Few studies have evaluated the epidemiology of patients who develop nosocomial BSI from a urinary source. A previous case-control study of patients with febrile UTI found that compared to 88 patients without BSI, the 80 patients with BSI were older and more frequently had an indwelling urethral catheter or obstructive urologic disease.5
Krieger and colleagues6
evaluated a prospective cohort of 40,718 patients, identifying 565 cases of nosocomial BSI (32 of which were felt to have originated from the urinary tract), and identified male sex and infection with Serratia marcescens
as risk factors for BSI. More recently, Saint and colleagues2
conducted a case-control study identifying 95 cases with concordant positive blood and urine cultures > 48 hours after admission, matched with 142 controls with only positive urine cultures > 48 hours after admission. Risk factors for urinary tract-related BSI included immunosuppressant therapy within 14 days of bacteriuria, malignancy, male sex, and cigarette use within 5 years. Age dependent effects were also detected, including the presence of diabetes mellitus conferring increased risk in patients < 70 years old.
In our study, we were able to more fully explore the extent to which a number of previously identified risk factors may alter the risk of developing urinary tract-related BSI. While women generally have a greater risk of developing UTI,13
we found that men were more likely than women to develop urinary tract-related BSI. While gender is clearly a non-modifiable risk factor, this result supports previous findings2,6
and suggests that prevention strategies to prevent the development of BSI from a urinary source may need to be gender-specific.
Diabetes mellitus is an extremely important cause of morbidity and mortality in the US, affecting over 25 million American adults in 2010.14
Individuals with diabetes mellitus may have elevated risks for a number of infections (including UTI) due to altered aspects of the immune system.15
Although we did not find diabetes mellitus to confer an increased risk towards the development of urinary tract-related BSI, we did detect an increased risk among patients who received insulin. A recent study investigating the influence of blood glucose levels among persons with diabetes mellitus on the risk of BSI found that short-term blood glucose levels of 110 to 139 mg/dL were associated with a 2-fold increased risk for BSI.16
Using the administration of insulin (within 2 days prior of the index date) as a proxy for short- term hyperglycemia, the results from our study are consistent with this phenomenon. Although it remains unclear whether short-term hyperglycemia is an effect of BSI rather than a contributing cause of BSI, elevated blood glucose levels may be an indicator of nosocomial BSI risk.16
Our study extends prior work by detecting several significant associations between a number of novel and time-dependent risk factors and urinary tract-related BSI. Although previous studies have shown the relationship between malignancy and urinary tract-related BSI,2
to our knowledge none have assessed the potential role of neutropenia explicitly. Using a sensitive definition of severe neutropenia based on confirmed laboratory values, approximately 20% of all neutropenic patients in our study did not have positive histories of malignancy. Severe neutropenia increases the risk and severity of bacterial and fungal infections.17
In our investigation, 70% of neutropenic patients with UTI developed a BSI. Other investigators have shown that as many as 30% of neutropenic patients develop BSI18
and maydevelop BSI an average of 2 days earlier than their non-neutropenic counterparts.19
Urine cultures are typically obtained from febrile, neutropenic patients and may demonstrate asymptomatic bacteriuria. Although treatment for asymptomatic bacteriuria is typically not indicated for many patient subgroups, treatment may be appropriate in neutropenic patients, given the high probability of developing urinary tract-related BSI in our study. UTI treatment recommendations may need to specifically address tailored approaches to the management of neutropenic patients.
Consistent with prior work suggesting that high serum creatinine and low serum albumin each confer an increased risk of BSI in patients with UTI,8
we found that patients with renal and liver disease were more likely to develop urinary tract-related BSI. The increased risk of BSI among patients with chronic kidney disease (CKD) receiving hemodialysis has been described and is in part attributable to the necessary and repeated vascular access.20
Recently, James and colleagues have described a similar increased risk of BSI among CKD patients not receiving hemodialysis.21
Although the mechanisms contributing to increased susceptibility to infection among CKD patients are not completely understood, it is possible that renal dysfunction is a marker for other conditions that increase host susceptibility.21,22
Alternately, it has been suggested that consequences of CKD (e.g., malnutrition, chronic inflammation, impaired immune function) may partially explain the association between CKD and increased risk of infection.21–23
Renal failure occurs in approximately 50% of end stage liver disease patients and the risk of mortality in such patients is increased, particularly in those with bacterial infections and hepatorenal syndrome.24
Our non-parametric CART model further suggests that patients with both renal and liver disease are at increased risk of developing urinary tract-related BSI, emphasizing the importance of careful infection management among this high-risk subgroup.
