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

Mycoplasma pneumoniae (M. pneumoniae) is the most frequently detected bacterial pathogen in community-acquired pneumonia (CAP) in hospitalized U.S. children. Prior to the COVID-19 pandemic, M. pneumoniae was responsible for 8-28% of childhood CAP and thus was substantially contributes to CAP being a leading cause of hospitalization in high-income settings and worldwide morbidity and mortality. After the corona virus disease (COVID)-19 pandemic, M. pneumoniae and its delayed re-emergence remains a thread to children's health. CAP accounts for more treatment days with antibiotics in children's hospitals in the U.S. than any other condition. Macrolides are the first-line treatment for M. pneumoniae infection. Still, there is a lack of evidence for macrolides' the effectiveness in the treatment of M. pneumoniae induced CAP; simultaneously there is an alarmingly increasing antimicrobial resistance among M. pneumoniae. Therefore, childhood CAP, and especially M. pneumoniae, is an important target for antimicrobial stewardship efforts and cost-effectiveness considerations.

The MYTHIC Study is a randomized, double-blind, placebo-controlled, multicenter, non-inferiority trial in 13 Swiss pediatric centers. Previously healthy ambulatory and hospitalized children aged 3-17 years with clinically diagnosed CAP will be screened for a M. pneumoniae infection with Immunoglobulin M (IgM) lateral flow assay. Patients will be randomized 1:1 to receive a 5-day-treatment of macrolides (azithromycin) or placebo.

Inclusion criteria

for screening phase:

• Children aged 3-17 years (from 3rd up to 18th birthday) presenting to the emergency department (ED) who will be managed ambulatory or will be admitted to general ward.
• Clinical diagnosis of CAP:

• Diagnosis defined as the treating physician's documented diagnosis of CAP; AND
• Fever ≥38.0°C (measured by any method [i.e., ear, axillary, rectal, or forehead site] in the ED or via parent report observed in the last 24h); AND
• 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 by parents/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 2 or 3).
• Written informed consent for participation in intervention phase signed by parents or 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; cardiovascular disease, 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/or trial management team (TMT).

• Underlying comorbidities: Cystic fibrosis or other chronic lung disorders (excluding asthma), primary or secondary immunodeficiency, sickle-cell anemia, or severe cerebral palsy.
• History of recurrent pneumonia (two or more episodes) or severe pneumonia (ICU admission or complications of CAP such as lung abscess, effusion, and empyema) in lifetime.
• 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).