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 bacteremia, does the addition of rifampin to standard treatment reduce the incidence of disease recurrence, treatment failure, or death?

Bottom Line

The addition of rifampin to standard treatment did not improve short- or long-term outcomes in adult patients with Staphylococcus aureus bacteremia.

Major Points

Staphylococcus aureus bacteremia (SAB) is a common life-threatening infection with an associated mortality of approximately 20%. Until ARREST was published in 2017, fewer than 1600 participants with SAB had been enrolled in randomized trials over the prior 50 years. A 2014 systematic review suggested a trend towards lower mortality and treatment failure with adjunctive rifampin but the evidence was weak.[1]

ARREST randomized nearly about 750 patients with SAB to standard of care antibiotics versus standard of care plus rifampin (called 'rifampicin' as it is the international generic name of rifampin). Patients were followed for the primary outcome of treatment failure, disease recurrence, or all-cause mortality, and events were tabulated up to 2 weeks and then 12 weeks from randomization. The primary analysis demonstrated no difference in the rates of the primary outcome between rifampin and placebo arms (17% versus 18%; P=0.81). There was a small but significant reduction in disease recurrence with the addition of rifampin, however, there was a higher rate of antibiotic modifying adverse events and drug-drug interactions in the rifampin arm. The authors conclude there is no overall benefit to using rifampin in SAB.

ARREST was the largest randomized trial to date in SAB and provided convincing evidence that adjunctive rifampin does not improve short- or long-term outcomes in these patients. One caveat remains generalizability. For example, prosthetic valve endocarditis and prosthetic joint infections comprised very small numbers and so it is difficult to draw any conclusions regarding these populations. Consequently, many continue to recommend rifampin in these indications.

Guidelines

As of August 2019, no guidelines have been published that reflect the results of this trial.

The IDSA projects new guidelines for SAB in Fall 2020.[2]

Design

  • Multicenter, randomized, double-blind, placebo-controlled trial
  • N=758 patients with Staphylococcus bacteremia included in the ITT analysis
    • rifampin (n=370)
    • Placebo (n=388)
  • Setting: 29 UK hospital groups
  • Enrollment: 2012-2016
  • Follow-up: 12 weeks
  • Analysis: Intention-to-treat
  • Primary outcome: Treatment failure, disease recurrence, or all-cause mortality at 12 weeks

Population

Inclusion Criteria

  • Age ≥18 years
  • Isolated MSSA or MRSA from at least 1 blood culture
  • Received less than 96 hours of therapy for current infection
  • No prior evidence of S. aureus resistant to rifampin
  • No contraindication to rifampin use

Exclusion Criteria

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

Baseline Characteristics

Demographics:

  • Women: 35%
  • Median age: 65 (IQR 50-76) years
  • Charlson comorbidity score: 2

SAB characteristics:

  • Mean CRP: 164 mg/L
  • Community acquired S. aureus: 64%
  • MRSA: 6%
  • Median antibiotic duration at randomization: 62 (IQR 42-74) hours

Main focus of infection:

  • Native valve endocarditis: 4%
  • Native joint: 8%
  • Prosthetic valve endocarditis: 0.9%
  • Prosthetic joint: 0.9%
  • Implanted vascular device (excludes intravascular catheters): 5%
  • Deep tissue infection or abscess: 23%
  • Central or peripheral intravenous catheter: 17%
  • Skin or soft tissue: 18%
  • Surgical wound: 3%
  • Pneumonia or UTI: 8%
  • Not established: 18%

Interventions

  • Weight-based rifampin 600 mg/d or 900 mg/d PO/IV
    • Administered as single dose or twice daily divided dose
    • 14 days duration or until backbone therapy stopped

Outcomes

All comparisons are presented rifampin vs. placebo group.

Primary Outcomes

Treatment failure, disease recurrence, or all-cause mortality 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

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.
  2. Staphylococcus aureus Bacteremia Clinical Guidelines from IDSA