title: Maternal administration of solithromycin, a new, potent, broad-spectrum fluoroketolide antibiotic, achieves fetal and intra-amniotic antimicrobial protection in a pregnant sheep model.
abstract: Solithromycin (CEM-101) is a new antibiotic that is highly potent against Ureaplasma and Mycoplasma spp. and active against many other antibiotic-resistant organisms. We have explored the maternal-amniotic-fetal pharmacokinetics of CEM-101 in a pregnant sheep model to assess its potential for treating intrauterine and antenatal infection. Chronically catheterized pregnant ewes (n = 6 or 7) received either a single maternal intravenous (i.v.) infusion of CEM-101 (10 mg/kg of body weight), a single intra-amniotic (i.a.) injection (1.4 mg/kg of estimated fetal weight), or a combined i.v. and i.a. dose. Maternal plasma (MP), fetal plasma (FP), and amniotic fluid (AF) samples were taken via catheter at intervals of 0 to 72 h postadministration, and concentrations of solithromycin and its bioactive polar metabolites (N-acetyl [NAc]-CEM-101 and CEM-214) were determined. Following maternal i.v. infusion, peak CEM-101 concentrations in MP, FP, and AF were 1,073, 353, and 214 ng/ml, respectively, representing a maternal-to-fetal plasma transfer efficiency of 34%. A single maternal dose resulted in effective concentrations (>30 ng/ml) in MP, FP, and AF sustained for >12 h. NAc-CEM-101 and CEM-214 exhibited delayed accumulation and clearance in FP and AF, resulting in an additive antimicrobial effect (>48 h). Intra-amniotic solithromycin injection resulted in elevated (∼50 μg/ml) and sustained CEM-101 concentrations in AF and significant levels in FP, although the efficiency of amniotic-to-fetal transfer was low (∼1.5%). Combined i.v. and i.a. administration resulted in primarily additive concentrations of CEM-101 in all three compartments. Our findings suggest that CEM-101 may provide, for the first time, an effective antimicrobial approach for the prevention and treatment of intrauterine infection and early prevention of preterm birth.
authors.affiliation: School of Women's and Infants' Health, The University of Western Australia, Perth, Western Australia, Australia.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Keelan
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Kemp
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Payne
authors.forename: David
authors.initials: D
authors.lastname: Johnson
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Stock
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Saito
authors.forename: Prabhavathi
authors.initials: P
authors.lastname: Fernandes
authors.forename: John P
authors.initials: JP
authors.lastname: Newnham
mesh_terms: D000653:Amniotic Fluid / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D005333:Fetus / Q000378:metabolism*; D006801:Humans; D018942:Macrolides / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011247:Pregnancy; D012756:Sheep; D014230:Triazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; D018942:Macrolides; D014230:Triazoles; C547755:solithromycin