title: Correlation of the extravascular pharmacokinetics of azithromycin with in-vivo efficacy in models of localized infection.
abstract: Infection models were used to clarify the roles of serum and extravascular concentrations in the in-vivo efficacy observed with azithromycin. In-vivo experiments were designed to give serum concentrations well below the MIC and tissue levels generally above the MIC at time of challenge and during the course of infection. The efficacy of azithromycin against a Salmonella enteritidis oral challenge (a tissue-associated infection model) in mice correlated directly with azithromycin liver levels, but not serum concentrations. The significance of extravascular pharmacokinetics was observed in a comparative study of azithromycin and ciprofloxacin against the salmonella challenge. Ciprofloxacin has a greater than 100-fold in-vitro potency advantage over azithromycin against this organism, but azithromycin (5 mg/kg) produced a greater reduction in cfu than ciprofloxacin (100 mg/kg) at the primary site of infection (liver). In another model, extravascular fluid levels, measured by bioassay of implanted paper discs, were compared with plasma levels in relation to control of a localized Staphylococcus aureus infection in rats. Extravascular fluid levels of azithromycin were greater than the MIC of the strain used for five days after a 100 mg/kg dose, while erythromycin levels were less than 20% of the MIC at 30 h after a 200 mg/kg dose. Serum concentrations of both compounds were less than 20% of the MIC at the time of challenge. The antibiotic levels at the site of infection correlated with the reduction of Staph. aureus cfu (99% with azithromycin compared with controls, P less than 0.01; 0% with erythromycin) recovered from inoculated discs. The significance of extravascular concentrations of azithromycin was further supported in other models of localized infections induced with Escherichia coli or a mixture of Staph. aureus and Bacteroides fragilis.
authors.affiliation: Central Research Division, Pfizer Inc., Groton, CT 06340.
authors.forename: A E
authors.initials: AE
authors.lastname: Girard
authors.forename: D
authors.initials: D
authors.lastname: Girard
authors.forename: J A
authors.initials: JA
authors.lastname: Retsema
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000032:analysis / Q000494:pharmacology; D017963:Azithromycin; D001424:Bacterial Infections / Q000188:drug therapy*; D001441:Bacteroides fragilis / Q000187:drug effects; D002939:Ciprofloxacin / Q000032:analysis / Q000494:pharmacology; D004195:Disease Models, Animal; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000032:analysis / Q000493:pharmacokinetics / Q000494:pharmacology; D004926:Escherichia coli / Q000032:analysis / Q000187:drug effects; D005260:Female; D008099:Liver / Q000032:analysis; D008297:Male; D051379:Mice; D051381:Rats; D012477:Salmonella enteritidis / Q000032:analysis / Q000187:drug effects; D013211:Staphylococcus aureus / Q000032:analysis / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D002939:Ciprofloxacin; D004917:Erythromycin; D017963:Azithromycin