1053 - The β-Lactamase Inhibitor QPX7728 Restores the Activity of β-Lactam Agents against Contemporary Extended-Spectrum b-lactamase (ESBL)-Producing and Carbapenem-Resistant Enterobacterales (CRE) Isolates, Including Isolates Producing Metallo-b-lactamases

The b-lactam (BL)/b-lactamase inhibitor (BLI) combinations approved in the last 10 years are active against most ESBL-producing Enterobacterales (ENT) and CRE isolates, but have limited activity against metallo-b-lactamase (MBL)-producing ENT. We evaluated the activity of QPX7728 (QPX), a novel BLI with intravenous (IV) and oral availability, in combination with BL agents. We tested ENT isolates carrying the most common BL genes such as bla_CTX-M, transferable AmpCs, oxacillinases, MBLs, and serine carbapenemases.

Methods:

A total of 1,027 ENT isolates were susceptibility (S) tested by reference broth microdilution against aztreonam (ATM), cefepime (FEP), cefdinir (CDR), ceftibuten (CTB), ceftolozane (CT) and piperacillin (PT) with fixed 4 mg/L of tazobactam, biapenem (BPM), meropenem (MER), and tebipenem (TEB) combined with QPX at fixed 4 and 8 mg/L. All isolates were genetically characterized using whole genome sequencing and included 520 ESBL-producers and 507 CRE with 168 producing MBLs.

Results:

BL agents tested alone had limited activity against this challenge set of isolates (MIC₉₀, ³32 mg/L); however, MIC₉₀ values decreased ³32-fold with the addition of QPX at the highest concentration tested (Table). Oral agents, CTB,CDR and TEB were tested with QPX at a fixed 4 mg/L and showed a 32- to 128-fold increase in potency (MIC₉₀, 0.5-4 mg/L). ATM and FEP were tested with QPX at a fixed 4 and 8 mg/L and displayed MIC₉₀ values ranging from 0.12-0.5 mg/L. ATM and FEP, tested with 8 mg/L of QPX, inhibited 99.8% of isolates at the breakpoint for the BL agent alone. BLI inhibitor combinations PT and CT displayed MIC₉₀ values of 2 and 4 mg/L with the addition of 8 mg/L QPX. MER with QPX at a fixed 4 mg/L and 8 mg/L inhibited 99.8% and 100% of isolates, respectively.

Conclusion:

The activity of all BLs evaluated was restored when combined with QPX tested against this challenging collection of 1,027 ENT isolates displaying various resistance mechanisms, including difficult to treat CRE isolates and MBL producers. Further development of QPX with various orally- and IV-available BL agents appears warranted. Table