Oral Switch in Bloodstream Infections in Immunocompromised Children

Background:

Bloodstream infections are among the leading causes of hospital admission and prolonged intravenous (IV) antibiotic therapy in children and adolescents. Current international guidelines recommend IV-only therapy or prolonged IV treatment before switching to oral antibiotics. However, these recommendations are primarily based on historical convention and low-quality evidence rather than randomized controlled trials (RCTs). Studies in both adults and children with serious infections other than bloodstream infections suggest that shorter IV courses followed by oral step-down therapy may be safe and effective. However, no RCT has specifically investigated an early switch to oral antibiotic therapy in immunocompromised children and/or those with a central venous catheter (CVC). Although these children may be at increased risk of infectious complications, they also experience a substantial proportion of pediatric bloodstream infections and prolonged IV antibiotic courses. Consequently, the potential impact of a safe early oral-switch strategy may be particularly important in this population.

Objective:

The trial objective is to determine whether early IV-to-oral antibiotic switch is non-inferior to continued standard IV therapy with respect to recurrence of bloodstream infection in clinically stable children and adolescents aged 4 weeks to 17 years with immunosuppression and/or have a CVC and have a bloodstream infection.

Study design:

This is an investigator-initiated, nationwide, open-label, parallel-group, randomized (1:1), controlled, non-inferiority trial, with randomization stratified by 1) Bacteria type (Gram positive vs. Gram negative), and 2) planned CVC removal (removal versus retention or no CVC, as determined before randomization).

Patients:

Children and adolescents aged 4 weeks to 17 years with underlying medical condition associated with immunosuppression and/or the presence of a CVC, and have a bloodstream infections will be recruited from all 18 pediatric departments in Denmark.

Procedure:

Eligible children will be randomized 1:1 to an early oral switch strategy or standard IV therapy. The choice of oral and IV antibiotics will not be determined by randomization but will be made by the treating clinician according to the isolated pathogen, antimicrobial susceptibility, and current treatment guidelines. The total antibiotic treatment duration will be the same in both treatment groups, according to Danish guidelines.

Participants will be randomized to the early oral switch arm (experimental arm) or the standard IV arm (control arm).

Participants allocated to the early oral switch arm will receive effective IV antibiotic therapy for at least 3 days and switch to oral therapy as soon as possible after clinical stability, but no later than day 6, to complete a total treatment duration of 10-14 days according to clinical treatment guidelines. Participants allocated to the standard IV arm (control arm) will receive IV antibiotic therapy for the full treatment course.

Sample size calculation:

The study aims to enroll a minimum of 114 participants. The sample size calculation is based on an expected treatment failure risk of 1.5% in both treatment arms, a non-inferiority margin of 10 percentage points, a one-sided alpha level of 2.5%, and the use of an appropriate statistical method that accounts for the expected low number of events. Assuming a dropout rate of up to 5%, enrollment of 114 participants will provide approximately 80% power to demonstrate non-inferiority.

Recruitment is planned for approximately 36 months and may be extended if required and feasible to achieve the target sample size. If 114 participants are enrolled within the initial 36-month recruitment period, enrollment will continue until the end of the 36-month recruitment period or until a maximum of 150 participants have been enrolled, whichever occurs first, to increase statistical power to approximately 90%.

Early Oral Switch

Drug: Oral antibiotic therapy

Standard Intravenous Therapy

Drug: Standard IV antibiotic therapy

Participants randomized to the experimental arm will switch from IV to oral antibiotic therapy after effective IV antibiotic therapy for at least 3 days, followed by oral therapy as soon as possible after clinical stability, but no later than day 6, and continue oral therapy to complete the recommended total treatment duration.

Participants randomised to the control arm will receive IV antibiotic therapy throughout the recommended total treatment duration.

Time frame: Within 6 weeks after randomization

Number of patients who experience growth of the same bacteria as in the index blood stream infection in a subsequent blood culture during the follow-up period.

Time frame: Within 6 weeks after randomization

Duration of IV antibiotic treatment from randomization until completion of IV antibiotic treatment for the index bloodstream infection, measured in hours.

Time frame: From randomization until discharge for the index bloodstream infection, assessed up to 42 days after randomization

Length of Hospital Stay for index infection

Time frame: From randomization until completion of treatment for the index bloodstream infection, assessed up to 42 days after randomization

Proportion of participants with at least one escalation of antibiotic treatment for the index bloodstream infection, defined as a switch from oral to intravenous antibiotics or from intravenous antibiotics to a broader-spectrum intravenous regimen.

Time frame: From randomization until completion of treatment for the index bloodstream infection, assessed up to 42 days after randomization

Re-initiation of antibiotics after completion of antibiotic treatment for the index infection (regardless of the indication)

Time frame: Within 6 weeks after randomization

Treatment failure, other than blood stream infection, defined as clinically and/or microbiologically confirmed disease progression or relapse, adjudicated by an independent, blinded adjudication committe

Time frame: Within 3 months after randomization

Long term treatment failure, including blood stream infection, defined as clinically and/or microbiologically confirmed disease progression or relapse, adjudicated by an independent, blinded adjudication committee

Time frame: Within 6 weeks after randomization

Safety outcomes are admission to an intensive care unit and death

Oral Switch Versus Standard Intravenous Antibiotics in Children and Adolescents Who Are Immunocompromised and/or a Central Venous Catheter and Uncomplicated Bloodstream Infections: a Nationwide Randomised Controlled Non-inferiority Trial