ARREST

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Thwaites GE, et al. "Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial". The Lancet. 2017. 391(10121):668-678.
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Clinical Question

In adults with Staphylococcus aureus bacteraemia (SAB), does the addition of rifampicin to standard treatment reduce disease recurrence, treatment failure or death?

Bottom Line

The addition of rifampicin to standard treatment did not reduce short term or long term mortality in adult patients with SAB.

Major Points

SAB is a common life threatening infection with an associated mortality of approximately 20%. Up until ARREST, fewer than 1600 participants with SAB had been enrolled in randomised trials over the past 50 years. A 2014 systematic review suggested a trend towards lower mortality and treatment failure with adjunctive rifampicin but the evidence was weak. [1]

ARREST is the largest randomised trial to date in SAB and provides convincing evidence that adjunctive rifampicin does not reduce short term or long term mortality. There was a small but significant reduction in disease recurrence with the addition of rifampicin, however, there was a higher rate of antibiotic modifying adverse events in the rifampicin arm. The authors conclude there is no overall benefit to using rifampicin in SAB.

Prosthetic valve endocarditis and prosthetic joint infections comprised very small numbers and so it is difficult to draw any conclusions regarding the these populations and rifampicin continues to be recommended treatment in these groups.

Guidelines

As of March 2018, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, randomised, double-blind, placebo controlled trial
  • n=758
    • Rifampicin (n=370)
    • Placebo (n=388)
  • Setting: 29 UK hospital groups
  • Enrollment: 10th December 2012 - 25th October 2016
  • Follow-up: 12 weeks
  • Analysis: Intention-to-treat
  • Primary outcome: Bacteriologically confirmed treatment failure or disease recurrence or death (all cause) at 12 weeks

Population

Inclusion Criteria

  • Adult inpatient (18 years old or over)
  • Isolated MSSA or MRSA from at least 1 blood culture
  • Received less than 96 hours of therapy for current infection (one off stat doses more than 96 hours previously were allowed)
  • No pre-existing evidence of S. aureus rifampicin resistance
  • No contraindication to rifampicin use

Exclusion Criteria

  • S. aureus considered to be contaminant or mixed with another organism causing current infection
  • Suspected active tuberculosis
  • Rifampicin use considered mandatory for any reason
  • Previous randomisation in ARREST

Baseline Characteristics

Baseline characteristic were similar between both trial arms with following combined characteristics:

  • Men: 65%
  • Median age: 65 (IQR 50 -76) years
  • Charlston comorbidity score: 2
  • Mean C-reactive protein: 164 mg/l
  • Community acquired S. aureus: n=485 (64%)
  • MRSA infection: n=47 (6%)
  • Median antibiotic duration at randomisation: 62 (IQR 42-74) hours

Main focus of infection:

  • Native valve endocarditis: n=33 (4%)
  • Native joint: n=63 (8%)
  • Prosthetic valve endocarditis: n=7 (0.9%)
  • Prosthetic joint: n=7 (0.9%)
  • Implanted vascular device (excludes intravascular catheters): n=36 (5%)
  • Deep tissue infection or abscess; n= 176 (23%)
  • Central or peripheral intravenous catheter: n=130 (17%)
  • Skin or soft tissue: n=138 (18%)
  • Surgical wound: n=25 (3%)
  • Pneumonia or UTI: n=60 (8%)
  • Not established: n=139 (18%)

Interventions

  • Rifampicin 600mg or 900mg PO/IV (weight dependent dosing)
    • administered as single dose or twice daily divided dose
    • 14 days duration or until backbone therapy stopped

Outcomes

All comparisons are presented rifampicin vs. placebo.

Primary Outcomes

Bacteriologically confirmed treatment failure or disease recurrence or death (all cause) at 12 weeks

17% vs. 18% (HR 0.96; 95% CI 0.68-1.35; P=0.81)

Secondary Outcomes

All cause mortality at 2 weeks

7% vs. 4% (HR 1.60; 95% CI 0.86-2.95; P=0.13)

Clinical treatment failure or disease recurrence or death at 12 weeks

21% vs. 22% (HR 0.97; 95% CI 0.71-1.32; P=0.84)

Grade 3-4 adverse events

35% vs. 34% (HR 1.12; 95% CI 0.88-1.43; log rank P=0.36)

Serious adverse events

27% vs. 24% (HR 1.21; 95% CI 0.92-1.61; log rank P=0.17)

Antibiotic modifying adverse events

17% vs. 10% (HR 1.78; 95% CI 1.20-2.65; log rank P=0.004)

Subgroup Analysis

Bacteriological treatment failure at 12 weeks

1% vs 1% (competing risks P=0.82)

Bacteriological recurrence at 12 weeks

1% vs. 4% (competing risks P=0.01)

Deaths at 12 weeks

15% vs. 14% (HR 1.10; 95% CI 0.76-1.60; P=0.60)

Renal grade 3-4 adverse event

5% vs. 2%; P=0.053

Criticisms

  • At the request of the funding body, the original co-primary outcome was downgraded to a single outcome due to slow recruitment and to allow trial completion with a smaller sample size.
  • Infections with prosthetic material were under-represented and it is therefore difficult to draw any conclusions in these clinical situations.
  • Mortality rates were lower than some other studies, due to difficulty recruiting more severely unwell patients.

Funding

UK National Institutes of Health Research Health Technology Assessment

Further Reading

Thwaites GE, Edgeworth JD, Gkrania-Klotsas E, Kirby A, Tilley R, Torok ME, et al. Clinical management of Staphylococcus aureus bacteraemia. Lancet Infect Dis. 2011;11:208-22.

References

  1. Russell CD et al. Adjunctive rifampicin may improve outcomes in Staphylococcus aureus bacteraemia: a systematic review. J. Med. Microbiol. 2014. 63:841-8.