About the Trial 

Adapted from Kim K, Jung S, Kim M, Park S, Yang HJ, Lee E. Global Trends in the Proportion of Macrolide-Resistant
Mycoplasma pneumoniae Infections: A Systematic Review and Meta-analysis. JAMA Netw Open. 2022 Jul 1;5(7):e2220949.

Mycoplasma pneumoniae is one of the most common causes of community-acquired pneumonia in school-aged children. Infections follow cyclical epidemic patterns, with outbreaks occurring every 4–7 years, most recently in 2024–2025 across Asia and Europe.

Macrolides such as azithromycin have been the standard first-line treatment for Mycoplasma pneumoniae pneumonia in children. However, macrolide resistance has risen dramatically over the past two decades, particularly in East Asia. In South Korea, China, and Japan, resistance rates now exceed 80%, driven predominantly by the A2063G mutation in the 23S rRNA gene.

When macrolide therapy fails, children experience prolonged fever, extended hospitalization, and delayed recovery. Recent evidence suggests doxycycline may be a safe and effective alternative, but no prospective RCT has directly compared these two agents in children.

DOMINO was designed to fill this critical evidence gap.

Design: Multicenter, randomized, open-label, parallel-group, superiority trial

Population: Children aged 3–17 years with suspected or confirmed MRMP pneumonia

Intervention: Doxycycline 2–4 mg/kg/day, oral, BID

Comparator: Azithromycin 10 mg/kg Day 1, then 5 mg/kg Days 2–5, oral

Randomization: 1:1, stratified by age (3–7 vs. 8–17 years)

Sample Size: 208 patients (104 per arm)

Duration: 3 years (2026–2028), 13 sites

V1 (Day 0) — Screening, enrollment, randomization. Baseline assessments, chest X-ray, respiratory specimen for Mycoplasma pneumoniae PCR.

V2 (Day 2~3) — Interim assessment at 48–72h. Treatment response evaluation. Rescue therapy permitted for azithromycin group.

V3 (Day 7±1) — Treatment completion. Symptom evaluation, compliance, adverse events.

V4 (Day 14±3) — Follow-up (in-person or telephone). Dental examination (doxycycline group).

V5 (Day 28±5) — End-of-study. Final assessment, laboratory tests (inpatients).

Primary Endpoint

Defervescence rate within 72 hours of randomization, defined as body temperature <37.5°C (axillary) sustained for ≥24 hours without antipyretics.

Secondary Endpoints

• Treatment failure rate at Day 7

• Time to defervescence (hours)

• Rescue therapy / step-up treatment rate

• Duration of hospitalization

• Symptom resolution (cough, dyspnea)

• Radiographic improvement

• Adverse events including dental discoloration

Patients on azithromycin without improvement after 48–72h may switch to doxycycline (rescue therapy). Patients on doxycycline who fail may receive step-up therapy. All patients continue follow-up through V5 and are included in the ITT analysis.