title: Assessment of the efficacy of telithromycin simulating human exposures against S. pneumoniae with ribosomal mutations in a murine pneumonia model.
abstract: Telithromycin (TEL) is a ketolide antimicrobial agent with in vitro activity against Streptococcus pneumoniae (SPN), including macrolide resistant strains. The purpose of this study was to assess the efficacy of TEL against clinical SPN isolates with various genotypic mutations including the newly recognized ribosomal mutations. Pneumonia was induced in either immunocompetent and immunosuppressed mice. Six isolates were included in the study and all were resistant to azithromycin (AZI) by MIC testing. Three oral regimens of TEL were chosen to simulate the human pharmacokinetic (PK) exposures observed in young healthy, healthy elderly (> or =65 years), and infected subjects. An additional group was given AZI in human simulated doses. Bacterial density in lung was determined after each treatment. Telithromycin administered simulating infected patients showed greater efficacy (i.e., change in logCFU) than the azithromycin treated group for all isolates except P1660008. The immune system was responsible for increased efficacy (ranging from 45-146%) for all but one of the telithromycin treatment regimens. Unlike other isolates studied in this in vivo model, P1660008 displayed a highly variable response to therapy, such that the reductions in CFU were not consistent with the microbiological and PK profiles of either compound. For all other isolates, the activity of AZI was comparable with untreated controls. Human simulated exposures of TEL displayed 0.5-3.4 log kill in vivo despite the ribosomal mutations studied. These data support the in vivo efficacy of TEL against a variety of genotypic resistance profiles observed in pneumococci, however, additional studies are required to fully characterize the killing profile of the compound against these recently determined ribosomal mutations.
authors.affiliation: Center of Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USA.
authors.forename: Prachi K
authors.initials: PK
authors.lastname: Dandekar
authors.forename: Peter
authors.initials: P
authors.lastname: Williams
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Tessier
authors.forename: David J
authors.initials: DJ
authors.lastname: Farrell
authors.forename: Charles H
authors.initials: CH
authors.lastname: Nightingale
authors.forename: David P
authors.initials: DP
authors.lastname: Nicolau
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D017963:Azithromycin / Q000494:pharmacology; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D024881:Drug Resistance, Bacterial / Q000235:genetics; D020459:Genes, rRNA / Q000235:genetics*; D048628:Ketolides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D008168:Lung / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D009154:Mutation; D011018:Pneumonia, Pneumococcal / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000235:genetics*
chemical_list: D000900:Anti-Bacterial Agents; D048628:Ketolides; D017963:Azithromycin; C106791:telithromycin