The association between undetected heteroresistance and antibiotic treatment failure in complicated urinary tract infection
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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.
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.
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This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/15220101.
Peer Review: The association between undetected heteroresistance and antibiotic treatment failure in complicated urinary tract infection
Introduction:
This preprint intended to fill a gap in literature surrounding heteroresistance and its impact on treatment failure. They identify that unexplained antibiotic treatment failure is a growing concern, with heteroresistance being an area with limited clinical knowledge about its impact on overall treatment failure. The authors aimed to study the impact on heteroresistance on treatment failure and clinical outcome. The authors utilized a population analysis profile from clinical isolates from subjects enrolled in a previous clinical trial …
This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/15220101.
Peer Review: The association between undetected heteroresistance and antibiotic treatment failure in complicated urinary tract infection
Introduction:
This preprint intended to fill a gap in literature surrounding heteroresistance and its impact on treatment failure. They identify that unexplained antibiotic treatment failure is a growing concern, with heteroresistance being an area with limited clinical knowledge about its impact on overall treatment failure. The authors aimed to study the impact on heteroresistance on treatment failure and clinical outcome. The authors utilized a population analysis profile from clinical isolates from subjects enrolled in a previous clinical trial comparing the efficacy of piperacillin/tazobactam versus cefepime/tazobactam in treating hospitalized patients with ongoing cUTI, and also evaluated the subject's treatment outcomes using data from the ALLIUM trial. They hypothesized that heteroresistant bacteria would have an increased rate of treatment failure as compared to bacteria without heteroresistance. The study found that 11.5% of patients were infected with heteroresistant isolates, and heteroresistant isolates had an increased rate of treatment failure ([OR] 2.13, 95% CI 1.02, 4.41). While the authors found significance in one of their analyses, the adjusted analysis was not significant and their research provides only limited insight on heteroresistance's impacts on treatment outcomes.
Strengths:
The study confirms that heteroresistance can increase treatment failure, helping to fill a gap in antibiotic-resistance research that was previously only hypothesized about.
The methodology for isolating and analyzing heteroresistant strains, particularly the use of population analysis profiles, is a strength that enhances the study's reliability. By using a PAP, the study effectively identified that 33/288 of the clinical isolates were heteroresistant, highlighting the potential frequency of heteroresistance in antibiotic-resistant patients.
Additionally, the study identifies ESBL-encoding to be on the causal pathway between heteroresistance and treatment failure. From here, they sequenced non-heteroresistant and heteroresistant E. coli isolates to create a phylogenetic tree, confirming the strong presence of E. coli heteroresistant isolates within ESBL-encoding clusters. Thus, they did not adjust for ESBL encoding isolates in the statistical analysis.
Concerns and Limitations:
While the paper finds significant findings of patients infected with piperacillin/tazobactam heteroresistance isolates having higher treatment failure than patients without heteroresistance, when adjusted for the propensity of heteroresistance, the difference between the heteroresistant and non-heteroresistance was not significant. The authors mention this in their results, but could further explain the generalizability of their results in the discussion considering the significance of their results. Adjusting for the propensity of heteroresistance in this case meant adjusting for acute pyelonephritis infection, BMI, and diabetes.
Another limitation is that some of the authors are affiliated with or employed by pharmaceutical companies. The last author is also noted to have pending patents related to heteroresistance. This would encourage further scrutiny of the results since positive results would garner support for a solution to heteroresistance.
Areas of Improvement
Urgent:
Non urgent:
Further clarifying the validity of the results in the discussion section would improve the strength of the study since it potentially overstates its findings.
In the introduction section, the authors could include information on previously known prevalence of heteroresistance, and existing treatment strategies for known heteroresistant strains.
Greater transparency on how conflicts were managed would strengthen the credibility of the findings.
Conclusion
The study found that heteroresistance increases the rate of treatment failure for piperacillin/tazobactam resistant isolates. However, because of the narrow generalizability and scope of the study, the overall claims are limited in significance and should be elaborated upon in greater detail in the discussion section.
Competing interests
The authors declare that they have no competing interests.
Use of Artificial Intelligence (AI)
The authors declare that they used generative AI to come up with new ideas for their review.
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