Adding the antibiotic rifampicin did not improve cure rates or reduce deaths for people with bacterial blood infections caused by Staphylococcus aureus. It increased the risk of adverse reactions requiring a change in treatment and the chances of drug interactions.
This NIHR-funded trial is the largest to date on adding rifampicin to standard antibiotic therapy. The study included 770 people in 29 UK hospitals. Half were assigned to 14 days of treatment with rifampicin on top of their existing antibiotic regime. Rifampicin could be either oral or intravenous.
Why was this study needed?
Blood stream infections with S. aureus are life-threatening and one of the most common causes of sepsis world-wide. Lack of evidence about the best treatment regime has led to wide variations in practice. Mortality rates in the UK range from 10% to 30%.
The usual treatment is with a penicillin or glycopeptide but varies by the subgroup of S. aureus and whether the strain is methicillin-resistant. Case series show around 30% of people treated for S. aureus bacteraemia in the UK also received rifampicin, despite a lack of evidence for its use. The drug can cause liver toxicity and interact with many other drugs.
A previous systematic review showed a potential reduction in mortality and treatment failure, but there were only 54 participants. Therefore, this study was intended to address the lack of large-scale studies to find out whether rifampicin, given alongside standard antibiotic treatment, reduced treatment failure, disease recurrence or mortality.
What did this study do?
The ARREST randomised controlled trial involved 29 hospitals in the UK. Researchers recruited 770 adults with S. aureus bacteraemia. They were assigned to either two weeks of rifampicin (oral or intravenous, 600mg or 900mg a day, depending on body weight), or placebo, in addition to their physician’s choice of standard antibiotic therapy.
Neither the doctor nor patient was aware of which treatment they were receiving, but as rifampicin causes discolouration of the urine, some might have guessed. Treating physicians followed a protocol and could change antibiotics or withdraw the patient from the trial if judged clinically necessary.
Recruitment for the trial was slow, and the outcome was modified to allow for a smaller patient population than initially intended.
What did it find?
- By the end of the 12-week follow-up 17% of patients who received rifampicin, and 18% who received placebo had experienced treatment failure, disease recurrence or had died (absolute risk difference -1.4%, 95% confidence interval [CI] -7.0 to 4.3). The difference is small, and the CI means it is unlikely that rifampicin gives 10% better results, which would be clinically important enough to justify its use.
- Serious adverse events were similar between the two groups, at 27% for rifampicin and 24% for placebo (hazard ratio [HR] 1.21, 95% CI 0.92 to 1.61). However, adverse events that required the antibiotic regime to be modified were more common with rifampicin (17% versus 10%; HR 1.78, 95% CI 1.20 to 2.65). Gastrointestinal disorders and urinary disorders were more common with rifampicin.
- Rifampicin caused more drug interactions. They occurred in 6% compared to 2% of those on placebo.
- The focus of infection was thought to be deep for 40% of participants, including 4% who had infective endocarditis (infection of the lining of the heart), 2% with infected prostheses, 17% with infected intravenous lines and 2% with an infected artificial heart valve.
What does current guidance say on this issue?
NICE guidelines on diagnosis and management of sepsis, issued in 2016, do not specify an antibiotic regime for treatment of bacteraemia, but state that doctors should use antibiotics from the agreed local formulary, and refer to local antimicrobial guidelines.
What are the implications?
Rifampicin routinely added to standard antibiotic treatment for patients with S. aureus bacteraemia provided no clinically important benefit, over standard antibiotic therapy. This implies that hospital microbiologists could update their policies to take account of this trial. The size of the trial, which is bigger than the combination of all previous randomised controlled trials for bacteraemia treatment, strengthens the evidence.
However, sub-groups were small, particularly for infections focused on prosthetic valves and joints. Many physicians see rifampicin as mandatory for endocarditis of prosthetic valves or infection of artificial joints, which may explain the low numbers recruited to the trial.
There may still be specific groups of patients for whom rifampicin remains an option.
Citation and Funding
Thwaites GE, Scarborough M, Szubert A, et al; United Kingdom Clinical Infection Research Group (UKCIRG). Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2018;391:668-78.
This project was funded by the National Institute for Health Research Health Technology Assessment (HTA) programme (project number 10/104/2).
Habib G, Lancellotti P, Antunes MJ, et al. 2015 ESC Guidelines for the management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur Heart J. 2015;36(44):3075-128.
Holland TL, Fowler VG Jr. Rifampicin for Staphylococcus aureus bacteraemia: give it ARREST. Lancet. 2017;391(10121):634-6.
NICE. Sepsis: recognition, diagnosis and early management. NG51. London: National Institute for Health and Care Excellence; 2016.
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