NIHR DC Discover

NIHR Signal Adding the extra antibiotic rifampicin did not improve cure rates after sepsis

Published on 17 April 2018

doi: 10.3310/signal-00584

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.

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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).

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).

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial

Published on 19 December 2017

Thwaites, G. E.,Scarborough, M.,Szubert, A.,Nsutebu, E.,Tilley, R.,Greig, J.,Wyllie, S. A.,Wilson, P.,Auckland, C.,Cairns, J.,Ward, D.,Lal, P.,Guleri, A.,Jenkins, N.,Sutton, J.,Wiselka, M.,Armando, G. R.,Graham, C.,Chadwick, P. R.,Barlow, G.,Gordon, N. C.,Young, B.,Meisner, S.,McWhinney, P.,Price, D. A.,Harvey, D.,Nayar, D.,Jeyaratnam, D.,Planche, T.,Minton, J.,Hudson, F.,Hopkins, S.,Williams, J.,Torok, M. E.,Llewelyn, M. J.,Edgeworth, J. D.,Walker, A. S.

Lancet , 2017

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.

Expert commentary

Many clinicians across adult and paediatric medical and surgical specialities have empirically used adjunctive or additional antibiotics to treat severe gram-positive infections.

This large well-conducted trial shows no benefit for the use of rifampicin as an additional antibiotic in adults with blood culture positive S. aureus infection. It highlights that rifampicin itself can interfere with other drug treatments.

Novel classes of drugs and better pathophysiological understanding are required to treat and eliminate biofilm-related infections rather than the addition of conventional antibiotics into current treatment regimens.

Saul N. Faust, Professor of Paediatric Immunology & Infectious Diseases, & Director, NIHR Wellcome Trust Clinical Research Facility, University of Southampton