Candida parapsilosis WGS

Antimicrobial resistance is a major problem in the prevention and treatment of infectious diseases. For patients on antimicrobial prophylaxis during cancer treatment and organ transplantation, breakthrough infections represent a significant and often unexplained cause of morbidity. Here, in high-risk patients on micafungin prophylaxis, we reveal that heteroresistance, the presence of a phenotypically unstable, low frequency subpopulation of resistant cells (~1 in 10,000), causes breakthrough bloodstream infections by Candida parapsilosis isolates that were 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 the detection of micafungin heteroresistance, we constructed a predictive machine learning framework that classifies heteroresistance via a maximum of ten genomic features. Our data directly connect heteroresistance to unexplained prophylaxis failure and demonstrate a proof-of-principle diagnostic approach that has the potential to inform clinical decisions.