In addition to bactericidal activity,
macrolide antibacterials possess clinically relevant properties such as immunomodulatory activity. Whether such activity extends to novel antibacterials that are structurally related to
macrolides, such as the
ketolides, remains largely unknown. The objective of this study was to evaluate the in vivo immunomodulatory profile of the first ketolide antibacterial -
telithromycin in a murine neutropenic thigh
infection model. Specific pathogen-free, female ICR mice were rendered transiently neutropenic with intraperitoneal
cyclophosphamide. Thighs were inoculated with 10(6) colony-forming units of a single clinical isolate of Streptococcus pneumoniae. Once inoculated, mice (n=500) received single oral doses of
telithromycin (10, 25 or 50 mg/kg of
body weight) or no treatment (control). Blood was obtained via cardiac
puncture prior to and at 2, 4, 8, and 24 h after dose administration for determination of
cytokine concentrations. Significant post-inoculation elevations of
interleukin (IL)-1beta,
IL-6, and
IL-10 were noted in untreated controls over 24 h.
Telithromycin attenuated these increases and the suppression of both
IL-6 and
IL-10 release was observed to be dose dependent. Systemic concentrations of
IL-2 and
tumor necrosis factor alpha showed an upward trend over the initial 8-h post-inoculation period in the
telithromycin group. These data therefore reveal novel in vivo immunomodulatory effects of
telithromycin. Further studies are warranted to determine whether such effects contribute to the therapeutic efficacy of the
drug in patients with acute
respiratory tract infections.