Candida glabrata causes persistent infections in patients treated with fluconazole and often acquires resistance following exposure to the drug. Here we found that clinical strains of C. glabrata exhibit cell-to-cell variation in drug response (heteroresistance). We used population analysis profiling (PAP) to assess fluconazole heteroresistance (FLCHR) and to ask if it is a binary trait or a continuous phenotype. Thirty (57.6%) of 52 fluconazole-sensitive clinical C. glabrata isolates met accepted dichotomous criteria for FLCHR. However, quantitative grading of FLCHR by using the area under the PAP curve (AUC) revealed a continuous distribution across a wide range of values, suggesting that all isolates exhibit some degree of heteroresistance. The AUC correlated with rhodamine 6G efflux and was associated with upregulation of the CDR1 and PDH1 genes, encoding ATP-binding cassette (ABC) transmembrane transporters, implying that HetR populations exhibit higher levels of drug efflux. Highly FLCHR C. glabrata was recovered more frequently than nonheteroresistant C. glabrata from hematogenously infected immunocompetent mice following treatment with high-dose fluconazole (45.8% versus 15%, P = 0.029). Phylogenetic analysis revealed some phenotypic clustering but also variations in FLCHR within clonal groups, suggesting both genetic and epigenetic determinants of heteroresistance. Collectively, these results establish heteroresistance to fluconazole as a graded phenotype associated with ABC transporter upregulation and fluconazole efflux. Heteroresistance may explain the propensity of C. glabrata for persistent infection and the emergence of breakthrough resistance to fluconazole.

Candida species rank high among nosocomial causes of bloodstream infection and are associated with higher rates of acute mortality compared to leading bacterial pathogens. 1,2 Clinical trials and meta-analyses have demonstrated the superiority of echinocandins over fluconazole for the treatment of invasive candidiasis, 3,4 driving the adoption of echinocandins as front-line agents. 5,6 There is concern, however, that this shift may promote the emergence of echinocandin-resistant Candida strains, a trend already apparent in some hospitals. 7 Current Infectious Diseases Society of America directives consider fluconazole an acceptable alternative to echinocandins for patients who are not critically ill and are considered unlikely to harbour fluconazole-resistant

Background: Mucormycosis is a rare but emerging life-threatening fungal disease with limited treatment options. Isavuconazole is a new triazole that has shown efficacy in adults for primary and salvage treatment of mucormycosis. However, data in children are scarce. Methods: The demographic and clinical data of pediatric patients with proven mucormycosis who were treated with isavuconazole in 2015 to 2019 at 2 centers were collected. Results: Four children of median age 10.5 years (range 7–14) met the study criteria. Three had underlying hematologic malignancies, and 1 had sustained major trauma. Isavuconazole was used as salvage therapy in all: in 3 patients for refractory disease, and in 1 after intolerance to another antifungal drug. Isavuconazole was administered alone or combined with other antifungal agents. Following treatment and surgical intervention, complete clinical, radiologic and mycologic responses were documented in all patients. A literature review identified 8 children with mucormycosis who were successfully treated with isavuconazole, as salvage therapy in the majority. Conclusion: Our limited experience supports the use of isavuconazole as salvage therapy in pediatric mucormycosis.

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