Clarithromycin beat azithromycin in hospitalised infants with pertussis

Design

multicentre retrospective cohort analysed as a target trial emulation with propensity-score weighting, 11 Italian centres

Population

196 infants aged ≤12 months hospitalised with pertussis, November 2023 to December 2024; median age 86 days; 146 clarithromycin, 50 azithromycin

Primary outcome

severe disease course, defined as Pertussis Severity Score >5

Effect

60% (30/50) with azithromycin vs 33% (48/146) with clarithromycin; odds ratio 1.80 (95% CI 1.01–3.21)

Both macrolides are recommended first-line for pertussis and the choice between them has been made on convenience — azithromycin's shorter course and once-daily dosing. No trial has compared them in infants. This study used a target trial emulation framework on a retrospective cohort from 11 Italian centres during the European pertussis resurgence: 196 infants aged 12 months or younger hospitalised between November 2023 and December 2024, median age 86 days, with propensity-score weighting for confounding.

A severe course — Pertussis Severity Score above 5 — occurred in 60% of the 50 infants given azithromycin and 33% of the 146 given clarithromycin, giving an odds ratio of 1.80 (95% CI 1.01–3.21) against azithromycin. Infants on azithromycin more often needed oxygen, had more complications and more intensive care admissions. Both deaths in the cohort were in the azithromycin group. Oxygen saturation and 30-day readmission were comparable.

Take the direction seriously and the magnitude cautiously. The confidence interval's lower bound sits at 1.01, the azithromycin group had only 50 infants, and treatment was chosen by clinicians rather than randomised — so sicker infants may have been more likely to receive azithromycin for reasons the propensity score could not capture. Target trial emulation is the right method for reducing that bias, not for eliminating it. But there is no trial coming, the direction is consistent across every secondary outcome, and clarithromycin is cheap and available everywhere.

• Use clarithromycin as the macrolide of choice for hospitalised infants with pertussis unless there is a specific reason not to.
• Azithromycin's advantage is a shorter course and better tolerance, which matters for outpatient prophylaxis of contacts — this finding concerns treatment of ill hospitalised infants.
• Median age here was 86 days: this is the group that gets admitted and the group that dies.
• Infantile hypertrophic pyloric stenosis is associated with macrolides in the first two weeks of life; that risk applies to both drugs and is not a reason to withhold treatment in suspected pertussis.
• Pertussis is under-diagnosed in India rather than absent; the resurgence driving this study is the same waning-immunity phenomenon.

Why it matters

The macrolide choice in infant pertussis has been made on dosing convenience, and this is the first evidence that it affects outcome.

Don't overread it

This was a retrospective cohort with treatment chosen by clinicians — propensity weighting reduces confounding by indication but does not remove it, and sicker infants may have been given azithromycin for unrecorded reasons.

The statistics, in plain English

An odds ratio of 1.80 with an interval from 1.01 to 3.21 only just excludes no difference — a handful of reallocated events would erase it. The stronger argument is consistency: oxygen requirement, complications, intensive care admission and both deaths all pointed the same way, and unrelated outcomes moving together like that is harder to produce by chance than a single endpoint. Target trial emulation is designed to mimic randomisation by specifying eligibility, assignment and follow-up in advance, which addresses some confounding by indication but cannot address what was never recorded.

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