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In vivo evaluation of three acid-stable azalide compounds, L-701,677, L-708,299 and L-708,365 compared to erythromycin, azithromycin and clarithromycin.

Abstract
L-701,677, L-708,299 and L-708,365 are novel azalide derivatives of erythromycin that exhibit improved acid stability over erythromycin, azithromycin and clarithromycin. The half-life in aqueous solution at pH = 2.1 of these compounds ranged from 0.3 hour for erythromycin to 16.2 hours for L-708,299. The rank order of half-life in acid solution from most to least stable was L-708,299 > L-701,677 > L-708,365 > azithromycin = clarithromycin > erythromycin. In a disseminated Streptococcus pyogenes mouse infection model, azithromycin and L-708,365 were slightly more efficacious than clarithromycin, L-701,677 and L-708,299; all 5 compounds being more active than erythromycin. In a Klebsiella pneumoniae pulmonary challenge mouse model, azithromycin, L-701,677, L-708,299 and L-708,365 were all equal in efficacy and at least four-fold more active than clarithromycin and erythromycin. Clarithromycin, L-708,365 and interestingly erythromycin, showed greater bacterial clearance than azithromycin, L-701,677 and L-708,299 in a localized infection model that measured clearance of Staphylococcus aureus from mouse thigh tissues. Our results indicate that L-701,677, L-708,299 and L-708,365 exhibit improved acid stability and were at least equally efficacious as presently marketed macrolide/azalide antibiotics.
AuthorsC J Gill, G K Abruzzo, A M Flattery, J G Smith, J Jackson, L Kong, R Wilkening, K Shankaran, H Kropp, K Bartizal
JournalThe Journal of antibiotics (J Antibiot (Tokyo)) Vol. 48 Issue 10 Pg. 1141-7 (Oct 1995) ISSN: 0021-8820 [Print] England
PMID7490222 (Publication Type: Comparative Study, Journal Article)
Chemical References
  • Anti-Bacterial Agents
  • L 701677
  • L 708299
  • L 708365
  • Macrolides
  • Erythromycin
  • Azithromycin
  • Clarithromycin
Topics
  • Animals
  • Anti-Bacterial Agents (pharmacokinetics, therapeutic use)
  • Azithromycin (pharmacokinetics, therapeutic use)
  • Bacterial Infections (drug therapy)
  • Clarithromycin (pharmacokinetics, therapeutic use)
  • Drug Evaluation, Preclinical
  • Drug Stability
  • Erythromycin (analogs & derivatives, pharmacokinetics, therapeutic use)
  • Female
  • Half-Life
  • Klebsiella Infections (drug therapy)
  • Macrolides
  • Mice
  • Mice, Inbred DBA
  • Molecular Structure
  • Staphylococcal Infections (drug therapy)
  • Streptococcal Infections (drug therapy)

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