Clinical Pearls & Morning Reports
Published April 6, 2022
There is a need for effective oral treatment options for patients with complicated urinary tract infection or acute pyelonephritis due to antimicrobial-resistant pathogens. Eckburg et al. evaluated oral tebipenem pivoxil hydrobromide as compared with intravenous ertapenem in hospitalized patients with complicated urinary tract infection or acute pyelonephritis. Read the NEJM Original Article here.
Q: How common is resistance to carbapenems?
A: Antimicrobial resistance is escalating worldwide, particularly among the common gram-negative pathogens that cause complicated urinary tract infection and acute pyelonephritis. Despite these increases, antimicrobial resistance to carbapenems remains low (<2%). The use of available oral agents is also limited by safety warnings (e.g., fluoroquinolones) or poor tissue penetration (e.g., nitrofurantoin and fosfomycin) that may predispose patients to treatment failure and selection of bacterial resistance.
Q: What is tebipenem pivoxil hydrobromide?
A: Tebipenem pivoxil hydrobromide is an orally bioavailable carbapenem prodrug that is rapidly converted to the active moiety, tebipenem, by enterocytes. Tebipenem has broad-spectrum activity against multidrug-resistant gram-negative pathogens, including fluoroquinolone-resistant and extended-spectrum beta-lactamase-producing Enterobacterales. Tebipenem pivoxil hydrobromide has shown in vivo efficacy in animal models of soft-tissue, pulmonary, and urinary tract infections.
A: Oral tebipenem pivoxil hydrobromide was noninferior to intravenous ertapenem with respect to the primary end point of overall response (a composite of clinical cure and microbiologic response) in the microbiologic intention-to-treat population at the test-of-cure visit (58.8% and 61.6% of the patients, respectively; weighted difference, −3.3 percentage points; 95% confidence interval [CI], −9.7 to 3.2). Overall response at the end-of-treatment visit was 97.3% in the tebipenem pivoxil hydrobromide group and 94.5% in the ertapenem group. Across all the subgroups, prespecified analysis of overall response at the test-of-cure visit according to baseline characteristics was consistent with the results of the primary analysis. Clinical cure (defined as the complete resolution or clinically significant improvement of baseline signs and symptoms, as well as no new symptoms) was observed at the test-of-cure visit in 93.1% of the patients in the tebipenem pivoxil hydrobromide group and in 93.6% of the patients in the ertapenem group (weighted difference, −0.6 percentage points; 95% CI, −4.0 to 2.8).
A: Potential limitations of the trial include the mandated inpatient 7-to-10-day course of antibiotic therapy (up to 14 days for patients with bacteremia), since this may not directly reflect the standard of care for complicated urinary tract infection or acute pyelonephritis in the United States. Patients were excluded for immunocompromise, severe renal impairment, and confirmed or suspected carbapenem-resistant pathogens. Trial sites were located in the United States, South Africa, and Europe (the latter to enrich for resistant pathogens); most patients were enrolled from Central and Eastern Europe, and most were White. Although the pathophysiology of complicated urinary tract infection or acute pyelonephritis and predominant pathogens is generally consistent around the world, the specific strains and resistance mechanisms that were observed in this trial may differ from those observed in other regions.