Evaluation of Factors Predictive of Efficacy Among Patients With Complicated Urinary Tract Infection and/or Acute Pyelonephritis.

Background: Antibiotic treatment for complicated urinary tract infections (cUTI)/acute pyelonephritis (AP) is often followed by recurrent bacteriuria in the absence of clinical symptoms. To understand factors predictive of clinical and microbiologic outcomes in patients with cUTI/AP, multivariable analyses were undertaken using pooled data from a global, phase 3 cUTI study.
Methods: Using data from 366 tebipenem pivoxil hydrobromide- and 378 ertapenem-treated patients from the Study to Assess the Efficacy, Safety and Pharmacokinetics of Orally Administered Tebipenem Pivoxil Hydrobromide (SPR994) Compared to Intravenous Ertapenem in Participants With Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP) infected with Enterobacterales uropathogens, multivariable analyses for dichotomous efficacy endpoints were performed using logistic regression and pharmacokinetic-pharmacodynamic relationships were evaluated.
Results: Urinary tract anatomical disorders and functional urinary tract or metabolic disorders were predictive of nonresponse across all efficacy endpoints assessed at test-of-cure (TOC) and late follow-up (LFU) visits, with greater impact on overall and microbiologic than clinical nonresponse. Independent variables predictive of increased probabilities of successful overall response at TOC and microbiologic response at TOC or LFU were baseline creatinine clearance >50 mL/min and baseline pathogen fluoroquinolone susceptibility. Infection with a phenotypic extended-spectrum beta-lactamase-positive Enterobacterales pathogen was predictive of reduced probabilities of success for microbiologic response at LFU and clinical response at TOC. Meaningful relationships between efficacy endpoints and plasma pharmacokinetic-pharmacodynamic indices were not identified.
Conclusions: Reductions of overall and microbiologic response in patients with cUTI/AP were associated with anatomical or functional urinary tract disorders, but not with the magnitude or duration of plasma antibiotic exposure. Results of these analyses serve to advance our understanding of factors predictive of outcome in patients with cUTI/AP.
Competing Interests: Potential conflicts of interest. S. M. B., J. P. H., C. M. R., K. L., and P. G. A. are employees of the Institute for Clinical Pharmacodynamics, Inc., which has received research support from Spero Therapeutics, Inc. A. K. T., V. K. G., and D. A. M. were employees of Spero Therapeutics, Inc. at the time the analyses were conducted. P. B. E. was a consultant for Spero Therapeutics, Inc. at the time the analyses were conducted. K. A. H. is an employee of Spero Therapeutics, Inc.
(© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)