To our knowledge, only one previous study2
has examined how time-dependent medication use alters risk of urinary tract-related BSI. Our study expands on this previous work by examining a wide range of medications administered at various time points during the hospital stay. We ultimately chose to investigate the influence of medication use during a relatively short time frame (2 days) preceding the index date, during which respective pharmacodynamic and pharmacokinetic properties of various drugs would potentially act to influence risk of progression to BSI. We found that a number of medications administered within this time frame may alter the risk of BSI progression. For example, immunosuppressant use was associated with an increased risk, while antibacterial use was associated with a reduced risk of BSI; these findings are consistent with previous work.2
Our findings regarding time-dependent statin use contribute to a growing body of literature investigating the potential effects that statins may have on infection risk. Although commonly prescribed for their lipid-lowering effects, statins have pleiotropic immunomodulatory properties including: improved endothelial and microvascular function, anti-inflammatory activity, and increased expression of endothelial nitric oxide synthase.25–28
A recent review of data from observational human studies concluded that statins may reduce the risk of sepsis in patients with bacterial infection.29
Randomized controlled trials are necessary to assess efficacy, particularly in this era of increasing antibiotic resistance.
We have previously described the microbial etiology of the patients that developed urinary tract-related BSI in our hospital-based sample, as well as temporal changes in the microorganisms isolated in these nosocomial infections.3
Our investigation provides new evidence that Enterococcus sp.
and coagulase-positive staphylococcus are microorganisms that may be more likely to spread from the urinary tract to the bloodstream. It is possible that the differences in the growth of certain microorganisms between cases and controls are reflective of selective pressure of empiric antibiotic treatment. Despite this, we did not find a difference in the frequency of antibacterial use between cases and controls. Although the underlying biological reasons for these findings could not be established in our study, understanding the microbial etiology remains important for decisions regarding antibiotic treatment.
Our study has several limitations. First, the retrospective nature of our study affected our ability to determine whether bacteriuria reflected a primary urinary infectious nidus or seeding from a hematogenous site. We addressed this by conducting manual chart reviews and excluding cases felt to have a clear competing bloodstream infectious source. Second, we did not examine the adequacy of antimicrobial therapies. Third, we did not confirm that isolates from the urine and blood were identical organisms using antimicrobial resistance patterns or molecular typing methods. Fourth, this was a single-site study performed in a Midwestern referral hospital that cares for complex patients, and the generalizability of our findings may be limited. Fifth, we were unable to consistently determine certain variables through administrative or clinical records. Of note, we were not able to obtain reliable data on the presence of urinary catheters. We do not have reason to believe that the proportions of urinary catheters would be significantly different between cases and controls, since all study subjects were required to have nosocomial bacteriuria, which is associated with urinary catheters in most patients. Still, failure to account for this (and other) potential confounding variables may have impacted our results. Finally, it should be noted that the associations between a number of the comorbid conditions and urinary tract-related BSI may be reflective of markers of severity of illness among the cases relative to the controls, rather than direct causal (and biologically plausible) links between “exposure” and urinary tract-related BSI. Additionally, while BSI likely contributed to higher mortality among cases relative to controls, we cannot rule out mortality attributable to other comorbid conditions. Nonetheless, such markers may prove valuable in helping guide infection prevention strategies.
Limitations notwithstanding, our study has helped develop a deeper understanding of the etiology of urinary tract-related BSI among hospitalized patients. The likelihood of BSI related to nosocomial bacteriuria among hospitalized patients can be predicted by several host-specific factors, and the heightened risk of urinary tract-related BSI associated with several comorbid conditions suggests that the management of nosocomial bacteriuria should perhaps be tailored to certain patient sub-groups. Considering time-dependent risk factors, including inpatient medications, may also help guide clinical decisions in reducing this critical and costly patient safety problem.