Rifampicin for Staphylococcus aureus bacteraemia: give it ARREST
Authors: Thomas L Holland, Vance G Fowler
Journal: The Lancet (2017)

Although Staphylococcus aureus bacteraemia is both common and potentially lethal, clinical decisions involving its treatment remain largely unencumbered by high-quality data.1Holland TL Arnold C Fowler Jr, VG Clinical management of Staphylococcus aureus bacteremia: a review.JAMA. 2014; 312: 1330-1341Crossref PubMed Scopus (297) Google Scholar With the ARREST multicentre, randomised, double-blind, placebo-controlled trial, Guy Thwaites and colleagues2Thwaites GE Scarborough M Szubert A et al.Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.Lancet. 2017; (published online Dec 14.)http://dx.doi.org/10.1016/S0140-6736(17)32456-XSummary Full Text Full Text PDF Scopus (95) Google Scholar have contributed high-quality evidence and addressed an unresolved question involving the role of adjunctive rifampicin in treatment regimens for patients with S aureus bacteraemia. Although the role of rifampicin as an adjunctive therapy for S aureus bacteraemia is biologically plausible, few studies have evaluated it clinically,3Russell 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: 841-848Crossref PubMed Scopus (21) Google Scholar and the results for patients with S aureus native valve endocarditis4Riedel DJ Weekes E Forrest GN Addition of rifampin to standard therapy for treatment of native valve infective endocarditis caused by Staphylococcus aureus.Antimicrob Agents Chemother. 2008; 52: 2463-2467Crossref PubMed Scopus (111) Google Scholar, 5Levine DP Fromm BS Reddy BR Slow response to vancomycin or vancomycin plus rifampin in methicillin-resistant Staphylococcus aureus endocarditis.Ann Intern Med. 1991; 115: 674-680Crossref PubMed Scopus (516) Google Scholar have thus far been disappointing. Adjunctive rifampicin remains standard therapy for S aureus prosthetic valve endocarditis and prosthetic joint infections; however, US treatment guidelines for meticillin-resistant S aureus infections advocate against its addition for S aureus bacteraemia or native valve endocarditis in adults,6Liu C Bayer A Cosgrove SE et al.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-e55Crossref PubMed Scopus (1897) Google Scholar and UK guidelines avoid making a recommendation altogether.7Gould FK Brindle R Chadwick PR et al.Guidelines (2008) for the prophylaxis and treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections in the United Kingdom.J Antimicrob Chemother. 2009; 63: 849-861Crossref PubMed Scopus (148) Google Scholar The result: heterogeneous practice patterns8Rieg S Joost I Weiss V et al.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.e8Summary Full Text Full Text PDF Scopus (37) Google Scholar and equipoise inviting the potential for a well designed clinical trial to confuse the issue with facts. In ARREST, 758 adults with S aureus bacteraemia were randomly assigned to 2 weeks of treatment with either rifampicin (600 mg or 900 mg per day; oral or intravenous) or placebo, in addition to standard antibiotic therapy. The primary outcome was time to bacteriological treatment failure or disease recurrence, or death (all-cause) from randomisation to 12 weeks. After 12 weeks, no significant difference in mortality or bacteriological failure was noted between the rifampicin-treated and placebo-treated groups (17% vs 18%; absolute risk difference −1·4%, 95% CI −7·0 to 4·3; hazard ratio 0·96, 0·68–1·35, p=0·81), but patients treated with rifampicin had more adverse events than those who received placebo (63 [17%] vs 39 [10%]) and were more likely to have drug interactions (24 [6%] vs six [2%]) that complicated their treatment. The ARREST trial was limited by the fact that few patients with conditions for which rifampicin is regarded as standard of care (eg, prosthetic cardiac valves [n=7] and joints [n=7]) were enrolled, limiting its ability to provide evidence of the use of rifampicin in these conditions. Nonetheless, the study provides a definitive result: clinicians should not use rifampicin for S aureus bacteraemia treatment in the absence of indwelling prosthetic material. Before ARREST, only one adequately powered randomised trial had been completed in patients with S aureus bacteraemia: an industry-sponsored study comparing daptomycin with standard therapy.9Fowler Jr, VG Boucher HW Corey GR et al.Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus.N Engl J Med. 2006; 355: 653-665Crossref PubMed Scopus (1243) Google Scholar Clinicians now have additional evidence to answer two S aureus bacteraemia antibiotic therapy questions: daptomycin is not inferior to standard antibiotic therapy, and adjunctive rifampicin does not improve outcomes. However, a daunting list of treatment-related questions remains. Would other antibiotic combinations fare better? What about monotherapy? How long is long enough to treat S aureus bacteraemia? Is an oral stepdown therapy for S aureus bacteraemia ever appropriate? Trialists face a more fundamental question: how can clinical trials in S aureus bacteraemia be completed? In general, clinical trials are complex; clinical trials in S aureus bacteraemia can verge on Sisyphean. ARREST was an enormous undertaking, requiring prolonged enrolment