Outcomes for Patients with Urinary Tract Infection After an Initial Intravenous Antibiotics Dose Before Emergency Department Discharge.

INTRODUCTION: To investigate the effect of single-dose intravenous antibiotics before emergency department (ED) discharge on the outcomes of patients with urinary tract infections (UTIs).
METHODS: This is a retrospective study conducted at the EDs of three medical centers. Patients aged over 18 years who presented to the ED with UTI and were discharged without admission between January 1, 2016 and December 31, 2017 were evaluated. The study group received a single dose of effective intravenous antibiotics on the basis of urine culture during the index ED visit following oral antibiotics, while the comparison group received oral antibiotics only. The primary outcomes were ED revisit within 72 h and admission following the return visit.
RESULTS: A total of 8168 patients were included. Of these, 20.9% received intravenous antibiotics before ED discharge. Patients who received effective intravenous antibiotics before ED discharge were associated with less than 72-h ED revisit (adjusted odds ratio [OR] 0.791, 95% confidence interval [CI] 0.640-0.979]), but not decreased admission following the return visit (adjusted OR 0.921, 95% CI [0.731-1.153]). In subgroup analysis, parenteral antibiotic use during the index ED visit was associated with decreased admission following ED revisit in patients who presented with fever (adjusted OR 0.605; 95% CI 0.443-0.932).
CONCLUSION: For patients with UTI and clinically well to be discharged from the ED, a single dose of effective intravenous antibiotics before ED discharge was associated with decreased 72-h ED revisit. In patients with febrile UTI, initial intravenous antibiotics were associated with decreased revisit leading to admissions.

Key Summary Points

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Introduction

With 11% prevalence in the general population [1], urinary tract infections (UTIs) were the leading cause of emergency department (ED) visits and accounted for approximately 2% of ED visits in the USA annually [2]. Optimal management of UTI in the ED is quite challenging because of increasing antimicrobial resistance and treatment plans are usually made in the absence of microbiologic data [3-5], making it one of the most common diagnoses made during ED revisits [6].

On the basis of the current practice guidelines, patients with acute UTI of mild to moderate illness who are able to tolerate oral intake can be treated in an outpatient setting with oral antibiotics [7]. The treatment outcomes of oral antibiotics were as effective as those of parenteral antibiotics in uncomplicated UTI [8, 9]. Decades ago, several studies suggested single-dose antibiotic treatment for UTIs, proven to be as effective as oral antibiotic regimen [10-12]. With time, increasing antibiotic resistance altered the management, and these practices were no longer recommended [13]. However, the administration of single intravenous antibiotics in addition to oral regimen before discharge from the ED remains a common practice for patients with UTIs.

To better understand the value of single-dose intravenous antibiotics for patients with presumed UTIs who were well enough to be discharged from the ED, this study investigated the data from multiple medical centers in Taiwan to evaluate the effect of intravenous antibiotics before ED discharge on outcomes in patients with UTI.

Methods

Study Design and Setting

This retrospective cohort study was conducted at the ED of three medical centers in Taiwan. They were located diversely in northern, middle, and southern Taiwan, and were all regarded as the largest medical centers in the metropolitan area. The diverse population and broad geographic regions in this study helped to provide a good representation of the population that experienced the same condition. The study was approved by the institutional review board of the Chang Gung Medical Foundation (date of approval 19/07/2018, number 201801085B0). The patient and physician records and information were anonymized and deidentified prior to the analysis.

Selection of Participants

We included all adult patients aged over 18 years who presented to the ED with UTI and were discharged without admission between January 1, 2016 and December 31, 2017 for analysis. Data of the enrolled patients diagnosed with UTI were collected from the research database using International Classification of Disease (ICD) codes (ICD 10th version).

Patients who were discharged against medical advice, had an ED length of stay longer than 24 h, received more than one dose of intravenous antibiotics, without urine culture study, and those with sterile or contaminated culture were excluded. A positive urine culture was defined as a bacterial count greater than 105/mL in urine culture. Urine cultures with three or more pathogens were regarded as contaminated [14]. As a result of increasing antimicrobial resistance in UTI cases, we also excluded patients who were ineffectively treated with intravenous antibiotics in the ED on the basis of urine culture findings.

