222. Clinical and microbiological outcomes for Enterobacterales uropathogens in the Phase 3 ADAPT-PO Study of oral tebipenem pivoxil hydrobromide
Authors: Critchley Ian A , Critchley Ian A , Eckburg Paul B , Muir Lori A , Muir Lori A , Dane Aaron , Moore Gary E , Melnick David , Talley Angela K 
Published: December 2022

Abstract

Background
Enterobacterales (ENT) are frequently implicated in complicated urinary tract infection, including acute pyelonephritis (cUTI/AP), with Escherichia coli (EC) being the most prevalent. Extended-spectrum β-lactamase (ESBL)-producing organisms are increasing and often coresistant to existing oral antibiotics such as the fluoroquinolones (FQ) and trimethoprim-sulfamethoxazole (TMP-SMX). Tebipenem pivoxil hyrdrobromide (TBP-PI-HBr) — a novel oral carbapenem under development — was shown to be non-inferior to IV ertapenem (ETP) in the treatment of cUTI/AP in the ADAPT-PO trial. The goal of this analysis was to assess clinical response (CR) and by-pathogen microbiological responses (MR) for ENT pathogens, including those with resistant phenotypes.

Methods
ADAPT-PO was a Phase 3 multinational, double-blind trial evaluating oral TBP-PI-HBr vs. IV ertapenem in 1372 hospitalized adult patients with cUTI/AP. Patients were randomized 1:1 to oral TBP-PI-HBr or IV ertapenem for 7-10 days. CR and MR at the test-of-cure (TOC) for patients with ENT including resistant phenotypes were assessed in the microbiological intent-to-treat population (micro-ITT).

Results
90.2% of patients in the micro-ITT population were infected with ENT; EC was the most prevalent (64.2%), followed by Klebsiella pneumoniae (14.3%), Proteus mirabilis (6.7%) and Enterobacter cloacae (2.2%). ESBL-positive, FQ non-susceptible (NS) and TMP-SMX-R phenotypes were 23.5%, 38.4% and 41.8% of ENT, respectively. MIC90 vales for both TBP and ETP against ENT were 0.12 µg/mL. At TOC, the CR for TBP-PI-HBr and ETP and all ENT were 92.7% and 94.0%, respectively, and MR was 59.7% and 65.9%, respectively. CR at TOC for ESBL positive ENT was 87.6% and 95.3%, respectively and MR was 54.7% and 61.6%, respectively. Similar MR rates were observed among EC and resistant EC phenotypes.

Conclusion
At TOC CR rates for ENT pathogens were high and similar between treatment groups, including resistant subsets. MR rates for all pathogens were lower in both treatment groups, translating to to a phenomenon consistent with other cUTI trials representing asymptomatic bacteriuria. TBP-PI-HBr and ETP showed similar MR rates for EC, the most prevalent uropathogens, including resistant phenotypes.

Disclosures
Ian A. Critchley, PhD, Spero Therapeutics: Employee|Spero Therapeutics: Stocks/Bonds Ian A. Critchley, PhD, Spero Therapeutics: Employee|Spero Therapeutics: Stocks/Bonds Paul B. Eckburg, MD, AN2 Therapeutics: Stocks/Bonds|Spero Therapeutics: Advisor/Consultant Lori A. Muir, B.Sc., Spero Therapeutics: Employee|Spero Therapeutics: Stocks/Bonds Lori A. Muir, B.Sc., Spero Therapeutics: Employee|Spero Therapeutics: Stocks/Bonds Aaron Dane, MSc, Amplyx: Advisor/Consultant|AN2 therapeutics: Advisor/Consultant|Artizan: Advisor/Consultant|Cidara: Advisor/Consultant|ContraFect: Advisor/Consultant|Correvio: Advisor/Consultant|Davolterra: Advisor/Consultant|Destiny Pharma: Advisor/Consultant|Entasis: Advisor/Consultant|F2G Limited: Advisor/Consultant|GSK: Advisor/Consultant|Humanigen: Advisor/Consultant|Kymab: Advisor/Consultant|Modis: Advisor/Consultant|Orca: Advisor/Consultant|Pfizer: Advisor/Consultant|Phico: Advisor/Consultant|Pled Pharma: Advisor/Consultant|Rare Thyroid: Advisor/Consultant|Roche: Advisor/Consultant|Scynexis: Advisor/Consultant|Sinovent: Advisor/Consultant|Spero Therapeutics: Advisor/Consultant|Transcrip: Advisor/Consultant|Venatorx: Advisor/Consultant Gary E. Moore, PhD, Spero Therapeutics: Advisor/Consultant David Melnick, MD, Spero Therapeutics: Employee|Spero Therapeutics: Stocks/Bonds Angela K. Talley, MD, Spero Therapeutics: Employee|Spero Therapeutics: Stocks/Bonds.