Document Detail

Assessment of the efficacy of telithromycin simulating human exposures against S. pneumoniae with ribosomal mutations in a murine pneumonia model.
MedLine Citation:
PMID:  15894464     Owner:  NLM     Status:  MEDLINE    
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.
Prachi K Dandekar; Peter Williams; Pamela R Tessier; David J Farrell; Charles H Nightingale; David P Nicolau
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  International journal of antimicrobial agents     Volume:  25     ISSN:  0924-8579     ISO Abbreviation:  Int. J. Antimicrob. Agents     Publication Date:  2005 Jun 
Date Detail:
Created Date:  2005-05-30     Completed Date:  2005-12-07     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9111860     Medline TA:  Int J Antimicrob Agents     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  530-4     Citation Subset:  IM    
Center of Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USA.
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MeSH Terms
Administration, Oral
Anti-Bacterial Agents / administration & dosage,  pharmacology*,  therapeutic use
Azithromycin / pharmacology
Colony Count, Microbial
Disease Models, Animal
Drug Resistance, Bacterial / genetics
Genes, rRNA / genetics*
Ketolides / administration & dosage,  pharmacology*,  therapeutic use
Lung / microbiology,  pathology
Mice, Inbred ICR
Microbial Sensitivity Tests
Pneumonia, Pneumococcal / drug therapy*,  immunology,  microbiology
Streptococcus pneumoniae / drug effects*,  genetics*
Reg. No./Substance:
0/Anti-Bacterial Agents; 0/Ketolides; 0/telithromycin; 83905-01-5/Azithromycin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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