Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial
Guy E Thwaites, Matthew Scarborough, Alexander Szubert, Emmanuel Nsutebu, Robert Tilley, Julia Greig, Sarah A Wyllie, Peter Wilson, Cressida Auckland, Janet Cairns, Denise Ward, Pankaj Lal, Achyut Guleri, Neil Jenkins, Julian Sutton, Martin Wiselka, Gonzalez-Ruiz Armando, Clive Graham, Paul R Chadwick, Gavin Barlow, N Claire Gordon, Bernadette Young, Sarah Meisner, Paul McWhinney, David A Price, David Harvey, Deepa Nayar, Dakshika Jeyaratnam, Tim Planche, Jane Minton, Fleur Hudson, Susan Hopkins, John Williams, M Estee Török, Martin J Llewelyn, Jonathan D Edgeworth, A Sarah Walker, United Kingdom Clinical Infection Research Group (UKCIRG)
Abstract
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.
Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
Figures
References
- Tong SY, Davis JS, Eichenberger E, Holland TL, Fowler VG., Jr Staphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management. Clin Microbiol Rev. 2015;28:603–661.
- Kaasch AJ, Barlow G, Edgeworth JD. Staphylococcus aureus bloodstream infection: a pooled analysis of five prospective, observational studies. J Infect. 2014;68:242–251.
- Thwaites GE, Edgeworth JD, Gkrania-Klotsas E. Clinical management of Staphylococcus aureus bacteraemia. Lancet Infect Dis. 2011;11:208–222.
- Naber CK, Baddour LM, Giamarellos-Bourboulis EJ. Clinical consensus conference: survey on Gram-positive bloodstream infections with a focus on Staphylococcus aureus. Clin Infect Dis. 2009;48(suppl 4):S260–S270.
- Liu C, Bayer A, Cosgrove SE. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:e18–e55.
- Norden CW, Shaffer M. Treatment of experimental chronic osteomyelitis due to Staphylococcus aureus with vancomycin and rifampin. J Infect Dis. 1983;147:352–357.
- Forrest GN, Tamura K. Rifampin combination therapy for nonmycobacterial infections. Clin Microbiol Rev. 2010;23:14–34.
- Thwaites GE, United Kingdom Clinical Infection Research Group (UKCIRG) The management of Staphylococcus aureus bacteremia in the United Kingdom and Vietnam: a multi-centre evaluation. PLoS One. 2010;5:e14170.
- Rieg S, Joost I, Weiss V. Combination antimicrobial therapy in patients with Staphylococcus aureus bacteraemia—a post hoc analysis in 964 prospectively evaluated patients. Clin Microbiol Infect. 2017;23:406.e1–406.e8.
- Holland TL, Arnold C, Fowler VG., Jr Clinical management of Staphylococcus aureus bacteremia: a review. JAMA. 2014;312:1330–1341.
- Russell CD, Lawson McLean A, Saunders C, Laurenson IF. Adjunctive rifampicin may improve outcomes in Staphylococcus aureus bacteraemia: a systematic review. J Med Microbiol. 2014;63(Pt 6):841–848.
- Thwaites G, Auckland C, Barlow G. Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia (ARREST): study protocol for a randomised controlled trial. Trials. 2012;13:241.
- US Department for Health and Human Services . National Institute of Health; 2010. Common terminology criteria for adverse events (CTCAE) Version 4.0. (accessed Nov 8, 2017).
- Duerden B, Fry C, Johnson AP, Wilcox MH. The control of methicillin-resistant Staphylococcus aureus blood stream infections in England. Open Forum Infect Dis. 2015;2:ofv035.
- Loubet P, Burdet C, Vindrios W. Cefazolin versus anti-staphylococcal penicillins for treatment of methicillin-susceptible Staphylococcus aureus bacteremia: a narrative review. Clin Microbiol Infect. 2017
- Watanakunakorn C. A general survey of antibiotic treatment of staphylococcal septicaemia and endocarditis. Scand J Infect Dis Suppl. 1983;41:151–157.
- Thwaites GE, Gant V. Are bloodstream leukocytes Trojan Horses for the metastasis of Staphylococcus aureus? Nat Rev Microbiol. 2011;9:215–222.
- Fowler VG, Jr, Boucher HW, Corey GR. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med. 2006;355:653–665.
- Vogel M, Schmitz RP, Hagel S. Infectious disease consultation for Staphylococcus aureus bacteremia—A systematic review and meta-analysis. J Infect. 2016;72:19–28.
- Sendi P, Zimmerli W. Antimicrobial treatment concepts for orthopaedic device-related infection. Clin Microbiol Infect. 2012;18:1176–1184.
- Harris PNA, McNamara JF, Lye DC. Proposed primary endpoints for use in clinical trials that compare treatment options for bloodstream infection in adults: a consensus definition. Clin Microbiol Infect. 2017;23:533–541.
- Wang R, Lagakos SW, Ware JH, Hunter DJ, Drazen JM. Statistics in medicine—reporting of subgroup analyses in clinical trials. N Engl J Med. 2007;357:2189–2194.
- Ruotsalainen E, Jarvinen A, Koivula I. Levofloxacin does not decrease mortality in Staphylococcus aureus bacteraemia when added to the standard treatment: a prospective and randomized clinical trial of 381 patients. J Intern Med. 2006;259:179–190.
Source: PubMed