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Table 2. Mixed-Effects Multivariable Logistic Regression Model of Clinical Failure
Variable ESC-R status
Need for hemodialysis Citrobacter species
Baseline respiratory disease Agea
aOR 7.07
24.09 42.01 0.22 0.99
95% CI
3.16–15.82 1.89–307.78 1.67–1058.12 0.07–0.64 0.97–1.01
P Value <.01 .01 .02 .01 .24
Note. aOR, adjusted odds ratio; ESC-R, extended-spectrum cephalosporin resistant;
CI, confidence interval. aConfounder of ESC-R status and clinical failure. The aOR for age is given per 1-year increase in age.
Judith A. Anesi et al
Delayed appropriate antibiotics confounded the relationship between ESC-R status and clinical failure, suggesting that prompt appropriate antibiotics impacts the relationship between ESC-R EB UTI and clinical outcomes. However, after adjusting for IIAT, a significant association remained between ESC-R EB UTI and clinical failure, suggesting that IIAT does not fully explain the impact of ESC-R EB on poor clinical outcomes in community- onset UTIs. The association between ESC-R EB UTI and clinical failure is
Table 3. Mixed-Effects Multivariable Logistic Regression Model of Inappropriate Initial Antibiotic Therapy (IIAT)
Variable ESC-R status Exposure to ESCa Culture taken in the ED
aOR 4.40 3.72 0.56
95% CI
2.64–7.33 1.12–12.32 0.31–1.01
P Value <.01 .03 .05
Note. aOR, adjusted odds ratio; CI, confidence interval; ED, emergency department; ESC,
extended-spectrum cephalosporin; ESC-R, extended-spectrum cephalosporin-resistance. aExposure within the 6 months prior to EB UTI presentation.
1.00–7.01; P=.05). The other independent risk factor for mod- ified clinical failure was need for hemodialysis.
Association of ESC-R EB UTI with IIAT
Within the entire cohort, 158 patients (53%) experienced IIAT. The initial antibiotics administered to the cohort are described in Supplemental Table 2. In the multivariable analysis (Table 3), ESC-R EB UTI was a significant independent risk factor for IIAT (aOR, 4.40; 95% CI, 2.64–7.33; P<.01). Exposure to an extended- spectrum cephalosporin in the 6 months before the index UTI was also a significant risk factor for IIAT, and having a urine culture obtained in the ED was associated with decreased odds of IIAT.
When IIAT was incorporated into the clinical failure model,
ESC-R status was still significantly associated with clinical failure, but the aOR was attenuated (aOR, 5.88; 95% CI, 2.58–13.38; P<.01 compared to an aOR of 7.07, as shown in Table 2). Also, IIAT was a confounder of this relationship. However, there was no effect modification by IIAT; the impact of IIAT on the asso- ciation between ESC-R status and clinical failure did not differ considerably between the ESC-R and ESC-susceptible (ESC-S) EB UTI groups.
Discussion
In this study, patients who presented with a community-onset ESC-R EB UTI experienced worse outcomes than those with an ESC-S EB UTI, with an increased odds of clinical failure through 7 days. Importantly, this study primarily included patients who did not have an associated bacteremia or pyelonephritis. Patients presenting with an ESC-R EB UTI were less likely to receive appropriate antibiotics within 48 hours of UTI evaluation.
consistent with prior literature that has shown bacteremic ESC-R EB UTIs, and hospital-acquired ESC-R EB UTIs are associated with increased length of stay and increased mortality.12–16 This association may be related to several factors. Our study shows that delay in appropriate antibiotics contributed to the patients’ worse outcomes, but this did not fully explain the association. Other potential explanations include increased virulence of the resistant organisms, resulting in more severe infections; unmeasured host factors that predisposed the patients to worse clinical outcomes; and more severe baseline infection not captured by pyelonephritis and bloodstream infections. This finding suggests that community-onset UTI with an ESC-R EB organism requires increased clinical monitoring after diagnosis to ensure clinical resolution, even in the absence of bacteremia, pyelonephritis, or hospital admission. The association between ESC-R EB UTI and IIAT is also
consistent with prior studies showing that ESC-R EB bloodstream infections are associated with increased odds of IIAT.21–23 Our study shows that the higher risk for IIAT observed with ESC-R EB infection extends to community-onset nonbacteremic UTIs. Thus, patients presenting with UTI in the outpatient setting who are at risk for ESC-R EB as the etiology should have urine cultures collected and vigilant follow-up to ensure appropriate therapy is administered. In addition to ESC-R status, we detected increased odds of
clinical failure associated with (1) UTI due to Citrobacter spp and (2) need for hemodialysis. The increased odds of clinical failure associated with Citrobacter UTIs may be related to the inducible ampC production observed among this species,24 which may result in the inadvertent use of a less effective antibiotic. However, the number of Citrobacter infections in this cohort was relatively small, so further study is needed to confirm this finding. The association between hemodialysis and clinical failure is consistent with prior studies that have shown renal dysfunction to be associated with increased susceptibility to bacterial infections and worse clinical outcomes due to uremia-induced immune dys- function.25 Baseline respiratory disease was associated with decreased odds of clinical failure. This finding may be due to recurrent respiratory infections among this group that results in broader empiric antibiotic regimens when presenting with infectious symptoms. Our study has several limitations. Misclassification is a con-
cern in retrospective studies. However, both the exposure and outcomes were validated through medical record review by physicians trained in infectious diseases rather than relying on diagnostic or billing codes. The assessment of the outcomes was limited to review of the UPHS medical record. Patients who experienced clinical failure and sought care from outside provi- ders would not have been captured. However, this missing information should be nondifferential between the exposed and unexposed groups. Furthermore, because the outcome was assessed at 7 days post-UTI evaluation, relocation of care is less likely in this short time frame. Finally, because the present study
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