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CSE (Ceftriaxone+ Sulbactam+ Disodium EDTA) Versus Meropenem for the Treatment of Complicated Urinary Tract Infections, Including Acute Pyelonephritis: PLEA, a Double-Blind, Randomized Noninferiority Trial.

ABSTRACT: BACKGROUND:CSE is a novel combination of ceftriaxone, sulbactam and disodium EDTA with activity against multidrug resistant gram-negative pathogens. METHODS:Adult patients aged ?18 years with a diagnosis of complicated urinary tract infections (cUTI), including acute pyelonephritis (AP), were randomized 1:1 to receive either intravenous CSE (1000mg ceftriaxone/500mg sulbactam/37mg disodium EDTA) every 12h or intravenous meropenem (1000mg) every 8h for up to 14 days. The primary objective was to show the noninferiority of CSE to meropenem at the test-of-cure visit (8-12 days after the end of therapy), with a noninferiority margin of 10 percent. RESULTS:Of 230 randomized patients, 74/143 and 69/143 were treated with CSE and meropenem respectively. Of these, 98% were ceftriaxone non-susceptible and 83% were ESBL-positive at baseline. Noninferiority of CSE to meropenem was demonstrated for both the US Food and Drug Administration defined co-primary endpoints of (1) symptomatic resolution at test-of-cure: 71/74 (95.9%) patients vs 62/69 (89.9%) [treatment difference, 6%; 95% CI, -2.6% to 16%] and (2) both symptomatic resolution and microbiological eradication at test-of-cure: 70/74 (94.6%) vs 60/69 (87.0%) (treatment difference, 7.6%; 95% CI, -2.0% to 18.4%). Microbiological eradication at test-of-cure (European Medical Agency's primary endpoint) was observed in 70/74 (94.6%) vs 61/69 (88.4%) [treatment difference, 6.2%; 95% CI, -3.2% to 16.6%] patients treated with CSE and meropenem respectively. Safety profile of CSE was consistent with that of ceftriaxone alone. CONCLUSIONS:The results support the use of CSE as a carbapenem-sparing treatment for patients suffering from cUTI/AP caused by resistant gram-negative pathogens. CLINICAL TRIAL REGISTRATION NUMBERS:NCT03477422; CTRI/2013/11/004133.

SUBMITTER: Mir MDA

PROVIDER: S-EPMC6767967 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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CSE (Ceftriaxone+ Sulbactam+ Disodium EDTA) Versus Meropenem for the Treatment of Complicated Urinary Tract Infections, Including Acute Pyelonephritis: PLEA, a Double-Blind, Randomized Noninferiority Trial.

Mir M D Amin MDA Chaudhary Saransh S Payasi Anurag A Sood Rajeev R Mavuduru Ravimohan S RS Shameem Mohd M

Open forum infectious diseases 20191001 10

<h4>Background</h4>CSE is a novel combination of ceftriaxone, sulbactam and disodium EDTA with activity against multidrug resistant gram-negative pathogens.<h4>Methods</h4>Adult patients aged ≥18 years with a diagnosis of complicated urinary tract infections (cUTI), including acute pyelonephritis (AP), were randomized 1:1 to receive either intravenous CSE (1000mg ceftriaxone/500mg sulbactam/37mg disodium EDTA) every 12h or intravenous meropenem (1000mg) every 8h for up to 14 days. The primary ob ...[more]

PMID: 31433059

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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 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. 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) (blaTEM, blaSHV, blaCTX-M), metallo-β-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.

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.

Project description:ImportanceChelation therapy with disodium EDTA has been used for more than 50 years to treat atherosclerosis without proof of efficacy.ObjectiveTo determine if an EDTA-based chelation regimen reduces cardiovascular events.Design, setting, and participantsDouble-blind, placebo-controlled, 2 × 2 factorial randomized trial enrolling 1708 patients aged 50 years or older who had experienced a myocardial infarction (MI) at least 6 weeks prior and had serum creatinine levels of 2.0 mg/dL or less. Participants were recruited at 134 US and Canadian sites. Enrollment began in September 2003 and follow-up took place until October 2011 (median, 55 months). Two hundred eighty-nine patients (17% of total; n=115 in the EDTA group and n=174 in the placebo group) withdrew consent during the trial.InterventionsPatients were randomized to receive 40 infusions of a 500-mL chelation solution (3 g of disodium EDTA, 7 g of ascorbate, B vitamins, electrolytes, procaine, and heparin) (n=839) vs placebo (n=869) and an oral vitamin-mineral regimen vs an oral placebo. Infusions were administered weekly for 30 weeks, followed by 10 infusions 2 to 8 weeks apart. Fifteen percent discontinued infusions (n=38 [16%] in the chelation group and n=41 [15%] in the placebo group) because of adverse events.Main outcome measuresThe prespecified primary end point was a composite of total mortality, recurrent MI, stroke, coronary revascularization, or hospitalization for angina. This report describes the intention-to-treat comparison of EDTA chelation vs placebo. To account for multiple interim analyses, the significance threshold required at the final analysis was P = .036.ResultsQualifying previous MIs occurred a median of 4.6 years before enrollment. Median age was 65 years, 18% were female, 9% were nonwhite, and 31% were diabetic. The primary end point occurred in 222 (26%) of the chelation group and 261 (30%) of the placebo group (hazard ratio [HR], 0.82 [95% CI, 0.69-0.99]; P = .035). There was no effect on total mortality (chelation: 87 deaths [10%]; placebo, 93 deaths [11%]; HR, 0.93 [95% CI, 0.70-1.25]; P = .64), but the study was not powered for this comparison. The effect of EDTA chelation on the components of the primary end point other than death was of similar magnitude as its overall effect (MI: chelation, 6%; placebo, 8%; HR, 0.77 [95% CI, 0.54-1.11]; stroke: chelation, 1.2%; placebo, 1.5%; HR, 0.77 [95% CI, 0.34-1.76]; coronary revascularization: chelation, 15%; placebo, 18%; HR, 0.81 [95% CI, 0.64-1.02]; hospitalization for angina: chelation, 1.6%; placebo, 2.1%; HR, 0.72 [95% CI, 0.35-1.47]). Sensitivity analyses examining the effect of patient dropout and treatment adherence did not alter the results.Conclusions and relevanceAmong stable patients with a history of MI, use of an intravenous chelation regimen with disodium EDTA, compared with placebo, modestly reduced the risk of adverse cardiovascular outcomes, many of which were revascularization procedures. These results provide evidence to guide further research but are not sufficient to support the routine use of chelation therapy for treatment of patients who have had an MI.Trial registrationclinicaltrials.gov Identifier: NCT00044213.

Dataset Information

CSE (Ceftriaxone+ Sulbactam+ Disodium EDTA) Versus Meropenem for the Treatment of Complicated Urinary Tract Infections, Including Acute Pyelonephritis: PLEA, a Double-Blind, Randomized Noninferiority Trial.

Publications

CSE (Ceftriaxone+ Sulbactam+ Disodium EDTA) Versus Meropenem for the Treatment of Complicated Urinary Tract Infections, Including Acute Pyelonephritis: PLEA, a Double-Blind, Randomized Noninferiority Trial.

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