Antibiotic prophylaxis for children with recurrent respiratory infections: towards evidence-based guidelines

Rationale: Recurrent respiratory tract infections (RTIs) affect 15-20% of children aged 0-5 years and cause high disease burden, frequent doctor visits and are one of the main reasons for hospital admission in childhood. Despite the common use of co-trimoxazole as a prophylactic agent in children with recurrent RTIs, there are no evidence-based guidelines for its use except for children suffering from exclusively otitis media. More evidence of the effect of co-trimoxazole prophylaxis on both clinical symptoms as well as microbiome deviation and antibiotic resistance is needed.

Objective: Primary: To determine whether antibiotic prophylaxis is more effective than placebo in prevention of respiratory symptoms in children with recurrent RTIs. Secondary: 1. To determine whether co-trimoxazole prophylactic therapy reduces time to resolution of symptoms, severity of symptoms, use of antipyretics/antibiotics, absenteeism from day-care or school and nutritional status. 2. To examine predictors (e.g. demographic, environmental, family history, mucosal, microbiological and immunological characteristics) for the (absence of) prophylactic treatment effect. 3. To examine whether cessation of antibiotic prophylactic treatment affects the presence of RTI symptoms and how this correlates with clinical, microbiological and immunological characteristics of the patients. 4. To record and evaluate adverse events. 5. To examine short-term and long-term effects of co-trimoxazole prophylaxis on microbiota deviation, AMR and (mucosal and systemic) immunological outcomes.

Study design: Randomized double-blind placebo-controlled clinical trial comparing co-trimoxazole with placebo treatment given for 3 months in children with recurrent RTIs.
Study population: A total of 158 children (aged 6 months – 10 years) presenting to one of the participating hospitals with recurrent RTIs and fulfilling inclusion criteria.

Intervention: One group receives co-trimoxazole 18mg/kg twice daily (36mg/kg/day) and the other group receives a placebo twice daily.

Main study parameters/endpoints: Primary: The number of days with respiratory symptoms from baseline to 3 months after inclusion. Secondary: The number of days with respiratory symptoms from baseline to 6 months after inclusion, microbiome deviation and antibiotic resistance of nasopharyngeal and gut bacteria.

Recurrent respiratory tract infections (RTIs) affect 15-20% of children aged 0-5 years and cause high disease burden, frequent doctor visits and are one of the main reasons for hospital admission in childhood. Despite the common use of co-trimoxazole as a prophylactic agent in children with recurrent RTIs, there are no evidence-based guidelines for its use except for children suffering from exclusively otitis media. More evidence of the effect of co-trimoxazole prophylaxis on both clinical symptoms as well as microbiome deviation and antibiotic resistance is needed.

T=0: Screening for inclusion, start trial medication, collection of samples, questionnaire and start daily diary

T=1 month: sample collection, monthly questtionaire (repeats every month)

T=3 months: stop trial medication, lab tests, sample collection

T=6 months: sample collection, stop diary, last questionnaire.

Children will be randomized to one of 2 oral regimens for 3 months: co-trimoxazole 36 mg/kg/day (2 x 18 mg/kg) (n=79) or placebo twice daily (n=79).