Individualized Antibiotic Therapy in Children With Acute Uncomplicated Febrile Urinary Tract Infection

Individualized Antibiotic Therapy Versus Standard Care in Children With Febrile Urinary Tract Infection

An investigator-initiated, open-label, multi-center, randomized, non-inferiority trial of children aged 3 months to 13 years with acute uncomplicated febrile urinary tract infection. The primary objective is to determine whether individualized antibiotic therapy based on an algorithm (experimental arm) versus standard antibiotic therapy of 10 days (control arm) can reduce the number of days with antibiotic therapy within 28 days after treatment initiation without increasing the risk of recurrent urinary tract infection regardless of the pathogen or death of any cause within 28 days after end of treatment. Children will be randomized 1:1. The medical treatments received are identical in both groups.

Study Overview

• Status: Completed
• Conditions: Febrile Urinary Tract Infection
• Intervention / Treatment: Other: Individualized antibiotic therapy; Other: Standard antibiotic therapy

• Study Type: Interventional
• Enrollment (Actual): 408
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • Copenhagen University Hospital Rigshospitalet
  • Herlev, Denmark, 2730
    • Copenhagen University Hospital Herlev
  • Hillerød, Denmark, 3400
    • Copenhagen University Hospital Hillerød
  • Holbæk, Denmark, 4300
    • Copenhagen University Hospital Holbæk
  • Hvidovre, Denmark, 2650
    • Copenhagen University Hospital Hvidovre
  • Nykøbing Falster, Denmark, 4800
    • Copenhagen University Hospital Nykøbing Falster
  • Roskilde, Denmark, 4000
    • Copenhagen University Hospital Roskilde
  • Slagelse, Denmark, 4200
    • Copenhagen University Hospital Slagelse

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 months to 12 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Clinical suspicion of febrile (≥38 °C) urinary tract infection.

2. Positive urine culture of uropathogenic bacteria obtained by either suprapubic bladder aspiration, sterile intermittent catheterization, or midstream urine.

   1. Suprapubic bladder aspiration: any growth of bacteria.
   2. Sterile intermittent catheterization: monoculture with ≥10^3 cfu/ml.
   3. Midstream urine x 2: Monoculture with the bacteria in both tests with ≥10^4 cfu/ml.
   4. Midstream urine x 2: Monoculture with the bacteria in both tests with ≥10^5 cfu/ml in one test and 10^3 cfu/ml in another test.
   5. Midstream urine x 1 (≥10 years of age): Monoculture with ≥10^5 cfu/ml.
3. 3 months to 13 years of age (corrected age in case of premature birth).
4. Parents fluent in Danish or English.
5. Informed consent both parents.

All children who do not receive any empirical antibiotic therapy but have a positive urine culture (approximately 48 hours after urine sample collection) can be included if fever (≥ 38.0 °C) is present and the child is initiated with relevant antibiotic therapy. ¨

Children can be included regardless of whether intravenous or oral antibiotics were given as empirical therapy.

Exclusion Criteria:

1. Non-Danish civil registration number.
2. Not resident in the Capital Region or Region Zealand in Denmark at primary visit.
3. Previous inclusion in the trial.
4. History of febrile (≥38 °C) urinary tract infection in the last 28 days before the primary visit.
5. Antibiotic treatment in the last two weeks before the primary visit.
6. Three or more episodes with febrile (≥38 °C) urinary tract infection within one year of the primary visit (including the current episode).
7. Previous complicated episode of febrile (≥38 °C) urinary tract infection (e.g., renal abscess or urosepticemia)
8. Non-compliance ≥3 doses of antibiotics during empirical therapy.
9. Elevated creatinine.
10. Prophylactic antibiotic treatment.
11. Known urogenital abnormalities (i.e., obstructing uropathies; vesicoureteral reflux; multicystic dysplasia; renal dysplasia; renal hypoplasia; renal agenesis; duplex kidney; polycystic kidney disease; neurogenic bladder dysfunction; hypospadias).
12. Septic.
13. Positive blood culture (if contamination is not suspected).
14. Immune deficiency.
15. Systemic immunosuppressive therapy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Individual group; In the individual group, the participants receive individualized antibiotic therapy.	Other: Individualized antibiotic therapy; Individualized antibiotic therapy is based on the duration of illness after treatment initiation, as the antibiotic therapy can be stopped three days after the participant has become healthy. The participant is classified as healthy if he/she is afebrile (<38.0 °C), has experienced significant clinical improvement, and have no flank pains or dysuria.
Active Comparator: Standard group; In the standard group, the participants receive standard antibiotic therapy as defined by the national guideline.	Other: Standard antibiotic therapy; Standard antibiotic therapy is 10 days of antibiotic therapy regardless of the duration of illness after treatment initiation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Proportion of participants with recurrent urinary tract infection regardless of the pathogen or death of any cause	within 28 days after end of treatment
Number of days with antibiotic therapy	within 28 days after treatment initiation

Secondary Outcome Measures

Outcome Measure	Time Frame
Number of days with absence from school or daycare due to illness	within 28 days after randomization
Proportion of participants with recurrent urinary tract infection regardless of the pathogen or death of any cause	within 100 days after end of treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of hospital days related to urinary tract infection symptoms		within 28 days after end of treatment
Proportion of participants with recurrent infection with a bacterium resistant to the antibiotic given for the primary infection		within 100 days after end of treatment
Proportion of participants with a serious adverse event	Defined as any untoward medical occurrence that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability, or jeopardizes the patient	within 100 days after randomization
Proportion of participants with an antibiotic-related non-serious adverse event		within 28 days after randomization
Number of days with a physical or virtual (phone or online) consultation		From date of randomization until the date of treatment stop for the baseline infection, assessed up to 14 days

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Collaborators: Hvidovre University Hospital
• Investigators: Principal Investigator: Naqash Sethi, MD, Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark; Study Chair: Ulrikka Nygaard, Ass. prof, Ph.D., Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2022
• Primary Completion (Actual): February 29, 2024
• Study Completion (Actual): June 8, 2024

Study Registration Dates

• First Submitted: March 11, 2022
• First Submitted That Met QC Criteria: March 19, 2022
• First Posted (Actual): March 29, 2022

Study Record Updates

• Last Update Posted (Actual): July 8, 2024
• Last Update Submitted That Met QC Criteria: July 5, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Urologic Diseases; Wounds and Injuries; Disease Attributes; Body Temperature Changes; Heat Stress Disorders; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Infections; Communicable Diseases; Urinary Tract Infections; Hyperthermia; Fever; Anti-Infective Agents; Antitubercular Agents; Anti-Bacterial Agents; Antibiotics, Antitubercular
• Other Study ID Numbers: H-21057310 (UVI RCT)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Study protocol and statistical analysis plan will be shared. Individual participant data (IPD) will be shared to facilitate the conduction of systematic reviews with meta-analysis of individual participant data.
• IPD Sharing Time Frame: Beginning 3 months and ending 5 years following article publication.
• IPD Sharing Access Criteria: Primarily for the conduction of individual participant data meta-analysis.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No