Echinocandin heteroresistance causes prophylaxis failure and facilitates breakthrough Candida parapsilosis infection
Zhai, B.; Liao, C.; Jaggavarapu, S.; Rolling, T.; Bergin, S. A.; Gjonbalaj, M.; Miranda, E.; Babady, N. E.; Butler, G.; Taur, Y.; Xavier, J. B.; Weiss, D.; Hohl, T.
Show abstract
Breakthrough infections of patients on antimicrobial prophylaxis represent a significant and often unexplained cause of morbidity. Here, we reveal that in high-risk patients on micafungin prophylaxis heteroresistance - the presence of a phenotypically unstable, low frequency subpopulation of resistant cells ([~]1 in 10,000) - underlies breakthrough bloodstream infections by Candida parapsilosis misclassified as susceptible by standard antimicrobial susceptibility testing. By analyzing 219 clinical C. parapsilosis isolates from North America, Europe, and Asia, we demonstrate widespread micafungin heteroresistance. To facilitate detection of micafungin heteroresistance, we constructed a predictive machine learning framework that classifies isolates as heteroresistant or susceptible by a maximum of ten genomic features. Our results connect heteroresistance to unexplained prophylaxis failure and demonstrate a proof-of-principle diagnostic approach with the potential to inform clinical decisions.
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