Gentamicin compared with ceftriaxone for the treatment of gonorrhoea (G-ToG): a randomised non-inferiority trial

Abstract

Summary Background Gonorrhoea is a common sexually transmitted infection for which ceftriaxone is the current first-line treatment, but antimicrobial resistance is emerging. The objective of this study was to assess the effectiveness of gentamicin as an alternative to ceftriaxone (both combined with azithromycin) for treatment of gonorrhoea. Methods G-ToG was a multicentre, parallel-group, pragmatic, randomised, non-inferiority trial comparing treatment with gentamicin to treatment with ceftriaxone for patients with gonorrhoea. The patients, treating physician, and assessing physician were masked to treatment but the treating nurse was not. The trial took place at 14 sexual health clinics in England. Adults aged 16–70 years were eligible for participation if they had a diagnosis of uncomplicated genital, pharyngeal, or rectal gonorrhoea. Participants were randomly assigned to receive a single intramuscular dose of either gentamicin 240 mg (gentamicin group) or ceftriaxone 500 mg (ceftriaxone group). All participants also received a single 1 g dose of oral azithromycin. Randomisation (1:1) was stratified by clinic and performed using a secure web-based system. The primary outcome was clearance of Neisseria gonorrhoeae at all initially infected sites, defined as a negative nucleic acid amplification test 2 weeks post treatment. Primary outcome analyses included only participants who had follow-up data, irrespective of the baseline visit N gonorrhoeae test result. The margin used to establish non-inferiority was a lower confidence limit of 5% for the risk difference. This trial is registered with ISRCTN, number ISRCTN51783227. Findings Of 1762 patients assessed, we enrolled 720 participants between Oct 7, 2014, and Nov 14, 2016, and randomly assigned 358 to gentamicin and 362 to ceftriaxone. Primary outcome data were available for 306 (85%) of 362 participants allocated to ceftriaxone and 292 (82%) of 358 participants allocated to gentamicin. At 2 weeks after treatment, infection had cleared for 299 (98%) of 306 participants in the ceftriaxone group compared with 267 (91%) of 292 participants in the gentamicin group (adjusted risk difference −6·4%, 95% CI −10·4% to −2·4%). Of the 328 participants who had a genital infection, 151 (98%) of 154 in the ceftriaxone group and 163 (94%) of 174 in the gentamicin group had clearance at follow-up (adjusted risk difference −4·4%, −8·7 to 0). For participants with a pharyngeal infection, a greater proportion receiving ceftriaxone had clearance at follow-up (108 [96%] in the ceftriaxone group compared with 82 [80%] in the gentamicin group; adjusted risk difference −15·3%, −24·0 to −6·5). Similarly, a greater proportion of participants with rectal infection in the ceftriaxone group had clearance (134 [98%] in the ceftriaxone group compared with 107 [90%] in the gentamicin group; adjusted risk difference −7·8%, −13·6 to −2·0). Thus, we did n...

Efficacy and Safety of Injectable and Oral Antibiotics in Treating Gonorrhea: A Systematic Review and Network Meta-Analysis

“…Our analysis identified gentamicin as an effective alternative to current cephalosporins such as ceftriaxone and cefotaxime. This is in line with a recent report showing that combination therapy of gentamicin and azithromycin is highly effective against uncomplicated gonorrhea [71].. A more recent randomized non-inferiority trial concluded that gentamicin is effective in clearing genital gonorrhea, but less so for pharyngeal and rectal infections [72]. Gentamicin resistance in culture has not been reported in clinical isolates of gonorrhea [73], and little is known about gentamicin resistance in the clinic due to its limited use.…”

Is there a future for the ongoing use of azithromycin for the treatment of Neisseria gonorrhoeae?

“…The results by Rob et al contrast with a similar RCT by Ross et al [6] who also compared gentamicin 240 mg with ceftriaxone 500 mg, but combined these treatments with 1 g rather than 2 g of azithromycin. Ross et al reported a similarly high efficacy for extragenital infections in the ceftriaxone arm (97%; 242/250) but not in the gentamicin arm (86%; 189/221).…”

Should we still use azithromycin for gonorrhoea treatment?

“…50 A relatively low efficacy using the 1 g dose also occurred in a recent UK trial where, even when given in combination with gentamicin, it was associated with a 9% failure rate. 51 There are several factors that may affect the interpretation of data from older studies that evaluated the efficacy of azithromycin as a treatment for gonorrhoea. First, gonococcal culture was used to assess cure, which may have overestimated treatment efficacy because culture has a relatively low sensitivity compared with nucleic acid amplification tests (NAAT); more recent studies, which assessed cure using NAATs, have reported lower cure rates.…”

“…53 A recent large trial found only a limited association between the MICs in those who cleared and did not clear gonorrhoea, and selecting treatment based on pre-treatment MIC breakpoints was not useful in predicting treatment failure. 51 There is therefore a danger that a low MIC report may provide false reassurance to clinicians.…”

“…Clinicians recommend sexual abstinence for 2-4 weeks following treatment until repeat testing is performed to confirm cure. Many patients do not adhere to this advice 51 and any new gonorrhoea infection acquired in the subsequent 14 days will be exposed to sub-therapeutic levels of azithromycin, with case reports illustrating the potential for resistance to develop rapidly after such exposure. [71][72][73] The significance of prior exposure to azithromycin for the development of resistance is unclear.…”