MANUSCRIPT CITATION

Viscardi RM, Terrin ML, Magder LS, et al. Randomised trial of azithromycin to eradicate Ureaplasma in preterm infants. Archives of Disease in Childhood – Fetal and Neonatal Edition Published Online First: 13 March 2020. doi: 10.1136/archdischild-2019-318122. PMID: 32170033.

REVIEWED BY

Hema Gandecha
Trainee in Paediatrics
University Hospitals of Leicester NHS Trust

Elaine M Boyle
Professor of Neonatal Medicine
University of Leicester, Leicester, UK

TYPE OF INVESTIGATION

Treatment

QUESTION 

In neonates born at less than 29 weeks of gestation and less than 72 hours at randomization who had received at least 1 hours of positive pressure ventilation(P), does a 3 day course of intravenous azithromycin(I) compared to equal volume of intravenous placebo(C) eradicate Ureaplasma(O) from birth to discharge from neonatal intensive care(T).

METHODS

• Design: Prospective, multi-centre, double-blind randomised, placebo-controlled trial
• Allocation: 1:1 Ratio
• Blinding: Participants, care providers and study staff were blinded. The placebo was the same volume as the azithromycin.
• Follow-up period: Infants were followed up until discharge from the neonatal unit
• Setting: 7 Level 3/4 neonatal units in the United States of America between July 2013 and August 2016
• Patients:
  • Inclusion Criteria
    • Gestational age >24 weeks and <29 weeks
    • < 72 hours of postnatal age
    • Given at least 1 hour of positive pressure ventilation
    • Parental consent for participation
  • Exclusion Criteria
    • Non-Viability or planned life support with withdrawal
    • Lethal congenital anomalies
    • More than twin gestation
    • Delivery for maternal indications
    • ECG with corrected QTC> 450ms
    • Significant hepatic impairment
    • Other systemic macrolide exposure
    • Clinically suspected Ureaplasma CNS infection or culture confirmed sepsis
    • Participation in other clinical trials
• Intervention:
  • Either azithromycin 20mg/kg in 5% dextrose at a concentration of 2mg/ml or placebo as 5% dextrose (10ml/kg) IV over 60 minutes once every 24 hours for 3 doses.
• Outcomes:
  • Primary outcome: Ureaplasma free survival defined by NICU discharge with three negative cultures taken 2 days, 4-5 days, and 21 days post treatment.
  • Secondary outcomes: all-cause mortality, ureaplasma clearance, physiological BPD at 36 weeks postmenstrual age and requiring positive pressure respiratory support, nasal cannula oxygen at more than 4L/min or a failed room air challenge (stepwise reduction to room air from oxygen)
• Analysis and sample size:
  • Infants were stratified by gestational age (24+0 – 26+6 and 27+0 – 28+6 weeks). The sample size of 140 was calculated based on an ability to detect an absolute difference of 40% in the primary outcome with a power of 0.8. There would need to be 30 Ureaplasma positive infants in each group and a 5% drop out rate.
• Patient Follow up:
  • A total of 982 patients were screened of which 434 were eligible (44%). 121 neonates were randomised as recruitment was ended early due to funding. Of those recruited, 98% of patients received at least one dose of the study drug. 1 from each arm were not given any doses. 4 were withdrawn from the azithromycin arm, (one parent request and 3 clinical team request).

MAIN RESULTS

Primary outcome:

44(36%) out of 121 participants were Ureaplasma positive of which 19 (32%) were in the treatment arm and 25(41%) were in the placebo arm. 55(92%) of those given azithromycin were Ureaplasma negative prior to discharge versus 37(61%) of those given placebo. For the Ureaplasma positive infants, Ureaplasma free survival was higher in the azithromycin arm (84%) versus the placebo group (12%).

Secondary outcomes: Main secondary outcomes as outlined in methodology

Other secondary outcomes looked at numbers requiring postnatal steroids, supplemental oxygen, duration of intermittent mandated ventilation and duration of hospitalisation, however the difference between the two arms were not found to be statistically significant.

