in spite of antibiotic and supportive therapy , bloodstream infection ( bsi ) is still a major cause of mortality and morbidity [ 13 ] . measures to improve outcomes from bsi are necessary . several observational studies have assessed the relation between prior use of statins [ 3-hydroxy-3-methylglutaryl coenzyme a ( hmg coa ) reductase inhibitors ] and the outcome of bsi . the majority of the studies suggest that statin use could have a beneficial effect in patients with bsi [ 48 ] , whereas some studies have shown no difference in mortality between statin users and non - users [ 911 ] . many former studies assessing the relation between statin use and outcome of infection have not had verified bsi , nor have they discriminated between gram - positive and gram - negative etiology . as gram - positive and gram - negative bacteria alert the innate immune system in different ways [ 12 , 13 ] , drugs that have anti - inflammatory properties may not have the same effect in gram - positive infection as they do in gram - negative infection . only a few authors have attempted to study this issue in patients [ 4 , 7 , 10 , 11 ] , and the results diverge . in this prospective observational cohort study on bsi , we chose to investigate the relation between prior statin use and 90-day mortality in gram - positive and gram - negative bsi separately . levanger hospital serves a population of 87,000 as an emergency facility in a defined geographical area . since 1994 , all positive blood cultures at the hospital have been prospectively recorded for surveillance purposes , and clinical information has been recorded , in the following way : whenever a positive blood culture was reported , a physician at the clinical ward filled out a registration form . a team of three research nurses , a subordinate doctor , and the main investigator reviewed the patients records to verify the data and record additional variables . data on statin use were prospectively included in the database from 2005 , when we became aware of the early studies on statin use and sepsis . information on the use of statins during the period 20022005 was recorded retrospectively from hospital records . the present study includes bsis occurring between january 1 , 2002 and december 31 , 2011 in patients 16  years of age . bactec 9240 ( becton dickinson diagnostic instrument systems , sparks , md ) was used for blood culture testing . if a blood culture was positive for bacteria known to cause sepsis , only one positive vial was required for inclusion in the present study . for common skin contaminants ( coagulase - negative staphylococci , alpha - hemolytic streptococci , corynebacteria , etc . ) , at least two positive vials from separate venipunctures were required . an episode of bsi was classified as polymicrobial if more than one organism was isolated from one or more blood cultures within a 72-h period . for patients who had more than one episode with positive blood culture in the 10-year period , the exposure variable was prior statin use , defined as taking a statin in the week before the time of positive blood culture . two patients , whose statins were discontinued more than one week before the date of the positive blood culture , were categorized as non - statin users . we recorded statin use and the specific statin and dosage from the patients hospital charts . the outcome variable was death from all causes within 90  days after the first positive blood culture . the date of death was obtained from the patients electronic records , which is updated by the civil registration system in norway . the following variables were a priori determined as possible confounders because they might be associated with both statin use and mortality from bsi ( table  1 ) : age ( < 65  years , 6579  years , 80  years ) ; sex ; comorbidities ; charlson comorbidity index , categorized as low ( no underlying disease score ) , medium ( score 12 ) , or high ( score > 2 ) ; nursing home resident ( yes / no ) ; functional status ( independent , partly independent , dependent , unknown ) ; immunosuppressive therapy ; alcohol abuse ; smoking ( no smoking , former smoker , present smoker ) ; focus of infection ( urinary tract , lungs , biliary tract , gastrointestinal tract , other , unknown ) ; use of antibiotics before admission ; and place of acquisition ( community , healthcare , hospital ) . whether the current bsi episode was nosocomial , healthcare - associated , or community - acquired was determined according to commonly used definitions [ 18 , 19].table 1baseline characteristics of 1,356 adult patients with gram - negative or gram - positive bloodstream infection ( bsi ) by statin use at levanger hospital , norway , 20022011variablegram - negative bsi ( n  =  784)gram - positive bsi ( n  =  572)no statin use ( n  =  646)statin use ( n  =  138 ) 
 p - valueno statin use ( n  =  474)statin use ( n  =  98 ) 
 p - valueage<0.0010.021  < 65  years185 ( 28.6)25 ( 18.1)159 ( 33.5)26 ( 26.5 )  6579 years189 ( 29.3)71 ( 51.4)153 ( 32.3)45 ( 45.9 )  80  years272 ( 42.1)42 ( 30.4)162 ( 34.2)27 ( 27.6)female sex367 ( 56.8)67 ( 48.6)0.060196 ( 41.4)35 ( 35.7)0.29chronic renal insufficiency52 ( 8.0)16 ( 11.6)0.1736 ( 7.6)19 ( 19.4)<0.001malignancy  solid tumor148 ( 22.9)32 ( 23.2)0.9499 ( 20.9)21 ( 21.4)0.93  hematological cancer35 ( 5.4)3 ( 2.2)0.1138 ( 8.0)3 ( 3.1)0.085diabetes mellitus87 ( 13.5)41 ( 29.7)<0.00170 ( 14.8)35 ( 35.7)<0.001hypertension186 ( 28.8)77 ( 55.8)<0.001127 ( 26.8)40 ( 40.8)0.003cardiovascular disease212 ( 32.8)91 ( 65.9)<0.001153 ( 32.3)67 ( 68.4)<0.001  coronary heart disease118 ( 18.3)65 ( 47.1)<0.00188 ( 18.6)50 ( 51.0)<0.001  congestive heart failure59 ( 9.1)16 ( 11.6)0.3649 ( 10.3)14 ( 14.3)0.25  peripheral vascular disease35 ( 5.4)15 ( 10.9)0.01630 ( 6.3)18 ( 18.4)<0.001  cerebral vascular disease77 ( 11.9)32 ( 23.2)<0.00152 ( 11.0)18 ( 18.4)0.041chronic liver disease10 ( 1.5)1 ( 0.7)0.5414 ( 3.0)1 ( 1.0)0.31chronic pulmonary disease94 ( 14.6)24 ( 17.4)0.4178 ( 16.5)16 ( 16.3)0.99rheumatological / immunological disease55 ( 8.5)13 ( 9.4)0.7244 ( 9.3)11 ( 11.2)0.56charlson comorbidity index0.014<0.001  low ( 0)187 ( 28.9)23 ( 16.7)144 ( 30.4)10 ( 10.2 )  medium ( 12)278 ( 43.0)69 ( 50.0)209 ( 44.1)43 ( 43.9 )  high ( > 2)181 ( 28.0)46 ( 33.3)121 ( 25.5)45 ( 45.9)nursing home resident85 ( 13.2)8 ( 5.8)0.02147 ( 9.9)2 ( 2.0)0.017functional status prior to the present bsi0.050 * 0.035 *  independent365 ( 56.5)87 ( 63.0)307 ( 64.8)70 ( 71.4 )  partly independent178 ( 27.6)38 ( 27.5)108 ( 22.8)26 ( 26.5 )  dependent97 ( 15.0)11 ( 8.0)52 ( 11.0)2 ( 2.1 )  unknown6 ( 0.9)2 ( 1.4)7 ( 1.5)0immunosuppressive therapy86 ( 13.3)19 ( 13.8)0.7962 ( 13.1)13 ( 13.3)0.93alcohol abuse30 ( 4.6)4 ( 2.9)0.4520 ( 4.2)2 ( 2.0)0.38smoking  non - smoker416 ( 64.4)74 ( 53.6)0.017278 ( 58.6)49 ( 50.0)0.14  former smoker110 ( 17.0)38 ( 27.5)0.004105 ( 22.2)33 ( 33.7)0.026  present smoker120 ( 18.6)26 ( 18.8)0.9291 ( 19.2)16 ( 16.3)0.65focus of infection  urinary tract358 ( 55.4)76 ( 55.1)0.9845 ( 9.5)10 ( 10.2)0.83  lungs46 ( 7.1)5 ( 3.6)0.15164 ( 34.6)31 ( 31.6)0.67  biliary tract95 ( 14.7)26 ( 18.8)0.2114 ( 3.0)5 ( 5.1)0.32  gastrointestinal tract49 ( 7.6)8 ( 5.8)0.3811 ( 2.3)2 ( 2.0)0.81  skin or soft tissue17 ( 2.6)2 ( 1.4)0.4566 ( 13.9)13 ( 13.3)0.71  other25 ( 3.9)4 ( 2.9)0.69105 ( 22.2)28 ( 28.6)0.16  unknown56 ( 8.7)17 ( 12.3)0.1769 ( 14.6)9 ( 9.2)0.16systemic antibiotic therapy before admission93 ( 14.4)20 ( 14.5)0.9949 ( 10.3)4 ( 4.1)0.076place of acquisition  community - acquired335 ( 51.9)76 ( 55.1)0.52262 ( 55.3)49 ( 50.0)0.44  acquired in hospital76 ( 11.8)21 ( 15.2)0.2873 ( 15.4)16 ( 16.3)0.81  healthcare - associated235 ( 36.4)41 ( 29.7)0.15139 ( 29.3)33 ( 33.7)0.51variables expressing the severity of infection  severe sepsis or septic shock at the time of diagnosis149 ( 23.1)25 ( 18.1)0.2295 ( 20.0)25 ( 25.5)0.22  severe organ failure ( sofa score > 2 in any organ ) at the time of diagnosis90 ( 13.9)19 ( 13.8)>0.9975 ( 15.8)21 ( 21.4)0.18  stay in intensive care unit ( icu)117 ( 18.1)26 ( 18.8)0.81107 ( 22.6)36 ( 36.7)0.005appropriate initial antibiotic therapy548 ( 84.8)122 ( 88.4)0.35397 ( 83.8)88 ( 89.8)0.16data are presented as number of patients ( % ) * excluding unknowns baseline characteristics of 1,356 adult patients with gram - negative or gram - positive bloodstream infection ( bsi ) by statin use at levanger hospital , norway , 20022011 data are presented as number