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

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 not find that a single dose of gentamicin 240 mg was non-inferior to a single dose of ceftriaxone 500 mg for the treatment of gonorrhoea, when both drugs were combined with a 1 g dose of oral azithromycin. The side-effect profiles were similar between groups, although severity of pain at the injection site was higher for gentamicin (mean visual analogue pain score 36 of 100 in the gentamicin group vs 21 of 100 in the ceftriaxone group). INTERPRETATION: Gentamicin is not appropriate as first-line treatment for gonorrhoea but remains potentially useful for patients with isolated genital infection, or for patients who are allergic or intolerant to ceftriaxone, or harbour a ceftriaxone-resistant isolate. Further research is required to identify and test new alternatives to ceftriaxone for the treatment of gonorrhoea. FUNDING: UK National Institute for Health Research.

Adverse effects of a single dose of gentamicin in adults: a systematic review.

AIMS: To systematically review the frequency and type of adverse events associated with a single dose of intravenous or intramuscular gentamicin in adults, for any indication, in studies where a comparator was available. METHODS: A review protocol was developed and registered (PROSPERO: CRD42013003229). Studies were eligible for review if they: recruited participants aged ≥16 years; used gentamicin intramuscularly or intravenously as a single one-off dose; compared gentamicin to another medication or placebo; and monitored adverse events. MEDLINE, EMBASE, Cochrane Library, trial registries, conference proceedings and other relevant databases were searched up to November 2016. Risk of bias was assessed on all included studies. RESULTS: In total, 15 522 records were identified. After removal of duplicates, screening of title/abstracts for relevance and independent selection of full texts by two reviewers, 36 studies were included. Across all the included studies, 24 107 participants received a single one-off dose of gentamicin (doses ranged from 1 mg kg-1 to 480 mg per dose). Acute kidney injury was described in 2520 participants receiving gentamicin. The large majority of cases were reversible. There were no cases of ototoxicity reported in patients receiving gentamicin. A meta-analysis was not performed due to study heterogeneity. CONCLUSIONS: A significant number of patients saw a transient rise in creatinine after a single dose of gentamicin at doses up to 480 mg. Persistent renal impairment and other adverse events were relatively rare.

Chlamydia and gonorrhoea contamination of clinic surfaces.

INTRODUCTION: Nucleic acid amplification tests, with their ability to detect very small amounts of nucleic acid, have become the principle diagnostic tests for Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC) in many sexual health clinics. The aim of this study was to investigate the extent of surface contamination with CT and GC within a city centre sexual health clinic and to evaluate the potential for contamination of containers used for the collection of self-taken swabs. METHOD: Surface contamination with CT and GC was assessed by systematically sampling 154 different sites within one clinic using transcription-mediated amplification (TMA), quantitative PCR and culture. The caps of containers used by patients to collect self-taken samples were also tested for CT and GC using TMA. RESULTS: Of the 154 sites sampled, 20 (13.0%) tested positive on TMA. Of these, five (3.2%) were positive for CT alone, 11 (7.1%) for GC alone and four (2.6%) for both CT and GC. The proportion of GC TMA-positive test results differed by gender, with 11 (18.3%) positive results from the male patient clinic area compared with one (1.6%) from the female area (p=0.002). Positive samples were obtained from a variety of locations in the clinic, but the patient toilets were more likely to be contaminated than examination rooms (p=0.015). Quantitative PCR and culture assays were negative for all samples. 46 caps of the containers used for self-taken swabs were negative for both CT and GC on TMA testing. CONCLUSIONS: Surface contamination with chlamydial and gonococcal rRNA can occur within sexual health clinics, but the quantity of nucleic acid detected is low and infection risk to patients and staff is small. There remains a potential risk of contamination of patient samples leading to false-positive results.

Gentamicin as an alternative to ceftriaxone in the treatment of gonorrhoea: the G-TOG non-inferiority RCT.

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.

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.

Gentamicin versus ceftriaxone for the treatment of gonorrhoea (G-TOG trial): study protocol for a randomised trial.

BACKGROUND: Gonorrhoea is a common sexually transmitted infection which causes genital pain and discomfort; in women it can also lead to pelvic inflammatory disease and infertility, and in men to epididymo-orchitis. Current treatment is with ceftriaxone, but there is increasing evidence of antimicrobial resistance which is reducing its effectiveness against gonorrhoea. A small, but increasing, number of patients have already been found to have highly resistant strains of gonorrhoea which has been associated with clinical failure. This trial aims to determine whether gentamicin is not clinically worse than ceftriaxone in the treatment of gonorrhoea. METHODS/DESIGN: This is a blinded, two-arm, multicentre, noninferiority randomised trial. Patients are eligible if they are aged 16-70 years with a diagnosis of genital, pharyngeal and/or rectal gonorrhoea. Exclusion criteria are: known concurrent sexually transmitted infection(s) (excluding chlamydia); bacterial vaginosis and/or Trichomonas vaginalis infection; contraindications or an allergy to gentamicin, ceftriaxone, azithromycin or lidocaine; pregnancy or breastfeeding; complicated gonorrhoeal infection; weight under 40 kg; use of ceftriaxone, gentamicin or azithromycin within the preceding 28 days. Randomisation is to receive a single intramuscular injection of either gentamicin or ceftriaxone, all participants receive 1 g oral azithromycin as standard treatment. The estimated sample size is 720 participants (noninferiority limit 5%). The primary outcome is clearance of Neisseria gonorrhoeae at all infected sites by a negative Nucleic Acid Amplification Test, 2 weeks post treatment. Secondary outcomes include clinical resolution of symptoms, frequency of adverse events, tolerability of therapy, relationship between clinical effectiveness and antibiotic minimum inhibitory concentration for N. gonorrhoeae, and cost-effectiveness. DISCUSSION: The options for future treatment of gonorrhoea are limited. Results from this randomised trial will demonstrate whether gentamicin is not clinically worse than ceftriaxone for the treatment of gonorrhoea. This will inform clinical practice and policy for the treatment of gonorrhoea when current therapy with cephalosporins is no longer effective, or is contraindicated. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number - ISRCTN51783227 , Registered on 18 September 2014. Current protocol version 2.0 17 June 2015.