Transplacental Transfer of Azithromycin and Its Use for Eradicating Intra-amniotic Ureaplasma Infection in a Primate Model

• Published in: The Journal of infectious diseases 2014-03, Vol.209 (6), p.898-904
• Main Authors: Acosta, Edward P., Grigsby, Peta L., Larson, Kajal B., James, Amanda M., Long, Mary C., Duffy, Lynn B., Waites, Ken B., Novy, Miles J.
• Format: Article
• Language: English
• Subjects: Administration, Intravenous; Amniotic fluid; Amniotic Fluid - metabolism; Amniotic Fluid - microbiology; Animals; Anti-Bacterial Agents - blood; Anti-Bacterial Agents - pharmacokinetics; Anti-Bacterial Agents - therapeutic use; Antibiotics; Azithromycin - administration & dosage; Azithromycin - blood; Azithromycin - pharmacokinetics; Azithromycin - therapeutic use; BACTERIA; Bacteriology; Biological and medical sciences; Chorioamnionitis; Chorioamnionitis - drug therapy; Chorioamnionitis - metabolism; Disease Models, Animal; Dosage; Drug design; Female; Fetal Blood - metabolism; Fetal Blood - microbiology; Fundamental and applied biological sciences. Psychology; Infections; Infectious diseases; Macaca mulatta; Major and Brief Reports; Medical sciences; Microbiology; Miscellaneous; Pharmacokinetics; Pregnancy; Pregnancy Complications, Infectious - drug therapy; Pregnancy Complications, Infectious - metabolism; Ureaplasma; Ureaplasma Infections - drug therapy; Ureaplasma Infections - metabolism; Ureaplasma urealyticum
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jit578

Background. Our goals were to describe azithromycin (AZI) pharmacokinetics in maternal plasma (MP), fetal plasma (FP), and amniotic fluid (AF) following intra-amniotic infection (IAI) with Ureaplasma in pregnant rhesus monkeys and to explore concentration-response relationships. Methods. Following intra-amniotic inoculation of Ureaplasma parvum, rhesus monkeys received AZI (12.5 mg/kg every 12 hours intravenously for 10 days; n = 10). Intensive pharmacokinetic sampling of MP, FP, and AF was scheduled following the first (ie, single) dose and the last (ie, multiple) dose. Noncompartmental and pharmacokinetic modeling methods were used. Results. The AF area under the concentration-time curve at 12 hours was 0.22 µg×h/mL following a single dose and 6.3 µg×h/mL at day 10. MP and AF accumulation indices were 8.4 and 19, respectively. AZI AF half-life following the single dose and multiple dose were 156 and 129 hours, respectively. The median MP:FP ratio in concomitantly drawn samples was 3.2 (range, 1.3-9.6; n = 9). Eradication of U. parvum occurred at 6.6 days, with a 95% effective concentration (EC₉₅) of 39 ng/mL for the maximum AZI AF concentration. Conclusions. Our study demonstrates that a maternal multiple-dose AZI regimen is effective in eradicating U. parvum IAI by virtue of intra-amniotic accumulation and suggests that antenatal therapy has the potential to mitigate complications associated with U. parvum infection in pregnancy, such as preterm labor and fetal sequelae.