CONCLUSION

A 3-day course of intravenous azithromycin effectively eradicates Ureaplasma in colonized infants but the results of this study do not support the treatment of all preterm infants with azithromycin. A phase III trial of Ureaplasma colonised infants would be needed to further assess the clinical efficacy.

COMMENTARY 

Bronchopulmonary dysplasia (BPD) is a significant problem in the very preterm population. It has implications including prolonged hospital stays and long-term effects on growth and neurodevelopment. The aetiology of BPD is multifactorial in preterm infants, and the role of Ureaplasma has long been debated. Some studies have shown that its presence increases the risk of developing BPD by 2.5;(1) its eradication, therefore, would seem a reasonable step to take in reducing this risk. Until now there have been no major clinical trials with high enough power looking at the association between the eradication of Ureaplasma and reducing the rate of BPD; this Phase II trial is a step forward in examining that association.

There is a controversy within the literature as to which macrolide most effectively eradicates Ureaplasma. A systematic review in 2014 looking at macrolide use in general showed that there was a trend towards the reduction of the composite outcome of BPD and death but this was not statistically significant. However when azithromycin was examined alone there was a statistically significant reduction in the rate of BPD.(2) A further systematic review, published in 2015 confirmed that Azithromycin reduced BPD, but highlighted a paucity of high quality evidence of safety and efficacy of different treatment regimens. (3)

This trial has shown that a 3-day course does effectively eradicate Ureaplasma from colonised infants but has not yet shown that this significantly reduces the rates of BPD. The authors looked to recruit a total of 140 participants to the study of which they hoped they would have around 30 Ureaplasma positive patients in each arm to achieve adequate powering of the study. Due to funding problems it seems that recruitment to the trial was stopped early and, despite changing the recruitment gestation to <27 weeks for the last 6 months in the hope of boosting numbers of Ureaplasma positive recruits, they were unable to achieve their targeted numbers. This has likely impacted their outcomes more so for the secondary outcomes compared to primary.

It is however important to remember that this is a phase IIb clinical trial. The main aims have been to test the feasibility of recruitment and detecting Ureaplasma, to test the safety and efficacy of the 3-day treatment regimen and finally look at harm versus benefit as compared to placebo. As mentioned in the article they will be looking at respiratory outcomes and will likely power their study as such in a phase III trial.

This trial does not, therefore, give us any answers sufficient to influence clinical practice in the management of preterm infants at risk of BPD. However, other ongoing research seeks to answer related questions. The AZTEC (Azithromycin Therapy for Chronic Lung Disease) trial, currently still ongoing in the United Kingdom, is a large randomised controlled trial looking at the efficacy of a 10 day course of Azithromycin in reducing the rates of chronic lung disease of prematurity in infants born at less than 30 weeks of gestation. It aims to recruit almost 800 babies. The combined results of such trials may help to answer whether treating Ureaplasma in the extreme preterm population does significantly improve their clinical outcomes; this phase IIb trial is a step in the right direction.

REFERENCES

1. Abele-Horn M, Genzel-Boroviczény O, Uhlig T, Zimmermann A, Peters J, Scholz M. Ureaplasma urealyticum colonization and bronchopulmonary dysplasia: a comparative prospective multicentre study. Eur J Pediatr. 1998;157(12):1004-1011.
2. Nair V, Loganathan P, Soraisham A, S: Azithromycin and Other Macrolides for Prevention of Bronchopulmonary Dysplasia: A Systematic Review and Meta-Analysis. Neonatology 2014;106:337-347
3. Smith C, Egunsola O, Choonara I, Kotecha S, Jacqz-Aigrain E, Sammons H. Use and safety of azithromycin in neonates: a systematic review. BMJ Open. 2015 Dec 9;5(12):e008194. doi: 10.1136/bmjopen-2015-008194.