Abstract
An emergent approach to bacterial infection is the use of host rather than bacterial-directed strategies. This approach has the potential to improve efficacy in especially challenging infection settings, including chronic, recurrent infection due to intracellular pathogens. For nearly two decades, the pleiotropic effects of statin drugs have been examined for therapeutic usefulness beyond the treatment of hypercholesterolemia. Interest originated after retrospective studies reported decreases in the risk of death due to bacteremia or sepsis for those on a statin regimen. Although subsequent clinical trials have yielded mixed results and earlier findings have been questioned for biased study design, in vitro and in vivo studies have provided clear evidence of protective mechanisms that include immunomodulatory effects and the inhibition of host cell invasion. Ultimately, the benefits of statins in an infection setting appear to require attention to the underlying host response and to the timing of the dosage. From this examination of statin efficacy, additional novel host-directed strategies may produce adjunctive therapeutic approaches for the treatment of infection where traditional antimicrobial therapy continues to yield poor outcomes. This review focuses on the opportunistic pathogen, Staphylococcus aureus, as a proof of principle in examining the promise and limitations of statins in recalcitrant infection.
Highlights
Staphylococcus aureus InfectionStaphylococcus aureus colonizes approximately 30% of the human population, yet colonized individuals typically remain asymptomatic [1,2]
An emergent approach to bacterial infection is the use of host rather than bacterial-directed strategies
Pleiotropic effects of simvastatin, as a host-directed therapeutic, limits S. aureus invasion into host cells through decreased synthesis of isoprenoid intermediates, sequestration of RAC, RHO, and CDC42 in the cytosol, decreased membrane localization of these small-GTPases coupled to PI3Kp85α, reduced actin stress fiber depolymerization, decreased host cell binding to fibronectin, and decreased internalization and recycling of β1-integrin receptor complexes to the host cell surface
Summary
Staphylococcus aureus colonizes approximately 30% of the human population, yet colonized individuals typically remain asymptomatic [1,2]. S. aureus is an opportunistic pathogen and is the causative agent in life-threatening infections associated with high morbidity and mortality. High mortality rates are associated with S. aureus infections. High morbidity and mortality rates are not merely attributable to antibiotic resistance, such as in the reporting of the 19% all-cause in-hospital mortality rate associated with methicillin-susceptible S. aureus (MSSA) bloodstream infections [7]. This opportunistic pathogen inflicts significant morbidity and mortality through infection by resistant strains and by strains susceptible to first-line antimicrobial treatment. In addition to acute pathogenesis, both MSSA and MRSA represent an important cause of severe, chronic infections associated with high mortality
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