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the University of Pennsylvania Health System (UPHS) as follows: (1) the ED at the Hospital of the University of Pennsylvania (HUP), a 776-bed quaternary-care medical center; (2) the ED at Penn Presbyterian Medical Center (PPMC), a 331-bed academic medical center, and (3) a network of 246 primary care physicians at community- and hospital-based practices.
Study population
The initial source population was composed of all patients pre- senting to an ED or outpatient practice who had a urine culture positive for EB between December 21, 2010, and April 22, 2013. Potentially eligible patients were identified through the HUP Clinical Microbiology Laboratory, which processes all cultures from HUP and PPMC, as well as >90% of urine cultures from UPHS outpatient practices. A patient was designated as having a community-onset urine culture if it was obtained in the ED, in outpatient practices, or within 72 hours of hospital admission. Subsequently, our exclusion criteria were as follows: patients <18 years old, those who expired during the follow-up period, long- term care-facility residents, and patients whose physician failed to consent. The remaining subjects were approached for consent. Subsequently, only patients with a true UTI were included because we sought to identify outcomes associated with ESC-R EB UTI rather than urinary colonization. The presence of a UTI was determined via medical record review, which was performed by an infectious diseases-trained physician (J.H.H.), who used the Centers for Disease Control and Prevention (CDC)/National Healthcare Safety Network (NHSN) criteria.19 Exposed patients were defined as those with an EB UTI demonstrating resistance to an ESC (ie, ceftriaxone or cefotaxime minimum inhibitory concentration [MIC] >1 mg/L) according to the criteria of the Clinical and Laboratory Standards Institute (CLSI).20 Unexposed patients were those who had a UTI with ESC-susceptible EB during the study period (ie, ceftriaxone and cefotaxime MICs ≤ 1 mg/L). Unexposed patients were randomly selected from among all patients with ESC-susceptible EB UTIs using a computerized random number generator and were mat- ched with exposed patients in a 1:1 ratio based on study year. Each patient was included as a subject only once. If an EB was
isolated on multiple occasions in the same patient, only the first episode of infection was considered in these analyses. The Insti- tutional Review Board of the University of Pennsylvania approved this study.
Outcomes
The primary outcome was clinical failure. Among outpatients, clinical failure was defined by a repeat clinical visit or phone call for ongoing UTI symptoms; a repeat positive urine culture with the same EB organism after 48 hours on initial therapy; or the use of a second antibiotic to treat the UTI due to ongoing UTI symptoms or in vitro resistance of the EB organism to the initial antibiotic. Among inpatients, clinical failure was defined by per- sistent fever, leukocytosis, or UTI symptoms without a docu- mented alternative etiology; a repeat positive urine culture with the same organism after 48 hours on initial therapy; or the use of a second antibiotic due to ongoing UTI symptoms or in vitro resistance of the EB organism to the initial antibiotic. In both outpatients and inpatients, clinical failure was assessed through 7 days following the initial evaluation for UTI (ie, the day of urine culture collection). Notably, clinical failure was not considered
Judith A. Anesi et al
present if antibiotics were changed due to adverse reactions or appropriate narrowing (ie, changing from one antibiotic to which the EB was susceptible to a second antibiotic to which the EB was susceptible that had a narrower spectrum of activity). Secondarily, a modified definition of the outcome was employed (“modified clinical failure”), in which clinical failure was defined by ongoing signs or symptoms of UTI or repeat positive cultures with the same EB organism after 48 hours on initial therapy. With this modified clinical failure definition, the addition or change of antibiotics did not constitute clinical failure. The second outcome was inappropriate initial antibiotic
therapy (IIAT). IIAT was defined as failure of the patient to receive an antibiotic to which the organism was susceptible within 48 hours of urine culture collection.
Data collection
Data on exposed and unexposed patients were abstracted from the UPHS electronic medical record system. Information was collected on demographics, comorbidities, urologic disorders, recent skilled nursing facility (SNF) or hospital stay, culture location (ED, inpatient, or outpatient practice), and all inpatient and outpatient antibiotic therapy in the 6 months preceding the UTI and in the 7 days following the UTI diagnosis. Ascertainment of the exposure and the outcomes were deter-
mined by review of the electronic medical record by physicians trained in infectious diseases (J.H.H. and J.A.A.).
Susceptibility testing of Enterobacteriaceae isolates
Susceptibility testing of EB isolates was performed by the HUP Clinical Microbiology Laboratory. All isolates identified from study subjects were tested as part of routine care for susceptibility to antibiotics using the semi-automated Vitek 2 identification and susceptibility system (bioMerieux, Durham, NC). Updated minimum inhibitory concentration (MIC) breakpoints for cef- triaxone and cefotaxime were used without confirmatory ESBL testing according to CLSI guidelines.20
Statistical analysis
Exposed and unexposed patients were characterized by potential confounders, such as demographics, comorbidities, and prior antibiotic use. For this paired data, continuous variables were compared using the Wilcoxon signed rank test, and categorical variables were compared using the McNemar test. Bivariable logistic regression was used to examine the relationship between ESC-R EB UTI and each of the outcomes: clinical failure, modified clinical failure, and IIAT. A mixed-effects multi- variable logistic regression model was fit to adjust for potential confounders with clustering by matched pair. Variables from bivariable analyses with P values<.20 or confounders of the primary association were considered for inclusion in the final multivariable model. The order in which variables were added was based on biologic plausibility. Variables were retained in the final model if they were confounders (ie, altered the effect estimate of the primary association by more than 15%), or if they had a P<.05 in the multivariable model. An odds ratio (OR) and 95% confidence interval (CI) were calculated to evaluate the strength of any association. All analyses were per- formed using STATA version 14.0 software (StataCorp, College Station, TX).
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