A Trial of Placebo Versus Macrolide for Mycoplasma Pneumoniae Childhood Pneumonia: MYTHIC Study

Inclusion criteria for screening phase:

• Children aged 3-17 years (from 3rd up to 18th birthday) presenting to the emergencydepartment (ED) who will be managed ambulatory or will be admitted to general ward.

• Clinical diagnosis of CAP:

1. Diagnosis defined as the treating physician's documented diagnosis of CAP; AND

2. Fever ≥38.0°C (measured by any method [i.e., ear, axillary, rectal, or foreheadsite] in the ED or via parent report observed in the last 24h); AND

3. Tachypnea (defined as respiratory rate (RR) above age-specific reference value)during the assessment in ED (triage or clinical examination).

• Written screening consent for participation in screening phase signed byparents/legal guardians and the patient if ≥14 years of age.

Additional inclusion criteria for intervention phase:

• Positive Mp screening test result with the Mp IgM lateral flow assay (LFA) (grade 2or 3).

• Written informed consent for participation in intervention phase signed by parentsor legal guardians and the patient if ≥14 years of age.

Exclusion criteria:

Exclusion criteria for screening phase:

• None.

Exclusion criteria for intervention phase:

• Contraindication to azithromycin: Documented allergy to azithromycin; cardiovasculardisease, including bradycardia, arrhythmias, and/or QT-interval prolongation*;myasthenia gravis.

*Co-medication with arrhythmogenic or QT-interval-prolonging drug (www.qtdrugs.org)is no exclusion criteria but will be discussed with the local investigators and/ortrial management team (TMT).

• Underlying comorbidities: Cystic fibrosis or other chronic lung disorders (excludingasthma), primary or secondary immunodeficiency, sickle-cell anemia, or severecerebral palsy.

• History of recurrent pneumonia (two or more episodes) or severe pneumonia (ICUadmission or complications of CAP such as lung abscess, effusion, and empyema) inlifetime.

• Antibiotic treatment against Mp within the previous 7 days, including macrolides,tetracyclines, or fluoroquinolones.

• Referral to ICU directly from the ED.

• Inability to take oral medication.

• Parents are unlikely to reliably complete follow up (FUP) visits and questionnaires (e.g., due to language barriers or living far from the study site).