Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial

Background Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. Methods In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. Findings Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18–45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference −1·4%, 95% CI −7·0 to 4·3; hazard ratio 0·96, 0·68–1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3–4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). Interpretation Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia

Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial

Background Results of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects. Methods FOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762. Findings Between Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839–1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26–6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38–2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months. Interpretation Fluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function. Funding UK Stroke Association and NIHR Health Technology Assessment Programme

Pink salmon (<i>Oncorhynchus gorbuscha</i>) osmoregulatory development plays a key role in sea louse (<i>Lepeophtheirus salmonis</i>) tolerance

Sea lice ( Lepeophtheirus salmonis ) of fish-farm origin have been implicated in reducing populations of pink salmon ( Oncorhynchus gorbuscha ) in British Columbia’s Broughton Archipelago. Owing to the physically disruptive nature of louse attachment to fish skin in a hyperosmotic environment, we hypothesize that the impacts on fish performance are ionoregulatory in origin. Therefore, ionoregulatory status was measured in juvenile pink salmon artificially infected in the laboratory and naturally infected in the wild. Body [Na+] of laboratory-infected fish (∼1 week seawater (SW); 0.2–0.4 g) increased significantly by 12% with a single chalimus-4 louse, and by 23% with 2–3 chalimus-3 lice. Mortality over this 24-day trial was 2.4% for fish initially infected with 1–3 lice. Body [Na+] for fish caught with natural infections (∼4–12 weeks SW; 0.5–1.5 g) did not differ from uninfected controls. Combining data sets revealed a “no effect” threshold of 0.5 g for body [Na+] of fish infected with one chalimus-4 louse. We propose that this size-related louse tolerance is associated with hypo-osmoregulatory development, adding to a previously suggested multifactorial mechanism based on epidermal and immune system development. We suggest management bodies consider this fish-mass threshold when planning to minimize risk to wild fish populations.</jats:p

Sea lice infection of juvenile pink salmon (Oncorhynchus gorbuscha): effects on swimming performance and postexercise ion balance

Sea lice ( Lepeophtheirus salmonis ) infection negatively affected swimming performance and postswim body ion concentrations of juvenile pink salmon ( Oncorhynchus gorbuscha ) at a 0.34 g average body mass but not at 1.1 g. Maximum swimming velocity (Umax) was measured on over 350 individual pink salmon (0.2–3.0 g), two-thirds of which had a sea lice infection varying in intensity (one to three sea lice per fish) and life stage (chalimus 1 to preadult). For fish averaging 0.34 g (caught in a nearby river free of sea lice and transferred to seawater before being experimentally infected), the significant reduction in Umax was dependent on sea lice life stage, not intensity, and Umax decreased only after the chalimus 2 life stage. Experimental infections also significantly elevated postswim whole body concentrations of sodium (by 23%–28%) and chloride (by 22%–32%), but independent of sea lice developmental stage or infection intensity. For fish averaging 1.1 g (captured in seawater with existing sea lice), the presence of sea lice had no significant effect on either Umax or postswim whole body ions. Thus, a single L. salmonis impacted swimming performance and postswim whole body ions of only the smallest pink salmon and with a sea louse stage of chalimus 3 or greater. </jats:p

Diel vertical distribution of early marine phase juvenile pink salmon (<i>Oncorhynchus gorbuscha</i>) and behaviour when exposed to salmon louse (<i>Lepeophtheirus salmonis</i>)

We observed diel vertical migration patterns in juvenile pink salmon ( Oncorhynchus gorbuscha (Walbaum, 1792)) and tested the hypothesis that fish behaviour is altered by exposure to sea lice copepodids. Experiments involved replicated field deployments of a large (9 m) plankton column, which provided a vertical distribution enclosure under natural light and salinity conditions. Diel vertical distributions of juvenile pink salmon were observed during the first 3 weeks of seawater acclimation in both the presence and the absence of the ectoparasitic salmon louse ( Lepeophtheirus salmonis (Krøyer, 1838)). Immediately upon entering seawater, juvenile pink salmon preferred the top 1 m of the water column, but they moved significantly deeper down the vertical water column as seawater acclimation time increased. A significant diel migration pattern was observed, which involved a preference for the surface at night-time, compared with daytime. When fish in the column were exposed to L. salmonis copepodids for 3 h, 43%–62% of fish became infected, fish expanded their vertical distribution range, and significant changes in vertical distribution patterns were observed. </jats:p