Design overview
We conducted an investigator-initiated, single-center, factorial design, randomized controlled (1:1) and open-label trial. Herein, we focus on the efficacy of an algorithm based on clinical symptoms, PCT, and pyuria to safely reduce the duration of antibiotic therapy compared to current guidelines [6,15,28]. Details of the full trial design and methods have been published elsewhere [29].
The trial was conducted in accordance with the ethical principles of the Helsinki Declaration. The local ethical review committee of the Canton Aargau, Switzerland, approved the study protocol. All patients or their next-of-kin provided written informed consent.
Setting and participants
From April 2012 to March 2014, we screened all consecutive immunocompetent adults with community-acquired non-catheter-related UTIs as the main diagnosis presenting to the emergency department of the cantonal hospital of Aarau, a tertiary-care 600-bed hospital in northwestern Switzerland.
A UTI was defined by at least one clinical symptom (temperature ≥38.0°C, urinary urgency, dysuria, suprapubic pain, flank pain, costovertebral angle tenderness, nausea, and vomiting) and one urinary criterion (pyuria >20 leukocytes/μL, obtained by flow cytometry UF1000i (Sysmex) [27,30], and/or evidence of nitrite). Presence of flank pain, costovertebral angle tenderness, and/or a body temperature ≥38.0°C defined a ‘febrile UTI/pyelonephritis’; otherwise, patients were considered to have a ‘simple UTI’. The criteria for a ‘complicated UTI’ included any patient of at least 70 years, male gender, duration of symptoms of more than 7 days, previous antibiotic therapy within 30 days, at least two prior UTIs in the last 6 months or at least three during the last 12 months, any urologic intervention within 30 days, functional or anatomic abnormality, diabetes mellitus, or immunosuppressive therapy; otherwise it was referred to as an ‘uncomplicated UTI’.
Patients were excluded if they presented with other infections that required antibiotic therapy or had been treated with antibiotics within 48 hours before presentation; pregnancy; prostatitis defined as painful digital rectal examination, a prostate-specific antigen value of >4 ng/mL or ≥2× baseline before infection; foreign bodies within the urinary tract; endovascular prostheses; non-endovascular prostheses within 6 months after implantation; insufficient language skills with no possibility for translation; foreseeable non-compliance for follow-up, e.g., current drug abuse; severe immunodeficiency: neutrophils <500/μL, CD4 cells <350/μL in patients with HIV-infection, leukemia, lymphoma, myeloma, cytotoxic medications, hemodialysis, transplant patients; or life-threatening medical comorbidities leading to possible imminent death.
Randomization and interventions
The allocation of patients to either the PCT-pyuria group or the control group was based on a pre-specified computer generated randomization list and was concealed on the study website.
Clinical presentation without (control group) or with PCT and pyuria (PCT-pyuria group) was used to guide initiation and duration of antibiotic therapy. The choice of antibiotics and the minimal duration of therapy were based on recent guidelines [6,15]. The algorithm is presented in Figure 1.
For simple UTIs, we used fosfomycin (3 g single dose) [31], trimethoprim-sulfamethoxazole (800/160 mg twice daily) for estimated glomerular filtration rates (eGFR) 30 to 59 mL/min/1.73 m2 or ciprofloxacin (250 mg twice daily) for eGFR <30 mL/min/1.73 m2. In the PCT-pyuria group, patients with uncomplicated simple UTIs were planned to receive only non-steroidal anti-inflammatory drugs (NSAIDs) for 3 days regardless of PCT-values [32,33].
For febrile UTIs/pyelonephritis, ciprofloxacin was chosen as standard oral treatment for better comparability with recent studies (500 mg orally twice daily, respectively ciprofloxacin 250 mg orally twice daily for eGFR <30 mL/min/1.73 m2), if intravenous therapy was necessary ceftriaxone (2 g once daily) was chosen. When known, antibiotic resistance profiles of prior or current pathogens were taken into account and antibiotic therapy was adjusted.
In inpatients in the PCT-pyuria group, antibiotic duration was based on absolute PCT-values and relative decreases of PCT-levels, as well as pyuria. PCT and pyuria were measured on admission in all patients; in hospitalized patients, the measurements were continued every other day till the end of antibiotic therapy. For outpatients in the PCT-pyuria group, antibiotic duration was calculated according to absolute values of PCT at baseline. In the control group, antibiotic therapy durations were recommended based on current guidelines [6,15] (Figure 1).
Urinalysis and urine culture with an antibiotic resistance profile were performed on admission. In patients with febrile UTI, blood cultures were taken prior to administration of antibiotics.
To determine microbiological cure and recurrence rates urinalysis and urine culture were performed on day 7 after end of therapy and day 30 after enrollment. Patients were instructed in collection of midstream urine for urinalysis and urine culture. These urine specimens were sent by mail and reached the laboratory within 48 hours.
Outcomes and follow-up
All endpoints were assessed at discharge from hospital and 30 and 90 days after enrollment through standardized telephone interviews by blinded members of the study team.
The primary endpoint was overall antibiotic exposure within 90 days. Each day of antibiotic therapy for any indication was counted as a full day of antibiotic exposure.
Secondary endpoints included duration of the initial antibiotic therapy; overall rate of recurrence, defined as any re-treated UTI; overall rate of rehospitalization for any cause within 90 days after enrollment; rate of persistent infection 7 days after end of therapy, defined as recovery of the initial uropathogen in the returned urine culture plus pyuria >20 leucocytes/μL in the concomitant urinalysis; and rate of persistent symptomatic infection 30 days after enrollment, defined as recovery of the initial uropathogen in the returned urine culture plus pyuria >20 leucocytes/μL in the concomitant urinalysis plus symptoms of an UTI in the 30 days phone interview.
All patients with positive urine cultures and pyuria in the follow-up samples were contacted by phone by members of the study team and advised to visit a general practitioner or an emergency room. The laboratory results were sent to the primary care providers when available, but no further guidance was given as to whether to prescribe an antibiotic.
Any serious adverse event, rehospitalization for any cause, recurrence, or death of any cause within 90 days after enrollment were monitored by the data safety and monitoring board, which consisted of three independent experts in infectious diseases, nephrology, and epidemiology.
Statistical analysis
The sample size was calculated assuming that duration of antibiotic therapy would be two days shorter in the PCT-pyuria group (8 days, standard deviation ±5) than in the control group (10 days, standard deviation ±5). Accordingly, 99 patients per arm would provide an 80% power at the 5% alpha level [29].
The primary analysis was performed including all randomized patients following an intention-to-treat (ITT) principle. The per-protocol (PP) analysis was performed in a defined population with microbiologically confirmed UTI and without patients who violated inclusion or exclusion criteria or were lost to follow-up. If the initial urine culture was missing, sterile, or contaminated but a uropathogen was isolated in concomitantly withdrawn blood cultures, the patients were still included in the PP analysis. We used predefined urine culture cut-offs for significance [29].
As the study was conceived in a two-by-two factorial design, we checked for interaction between the two randomization arms. As there was no evidence for interaction, the second randomization (proadrenomedullin-assisted site of care decision [29]) was no longer considered for this analysis.
Discrete variables were expressed as counts (percentage); continuous variables as medians and interquartile range, unless stated otherwise. For the analysis of the primary endpoint of antibiotic exposure, we used the Mann–Whitney U test for similarly shaped not normally distributed continuous data. In sensitivity analysis, we also used median regression to model the primary endpoint and adjusted the analysis for bacteremia. Logistic regression analyses of persistent infection, recurrence, and rehospitalization rates were performed to assess safety endpoints. Since this was a feasibility study we did not plan to have enough power for non-inferiority testing.