In vitro activity of solithromycin and its metabolites, CEM-214 and N-acetyl-CEM-101, against 100 clinical Ureaplasma spp. isolates compared with azithromycin

Abstract

There is a strong association between vaginal and/or amniotic fluid Ureaplasma spp. colonisation and risk of preterm birth. The novel fluoroketolide antibiotic solithromycin (CEM-101) is active against Ureaplasma spp. in vitro. Evidence from ex vivo and in vivo models suggests that, unlike most macrolide antibiotics, solithromycin readily crosses the placenta. Solithromycin metabolism varies according to species; in pregnant sheep, the bioactive metabolites CEM-214 and N-acetyl-CEM-101 (NAc-CEM-101) have been shown to accumulate in the amniotic cavity following maternal solithromycin administration, potentially contributing to its antimicrobial effects. To determine the antimicrobial activity of these metabolites against Ureaplasma spp., the effects of solithromycin, CEM-214, NAc-CEM-101 and the comparator azithromycin were tested on a collection of 100 clinical Ureaplasma spp. isolates from the UK and Australia using a modified 96-well broth microdilution method. MIC90 values observed for the combined cohort were: solithromycin, 0.125 mg/L; CEM-214, 0.5mg/L; NAc-CEM-101, 0.5mg/L; and azithromycin, 2mg/L. Solithromycin showed 34-fold greater activity against Ureaplasma spp. isolates than azithromycin, whilst CEM-214 and NAc-CEM-101 possessed ca. 22% and 17% of the activity of solithromycin, respectively, significantly greater than that of azithromycin. One bacterial isolate showed resistance to azithromycin (MIC=16 mg/L) but had a much lower MIC for solithromycin (MIC=0.25mg/L). In conclusion, the metabolites of solithromycin had reduced, but still potent, activity against 100 clinical Ureaplasma spp. isolates in vitro. This may be important in some instances such as pregnancy, however studies to determine levels of the metabolites in these settings are required.

The Human Ureaplasma Species as Causative Agents of Chorioamnionitis

“…The transplacental transfer of solithromycin was significantly higher than that reported for other macrolides, including azithromycin, and a maternal intravenous infusion resulted in sustained therapeutic concentrations within maternal plasma, fetal plasma, and amniotic fluid for Ͼ12 h (302). In vitro, solithromycin has potent activity against human clinical Ureaplasma isolates (303,304), in addition to a range of other important pathogens (305)(306)(307)(308)(309). Both maternal intravenous solithromycin and maternal intravenous solithromycin combined with intra-amniotic solithromycin effectively eradicated U. parvum from the amniotic cavity of pregnant sheep but, similarly to azithromycin, failed to reduce inflammation of the chorioamnion and fetal lung (299).…”

Current understanding and treatment of intra‐amniotic infection with Ureaplasma spp.

“…Some Ureaplasma spp. isolates that showed resistance against azithromycin had a much lower MIC for solithromycin (MIC = 0.25 mg/L) . Solithromycin exhibited the most potent antibacterial activity against human isolates of U. parvum (MIC = 0.002–0.031 μg/mL) and U. urealyticum (MIC = 0.004–0.063 μg/mL) than azithromycin, telithromycin, doxycycline, levofloxacin, clindamycin, and linezolid …”

A New, Potent, and Placenta-Permeable Macrolide Antibiotic, Solithromycin, for the Prevention and Treatment of Bacterial Infections in Pregnancy

“…We recently showed that its potency against Ureaplasma spp. is ~30 times greater than azithromycin in vitro ( 75 ). Importantly, no strains of Ureaplasma were resistant to solithromycin, and both Ureaplasma parvum and Ureaplasma urealyticum were susceptible, with overall MIC 90 values 125 ng/ml (compared to 2000 ng/ml for azithromycin).…”