Data from a phase 3 clinical trial published yesterday in the New England Journal of Medicine indicate that an oral carbapenem antibiotic may be an option for treating complicated urinary tract infections (cUTIs) caused by multidrug-resistant bacteria.
The results of the trial, which were initially announced in September 2020, showed that, in more than 1,300 patients hospitalized with cUTIs or acute pyelonephritis (a type of kidney infection), 7 to 10 days of oral tebipenem pivoxil hydrobromide (HBr) was non-inferior to 7 to 10 days of intravenous (IV) ertapenem, with a similar safety profile.
The investigators say that, with currently available oral antibiotics for cUTIs limited by escalating antibiotic resistance, safety issues, and poor tissue penetration, tebipenem HBr could fill the need for effective oral treatment options.
Similar response at test-of-cure
In the double-blind, randomized trial, conducted at 95 hospitals in 15 countries from June 2019 through May 2020 and designed by Spero Therapeutics (maker of the drug candidate), 1,372 patients were assigned to receive oral tebipenem HBr (at a dose of 600 milligrams every 8 hours) or IV ertapenem (1 gram every 24 hours) for 7 to 10 days.
The primary efficacy end point was overall response (a composite of clinical cure and favorable microbiologic response) at a test-of-cure visit (day 19) in the microbiologic intention-to-treat (ITT) population. The non-inferiority margin was 12.5%.
A total of 868 patients (mean age 58.1 years) were included in the microbiologic ITT population. Of these patients, 50.8% had a cUTI and 49.2% had acute pyelonephritis, with 24.3% infected with uropathogens that met the phenotypic criteria for extended-spectrum beta-lactamase (ESBL)-producing uropathogens, 39% with fluoroquinolone-nonsusceptible uropathogens, and 43% with uropathogens resistant to trimethoprim-sulfamethoxazole.
Overall response at test-of-cure was seen in 264 of 449 patients (58.8%) who received tebipenem HBr, compared with 258 of 419 patients (61.6%) who received IV ertapenem (weighted difference, –3.3 percentage points; 95% confidence interval [CI], –9.7 to 3.2). Overall response at the end-of-treatment visit was 97.5% in the tebipenem HBr group and 94.5% in the ertapenem group.
Clinical cure was observed in 90% or more of the patients in both treatment groups at both the test-of-cure and end-of-treatment visits and was sustained in follow-up. Secondary and sub-group analyses, including in groups with more severe disease, were consistent with the primary analysis.
The overall incidence of adverse events was 25.7% in the patients who received tebipenem HBr and 25.6% in those who received ertapenem, with diarrhea, headache, and nausea the most commonly reported events. Serious adverse events were infrequent in both groups (1.3% for tebipenem HBr patients vs 1.7% for IV ertapenem patients).
The investigators also found that tebipenem HBr did not lead to a greater risk of post-treatment enteric colonization with carbapenem-resistant Enterobacterales than ertapenem.
"In the absence of other effective oral agents, tebipenem pivoxil hydrobromide may provide an option for the treatment of complicated urinary tract infection and acute pyelonephritis due to antibiotic-resistant uropathogens," the study authors wrote.
The US Food and Drug Administration (FDA) is currently reviewing a New Drug Application from Spero seeking approval of the drug for cUTIs caused by certain microorganisms in adult patients who have limited oral treatment options. The FDA has assigned a Prescription Drug User Fee Act target date of Jun 27. If approved, it would be the first oral carbapenem to receive marketing approval in the United States.