The study group included patients who received a single dose of intravenous antibiotics during the index ED visit following oral antibiotic treatment, and the comparison group received oral antibiotic treatment only. In this study, the index ED visit was defined as the first ED visit for a unique patient or visits in which the patient had no prior ED visit during the past 3 days or hospitalization during the preceding 14 days. During the index ED, clinical variables, including age, sex, vital signs at triage, underlying comorbidities, and complicated UTI were used to analyze the use of intravenous antibiotics and their associated outcomes. UTI was considered complicated in cases of advanced age (at least 65 years old), male sex, abnormal urinary tract, and immunocompromised state with conditions of active cancer, end-stage renal disease, diabetes mellitus, and liver cirrhosis.

Outcome Measurement and Statistical Analysis

The primary outcomes were ED revisit and admission following a return visit within 72 h from discharge of the index visit. An ED revisit was not counted if the diagnosis was not related to the UTI. For patients with multiple ED visits during the study period, we included the first ED visit for UTI.

We performed the Mann–Whitney U test and chi-square analysis to determine the clinical characteristics that were correlated with intravenous antibiotic use. Logistic regressions assessing the association of measured outcomes with intravenous antibiotic treatment were performed after adjusting for confounding factors. Statistical significance was defined as a two-sided P value less than 0.05. Stratified regression analyses assessing the relationship between intravenous antibiotic use and clinical outcomes at different ages, vital signs, and comorbidities were also performed. All statistical analyses were conducted using the IBM SPSS Statistics for Mac (version 26).

Results

Characteristics of Study Subjects

During the study period, 15,976 patients were discharged from the ED with a diagnosis of UTI. Of them, 6392 were not subjected to a culture test or had negative urine culture results, while 201 patients who received ineffective antibiotics were excluded. Thus, a total of 8168 patients who met the inclusion criteria were included in the study. The inclusion flowchart is shown in Fig. 1. Their median age was 57 (range 39–74) years, and 79.4% were female. A total of 1704 (20.9%) patients received intravenous antibiotics during the index ED visit. Patients with intravenous antibiotics treatment were significant older (median 63 [44-78] vs 55 [38-72] years, p < 0.001), tachycardiac (median 94 [81-108] vs 87 [77-100] beats per minute, p < 0.001), and hypotensive for both systolic blood pressure (median 139 [121-159] vs 140 [121-160] mmHg, p = 0.045) and diastolic blood pressure (median 81 (72–92) vs 84 (74–94) mmHg, p < 0.001) compared to those with oral antibiotic treatment only. Patients with complicated UTIs (61.6% vs 45.5%, p < 0.001) were also associated with intravenous antibiotic treatment during the ED visit. The other clinical variables are shown in Table 1. Regarding clinical outcomes, there was no statistical difference in return ED visits (8.4% vs 7.3%, p = 0.135) between the two patient groups. However, a higher percentage of patients receiving intravenous therapy had an ED revisit (6.2% vs 3.9%, p < 0.001).

Fig. 1

Study inclusion flowchart

Table 1

Demographic features and outcomes in patients with and without single-dose intravenous antibiotics before emergency department discharge

	With intravenous antibiotics treatment	Without intravenous antibiotics treatment	p value
	N = 1704	N = 6464
Age (year), median (IQR)	63 (44–78)	55 (38–72)	< 0.001
Male, n (%)	426 (24.7%)	1289 (19.4%)	< 0.001
Vital sign at presentation
Temperature (°C), median (IQR)	37.2 (36.4–38.2)	36.6 (36.2–37.0)	< 0.001
Heart rate (/min) median (IQR)	94 (81–108)	87 (77–100)	< 0.001
Systolic blood pressure (mmHg), median (IQR)	139 (121–159)	140 (121–160)	0.045
Diastolic blood pressure (mmHg), median (IQR)	81 (72–92)	84 (74–94)	< 0.001
Underlying disease
Hypertension, n (%)	665 (40.2%)	1779 (26.9%)	< 0.001
Diabetes mellitus, n (%)	485 (28.9%)	1169 (17.7%)	< 0.001
End-stage renal disease, n (%)	65 (4.0%)	215 (3.2%)	0.110
Liver cirrhosis, n (%)	280 (17.2%)	794 (12.0%)	< 0.001
Stroke, n (%)	97 (6.4%)	292 (4.3%)	< 0.001
Malignancy, n (%)	69 (4.2%)	135 (2.0%)	< 0.001
Abnormal urinary tract structure, n (%)	326 (19.6%)	850 (12.9%)	< 0.001
Complicated UTI, n (%)	1050 (62.9%)	2942 (44.8%)	< 0.001
Outcome
Return ED visit	143 (8.4%)	473 (7.3%)	0.135
Admission following return ED visit	105 (6.2%)	255 (3.9%)	< 0.001

Table 2 presents the use of intravenous antibiotics in the study patients. The most commonly prescribed antibiotics were cephalosporins (78.3%), followed by fluoroquinolones (9.4%), carbapenems (5.9%), and penicillin (1.3%). The common bacteria isolated from the urine cultures in this study are shown in Table 3. The most commonly isolated bacteria were Escherichia coli, accounting for 65.3% of the included patients, followed by Klebsiella pneumoniae (5.2%), Enterococcus species (4.7%), group B Streptococcus (4.5%), Proteus mirabilis (2.8%), and Pseudomonas aeruginosa (2.1%).

