title: In vivo immunomodulatory profile of telithromycin in a murine pneumococcal infection model.
abstract: 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.
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut 06102, USA. dnicola@harthosp.org
authors.forename: D P
authors.initials: DP
authors.lastname: Niclau
authors.forename: p R
authors.initials: pR
authors.lastname: Tessier
authors.forename: I
authors.initials: I
authors.lastname: Rubinstein
authors.forename: C H
authors.initials: CH
authors.lastname: Nightingale
mesh_terms: D000818:Animals; D005260:Female; D007155:Immunologic Factors; D007375:Interleukin-1 / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D007376:Interleukin-2 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D048628:Ketolides / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D011008:Pneumococcal Infections / Q000097:blood / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D007155:Immunologic Factors; D007375:Interleukin-1; D007376:Interleukin-2; D015850:Interleukin-6; D048628:Ketolides; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; C106791:telithromycin