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...

Understanding the interactions between rabies virus (RABV) and individual host cell proteins is critical for the development of targeted therapies. Here we report that interferon-induced protein with tetratricopeptide repeats 2 (Ifit2), an interferon-stimulated gene (ISG) with possible RNA-binding capacity, is an important restriction factor for rabies virus. When Ifit2 was depleted, RABV grew more quickly in mouse neuroblastoma cells This effect was replicated, where Ifit2 knockout mice displayed a dramatically more severe disease phenotype than wild-type mice after intranasal inoculation of RABV. This increase in pathogenicity correlated to an increase in RABV mRNA and live viral load in the brain, as well as to an accelerated spread to brain regions normally affected by this RABV model. These results suggest that Ifit2 exerts its antiviral effect mainly at the level of viral replication, as opposed to functioning as a mechanism that restricts viral entry/egress or transports RABV particles through axons. Rabies is a fatal zoonotic disease with a nearly 100% case fatality rate. Although there are effective vaccines for rabies, this disease still takes the lives of about 50,000 people each year. Victims tend to be children living in regions without comprehensive medical infrastructure who present to health care workers too late for postexposure prophylaxis. The protein discussed in our report, Ifit2, is found to be an important restriction factor for rabies virus, acting directly or indirectly against viral replication. A more nuanced understanding of this interaction may reveal a step of a pathway or site at which the system could be exploited for the development of a targeted therapy.

Inflammasome activation is important for the development of an effective host defense against many pathogens, including RNA viruses. However, the mechanism by which the inflammasome recognizes RNA viruses and its role in rabies virus (RABV) pathogenicity and immunogenicity remain poorly defined. To determine the function of the inflammasome in response to RABV infection, we infected murine bone marrow-derived dendritic cells (BMDCs) with RABV. Our results indicate that the infection of BMDCs with RABV induces both the production of pro-interleukin-1␤ (pro-IL-1␤) and its processing, resulting in the secretion of active IL-1␤ through activation of the NLRP3-, ASC-, and caspase-1-dependent inflammasome. As previously shown for the induction of type I interferon by RABV, the induction of pro-IL-1␤ also depends upon IPS-1. We demonstrate that both the production of pro-IL-1␤ and activation of the inflammasome require viral replication. We also demonstrate that increased viral replication in BMDCs derived from IFNAR-deficient mice resulted in significantly more IL-1␤ release. Additionally, IL-1 receptor-deficient mice show an increase in RABV pathogenicity. Taken together, these results indicate an important role of the inflammasome in innate immune recognition of RABV.

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.