Noninferiority of Ceftriaxone, Sulbactam, and Disodium EDTA to Meropenem in Complicated UTIs

Table of Content

Introduction

Urinary tract infections (UTIs) represent a significant proportion of multidrug resistant bacterial (MDR) infections across the world. Extended-spectrum β-lactamase-producing organisms exhibit cross-resistance to many other classes of antibiotics, hence limiting the therapeutic options to treat such infections. Carbapenems, being structurally stable against ESBL enzymes, are considered to have a very vital place in the therapeutic regimen for these MDR infections. However, the rise of carbapenem-resistant bacteria over the past decade has undermined the effectiveness of carbapenems in treating such drug-resistant infections. CSE was approved in India based on a phase 3 multiple indication trial assessing efficacy and safety of CSE versus ceftriaxone for the treatment of various bacterial infections, including complicated UTIs.

Aim

The preserving life of existing antibiotics (PLEA) clinical study evaluated the noninferiority of CSE vs meropenem in adults with cUTIs including acute pyelonephritis (AP).

Methods

Study Design

  • Phase 3, prospective, randomized, multicenter, double-blind, double-dummy, parallel-group, noninferiority trial
  • Conducted in accordance with the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidance for cUTI trials and good clinical practice guidelines and reported in accordance with CONSORT 2010 recommendations 

Patient Profile

Inclusion Criteria

  • Patients aged >18 years with clinically suspected cUTI caused by Gram-negative pathogens
  • Patients with UTIs in men with a documented history of chronic urinary retention, or UTI associated with obstruction, foreign bodies, recent urinary instrumentation, or urologic abnormalities

Exclusion Criteria

Patients with-

  • Perinephritic abscess or renal corticomedullary abscess
  • Polycystic kidney disease
  • Only 1 functional kidney
  • Chronic vesicoureteral reflux
  • Uncomplicated UTI
  • Creatinine clearance ≤30 mL/minutes

Treatment Strategy

  • Cohort was randomized 1:1 to receive either intravenous CSE (1000 mg ceftriaxone/500 mg sulbactam/37 mg disodium EDTA) every 12 hours or intravenous meropenem (1000 mg) every 8 hours for up to 14 days.
  • Clinical and microbiological outcomes were evaluated at the end of treatment (EOT) i.e. 5–14 days postrandomization), test-of-cure (TOC) 8–12 days post-EOT and late follow-up (LFU) 5–9 days post-TOC). 
  • 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%.

Endpoints

Primary Endpoints

  • The FDA coprimary endpoints were
    • The proportion of patients with clinical cure at TOC in the microbiologic modified intent-to-treat (mMITT) population
    • The proportion of patients with clinical cure and microbiological eradication at TOC in the mMITT population.
  • The EMA primary endpoint was microbiological eradication at TOC in the mMITT population

Secondary Endpoints

  • Per-patient and per-pathogen clinical and microbiological response at EOT and LFU
  • Per-patient and per-pathogen clinical and microbiological response at EOT, TOC, and LFU in patients infected with an ESBL-producing pathogen. 

Results

  • A total of 230 patients were randomized
  • The mMITT population comprised 143 patients; out of which 63.6% had cUTIs and 36.4% had AP
  • 74 of 143 and 69 of 143 were treated with CSE and meropenem, respectively.
  • At baseline, 98% were ceftriaxone nonsusceptible and 83% were ESBL-positive
  • The summary of primary endpoints is shown in figure 1.
Figure 1. Summary of primary endpoints at TOC visit

  • Noninferiority of CSE to meropenem was demonstrated for both the US FDA-defined coprimary endpoints as well as EMA primary endpoint
  • The secondary endpoints were also comparable between the 2 treatment arms at the EOT
  • The results revealed noninferiority of CSE to meropenem at the −10% noninferiority margin.
  • The incidence of adverse events (AEs) was 11.3% in the CSE group as compared to 12.5% in the meropenem group
  • The most common AEs reported were general weakness, thrombophlebitis, phlebitis  gastritis, and vomiting
  • Safety profile of CSE was consistent with that of ceftriaxone alone.

Conclusion

  • This study demonstrated the noninferiority of the novel combination of ceftriaxone, sulbactam, and disodium ethylenediaminetetraacetic acid (CSE) to meropenem in patients with complicated urinary tract infections (cUTIs) including acute pyelonephritis
  • CSE might be a potential alternative to carbapenems in patients with cUTIs including the infections caused by extended spectrum β lactamase producing gram-negative microorganisms.

Open Forum Infect Dis. 2019;6(10). Doi:10.1093/ofid/ofz373.