Twelve-year surveillance identifies parent B Candida orthopsilosis causing breakthrough candidemia during caspofungin therapy with echinocandin heteroresistance

Abstract

Abstract Background Echinocandin breakthrough infection can occur despite conventional susceptibility results that do not indicate resistance, suggesting that population-level minimum inhibitory concentration (MIC) testing may miss clinically relevant within-isolate heterogeneity. Most clinical Candida orthopsilosis isolates are hybrids, whereas parent B has previously been represented only by marine isolates despite evidence of pathogenic potential and echinocandin fitness. It remains unknown whether parent B can contribute to invasive infection under echinocandin exposure and whether conventional susceptibility testing adequately captures its antifungal response. Results We analysed C. orthopsilosis bloodstream isolates recovered at a tertiary hospital in Guangzhou, within the coastal Pearl River Delta of southern China, from 2010 to 2021. Among 197 C. parapsilosis species-complex isolates, 17 were confirmed as C. orthopsilosis , including six bloodstream isolates. Nuclear and mitochondrial genome analyses assigned one highly homozygous isolate, BS03, to parent B, a lineage previously represented only by marine isolates. A blood culture yielding BS03 was collected after 12 days of ongoing caspofungin therapy. The patient developed septic shock and died two days later. In a Galleria mellonella model, BS03 showed pathogenic potential without significantly greater virulence than the tested fungal comparators. Its caspofungin MIC was 0.5 mg/L, within the wild-type range. Population analysis profiling nevertheless detected resistant subpopulations at 2, 4, and 8 mg/L caspofungin, corresponding to 4×, 8×, and 16× MIC, respectively. BS03 thus fulfilled the predefined criterion for caspofungin heteroresistance. Comparison of GSC1 ( FKS1 ), GSL1 , and GSL2 identified no BS03-specific canonical Fks1 hot spot resistance substitution. Conclusions These findings extend the known clinical spectrum of C. orthopsilosis parent B beyond its previously recognised marine context. The coexistence of a wild-type-range caspofungin MIC with a resistant minority population further highlights within-isolate heterogeneity as an additional dimension of echinocandin susceptibility that may be missed by population-level MIC testing. Clinical trial number Not applicable.

The authors' abstract, as published at the source. BMC Microbiology, 2026 · DOI ↗