1984. Ceftriaxone-Sulbactam-EDTA vs. Meropenem: Analysis of Failed Patients With Assessment of MIC Increases and Changes in Genotypic Profile in PLEA (a Phase 3, Randomized, Double-Blind Clinical Trial in Adults With Complicated Urinary Tract Infections or Acute Pyelonephritis)

BACKGROUND: Ceftriaxone–sulbactam–EDTA (CSE) is a novel combination being developed to treat serious infections caused by Gram-negative bacteria. In vitro molecular biology studies have shown that the addition of EDTA in the combination helps to prevent horizontal gene transfer during conjugation by chelating the divalent magnesium ions (Mg(2+)) required for the activity of DNA relaxases enzyme. An assessment of acquisition of resistant genes and a concomitant increase in MIC for patients that failed therapy in the Phase 3 clinical trial (NCT03477422) was conducted. METHODS: MICs were conducted on baseline and post-treatment isolates recovered during treatment period. MICs were determined using CLSI reference methods and MIC changes from baseline were further assessed. Bacterial DNA was extracted by the alkaline lysis method. β-Lactamase (BL) genes were amplified in single PCRs using a panel of primers for detection of most β-lactamase enzymes, including extended-spectrum β-lactamases (ESBLs) (bla(TEM), bla(SHV), bla(CTX-M)), metallo-β-lactamases (MBLs) (bla(VIM), bla(NDM), bla(IMP)), carbapenemases (bla(OXA), bla(KPC)) and class C cephalosporinases (bla(AmpC)). RESULTS: Nine of 143 [2/74 (2.7%) in CSE; 7/69 (10.1%) in MR (meropenem)] patients had a microbiological failure at the TOC visit. Of these nine patients (all E. coli), a variation in the post-treatment genotypic profile was noted for four patients (44.4%) in the MR group and two of these patients also reported a ≥4-fold increase in post-treatment MIC. Both patients harbored four distinct BL genes (bla(TEM) + bla(SHV) + bla(CTX-M) + bla(AmpC)) at baseline, and had acquired two additional genes (bla(OXA), bla(KPC)), both carbapenemases, as a result of treatment failure (after 6 days and 8 days of IV therapy respectively) with MR. In the first case, MIC increased 16-fold (1 µg/mL to 16 µg/mL for MR and 2 µg/mL to 32 µg/mL for CSE), while in the second case, MIC increased 8-fold (1 µg/mL to 8 µg/mL) for MR and 32-fold (1 µg/mL to 32 µg/mL) for CSE. No such increase in MIC or acquisition of resistant genes was noted in patients that failed therapy with CSE. CONCLUSION: These findings highlight the need for an effective choice of empirical therapy as failed treatments could lead to selection for resistant genes, rendering once susceptible drug non-susceptible. 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. A. Pyasi, Venus Medicine Research Centre: Employee, Salary. R. Girotra, Venus Medicine Research Centre: Employee, Salary.