of patients ( % ) variables expressing the severity of the current bsi ( systemic inflammatory response syndrome , organ failure , hypotension , hypoperfusion , sepsis , severe sepsis , and septic shock ) , severe organ failure ( defined as sofa score > 2 in any organ [ 15 , 21 ] ) , and admission to an intensive care unit ( icu ) were recorded , but not considered confounders . instead , they may be mediators in the pathway between prior statin use and mortality and , therefore , should not be adjusted for in the analyses [ 7 , 22 , 23 ] . appropriate initial antibiotic therapy was defined as correctly dosed intravenous antibiotic therapy given within 24  h of the time that the blood culture specimen was obtained , with a regimen that was active in vitro against the microbe(s ) isolated from blood culture(s ) . this variable was not adjusted for in the main analyses , as it was not considered a confounder . appropriate initial antibiotic therapy is , indeed , strongly associated with outcome of bsi , but it is not associated with prior statin use in such a way that it influences whether a person has been prescribed statin medication . prior statin use may be associated with the initial antibiotic therapy if statin use mitigates the inflammatory response so that symptoms are masked and , therefore , appropriate initial antibiotic therapy , is delayed . in this case , appropriate initial antibiotic therapy is a mediator in the pathway between statin use and death , and not a confounder . on the other hand , one might postulate some unknown variable that influences whether people are prescribed statin medication and also influences whether they receive appropriate initial antibiotic therapy ( e.g. , some underlying condition that is not included in the charlson comorbidity index ) . to reduce the influence of such an unknown confounder the regional committee for ethics in medical research , health region iv , norway approved the study . the ethics committee waived the need for informed consent because this was an observational study , the treatment of the patients was standard , and no samples were taken for the purposes of the research . proportions were compared using the unconditional z - pooled test , which is the unconditional version of the pearson chi - squared test . unordered r  c tables were analyzed using the exact version of the pearson chi - squared test . the relation between prior statin use and 90-day total mortality was analyzed using logistic regression . the regional committee for ethics in medical research , health region iv , norway approved the study . the ethics committee waived the need for informed consent because this was an observational study , the treatment of the patients was standard , and no samples were taken for the purposes of the research . proportions were compared using the unconditional z - pooled test , which is the unconditional version of the pearson chi - squared test . unordered r  c tables were analyzed using the exact version of the pearson chi - squared test . the relation between prior statin use and 90-day total mortality was analyzed using logistic regression . during the 10-year period , 784 patients with gram - negative bsi and 572 with gram - positive bsi were identified . 17.6 % of those with gram - negative and 17.1 % of those with gram - positive bsi were statin users . the patient characteristics are shown in table  1 . in both gram - negative and gram - positive bsi , statin users had a higher burden of comorbid diseases , such as diabetes , hypertension , and cardiovascular disease , and they also had a higher charlson comorbidity index . variables expressing the severity of infection at the time of diagnosis were not significantly different in statin users and non - users . in gram - positive bsi , the distribution of the microbial agents in relation to statin use is shown in table  2 . the distribution of microbes was essentially similar among statin users and non - users , except that klebsiella spp . were more common among statin users and that some gram - negative microbes ( haemophilus influenzae , neisseria meningitidis and  other aerobic gram - negative organisms  ) did not occur in statin users.table 2microbial agents in 784 episodes of gram - negative bsi and 572 episodes of gram - positive bsi , total and by statin usemicrobial agent(s)no statinstatintotal 
