Trial of Intravenous Azithromycin to Eradicate Ureaplasma Respiratory Tract Infection in Preterm Infants (AZIPIII)

• Survival with microbiological eradication of Ureaplasma [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 10 weeks ] [ Designated as safety issue: Yes ]
  Bacterial clearance (eradication) will be defined as 3 negative cultures obtained 2 and 5 days post-third dose and 21 d of age. Survival is defined as survival at time of discharge or transfer from the neonatal intensive care unit (NICU).
  
  

• Physiologic defined bronchopulmonary dysplasia (BPD) at 36 weeks post menstrual age [ Time Frame: 36 weeks post menstrual age (one month prior to due date) ] [ Designated as safety issue: Yes ]
  Physiologic definition of BPD based on oxygen-saturation monitoring
  
  
• Death or Neurodevelopmental impairment [ Time Frame: 18-22 months ] [ Designated as safety issue: Yes ]
  Neurodevelopmental impairment will be assigned if any of the following are present at 18-22 months adjusted age: moderate to severe cerebral palsy, bilateral blindness, bilateral hearing impairment requiring amplification, Gross Motor Function Classification System score ≥ 2, or Bayley Scale of Infant and Toddler Development, 3rd edition (BSID-III) cognitive or motor score <70.
  
  
• Pulmonary impairment [ Time Frame: 6-22 months ] [ Designated as safety issue: Yes ]
  Parent report of recurrent wheezing and/or chronic cough
  
  
• Death [ Time Frame: 18-22 months ] [ Designated as safety issue: Yes ]
  Mortality from any cause
  
  
• Duration of positive pressure support [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 10 weeks ] [ Designated as safety issue: Yes ]
  Combined number of days receiving mechanical ventilation plus non-invasive modes of positive pressure support.
  
  
• Duration of oxygen supplementation [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 10 weeks ] [ Designated as safety issue: Yes ]
  Receipt of supplemental oxygen
  
  
• Air leaks [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 10 weeks ] [ Designated as safety issue: Yes ]
  Any pulmonary air leak (pulmonary interstitial emphysema, pneumothorax, pneumomediastinum) confirmed by chest x-ray
  
  
• Received postnatal steroids [ Time Frame: 36 weeks ] [ Designated as safety issue: Yes ]
  Receipt of steroid medications (hydrocortisone, dexamethasone)
  
  
• Received Non-Study antibiotics [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 10 weeks ] [ Designated as safety issue: Yes ]
  Received Non-study antibiotics following study drug intervention period.
  
  
• Pharmacokinetics (PK)/Pharmacodynamics (PD) modelling of time course of azithromycin plasma concentrations [ Time Frame: Study day 1-day 7 ] [ Designated as safety issue: No ]
  Population PK model will be refined with additional plasma concentrations in 15 subjects who receive azithromycin.
  
  

• Threshold Retinopathy of Prematurity (ROP) [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 10 weeks ] [ Designated as safety issue: Yes ]
  Threshold ROP requiring surgical intervention as diagnosed by ophthalmologic examination
  
  
• Necrotizing enterocolitis (NEC) [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 10 weeks ] [ Designated as safety issue: Yes ]
  Necrotizing enterocolitis ≥ Bell Stage II by radiographic and clinical criteria.
  
  
• Infections [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 10 weeks ] [ Designated as safety issue: Yes ]
  Culture-confirmed bacterial or fungal infection based on culture from sterile site (blood, cerebral spinal fluid, or urine)
  
  
• Severe Intraventicular hemorrhage (IVH) [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 10 weeks ] [ Designated as safety issue: Yes ]
  Grade III or IV IVH confirmed by cranial ultrasound
  
  
• Periventricular leukomalacia (PVL) [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 10 weeks ] [ Designated as safety issue: Yes ]
  Cranial ultrasound confirmed PVL
  
  
• Patent ductus arteriosus (PDA) [ Time Frame: 14 days ] [ Designated as safety issue: Yes ]
  Detection of PDA by cardiac echocardiogram with left to right shunting, or clinical evidence of murmur, bounding pulses, and widened pulse pressure.
  
  
• Cardiac arrhythmia [ Time Frame: 3 days ] [ Designated as safety issue: Yes ]
  EKG evidence of prolonged QT (QTc > 450 ms)
  
  

The study design will be a double-blind, placebo-controlled clinical trial to test the efficacy and safety of azithromycin 20 mg/kg x 3 days to eradicate Ureaplasma spp from the respiratory tract of preterm infants 24 weeks 0 days to 28 weeks 6 days gestation exposed to positive pressure ventilation. The primary outcome will be survival with microbiological eradication of Ureaplasma defined as survival to discharge or transfer with 3 negative cultures obtained post-therapy. Secondary outcomes will include physiologic BPD at 36 weeks post-menstrual age (PMA), overall mortality, incidence of co-morbidities of prematurity such as intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, bacterial and fungal nosocomial infection, pulmonary air leak, patent ductus arteriosus, retinopathy of prematurity, number of days of positive pressure ventilation, number of days of oxygen supplementation, use of postnatal steroids, and use of non-study antibiotics. At 6 and 18 months adjusted age, a pulmonary outcome questionnaire will be administered by phone or in person interview. At 18-22 months adjusted age, neurodevelopmental outcomes will be assessed by 1) Bayley Scale of Infant and Toddler Development, 3rd edition (BSID-III); 2) Amiel-Tison neurologic examination; 3) Gross Motor Function Classification System; and 4) medical record review for hearing impairment with or without amplification and vision impairment (vision <20/200).