Maternal Administration of Solithromycin,a New,Potent, Broad-Spectrum Fluoroketolide Antibiotic,Achieves Fetal and Intra-Amniotic Antimicrobial Protection in a Pregnant Sheep Model |
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| Authors: | Jeffrey A. Keelan Matthew W. Kemp Matthew S. Payne David Johnson Sarah J. Stock Masatoshi Saito Prabhavathi Fernandes John P. Newnham |
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| Affiliation: | aSchool of Women''s and Infants'' Health, The University of Western Australia, Perth, Western Australia, Australia;bMicroConstants Inc., San Diego, California, USA;cDepartment of Obstetrics & Gynecology, University of Edinburgh, Edinburgh, United Kingdom;dDivision of Perinatal Medicine, Tohoku University Hospital, Sendai, Japan;eCempra, Inc., Chapel Hill, North Carolina, USA |
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| 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. |
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