 p - valuegram - negative microorganisms 
 escherichia coli 
 400 ( 61.9)95 ( 68.8)495 ( 63.1)0.13 
 klebsiella spp.54 ( 8.4)20 ( 14.5)74 ( 9.4)0.025 
 proteus spp.29 ( 4.5)3 ( 2.2)32 ( 4.1)0.21 
 enterobacter spp.20 ( 3.1)3 ( 2.2)23 ( 2.9)0.69  other enterobacteriaceae 
 19 ( 2.9)6 ( 4.3)25 ( 3.2)0.44 
 pseudomonas spp.35 ( 5.4)5 ( 3.6)40 ( 5.1)0.44 
 haemophilus influenzae 
 15 ( 2.3)015 ( 1.9)0.079 
 neisseria meningitidis 
 8 ( 1.2)08 ( 1.0)0.20  other aerobic gram - negative organisms10 ( 1.5)010 ( 1.3)0.14  anaerobic gram - negative rods28 ( 4.3)5 ( 3.6)33 ( 4.2)0.88  mixed gram - negative aerobic or anaerobic rods28 ( 4.3)1 ( 0.7)29 ( 3.7)0.079  total gram - negative microorganisms646 ( 100)138 ( 100)784 ( 100)gram - positive microorganisms 
 streptococcus pneumoniae 
 162 ( 34.2)27 ( 27.6)189 ( 33.0)0.23 
 staphylococcus aureus 
 120 ( 25.3)32 ( 32.7)152 ( 26.6)0.12  beta - hemolytic streptococci70 ( 14.8)13 ( 13.3)83 ( 14.5)0.74 
 enterococcus spp.42 ( 8.9)10 ( 10.2)52 ( 9.1)0.66  viridans group streptococci33 ( 7.0)7 ( 7.1)40 ( 7.0)0.94  coagulase - negative staphylococci33 ( 7.0)6 ( 6.1)39 ( 6.8)0.88 
 listeria monocytogenes 
 3 ( 0.6)1 ( 1.0)4 ( 0.7)0.88  anaerobic gram - positive microorganisms6 ( 1.3)1 ( 1.0)7 ( 1.2)0.89  mixed gram - positive aerobic or anaerobic bsi5 ( 1.1)1 ( 1.0)6 ( 1.0)0.68  total gram - positive microorganisms474 ( 100)98 ( 100)572 ( 100)data are presented as number of patients ( % ) microbial agents in 784 episodes of gram - negative bsi and 572 episodes of gram - positive bsi , total and by statin use data are presented as number of patients ( % ) figure  1 shows the mortality curves for patients with gram - negative and gram - positive bsi . in gram - negative bsi , the total 90-day mortality was 10.1 % ( 14/138 ) in statin users and 21.4 % ( 138/645 ) in non - statin users , p  =  0.002 . in gram - positive bsi , the total 90-day mortality was 28.6 % ( 28/98 ) in statin users and 27.0 % ( 128/474 ) in non - statin users , p  =  0.90.fig . 1mortality curves for patients with gram - negative and gram - positive bloodstream infection ( bsi ) stratified by statin use mortality curves for patients with gram - negative and gram - positive bloodstream infection ( bsi ) stratified by statin use the results of logistic regression analysis of the relation between statin use and 90-day total mortality are shown in table  3 . for the total bsi cohort , we found a negative association between prior statin use and 90-day mortality [ odds ratio ( or ) 0.69 , 95 % ci 0.490.98 , p  =  0.040 ) . the association was not mitigated by adjustment for possible confounding factors . among patients with gram - negative bsi , the mortality was significantly lower in statin users ( or 0.42 , 95 % ci 0.230.75 , p  =  0.003 ) . in gram - positive bsi , there was no association between statin use and mortality . adjustment for variables considered confounders did not weaken the association between statin use and 90-day mortality in gram - negative bsi ( adjusted or 0.38 , 95 % ci 0.200.72 , p  =  0.003 ) . the relations between prior statin use and 90-day mortality in gram - negative and gram - positive bsi were significantly different ; the adjusted or for the interaction term was 2.95 ( 95 % ci 1.266.89 , p  =  0.012).table 3logistic regression analysis of the relation between prior statin use and 90-day total mortalityno . of deaths / patients ( % ) unadjusted or ( 95 % ci ) 
 p - valueadjusted * or ( 95 % ci ) 
