Trans-placental passage and anti-inflammatory effects of solithromycin in the human placenta

Introduction: Solithromycin is a 4th generation macrolide/fluoroketolide antibiotic that has potential applications in the treatment and prevention of intrauterine and fetal infections in pregnancy; it has also been reported to exert anti-inflammatory effects. The objective of the present study was to determine its ability to cross the human placenta and inhibit cytokine production by placental and decidual cells in culture. Methods: Maternal-to-fetal passage of solithromycin was determined using the dual recycling ex vivo placental perfusion model; normal healthy term placentas delivered by Caesarean section were employed for the study. Creatinine transfer was also assessed as a diffusion-limited perfusion control. Purified primary decidual and trophoblast cells were treated in vitro for 20 h with solithromycin (0 -100 mu g/mL) and cytokine production and cell viability were assessed. Results: The mean +/- SD maternal-to-fetal transfer ratio (TRf: concentration in maternal divided by fetal circuit) of solithromycin after 3 h perfusion was 40.3 +/- 23.6% (n = 4 placentas), with values from individual experiments ranging from 18 to 65%. The peak TRf of creatinine was 54%, and the clearance index for solithromycin (TRf(soli)/TRf(creat)) was 87% at 3 h. Solithromycin did not inhibit production of IL-6 and TNF-alpha by trophoblasts and decidual cells at non-toxic pharmacological concentrations (<= 11 mu g/mL). Discussion: Solithromycin is the first antibiotic of its class to exhibit efficient maternal-to-fetal transfer across the human placenta and is thus an ideal candidate for evaluation for the treatment of intrauterine and fetal infections in pregnancy. At pharmacological concentrations it does not appear to inhibit proinflammatory cytokine production by placental cells. (C) 2014 Elsevier Ltd. All rights reserved.