Pharmacology & Pharmacy, 2013, 4, 573-577
Published Online November 2013 (
Open Access PP
Statins and Sepsis Literature Review
Alicia Hernández Torres1, Ana Belén Hernández Cascales2, Pedro Pujante Alarcón2,
Alfonso López Ruiz3, María Ángeles Ibáñez Gil4, María Dolores Hellín Gil2
1Hospital University Virgen de la Arrixaca de Murcia, Murcia, Spain; 2Hospital University Virgen de la Arrixaca de Murcia, Murcia,
Spain; 3Pharmaceutical Care Research at the University of Granada, Granada, Spain; 4Health Center Mariano Yago, Murcia, Spain.
Received September 8th, 2013; revised October 12th, 2013; accepted October 21st, 2013
Copyright © 2013 Alicia Hernández Torres et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Recent data suggest that, in addition to improving dyslipidemia, statin may reduce the risk of infections and infection-
related complications. The aim of this study is to make a review of the literature about the effects of statins on clinically
relevant outcomes of patients admitted to the hospital and having an infection and/or sepsis, principally in terms of in-
tensive care unit admissions and related death.
Keywords: Statins; Pravastatin; Simvastatin; Sepsis; Bacteremia; Mortality
1. Introduction
The hallmark of sepsis syndrome is an intense inflam-
matory response, which reflects a delicate interaction
between the extensive activation of host defense mecha-
nisms and direct and indirect effects of the invading mi-
croorganisms and their toxins. As a result, a number of
important abnormalities occur during sepsis, including
endothelial dysfunction and apoptosis, activation and
increased production of cytokines and other proinflam-
matory mediators, activation and extravascular transmi-
gration of leukocytes, and activation of platelets and co-
agulation and complement systems [1-3]. For this reason,
because numerous cascades are triggered during sepsis,
selective blocking of inflammatory mediators may be
insufficient to arrest this process [4].
Recent studies have demonstrated a wide variety of
statin properties independent of their lipid-lowering abil-
ity [5-8]. Statins inhibit 3-hydroxy-3 methylgutaryl co-
enzyme A (HMG CoA) reductase, were developed as
lipid level-lowering agents, and have been studied exten-
sively in relation to atherosclerosis. However, statins not
only reduce cholesterol level but also decrease the levels
of intermediate products of cholesterol synthesis, princi-
pally mevalonate, precursor of a lot of isoprenoids which
play a crucial role in several intracellular signaling path-
ways in inflammatory response. Apparently, this effect is
the major explanation for the observed pleiotropic effects
of statins, which include the modulation of both innate
and adaptative immune system, antiinflammatory effects,
the direct activation of heme oxygenase, direct interfer-
ence in leucocyte-endothelial interactions, with limita-
tions of the activation of endothelial cells and improve-
ment of endothelial function, up-regulation of endothelial
nitric oxide synthase and direct inhibition of major his-
tocompatibility complex class II (MHCII), counteraction
of the deleterious effects of sepsis on the coagulation
system by inhibiting tissue factor expression and reduc-
ing prothrombin fragment levels and by strongly increas-
ing the expression of thrombomodulin [9-12]. Moreover,
they have direct effects on pathogenic microorganisms,
such as Salmonella typhimurium, HIV, CMV ordifferent
fungi species [13-15]. Such anti-inflamatory, antioxidant,
inmunomodulatory, and antiapoptotic features have been
collectively referred to as pleiotropic effects [4].
2. Effects of the Use of Statins in Sepsis
All of us known the effect of the statins in the reduction
of pro-inflammatory cytoquines, as have been demon-
strated in a randomized and prospective study comparing
simvastatin to placebo, where there was a significant
reduction in tumor necrosis factor alpha (TNF-α) and
interleukin 6 (IL-6) in the statin group [16]. The same
effect was demonstrated with atorvastatin in a study with
septic rats; it showed that atorvastatin improves survival
in septic rats, decreases circulating inflammatory cyto-
Statins and Sepsis Literature Review
kines, attenuating higher levels of IL-6 and TNF-α, and
improves insulin resistance. If we take into account that,
in septic patients, insulin resistance is accompanied by a
reduction in the insulin-induced Akt (proteína kinase B)
phosphorylation in liver, muscle and adipose tissue, and
that this protein plays an important role in the protection
against apoptosis, it is possible that the reduced insulin
signaling through this pathway, in sepsis, may contribute
to multiorgan failure by preventing or delaying apoptosis
[17]. It seems that statins can have a protector activity in
yeast sepsis; we know that yeast use the same HMG CoA
reductase as humans, however, their end-product is er-
gosterol rather than colesterol [18]; probably, this is the
explanation of why simvastatin inhibit the growth of dif-
ferent species of Candida [19], independently of the ef-
fect in the reduction of pro-inflammatory cytokines. The
population-based cohort study performed by Thomsen et
al. C-reactive protein levels at admisión tended to be
lower in statin users than in non users, perhaps because
of the antiinflammatory effects of statins [20].
