Trial design

We performed a stepped wedge cluster-randomized trial involving consecutive patients presenting with a presumptive diagnosis of FUTI, at the EDs of 7 hospitals in the Netherlands, between January 2010 and June 2014 [11]. These centers also participated in the validation cohort study (see Additional file 1). All participating centers started with a control period, in which routine clinical practice with regard to hospitalization policy was applied. The intervention (use of the PRACTICE) was introduced at the participating centers sequentially, in random order. By the end of the allocation all sites, except one, used the PRACTICE to guide admission policy.

Inclusion criteria were age ≥ 18 years, fever (≥38.0 °C) and/or a history of fever or shaking chills within 24 h before presentation, at least one symptom of UTI (dysuria, perineal pain or flank pain) and a positive nitrite dipstick test or leucocyturia. Exclusion criteria were pregnancy, hemodialysis or peritoneal dialysis, a history of kidney transplantation or polycystic kidney disease. The study protocol was approved by the local Ethics Committee, and all participants signed an informed consent form prior to enrollment.

Intervention and treatment

The PRACTICE score ranges from 8 to >125. Based on the validation cohort it was divided into three risk classes (low <75 points; intermediate 75–100 points; high >100 points) with corresponding recommendations regarding hospitalization policy (Table 1). During the control period, the decision to treat the patient at home or admission to hospital was made at the discretion of the ED physician. At the start of the intervention period the ED physicians were instructed to calculate the PRACTICE score and on that basis decide on hospital-based or home-based treatment. Preferably admission policy was done according to the guidance as described in Table 1, however, the attending physician was responsible for the final decision on treatment location.

Throughout the whole study period the antibiotic therapy was left at the discretion of the treating physician. According to local guidelines, outpatient treatment for FUTI consisted of a 10–14 day course of oral antimicrobials (first choice ciprofloxacin 500 mg b.i.d.) [12]. In case of risk factors for quinolone resistance a single dose of a long-acting parental antimicrobial, e.g. ceftriaxone or an aminoglycoside, at the initiation of therapy was advised while culture results were pending [13].

Admitted patients started with empirical antimicrobials intravenously according to local policy and were switched to an oral antibiotic based on antimicrobial sensitivity testing of the uropathogen cultured.

Study procedures

Within 24–48 h of notification, qualified research nurses collected demographic and clinical data by reviewing the medical record completed with an interview by telephone or in person, using a standardized questionnaire. A midstream-catch urine culture and a set of blood cultures were taken before commencement of antimicrobial therapy. All patients were contacted in person 3–4 days and 28–32 days after enrollment, and contacted by phone at day 13–15 and day 84–92, to assess clinical outcome. Urine culture was repeated at the 28–32 day follow-up visit. In case of (re) admission during the study period, related data were obtained from the medical record and interview. In case a patient was lost to follow up, survival and readmission were assessed by inquiry with the patient’s primary care physicians, hospital chart and/or local governmental mortality registries.

Urine and blood cultures were performed using standard microbiological methods at local certified laboratories. Data collection of patients included during the validation period was identical (see Additional file 1).

Endpoints

The primary endpoints were primary hospital admission rate (the percentage of patients who were directly admitted to hospital) and secondary hospital admission rate (the percentage of patients who needed to be hospitalized for FUTI after initial home-based treatment). Secondary outcome measures were 30- and 90-day all-cause mortality rate, ICU admission rate, the total number of hospitalization days over a 3-month follow-up and clinical- and microbiological cure rate through the 10- to 18-day post-treatment visit. Clinical cure was defined as being alive with absence of fever and resolution of UTI symptoms (either absence of symptoms or at least 2 points improvement on a 0 through 5 points severity score), without additional antimicrobial therapy for relapse of UTI [14]. Bacteriologic cure was defined as eradication of the study entry uropathogen with no recurrence of bacteriuria (pathogen growth <10⁴ cfu/mL in women or <10³ cfu/mL in men combined with disappearance of leucocyturia) [15].

A Data Safety Monitoring Board (DSMB) monitored the study and prescheduled interim analyses were performed according to predefined stopping rules. For the analysis of secondary hospital admission only low risk patients PRACTICE-score = < 100 points were considered.

Definitions

UTI in men, postmenopausal women and in women with any structural or functional abnormality of the urinary tract were considered ‘complicated’ whereas in all others it was considered ‘uncomplicated’ UTI [13, 15]. Comorbidity was defined as the presence of any urinary tract disorder, heart failure, cerebrovascular disease, renal insufficiency, diabetes mellitus, malignancy or chronic obstructive pulmonary disease.

Statistical analysis

The primary endpoints were analyzed on the intention-to-treat (ITT) and per-protocol (PP) population. Evaluable patients for ITT analysis included all patients who met the inclusion criteria and had at least 1 follow up visit. The PP population consisted of cases in which PRACTICE-hospitalization recommendations were actually followed in the intervention period and all cases in the control period. Binomial or categorical outcome measures were analyzed using Chi-square tests (Pearson’s or Fisher’s). Risk difference with 95% confidence interval (CI) was used to compare the differences of categorical outcomes. Tests of significance were at 0.05 level, two-tailed, for primary hospital admission rate.

A study sample size of 326 patients in both arms was calculated on the basis of secondary hospital admission rate, which was estimated to be approximately 5%, based on our previous study on FUTI [16], to have a power of 90% to show that the secondary admission rate in the intervention period (PRACTICE-guided management) is at least as low as the control period. As we were only interested for non-inferiority and not in equivalence in secondary hospital admission rate, the sample size calculation was based on a one-tailed alpha of 0.025. This implies that the 90% CI of a two-tailed Chi-square test should not cross the predefined risk difference of 2.5% higher secondary admission rates. All analyses were performed using SPSS 20.0 (SPPS Inc., USA).

