Statins in Candidemia: clinical outcomes from a matched cohort study

Candidemia is the fourth common cause of nosocomial blood stream infections and is associated with a significant mortality [1, 2]. Delays in antifungal therapy have been associated with increased hospital costs of over $6,000 per patient and overall mortality [3, 4]. The role of 3-hydroxy-3methylglutaryl-coenzyme A (HMG CoA) reductase inhibitors (statins) in improving outcomes bacteremic sepsis is currently being debated with recent papers showing significantly improved survival in patients with systemic inflammatory response syndrome (SIRS) in the intensive care unit (ICU), in patients with chronic kidney renal disease and patients with community acquired pneumonia and influenza [5–9]. One explanation of this effect is that statins in animal models have shown to reduce inflammatory markers, in particular the release of cytokines and cytotoxic effects of neutrophils [10, 11]. The reduction in inflammatory cytokines has also been demonstrated in patients in a prospective randomized 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 [12].

Yeasts use the same HMG CoA reductase as humans, however their end-product is ergosterol rather than cholesterol [13, 14]. In-vitro studies have demonstrated that simvastatin greatly inhibits the growth of Candida species [15, 16]. We performed a review to determine if there was a clinical benefit of statin therapy throughout antifungal therapy in intensive care unit patients with confirmed candidemia.

This is the first study to evaluate the effects of statins on sepsis caused by candidemia in isolation from other causes. This study finds that there may be a clinical benefit of statin therapy in ICU patients with candidemia and an associated SIRS response. Within this small cohort, our data suggest statins given concurrently with antifungal therapy for candidemia were associated with a 91% reduction in mortality in the bivariable analysis and an attenuated 78% reduction in odds of mortality when controlling for severity of illness with APACHE II score. However the odds ratio (OR) can overestimate the relative risk (RR). In this case the RR = 0.42 for mortality in Table 1 (27%/63%) is much less protective than the OR would suggest. Candidemia is a marker of severe illness in the ICU and diagnosis is often delayed because of low blood culture yields [3, 19]. With the overall candidemia related mortality over 30% in this setting, any extra benefit for drugs that modulate the immune system may be useful.

This finding is supported by in-vitro models suggesting that statins may interfere with ergesterol production in yeast [20]. The effect of statins on ergesterol production and cytokines may also explain why the statin group had a reduced inflammatory response compared to the controls in our study [10, 15]. Macreadie et al. have demonstrated in-vitro that by supplementing Candida albicans with ergesterol in aerobic culture can overcome the inhibition caused by statins [13]. Importantly, Nash et al have demonstrated that the addition of pravastatin or lovastatin does not affect fluconazole activity [21].

There are now several larger retrospective studies showing the benefits of statins in bacterial sepsis. Initially, Liappis et al demonstrated that patients on statins had greater than 7 times greater chance of survival with sepsis [22]. Two recent prospective observational studies using large cohorts have also demonstrated similar findings. 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 not on a statin [9]. Gupta et al also found that hemodialysis patients taking statins were also significantly less likely to be hospitalized for severe sepsis [5]. There have been several other retrospective and observational studies with similar findings with bacteremia [23–25].

The timing of initiation of statins with regards to the onset of sepsis is still being determined. This is because it takes several days for statin to achieve desirable concentrations [26]. Pre-admission use of a statin has shown relative risk reductions in large cohort studies evaluating community acquired pneumonia and ICU admission [27, 28]. Thomsen et al showed that the use of preadmission statin up to 180 days prior to admission demonstrated a 25-30% mortality rate reduction at 90 days [27]. Also, Christensen et al showed about a 20% mortality rate reduction between statin users and non-users [28]. However Majumdar et al showed in a prospective cohort study for pneumonia that the benefit of statins disappeared after adjustment for confounders [6]. These confounders which Thomsen et al discuss include the "healthy-user" effects of patients being on statins with patients being better educated and socioeconomically better off than non-users [27]. We were unable to control for these "healthy-user" factors, but in an ICU setting may be less relevant. Based on our exclusion criteria to identify only SIRS induced by candidemia, every effort was made to find matching controls. Major differences were that statin-users were more likely to have heart failure, renal insufficiency, stroke, and peripheral vascular disease. Since our hypothesis was that statins would be protective and statins had higher comorbidity, we expect this to bias our findings to the null. Thus, if we were able to obtain perfect matching, we would have seen statins as being more protective.

The differences in APACHE II scores between the statin-users and unexposed groups, despite the statin-users having a higher Charlson comorbidity score could be either due to statin effect or how patients were matched. A prospective study by Novack et al randomly assigned ICU patients to receive a statin or not and evaluated their cytokine responses [12]. They found that statins significantly reduced TNF-α and IL-6 despite the statin goup having a higher APACHE II score [12]. Similarly, Schmidt et al showed that statin-users in the ICU with multi-organ dysfunction may have better survival with reduction in inflammatory markers [29].

We recognize our study limitations being the small sample size, with associated limited power, and patients were from a single center. In addition, we were not able to standardize the statins used given the retrospective nature of the study. There was exceptional difficulty in obtaining enough patients with candidemia without another cause of their SIRS and remaining on a statin throughout their antifungal therapy and then matching the cases and controls as closely as possible to our definitions. We suspect that most patients have their statins discontinued because of the lack of an intravenous formulation despite being able to deliver the drug down feeding tubes, although recent data suggest that this method may lead to elevated plasma levels of the statins [30].Our limitations presented are similar to other studies published on statins and bacteremic sepsis [27, 28, 31].

This retrospective matched-cohort study suggests that there may be a survival benefit to remaining on a statin with a SIRS response from candidemia, but an overall statistically significant survival benefit was not observed when adjusted by APACHE II score. Further studies are warranted to define the optimal dose of statin and timing of therapy in a prospective manner. Additionally, larger studies are warranted to validate and further explore this association.

All abbreviations are defined within the manuscript.