ARREST trial confirms lack of benefit of adjunct rifampicin for S. aureus bacteraemia
Adding rifampicin to standard antibiotic therapy does not improve outcomes in individuals with Staphylococcus aureus (S. aureus) bacteraemia, the ARREST* trial shows. However, rifampicin may contribute towards a minor reduction in bacteraemia recurrence.
“Although adjunctive rifampicin does not reduce mortality from S. aureus bacteraemia, it might reduce the risk of disease recurrence, but our results suggest this effect had no impact on short-term or long-term mortality. Furthermore, rifampicin complicates other drug treatment. We consider that adjunctive rifampicin provides no overall benefit over standard antibiotic therapy in adults with S. aureus bacteraemia,” said the researchers.
In this multicentre (29 hospitals in the UK), double-blind trial, 758 patients aged ≥18 years (median age 65 years, 65 percent male) with S. aureus bacteraemia who had received antibiotic treatment for up to 96 hours were randomized to receive oral or intravenous adjunctive rifampicin (600 or 900 mg per day; weight dependent; n=370) or placebo (n=388) in addition to their standard antibiotics for 2 weeks or until cessation of standard antibiotic treatment.
The incidence of treatment failure (ongoing S. aureus infection beyond 14 days post-randomization), disease recurrence (S. aureus infection after >7 days of clinical improvement), or death at 12 weeks was comparable between patients prescribed rifampicin and placebo (17 percent vs 18 percent; hazard ratio [HR], 0.96, 95 percent confidence interval, 0.68–1.35; p=0.81). [Lancet 2017;doi:10.1016/S0140-6736(17)32456-X]
An exploratory post-hoc analysis indicated a trend towards fewer disease recurrences with rifampicin treatment vs placebo, be it bacteriological (1 percent vs 4 percent) or clinical recurrence (2 percent vs 6 percent; p=0.01 for each comparison).
There were 56 deaths in each treatment group by week 12 (p=0.60), of which 14 and 16 deaths in the rifampicin and placebo groups, respectively, were deemed “definitely S. aureus-related”, while 18 and 23 deaths, respectively, were considered unrelated to S. aureus. Survival beyond the 12-week trial period was similar between patients on rifampicin and placebo (p=0.69).
Incidence of grade 3–4 adverse events (AEs) was also comparable between patients on rifampicin and placebo (35 percent vs 34 percent; HR, 1.12; p=0.36). Grade 3–4 renal-related AEs were more common among rifampicin recipients (5 percent vs 2 percent; p=0.053), as were gastrointestinal and renal disorders (n=24 vs 8; p=0.003 and n=8 vs 1; p=0.02, respectively).
Antibiotic or trial drug-modifying AEs and drug interactions were also more frequent among rifampicin compared with placebo recipients (17 percent vs 10 percent; p=0.004 and 6 percent vs 2 percent; p=0.0005, respectively).
“[T]he optimal antibiotic treatment [for S. aureus bacteraemia] is uncertain … [with] most treatment recommendations … based on observational studies and clinical experience,” said the researchers.
“The small but statistically significant reduction in recurrences in the rifampicin group indicates the drug had some biological activity, although its clinical significance is debatable. In addition, [an] independent, masked review committee adjudicated that recurrences were more commonly caused by failure to recognize or remove the primary infection focus than a failure of antibiotic treatment. Therefore, rifampicin might assist in the sterilization of deep S. aureus infection foci and prevent a few recurrences, but it does not replace the need to define and, when possible, drain or remove the infection focus,” they said.