Table 2

Intravenous antibiotics used in studied patients

Rank	Name	N (%)
	Total	1704
1st	1st generation cephalosporin	568 (33.3%)
2nd	2nd generation cephalosporin	401 (23.5%)
3rd	3rd generation cephalosporin	366 (21.5%)
4th	Fluoroquinolone	160 (9.4%)
5th	Carbapenem	100 (5.9%)
6th	Penicillin	23 (1.3%)

Table 3

Common urinary tract infection pathogens in included patients

Rank	Name	N (%)
	Total	8168
1st	Escherichia coli	5334 (65.3)
2nd	Klebsiella pneumoniae	423 (5.2)
3rd	Enterococcus species	387 (4.7)
4th	Group B Streptococcus	370 (4.5)
5th	Proteus mirabilis	232 (2.8)
6th	Pseudomonas aeruginosa	168 (2.1)
7th	Staphylococcus saprophyticus	121 (1.5)

Logistic regression analysis was performed to identify the correlation between intravenous antibiotics and ED revisits. Since systolic and diastolic blood pressure were included in the regression model, we used median arterial blood pressure to replace these two variables to prevent multicollinearity. After adjustment for confounding factors, including age, sex, vital signs, and underlying diseases, receiving intravenous antibiotics during the index ED visit was associated with reduced 72-h ED revisits (adjusted OR 0.774; 95% CI 0.625–0.959]), but not with decreased admission following the return visit (adjusted OR 0.900; 95% CI 0.694–1.168), as shown by the logistic regression analysis. Other factors associated with both return ED visits and admission following return visits were older age, higher temperature, higher heart rate, and comorbidities, such as diabetes mellitus and liver cirrhosis (Table 4).

Table 4

Logistic regression analysis of confounding factors for return emergency department (ED) visit and admission following the return visit

	Return ED visit		Return ED visit with admission
	Adjusted OR (95% CI)	p value	Adjusted OR (95% CI)	p value
With intravenous antibiotics	0.774 (0.625–0.959)	0.019	0.900 (0.694–1.168)	0.428
Age	1.003 (0.997–1.476)	0.360	1.005 (0.998–1.012)	0.161
Temperature	1.346 (1.227–1.476)	< 0.001	1.575 (1.407–1.763)	< 0.001
Heart rate	1.007 (1.002–1.013)	0.005	1.010 (1.003–1.017)	0.004
Mean arterial pressure	1.000 (0.997–1.003)	0.931	0.997 (0.992–1.002)	0.231
Hypertension	1.225 (0.984–1.526)	0.069	1.211 (0.913–1.606)	0.184
Diabetes mellitus	1.536 (1.235–1.910)	< 0.001	1.506 (1.139–1.990)	0.004
End-stage renal disease	0.865 (0.563–1.329)	0.508	0.628 (0.334–1.181)	0.149
Liver cirrhosis	1.401 (1.116–1.758)	0.004	1.416 (1.061–1.889)	0.018
Stroke	0.943 (0.654–1.360)	0.754	1.014 (0.638–1.611)	0.953
Malignancy	0.927 (0.570–1.509)	0.761	1.021 (0.563–1.852)	0.945
Abnormal urinary tract structure	1.030 (0.814–1.303)	0.805	1.032 (0.764–1.393)	0.837

We further performed a subgroup regression analysis of specific age groups, sex, initial vital signs, and comorbidities (Table 5). Intravenous antibiotic use during the index ED visit was correlated with decreased 72-h ED revisit in patients aged 65 years or older (adjusted OR 0.719; 95% CI 0.536–0.905), those who presented with fever (adjusted OR 0.570; 95% CI 0.392–0.830) or tachycardia (adjusted OR 0.671; 95% CI 0.478–0.943); and those with underlying hypertension (adjusted OR 0.724; 95% CI 0.526–0.996), diabetes mellitus (adjusted OR 0.693; 95% CI 0.480–0.999), or complicated UTI (adjusted OR 0.770; 95% CI 0.598–0.991). Among them, intravenous antibiotic use was further associated with decreased admission following ED revisit in those who presented with fever (adjusted OR 0.591; 95% CI 0.389–0.898).

