An emerging therapeutic approach in the treatment of infectious disease is to augment the host response through repurposing of well-tolerated, non-antibiotic, host-directed therapeutics. Earlier retrospective studies identify a positive association between statin use and a decreased risk of death due to sepsis or bacteremia. However, more recent randomized control trials fail to detect a therapeutic benefit in these complex infection settings. It is postulated that unrecognized biases in certain observational studies may have led to an overestimation of benefit and that statin use is instead a marker for health status, wealth, and demographic characteristics which may separately affect death due to infection. What remains unresolved is that in vitro and in vivo evidence reproducibly indicates that statin pharmacology limits infection and augments immunomodulatory responses, suggesting that therapeutic benefits may be attainable in certain infection settings, such as intracellular infection by S. aureus. Carefully considering the biological mechanisms capable of driving the relationship between statins and infections and constructing a methodology to avoid potential biases in observational studies would enable the examination of protective effects against infection and limit the risk of underestimating statin efficacy. Such an approach would rely on the examination of statin use in defined infection settings based on an underlying mode-of-action and pharmacology, where the inhibition of HMG-CoA-reductase at the rate-limiting step in cholesterol biosynthesis diminishes not only cholesterol levels but also isoprenoid intermediates central to host cell invasion by S. aureus. Therapeutic benefit in such settings, if existent, may be of clinical importance.
Keywords: Staphylococcus aureus; intracellular infection; statins.