A novel antibiotic recently approved for treatment of urinary tract infections also shows efficacy against gonorrhea, according to the results of a phase 3 randomized trial published yesterday in The Lancet.
The multicenter trial, which involved more than 600 people in 5 countries with Neisseria gonorrhoeae infections, found that oral gepotidacin was noninferior to the standard regimen of intramuscular ceftriaxone plus azithromycin, with a treatment success rate of 93% and no new safety concerns. Gepotidacin is a first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by targeting a distinct binding site.
The findings are significant given the lack of alternative treatment options for one of the most prevalent sexually transmitted infections in the world. Ceftriaxone is the last remaining empiric treatment option for N gonorrhoeae, a bacterium that has quickly developed resistance to every antibiotic that's been used for treatment. But resistance to ceftriaxone is already high in parts of Asia and has been spreading to other parts of the world.
The threat of untreatable gonorrhea, which can cause pelvic inflammatory disease, ectopic pregnancy, and infertility in women, has led the World Health Organization (WHO) and Centers for Disease Control and Prevention to label drug-resistant N gonorrhoeae a serious and urgent public health threat. The last new antibiotic for gonorrhea was introduced in the 1990s.
"The potential introduction of a novel oral antibacterial with proven in-vitro activity and in-vivo efficacy would represent a significant advancement in patient care for uncomplicated gonorrhoea," trial investigators wrote.
Benefits of an oral option
For the EAGLE-1 trial, US, UK, and Australian investigators enrolled 628 participants from Australia, Germany, Mexico, Spain, and the United States who were ages 12 and over and had suspected uncomplicated urogenital gonorrhea, a positive lab test for N gonorrhoeae, or both. Participants were randomized 1:1 to receive two 3,000 milligram (mg) doses of oral gepotidacin or 500 mg intramuscular ceftriaxone plus 1 gram of oral azithromycin.
The primary efficacy endpoint was microbiologic success, defined as culture-confirmed bacterial eradication of N gonorrhoeae at test-of-cure (days 4 to 8). The outcome was assessed in the microbiologic intention-to-treat (micro-ITT) population, which included 406 participants (202 in the gepotidacin group and 204 in ceftriaxone plus azithromycin group), most of whom were male (92%), White (74%), and men who have sex with men (71%). The noninferiority margin was –10%.
The primary outcome analysis found microbiologic success rates of 92.6% (95% confidence interval [CI], 88.0% to 95.8%) in the gepotidacin group and 91.2% (95% CI, 86.4% to 94.7%) in the ceftriaxone plus azithromycin group, for an adjusted treatment difference of –0.1% (95% CI, –5.6% to 5.5%). No bacterial persistence for urogenital N gonorrhoeae was observed at test-of-cure for either treatment group. Gepotidacin also maintained efficacy against drug-resistant or non-susceptible N gonorrhoeae isolates, and no reduction in gepotidacin susceptibility was identified.
The potential introduction of a novel oral antibacterial with proven in-vitro activity and in-vivo efficacy would represent a significant advancement in patient care for uncomplicated gonorrhoea.
In the safety population (309 in the gepotidacin group and 311 in the ceftriaxone plus azithromycin group), the percentage of patients with at least one treatment-emergent adverse event was higher in the gepotidacin group (74% vs 33%) than the ceftriaxone plus azithromycin group. A similar pattern was observed with drug-related adverse events (68% vs 14%). Adverse events were mainly gastrointestinal and almost all were mild or moderate.
The investigators say one of the benefits of gepotidacin is that it can be taken orally, which could make it a more attractive option for patients than receiving an injection of ceftriaxone.
"New oral treatment options, which are often an appealing alternative to parenteral therapy due to their ease of administration, lower health-care resource use, decreased risk of needle-stick injuries, and increased patient satisfaction by avoiding injections, especially in those with needle phobias, are urgently required," they wrote.
Challenges remain for gonorrhea control
The results are more good news for British drugmaker GSK, which developed gepotidacin in collaboration with the US government's Biomedical Advanced Research and Development Authority. Late last month, the US Food and Drug Administration approved gepotidacin for uncomplicated urinary tract infections (uUTIs).
But in an accompanying commentary, experts from the WHO caution regular use of gepotidacin for uUTIs raises concerns for resistance selection in N gonorrhoeae, which could limit its effectiveness.
"Implementation of gepotidacin for the treatment of uUTIs and gonorrhoea must use evidence-based guidelines and stewardship strategies to minimise the risk of resistance development," Magnus Unemo, PhD, and Teodora Wi, MD, wrote.
Furthermore, they note that gonococci's ability to quickly develop resistance means that clinical work on other gonorrhea treatment options remains necessary. One candidate, zoliflodacin, has also demonstrated noninferiority to ceftriaxone plus azithromycin in a phase 3 trial, but the full results of that study have yet to be published.
In addition to new treatments, Unemo and Wi say multiple strategies are needed to maintain effective control and management of gonorrhea, which caused 82.4 million infections in people ages 15 to 49 years in 2020. These include improved prevention, development of rapid and affordable point-of-care diagnostic tests, prompt treatment of patients and contacts, enhanced surveillance, antimicrobial stewardship, and creation of a gonococcal vaccine.
"In conclusion, gepotidacin is promising for the treatment of gonorrhoea, but the challenges to retain gonorrhoea as a treatable infection will continue," they wrote.
