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.

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. Competing Interest Statement 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. Funding Statement 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. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Electronic health records associated with the previously reported NCT03687255 were used in this study. The original study protocol and informed consent form were approved for each of the 90 sites by the respective competent institutional review board or independent ethics committees at each site. All participants provided written informed consent. The original study protocol is available (PMID: 36194218). The study used individual level data that had all been deidentified prior to this study. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data produced in the present study are available upon reasonable request to the authors