Table 5

Subgroup regression analysis of single-dose intravenous antibiotics use before emergency department (ED) discharge to outcomes

Specified subgroup	Return ED visit		Return ED visit with admission
	Adjusted OR (95% CI)	p value	Adjusted OR (95% CI)	p value
Sex
Female	0.815 (0.656–1.011)	0.063	0.959 (0.730–1.257)	0.756
Male	0.735 (0.534–1.013)	0.06	0.872 (0.567–1.337)	0.530
Age
Age ≥ 65 years old	0.719 (0.536–0.905)	0.037	1.095 (0.789–1.520)	0.588
Age < 65 years old	0.805 (0.598–1.085)	0.155	0.757 (0.523–1.097)	0.141
Initial fever
Yes	0.570 (0.392–0.830)	0.003	0.591 (0.389–0.898)	0.014
No	0.883 (0.684–1.140)	0.340	1.159 (0.846–1.589)	0.358
Initial tachycardia
Yes	0.671 (0.478–0.943)	0.022	0.755 (0.512–1.114)	0.156
No	0.841 (0.639–1.107)	0.217	1.021 (0.724–1.442)	0.904
With underlying disease
Hypertension	0.724 (0.526–0.996)	0.047	0.850 (0.575–1.258)	0.418
Diabetes mellitus	0.693 (0.480–0.999)	0.049	0.872 (0.589–1.274)	0.551
Liver cirrhosis	0.730 (0.463–1.150)	0.175	0.933 (0.542–1.605)	0.802
Stroke	1.071 (0.494–2.501)	0.862	1.057 (0.394–2.835)	0.912
Malignancy	0.817 (0.273–2.446)	0.718	1.014 (0.277–3.903)	0.953
Complicated UTI	0.770 (0.598–0.991)	0.042	0.999 (0.706–1.362)	0.996
Noncomplicated UTI	0.911 (0.641–1.296)	0.605	0.793 (0.510–1.235)	0.305

Discussion

In this multicenter retrospective study, we found that a single dose of intravenous antibiotics was administered to one out of every five patients with UTIs who could be discharged from the ED and managed as outpatients. Generally, patients with UTIs receiving intravenous antibiotics before ED discharge were associated with decreased 72-h ED revisits, but not on admission following return visits.

Prescribing intravenous antibiotics before ED discharge is a multifactorial decision. In this study, we found that patients who tended to receive a single dose of antibiotics before discharge were those with older age, male sex, worse vital signs, and more comorbidities. Previous studies have shown that UTIs account for approximately 25% of the source of sepsis in adult patients [15]. Mortality rates for patients with urosepsis range from 25% to 60%, and are especially high in the elderly, in patients with anatomical or functional abnormalities, or in immunosuppressed individuals [16-18]. This may explain why ED clinicians tend to provide more treatment in patients with immunosuppressed conditions alone than in those with worsening vital signs. Although oral antibiotics were shown to be as effective as parenteral antibiotics, the clinical severity and comorbidities of patients may affect the clinician’s decision to administer parenteral antibiotics before they discharge the patient. As a result, patients who received intravenous antibiotics generally had a higher rate of return ED visits and subsequent admissions. However, we believe that this initial observational finding is biased because of significant differences in clinical characteristics between the two patient groups.

Cephalosporins were the most commonly chosen intravenous antibiotics, accounting for 78.3% of all intravenous antibiotic therapies. According to a recent study, first-generation cephalosporins had 72.1–83.4% drug susceptibility for lower UTI cases and 77% for upper UTI cases, making them not the first choice to cover possible resistance pathogens in UTI cases [19-21]. While one-third of patients received first-generation cephalosporins, 45% of patients received second-generation or newer cephalosporin antibiotics. On the other hand, fluoroquinolone and carbapenem were also chosen as suggested by recent practice guidelines [22].

Common pathogens that caused UTIs in the included population were comparable to those in previous studies; E. coli, K. pneumoniae, Enterococcus spp., and group B Streptococcus accounted for the majority of uropathogens [23]. On the other hand, P. aeruginosa, as previously reported to be more common in complicated UTIs, was found to constitute approximately 2% of the patients who could be discharged directly from the ED in this study [24].

