percentage of isolates were previously reported to have elevated fluconazole MICs. We reviewed our recent azole MICs against Coccidioides and examined temporal trends over a 20-year period. Our clinical laboratory database was queried for data against Coccidioides between 2006 and 2025, and trends in GM MICs and the percentage of isolates with elevated MICs to the azoles were assessed. All testing had been performed by broth dilution according to Clinical and Laboratory Standards Institute (CLSI) M38 methods. The results over the 10-year period from 2016 to 2025 were compared to those previously reported by our group from 2001 to 2015. Overall, the results between the two periods showed similar MIC parameters and distributions for fluconazole, itraconazole, posaconazole, and voriconazole, with posaconazole demonstrating the most potent activity, while fluconazole demonstrated reduced susceptibility. Isavuconazole MIC parameters were available during the second period and similar to those of voriconazole. Weak correlations were observed between fluconazole MICs and those of the other azoles. Fluctuations in GM MICs and the percentage of isolates with elevated MICs were observed with fluconazole, itraconazole, and posaconazole, with elevated values observed between 2011 and 2019. Continued surveillance is needed, and outcome data are required to determine if the consistently reduced susceptibility observed with fluconazole or in those infected with strains that have higher MICs results in poorer outcomes in patients with coccidioidomycosis.

Invasive fungal diseases are difficult to diagnose because of the limited sensitivity of culture. Panfungal PCR amplicon sequencing assays (targeting ribosomal RNA, such as 18S, 28S, ITS) are recommended for fungal identification in histopathology samples showing fungal elements. However, data describing its overall performance and consistency are lacking. This systematic literature review and meta-analysis assessed the performance of panfungal PCR on formalin-fixed paraffin-embedded (FFPE) and non-fixed (fresh or frozen) tissue samples. A systematic literature search was performed to include studies reporting the use of panfungal PCR for fungal identification in FFPE or non-fixed tissue samples. PCR sensitivity and specificity were assessed using the reference standard of histopathology showing fungal elements. Quality assessment was performed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Pooled estimates were obtained using random-effects meta-analysis. Twenty-eight studies were included. In FFPE samples (18 studies, 852 samples), sensitivity and specificity were 75.4% (95% confidence interval [CI], 59.2–86.6) and 93.5% (70.2–98.9), respectively. Sensitivity in non-fixed samples (13 studies, 207 samples) was 86.5% (74.7–93.3), while specificity could not be assessed (insufficient data). Comparative analyses showed a significantly higher sensitivity of panfungal PCR over culture (88.2%; 76–94.7 vs 52.2%; 39–65, P = 0.001). Sub-analyses could not demonstrate the superiority of one PCR target over another due to limited data. Panfungal PCR exhibited adequate sensitivity and good specificity in FFPE samples. Sensitivity was even higher in non-fixed samples and largely superior to culture. Nevertheless, large interstudy variability was observed, warranting interlaboratory studies to define the optimal PCR target and standardized protocols. IMPORTANCE: Invasive fungal diseases are difficult to diagnose because of the low sensitivity of culture. Panfungal PCRs are widely used for fungal identification in tissue specimens but suffer from heterogeneous procedures and performance. This meta-analysis shows an acceptable sensitivity (75.4% and 86.5% in fixed and non-fixed samples, respectively) and good specificity (93.5%) of panfungal PCR, supporting its use, not only on histopathology-positive fixed samples but also in non-fixed samples concomitantly with other diagnostic tools (cultures and fungal-specific PCRs if available). These results provide a strong basis for further standardization of panfungal PCR techniques via interlaboratory assays to assess reproducibility and optimize analytical protocols. CLINICAL TRIALS: This study is registered with PROSPERO as CRD42023461148 .

Olorofim, a novel dihydroorotate dehydrogenase inhibitor, may be efficacious in patients with disseminated coccidioidomycosis (DCM) who lack alternative treatment options. This single-group, open-l... Visual Olorofim in Treatment of Patients With Poorly Controlled Disseminated Coccidioidomycosis Olorofim, a novel dihydroorotate dehydrogenase inhibitor, may be efficacious in patients wit... Background: Olorofim, a novel dihydroorotate dehydrogenase inhibitor, may be efficacious in patients with disseminated coccidioidomycosis (DCM) who lack alternative treatment options. Objective: To...