 p - valueany bsi  no statin285/1,164 ( 24.5)1 ( reference)1 ( reference )  statin45/245 ( 18.4)0.69 ( 0.490.98)0.0400.63 ( 0.430.95)0.025gram - negative bsi  no statin138/646 ( 21.4)1 ( reference)1 ( reference )  statin14/138 ( 10.1)0.42 ( 0.230.75)0.0030.38 ( 0.200.72)0.003gram - positive bsi  no statin128/474 ( 27.0)1 ( reference)1 ( reference )  statin28/98 ( 28.6)1.08 ( 0.671.75)0.751.22 ( 0.692.17)0.49*adjusted for age ( < 65  years , 6579 years , 80  years ) ; sex ; charlson comorbidity index ; nursing home resident ; functional status ( independent , partly independent , dependent , unknown ) ; immunosuppressive therapy ; alcohol abuse ; smoking ( no smoking , former smoker , present smoker ) ; focus of infection ( urinary tract , lungs , biliary tract , gastrointestinal tract , other , unknown ) ; use of antibiotics before admission ; and place of acquisition ( community , healthcare , hospital ) logistic regression analysis of the relation between prior statin use and 90-day total mortality * adjusted for age ( < 65  years , 6579 years , 80  years ) ; sex ; charlson comorbidity index ; nursing home resident ; functional status ( independent , partly independent , dependent , unknown ) ; immunosuppressive therapy ; alcohol abuse ; smoking ( no smoking , former smoker , present smoker ) ; focus of infection ( urinary tract , lungs , biliary tract , gastrointestinal tract , other , unknown ) ; use of antibiotics before admission ; and place of acquisition ( community , healthcare , hospital ) in an analysis including adjustment for appropriate initial antibiotic therapy , the effect estimates did not change ( adjusted or 0.38 , 95 % ci 0.200.73 , p  =  0.004 and or 1.21 , 95 % ci 0.682.14 , p  =  0.52 for gram - negative and gram - positive bsi , respectively ) . adjusted ors for the relation between statin use and 90-day mortality were similar when disease categories ( e.g. , diabetes , cardiovascular disease ) were used instead of the charlson comorbidity index for the total cohort ( or 0.62 , 95 % ci 0.410.94 , p  =  0.026 ) , gram - negative bsi ( or 0.37 , 95 % ci 0.180.74 , p  =  0.005 ) , and gram - positive bsi ( or 1.13 , 95 % ci 0.622.07 ) . after excluding bacterial subgroups with zero statin users ( n  =  33 ) , the association between statin use and 90-day mortality in gram - negative bsi did not change , either unadjusted ( or 0.44 , 95 % ci 0.240.78 , p  =  0.006 ) or after adjustment for confounders ( or 0.41 , 95 % ci 0.210.78 , p  =  0.007 ) . for some variables included in the main analysis ( focus of infection , use of antibiotics before admission , and place of acquisition ) , the association with prior statin use is unclear , and it is uncertain whether these variables fulfil the criteria for being a confounder . additionally , we repeated the analysis after excluding these variables from the model , but the relations between prior statin use and 90-day mortality in gram - negative ( or 0.37 , 95 % ci 0.200.70 , p  =  0.002 ) and gram - positive bsi ( or 1.00 , 95 % ci 0.581.75 ) remained unchanged . in this cohort study of patients with bsi , prior statin use was associated with reduced 90-day mortality in gram - negative , but not in gram - positive , bsi . to our best knowledge the effect measures were not changed by adjustment for variables that were considered confounding factors . in the total cohort of bsi , the unadjusted or for mortality among statin users compared with non - users did not differ much from what has been found by other investigators [ 7 , 9 , 11 ] . in one study , adjustment for possible confounding factors attenuated the effect measure to a value above 1 . a population - based prospective cohort study on statin use and community - acquired pneumonia   raised concerns that previous studies indicating benefits of statins in patients with sepsis had been measuring and reporting a healthy user effect . in that study , statin users were less likely to die or to be admitted to an icu . after adjusting for confounding factors that reflect patient frailty or healthy user behavior , no reduction in either mortality or the need for admission to an icu in statin users a significantly lower proportion of statin users were functionally dependent patients or nursing home residents compared with non - users . the proportion of former smokers was significantly higher among statin users . however , these associations of statin use were essentially similar in gram - negative and gram - positive bsi . therefore , it seems unlikely that the observed difference in the possible preventive effect of statins between gram - negative bsi and gram - positive bsi in our study could be explained by a healthy user effect . most previous investigators have dealt with infection , sepsis , or bsi as if these categories represent homogenous groups with regard to pathogenesis or assumed preventive effect of statins . a few articles reported some data on the relations between statin use and death in gram - positive and gram - negative bsi separately . reported trends of reduced mortality rates in statin users with gram - negative infection ( 1/19 vs. 48/223 , p  =  0.13 ) or staphylococcus aureus infection ( 0/15 vs. 22/130 , p  =  0.13 ) . yang et al .   