tebipenem and Urinary-Tract-Infections

There is a need for oral antibiotic agents that are effective against multidrug-resistant gram-negative uropathogens. Tebipenem pivoxil hydrobromide is an orally bioavailable carbapenem with activity against uropathogenic Enterobacterales, including extended-spectrum beta-lactamase-producing and fluoroquinolone-resistant strains.. In this phase 3, international, double-blind, double-dummy trial, we evaluated the efficacy and safety of orally administered tebipenem pivoxil hydrobromide as compared with intravenous ertapenem in patients with complicated urinary tract infection or acute pyelonephritis. Patients were randomly assigned, in a 1:1 ratio, to receive oral tebipenem pivoxil hydrobromide (at a dose of 600 mg every 8 hours) or intravenous ertapenem (at a dose of 1 g every 24 hours) for 7 to 10 days (or up to 14 days in patients with bacteremia). The primary efficacy end point was overall response (a composite of clinical cure and favorable microbiologic response) at a test-of-cure visit (on day 19, within a ±2-day window) in the microbiologic intention-to-treat population. The noninferiority margin was 12.5%.. A total of 1372 hospitalized adult patients were enrolled; 868 patients (63.3%) were included in the microbiologic intention-to-treat population (50.8% of whom had complicated urinary tract infections and 49.2% of whom had pyelonephritis). An overall response was seen in 264 of 449 patients (58.8%) who received tebipenem pivoxil hydrobromide, as compared with 258 of 419 patients (61.6%) who received ertapenem (weighted difference, -3.3 percentage points; 95% confidence interval [CI], -9.7 to 3.2). Clinical cure at the test-of-cure visit was observed in 93.1% of the patients in the microbiologic intention-to-treat population who received tebipenem pivoxil hydrobromide and 93.6% of patients who received ertapenem (weighted difference, -0.6 percentage point; 95% CI, -4.0 to 2.8); the majority of patients with microbiologic response failures at the test-of-cure visit were asymptomatic patients with recurrent bacteriuria. Secondary and subgroup analyses were supportive of the primary analysis. Adverse events were observed in 25.7% of patients who received tebipenem pivoxil hydrobromide and in 25.6% of patients who received ertapenem; the most common adverse events were mild diarrhea and headache.. Oral tebipenem pivoxil hydrobromide was noninferior to intravenous ertapenem in the treatment of complicated urinary tract infection and acute pyelonephritis and had a similar safety profile. (Funded by Spero Therapeutics and the Department of Health and Human Services; ADAPT-PO ClinicalTrials.gov number, NCT03788967.).

Topics: Administration, Intravenous; Administration, Oral; Adult; Anti-Bacterial Agents; Carbapenems; Double-Blind Method; Drug Resistance, Multiple, Bacterial; Ertapenem; Humans; Pyelonephritis; Urinary Tract Infections

Topics: Administration, Oral; Anti-Bacterial Agents; Carbapenems; Humans; Monobactams; Prodrugs; Pyelonephritis; Urinary Tract Infections

Topics: Carbapenems; Humans; Urinary Tract Infections

This study investigated the activity of an oral carbapenem, tebipenem, against various molecularly characterized subsets of Escherichia coli. A total of 15.0% of E. coli isolates (360/2,035 isolates) met the MIC criteria for screening for β-lactamases. Most of those isolates (74.7% [269/360 isolates]) carried

Topics: Anti-Bacterial Agents; beta-Lactamases; Carbapenems; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Humans; United States; Urinary Tract Infections

The continued evolution of bacterial resistance to the β-lactam class of antibiotics has necessitated countermeasures to ensure continued effectiveness in the treatment of infections caused by bacterial pathogens. One relatively successful approach has been the development of new β-lactam analogs with advantages over prior compounds in this class. The carbapenems are an example of such β-lactam analogs possessing improved stability against β-lactamase enzymes and, therefore, a wider spectrum of activity. However, all carbapenems currently marketed for adult patients are intravenous agents, and there is an unmet need for an oral agent to treat patients that otherwise do not require hospitalization. Tebipenem pivoxil hydrobromide (tebipenem-PI-HBr or SPR994) is an orally available prodrug of tebipenem, a carbapenem with activity versus multidrug-resistant (MDR) Gram-negative pathogens, including quinolone-resistant and extended-spectrum-β-lactamase-producing

Topics: Adult; Animals; Anti-Bacterial Agents; Carbapenems; Humans; Meropenem; Mice; Urinary Tract Infections

Carbapenems are potent antibacterials with broad-spectrum activity. However, poor oral absorption generally confines this important drug class to in-hospital use by intravenous (IV) administration. The continued rise in drug resistant pathogens creates a need for alternative oral therapies with broad-spectrum activity. SPR994 is a novel formulation of the orally bioavailable pivoxil prodrug of SPR859 (tebipenem) and is being developed as the first oral carbapenem for treatment of complicated urinary tract infections (cUTIs) in adults. Herein, we describe characteristics beneficial to oral administration and compare the in vitro and in vivo activity of SPR859 or SPR994 with IV carbapenems.

Topics: Administration, Intravenous; Administration, Oral; Adult; Animals; Anti-Bacterial Agents; Biological Availability; Carbapenems; Disease Models, Animal; Gastrointestinal Microbiome; Gram-Negative Bacteria; Gram-Positive Bacteria; Hospitalization; Humans; Male; Mice; Microbial Sensitivity Tests; Treatment Outcome; Urinary Tract Infections

Tebipenem is the active metabolite of ME1211, tebipenem pivoxil, a novel oral carbapenem that possesses potent activity against almost pathogens except for Pseudomonas aeruginosa. In this study, we compared the susceptibility of tebipenem with current antibiotics against various organisms isolated from various specimen, mainly urinary tract. Tebipenem had a potent activity against Neisseria gonorrhoeae; its activity was comparable to it of cefixime that has most potent activity among oral antibiotics. Against Enterococcus faecalis, the activity of tebipenem was comparable to the activities of ampicillin and amoxicillin, and superior to it of faropenem. Against Citrobacter freundii, Escherichia coli , Klebsiella pneumoniae, and Enterobacter spp. including extended-spectrum beta-lactamase producers, tebipenem had a potent activity with or without ceftazidime-resistance.

Topics: Carbapenems; Citrobacter freundii; Drug Resistance, Bacterial; Enterobacter; Enterococcus faecalis; Escherichia coli; Humans; Klebsiella pneumoniae; Urinary Tract Infections