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.

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.