To the Editor:
We read with great interest the recent article by Smit et al
1
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.
2
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.1
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
3
found that steroid hormones with the 3-hydroxy moiety (eg, cholesterol and estradiol) increased carotenoid levels in S aureus, which potentially increases bacterial virulence.4
Patients with chronic kidney disease usually have low levels of sex steroid hormones,5
but high levels of estradiol may present in septic patients.6
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,
7
, 8
statin users with diabetes might be expected to have a higher risk of CA-SAB. However, the results of Smit et al1
revealed otherwise. Other conflicts yet to be reconciled include opposing evidence that statins do not produce neutrophil extracellular trap production9
or why meta-analysis of clinical trials examining the outcome of statins in septic patients differ.10
, 11
In addition, when statins influence the human gut microbiota12
or activate nuclear receptors,13
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
- Statin use and risk of community-acquired Staphylococcus aureus bacteremia: a population-based case-control study.Mayo Clin Proc. 2017; 92: 1469-1478
- Statins: antimicrobial resistance breakers or makers?.Peer J. 2017; 5: e3952
- Attenuation of antimicrobial activity by the human steroid hormones.Steroids. 2017; 128: 120-127
- Color me bad: microbial pigments as virulence factors.Trends Microbiol. 2009; 17: 406-413
- Chronic kidney disease and hypothalamic-pituitary axis dysfunction: the chicken or the egg?.Arch Med Res. 2013; 44: 591-600
- Sex steroid hormones in circulatory shock, sepsis syndrome, and septic shock.Circ Shock. 1994; 43: 171-178
- Susceptibility to infections in persons with diabetes mellitus. UpToDate website.(Updated December 5, 2016. Accessed November 2, 2017)
- The diabetogenic action of statins—mechanisms and clinical implications.Nat Rev Endocrinol. 2016; 12: 99-110
- Neutrophil extracellular traps—the dark side of neutrophils.J Clin Invest. 2016; 126: 1612-1620
- The effect of statins on mortality from severe infections and sepsis: a systematic review and meta-analysis.J Crit Care. 2010; 25 (656.e7-656.e22)
- Statin therapy and mortality from sepsis: a meta-analysis of randomized trials.Am J Med. 2015; 128: 410-417.e1
- Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity.Science. 2016; 352: 565-569
- 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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- Statin Use and Risk of Community-Acquired Staphylococcus aureus Bacteremia: A Population-Based Case-Control StudyMayo Clinic ProceedingsVol. 92Issue 10
- In Reply—Statin Use Associated With a Decreased Risk of Community-Acquired Staphylococcus aureus BacteremiaMayo Clinic ProceedingsVol. 93Issue 4
- PreviewWe appreciate Dr Ko and colleagues’ interesting reflections on our findings concerning the influence of statin use on the risk of community-acquired Staphylococcus aureus bacteremia (CA-SAB). Because the aim of our study was to provide epidemiological in vivo data on this association, Ko and colleagues’ review of the literature and considerations on the potential underlying pathophysiologic mechanisms constitute a very valuable supplement to our paper. We agree that the risk of CA-SAB appeared to differ slightly across the different types of statins (simvastatin, atorvastatin, and others).
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