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. FUNDING: UK National Institute for Health Research Health Technology Assessment

Evaluation of an adaptive, multimodal intervention to reduce postoperative infections following cesarean delivery in Ethiopia: study protocol of the CLEAN-CS cluster-randomized stepped wedge interventional trial.

BackgroundWe previously developed and pilot tested Clean Cut, a program to prevent postoperative infections by improving compliance with the WHO Surgical Safety Checklist (SSC) and strengthening adherence to infection control practices. This protocol describes the CheckList Expansion for Antisepsis and iNfection Control in Cesarean Section (CLEAN-CS) trial evaluating our program's ability to reduce infections following CS and other obstetric and gynecological operations in Ethiopia.Methods/designCLEAN-CS is a cluster-randomized stepped wedge interventional trial with five clusters (two hospitals per cluster). It aims to assess the impact of Clean Cut on six critical perioperative infection prevention standards including antiseptic practices, antibiotic administration, and routine SCC use. The trial involves baseline data collection followed by Clean Cut training and implementation in each cluster in randomized order. The intervention consists of (1) modifying and implementing the SSC to fit local practices, (2) process mapping each standard, (3) coupling data and processes with site-specific action plans for improvement, and (4) targeted training focused on process gaps. The primary outcome is 30-day CS infection rates; secondary outcomes include other patient-level complications and compliance with standards. Assuming baseline SSI incidence of 12%, an effect size of 25% absolute reduction, and the ability to recruit 80-90 patients per cluster per month, we require a sample of 8100 patients for significance. We will report our study according to CONSORT.DiscussionA cluster-randomized stepped wedge design is well-suited for evaluating this type of surgical safety program. The targeted standards are not in doubt, yet compliance is frequently difficult. Solutions are available and may be recognized by individuals, but teams dedicated to improvement are often lacking. Clean Cut was successfully piloted but requires a more rigorous methodological assessment. We seek to understand the qualities, characteristics, and resources needed to implement the program, the magnitude of effect on processes and outcomes, and to what degree it can enhance compliance with care standards. Challenges include a fraught social and political environment, pandemic travel restrictions, and a limited budget.Trial registrationClinicalTrials.gov NCT04812522 (registered on March 23, 2021); Pan-African Clinical Trials Registry PACTR202108717887402 (registered on August 24, 2021)