701 Views
A1. Novel Agents
Poster Session: Novel Agents
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 blaCTX-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
Jill Lindley
Drug Development Specialist
JMI Laboratories
North Liberty, Iowa, United States
Disclosure: Bravos Biosciences (Research Grant or Support)ContraFect Corporation (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Qpex Biopharma (Research Grant or Support)
Yahse Edah, AS
Microbiologist I
JMI Laboratories
North Liberty, Iowa, United States
Disclosure: Qpex (Research Grant or Support)
Olga Lomovskaya, PhD
VP, Biology
Qpex Biopharma
San Diego, California, United States
Disclosure: Qpex Biopharma (Employee)
Mariana Castanheira, PhD
Chief Scientific Officer
JMI Laboratories
North Liberty, Iowa, United States
Disclosure: AbbVie (formerly Allergan) (Research Grant or Support)Bravos Biosciences (Research Grant or Support)Cidara Therapeutics, Inc. (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, LLC (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Qpex Biopharma (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support)