TITLE OF WRITE-UP

EBNEO COMMENTARY: Azithromycin therapy for prevention of chronic lung disease.

MANUSCRIPT CITATION

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.

REVIEWED BY

Dustin Beyer M.Sc.

Department of Pediatric and Adolescent Medicine, Division Neonatology and Pediatric Intensive Care, University Hospital Jena, Jena, Germany.

dustin.beyer@med.uni-jena.de

TYPE OF INVESTIGATION

Randomized, placebo-controlled trial

QUESTION

In preterm infants born at less than 30 weeks’ gestation requiring at least 2h of respiratory support within the first 72h of birth (P), does intravenous azithromycin administered for 10 days (I) compared to placebo (C) improve survival without development of physiologically defined moderate or severe chronic lung disease of prematurity (O) when assessed at 36 weeks’ postmenstrual age (T)?

METHODS

• Design: Double-blind, randomised, placebo- controlled trial
• Allocation: Preterm infants born before 30 weeks’ gestation that had received at least 2 h of either non-invasive (continuous positive airway pressure (CPAP) or humidified high flow nasal cannula (HHFNC) therapy) or invasive respiratory support (via endotracheal tube) within 72 h of birth.

Allocation ratio 1:1 using random permuted blocks of four by a computer program (Sortition, Oxford Innovation, Oxford, UK)

• Blinding: Double-blind. active and placebo investigational medicinal product (IMP) were packaged in identical 10 ml vials, while IMP was colourless.
• Follow-up period: ending at corrected 36 weeks’ gestation for primary outcome or discharge from the neonatal intensive care unit (NICU)
• Setting: 28 tertiary neonatal intensive care units in the UK
• Patients: 1739 eligible preterms were screened between Oct 9, 2019, and March 22, 2022, finally 769 preterms were included in the analysis (394 allocated to azithromycin, 402 allocated to placebo). A subgroup of 148 preterm infants positive for Ureaplasma, with 66 infants randomized to the azithromycin group.
  • Inclusion criteria:
    • Preterms born before 30 weeks’ gestation
    • At least 2 h of either CPAP, HHFNC therapy, or invasive respiratory support (via endotracheal tube) within 72 h of birth.
    • Intravenous line for drug administration for ten days
    • Written informed consent
  • Exclusion criteria:
    • serious congenital anomaly
    • previous exposure to macrolide antibiotics (not maternal)
    • the local investigator’s opinion, that survival beyond 72 h was unlikely

• Intervention: Therapy with intravenous azithromycin (intervention) given once daily at 20 mg/kg (corresponding to 10mL/kg IV) for the first 3 days, followed by 10 mg/kg (corresponding to 5mL/kg IV) for a further 7 days. Plecebo therapy consisted of a 3-day course of sterile water given at 10mL/kg IV followed by a 7-day course at 5mL/kg IV, by slow intravenous infusion.
• Outcomes:
• Primary outcome: Survival without development of physiologically defined moderate or severe CLD at 36 weeks’ PMA
• Secondary outcomes: death, comprised mortality, severity of CLD, effect of baseline pulmonary Ureaplasma spp colonisation, the number of days of supplemental oxygen, number of days of invasive or non- invasive ventilation, treatment for patent ductus arteriosus (PDA), treatment of nosocomial infections (positive blood culture, cerebrospinal fluid culture, or both, or antibiotic treatment for ≥5 days), severe intraventricular haemorrhage (IVH, grade III or IV); necrotising enterocolitis ([NEC] Bell stage ≥II), treatment for retinopathy of prematurity (ROP), the highest liver and renal function measures, and serious adverse events or reactions
• Analysis and Sample Size: 796 preterms were included in the analysis with a two-sided α-level of 5% and power of 90%. Estimation was that 716 infants would be required to adequately power the study. Assuming an estimated 10% drop out rate, 796 infants were calculated to be recruited. Outcomes and safety were analyzed on an intention-to-treat basis.

