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Statin Use Associated With a Decreased Risk of Community-Acquired Staphylococcus aureus Bacteremia

      To the Editor:
      We read with great interest the recent article 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.
      on statin use associated with a decreased risk of community-acquired Staphylococcus aureus bacteremia (CA-SAB), particularly in patients with chronic kidney disease and patients with diabetes. They explained that these results were unlikely due to direct antimicrobial effects of statins on S aureus but more likely due to the pleiotropic effects of statins reducing important isoprenoid intermediates, resulting in decreased bacterial invasion and inducing neutrophil extracellular traps.
      By reviewing the available literature of statins’ in vitro antibacterial effects, we observed that simvastatin, followed by atorvastatin, generally exerted the greatest direct antibacterial effect (lowest minimum inhibitory concentration) against S aureus compared with other statins.
      • Ko H.H.T.
      • Lareu R.R.
      • Dix B.R.
      • Hughes J.D.
      Statins: antimicrobial resistance breakers or makers?.
      This finding supports the view that direct antimicrobial effects were unlikely responsible for statins’ protective effects because Smit et al have provided complementary evidence that the risk of contracting CA-SAB was higher, rather than lower, in patients taking simvastatin or atorvastatin compared with the other statins.
      • 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.
      As such, it is more probable that statins reduce CA-SAB risk through other host-related mechanisms.
      Interestingly, a recent study by Plotkin and Konakieva
      • Plotkin B.J.
      • Konakieva M.I.
      Attenuation of antimicrobial activity by the human steroid hormones.
      found that steroid hormones with the 3-hydroxy moiety (eg, cholesterol and estradiol) increased carotenoid levels in S aureus, which potentially increases bacterial virulence.
      • Liu G.Y.
      • Nizet V.
      Color me bad: microbial pigments as virulence factors.
      Patients with chronic kidney disease usually have low levels of sex steroid hormones,
      • Meuwese C.L.
      • Carrero J.J.
      Chronic kidney disease and hypothalamic-pituitary axis dysfunction: the chicken or the egg?.
      but high levels of estradiol may present in septic patients.
      • Fourrier F.
      • Jallot A.
      • Leclerc L.
      • et al.
      Sex steroid hormones in circulatory shock, sepsis syndrome, and septic shock.
      Knowledge of the antibiotic treatment outcomes for patients with chronic kidney who have CA-SAB and are statin users, compared with nonusers, might provide clues as to whether statins could offer additional benefits by suppressing the antagonistic precursor cholesterol molecule and downstream steroidal hormones sufficiently, resulting in efficacious antibiotic therapy.
      Because statins may induce new-onset diabetes and the colonization of skin and mucosae with S aureus predisposes diabetic patients to infections,
      • Weintrob A.C.
      • Sexton D.J.
      Susceptibility to infections in persons with diabetes mellitus. UpToDate website.
      • Betteridge D.J.
      • Carmena R.
      The diabetogenic action of statins—mechanisms and clinical implications.
      statin users with diabetes might be expected to have a higher risk of CA-SAB. However, the results of 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.
      revealed otherwise. Other conflicts yet to be reconciled include opposing evidence that statins do not produce neutrophil extracellular trap production
      • Sørensen O.E.
      • Borregaard N.
      Neutrophil extracellular traps—the dark side of neutrophils.
      or why meta-analysis of clinical trials examining the outcome of statins in septic patients differ.
      • Janda S.
      • Young A.
      • Fitzgerald J.M.
      • Etminan M.
      • Swiston J.
      The effect of statins on mortality from severe infections and sepsis: a systematic review and meta-analysis.
      • Deshpande A.
      • Pasupuleti V.
      • Rothberg M.B.
      Statin therapy and mortality from sepsis: a meta-analysis of randomized trials.
      In addition, when statins influence the human gut microbiota
      • Zhernakova A.
      • Kurilshikov A.
      • Bonder M.J.
      • et al.
      Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity.
      or activate nuclear receptors,
      • Howe K.
      • Sanat F.
      • Thumser A.E.
      • Coleman T.
      • Plant N.
      The statin class of HMG-CoA reductase inhibitors demonstrate differential activation of the nuclear receptors PXR, CAR and FXR, as well as their downstream target genes.
      the resultant impact to the human immune system has not been elucidated.
      The work of Smit et al is interesting and timely and should stimulate further investigation into the role of statins in preventing bacteremia.

      References

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        • 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
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        • Lareu R.R.
        • Dix B.R.
        • Hughes J.D.
        Statins: antimicrobial resistance breakers or makers?.
        Peer J. 2017; 5: e3952
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        • Konakieva M.I.
        Attenuation of antimicrobial activity by the human steroid hormones.
        Steroids. 2017; 128: 120-127
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        • Nizet V.
        Color me bad: microbial pigments as virulence factors.
        Trends Microbiol. 2009; 17: 406-413
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        Chronic kidney disease and hypothalamic-pituitary axis dysfunction: the chicken or the egg?.
        Arch Med Res. 2013; 44: 591-600
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        • Jallot A.
        • Leclerc L.
        • et al.
        Sex steroid hormones in circulatory shock, sepsis syndrome, and septic shock.
        Circ Shock. 1994; 43: 171-178
        • Weintrob A.C.
        • Sexton D.J.
        Susceptibility to infections in persons with diabetes mellitus. UpToDate website.
        (Updated December 5, 2016. Accessed November 2, 2017)
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        • Carmena R.
        The diabetogenic action of statins—mechanisms and clinical implications.
        Nat Rev Endocrinol. 2016; 12: 99-110
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        Neutrophil extracellular traps—the dark side of neutrophils.
        J Clin Invest. 2016; 126: 1612-1620
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        Statin therapy and mortality from sepsis: a meta-analysis of randomized trials.
        Am J Med. 2015; 128: 410-417.e1
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        Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity.
        Science. 2016; 352: 565-569
        • Howe K.
        • Sanat F.
        • Thumser A.E.
        • Coleman T.
        • Plant N.
        The statin class of HMG-CoA reductase inhibitors demonstrate differential activation of the nuclear receptors PXR, CAR and FXR, as well as their downstream target genes.
        Xenobiotica. 2011; 41: 519-529

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