By Stan Deresinski, MD, FACP, FIDSA
Clinical Professor of Medicine, Stanford University
Dr. Deresinski reports no financial relationships relevant to this field of study.
SYNOPSIS: The addition of rifampin to standard therapy failed to provide significant benefit to patients with bacteremia due to Staphylococcus aureus.
SOURCE: 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 2017 Dec 14. pii: S0140-6736(17)32456-X. doi: 10.1016/S0140-6736(17)32456-X. [Epub ahead of print].
The ARREST trial was a randomized, double-blind, placebo-controlled trial performed at 29 hospitals in the United Kingdom that was designed to determine whether the addition of rifampin to standard therapy improved outcomes in patients with Staphylococcus aureus bacteremia. Patients were randomized to receive either rifampin (600 mg or 900 mg daily) or placebo for 14 days. The choice of the base antibiotic was left to the clinician, as was its duration of administration; flucloxacillin was used in 82% of patients, and many patients also received an aminoglycoside for some duration. A total of 758 patients were included in the final analysis. Sixty-four percent of infections were community acquired. Overall, 40% of bacteremias were considered to arise from a “deep” focus, but very few involved native heart valves or prosthetic devices, although almost one-fifth arose from intravenous catheters. Only 47 (6%) isolates were methicillin resistant (MRSA).
The base antibiotic was administered for a median of 29 days (IQRm 18-45 days). Treatment failure, disease recurrence, or death at 30 days occurred in 17% and 18% of rifampin and placebo recipients, respectively. There was no significant difference in composite failure rates when patients with MRSA infection were excluded from the analysis, and there also was no statistically significant difference in those with MRSA infection: 3/21 (14.3%) in placebo recipients and 9/26 (34.6%; hazard ratio [HR], 2.74; 95% confidence interval, 0.74-10.15) in those assigned rifampin. Infection recurred in 16 (4%) placebo recipients and three (1%; P = 0.01) rifampin recipients. There were significantly more adverse events leading to treatment modification in those assigned rifampin.
This is an impressive trial that goes a long way toward answering the question of when and whether adjunctive rifampin administration provides benefit in patients with S. aureus bacteremia. However, firm conclusions to be drawn from it must be tempered by several observations.
The circumstance in which there has been the most enthusiasm for adjunctive use of rifampin is in the treatment of retained foreign material, such as joint prostheses, but the number of such cases in this study was small. In addition, the fact that only 6% of isolated pathogens were MRSA means that application of these results to infections with that organism undoubtedly will be questioned by some. Seventeen percent of patients had infection related to central or peripheral intravenous catheters and presumably had these removed, although no data regarding source control in these or other infections were presented.
On the other hand, the greater risk of adverse events or drug interactions important enough to warrant alteration of treatment in rifampin recipients suggests that the small number of patients who might have benefited from adjunctive rifampin may be insufficient to overcome this problem. It should be noted that 11% of screened patients were excluded from participation because of potential drug interactions with rifampin.
The arguments for adjunctive rifampin include its potent in vitro bactericidal activity, its intracellular penetration, and its activity against organisms growing in biofilm. However, with the exception of its use with ciprofloxacin (an antibiotic with limited antistaphylococcal activity) in orthopedic device infections, for example, evidence of its benefit is limited. In fact, many in vitro studies indicate the presence of antagonism when combined with other anti-staphylococcal agents.
Overall, it can be concluded that the available evidence does not support the use of adjunctive rifampin therapy in patients with S. aureus bacteremia.