The association between undetected heteroresistance and antibiotic treatment failure in complicated urinary tract infection.

BACKGROUND: Antibiotic resistance is a worsening public health threat. One poorly understood aspect of this problem is unexpected antibiotic treatment failure; when an infecting isolate is deemed susceptible to a given antibiotic, yet treatment with that drug fails. It has been proposed that heteroresistance may be an explanation for at least some unexplained treatment failures. Heteroresistance occurs when a bacterial isolate harbors a minor subpopulation of resistant cells which coexists with a majority susceptible population. The clinical relevance of heteroresistance is not clear. METHODS: We obtained 291 index isolates from 288 unique patients in the piperacillin/tazobactam arm of the ALLIUM phase 3 clinical trial for the treatment of Gram-negative pathogens causing complicated urinary tract infections. The MIC for all isolates was below the piperacillin/tazobactam resistance breakpoint according to standard antimicrobial susceptibility testing. We performed population analysis profiles on these isolates to detect piperacillin/tazobactam heteroresistance and conducted a post hoc analysis to examine the impact of heteroresistance on clinical outcomes. FINDINGS: We observed that 33/288 (11.5%) of the patients were infected with isolates that were heteroresistant to piperacillin/tazobactam and that patients infected with heteroresistant isolates had an increased rate of treatment failure when compared to patients infected with a non-heteroresistant isolate (odds ratio [OR] 2.13, 95% CI 1.02, 4.41; adjusted OR 1.74, 95% CI 0.82, 3.71). Further, patients without a removable catheter were at particular risk of treatment failure from infection with heteroresistant isolates. INTERPRETATION: These data demonstrate that patients infected with a piperacillin/tazobactam heteroresistant isolate are at an increased risk for piperacillin/tazobactam treatment failure. The results help contextualize commonly observed unexpected antibiotic treatment failure and highlight heteroresistance as a potential cause.