Randomised trial of azithromycin to eradicate Ureaplasma in preterm infants

Abstract

Objective To test whether azithromycin eradicates Ureaplasma from the respiratory tract in preterm infants. Design Prospective, phase IIb randomised, doubleblind, placebo-controlled trial. setting Seven level III-IV US, academic, neonatal intensive care units (NICUs). Patients Infants 24 0 -28 6 weeks' gestation (stratified 24 0 -26 6 ; 27 0 -28 6 weeks) randomly assigned within 4 days following birth from July 2013 to August 2016. Interventions Intravenous azithromycin 20 mg/kg or an equal volume of D5W (placebo) every 24 hours for 3 days. Main outcome measures The primary efficacy outcome was Ureaplasma-free survival. Secondary outcomes were all-cause mortality, Ureaplasma clearance, physiological bronchopulmonary dysplasia (BPD) at 36 weeks' postmenstrual age, comorbidities of prematurity and duration of respiratory support. results One hundred and twenty-one randomised participants (azithromycin: n=60; placebo: n=61) were included in the intent-to-treat analysis (mean gestational age 26.2±1.4 weeks). Forty-four of 121 participants (36%) were Ureaplasma positive (azithromycin: n=19; placebo: n=25). Ureaplasma-free survival was 55/60 (92% (95% CI 82% to 97%)) for azithromycin compared with 37/61 (61% (95% CI 48% to 73%)) for placebo. Mortality was similar comparing the two treatment groups (5/60 (8%) vs 6/61 (10%)). Azithromycin effectively eradicated Ureaplasma in all azithromycin-assigned colonised infants, but 21/25 (84%) Ureaplasma-colonised participants receiving placebo were culture positive at one or more follow-up timepoints. Most of the neonatal mortality and morbidity was concentrated in 21 infants with lower respiratory tract Ureaplasma colonisation. In a subgroup analysis, physiological BPD-free survival was 5/10 (50%) (95% CI 19% to 81%) among azithromycin-assigned infants with lower respiratory tract Ureaplasma colonisation versus 2/11 (18%) (95% CI 2% to 52%) in placebo-treated infants. Conclusion A 3-day azithromycin regimen effectively eradicated respiratory tract Ureaplasma colonisation in this study. Trial registration number NCT01778634.

Antenatal Infections and Respiratory Outcome in Preterm Infants

“…19 A recent publication reported the results of a multicenter RCT to test the effectiveness of azithromycin in eradicating Uu from the respiratory tract in preterm infants. 20 Eligible infants received intravenous azithromycin 20 mg/kg or placebo every 24 hours for 3 days. A total of 121 randomized infants were included in the intent-to-treat analysis (mean gestational age ¼ 26.2 AE 1.4 weeks).…”

Study protocol: azithromycin therapy for chronic lung disease of prematurity (AZTEC) - a randomised, placebo-controlled trial of azithromycin for the prevention of chronic lung disease of prematurity in preterm infants

“…To explore the extent to which there may be a differential treatment effect by presence of Ureaplasma spp, the model fitted for the primary analysis will be extended by including a main and treatment group interaction term for Ureaplasma spp colonisation at baseline. Since patterns of Ureaplasma colonisation may vary, 22 32 the approach to this analysis may be modified in respect of emerging trends identified the placebo group samples. The final analytical approach will be agreed prior to database lock.…”

“…Azithromycin is most likely to have an effect when administered early to establish a sufficient concentration to eliminate Ureaplasma ; a 20 mg/kg dose for 3 days has recently been shown to be highly effective. 22 Treatment for a further 7 days is justified to treat the rise in pulmonary inflammation which peaks between 7 and 10 days after birth. 9 25 Sites have therefore been asked to target initiation of trial treatment at the earliest opportunity (and within 72 hours after birth at the latest).…”

“…19 Dosefinding work in respect of Ureaplasma spp eradication has been undertaken in a series of studies by Viscardi and colleagues. [20][21][22] Importantly, all previous studies did not note any serious adverse reactions to azithromycin and add to the existing safety information. 23 Antimicrobial resistance among Ureaplasma remains low.…”

Perspectives on Probiotics and Bronchopulmonary Dysplasia

“…Another longitudinal investigation of two research centers found that preterm infants with severe BPD contained abundant Ureaplasma after birth, and diversity in lung microbiota was more prominent with age (13). Ureaplasma colonization is considered an independent risk factor for BPD (21). On the one hand, it causes chronic infection of the uterine cavity to promote preterm delivery (22), whereas preterm birth is one of the most important causes of BPD.…”