Abstract
Background. CSE is a novel combination of ceftriaxone, sulbactam, and disodium ethylenediaminetetraacetic acid (EDTA) with activity against multidrug-resistant Gram-negative pathogens. Methods. Adult patients aged =18 years with a diagnosis of complicated urinary tract infections (cUTIs), including acute pyelonephritis (AP), were 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. 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%. Results. Of 230 randomized patients, 74 of 143 and 69 of 143 were treated with CSE and meropenem, respectively. Of these, 98% were ceftriaxone nonsusceptible and 83% were ESBL-positive at baseline. Noninferiority of CSE to meropenem was demonstrated for both the US Food and Drug Administration-defined coprimary endpoints of (1) symptomatic resolution at test-of-cure (71 of 74 [95.9%] patients vs 62 of 69 [89.9%]; treatment difference, 6%; 95% confidence interval [CI] -2.6% to 16%) and (2) symptomatic resolution as well as microbiological eradication at test-of-cure (70 of 74 [94.6%] vs 60 of 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 of 74 (94.6%) vs 61 of 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.