Advertisement
Mayo Clinic Proceedings Home

Beyond Vasoprotection: Statins and Risk Reduction for Community-Acquired Staphylococcus aureus Bacteremia

      Widely and effectively employed as vasoprotective agents, statins are considered as drugs that may be beneficial in other diseases. One such disease is community-acquired Staphylococcus aureus bacteremia (CA-SAB), as delineated by the study by Smit et al
      • Smit J.
      • López-Cortés L.E.
      • Thomsen R.W.
      • et al.
      Statin use and risk of community-acquired Staphylococcus aureus bacteremia: a population-based case-control study.
      in this issue of Mayo Clinic Proceedings. The authors examined the impact of statin use on the risk of CA-SAB in a large patient population in northern Denmark over a 12-year study period.
      Staphylococcus aureus, a nasal commensal in almost half of the general population, is a major cause of bloodstream infection in both the community and health care settings and incurs significant morbidity and mortality.
      • Hill P.C.
      • Birch M.
      • Chambers S.
      • et al.
      Prospective study of 424 cases of Staphylococcus aureus bacteraemia: determination of factors affecting incidence and mortality.
      • Sohail M.R.
      • Palraj B.R.
      • Khalid S.
      • et al.
      Predicting risk of endovascular device infection in patients with Staphylococcus aureus bacteremia (PREDICT-SAB).
      Staphylococcus aureus is a gram-positive cocci that frequently colonizes human skin and mucosa and can cause a range of infections including cellulitis, abscesses, osteomyelitis, pneumonia, bacteremia, and endocarditis.
      In addition, S aureus possesses several virulence factors—cytotoxins, enzymes, and superantigens—that contribute to both direct and indirect effects of infection. Furthermore, S aureus is both adaptable and robust, with an ability to survive in a variety of environments. Such resilience of S aureus reflects the vast number of surface proteins and capsular polysaccharides that facilitate adhesion, colonization of tissues, immune evasion, and the ability to form biofilms; these are structured on an extracellular matrix that allows S aureus to protect itself against the host defense system and antibiotics.
      • Graziano T.S.
      • Cuzzullin M.C.
      • Franco G.C.
      • et al.
      Statins and antimicrobial effects: simvastatin as a potential drug against Staphylococcus aureus biofilm.
      Population-based studies have consistently identified male, diabetic, and elderly individuals and those who require dialysis as patients at increased risk for S aureus infections.
      The development of antibiotic resistance, particularly methicillin-resistant S aureus (MRSA), occurs worldwide and is associated with increased mortality, greater durations of hospital stay, and increased costs to the health care system and is now a key target for antistaphylococcal strategies.
      Statins competitively inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the cellular biosynthesis of cholesterol.
      • Davies J.T.
      • Delfino S.F.
      • Feinberg C.E.
      • et al.
      Current and emerging uses of statins in clinical therapeutics: a review.
      The inhibition of the conversion of HMG-CoA to mevalonic acid, which is a precursor in the de novo cholesterol biosynthetic pathway, results in decreased cholesterol production and reduces intracellular storage. This process triggers an increase in low-density lipoprotein (LDL) receptors at the cellular surface to bind free LDL, triggering a cascade of endocytosis and lysosomal degradation that culminates in reduction in circulating LDL blood levels.
      • Davies J.T.
      • Delfino S.F.
      • Feinberg C.E.
      • et al.
      Current and emerging uses of statins in clinical therapeutics: a review.
      The relationship between high levels of LDL cholesterol and the development of cardiovascular disease is well established.
      • Davies J.T.
      • Delfino S.F.
      • Feinberg C.E.
      • et al.
      Current and emerging uses of statins in clinical therapeutics: a review.
      Not surprisingly, statins have been integral in both primary and secondary prevention, as well as putatively slowing disease progression and reducing cardiovascular-associated morbidities and mortality. Consequently, clinical guidelines have significantly expanded the population of patients eligible and recommended for statin therapy.
      • Davies J.T.
      • Delfino S.F.
      • Feinberg C.E.
      • et al.
      Current and emerging uses of statins in clinical therapeutics: a review.
      Statins exert a variety of beneficial vascular effects that cannot be readily ascribed to their lipid-lowering effects. This includes improved vasorelaxant responses, suppression of vascular inflammation, increased stability of the atherosclerotic plaque, antithrombotic effects, and antioxidant actions. Indeed, the pleotropic effects of statins are of increasing interest and are due to both mevalonate-dependent and mevalonate-independent mechanisms.
      • Davies J.T.
      • Delfino S.F.
      • Feinberg C.E.
      • et al.
      Current and emerging uses of statins in clinical therapeutics: a review.
      • Banfi C.
      • Baetta R.
      • Gianazza E.
      • Tremoli E.
      Technological advances and proteomic applications in drug discovery and target deconvolution: identification of the pleiotropic effects of statins.
      Mevalonate is the precursor to cholesterol but also to other isoprenoids and prenylatated proteins, both of which influence cellular response to injury; by inhibiting the synthesis of these mevalonate-dependent, cholesterol-independent products (isoprenoids and prenylated proteins), statins may exert these beneficial effects. Mevalonate-independent effects of statins include the inhibition of signaling molecules such as lymphocyte function–associated antigen 1, intercellular adhesion molecule 1, and transcription factors involved in proinflammatory responses such as nuclear factor NF-kB.