MAIN RESULTS

Primary outcome:

The study did not show any superiority in survival without the development of moderate or severe CLD with azithromycin treatment compared to placebo. Event-free survival occurred in 42% and 45% of the azithromycin and the placebo group, respectively (three-level adjusted OR 0.84, 95% CI 0.55-1.29, p=0.43). This insignificant result was consistent across various sensitivity and subgroup analyses, including the presence of pulmonary Ureaplasma spp colonization, which is known to be a risk factor for CLD.

Secondary outcome:

Azithromycin treatment did not alter the rates of mortality, severity of CLD, days of invasive or non-invasive respiratory support, use of postnatal corticosteroids, or other major morbidities of prematurity such as treated PDA, nosocomial infections, severe IVH and NEC. A markable difference was the reduction in the rate of treated ROP in survivors of the azithromycin group (4%) compared to the placebo group (7%) (adjusted OR 0.42, 95% CI 0.18-0.95), however, this effect was no longer present after including mortality within the outcome analysis. The safety profile of azithromycin was generally reassuring, presenting a similar incidence of serious adverse events in both groups.

CONCLUSION

The AZTEC trial could not show any preventive effect of 10 days postnatal azithromycin therapy in premature infants for avoiding CLD. The authors conclude that a single intervention may be insufficient, and apply for novel, multifaceted approaches to further analyze the combination of different treatment strategies with regard to outcome improvement. A long-term follow-up analysis may generate further insights.

COMMENTARY

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)

REFERENCES

1. Watterberg, K. L., Walsh, M. C., Li, L., Chawla, S., D’Angio, C. T., Goldberg, R. N., Hintz, S. R., Laughon, M. M., Yoder, B. A., Kennedy, K. A., McDavid, G. E., Backstrom-Lacy, C., Das, A., Crawford, M. M., Keszler, M., Sokol, G. M., Poindexter, B. B., Ambalavanan, N., Hibbs, A. M., Truog, W. E., … Eunice Kennedy Shriver NICHD Neonatal Research Network (2022). Hydrocortisone to Improve Survival without Bronchopulmonary Dysplasia. The New England journal of medicine, 386(12), 1121–1131. https://doi.org/10.1056/NEJMoa2114897
2. Razak, A., & Alshehri, N. (2021). Azithromycin for preventing bronchopulmonary dysplasia in preterm infants: A systematic review and meta-analysis. Pediatric pulmonology, 56(5), 957–966. https://doi.org/10.1002/ppul.25230
3. Ballard, H. O., Anstead, M. I., & Shook, L. A. (2007). Azithromycin in the extremely low birth weight infant for the prevention of bronchopulmonary dysplasia: a pilot study. Respiratory research, 8(1), 41. https://doi.org/10.1186/1465-9921-8-41
4. Ballard, H. O., Shook, L. A., Bernard, P., Anstead, M. I., Kuhn, R., Whitehead, V., Grider, D., Crawford, T. N., & Hayes, D., Jr (2011). Use of azithromycin for the prevention of bronchopulmonary dysplasia in preterm infants: a randomized, double-blind, placebo controlled trial. Pediatric pulmonology, 46(2), 111–118. https://doi.org/10.1002/ppul.21352
5. Simpson, S. J., Du Berry, C., Evans, D. J., Gibbons, J. T. D., Vollsæter, M., Halvorsen, T., Gruber, K., Lombardi, E., Stanojevic, S., Hurst, J. R., Um-Bergström, P., Hallberg, J., Doyle, L. W., Kotecha, S., & PELICAN (2024). Unravelling the respiratory health path across the lifespan for survivors of preterm birth. The Lancet. Respiratory medicine, 12(2), 167–180. https://doi.org/10.1016/S2213-2600(23)00272-2
6. Kotecha, S. J., Gibbons, J. T. D., Course, C. W., Evans, E. E., Simpson, S. J., Watkins, W. J., & Kotecha, S. (2022). Geographical Differences and Temporal Improvements in Forced Expiratory Volume in 1 Second of Preterm-Born Children: A Systematic Review and Meta-analysis. JAMA pediatrics, 176(9), 867–877. https://doi.org/10.1001/jamapediatrics.2022.1990