By Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC
Professor of Internal Medicine, Northeast Ohio Medical University, Rootstown, OH
SYNOPSIS: A randomized clinical trial that compared oral tebipenem with intravenous ertapenem in patients with complicated urinary tract infection or acute pyelonephritis found tebipenem to be noninferior in efficacy. The safety profile was similar between the two drugs.
SOURCE: Eckburg PB, Muir L, Critchley IA, et al. Oral tebipenem pivoxil hydrobromide in complicated urinary tract infection. N Engl J Med 2022;386:1327-1338.
There are few oral options for a complicated urinary tract infection (UTI) caused by multidrug-resistant uropathogens. Tebipenem is an orally bioavailable carbapenem with broad-spectrum activity against multidrug-resistant gram-negative pathogens, including fluoroquinolone-resistant and extended spectrum beta-lactamase (ESBL)-producing Enterobacterales. Eckburg and colleagues compared oral tebipenem to intravenous (IV) ertapenem in hospitalized patients with a complicated UTI or acute pyelonephritis.
The study was a Phase III randomized, double-blind, double-dummy, noninferiority clinical trial conducted at 95 sites in Europe, South Africa, and the United States. Patients were included who were at least 18 years of age and hospitalized with a diagnosis of complicated UTI or acute pyelonephritis. Exclusion criteria included having confirmed or suspected infection with a carbapenem-resistant pathogen, a creatinine clearance of 30 mL per minute or less, receipt of more than one dose of a short-acting antibiotic within 72 hours before randomization, septic shock, severe hepatic impairment, pregnancy, immunocompromised status, and hypersensitivity to any beta-lactam antibiotic. The primary end point was overall response (a composite of clinical cure and microbiologic response) in the microbiologic intention-to-treat (ITT) population at the test-of-cure visit. Clinical cure was defined as a complete resolution or clinically significant alleviation of baseline signs and symptoms of complicated UTI or acute pyelonephritis, along with no new symptoms. Microbiologic response was defined as a reduction in the uropathogen level from baseline to < 103 colony forming units (CFU) per milliliter in a post-baseline urine culture, and a negative repeat blood culture if a blood culture was positive at baseline.
Eligible patients were randomly assigned in a 1:1 ratio to receive either tebipenem 600 mg (two 300-mg tablets) orally every eight hours plus a dummy ertapenem infusion every 24 hours, or ertapenem at a dose of 1 g IV over a period of 30 minutes every 24 hours plus dummy tebipenem tablets administered orally every eight hours. Both groups received treatment for seven to 10 days for UTI or pyelonephritis and up to 14 days for bacteremia. A dose adjustment of the tebipenem was made for patients with moderate renal insufficiency (baseline creatinine clearance > 30 mL/min to ≤ 50 mL/min).
There were 868 patients randomized in the microbiologic ITT population, of whom 449 received tebipenem and 419 received ertapenem. Demographic and clinical characteristics were well-balanced between the two groups. The mean age of the patients was 58.1 years, with 46.1% being 65 years of age or older. At the time of enrollment, 50.8% had a complicated UTI and 49.2% had acute pyelonephritis. Furthermore, 11.5% of the patients had bacteremia at enrollment. About 90% of the baseline pathogens were Enterobacterales, mainly Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, and Proteus mirabilis. In the microbiologic ITT population, 24.3% of the patients were infected with pathogens that met phenotypic criteria for ESBL-producing uropathogens, 39% with fluoroquinolone-nonsusceptible uropathogens, and 43% with uropathogens resistant to trimethoprim-sulfamethoxazole.
Compared to ertapenem, tebipenem was noninferior with respect to the primary end point of overall response at the test-of-cure visit (61.6% vs. 58.8%, respectively). The overall response at the end-of-treatment visit was 97.3% in the tebipenem group and 94.5% in the ertapenem group. Both groups had similar safety outcomes. The overall incidence of adverse events was approximately 26%, with diarrhea, headache, and nausea the only events occurring in > 1% of patients in either treatment group. Most of the adverse events were mild or moderate in severity, with only one (0.1%) patient in the tebipenem group having an adverse event that led to discontinuation of the trial drug, compared to eight (1.2%) in the ertapenem group.
COMMENTARY
This randomized Phase III trial showed oral tebipenem to be safe and effective therapy for complicated UTIs and acute pyelonephritis compared to IV ertapenem. Having an oral antibiotic that can treat many UTIs caused by multidrug-resistant uropathogens will be an important advancement. It seems likely that the majority of post-therapy microbiologic persistence, which was evident in the overall response at the test-of-cure visit, represented asymptomatic bacteriuria. Indeed, clinical cure was observed in more than 90% of the patients in both treatment groups and was sustained in follow-up. It also was notable that oral tebipenem was as effective as IV ertapenem across all subgroups, including in patients with more severe disease (i.e., bacteremia). Tebipenem probably will be expensive, so it will be interesting to see how hospital antibiotic stewardship programs and payers respond once it is approved. Pharmacoeconomic analyses will need to be conducted that weigh the benefits of oral therapy (e.g., fewer IV-related complications) against the likely high cost of tebipenem.
The study had a few limitations. Patients were mandated to inpatient hospital stays of seven to 14 days to receive their course of antibiotic therapy, which is unrealistic in terms of standard medical practice for complicated UTIs and pyelonephritis in the United States. Patients were excluded who were immunocompromised or had severe renal impairment, conditions which commonly are encountered in clinical practice. Finally, the observed uropathogens and resistant patterns from the study sites may not be generalizable to other geographic areas.
Adding a new oral option for multidrug-resistant uropathogens to our antibiotic armamentarium is an exciting possibility. However, the Food and Drug Administration has asked for additional data prior to consideration, and the further development of the drug has been halted. Whether tebipenem will clear all the remaining hurdles on its path to approval remains to be seen, along with its price tag.
A randomized clinical trial that compared oral tebipenem with intravenous ertapenem in patients with complicated urinary tract infection or acute pyelonephritis found tebipenem to be noninferior in efficacy. The safety profile was similar between the two drugs.
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