Statins and Infection
Source: Liappis AP, et al. Clin Infect Dis. 2001;33:1352-1357.
Liappis and colleagues analyzed 243 episodes of aerobic Gram-negative bacteremia and 145 cases of Staphylococcus aureus bacteremia occurring in Veterans Administration patients to evaluate the effect of statin therapy on mortality. Thirty-five (9%) of patients were receiving a statin at the time of admission and continued it during hospitalization—20 had Gram-negative bacteremia and 15 had S aureus bacteremia. Most statin recipients were receiving simvastatin. All but 2 of the total patients were male.
While 100 of 353 (28%) bacteremic patients not receiving statins died, only 2 of 35 (6%) bacteremic statin recipients did so (P = 0.002). Mortality rates attributable to infection were, respectively, 70 of 353 (20%) and 1 of 35 (3%) (P = 0.10). Multivariate analysis found that, while use of ACE was associated with an increased risk of mortality, only statin use was associated with improved survival (OR. 7.63; 95% CI, 1.0157.5). Also noted was that skin and soft tissue infections were more commonly identified as sources of bacteremia in the statin recipients (P = 0.008).
Comment by Stan Deresinski, MD, FACP
A subsequent retrospective analysis of 9651 diabetic patients by the same investigative group confirmed a reduced mortality as well as an increased incidence of lower extremity infections among those receiving statin (HMG-CoA reductase inhibitor) therapy.1 Thus, 596 of 1932 (30.8%; P < 0.00001) statin recipients had lower extremity infection compared to only 1287 of 7719 (11.6%; P < 0.00001).
Liappis and colleagues reviewed some experimental work that might provide a potential explanation for these remarkable findings. Studies have suggested that statins reduce the inflammatory reactions within atherosclerotic plaques by a mechanism that does not involve lowering of serum lipid levels.2 Statin administration reduces neutrophil migration into lung after intranasal instillation of endotoxin and diminishes TNF production in a murine model.3 Pravastatin has been demonstrated to inhibit neutrophil and monocyte chemotaxis in vitro.4,5 In addition, cerivastatin reduces in vitro monocyte adhesion to vascular endothelium by down regulation of adhesion molecules and by inhibition of actin polymerization by inactivation of the G protein, RhoA.6 Fluvastatin increases nitric oxide synthase activity in endothelial cell cultures while reducing expression of the adhesion molecules, E-selectin, and ICAM-1.7 Statins improve endothelial function by stimulation of endothelial constitutive nitric oxide synthase activity.8
Thus, a variety of studies provide evidence that statins, in a manner independent of their lipid-lowering activity, significantly modify the inflammatory response. Liappis et al speculate that these effects may result from the statin-induced depletion of isoprenoids. These non-sterol cholesterol precursors are required for covalent binding of farnesyl and geranyl groups to membrane G proteins involved in signal transduction pathways. These critical pathways regulate cell signaling, migration, and proliferation.
Thus, it is possible that the observed reduced mortality in bacteremic males may be the consequence of the anti-inflammatory effects of the statins. In addition, the statin-induced reduction in chemotactic activity may provide an explanation for the observed increased incidence of skin and soft tissue infections and of infections of the lower extremities in diabetic patients since defects in neutrophil chemotactic activity are generally associated with an increased risk of skin and soft tissue infection.
It will be interesting to see where these novel observations ultimately lead.
References
1. Seraphin LM, et al. 2001 ICAAC, Abstract #2203.
2. Koh KK. Cardiovasc Res. 2000;47:648-657.
3. Winn RK, et al. 1998 ICAAC, Abstract #764.
4. Dunzendorfer S, et al. Circ Res. 1997;81:963-969.
5. Kreuzer J, et al. Atherosclerosis. 1991;90:203-209.
6. Yoshida M, et al. Arterioscler Thromb Vasc Biol. 2001; 21:1165-1171.
7. Mueck AO, et al. Exp Clin Endocrinol Diabetes. 2001; 109:181-183.
8. Laufs U, et al. Circulation. 1998;97(12):1129-1135.
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