Background: Gonorrhoea is a common sexually transmitted infection that can cause pain and discomfort, affect fertility in women and lead to epididymo-orchitis in men. Current treatment is with ceftriaxone, but there is increasing evidence of antimicrobial resistance reducing its effectiveness. Gentamicin is a potential alternative treatment requiring further evaluation.
Objectives: To assess the clinical effectiveness and cost-effectiveness of gentamicin as an alternative treatment to ceftriaxone in the treatment of gonorrhoea.
Design: A multicentre, parallel-group, blinded, non-inferiority randomised controlled trial.
Setting: Fourteen sexual health clinics in England.
Participants: Adults aged 16-70 years with a diagnosis of uncomplicated, untreated genital, pharyngeal or rectal gonorrhoea based on a positive Gram-stained smear on microscopy or a positive nucleic acid amplification test (NAAT).
Randomisation and blinding: Participants were randomised using a secure web-based system, stratified by clinic. Participants, investigators and research staff assessing participants were blinded to treatment allocation.
Interventions: Allocation was to either 240 mg of gentamicin (intervention) or 500 mg of ceftriaxone (standard treatment), both administered as a single intramuscular injection. All participants also received 1 g of oral azithromycin.
Main outcome measure: The primary outcome measure was clearance of Neisseria gonorrhoeae at all infected sites, confirmed by a negative Aptima Combo 2® (Hologic Inc., Marlborough, MA, USA) NAAT, at 2 weeks post treatment.
Results: We randomised 720 participants, of whom 81% were men. There were 358 participants in the gentamicin group and 362 in the ceftriaxone group; 292 (82%) and 306 (85%) participants, respectively, were included in the primary analysis. Non-inferiority of gentamicin to ceftriaxone could not be demonstrated [adjusted risk difference for microbiological clearance -6.4%, 95% confidence interval (CI) -10.4% to -2.4%]. Clearance of genital infection was similar in the two groups, at 94% in the gentamicin group and 98% in the ceftriaxone group, but clearance of pharyngeal infection and rectal infection was lower in the gentamicin group (80% vs. 96% and 90% vs. 98%, respectively). Reported pain at the injection site was higher for gentamicin than for ceftriaxone. The side-effect profiles were comparable between the groups. Only one serious adverse event was reported and this was deemed not to be related to the trial medication. The economic analysis found that treatment with gentamicin is not cost neutral compared with standard care, with average patient treatment costs higher for those allocated to gentamicin (£13.90, 95% CI £2.47 to £37.34) than to ceftriaxone (£6.72, 95% CI £1.36 to £17.84).
Limitations: Loss to follow-up was 17% but was similar in both treatment arms. Twelve per cent of participants had a negative NAAT for gonorrhoea at their baseline visit but this was balanced between treatment groups and unlikely to have biased the trial results.
Conclusions: The trial was unable to demonstrate non-inferiority of gentamicin compared with ceftriaxone in the clearance of gonorrhoea at all infected sites. Clearance at pharyngeal and rectal sites was lower for participants allocated to gentamicin than for those allocated to ceftriaxone, but was similar for genital sites in both groups. Gentamicin was associated with more severe injection site pain. However, both gentamicin and ceftriaxone appeared to be well tolerated.
Future work: Exploration of the genetic determinants of antibiotic resistance in N. gonorrhoeae will help to identify accurate markers of decreased susceptibility. Greater understanding of the immune response to infection can assist gonococcal vaccine development.
Trial registration: Current Controlled Trials ISRCTN51783227.
Funding: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 20. See the NIHR Journals Library website for further project information.
Keywords: ANTIBACTERIAL AGENTS; CEFTRIAXONE; GENTAMICIN; GONORRHOEA; MICROBIAL DRUG RESISTANCE; NON-INFERIORITY; RANDOMISED TRIAL; TREATMENT.
Gonorrhoea is a common infection, spread by having sex, that causes genital pain and discomfort. In women it can lead to pelvic inflammation and infertility, and in men it can lead to swelling and pain in the testicles. Currently, an antibiotic called ceftriaxone is used to treat gonorrhoea. However, there is evidence that this is becoming less effective over time and it could stop curing patients with gonorrhoea within the next few years. In this study, we wanted to find out if another antibiotic called gentamicin is as good as ceftriaxone in the treatment of gonorrhoea and whether or not gentamicin could be used to treat gonorrhoea if ceftriaxone stops being effective. We recruited 720 adults with gonorrhoea and randomly allocated them (by chance) to receive treatment with an injection of either gentamicin (240 mg) or ceftriaxone (500 mg). They all also received a single dose of azithromycin (1 g) taken by mouth. Overall, 98% of participants given ceftriaxone had their gonorrhoea cured, compared with 91% of participants given gentamicin, a difference of 7%. Therefore, it is likely that doctors will continue to use ceftriaxone (plus azithromycin) as the preferred treatment. Gentamicin did have a cure rate of 94% for genital gonorrhoea and so it might be useful when ceftriaxone is not available or appropriate to use. Cure rates using gentamicin were lower than cure rates using ceftriaxone for gonorrhoea infecting the rectum (90%) and throat (80%), so it may be less useful for patients with infections at these sites. We also found that gentamicin is likely to cost the NHS more than ceftriaxone. Gentamicin caused few side effects and seems to be as safe as ceftriaxone, which is reassuring.