      • Davies J.T.
      • Delfino S.F.
      • Feinberg C.E.
      • et al.
      Current and emerging uses of statins in clinical therapeutics: a review.
      Multiple studies have examined the use of statins in infectious diseases, most notably against S aureus infections. Statins have been found to have an antimicrobial effect against methicillin-susceptible S aureus and to a lesser extent against MRSA.
      • Jerwood S.
      • Cohen J.
      Unexpected antimicrobial effect of statins.
      Such an effect may arise from several mechanisms: (1) inhibition of host cell invasion,
      • Graziano T.S.
      • Cuzzullin M.C.
      • Franco G.C.
      • et al.
      Statins and antimicrobial effects: simvastatin as a potential drug against Staphylococcus aureus biofilm.
      • Horn M.P.
      • Knecht S.M.
      • Rushing F.L.
      • et al.
      Simvastatin inhibits Staphylococcus aureus host cell invasion through modulation of isoprenoid isolates.
      (2) inhibition of adhesion and biofilm formation, (3) action against mature biofilms, and (4) reduction in cell viability and extracellular polysaccharide production.
      • Graziano T.S.
      • Cuzzullin M.C.
      • Franco G.C.
      • et al.
      Statins and antimicrobial effects: simvastatin as a potential drug against Staphylococcus aureus biofilm.
      Furthermore, an antibacterial class effect for statins has been reported not only in methicillin-susceptible S aureus and MRSA but also in multidrug-resistant organisms including vancomycin-resistant enterococci, Acinetobacter baumannii, and Enterobacter aerogenes.
      • Masadeh M.
      • Mhaidat N.
      • Alzoubi K.
      • Al-Azzam S.
      • Alnasser Z.
      Antibacterial activity of statins: a comparative study of atorvastatin, simvastatin, and rosuvastatin.
      Such studies raise the possibility that statins may be considered as adjunctive and/or therapeutic strategies for infections caused by these organisms.
      Smit et al
      • Smit J.
      • López-Cortés L.E.
      • Thomsen R.W.
      • et al.
      Statin use and risk of community-acquired Staphylococcus aureus bacteremia: a population-based case-control study.
      contribute substantially to this field by identifying the use of statins and its association with a decreased risk of bacteremia, including CA-SAB. The study was conducted in northern Denmark over a 12-year period in 2638 patients with a 10:1 control population. The use of statins was associated with a reduced risk for CA-SAB of approximately 30%, especially in long-term statin users. Importantly, there was a dose effect found in the study in which the risk of CA-SAB decreased with increasing dosage of statin use when compared with nonusers. Furthermore, this association remained consistent across different statin medications, age, sex, comorbidity level, and even in patients with chronic kidney disease and diabetes.
      This work by Smit et al raises the exciting possibility that the pleiotropic antimicrobial effects of statins may exert a clinically relevant benefit by conferring resistance to CA-SAB. This persuasive study should stimulate randomized, placebo-controlled trials examining this effect of statins. Such trials in the case of statins are appealing because these drugs are relatively low-cost, can easily be matched against a placebo, and would allow for enrollment at the time of an already necessary antibiotic prescription. Additionally, complementary strategies may involve the use of statins in the prevention of S aureus bacteremia. A possible setting for such preventive strategy involves the field of cardiac prosthesis (ie, valves, pacemakers, defibrillators) in which infection with S aureus causes considerable morbidity and mortality. Rifampin is often used as an adjunctive strategy to antistaphylococcal therapy because of its ability to penetrate S aureus biofilms.
      • Baddour L.M.
      • Wilson W.R.
      • Bayer A.S.
      • et al.
      American Heart Association Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young, Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and Stroke Council
      Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications; a scientific statement for healthcare professionals from the American Heart Association.
      • Osmon D.R.
      • Berbari E.F.
      • Berendt A.R.
      • et al.
      Executive summary: diagnosis and management of prosthetic joint infection; clinical practice guidelines by the Infectious Diseases Society of America.
      However, rifampin is fraught with multiple drug-drug interactions and adverse effects such as liver toxicity. Examining the role of a statin prescribed at the time of prosthetic device implantation to reduce the risk of S aureus bacteremia as well as biofilm formation may be considered for future clinical trials.
      In summary, S aureus bacteremia has devastating consequences in those afflicted. Although there is a range of treatment options for S aureus bacteremia, preventing its occurrence in the first place is obviously preferred, especially in the sickest patients who in turn would have the most to gain from an agent with a relatively low adverse effect profile. Based on the extensive research in this field, and now this study, we believe that the use of non-traditional antibiotic options such as statins to prevent and/or treat S aureus bacteremia should be considered and further studied, especially in light of mounting antimicrobial resistance, the incidence of Clostridium difficile, and associated health care costs. Finally, there is an increasing awareness that statins may have a role in a number of diseases other than cardiovascular diseases, such as cancer and autoimmune disorders. The study by Smit et al
      • Smit J.
      • López-Cortés L.E.
      • Thomsen R.W.
      • et al.
      Statin use and risk of community-acquired Staphylococcus aureus bacteremia: a population-based case-control study.
      points to another disease for consideration—CA-SAB.

