1695. Tebipenem: An Oral Carbapenem with activity against Multi-drug Resistant Urinary Tract Infection isolates of Escherichia coli collected from US Medical Centers during 2019
Authors: Critchley Ian A , Cotroneo Nicole S , Pucci Michael J , Jain Akash , Mendes Rodrigo E 
Published: January 2021

Abstract

Background
Escherichi coli (EC) is a predominant urinary tract infection (UTI) pathogen where increasing prevalence of extended spectrum-β-lactamase (ESBL) continues to compromise the use of currently available oral antibiotics. ESBL-producing EC exhibit coresistance to the fluoroquinolones (FQs) and trimethoprim-sulfamethoxazole (TMP-SMX) making treatment of UTIs outside the hospital difficult and intravenous (IV) agents are often needed. Tebipenem (TBP) is an oral carbapenem with similar activity to IV carbapenems in clinical development for treating complicated UTIs (cUTI). This study assessed the activity of TBP against EC collected from UTIs in the US including isolates R to oral agents.

Methods
1133 EC from UTIs in the 2019 STEWARD Surveillance Program were tested for susceptibility to TBP and comparators. Isolates were collected from medical centers geographically distributed across the US Census regions, centrally tested, and susceptibility (S) interpreted according to CLSI criteria.

Results
Overall prevalence of ESBL EC from UTI was 15.4% and R to oral cefuroxime, levofloxacin and TMP-SMX were: 15.6%, 23.9% and 33.5%, respectively. In contrast, low R was observed for the IV carbapenems. All EC were inhibited by TBP at ≤0.5 µg/mL and the MIC90 was 0.015 µg/mL compared with MIC90s of 0.03 µg/mL for meropenem (MER) and ertapenem (ETP). Using a tentative PK/PD cut off of 0.12 µg/mL 99.7% of EC were inhibited by TBP. The MIC90s for LEV and TMP-SMX were 32 and &gt;16 µg/mL, respectively, against ESBL EC with R rates at ≥66.3%. MIC90s of 0.03, 0.03 and 0.12 µg/mL, respectively, were noted for TBP, MER (100% S) and ETP (99.6% S). TBP was active against LEV-R, TMP-SMX-R and MDR (≥3 classes) EC with MIC90s of 0.03 µg/mL.

Conclusion
R to oral agents remains high, raising concerns on empiric use. Carbapenems remain active against EC due to their stability to ESBLs and are not compromised by co-resistance. TBP is an oral carbapenem with similar activity to IV carbapenems based on comparison of MIC90 values. Although no breakpoints are available, ≥99.7% of EC were inhibited by TBP at ≤0.12 µg/mL highlighting potential as a new oral option for cUTIs in an era of ESBL mediated co-resistance to the FQs and TMP-SMX.

Disclosures
Ian A. Critchley, PhD, Spero Therapeutics (Employee, Shareholder) Nicole S. Cotroneo, BS, Spero Therapeutics (Employee, Shareholder) Michael J. Pucci, PhD, Spero Therapeutics (Employee)Spero Therapeutics (Employee) Akash Jain, PhD, Spero Therapeutics (Employee) Rodrigo E. Mendes, PhD, A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Allergan (Research Grant or Support)Basilea Pharmaceutica International, Ltd (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Department of Health and Human Services (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Merck (Research Grant or Support)Merck (Research Grant or Support)Pfizer (Research Grant or Support)