The inequality paradox: How Gepotidacin addresses the hidden social Gradient of antimicrobial Resistance

Niha Hussain is an academic FY2 doctor with research interests centered on health inequalities and equity in healthcare delivery.

In 2024, patients living in England’s areas of lowest socioeconomic status (SES) faced a 47.2% higher rate of antibiotic-resistant bloodstream infections compared to higher socioeconomic areas.¹ This represents a 29% increase from 2019 and reveals an uncomfortable truth: antimicrobial resistance (AMR) is not just a microbiological crisis, but a social injustice. Important stakeholders in this are General practitioners (GPs), who balance antimicrobial stewardship with the realities of time pressure, diagnostic uncertainty, and higher infectious disease burden in disadvantaged populations. The recent approval of Gepotidacin, the first new antibiotic class for urinary tract infections (UTIs) in nearly three decades, represents hope for health equity in an era where society’s behaviours have created a two-tier system of infectious disease outcomes.

Gepotidacin is a ‘first-in-class’ triazaacenaphthylene antibiotic which inhibits bacterial DNA replication through dual targeting of DNA gyrase and topoisomerase IV. This novel drug is promising, since mutations would be required in both enzymes for resistance to emerge. The drug’s development was evaluated across three phase III trials: EAGLE-1 (which considered its efficacy in treating uncomplicated urogenital gonorrhoea), and the EAGLE-2 and EAGLE-3 trials (measuring efficacy in treating UTIs).^2,3

The EAGLE-1 trial, enrolling 628 participants, demonstrated that oral Gepotidacin achieved 92.6% microbiological success versus 91.2% for intramuscular ceftriaxone plus oral azithromycin.² The EAGLE-2 and EAGLE-3 trials enrolled over 3,000 female patients, comparing Gepotidacin 1,500mg twice daily for five days against nitrofurantoin.³ Non-inferiority was demonstrated, with both trials terminated early for efficacy. Critically, Gepotidacin showed activity against fluoroquinolone-resistant and trimethoprim-sulfamethoxazole-resistant strains, directly addressing resistance patterns disproportionately affecting lower SES communities.

Why does the AMR crisis unequally affect areas of lower SES? Approximately 90% of antibiotic prescriptions originate in primary care, with evidence suggesting 30-50% may be inappropriate.⁴ GPs in deprived areas navigate additional complexities: patients with multiple comorbidities, poor health literacy, and limited ability to return for review if initial treatment fails. These factors create prescribing dilemmas where the safest individual choice may inadvertently contribute to population-level resistance.

These challenges are compounded by the increasing rates of AMR seen in all parts of the UK. Resistance rates have gradually climbed: third-generation cephalosporin resistance increased from 14.5% in 2019 to 16.9% in 2024, whilst gentamicin resistance rose from 10.7% to 12.4%.¹ Regional data reveal that one-quarter of urine samples demonstrated resistance to first-line antibiotics, with trimethoprim failing 27% of the time and nitrofurantoin resistance reaching 8.8%.⁵

For GPs serving disadvantaged populations, Gepotidacin is a potential equaliser in a system where health outcomes increasingly correlate with postcode. Gepotidacin’s oral formulation addresses a critical barrier: patients from socioeconomically disadvantaged communities often face transportation difficulties, work inflexibility and caring constraints that make attending for parenteral treatments difficult. Furthermore, Gepotidacin’s activity against multidrug-resistant organisms directly confronts the resistance burden disproportionately borne by disadvantaged communities. These populations experience higher rates of recurrent infections, poor compliance with courses of treatment, greater antibiotic exposure through repeated treatment failures, and increased likelihood of harbouring resistant organisms.⁶ This creates a vicious cycle wherein those with least access to healthcare resources face the greatest microbiological challenges. By providing an effective option when first-line antibiotics fail, Gepotidacin offers an approach to narrow the gap in infectious disease outcomes between higher and lower areas of SES.

The thirty-year antibiotic innovation drought appears to be ending, yet Gepotidacin’s discovery should prompt reflection. We have created a system where the most vulnerable bear the greatest burden of resistance our collective behaviours have generated. As gatekeepers of antimicrobial stewardship, GPs must recognise that every prescription decision carries implications for health equity. In addressing AMR, we must simultaneously address inequality, as the two remain inextricably linked.

References

1. UK Health Security Agency. English surveillance programme for antimicrobial utilisation and resistance (ESPAUR) report 2024 to 2025. London: UKHSA; 2024.
2. Unemo M, Lewis DA, Scangarella-Oman NE, Flight W, Gatsi S, Jakielaszek C, et al. Oral gepotidacin for the treatment of uncomplicated urogenital gonorrhoea (EAGLE-1): a phase 3 randomised, open-label, non-inferiority, multicentre study. Lancet. 2025; 405(10472): 1525-1536.
3. Wagenlehner F, Perry CR, Hooton TM, Scangarella-Oman NE, Storey J, Siddiqui S, et al. Oral gepotidacin versus nitrofurantoin in patients with uncomplicated urinary tract infection (EAGLE-2 and EAGLE-3): two randomised, controlled, double-blind, double-dummy, phase 3, non-inferiority trials. Lancet. 2024;403(10427):741-755.
4. Ventola CL. The antibiotic resistance crisis. Part 1: causes and threats. P T. 2015;40(4):277-283.
5. UK Health Security Agency. Nearly 400 antibiotic-resistant infections each week in 2024 [press release]. London: UKHSA; 13 Nov 2024.
6. Gupta K, Grigoryan L, Zervos M, et al. Sociodemographic Inequalities in Urinary Tract Infection in 2 Large California Health Systems. Open Forum Infect Dis. 2020;7(8):ofaa251.

Featured image by am JD on Unsplash