Vancomycin heteroresistance (hVISA) in MRSA links to treatment failure and supports a revised PAP-AUC threshold.

Heteroresistance to vancomycin among methicillin-resistant Staphylococcus aureus (MRSA) remains a diagnostic and therapeutic problem in clinical microbiology. In this prospective cohort study of 842 adult patients with MRSA bacteremia in S. Korea, we investigate the prevalence, risk factors, and clinical implications of the heteroresistant vancomycin-intermediate S. aureus (hVISA) phenotype. The hVISA phenotype is detected in 22% of cases. Multivariable regression analysis reveals strong positive associations between hVISA and hospital-acquired infection, prior anti-MRSA therapy, vancomycin exposure, and particularly vancomycin MIC (odds ratio 15.2 per 1 mg/L increase, p < 0.001). Strikingly, patients infected with hVISA strains have a lower 90-day mortality compared to those with fully susceptible strains (hazard ratio 0.66, p = 0.019), suggesting a possible trade-off between resistance and virulence. However, in hVISA strains treated with vancomycin, outcomes reverse: mortality more than doubled (HR 2.5, p < 0.001), bacteremia persisted longer, and relapse rates increased fivefold. Using maximally selected rank statistics, we identify a PAP-AUC threshold of 0.65 as the first clinically derived breakpoint predictive of mortality risk, providing an actionable definition of vancomycin heteroresistance. These findings underscore the clinical relevance of hVISA, and support routine testing for heteroresistance to inform treatment decisions.