ABSTRACT

The worldwide increase in antimicrobial resistance (AMR) among uropathogens has reduced the reliability of several conventional oral antibiotics, particularly fluoroquinolones and β-lactams. Gepotidacin is a first-in-class triazaacenaphthylene antibacterial agent that inhibits bacterial DNA replication through a mechanism distinct from that of fluoroquinolones. In contrast to fluoroquinolones, gepotidacin binds to distinct locations on bacterial DNA gyrase and topoisomerase IV that do not involve the water–metal ion bridge and so retains efficacy against resistant strains. In vitro studies demonstrate activity against common uropathogens, including fluoroquinolone-resistant Escherichia coli, although susceptibility varies by organism and resistance phenotype. Pharmacokinetic and pharmacodynamic (PK/PD) research suggest that the area under the concentration-time curve to MIC ratio (AUC/MIC) is the primary predictor of efficacy, and that there is a high chance of target attainment (PTA) at clinically authorized dosage regimens. Phase 3 randomized controlled trials of gepotidacin in uncomplicated urinary tract infections (uUTIs) have showed non-inferiority to nitrofurantoin with microbiological cure rates >90%. The most frequent adverse reactions are gastrointestinal, while the current U.S. prescribing information includes dose- and concentration-dependent QTc prolongation and acetylcholinesterase-inhibition-related warnings. Resistance is associated primarily with target-site mutations involving GyrA and ParE, and cross-resistance with fluoroquinolones is limited but not absent. From an antimicrobial stewardship standpoint, gepotidacin offers a useful oral option for resistant infections, but its use must be careful to maintain its long-term efficacy. This study critically assesses the molecular, pharmacological, clinical and stewardship implications of gepotidacin in the contemporary management of UTIs.