Ceftibuten and ledaborbactam etzadroxil demonstrated no clinically relevant effects on cardiac repolarization or ECG parameters, and concentration-QTc analyses excluded clinically meaningful QTc effects at and above anticipated therapeutic plasma concentrations.
Key Findings
Results
Concentration-QTc analyses found no statistically or clinically meaningful relationship between plasma concentrations of ceftibuten or ledaborbactam etzadroxil and placebo-corrected change from baseline in QTcF (ΔΔQTcF).
Data came from two randomized, single-centre, double-blind, placebo-controlled, phase I dose-escalation studies in healthy adults (NCT04314206 and NCT04243863).
Linear mixed-effects models characterized the relationship between plasma concentrations and ΔΔQTcF.
Neither agent produced clinically relevant changes in ECG parameters.
Results
An effect on ΔΔQTcF exceeding the 10 ms regulatory threshold could be excluded up to specified plasma concentrations for each ceftibuten isomer, ledaborbactam, and ledaborbactam etzadroxil.
Cis-ceftibuten (the predominant and more potent isomer): up to 44 µg/mL.
Trans-ceftibuten: up to 2.2 µg/mL.
Ledaborbactam (active drug): up to 30.3 µg/mL.
Ledaborbactam etzadroxil (prodrug): up to 2.6 µg/mL.
Results
Ceftibuten was associated with a small, transient, not clinically relevant increase in heart rate.
The heart rate increase was described as small and transient.
It was judged not clinically relevant.
Results
Ledaborbactam etzadroxil had no clinically meaningful effect on heart rate.
This was assessed in the ledaborbactam etzadroxil dose-escalation study alongside other ECG parameters.
No clinically relevant ECG changes were observed.
Methods
The two phase I studies enrolled 84 healthy adults in total, with active drug and placebo groups.
Both were dose-escalation designs with ECG and pharmacokinetic data.
Conclusions
The findings support the cardiac safety profile of the oral fixed-dose combination of ceftibuten and ledaborbactam etzadroxil.
The combination is being developed for complicated urinary tract infections caused by multidrug-resistant Enterobacterales.
Clinically meaningful QTc effects were excluded at and above anticipated therapeutic plasma concentrations.
What This Means
This research looked at whether two antibiotic components, ceftibuten and ledaborbactam etzadroxil, affect the heart's electrical recharging time, measured as the QT interval on an ECG. Some drugs lengthen this interval, which can raise the risk of dangerous heart rhythms, so regulators require it to be checked. The two drugs are being developed together as a pill for complicated urinary tract infections caused by multidrug-resistant bacteria.
The researchers analysed data from two early-phase studies in healthy adults: 36 people in the ceftibuten study and 48 in the ledaborbactam etzadroxil study, with some in each receiving placebo. They tested whether higher drug levels in the blood were linked to changes in QTc. They found no meaningful relationship, and they could rule out a QTc effect greater than 10 ms (the regulatory concern threshold) across the drug concentrations studied, which covered expected therapeutic levels. Ceftibuten caused a small, short-lived rise in heart rate that was not considered clinically relevant, while ledaborbactam etzadroxil did not meaningfully change heart rate.
This research suggests that these drugs are unlikely to cause QT-related heart problems at expected treatment levels. The studies were in healthy volunteers, so the results do not directly address people with existing heart conditions or other risk factors.
Darpo B, Xue H, Hamed K, Litherland K, Engelhardt M, Lowe K, et al.. (2026). No clinically relevant QTc prolongation with ceftibuten or ledaborbactam etzadroxil: concentration-QTc analyses from two phase I studies.. The Journal of antimicrobial chemotherapy. https://doi.org/10.1093/jac/dkag365