Study participants

A total of 370 patients was included, 237 in the control period and 133 in the intervention period (see the flowchart in Fig. 1). In the ITT-population, baseline demographic characteristics were similar in the two groups (Table 2), except for a difference in history of cerebrovascular and chronic renal disease. Patients in who PRACTICE recommendations were followed (the PP-analysis) were significantly older, had more comorbidity and more often suffered complicated UTI than control patients (Table 2).

	Control group	Intervention group		p
	ITT = PP	ITT	PP	Control vs ITT	Control vs PP
	n = 237	n = 133	n = 81
Age in years; median, (IQR)	60 (30)	61 (34)	71 (26)	ns	<0,01
Sex – female	148 (62)	74 (56)	33 (41)	ns	<0,01
Febrile uncomplicated UTI	54 (23)	30 (23)	9 (11)	ns	0,02
Antimicrobial treatment at inclusion	90 (38)a	44 (33)	22 (27)	ns	ns
Urologic history
Present urinary catheter	17 (7)	9 (7)	8 (10)	ns	ns
History of urinary tract disordera	73 (31)	33 (25)	29 (36)	ns	ns
Recurrent UTIb	30 (13)c	11 (9)c	5 (7)	ns	ns
Comorbidity
Any	124 (52)	77 (58)	57 (70)	ns	<0,01
Diabetes mellitus	36 (15)	29 (22)	25 (31)	ns	<0,01
Malignancy	13 (5)	11 (8)	10 (12)	ns	ns
Heart failure	32 (13)	12 (9)	11 (14)	ns	ns
Cerebrovascular disease	17 (7)	20 (15)	18 (22)	0.02	<0,01
Cirrhosis	1 (0)	2 (1)	1 (1)	ns	ns
Renal insufficiency	12 (5)	20 (15)	18 (22)	<0.01	<0,01
Immunocompromised	19 (8)	10 (8)	5 (6)	ns	ns

Data are presented as n (%) unless otherwise stated. ITT intention to treat analysis, PP per protocol analysis, IQR interquartile range, ns not significant (at 0,05 level), UTI urinary tract infection. ^aUrinary tract disorder: presence of any functional or anatomical abnormality of the urinary tract excluding the presence of a urinary catheter. ^bRecurrent UTI: two or more episodes in the last 6 months or three or more episodes of UTI in the last year. ^cUTI history was unknown in 13 subjects in control period and 6 subjects in intervention period

Fifteen patients who were included in the study by ED-physicians did not completely meet the predefined inclusion criteria, but discharge diagnosis as concluded by the attending physician was FUTI in all cases. On hospital presentation, ten of these patients had no specific symptoms of UTI, 8 of these 10 patients had cultures of blood (3) and/or urine (5) positive with significant growth of an uropathogen, 2 had negative urine cultures, and 1 of them used antibiotics at inclusion. The other 5 patients did not have or report fever at inclusion, 1 of them was on TNFα-inhibitors.

Follow up was not completed in 37 patients in the control group and in 13 patients in the intervention group. Based on review of medical charts and governmental records these patients were all alive and without secondary admission, and included as such in the analysis.

Cultures

Outcome

The mean PRACTICE scores in the control and intervention groups (ITT analysis) were 62 (95% CI: 57.7 to 65.4) and 64 (95% CI: 58.3 to 69.7), respectively. Mean PRACTICE score in the PP population was 76 (95% CI: 69.0 to 83.3; p < 0,01).

The attending physician overruled the PRACTICE rule in 50 out of 153 patients categorized as low risk, who were admitted to the hospital because of ‘sick appearance’ (n = 9), severe flank pain (n = 2), antibiotic treatment at presentation (n = 7), comorbidity (n = 5), nausea (n = 3), uncertain diagnosis (n = 4), unknown (n = 7) or other reasons (n = 13). On the other hand, two patients categorized as high risk were treated at home because they insisted on home based treatment.

The median number of hospitalization days over a 3-month follow-up was 5 days (95% CI 5.6 to 7.0) vs 4 days (95% CI 4.4 to 6.7) for the control and intervention period, respectively.

Clinical and microbiological cure on day 30 did not differ significantly between both groups (Table 4).

Safety

In the control period, 18 patients were treated at home (1 high risk and 17 low risk patients), of which 1 low risk patient was admitted 5 days after start of home treatment because of flank pain shown to be due to renal vein thrombosis.

Of the 37 patients in the intervention group who received initial home-based treatment (29 low risk, 6 intermediate risk and 2 high risk patients), 10 patients (27%) had a secondary hospital admission. These 10 patients (7 females; median age 61, range 18–85 years) had a low or intermediate risk for adverse events according to the PRACTICE-score (6 low, 4 intermediate), and were treated with oral ciprofloxacin (n = 9) or amoxicillin-clavulanic-acid (n = 1). Four out of 10 patients consulted the ED for re-evaluation on their own initiative because of worsening of symptoms such as fever or nausea. Six patients (60%) were contacted by phone by the treating physician to return to the hospital because of positive results of blood cultures, which grew Escherichia coli (n = 2, both ciprofloxacin sensitive), Salmonella paratyphi (n = 1), Staphylococcus aureus (n = 1) and Streptococcus Lancefield group A (n = 1) and G (n = 1). Median hospital stay was 2 days (range 1–14 days). In none of these secondary admissions intensive care treatment was required, and no complications were noted.

The first interim analysis, that took place after inclusion of 133 patients in the intervention group, showed an absolute risk difference in secondary hospital admission rate between intervention and control cohort of 23% (10/35 (29%) subjects in the intervention cohort, vs 1/17 (6%) in the control group). Because the difference in secondary admission rate exceeded the predefined stopping criterion of 20%, the DSMB advised to stop the trial.