<scp>EBNEO Commentary</scp>: Azithromycin therapy for prevention of chronic lung disease

Lowe, J., Gillespie, D., Aboklaish, A., Lau, T. M. M., Consoli, C., Babu, M., Goddard, M., Hood, K., Klein, N., Thomas-Jones, E., Turner, M., Hubbard, M., Marchesi, J., Berrington, J., & Kotecha, S. (2024). Azithromycin therapy for prevention of chronic lung disease of prematurity (AZTEC): a multicentre, double-blind, randomised, placebo-controlled trial. Lancet Respir Med, 12(8), 608–618. PMID: 38679042. The findings of the AZTEC trial can be contextualised within the broader landscape of current developments in neonatology, regarding the area of chronic lung disease (CLD). This trial investigated whether or not early intravenous azithromycin improves survival without moderate or severe BPD in preterm infants, irrespective of the Ureaplasma colonisation. In recent years, there have been several other major trials evaluating interventions to prevent CLD in preterms. A notable example is the trial by Watterberg et al., which examines the role of hydrocortisone on CLD-free survival in preterm infants less than 30 weeks gestation.1 This study, along with the AZTEC trial, highlights the continued challenge of exploring effective strategies to overcome this complex, multifactorial health burden. Interestingly, Azithromycin treatment does not improve the overall outcome of preterm infants regarding CLD-free survival. These findings strongly contradict the results of multiple studies published recently. The lack of a significant effect within the AZTEC trial is consistent with the results of a 2021 systematic review by Razak and Alshehri, which also could not show a significant reduction in CLD rates and death by azithromycin treatment. This is of interest, as those preterm infants colonised with Ureaplasma spp. could significantly benefit in terms of decreased rate of BPD and death.2 A limitation regarding this secondary outcome is the relatively small number of preterm infants colonised with Ureaplasma compared to the overall study population. In contrast, the AZTEC trial implemented a distinctive azithromycin dosing regimen compared to previous randomised controlled trials. The protocol consisted of 20 mg/kg for the first 3 days—a dose known to eradicate respiratory Ureaplasma colonisation—followed by 10 mg/kg for an additional 7 days to benefit from anti-inflammatory properties.2 Two landmark studies by Ballard et al. used a longer, 6-week azithromycin course. This significant variation in treatment duration makes direct comparison of results challenging.3, 4 Interestingly, the AZTEC trial found a reduction in the rate of treated ROP in survivors receiving azithromycin, although this effect was missing if mortality was included. This observation is engaging, as it suggests a potential secondary benefit of the intervention, possibly related to reduced oxygen requirements or systemic inflammation. Further investigation of this finding could provide insights into possible interactions of azithromycin with the progression or deterioration of ROP. In this context, the AZTEC trial emphasises the need for a more comprehensive, multifaceted approach to prevent and manage CLD in preterm infants born before 30 weeks gestation. The trial demonstrates that there is no evidence supporting the routine use of azithromycin for CLD prevention in preterm infants. Future research, as suggested by the authors, should focus on evaluating azithromycin specifically in Ureaplasma-colonised preterm infants, potentially employing novel intervention combinations and innovative trial designs to address this persistent challenge in neonatal care.5, 6 URL LINK: https://ebneo.org/ebneo-commentary-azithromycin-to-prevent-chronic-lung-disease/. Dustin Beyer: Conceptualization; investigation; writing – original draft. Hans Proquitté: Supervision. None. The authors declare no conflicts of interest.