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

  • medRxiv. 2025 Mar 13:2025.03.11.25323422. doi: 10.1101/2025.03.11.25323422.
Carter N Abbott  1  2  3 ,  Aditi Dhillon  1  2  3 ,  Sushma Timalsina  1  2  3 ,  Elise Furr  1  2  3 ,  Patrick Velicitat  4 ,  Adam Belley  4 ,  Navaneeth Narayanan  5  6 ,  Keith S Kaye  6 ,  David S Weiss  1  2  3
Affiliations
  • 1. Emory Antibiotic Resistance Center, Atlanta, Georgia, USA.
  • 2. Emory Vaccine Center, Atlanta, Georgia, USA.
  • 3. Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
  • 4. Allecra Therapeutics, St-Louis, France.
  • 5. Department of Pharmacy Practice and Administration, Rutgers University Ernest Mario School of Pharmacy.
  • 6. Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ.
PMID: 40162257 DOI: 10.1101/2025.03.11.25323422
Abstract

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.

Products