      References

        • Smit J.
        • López-Cortés L.E.
        • Thomsen R.W.
        • 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
        • Hill P.C.
        • Birch M.
        • Chambers S.
        • et al.
        Prospective study of 424 cases of Staphylococcus aureus bacteraemia: determination of factors affecting incidence and mortality.
        Intern Med J. 2001; 31: 97-103
        • Sohail M.R.
        • Palraj B.R.
        • Khalid S.
        • et al.
        Predicting risk of endovascular device infection in patients with Staphylococcus aureus bacteremia (PREDICT-SAB).
        Circ Arrhythm Electrophysiol. 2015; 8: 137-144
      1. Bennet J.E. Dolin R. Blaser M.J. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 8th ed. Elsevier Inc, Philadelphia, PA2015: 2237-2271.e9
        • Graziano T.S.
        • Cuzzullin M.C.
        • Franco G.C.
        • et al.
        Statins and antimicrobial effects: simvastatin as a potential drug against Staphylococcus aureus biofilm.
        PLoS One. 2015; 10: e0128098
        • Davies J.T.
        • Delfino S.F.
        • Feinberg C.E.
        • et al.
        Current and emerging uses of statins in clinical therapeutics: a review.
        Lipid Insights. 2016; 9: 13-29
        • Banfi C.
        • Baetta R.
        • Gianazza E.
        • Tremoli E.
        Technological advances and proteomic applications in drug discovery and target deconvolution: identification of the pleiotropic effects of statins.
        Drug Discov Today. 2017; 22: 848-869
        • Jerwood S.
        • Cohen J.
        Unexpected antimicrobial effect of statins.
        J Antimicrob Chemother. 2008; 61: 362-364
        • Horn M.P.
        • Knecht S.M.
        • Rushing F.L.
        • et al.
        Simvastatin inhibits Staphylococcus aureus host cell invasion through modulation of isoprenoid isolates.
        J Pharmacol Exp Ther. 2008; 326: 135-143
        • Masadeh M.
        • Mhaidat N.
        • Alzoubi K.
        • Al-Azzam S.
        • Alnasser Z.
        Antibacterial activity of statins: a comparative study of atorvastatin, simvastatin, and rosuvastatin.
        Ann Clin Microbiol Antimicrob. 2012; 11: 13
        • Baddour L.M.
        • Wilson W.R.
        • Bayer A.S.
        • et al.
        • American Heart Association Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young, Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and Stroke Council
        Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications; a scientific statement for healthcare professionals from the American Heart Association.
        Circulation. 2015; 132 ([published corrections appear in Circulation. 2015;132(17):e215 and Circulation. 2016;134(8):e113]): 1435-1486
        • Osmon D.R.
        • Berbari E.F.
        • Berendt A.R.
        • et al.
        Executive summary: diagnosis and management of prosthetic joint infection; clinical practice guidelines by the Infectious Diseases Society of America.
        Clin Infect Dis. 2013; 56: 1-10

      Linked Article