From Pages to Practice
Mrs. Smith is a 61-year-old woman with a history of recurrent urinary tract infections (UTIs). She reported the onset of dysuria and hematuria a few days ago and thought the symptoms felt similar to prior UTI episodes. She promptly made an appointment to see her primary care doctor the next day, however, the following morning, she woke up with fevers and back pain and is now admitted to the hospital for pyelonephritis. After review of her microbiologic data, she was initiated on intravenous meropenem. A urine culture the next day noted ESBL-producing Escherichia coli. She says she finds having an IV in for too long uncomfortable and asks if an oral medication is available to treat her infection.
Although UTIs and pyelonephritis remain common, with a growing number of infections attributable to drug-resistant pathogens, oral treatment options are limited. Often, patients are admitted to the hospital for IV administration of carbapenem therapy. Unfortunately, maintaining IV access places patients at risk of infection and is inconvenient for patients. As such, oral treatment options would be valuable additions to the armamentarium for certain patients.
Tebipenem pivoxil hydrobromide is an orally bioavailable carbapenem that has been shown to have broad-spectrum activity against multidrug-resistant gram-negative pathogens in animal models. In a recently published phase 3, international, double-blinded noninferiority trial published in NEJM, researchers randomized 1372 hospitalized adults with complicated UTIs or acute pyelonephritis to receive oral tebipenem pivoxil hydrobromide or IV ertapenem. Immunocompromised patients and those with severe renal dysfunction and infections due to carbapenem-resistant organisms were excluded. The primary end point was overall response, including clinical cure and microbiologic response. The results indicated that oral tebipenem pivoxil hydrobromide was noninferior to IV ertapenem in the treatment of complicated UTI and had a similar safety profile.
Overall, this trial may represent a leap forward in broadening the options for treatment of UTIs due to drug-resistant gram-negative bacteria to include an oral carbapenem. For Mrs. Smith, in the absence of immunocompromise or significant renal impairment, tebipenem pivoxil hydrobromide may be a good alternative to IV-administered carbapenem.
The following NEJM Journal Watch summary provides more details of the study:
Hana M. El Sahly, MD, reviewing Eckburg PB et al. N Engl J Med 2022 Apr 7
Drug-resistant Enterobacterales — for which parenteral drugs are the only treatment options — cause increased burden on patients and healthcare systems alike. Tebipenem is an orally bioavailable carbapenem with an activity spectrum comparable to ertapenem. In a placebo-controlled, blinded study, investigators randomized 1372 patients hospitalized with complicated urinary tract infections (UTIs) or pyelonephritis (mean age, 58; 58% female, 24% positive for extended-spectrum β-lactamase–producing Enterobacterales) to receive oral tebipenem (600 mg every 8 hours) or intravenous ertapenem (1 g every 24 hours). The primary endpoint was a composite of clinical cure and microbiologic response (defined as reduction of bacterial count to <103 CFU/mL in a urine culture) at 19 days after treatment initiation.
The primary endpoint occurred at comparable frequencies between the tebipenem and ertapenem groups (58.8% and 61.6%, respectively), as did clinical improvement at Day 5 (74.8% and 76.6%), Day 19 (93.1% and 93.6%), and at late follow-up (88.6% and 90.0%). Rates of adverse events leading to discontinuation were 0.1% (tebipenem) and 1.2% (ertapenem). Post-enrollment enteric colonization with carbapenem-resistant Enterobacterales occurred in 1.9% and 3.1% of the tebipenem and ertapenem groups.
Comment: These data demonstrate that tebipenem is safe and effective in patients with complicated UTIs. The relatively low frequency of the primary endpoint in both study groups was a function of asymptomatic bacteriuria at Day 19. Study limitations include exclusion of septic or immunocompromised patients. Having an oral carbapenem in the antibiotic repertoire represents a milestone; however, it raises a concern regarding misuse of this antibiotic in asymptomatic bacteriuria or other instances where alternative or no antibiotics are preferred, which may in turn have deleterious effects on the utility of the carbapenem class as a whole. We'll need creative antibiotic stewardship plans whenever this promising drug reaches the market.