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.

Article history

The research reported in this issue of the journal was funded by the HTA programme as project number 12/127/10. The contractual start date was in July 2014. The draft report began editorial review in August 2017 and was accepted for publication in October 2017. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

Jonathan DC Ross reports personal fees from GlaxoSmithKline (GSK) Pharma, Hologic, Inc. and Janssen Pharmaceutica outside the submitted work as well as ownership of shares in GSK Pharma and AstraZeneca Pharmaceuticals. In addition, he is author of the UK and European Guidelines on Pelvic Inflammatory Disease, is a member of the European Sexually Transmitted Infections Guidelines Editorial Board, is a member of the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Commissioning Board, was previously a member of the NIHR HTA Primary Care, Community and Preventative Interventions Panel (2013–16) and is a member of the NIHR Journals Library Editorial Group. Alan A Montgomery is a member of the NIHR HTA Clinical Evaluation and Trials Board. Janet Wilson reports non-financial support from Hologic/Gen-Probe and personal fees from Becton, Dickinson and Company (BD) outside the submitted work. John White reports personal fees from Hologic, GSK Pharma and BD UK Pty Ltd outside the submitted work, as well as personal fees from SAGE publishing, and is Editor-in-Chief of the International Journal of STD & AIDS. Trish Hepburn reports ownership of shares in AstraZeneca Pharmaceuticals. During the trial, Lelia Duley was the Director of the Nottingham Clinical Trials Unit, a unit with NIHR clinical trials unit support funding.