Pivotal phase III trial shows Tx potential of oral carbapenem for cUTI or acute pyelonephritis

Results from the phase III PIVOT-PO study demonstrate the potential of tebipenem pivoxil hydrobromide (TBP-PI) as an effective oral carbapenem antibiotic for the treatment of complicated urinary tract infections (cUTI).

“Oral TBP-PI was noninferior to IV imipenem-cilastatin (IMI-CIL) for the treatment of cUTI, including acute pyelonephritis (AP),” said presenting author Dr David Hong from Spero Therapeutics, Cambridge, Massachusetts, US, at IDWeek 2025.

In the microbiological intent-to-treat population, the overall response rates at test-of-cure (ToC) were comparable between the TBP-PI and IMI-CIL groups (58.5 percent vs 60.2 percent; treatment difference, -1.3 percent, 95 percent confidence interval [CI], -7.5 to 4.8). Overall response at ToC had two components: Clinical cure* and microbiological eradication**.

“The lower bound of the 95 percent CI was above the 10 percent noninferiority margin. This translated to a noninferiority p-value of 0.003,” said Hong.

The clinical and microbiological response rates remained high at end-of-treatment (EoT; >90 percent), with no significant differences between groups, Hong noted.

Looking at the drug-resistant phenotypes (ESBL+, FQ-NS, TMP-SMX-R, MDR***), the overall response for ESBL+ aligned with the primary analysis (52.2 percent [TBP-PI] vs 56.8 percent [IMI-CIL]). The between-group difference of -4.7 percent fell short of statistical significance.

“Even among participants with microbiological persistence, they achieved clinical cure at all timepoints. This was consistent across drug-resistant phenotypes of clinical importance, including ESBL-producing Enterobacterales,” Hong explained.

The safety profile of TBP-PI was comparable to that of IMI-CIL, with the most common treatment-emergent adverse events (TEAEs) being diarrhoea (8.1 percent vs 2.7 percent) and headache (3 percent vs 3.4 percent). There were low incidences of TEAEs leading to study withdrawal, drug discontinuation, or death (<1 percent for all). [IDWeek 2025, abstract 173]

Antimicrobial resistance a challenge

cUTIs are frequently caused by MDR pathogens and carry serious risks, including organ failure, sepsis, and even death. [https://www.ncbi.nlm.nih.gov/books/NBK436013, accessed November 19, 2025; BMJ Open 2018;8:e020251; Infect Drug Resist 2023:16:1391-1405] The current standard of care for cUTIs includes carbapenem antibiotics in cases of sepsis or resistance to other antibiotics.

“[However,] effective oral treatment alternatives for cUTI are becoming increasingly limited due to rising antimicrobial resistance. As a result, many patients need to be admitted to the hospital or given IV antibiotics, which are associated with complications and higher costs compared with oral therapy. [Hence,] there really is an unmet need for oral treatment options for these infections,” noted Hong.

TBP-PI is an investigational oral carbapenem with activity against antimicrobial-resistant Enterobacterales and select gram-positive pathogens. [Antimicrob Agents Chemother 2020;64:e02240-e022419; Pharmacotherapy 2021;41:748-761]

This global double-blind study included 929 hospitalized patients (mean age 64.4 years, 57.8 percent women) with a clinical diagnosis of cUTI or AP. Approximately two-thirds of participants had cUTI with (22.3 percent) or without AP (43.4 percent), while a third had AP only.

The participants were randomized 1:1 to oral TBP-PI 600 mg or IV IMI-CIL 500 mg Q6H for 7–10 days. The primary efficacy analysis was conducted at the ToC visit, which occurred about 7 days after EoT.

The most common baseline Enterobacterales was Escherichia coli (73.3 percent), followed by Klebsiella pneumoniae (20.1 percent). Thirty-seven percent of participants were ESBL+, and about 50 percent had MDR pathogens.

Insights

“These groundbreaking data show for the first time that cUTIs, including AP, can be treated with an oral carbapenem antibiotic as effectively as with an IV one,” said GSK Chief Scientific Officer Tony Wood in a news release.

“The therapeutic flexibility of a new oral antibiotic may reduce the need for IV antibiotics to treat cUTI, providing benefit to patients and improving treatment options,” commented Dr George Sakoulas from the University of California San Diego School of Medicine in the US, who was not involved in the study.