By Richard R. Watkins, MD, MS, FACP, FIDSA

Associate Professor of Internal Medicine, Northeast Ohio Medical University; Division of Infectious Diseases, Cleveland Clinic Akron General, Akron, OH

Dr. Watkins reports that he has received research support from Allergan.

SYNOPSIS: A population-based case-control study from Denmark found the use of statins was associated with a decreased risk for community-associated Staphylococcus aureus bacteremia, with the greatest benefit from higher doses.

SOURCE: Smit J, López-Cortés LE, Thomsen RW, et al. Statin use and risk of community-acquired Staphylococcus aureus bacteremia: A population-based case-control study. Mayo Clin Proc 2017;92:1469-1478.

Staphylococcus aureus bacteremia (SAB) is a serious and often fatal infection despite appropriate therapy. There is some evidence that statins have anti-staphylococcal activity. Therefore, Smit and colleagues sought to determine whether patients who took statins to lower their cholesterol had a reduced risk for developing community-acquired SAB.

The study was conducted in Denmark between Jan. 1, 2000, and Dec. 31, 2011. The investigators compiled data from multiple population-based medical registries. Patients were included if they were 15 years of age or older and had one or more positive blood cultures for S. aureus as the sole isolate collected within two days of hospital admission. For each case, 10 randomly selected controls were matched according to age, sex, and area of residence. Researchers used another database to identify all prescriptions filled for statins by cases and controls before the index date. Statin usage was defined further as new users, who filled their first-ever statin prescription within 90 days of the index date, and long-term users, who had previously filled a statin prescription. The databases also were used to record comorbid conditions and other prescriptions, including those for corticosteroids, immunomodulating drugs, chemotherapy drugs, and nonsteroidal anti-inflammatory drugs (NSAIDs).

The researchers identified 2,638 cases of community-acquired SAB. Only 13 (0.5%) of the cases were due to methicillin-resistant Staphylococcus aureus (MRSA). The median age was 69 years and the majority were males (61%). The patients with SAB were more likely than the controls to have comorbidities, including peripheral arterial disease, congestive heart failure, diabetes mellitus, and cancer. They also were more likely to have filled prescriptions for corticosteroids and NSAIDs. Compared to non-statin users, the adjusted odds ratio (aOR) was 0.96 (95% confidence interval [CI], 0.60-1.51) for new users, 0.71 (95% CI, 0.62-0.82) for long-term users, and 1.12 (95% CI, 0.94-1.32) for former users. The risk of SAB decreased with increasing statin doses, such that the aOR was 0.84 (95% CI, 0.68-1.04) for current users with daily doses < 20 mg/d compared to 0.63 (95% CI, 0.49-0.81) for current users with daily doses of 40 mg/d or more. The decrease in SAB risk was most pronounced in patients with chronic kidney disease (aOR, 0.51; 95% CI, 0.34-0.76) and patients with diabetes mellitus (aOR, 0.65; 95% CI, 0.50-0.85). There were no differences in the risk of SAB according to sex, age, Charlson comorbidity index, or between the different brands of statins.

COMMENTARY

In this study, current users of statins experienced an almost 30% reduction in the risk of SAB compared to nonusers. The risk decreased as the statin dose increased, with the association most pronounced in patients with chronic kidney disease and diabetes. These findings are consistent with other evidence showing statins to be associated with a lower risk of pneumonia, sepsis, and post-operative infections.

In vitro studies suggest that statins exert several pleiotropic effects that theoretically could decrease the risk for SAB. First, statins have a direct antimicrobial effect against S. aureus. The minimum inhibitory concentration of simvastatin against S. aureus ranges from 15 to 32 mg/mL, although this is considerably higher than the concentration of 0.02 mg/mL attained from 40 mg of the drug. Second, statins inhibit host cell invasion and biofilm formation by S. aureus. Third, statins enhance the ability of neutrophils to kill S. aureus. Thus, it would appear that statins may have a role as a complementary strategy in preventing SAB.

The study by Smit and colleagues should serve as a foundation for a randomized, placebo-controlled clinical trial to confirm the beneficial effects of statin use in reducing the risk for SAB. This possibility is exciting because statins are relatively inexpensive, have a favorable safety profile, and do not have the drawbacks associated with using antibiotics for SAB prevention, such as increasing the spread of antimicrobial resistance and Clostridium difficile infection.

The study had a few limitations that deserve mentioning. First, the investigators assumed that by patients filling their statin prescription they actually were taking it, which is unlikely in all cases. Second, the rate of SAB due to MRSA (0.5%) in the study was extremely low compared to what is seen in the United States (approximately 40%), which hinders extrapolation of the results to other settings where the incidence of MRSA is higher. Third, there may have been bias from the so-called “healthy user” effect, whereby statin users are more likely to engage in other healthy behaviors (e.g., less obesity, not smoking, more exercise, etc.) compared to non-statin users.

Smit and colleagues have presented persuasive evidence for a beneficial effect from statins in preventing community-acquired SAB. However, a randomized, placebo-controlled trial will be necessary before a strong evidence-based recommendation for this indication can be endorsed.