Staphylococcus aureus bacteriuria as a prognosticator for outcome of Staphylococcus aureus bacteremia: a case-control study

Bacteriuria with Staphylococcus aureus is postulated to occur through a limited number of mechanisms--primarily ascending spread after instrumentation (e.g., urologic procedures or urethral catheterization) or hematogenous seeding of the genitourinary tract. The finding by Lee et al., that bacteremia is strongly associated with bacteriuria among patients infected with S. aureus, supports the notion that bacteremia is an important precursor for bacteriuria [1]. What is less clear, however, is whether in patients with S. aureus bacteremia, the finding of S. aureus in the urine holds any prognostic significance.

Among patients with S. aureus bacteremia, there are many prognostic factors, including host factors or comorbidities (age [2‐10], Charlson score [2, 11], immunosuppression [4], alcoholism [4], hemodialysis [4], acute renal failure [4], diabetes mellitus [8], recent hospitalization [11], mechanical ventilation [5], and acute severity of illness [12]); pathogen-specific factors (MRSA [3, 13] superantigenic toxin production [14]); or characteristics of clinical presentation or management (meningitis [13] or altered mental status [11, 12], community-acquired infection [4], severe sepsis or septic shock [3, 4, 6, 7], lack of an infectious disease consult [4, 15], prior antibiotic therapy [6], unknown [8] or persisting foci of infection [16], daily dose of penicillinase-stable penicillin < 4 grams [16], and inappropriate empiric treatment [6, 12] or duration of treatment < 14 days [16]). The relation of occurrence of bacteriuria to outcome has been postulated [17], but the interactions with other risk factors warrant investigation. That bacteriuria might be a predictor of worse outcome in S. aureus bacteremia has biologic plausibility. For example, several innate defense mechanisms exist that prevent the development of urinary tract seeding in bacteremic patients: defensins, Toll-like receptor 4, and chemokine receptor CXCR1 [18, 19], and these innate defenses may be overcome and the urinary tract seeded in the setting of higher bacterial loads [20].

Over the last 20 years, MRSA has emerged as an important cause of nosocomial bacteremia [21], and significant increases in the incidence of MRSA infections in community patients have been observed in the past few years [22‐24]. Methicillin-resistance is a major risk for increased morbidity and mortality in S. aureus infection. Given the increasing burden of infection by community-associated MRSA (CA-MRSA) infections [22‐24] and the suggestion that CA-MRSA strains may have greater virulence, predictors of morbidity and mortality are essential for allocation of clinical infections.

We hypothesized that for patients with S. aureus bacteremia, bacteriuria is an important marker of disease severity and predictor of worse outcomes. We examined this hypothesis by evaluating outcomes of S. aureus bacteremia in patients with and without bacteriuria. We also examined the impact of methicillin-resistance on outcomes among patients with S. aureus bacteremia with and without bacteriuria. Finally, using our cohort, we examined the predictors of bacteriuria.

The mean age of pooled dataset, created by joining case and control patients was 48.3 years; 68.5% were male, 181 (58.8%) were African-American, and 37 (12.0%) died during hospital admission. Sites involved by bacteremia were cardiac valves [31 (10.7%)], vascular catheters [59 (19.2%)], skin/soft tissue [57 (18.5%)], bone/joints [27 (8.8%)], lungs [41 (13.3%)], genitourinary tracts [22 (7.1%)], and other sites [11 (3.6%)]; for 106 (36.7%) patients, there was no documented organ involvement other than bloodstream.

Hospital mortality rates were higher in S. aureus bacteremia patients with bacteriuria compared to patients without bacteriuria (39% vs 17%, respectively, p = 0.002) (table 1). In multiple Cox regression (table 2), significant predictors of death were positive urine culture (Hazard ratio 2.9; 95% CI, 1.4-5.9, p = 0.004), indwelling bladder catheter (2.0; 95% CI, 0.97-4.0, p = 0.06), and Charlson score (1.2; 95% CI, 1.1-1.3, p = 0.02); vascular catheter infection or phlebitis was associated with lower risk of death (0.27; 95% CI, 0.060-1.2, p = 0.09). Cox regression showed a significantly higher mortality rate in case than in control patients (figure 1). Neither methicillin-resistance nor the specific strain types of MRSA were predictors of mortality in univariate or multivariable analysis.

