Comment

Azithromycin for the prevention of chronic lung disease of

prematurity: not a silver bullet
Chronic lung disease of prematurity (CLD), often defined infants in the azithromycin group might not have Lancet Respir Med 2024
as the need for oxygen or positive pressure ventilation survived long enough to develop ROP. Published Online
April 25, 2024
at 36 weeks post-menstrual age, is a significant concern One crucial observation regarding the primary https://doi.org/10.1016/
among preterm infants, affecting nearly 50% of those outcome is that the authors initially estimated S2213-2600(24)00086-9

born before 28 weeks gestation.1 Efforts to address
CLD include exploring azithromycin as a potential
therapy, supported by small randomised trials2,3 and
systematic reviews.4 Azithromycin’s effectiveness
against Ureaplasma spp, a bacterial pathogen commonly
the sample size, assuming a baseline incidence of See Online/Articles
https://doi.org/10.1016/
survival without CLD at 50%, but it turned out lower S2213-2600(24)00079-1
at 44%. Additionally, the effect estimates suggest
that azithromycin could potentially decrease survival
without CLD by 2% (95% CI –0·09 to 0·05). Given that T.ME/NEONATOLOGY

found in the respiratory tracts of preterm infants which a slight increase or decrease in survival holds clinical
is associated with CLD,5 and its immunomodulatory significance, it raises questions as to whether the trial
properties6 suggest it might reduce the risk of CLD. was sufficiently large to address this issue, despite being

t.me/neonatology
However, the absence of large-scale trials led to the the largest trial conducted to date.
design of the Azithromycin Therapy for Prevention of Why did azithromycin therapy not produce the
CLD (AZTEC) trial, aimed at exploring azithromycin’s anticipated results? Were infants in the trial colonised
role in mitigating CLD risk in preterm infants.7 with Ureaplasma spp, and did azithromycin effectively
In this trial from the UK, published in The Lancet clear this colonisation? Was the dosage sufficient to
Respiratory Medicine by John Lowe and colleagues,7 trigger an anti-inflammatory response? First, only
preterm infants born at less than 30 weeks’ gestation one in five enrolled infants had Ureaplasma spp in
received either a 10-day regimen of azithromycin their respiratory tract at baseline, suggesting a lower
(20 mg/kg per day for the initial 3 days, followed by infection rate which might have contributed to the
10 mg/kg for the subsequent 7 days) or a placebo. observed absence of therapeutic effect. Second, a
Eligibility criteria also included the need for invasive or higher percentage of infants in both groups showed
non-invasive respiratory support for at least 2 h within Ureaplasma colonisation upon retesting between the
72 h of birth, but approximately 80% of infants required 2nd and 3rd postnatal weeks (66 [45%] of 148 in the
invasive ventilation before random allocation. The azithromycin group and 82 [55%] of 148 in the placebo
authors anticipated a 12% absolute increase in survival
without CLD with azithromycin therapy. Contrary to
expectations there was no observed improvement;
166 (42%) of 394 infants in the azithromycin group
and 179 (45%) of 402 infants in the placebo group had
the primary outcome of survival without moderate
or severe CLD. Additionally, the differences remained
nonsignificant when analysed according to the presence
or absence of Ureaplasma spp at baseline, although it
is worth noting that this was a subgroup analysis and
was not originally planned with adequate statistical
power. Additionally, no differences in other outcomes
Garry Watson/Science Photo Library

were observed, except for decreased retinopathy of

prematurity (ROP) with azithromycin. Nonetheless,
this finding was exploratory and was not adjusted
for multiple comparisons. Notably, when considering
mortality, this effect disappeared, indicating that more

www.thelancet.com/respiratory Published online April 25, 2024 https://doi.org/10.1016/S2213-2600(24)00086-9 1

t.me/neonatology
 Comment
group). Whether this indicates persistent colonisation or
infection in the same infants, possibly underestimated
when tested initially due to early assessment, or new
colonisation or infection in untreated infants, remains
unclear. This distinction is crucial, especially since
many infants in the azithromycin group still showed
Ureaplasma colonisation despite therapy, raising
questions about the drug’s effectiveness in eliminating
the bacteria without reinfection or recolonisation. Third,
although the dosage administered in the trial is thought
to have anti-inflammatory properties, it remains unclear
whether it conferred such benefits in this cohort—an
aspect the authors have yet to investigate. Conversely,
it is equally important to contemplate whether any
potential reduction in inflammation, if present, is as
potent as postnatal corticosteroids in significantly
alleviating inflammation-induced lung injury.
Regardless of whether azithromycin provided
anti-inflammatory effects or effectively eliminated
Ureaplasma spp, it did not yield clinically significant
differences in the outcome, and therefore the immediate
findings from the AZTEC trial do not advocate for using
azithromycin in preterm infants; however, it is crucial
to await additional long-term data and additional
analyses. That said, CLD is a multifaceted condition
that is influenced not only by perinatal infections such
as Ureaplasma spp, but also by various other factors,
and simply administering azithromycin might not
2 www.thelancet.com/respiratory Published online April 25, 2024 https://doi.org/10.1016/S2213-2600(24)00086-9
t.me/neonatology
adequately address the intricate interplay of factors
associated with CLD. There will almost certainly never be
a single solution—neither golden nor silver—to reduce
or prevent CLD. Efforts must be collective, ongoing, and
initiated from the outset.
AR declares research funding from Monash University and the Lions Cord Blood
Foundation, outside of the submitted work.
Abdul Razak
abdul.razak@monash.edu
Department of Paediatrics, Monash University, Melbourne VIC, Australia (AR),
Monash Newborn, Monash Children’s Hospital, Melbourne VIC, Australia (AR),
The Ritchie Centre, Hudson Institute of Medical Research, Melbourne VIC,
Australia
1 Bell EF, Hintz SR, Hansen NI, et al. Mortality, in-hospital morbidity, care
practices, and 2-year outcomes for extremely preterm infants in the US,
2013-2018. JAMA 2022; 327: 248–63.
2 Nunes CR, Procianoy RS, Corso AL, Silveira RC. Use of azithromycin for the
prevention of lung injury in mechanically ventilated preterm neonates:
a randomized controlled trial. Neonatology 2020; 117: 522–28.
3 Viscardi RM, Terrin ML, Magder LS, et al. Randomised trial of azithromycin
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2020; 105: 615–22.
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7 Lowe J, Gillespie D, Aboklaish A, et al. Azithromycin therapy for prevention
of chronic lung disease of prematurity (AZTEC): a multicentre, double-blind,
randomised, placebo-controlled trial. Lancet Respir Med 2024; published
online April 25. https://doi.org/10.1016/S2213-2600(24)00079-1.
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