Comparative effectiveness of clarithromycin and azithromycin for pertussis in hospitalised infants in Italy: a multicentre target trial emulation study

Background: Pertussis has re-emerged in Europe, representing a major public health concern and a substantial cause of infant morbidity and mortality. The macrolide antibiotics clarithromycin and azithromycin are recommended as first-line therapy; however, their comparative effectiveness in infants remains poorly characterised. This study aimed to compare the real-world effectiveness of clarithromycin and azithromycin in infants with pertussis. Methods: This multicentre retrospective cohort study was designed and analysed using a target trial emulation framework, following the established TARGET reporting guidelines. Infants aged 12 months or younger who were hospitalised for pertussis between Nov 1, 2023, and Dec 1, 2024, at 11 Italian health centres were included. Infants with incomplete data, concomitant severe infections at the time of hospitalisation, and previous receipt of any antibiotic potentially active against Bordetella pertussis were excluded. Treatment with either clarithromycin or azithromycin was administered according to clinical judgment. The primary outcome was a severe disease course, defined as a Pertussis Severity Score (PSS) of more than 5. Secondary outcomes included intensive care unit (ICU) admission, need for oxygen therapy, complications, length of stay, 30-day readmission, and mortality. Confounding was addressed using propensity-score-weighting methods. Findings: Among 196 infants included (90 [46%] female, 106 [54%] male; median age 86 days [IQR 47-122]), 146 (74%) received clarithromycin and 50 (26%) received azithromycin. In propensity-score-weighted analyses, azithromycin was associated with higher odds of severe disease compared with clarithromycin (PSS >5: 60% [30 of 50] vs 33% [48 of 146]; odds ratio 1·80, 95% CI 1·01-3·21). Compared with infants treated with clarithromycin, infants treated with azithromycin more frequently required oxygen therapy and had more complications and ICU admissions, although median oxygen saturation levels and 30-day readmissions were comparable between groups. Two deaths occurred, both in the azithromycin group. Interpretation: Clarithromycin was associated with more favourable clinical outcomes than azithromycin among infants hospitalised with pertussis. Funding: EU, Next Generation PNRR Extended Partnership initiative on Emerging Infectious Diseases.