Gentamicin, azithromycin and ceftriaxone in the treatment of gonorrhoea: the relationship between antibiotic MIC and clinical outcome.

OBJECTIVES: To investigate the relationship between MIC and clinical outcome in a randomized controlled trial that compared gentamicin 240 mg plus azithromycin 1 g with ceftriaxone 500 mg plus azithromycin 1 g. MIC analysis was performed on Neisseria gonorrhoeae isolates from all participants who were culture positive before they received treatment. METHODS: Viable gonococcal cultures were available from 279 participants, of whom 145 received ceftriaxone/azithromycin and 134 received gentamicin/azithromycin. Four participants (6 isolates) and 14 participants (17 isolates) did not clear infection in the ceftriaxone/azithromycin and gentamicin/azithromycin arms, respectively. MICs were determined by Etest on GC agar base with 1% Vitox. The geometric mean MICs of azithromycin, ceftriaxone and gentamicin were compared using logistic and linear regression according to treatment received and N. gonorrhoeae clearance. RESULTS: As the azithromycin MIC increased, gentamicin/azithromycin treatment was less effective than ceftriaxone/azithromycin at clearing N. gonorrhoeae. There was a higher geometric mean MIC of azithromycin for isolates from participants who had received gentamicin/azithromycin and did not clear infection compared with those who did clear infection [ratio 1.95 (95% CI 1.28-2.97)], but the use of categorical MIC breakpoints did not accurately predict the treatment response. The geometric mean MIC of azithromycin was higher in isolates from the pharynx compared with genital isolates. CONCLUSIONS: We found that categorical resistance to azithromycin or ceftriaxone in vitro, and higher gentamicin MICs in the absence of breakpoints, were poorly predictive of treatment failure.

Acceptability of and treatment preferences for recurrent bacterial vaginosis-Topical lactic acid gel or oral metronidazole antibiotic: Qualitative findings from the VITA trial.

BACKGROUND: Bacterial vaginosis (BV) is associated with an elevated vaginal pH and the presence of abnormal offensive discharge. It is common, often recurrent, and the most effective treatment regimen is unknown. 'Metronidazole Versus lactic acId for Treating bacterial vAginosis' (VITA) is a UK-based randomised controlled trial assessing clinical and cost-effectiveness of topical lactic acid gel compared to oral metronidazole antibiotic for treating second and subsequent BV episodes. Few BV trials report on women's preferences for treatment in the context of their own experiences. METHOD: This qualitative study investigated the acceptability and tolerability of the two treatments. During the trial, semi-structured telephone interviews were undertaken between January-May 2018. A total of 33 women diagnosed with BV were consecutively sampled then interviewed from six sites across England. Thematic analysis was guided by the acceptability of health interventions framework. Potential causes of BV and its impact on women's lives were explored in addition to women's treatment preference and perceived treatment effectiveness. RESULTS: Although women felt antibiotics treat BV effectively, and were associated with longer time periods between episodes, they generally preferred using the lactic acid gel because of ease of use, once daily application and less side-effects. Women would recommend the lactic acid gel to others for mild cases of BV but to take antibiotics when more severe. The risk of antibiotic drug resistance was a common concern. Self-help medicating or self-decision to not treat was also evident due to prior experience of poor outcomes from treatment. Triggers of BV were attributed to personal hygiene habits-soaps used to wash the vagina and sexual practices such as unprotected sex. CONCLUSION: Acceptability and preference for topical lactic acid gel or oral metronidazole tablets in the treatment of recurrent BV was affected by personal choice relating to affective attitude, burden, ethicality, intervention coherence, opportunity costs, and self-efficacy. These differed depending on ease of use, tolerability and past experiences, but not necessarily based on perceived drug effectiveness. Knowledge of a patient preference for topical lactic acid gel therapy despite lower perceived effectiveness may be useful for clinicians when making treatment decisions.

Metronidazole versus lactic acid for treating bacterial vaginosis (VITA): protocol for a randomised controlled trial to assess the clinical and cost effectiveness of topical lactic acid gel for treating second and subsequent episodes of bacterial vaginosis.

BACKGROUND: Bacterial vaginosis (BV) affects 30-50% of women at some time in their lives and is an embarrassing and distressing condition which can be associated with potentially serious comorbidities. Current antibiotic treatments such as metronidazole are effective but can result in side effects, and recurrence is common. This trial aims to investigate whether lactic acid gel is clinically effective and cost effective in the treatment of recurrent BV compared with metronidazole. METHODS: VITA is an open-label, multicentre, parallel group randomised controlled trial for women with a clinical diagnosis of BV and at least one previous BV episode in the past 2 years. Participants will be randomised 1:1 to intravaginal lactic acid gel 5 ml once daily for 7 days or oral metronidazole tablets 400 mg twice daily for 7 days. All participants will be followed up for 6 months to assess health status and healthcare costs. A subgroup will be interviewed to further explore adherence, tolerability and acceptability of treatment. The estimated sample size is 1900 participants to detect a 6% absolute increase in response rate to 86% in those receiving lactic acid gel. The primary outcome is participant-reported resolution of BV at Week 2. DISCUSSION: Results from this trial will help inform UK treatment guidelines for BV and may provide an alternative effective treatment for recurrent episodes of this condition which avoids repeated exposure to antibiotics. TRIAL REGISTRATION: ISRCTN, ISRCTN14161293. Registered on 8 September 2017.

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.

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.

Group-I metabotropic glutamate receptors, mGlu1a and mGlu5a, couple to extracellular signal-regulated kinase (ERK) activation via distinct, but overlapping, signalling pathways.

The coupling of the group I metabotropic glutamate receptors, mGlu1a and mGlu5a, to the extracellular signal-regulated protein kinase (ERK) pathway has been studied in Chinese hamster ovary cell-lines where receptor expression is under inducible control. Both mGlu receptors stimulated comparable, robust and agonist concentration-dependent ERK activations in the CHO cell-lines. The mGlu1a receptor-mediated ERK response was almost completely attenuated by pertussis toxin (PTx) pretreatment, whereas the mGlu5a-ERK response, and the phosphoinositide response to activation of either receptor, was PTx-insensitive. mGlu1a and mGlu5a receptor coupling to ERK occurred via mechanisms independent of phosphoinositide 3-kinase activity and intracellular and/or extracellular Ca2+ concentration. While acute treatment with a protein kinase C (PKC) inhibitor did not attenuate agonist-stimulated ERK activation, down-regulation of PKCs by phorbol ester treatment for 24 h did attenuate both mGlu1a and mGlu5a receptor-mediated responses. Further, inhibition of Src non-receptor tyrosine kinase activity by PP1 attenuated the ERK response generated by both receptor subtypes, but only mGlu1a receptor-ERK activation was attenuated by PDGF receptor tyrosine kinase inhibitor AG1296. These findings demonstrate that, although expressed in a common cell background, these closely related mGlu receptors utilize different G proteins to cause ERK activation and may recruit different tyrosine kinases to facilitate this response.