Pharmacokinetics, microbial response, and pulmonary outcomes of multidose intravenous azithromycin in preterm infants at risk for Ureaplasma respiratory colonization.
The study objectives were to refine the population pharmacokinetics (PK) model, determine microbial clearance, and assess short-term pulmonary outcomes of multiple-dose azithromycin treatment in preterm infants at risk for Ureaplasma respiratory colonization. Fifteen subjects (7 of whom were Ureaplasma positive) received intravenous azithromycin at 20 mg/kg of body weight every 24 h for 3 doses. Azithromycin concentrations were determined in plasma samples obtained up to 168 h post-first dose by using a validated liquid chromatography-tandem mass spectrometry method. Respiratory samples were obtained predose and at three time points post-last dose for Ureaplasma culture, PCR, antibiotic susceptibility testing, and cytokine concentration determinations. Pharmacokinetic data from these 15 subjects as well as 25 additional subjects (who received either a single 10-mg/kg dose [n = 12] or a single 20-mg/kg dose [n = 13]) were analyzed by using a nonlinear mixed-effect population modeling (NONMEM) approach. Pulmonary outcomes were assessed at 36 weeks post-menstrual age and 6 months adjusted age. A 2-compartment model with all PK parameters allometrically scaled on body weight best described the azithromycin pharmacokinetics in preterm neonates. The population pharmacokinetics parameter estimates for clearance, central volume of distribution, intercompartmental clearance, and peripheral volume of distribution were 0.15 liters/h · kg(0.75), 1.88 liters · kg, 1.79 liters/h · kg(0.75), and 13 liters · kg, respectively. The estimated area under the concentration-time curve over 24 h (AUC24)/MIC90 value was ∼ 4 h. All posttreatment cultures were negative, and there were no drug-related adverse events. One Ureaplasma-positive infant died at 4 months of age, but no survivors were hospitalized for respiratory etiologies during the first 6 months (adjusted age). Thus, a 3-day course of 20 mg/kg/day intravenous azithromycin shows preliminary efficacy in eradicating Ureaplasma spp. from the preterm respiratory tract.
Department of Pediatrics, University of Maryland, Baltimore School of Medicine, Baltimore, Maryland, USA.
L Marcela
LM
Merchan
University of Maryland School of Pharmacy, Baltimore, Maryland, USA Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Helwan University, Cairo, Egypt.
Hazem E
HE
Hassan
Department of Epidemiology and Preventive Medicine, University of Maryland, Baltimore School of Medicine, Baltimore, Maryland, USA.
Michael L
ML
Terrin
Departments of Pathology and Pediatrics, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA.
Ken B
KB
Waites
Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
David A
DA
Kaufman
Departments of Pathology and Pediatrics, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA.
Namasivayam
N
Ambalavanan
Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Pamela
P
Donohue
Department of Pediatrics, University of Maryland, Baltimore School of Medicine, Baltimore, Maryland, USA.
Susan J
SJ
Dulkerian
Department of Pediatrics, Oregon Health and Science University, Portland, Oregon, USA.
Robert
R
Schelonka
Department of Epidemiology and Preventive Medicine, University of Maryland, Baltimore School of Medicine, Baltimore, Maryland, USA.
Laurence S
LS
Magder
University of Maryland School of Pharmacy, Baltimore, Maryland, USA.
Sagar
S
Shukla
University of Maryland School of Pharmacy, Baltimore, Maryland, USA.
Natalie D
ND
Eddington
Department of Pediatrics, University of Maryland, Baltimore School of Medicine, Baltimore, Maryland, USA rviscard@umaryland.edu.
Rose M
RM
Viscardi
D061605:Administration, Intravenous; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D017963:Azithromycin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001997:Bronchopulmonary Dysplasia / Q000188:drug therapy / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007234:Infant, Premature; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D017711:Nonlinear Dynamics; D012141:Respiratory Tract Infections / Q000188:drug therapy* / Q000382:microbiology; D016896:Treatment Outcome; D014509:Ureaplasma / Q000187:drug effects* / Q000302:isolation & purification / Q000472:pathogenicity; D016869:Ureaplasma Infections / Q000188:drug therapy*
D000900:Anti-Bacterial Agents; D016207:Cytokines; D017963:Azithromycin