2. Academic Validation
  3. The association between undetected heteroresistance and antibiotic treatment failure in complicated urinary tract infection

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

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.

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