found a trend of lower mortality in statin users with gram - negative bacteremia ( 10.3 % vs. 16.4 % , p  =  0.25 ) , but not in gram - positive bacteremia ( 33.3 % vs. 27.8 % , p  =  0.50 ) . thomsen et al .   did not find such a trend in the enterobacterial group of gram - negative bacteria ( adjusted 30-day mortality rate ratio 1.07 , 95 % ci 0.611.86 , p  =  0.82 ) , nor did leung et al . find a negative association between statin use and death in gram - negative bsi ( adjusted hazard ratio 1.10 , 95 % ci 0.871.39 ) . however , the latter had adjusted for variables expressing the severity of the current infection , i.e. , factors that should be considered as mediators rather than confounders , and such an adjustment may attenuate the true associations . found a negative association between statin use and death within 14  days from staphylococcus aureus bsi ( adjusted or 0.08 , 95 % ci 0.010.66 , p  =  0.02 ) . statins are renowned for their anti - inflammatory and pleiotropic lipid - lowering independent effects . they exert their anti - inflammatory effects through their implication on a variety of molecular pathways of the innate and adaptive immune system , such as their impact on the circulating levels of inflammatory cytokines , as well as anti - coagulant and anti - proliferative effects [ 27 , 28 ] . with regards to sepsis , many in vitro and animal studies have demonstrated that statins attenuate endotoxin - induced inflammatory responses . similarly , statins have been found to diminish inflammatory responses induced by staphylococcus aureus lipoteichoic acid . however , there are few studies that have explored the mechanisms for differential effects of statins in gram - positive and gram - negative bsi , as observed in the present study . gram - positive and gram - negative bacteria have different cell wall components and may stimulate different toll - like receptors ( tlrs ) on cells of the innate immune system , initiating the transcription of different inflammatory mediator genes . interestingly , there are several studies showing that statins decrease lipopolysaccharide ( lps ) signaling through the downregulation of tlr4 expression on monocytes . although some studies suggest that statins may also suppress tlr2 signaling in gram - positive infection , statins may not inhibit the lipoprotein - induced pathway via tlr2 and the lps - induced pathway via tlr4 to the same extent . indeed , there are some studies showing that statins inhibit tlr4-mediated activation of interferon regulatory factor 3 ( irf3 ) and interferon - beta production in macrophages stimulated by lps , while no such effects were observed for tlr2 stimulation . the clinical relevance of these findings is , however , unknown and require further examination . nevertheless , they illustrate that there may be molecular mechanisms supporting the findings of different effects of statins in gram - positive and gram - negative bsi . our findings indicate that the possible preventive effect of statins in bsi may be a subgroup effect seen in gram - negative , but not in gram - positive , infection . whether a negative association between statin use and mortality in gram - negative bsi really exists as a biological interaction should be further investigated , preferably by randomized controlled studies ( rcts ) . as of yet , few rcts have been performed [ 34 , 35 ] , and though several are presently in progress , they are designed to study the effect of statin treatment in ongoing infection , not the prophylactic effect of statin use prior to infections . one rct has shown improved survival in atorvastatin - treated icu patients with severe sepsis if they had been prior statin users , but no effect was found in patients who received de novo statin therapy . rcts , so far , have not assessed whether different etiologic agents influence the relation between prior statin use and the outcome of infections . the strength of our study is that our bacteremia database contains confirmed diagnoses and variables collected from the patients hospital data , which include medical records . our cohort has a sufficient number of patients in the different groups , which makes it possible to assess the relation between statin use and 90-day mortality , an important endpoint in prior studies . the study has the weakness of being an observational study , burdened with the risk of confounding . socioeconomic factors have not been adjusted for , but severe confounding by socioeconomic differences seems unlikely because statin prescriptions are reimbursed , and access to hospital treatment is the same for all citizens in norway . in addition , we have not adjusted for vaccinations , e.g. , pneumococcus vaccine or influenza vaccine , which some previous authors have regarded as  healthy user nonetheless , we are not aware of confounders that would be likely to cause a strong association of statin use with reduced mortality in gram - negative , but not in gram - positive , bsi . the strength of our study is that our bacteremia database contains confirmed diagnoses and variables collected from the patients hospital data , which include medical records . our cohort has a sufficient number of patients in the different groups , which makes it possible to assess the relation between statin use and 90-day mortality , an important endpoint in prior studies . the study has the weakness of being an observational study , burdened with the risk of confounding . socioeconomic factors have not been adjusted for , but severe confounding by socioeconomic differences seems unlikely because statin prescriptions are reimbursed , and access to hospital treatment is the same for all citizens in norway . in addition , we have not adjusted for vaccinations , e.g. , pneumococcus vaccine or influenza vaccine , which some previous authors have regarded as  healthy user  markers . nonetheless , we are not aware of confounders that would be likely to cause a strong association of statin use with reduced mortality in gram - negative , but not in gram - positive , bsi . in the present study , the relation between statin use and 90-day total mortality was different in gram - positive and gram - negative bloodstream infection ( bsi ) . in gram - negative bsi , statin use was associated with lower 90-day mortality , which was not the case in gram - positive bsi .
in several studies on patients with bloodstream infection ( bsi ) , prior use of statins has been associated with improved survival . 
 gram - positive and gram - negative bacteria alert the innate immune system in different ways . 
 we , therefore , studied whether the relation between prior statin use and 90-day total mortality differed between gram - positive and gram - negative bsi . 
 we conducted a prospective observational cohort study of 1,408 adults with bsi admitted to levanger hospital between january 1 , 2002 , and december 31 , 2011 . 
 data on the use of statins and other medications at admission , comorbidities , functional status , treatment , and outcome were obtained from the patients hospital records . 
 the relation of statin use with 90-day mortality differed between gram - negative and gram - positive bsi ( p - value for interaction 0.01 ) . among patients with gram - negative bsi , 
 statin users had significantly lower 90-day total mortality [ odds ratio ( or ) 0.42 , 95 % confidence interval ( ci ) 0.230.75 , p  =  0.003 ] . 
 the association remained essentially unchanged after adjusting for the effect of sex , age , functional status before the infection , and underlying diseases that were considered confounders ( adjusted or 0.38 , 95 % ci 0.200.72 , p  =  0.003 ) . 
 a similar analysis of patients with gram - positive bsi showed no association of statin use with mortality ( adjusted or 1.22 , 95 % ci 0.692.17 , p  =  0.49 ) . 
 the present study suggests that prior statin use is associated with a lower 90-day total mortality in gram - negative bsi , but not in gram - positive bsi .