More positive urine cultures were seen in community-onset (both community-acquired and healthcare-associated) compared to hospital-acquired bacteremia (46% vs 23%, respectively, p < 0.001); in HIV-positive patients compared to HIV-negative patients (19% vs 10%, p = 0.05); and in patients with recent urological surgery (11% vs 3%, p = 0.03) or genitourinary infection (21% vs 4%, p < 0.001) compared with those without genitourinary problems (table 3). In multivariable analysis (table 4), urological surgery (OR 4.5, p = 0.045) and genitourinary infection (OR 5.7, p = 0.002) were significantly associated with positive urine cultures.

In our case-control study, patients who had S. aureus bacteremia and a positive urine culture for S. aureus had significantly higher mortality than did bacteremic patients with a negative urine culture. This was true even after adjustment for multiple covariates including use of bladder catheters, presence or absence of lower urinary tract symptoms, or recent urological surgeries, which are known risk factors for a positive urine culture, significant factor in the multivariable analysis such as presence of line infection or phlebitis or presence of comorbidities as measured by the Charlson score [2, 11]. The conclusion that S. aureus bacteriuria patients have worse prognosis compared to patients without S. aureus bacteriuria among S. aureus bacteremia patients may be useful to clinicians when deciding whether to monitor a patient on the ward or the ICU and when explaining the prognosis of the illness to the patient and his family.

S. aureus is a common pathogen in the community and in hospitals. S aureus causes significant mortality and morbidity but is an infrequent cause of urinary tract infection [27]. In patients with S. aureus bacteremia, a positive urine culture is typically attributed to ascending infection or to hematogenous spread. Predictors of a positive urine culture for S. aureus include presence of indwelling bladder catheters, urinary tract obstruction, instrumentation, or surgery [27, 28]. We hypothesized that S. aureus appears in the urine in bacteremic patients because of higher burden of organisms and thus may portend worse outcome.

A recent study examining the relationship of bacteriuria with mortality found a two-fold increased risk of death in patients with concomitant S. aureus bacteriuria and bacteremia [17]. The current study adds to published literature by including significant numbers of methicillin-resistant isolates and by using statistical methods appropriate for varying time at risk. The association of bacteriuria with increased risk of mortality even after adjustment for comorbidities was similar in both studies, suggesting that bacteriuria provides useful prognostic information in the setting of S. aureus bacteremia. In addition, based on our findings, it appears that this is an effect independent of methicillin-resistance and that secular trends in incidence of MRSA are unlikely to alter this association.

There are several limitations to our study. The patients in the study were cared for at a single center and it may be difficult to generalize our findings to other hospitals. The Cook County Bureau of Health Services is the largest provider of indigent care in Cook County and has seen large increases in rates of community-associated S. aureus infection, and our estimates likely represent robust measures of risk for mortality. A second limitation is that this was a retrospective study and depended on documentation in the chart, which may have resulted in misclassification errors in assessing comorbidities and other covariates. Non-differential misclassification tends to bias towards the null, which suggests that our estimates of risk are likely conservative. In addition, electronic data were used in this study and were prospectively collected at the time of care; these data were not subject to problems inherent in reviews of written documentation Finally, in our study, we had an overall mortality rate of 12% which was at the lower end of published mortality rates--12-46% [3‐13, 27, 29, 30]--in this setting, suggesting that our cohort may have had fewer comorbidities and lower attributable mortality that in other published data. This may be a result of the significant burden of CA-MRSA in our patient population.

In patients with S. aureus bacteremia, a positive urine culture for S. aureus may be used to identify patients at higher risk of death. Patients who have S. aureus bacteremia and more comorbidities are at increased risk for higher mortality rate.