and an eventual change in study design to adapt to a smaller sample size than was initially planned. At present, a handful of other investigator-initiated trials are ongoing (table). One study tests a treatment algorithm to establish the antibiotic duration for S aureus bacteraemia (NCT01191840). A second examines the role of combination therapy with a β-lactam antibiotic for meticillin-resistant S aureus bacteraemia (CAMERA-2, NCT02365493). Most challenging are registration trials seeking antibiotic licensure for S aureus bacteraemia. Several novel agents are currently undergoing phase 2 (CF-301, NCT03163446) or phase 3 trials (telavancin, NCT02208063; ceftobiprole NCT03138733) for S aureus bacteraemia. These trials will provide much needed data for clinicians managing these challenging infections. However, the pace of completion for S aureus bacteraemia trials has been outstripped by the urgent clinical need for these data. Outcomes for patients with S aureus bacteraemia remain poor; in ARREST, 12-week mortality was almost 15%, and mortality rates are even higher in clinical practice.10Kaasch AJ Barlow G Edgeworth JD et al.Staphylococcus aureus bloodstream infection: a pooled analysis of five prospective, observational studies.J Infect. 2014; 68: 242-251Summary Full Text Full Text PDF PubMed Scopus (161) Google Scholar Now, more than ever, a clinical trials network of experienced sites is needed to prioritise the most pressing clinical questions and conduct pragmatic trials in S aureus bacteraemia and other bacterial syndromes. Ultimately, the responsibility for such a network falls to the clinical community, as we define fundamental questions on how to best treat patients with S aureus bacteraemia.TableOngoing Staphylococcus aureus bacteraemia trialsInterventionProposed sample size (N)OutcomeStatusInvestigator-initiated trialsNIH algorithm (NCT01191840)Algorithm-based therapy for staphylococcal bacteraemia509Treatment success, safety, and duration of antibiotic therapyEnrolment completedCAMERA-2 (NCT02365493)Addition of a β-lactam antibiotic to standard therapy for MRSA-BSI440Complication-free 90-day survivalRecruitingSABATO (NCT01792804)Early intravenous to oral antibiotic switch in uncomplicated SAB430SAB-related complications at 90 daysRecruitingFosfomycin (NCT01898338)Fosfomycin versus placebo, in combination with daptomycin, for MRSA bacteraemia206Clinical response 6 weeks after the end of therapyRecruitingIndustry-sponsored trialsDalbavancin (NCT03148756)Dalbavancin versus standard of care for therapy completion for complicated bacteraemia and endocarditis··Success at 12 weeksStudy terminated by sponsorTelavancin (NCT02208063)Telavancin versus standard of care for SAB, including right-sided endocarditis248Success at 8 weeksRecruitingCeftobiprole (NCT03138733)Ceftobiprole versus daptomycin for SAB, including right-sided endocarditis390Success at 10 weeksNot yet recruitingCF-301 (NCT03163446)CF-301 (a lysin) versus placebo added to standard therapy for SAB115Adverse events, day 14 clinical outcomeRecruitingSAL200 (NCT03089697)SAL200 (a lysin) versus placebo for patients with persistent SAB50SafetyRecruitingNIH=National Institutes of Health. CAMERA=combination antibiotic therapy for meticillin-resistant S aureus infection. MRSA=meticillin-resistant S aureus. BSI=bloodstream infection. SABATO=S aureus bacteraemia antibiotic treatment options. SAB=S aureus bacteraemia. Open table in a new tab NIH=National Institutes of Health. CAMERA=combination antibiotic therapy for meticillin-resistant S aureus infection. MRSA=meticillin-resistant S aureus. BSI=bloodstream infection. SABATO=S aureus bacteraemia antibiotic treatment options. SAB=S aureus bacteraemia. More than a decade since the publication of the daptomycin registration trial for S aureus bacteraemia, ARREST is a welcome addition to the still sparse collection of high-quality S aureus bacteraemia trials. The challenge now is to build on the lessons of ARREST to inform the next generation of studies. Our patients should not wait another decade to see the next big question answered. TLH has received grant support from the US National Institutes of Health (NIH), and has been a paid consultant for The Medicines Company, Genentech, Theravance, and Basilea, and all are related to S aureus therapies; and he receives consulting fees as a member of the scientific advisory board for Motif Bio. VGF served as Chair of the Scientific Advisory Committee for the V710 S aureus vaccine for Merck; has received grant support from Allergan and its predecessors (Cerexa and Actavis), and Pfizer, Advanced Liquid Logics, NIH, MedImmune, Cubist/Merck, Karius, Contrafect, and Genentech, and all are related to S aureus therapies. VGF has also been a paid consultant for Achaogen, Astellas, Arsanis, Affinergy, Basilea, Bayer, Cerexa, Contrafect, Cubist, Debiopharm, Durata, Grifols, Genentech, MedImmune, Merck, Medicines Co, Pfizer, Novartis, Novadigm, Theravanc, xBiotech; has received speakers' fees from Theravance, Green Cross, and Debiopharm; and has a patent pending in sepsis diagnostics, and all are related to S aureus therapies. Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trialAdjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. Full-Text PDF Open Access