Abstract：
Lefamulin, a semisynthetic pleuromutilin antibiotic approved in the United States, Canada, and Europe for intravenous and oral treatment of community-acquired bacterial pneumonia, is highly active in vitro against bacterial pathogens that cause sexually transmitted infections (STIs), including multidrug-resistant strains of Neisseria gonorrhoeae, Chlamydia trachomatis, and Mycoplasma genitalium. This nonclinical study used quantitative whole-body autoradiography (QWBA) and qualitative tape-transfer microautoradiography (MARG) to investigate lefamulin distribution into urogenital tract tissues down to a cellular level in male and female rats. A single intravenous dose (30 mg/kg) of [14C]-lefamulin was administered to 3 male and 3 female Sprague-Dawley rats. At 0.5, 6, and 24 h post dose, rats were euthanized and [14C]-lefamulin distribution was investigated using QWBA and MARG of sagittal planes. [14C]-lefamulin was well distributed throughout the carcasses of male and female rats, with the highest concentrations observed in male bulbourethral gland, urethra, prostate in female clitoral gland, uterus (particularly endometrium), and ovary. In these areas, concentrations were similar to or higher than those observed in the lungs. Concentrations peaked at 0.5 h post dose, remaining detectable in the urogenital tract up to 24 h post dose. [14C]-lefamulin in rats showed rapid, homogeneous distribution into urogenital tissues down to a cellular level, with high tissue:blood ratios in tissues relevant to STI treatment. These results, and the potent in vitro activity of lefamulin against multidrug-resistant bacteria known to cause STIs, will help inform further assessment of lefamulin, including potential clinical evaluation for treatment of STIs.
摘要：
Lefamulin,一种在美国批准的半合成截短侧耳素抗生素，加拿大,和欧洲静脉和口服治疗社区获得性细菌性肺炎，在体外对引起性传播感染（STIs）的细菌病原体具有高度活性，包括淋病奈瑟菌的多重耐药菌株，沙眼衣原体,和生殖支原体.这项非临床研究使用了定量全身放射自显影（QWBA）和定性胶带转移微放射自显影（MARG）来研究利福蛋白在雄性和雌性大鼠泌尿生殖道组织中的分布，直至细胞水平。向3只雄性和3只雌性Sprague-Dawley大鼠施用单次静脉内剂量(30mg/kg)的[14C]-lefamulin。在给药后0.5、6和24小时，将大鼠安乐死，并使用矢状面的QWBA和MARG研究[14C]-lefamulin分布。[14C]-lefamulin在雄性和雌性大鼠的尸体中分布良好，在男性尿道球腺中观察到的浓度最高，尿道,女性阴蒂腺中的前列腺，子宫（尤其是子宫内膜），和卵巢。在这些地区,浓度与肺部观察到的浓度相似或更高。浓度在给药后0.5小时达到峰值，在泌尿生殖道中保持可检测到剂量后24小时。[14C]-lefamulin在大鼠中显示快速，均匀分布在泌尿生殖组织中，直至细胞水平，在与STI治疗相关的组织中具有高组织:血液比率。这些结果,以及lefamulin对已知引起性传播感染的多重耐药细菌的有效体外活性，将有助于进一步评估lefamulin，包括性传播感染治疗的潜在临床评估。