3. Clinical Effect s of Statins in Sepsis
Many, but not all studies, have demonstrated the benefits
of statins in patients with sepsis [21]. Liappis et al. dem-
onstrated that patients on statins had greater than 7 times
greater chance of survival with sepsis [22]. Almog et al.
showed in an ICU that only 2.4% of patients on a statin
developed bacterial sepsis compared with 19% (p <
0.001) who were no at statin [23]. Gupta et al. also found
that hemodiálisis patients taking statins were also sig-
nificantly less likely to be hospitalizad for severe sepsis
[24], and Van de Garde et al. showed a significant reduc-
tion of the risk of pneumonia among patients with diabe-
tes mellitus [25]. Kruger et al. studied a cohort of bac-
teriemic patients and found a significantly lower inci-
dence of mortality and bacteraemia-related mortality
with statin therapy [26]. There have been several other
retrospective observational studies with similar findings
with bacteremia. Also, statins reduce the risk of nosoco-
mial sepsis among patients hospitalized for acute coro-
nary syndrome, ischemic stroke, or revascularization [27],
and the risk of infection-related mortality among patients
with atherosclerotic disease [28]. Furthermore, in pa-
tients with sepsis [29], bacteremia [30] or community-
acquired pneumonia [31] and in patients admitted to the
intensive care unit with Acute Physiology and Chronic
Health Evaluation II scores of 20 [32], statins prevented
sepsis from becoming severe or decreased 28-day, 30-
day, or 31 - 180-day mortality, hospital mortality, or
bacteremia-related mortality. Al Harbi et al. found that
statin therapy in critically ill patiens (specially those eld-
erly, diabetics, patient with higuer severity of illness,
with a low GCS, with several sepsis or with simvastatin)
had a lower hospital mortality [33]. Statins also improved
mortality among patients with angiographically defined
coronary artery stenosis >70% and with concurrent cy-
tomegalovirus seroposivity and high C-reactive protein
levels. Patiens who received statins had a lower risk of
death due to influenza, pneumonia, or chronic obstructive
pulmonary disease in one study [34] and a lower risk of
fatal pneumonia in another study [35]. In another hand,
in a study which compared the outcomes of inmunocom-
promised patients who received or not statins, the prior
use of them was not associated with an increase of the
survival [36]. Other investigations haven’t demonstrated
benefits with statins in patients with sepsis, as Fernandez
et al., who found that the hospital mortality was even
higher in patients receiving statins and mechanical venti-
lation [37], or Yang et al. [38] who conducted a retro-
spective study and found no differences in mortality be-
tween the two groups. However, Kopterides et al., in a
critical review of 22 studies with 177,260 patients (7
prospective cohorts, 12 retrospective cohorts and 1 alea-
torized clinic assay), concluded that the majority of stud-
ies show that statins have a beneficial effect over the
result of the infection; nevertheless, its observational
design don’t let us to get firm conclusions [39].
Similar effects have been demonstrated with candidi-
asis. The beneficial effect in the reduction of mortality in
patients admitted to an ICU with candidemia associated
to a systemic inflammatory response syndrome, was de-
monstrated in the study performed by Forrest et al. [40],
although the reduction in mortality wasn’t statistically
significant in the multivariant analysis. In this study, the
reduction of the inflammatory response in comparation
with the control group, is probably due to the effects of
statins in the production of cytokines and ergosterol.
Evaluating the effects of statins in sepsis caused by
concrete microorganisms, we can observe how, in a cli-
nical study, patients who received statins had signifi-
cantly lower overall and attributable mortality associated
with bacteremic infections caused by gram-negative ba-
cilli and S. aureus than did those not receiving statins.
Simvastatin demonstrated a statistically significant an-
timicrobial effect against methicillin-susceptible S. au-
reus and, to a lesser extent, against methicillin-resistant S.
aureus. Fluvastatin also showed a statistically significant
but less marked antimicrobial effect, compared with that
of simvastatin. Moreover, fluvastatin might have a po-
tential role in the treatment of tuberculosis as a result of
the enhacement of the host T-helper response agaisnt M.
tuberculosis. In relation to fungi, we can see that statins
show antifungal activity against Candida species; they
inhibit the growth of Candida by decreasing the ergos-
terol levels. It seems that lovastatin with fluconazole and
fluvastatin with fluconazole or itraconazole had synergis-
tic effects on Candida species, whereas pravastatin or
fluvastatin with fluconazol haven’t demonstrated these
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Statins and Sepsis Literature Review 575
effects. The combination of amphotericin B and fluvas-
tatin had additive effects, too. Different statins have
demonstrated activity against zygomycetes, Aspergillus,
C. neoformans, or viruses as cytomegalovirus, Epstein-
Barr virus or HIV [41].
4. Are Statins Indicated in the Treatment of
Septic Patients?
The timing of initiation of statins with regards to the on-
set of sepsis is still being determined. This is because it
takes several days for statins to achieve desiderable con-
centrations [42]. Moreover, the majority of patients who
are statin-users don’t receive statins after the admission,
because of the lack of intravenous formulation, although
recent data suggest that this method may lead to elevated
plasma levels of the statins [43]. Pre-admission use of a
statin has shown relative risk reductions in large cohort
studies evaluating community acquired pneumonia and
ICU admission [20,44]. Thomsen et al. showed that the
use of preadmisión statin up to 180 days prior to admis-
sion demonstrated a 25% - 30% mortality rate reduction
at 90 days [20]. Also, Christensen et al. showed about a
20% mortality rate reduction between statin users and
non users [44]. However, Majumdar et al. showed in a
prospective cohort study for pneumonia that the benefit
of statins disappeared after adjustment for confounders
[45]. We will need, because of all these reasons, more
exhaustive studies to be able to make conclusions.
5. Conclusion
Our review suggests that statin use is associated with a
beneficial effect in treating and preventing different in-
fections. Further studies are warranted to define the op-
timal dose of statin and timing of therapy in a prospec-
tive manner.
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