In the early 1990s, an unscheduled ED revisit within 72 h after being discharged from a previous ED visit became a widely reviewed medical quality assessment tool [25, 26]. Return visits to the ED are resource consuming and can add strain to the already overburdened ED [27]. As one of the most common diagnoses associated with ED revisit, one recent study showed that UTI-associated return visits were significantly higher in patients with advanced age, obstructive uropathy, fever, and tachycardia [3]. We found similar results in our study: older age, higher temperature, tachycardia, Foley indwelling, and comorbidities, such as hypertension, diabetes, and liver cirrhosis were associated with return ED visits after regression analysis. On regression analysis, the patients with comorbidities who received parenteral antibiotics and were then shifted to oral antibiotics had a lower likelihood of an ED revisit.

A recent study evaluated the effect of single-dose intravenous antibiotics for UTIs in children and found that it had no benefit in both ED revisit and readmission [28]. Our study showed that intravenous antibiotics before discharge were associated with decreased ED revisit, but not with admission following a return visit. To further investigate the effect of single-dose intravenous antibiotics for UTIs, we performed a subgroup analysis based on the patient’s age, sex, vital signs, comorbidity, and complicated UTI. Single-dose intravenous antibiotics were still associated with decreased ED revisit in several subgroups, such as the elderly (age greater than 65 years), those presenting with fever, tachycardia, comorbid hypertension, diabetes mellitus, and complicated UTI.

Among these subgroups, patients with UTI who presented with fever may benefit from single-dose intravenous antibiotics before discharge, resulting in a decreased rate of admission following ED revisit. In infected individuals, fever represents a systemic host response to a microbial infection. Febrile UTI cases usually involve tissue invasion and systemic inflammation resulting from an upper UTI, such as pyelonephritis, which may be accompanied by sepsis syndrome progressing to life-threatening circulation failure [22]. For patients with an upper UTI who do not require hospitalization, current expert opinions suggest loading intravenous antibiotics followed by an oral regimen until results are obtained from the culture test [7]. Although it was difficult to distinguish upper UTI and lower UTI in ED most of the time, the results of our study accord with this idea. From the perspective of pharmokinetics, there was a clear gap in bioavailability between intravenous and oral antibiotics for treating bacterial infections, especially in the early phase [29]. While most oral antibiotics require days to catch up from their initial 50–90% bioavailability, early intravenous antibiotics are recommended for treating patients with sepsis [30, 31]. In addition, intravenous antibiotics were more rapidly absorbed and enhanced the time to peak serum concentrations, particularly cephalosporins and penicillin [32]. It is therefore reasonable that intravenous antibiotic use in febrile patients with UTI is associated with decreased ED readmission for patients who can be discharged and managed as outpatients.

There are several important limitations to our study. First, this was a retrospective multi-hospital database study, and we were unable to review individual medical records to collect other clinical confounding factors that may influence the cause of the ED revisits. It was difficult to distinguish UTI type (upper vs lower) using the retrospective data. This may have limited the detailed analysis of the effect of intravenous antibiotic use by UTI type. In addition, the decision to administer a single dose of intravenous antibiotics before discharge can be multifactorial. Patients’ social education status, medication compliance, and family support may change clinicians’ minds about whether to administer extra antibiotics. This unstructured information may not be present in a retrospective database review. Second, we included patients on the basis of ICD codes documented in the electronic health record system, which may have limited the number of UTI-related visits identified in the study. Third, we tracked the ED visits of included patients longitudinally in the same medical hospitals, and we do not know if the patients visited different hospitals for follow-up. This may have underestimated the general revisit rate in this study.

Conclusion

Administration of an initial single-dose intravenous antibiotic for patients with UTIs before ED discharge was associated with a decrease in ED revisit within 72 h of discharge. For patients with febrile UTIs, initial intravenous antibiotics were further associated with decreased admission following ED revisit within 72 h.

Why carry out this study?

UTI were the leading cause of ED visits and accounted for approximately 2% of ED visits in the USA annually.

Optimal management of UTI in the ED is quite challenging.

To better understand the value of single-dose intravenous antibiotics for patients with presumed UTIs who were well enough to be discharged from the ED.

What was learned from the study?

Effective intravenous antibiotic use before ED discharge was associated with decreased ED revisit in patients with UTIs (adjusted OR 0.774; 95% CI 0.625–0.959).

Intravenous antibiotic use in febrile patients with UTI is associated with decreased ED readmission (adjusted OR 0.591; 95% CI 0.389–0.898) for patients who can be discharged and managed as outpatients.