Candida glabrata is a major cause of invasive candidiasis and is considered a high-priority fungal pathogen by the World Health Organization. SCY-247 is a second-generation IV/oral triterpenoid antifungal that targets the fungal cell wall by inhibiting glucan synthase. We evaluated the in vitro activity and in vivo efficacy of SCY-247 against echinocandin-resistant C. glabrata . Susceptibility testing was performed against 34 C. glabrata clinical strains, including 29 echinocandin non-susceptible or resistant strains, by the CLSI broth microdilution method. Neutropenic mice were infected intravenously with either an echinocandin-susceptible or resistant strain. Treatment with vehicle control, SCY-247 (16, 32, and 48 mg/kg PO BID), fluconazole (20 mg/kg PO QD), or caspofungin (5 mg/kg IP QD) was initiated 24 hours post-inoculation. Treatment continued for 7 days, and kidney and lung tissues were collected on day 8 for analysis of fungal burden. SCY-247 maintained in vitro activity against 24 of the 29 echinocandin non-susceptible/resistant strains; SCY-247 was also efficacious against echinocandin-susceptible and resistant C. glabrata invasive candidiasis. Dose-dependent reductions in kidney and lung fungal burdens were observed in mice treated with SCY-247. In contrast, neither fluconazole nor caspofungin led to reductions in fungal burden in mice infected with the resistant strain. SCY-247 concentrations measured 12 hours after the last dose increased in a dose-dependent fashion, and those within the kidneys and lungs were markedly higher than the SCY-247 MIC ₉₀ value calculated against all strains tested. These data support the potential utility of SCY-247 therapy against invasive infections caused by resistant C. glabrata .

We evaluated the in vivo activity of EL219 against central nervous system coccidioidomycosis. Mice were inoculated intracranially with arthroconidia of Coccidioides immitis , and treatment with EL219 (5, 10, or 20 mg/kg QD by intraperitoneal injection) or fluconazole (25 mg/kg orally BID) began 2 days later. Each dose of EL219 and fluconazole significantly improved survival. Brain fungal burden was also reduced compared to vehicle control. Further studies of EL219 against coccidioidomycosis are warranted.

The epidemiology of invasive aspergillosis (IA) is evolving. To define the patient groups who will most likely benefit from primary or secondary Aspergillus prophylaxis, particularly those whose medical conditions and IA risk change over time, it is helpful to depict patient populations and their risk periods in a temporal visual model. The Sankey approach provides a dynamic figure to understand the risk of IA for various patient populations. While the figure depicted within this article is static, an internet-based version could provide pop-up highlights of any given flow's origin and destination nodes. A future version could highlight links to publications that support the color-coded incidence rates or other actionable items, such as bundles of applicable pharmacologic or non-pharmacologic interventions. The figure, as part of the upcoming Infectious Diseases Society of America's aspergillosis clinical practice guidelines, can guide decision-making in clinical settings.

Candidiasis is one of the most frequent nosocomial infections affecting an increasing number of at-risk patients. Candida albicans remains the most frequent causative agent of candidiasis, but, in the last decade, C. auris has emerged as a formidable multi-drug-resistant pathogen. Both species are fully capable of forming biofilms, which contribute to resistance, increasing the urgency for new effective antifungal therapies. Repurposing existing drugs could significantly accelerate the development of novel therapies against candidiasis. Here, we have screened the Repurposing Hub library from the Broad Institute, containing over 6000 compounds, in search for inhibitors of C. albicans and C. auris biofilm formation. The primary screen identified 57 initial hits against C. albicans and 33 against C. auris. Confirmatory concentration-dependent assays were used to validate the activity of the initial hits and, at the same time, establish their anti-biofilm potency. Based on these results, ebselen, temsirolimus, and compound BAY 11-7082 emerged as the leading repositionable compounds. Subsequent experiments established their spectrum of antifungal activity against yeasts and filamentous fungi. In addition, their in vivo activity was examined in the murine models of hematogenously disseminated C. albicans and C. auris infections. Although promising, further in vitro and in vivo studies are needed to confirm their potential use for the therapy of candidiasis and possibly other fungal infections.