Tissue Distribution of [14C]-Lefamulin into the Urogenital Tract in Rats

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.

Keywords: antibacterial agents; lefamulin; pleuromutilin; sexually transmitted infection; tissue distribution.

FIG 1

QWBA images of male rat showing distribution of [¹⁴C]-lefamulin at 0.5, 6, and 24 h after a single 30 mg/kg intravenous dose. Level 1 images were collected to investigate the distribution of radioactivity in the kidney; Level 2 images were collected to investigate the distribution of radioactivity in the reproductive organs/tissues associated with renal elimination. MARG samples were all approximately 5 cm in width. MARG indicates microautoradiographic; QWBA, quantitative whole-body autoradiography.

FIG 2

Microautoradiographs of individual tissues (A, bulbourethral gland; B, seminal vesicles; C, prostate gland; D, epididymis; and E, urinary bladder) within male rat showing distribution of [¹⁴C]-lefamulin after a single 30 mg/kg intravenous dose. Images are presented in both bright (hematoxylin and eosin) and dark field. Under bright field conditions, tissue histology can be viewed, and radioactivity (silver grains) shows as small black particles. Under dark field conditions, silver grains show up bright white against a dark, false-color background.

FIG 3

QWBA images of female rat showing distribution of [¹⁴C]-lefamulin at 0.5, 6, and 24 h after a single 30 mg/kg intravenous dose. Level 1 images were collected to investigate the distribution of radioactivity in the kidney and ovary/uterus; Level 2 images were collected to investigate the distribution of radioactivity in the reproductive organs/tissues associated with renal elimination. MARG samples were all approximately 5 cm in width. MARG indicates microautoradiographic; QWBA, quantitative whole-body autoradiography.

FIG 4

Microautoradiographs of individual tissues (A, clitoral; B, ovary; and C, urethra) within female rat showing distribution of [¹⁴C]-lefamulin after a single 30 mg/kg intravenous dose. Images are presented in both bright (hematoxylin and eosin) and dark field. Under bright field conditions, tissue histology can be viewed and radioactivity (silver grains) shows as small black particles. Under dark field conditions, silver grains show up bright white against a dark, false-color background.