SummaryBackgroundStaphylococcus 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.MethodsIn 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.FindingsBetween 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).InterpretationAdjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia.FundingUK National Institute for Health Research Health Technology Assessment.

Increasing antibiotic resistance makes choosing antibiotics for suspected Gram-negative infection challenging. This study set out to identify key determinants of mortality among patients with Gram-negative bacteraemia, focusing particularly on the importance of appropriate empiric antibiotic treatment. We conducted a prospective observational study of 679 unselected adults with Gram-negative bacteraemia at ten acute english hospitals between October 2013 and March 2014. Appropriate empiric antibiotic treatment was defined as intravenous treatment on the day of blood culture collection with an antibiotic to which the cultured organism was sensitive in vitro. Mortality analyses were adjusted for patient demographics, co-morbidities and illness severity. The majority of bacteraemias were community-onset (70%); most were caused by Escherichia coli (65%), Klebsiella spp. (15%) or Pseudomonas spp. (7%). Main foci of infection were urinary tract (51%), abdomen/biliary tract (20%) and lower respiratory tract (14%). The main antibiotics used were co-amoxiclav (32%) and piperacillin-tazobactam (30%) with 34% receiving combination therapy (predominantly aminoglycosides). Empiric treatment was inappropriate in 34%. All-cause mortality was 8% at 7 days and 15% at 30 days. Independent predictors of mortality (p <0.05) included older age, greater burden of co-morbid disease, severity of illness at presentation and inflammatory response. Inappropriate empiric antibiotic therapy was not associated with mortality at either time-point (adjusted OR 0.82; 95% CI 0.35-1.94 and adjusted OR 0.92; 95% CI 0.50-1.66, respectively). Although our study does not exclude an impact of empiric antibiotic choice on survival in Gram-negative bacteraemia, outcome is determined primarily by patient and disease factors.

We read with interest two recent reports of Comamonas kerstersii-related infections in the abdomen (1) and bloodstream (2). We wish to add our own experience with C. kerstersii-related abdominal infections.Case 1. A 10-year-old boy presented with a 1-day history of abdominal pain. Examination revealed peritonitis in the right iliac fossa. On admission, his white blood cell count was 10.3 ϫ10 9 / liter and his C-reactive protein level was 228 mg/liter. A diagnosis of appendicitis was made, and an open appendectomy revealed a perforated appendix. Microscopic examination of peritoneal pus showed small numbers of Gram-negative bacilli that were plated onto Columbia blood agar (Oxoid), chocolate agar (Oxoid), and fastidious anaerobic agar with blood (Oxoid). After 48 h of incubation at 36°C in ambient air, colonies on the blood agar plate were identified by matrix-assisted laser desorption ionizationtime of flight (MALDI-TOF) mass spectrometry (Bruker) as C. kerstersii and a fine growth on the anaerobic plate was identified by MALDI-TOF as Streptococcus constellatus. These were the only organisms isolated. Postoperatively, the patient received piperacillin-tazobactam for 5 days and was discharged on amoxicillinclavulanic acid and ciprofloxacin, making a full recovery.Case 2. A 9-year-old boy presented with a 3-day history of right-sided constant abdominal pain associated with pyrexia. Examination revealed a tender right iliac fossa with localized peritonitis. On admission, his white blood cell count was measured at 13.6 ϫ10 9 /liter and his C-reactive protein level was 65 mg/liter. He developed septic shock and underwent emergency surgery, during which a perforated appendix was resected. Microscopic analysis of intraoperative peritoneal pus and an operative swab of the perforated appendix showed numerous pus cells but no organisms. After 48 h of incubation (as detailed above), the peritoneal fluid grew S. constellatus, Bacteroides fragilis, and C. kerstersii, as identified by MALDI-TOF, and the appendix swab revealed a pure growth of C. kerstersii. The patient received 3 days of intravenous amoxicillin-clavulanic acid, gentamicin, and metronidazole and was discharged on oral amoxicillin-clavulanic acid. He made a full recovery.C. kerstersii, which has undergone extensive reclassification (3, 4), was isolated from our patients as part of a polymicrobial growth from peritoneal fluid. MALDI-TOF appeared to be a reliable tool for identifying these organisms. In case 1, C. kerstersii was identified with a score of 2.275, followed by Comamonas testosteroni (1.664) and Comamonas aquatica (1.579), and in case two, C. kerstersii was identified with a score of 2.294, followed by C. aquatica (1.585), Brenneria nigrifluens (1.299), and C. testosteroni (1.222). The antibiotic sensitivities of the isolates obtained are shown in Table 1. In addition, disc diffusion testing of the isolate from case 2 for amoxicillin-clavulanic acid showed a large zone of Ͼ25 mm, suggesting sensitivity, and the use of amoxicillin-clavulanic acid resu...