Treatment Of Uncomplicated Urogenital Gonorrhea Research Articles

Efficacy and Safety of Gepotidacin as Treatment of Uncomplicated Urogenital Gonorrhea (EAGLE-1): Design of a Randomized, Comparator-Controlled, Phase 3 Study.

Gonorrhea, caused by Neisseria gonorrhoeae (NG), is the second most common bacterial sexually transmitted infection (STI). Rates of antimicrobial resistance to standard care are increasing worldwide, with many antibiotic classes now ineffective against NG. Gepotidacin is a first-in-class,bactericidal, triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by inhibition of two enzymes, where a single target-specific mutation does not significantly impact susceptibility. Gepotidacin confers activity against NG, including most strains resistant to marketed antibiotics. Here, we describe the design of a phase 3 clinical trial (EAGLE-1; NCT04010539) evaluating gepotidacin for the treatment of uncomplicated urogenital gonorrhea. This phase 3, randomized, multicenter, sponsor-blinded, noninferiority study across six countries is comparing the efficacy of gepotidacin with ceftriaxone plus azithromycin in 400 patients with uncomplicated urogenital gonorrhea (microbiological intent-to-treat population) and assessing the safety of gepotidacin in approximately 600 patients (intent-to-treat population). Eligible participants 12years of age or older with clinical suspicion of urogenital gonococcal infection and a NG-positive urogenital sample and/or purulent discharge are randomized 1:1 to receive oral gepotidacin (2 × 3000mg 10-12h apart) or ceftriaxone (500mg, intramuscular) plus azithromycin (1g, oral). The primary endpoint is culture-confirmed bacterial eradication of NG from the urogenital site at the test-of-cure (days 4-8) visit. This trial was designed in accordance with US Food and Drug Administration (2015) and European Medicines Agency (2011) guidance, particularly the primary endpoint and microbiological evaluability requirements. This study will help characterize the risk-benefit profile of gepotidacin for treating uncomplicated urogenital gonorrhea. Gepotidacin is an important potential treatment for gonorrhea to help address the urgent unmet need of multidrug resistance and the increasingly limited number of oral treatment options. ClinicalTrials.gov identifier, NCT04010539.

A Study Evaluating Efficacy and Safety of Gepotidacin Compared With Ceftriaxone Plus Azithromycin in the Treatment of Uncomplicated Urogenital Gonorrhea

A Study Evaluating Efficacy and Safety of Gepotidacin Compared With Ceftriaxone Plus Azithromycin in the Treatment of Uncomplicated Urogenital Gonorrhea

Mechanistic and Structural Basis for the Actions of the Antibacterial Gepotidacin against Staphylococcus aureus Gyrase.

Gepotidacin is a first-in-class triazaacenaphthylene novel bacterial topoisomerase inhibitor (NBTI). The compound has successfully completed phase II trials for the treatment of acute bacterial skin/skin structure infections and for the treatment of uncomplicated urogenital gonorrhea. It also displays robust in vitro activity against a range of wild-type and fluoroquinolone-resistant bacteria. Due to the clinical promise of gepotidacin, a detailed understanding of its interactions with its antibacterial targets is essential. Thus, we characterized the mechanism of action of gepotidacin against Staphylococcus aureus gyrase. Gepotidacin was a potent inhibitor of gyrase-catalyzed DNA supercoiling (IC50 ≈ 0.047 μM) and relaxation of positively supercoiled substrates (IC50 ≈ 0.6 μM). Unlike fluoroquinolones, which induce primarily double-stranded DNA breaks, gepotidacin induced high levels of gyrase-mediated single-stranded breaks. No double-stranded breaks were observed even at high gepotidacin concentration, long cleavage times, or in the presence of ATP. Moreover, gepotidacin suppressed the formation of double-stranded breaks. Gepotidacin formed gyrase-DNA cleavage complexes that were stable for >4 h. In vitro competition suggests that gyrase binding by gepotidacin and fluoroquinolones are mutually exclusive. Finally, we determined crystal structures of gepotidacin with the S. aureus gyrase core fusion truncate with nicked (2.31 Å resolution) or intact (uncleaved) DNA (2.37 Å resolution). In both cases, a single gepotidacin molecule was bound midway between the two scissile DNA bonds and in a pocket between the two GyrA subunits. A comparison of the two structures demonstrates conformational flexibility within the central linker of gepotidacin, which may contribute to the activity of the compound.

Impact of Eligibility Criteria on Participant Enrollment for a Randomized Clinical Trial of Gonorrhea Treatment.

High rates of failure to qualify for clinical trial participation increase time and cost required for study completion. Identification of remediable reasons for prescreen failure can help reduce prescreen failure rates and improve study cost effectiveness. Reasons for prescreen failure to qualify for participation in a phase 2 randomized clinical trial of treatment of uncomplicated urogenital gonorrhea were collected from prescreening logs. Reasons were categorized based on whether the reason was that the subject failed to meet eligibility criteria or declined participation. Subjects who failed prescreening but could have been enrolled under protocol amendments were used to estimate potential cost savings had enrollment completed sooner. Over 88% (1373/1554) of potential study candidates were not enrolled. The majority (68.8%) of nonenrolled subjects failed prescreening due to not meeting eligibility criteria, whereas 31.0% declined to participate. The most common reasons for failure to qualify were having only nonurogenital gonorrhea (16.4%), limited time (13.1%), and being on antiretroviral therapy (7.5%). Potential cost savings if protocol amendments affecting eligibility had been instituted earlier were estimated at US $127,500. Careful attention to reasons for prescreen failure can inform clinical trial protocol development to address trial design features that may impact successful enrollment. More efficient subject enrollment can result in substantial cost savings.

Single Dose Enoxacin for the Treatment of Uncomplicated Urogenital Gonorrhea

Enoxacin, a new broad spectrum azaquinolone, has demonstrated in-vitro activity against Neisseria gonorrhoeae including penicillinase producing strains. We evaluated the safety and efficacy or oral enoxacin 400 mg versus intramuscular ceftriaxone 250 mg for the treatment of uncomplicated genital N. gonorrhoeae infections. Of the 57 patients enrolled, 48 patients (26 men, 22 women) were culture positive and returned for the follow up visit. Six patients (12.5%) had penicillinase producing strains of N. gonorrhoeae, and eleven patients (23%) had concomitant Chlamydia trachomatis infections. Genital gonorrhea was eradicated in 98% of the patients, with a cure rate of 22/23 (96%) in the enoxacin group and 25/25 (100%) in the ceftriaxone group. There were no consequential side effects noted for either agent. Oral enoxacin is a safe and efficacious alternative for the treatment of uncomplicated N. gonorrhoeae infections.