1959. Ceftriaxone-Sulbactam-EDTA (CSE) vs. Meropenem (MR) in PLEA (a Phase 3, Randomized, Double-Blind Trial): Outcomes in Patients Infected With Ceftriaxone Non-Susceptible, Extended-Spectrum β-Lactamase and Multi-Drug-resistant Pathogens at Baseline

Abstract

BackgroundCSE, a novel combination of Ceftriaxone, Sulbactam and Disodium EDTA (Class 1 Antibiotic Resistance Breaker), is being developed for the treatment of patients with serious Gram-negative infections and has completed a Phase-3 clinical trial (NCT03477422) for treatment of complicated urinary tract infections (cUTI), including acute pyelonephritis (AP). It restores and enhances the in vitro activity of Ceftriaxone against various β-lactamases (BLs), including enzyme families that belong to Ambler class A (TEM, SHV, CTX-M), class B (NDM, VIM, IMP), class C (some variants of AmpC), and class D {OXA extended spectrum BLs (ESBLs)}. This analysis was performed to assess the clinical and microbiological outcomes in patients infected with Ceftriaxone non-susceptible (C-NS), MDR and ESBL-producing Gram-negative pathogens at baseline.MethodsPatients were randomized 1:1 to receive either CSE (1g Ceftriaxone/500 mg Sulbactam/37 mg EDTA) every 12 hours or Meropenem (MR) 1 g every 8 hours as 30 minutes IV infusion for 5–14 days. Oral step-down therapy was not allowed. Biological specimens were analyzed, and resistant pathogens identified. MDR was defined as resistance to at least three categories of antimicrobials. Identification of pathogens and antibiotic susceptibility testing were performed and interpreted according to Clinical and Laboratory Standards Institute methodologies. Combined Disc Diffusion Test was used to detect ESBL-production in pathogens.ResultsOf 230 randomized patients, 143 (62.2%) were included in m-MITT [72/74 (97.3) in CSE and 68/69 (98.6%) in MR groups had C-NS pathogens; 63/74 (85.1%) in CSE and 56/69 (81.2%) in MR groups had ESBL-producing pathogens; 55/74 (74.3%) in CSE and 45/69 (65.2%) in MR group had MDR pathogens]. Mean duration of IV therapy was 7 days. The clinical cure and microbiological eradication rates for CSE and MR at the test of cure (TOC) visit in C-NS, ESBL and MDR pathogens is shown in Figures 1, 2, and 3, respectively. ConclusionAt TOC, clinical cure and microbiological eradication rates were higher for CSE as compared with MR across all three analyses sets. Overall, CSE was effective in the treatment of patients with cUTI and AP caused by resistant Gram-negative pathogens.Disclosures M. A. Mir, Venus Medicine Research Centre: Employee, Salary. S. Chaudhary, Venus Medicine Research Centre: Employee and Shareholder, Salary. M. Chaudhary, Venus Medicine Research Centre: Board Member and Shareholder, Salary. G. Shiekh, Venus Medicine Research Centre: Employee, Salary.