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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.

Funding

This work was, in part, funded by the United States Government, Advanced Research Projects Agency for Health (ARPA-H) grant AY1AX000002, National Institutes of Health (NIH) grant AI158080, and Department of Veterans Affairs (VA) grant BX005985 to DSW. DSW was also supported by a Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Disease award. NN was supported by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under Award Number K23AI159396. The views and conclusions contained in this document are those of the authors and should not be interpreted as representing the official policies, either expressed or implied, of the United States Government.

Competing Interests

PV is an employee of Allecra Therapeutics. AB was a paid consultant for Allecra at the time of the study. NN reports grants/contracts from Merck and Shionogi; consulting/speaker fees from Astellas. KSK has received consulting fees from Merck, Shionogi, GlaxoSmithKline, MicuRx Pharmaceuticals, AbbVie, Venatorx Pharmaceuticals, and Allecra Therapeutics, and owns stock options in Merck. DSW has pending patents related to heteroresistance.