P1862 Activity of tebipenem, an oral carbapenem, against multidrug-resistant urinary tract infection-causing pathogens with characterized resistance mechanisms collected in Europe and the United States in 2016 Nicole Cotroneo*1, Katherine Sulham1, David Melnick1, Aileen Rubio1, Rodrigo E. Mendes2, Ian Critchley1

1 Spero Therapeutics, Inc., Cambridge, United States, 2 JMI Laboratories, North Liberty, United States Background: Oral antibiotics such as cephalosporins (CEF’s), fluoroquinolones (FQ’s) and trimethoprim- sulfamethoxazole (TMP-SMX) are widely used to treat Gram-negative urinary tract infections (UTI’s). Their utility is being eroded by increasing prevalence of extended-spectrum β-lactamase-producing (ESBL) organisms where considerable co-resistance exists among UTI isolates of Escherichia coli (EC) and Klebsiella pneumoniae (KP). Managing UTIs caused by ESBL-producing organisms is challenging due to limited treatment options outside the hospital setting. Carbapenems exhibit the broadest spectrum and potency due to stability to most ESBLs that are prevalent among UTI pathogens. This study evaluated the activity of tebipenem (TBP) against multidrug resistant (MDR) UTI isolates of EC and KP possessing ESBLs characterized by whole genome sequencing. Materials/methods: All EC (n=101) and KP (n=208) were collected from UTI’s during the 2016 SENTRY Surveillance program conducted in the EU and US, and tested for susceptibility to TBP, ertapenem, imipenem, CEF’s, FQ’s and TMP-SMX using CLSI methods. Susceptibility was interpreted using CLSI breakpoint criteria. ESBLs were identified by sequencing bacterial genomes and blasting these against a curated database to confirm resistance genes. Results: TBP was active against FQ-R (n=32) or TMP-SMX-R EC (n=39) with an MIC90 of 0.06 µg/mL and against FQ-R (n=33) or TMP-SMX-R (n=49) KP (non-carbapenem-resistant isolates) with an MIC90 of 0.25 µg/mL. Among the 9 EC with confirmed R (CTX-M, OXA-1/30, CMY-2), all but one were R to either FQ’s or TMP-SMX and inhibited by TBP at ≤0.12 µg/mL. Among the 26 KP with confirmed R, 19 were FQ-R and 22 were TMP-SMX-R. TBP MICs ranged from 0.03 to >32 µg/mL and isolates with elevated TBP MICs were KPC-producers. Most prevalent R mechanism was CTX-M-15/OXA-1/30. Many EC and KP also were positive for TMP-SMX, aminoglycoside, tetracycline and fosfomycin R mechanisms. Conclusions: MDR (co-resistance) mechanisms were confirmed among ESBL-producing EC and KP UTI isolates. Carbapenems represent broadest spectrum and potency due to stability to most ESBLs produced by UTI pathogens. The activity of TBP against MDR ESBL EC and KP from UTI supports development as a new oral option for treating UTI’s in an era of ESBLs and co-resistance to many of the current agents.

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