Dataset Information

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)

ABSTRACT: Abstract

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 (Mg2+) 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. ?-Lactamase (BL) genes were amplified in single PCRs using a panel of primers for detection of most ?-lactamase enzymes, including extended-spectrum ?-lactamases (ESBLs) (blaTEM, blaSHV, blaCTX-M), metallo-?-lactamases (MBLs) (blaVIM, blaNDM, blaIMP), carbapenemases (blaOXA, blaKPC) and class C cephalosporinases (blaAmpC).

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 (blaTEM + blaSHV + blaCTX-M + blaAmpC) at baseline, and had acquired two additional genes (blaOXA, blaKPC), 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.

SUBMITTER: Mir M

PROVIDER: S-EPMC6253802 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Project description:Abstract Background CSE, 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. Methods Patients 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. Results Of 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. Conclusion At 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.

Project description:Abstract Background Ceftriaxone–Sulbactam–EDTA (CSE) is the first cephalosporin–β-lactamase inhibitor combination with an antibiotic resistance breaker–disodium edetate, recently evaluated in a Phase 3 clinical trial for treatment of adults with complicated urinary tract infections (NCT03477422). The addition of Sulbactam and EDTA expands the spectrum of activity of Ceftriaxone to include extended-spectrum-β-lactamase (ESBL) and metallo-β-lactamase (MBL) producing bacteria. This study evaluated the in vitro activity of CSE against 3,150 isolates (716 (22.73%) E. coli; 435 (13.81%) K. pneumoniae; 1,075 (34.13%) A. baumannii; 924 (29.33%) P. aeruginosa) collected from 22 hospitals in India during 2013–2016. Methods A total of 3,150 nonduplicate Gram-negative clinical isolates were collected, and susceptibility testing was conducted using reference broth microdilution method for CSE and comparators. CLSI defined phenotypic methods were used for ESBL and MBL detection, and thereafter, all isolates were further characterized genotypically using single PCRs and a panel of primers for detection of most β-lactamase enzymes, including blaTEM, blaSHV, blaCTX-M, blaAmpC, blaOXA, blaKPC, blaVIM, blaNDM, and blaIMP. Results Of the 3,150 isolates, 2,717 (86.25%) were β-lactamase producers, of which, 851 (31.32%) tested positive for ESBL, 1,591 (58.56%) tested positive for MBL, while 275 (10.12%) tested positive for both ESBL and MBL production during phenotypic evaluation. Once the genotype data were available, isolates were re-characterized as per the functional classification of β-lactamases into four distinct categories, including ESBL, AmpC, Carbapenemase and MBL. An astonishing 1,866 (59.23%) isolates harbored at least one MBL gene, of which, the prevalence was the highest in A. baumannii (78.6%), followed by K. pneumoniae (63%), P. aeruginosa (46.6%) and E. coli (44.1%). A summary of the results of susceptibility testing is shown in Figures 1, 2, and 3. Conclusion CSE showed a high overall susceptibility in ESBL- and MBL-producing bacteria and could provide a useful alternative to carbapenems and colistin in clinical settings. Disclosures R. Girotra, Venus Medicine Research Centre: Employee, Salary. A. Pyasi, Venus Medicine Research Centre: Employee, Salary. M. Chaudhary, Venus Medicine Research Centre: Board Member and Shareholder, Salary. M. A. Mir, Venus Medicine Research Centre: Employee, Salary. S. Chaudhary, Venus Medicine Research Centre: Employee and Shareholder, Salary. P. Mandale, Venus Medicine Research Centre: Employee, Salary.