This article is available to subscribers. Subscribe now. Already have an account? Sign in

Original ArticleFree Preview

Oral Tebipenem Pivoxil Hydrobromide in Complicated Urinary Tract Infection

List of authors.
  • Paul B. Eckburg, M.D.,
  • Lori Muir, B.Sc.,
  • Ian A. Critchley, Ph.D.,
  • Susannah Walpole, Ph.D.,
  • Hanna Kwak, B.S.,
  • Anne-Marie Phelan, M.A.,
  • Gary Moore, M.S.,
  • Akash Jain, Ph.D.,
  • Tim Keutzer, B.A.,
  • Aaron Dane, M.Sc.,
  • David Melnick, M.D.,
  • and Angela K. Talley, M.D.

Abstract

Background

There is a need for oral antibiotic agents that are effective against multidrug-resistant gram-negative uropathogens. Tebipenem pivoxil hydrobromide is an orally bioavailable carbapenem with activity against uropathogenic Enterobacterales, including extended-spectrum beta-lactamase–producing and fluoroquinolone-resistant strains.

Methods

Download a PDF of the Research Summary.

In this phase 3, international, double-blind, double-dummy trial, we evaluated the efficacy and safety of orally administered tebipenem pivoxil hydrobromide as compared with intravenous ertapenem in patients with complicated urinary tract infection or acute pyelonephritis. Patients were randomly assigned, in a 1:1 ratio, to receive oral tebipenem pivoxil hydrobromide (at a dose of 600 mg every 8 hours) or intravenous ertapenem (at a dose of 1 g every 24 hours) for 7 to 10 days (or up to 14 days in patients with bacteremia). The primary efficacy end point was overall response (a composite of clinical cure and favorable microbiologic response) at a test-of-cure visit (on day 19, within a ±2-day window) in the microbiologic intention-to-treat population. The noninferiority margin was 12.5%.

Results

A total of 1372 hospitalized adult patients were enrolled; 868 patients (63.3%) were included in the microbiologic intention-to-treat population (50.8% of whom had complicated urinary tract infections and 49.2% of whom had pyelonephritis). An overall response was seen in 264 of 449 patients (58.8%) who received tebipenem pivoxil hydrobromide, as compared with 258 of 419 patients (61.6%) who received ertapenem (weighted difference, −3.3 percentage points; 95% confidence interval [CI], −9.7 to 3.2). Clinical cure at the test-of-cure visit was observed in 93.1% of the patients in the microbiologic intention-to-treat population who received tebipenem pivoxil hydrobromide and 93.6% of patients who received ertapenem (weighted difference, −0.6 percentage point; 95% CI, −4.0 to 2.8); the majority of patients with microbiologic response failures at the test-of-cure visit were asymptomatic patients with recurrent bacteriuria. Secondary and subgroup analyses were supportive of the primary analysis. Adverse events were observed in 25.7% of patients who received tebipenem pivoxil hydrobromide and in 25.6% of patients who received ertapenem; the most common adverse events were mild diarrhea and headache.

Conclusions

Oral tebipenem pivoxil hydrobromide was noninferior to intravenous ertapenem in the treatment of complicated urinary tract infection and acute pyelonephritis and had a similar safety profile. (Funded by Spero Therapeutics and the Department of Health and Human Services; ADAPT-PO ClinicalTrials.gov number, NCT03788967.)

Digital Object ThumbnailQUICK TAKE VIDEO SUMMARY
Oral Antibiotic for Complicated Urinary Tract Infection
 02:19

Continue reading this article

Select an option below:

Create your account to get 2 free subscriber-only articles each month.

Get Free Access Now Subscribe For Full Access

Already have an account?

Sign In

Print subscriber?

Activate your online access.

Funding and Disclosures

Supported by Spero Therapeuticsand a contract (HHSO100201800015C) for clinical trial drug supply with the Office of the Assistant Secretary for Preparedness and Response Biomedical Advanced Research and Development Authority of the Department of Health and Human Services.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

This article was updated on April 7, 2022, at NEJM.org.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

We thank Patricia Warfel for database management oversight and Richard S. Perry for editorial assistance in the development of an earlier version of the manuscript, both funded by Spero Therapeutics.

Author Affiliations

From Spero Therapeutics, Cambridge, MA (P.B.E., L.M., I.A.C., S.W., H.K., A.-M.P., A.J., T.K., D.M., A.K.T.); Moore Computing Services, Little Rock, AR (G.M.); and DaneStat Consulting, Macclesfield, United Kingdom (A.D.).

Dr. Talley can be contacted at or at Spero Therapeutics, 675 Massachusetts Ave., 14th Fl., Cambridge, MA 02139.

A full list of the ADAPT-PO investigators is provided in the Supplementary Appendix, available at NEJM.org.

Print Subscriber? Activate your online access.