EBNEO COMMENTARY: AZITHROMYCIN THERAPY FOR PREVENTION OF CHRONIC LUNG DISEASE

Dustin Beyer and Hans Proquitté review the paper "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. The Lancet. Respiratory medicine, 12(8), 608–618. PMID: 38679042." for EBNEO & Acta Paediatrica.

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Acta Commentary:

Acta Paediatrica - 2024 - Beyer - EBNEO Commentary Azithromycin therapy for prevention of chronic lung disease.pdf

The findings of the AZTEC trial can be contextualized 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 colonization.

 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 of CLD rates and death by azithromycin treatment. This is of interest, as those preterm infants colonized 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 colonized with Ureaplasma compared to the overall study population. In contrast, the AZTEC trial implemented a distinctive azithromycin dosing regimen compared to previous randomized controlled trials. The protocol consisted of 20mg/kg for the first three days – a dose known to eradicate respiratory Ureaplasma colonization – followed by 10mg/kg for additional seven days to may 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 of possible interactions of azithromycin with the progression or deterioration of ROP.

 In this context, the AZTEC trial emphasizes 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-colonized preterm infants, potentially employing novel intervention combinations and innovative trial designs to address this persistent challenge in neonatal care. (5, 6)