Results of a Phase 3 randomized clinical trial (RCT) suggest that a combination carbapenem/beta-lactamase inhibitor may have potential in treatment of severe drug-resistant gram-negative urinary tract infections (UTI).
Results of a Phase 3 randomized clinical trial (RCT) suggest that a combination carbapenem/beta-lactamase inhibitor may have potential in treatment of severe drug-resistant gram-negative urinary tract infections (UTI). The findings were published in JAMA.
The multicenter, international trial, known as TANGO, enrolled patients aged 18 or older with complicated UTI who were stratified by infection type and geographic region. The research was conducted from November 2014 to April 2016 in the United States and 8 other countries.
A total of 274 patients were randomized to meropenem-vaborbactam (2g/2g over 3 hours) and 276 to piperacillin-tazobactam (4 g/0.5g over 30 minutes) every 8 hours. After 15 or more doses, patients could be switched to oral levofloxacin if they met prespecified criteria for improvement, for a total of 10 days of treatment.
Meropenem-vaborbactam has in vitro activity against nearly 99% of Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae. It is US Food and Drug Administration (FDA)-approved for treatment of adults with complicated UTIs including pyelonephritis.
The trial included endpoints for both FDA and European Medicines Agency (EMA) criteria. The primary FDA endpoint was clinical cure or improvement and microbial eradication composite of intravenous treatment in the intent-to-treat (ITT) population. For EMA, it was microbial eradication at test-of-cure visit in the microbiologic modified ITT and microbiologic evaluable populations. The prespecified noninferiority margin was -15% and 2-sided confidence intervals (Cis) were calculated because the protocol specified superiority testing in the event of noninferiority.
Of the 550 patients randomized, 545 received the study drug, 361 of whom (66.2%) were women. The primary FDA endpoint was met in 189 of 192 (98.4%) of patients who received meropenem-vaborbactam versus 171 of 182 (94.0%) of those who received piperacillin-taxobactam (95% CI, 0.7% to 9.1%; P < .001 for noninferiority). The EMA endpoint was met in 128 of 192 (66.7%) of patients who received meropenem-vaborbactam versus 105 of 182 (57.7%) who received piperacillin-tazobactam (95% CI; -0.9% to 18.7%; P <.001 for noninferiority). In 118 of 178 of those who received meropenem-vaborbactam, microbial eradication occurred versus 102 of 169 (60.4%) patients who received piperacillin-taxobactam (95% CI, -4.2% to 16.0%; P < .001).
Thirty-nine percent of patients who took meropenem-vaborbactam experienced adverse events versus 35% of those who took piperacillin-tazobactam.
Meropenem-vaborbactam, the authors concluded, “resulted in a composite outcome of complete resolution or improvement of symptoms along with microbial eradication that met the noninferiority criterion.” They said more research is needed to understand for which patients meropenem-vaborbactam offers a clinical advantage.