Minocycline pharmacokinetics and pharmacodynamics in dogs: dosage recommendations for treatment of meticillin-resistant Staphylococcus pseudintermedius infections

摘要

BackgroundAlthough minocycline is not licensed for use in dogs, this tetracycline has therapeutic potential against meticillin-resistant Staphylococcus pseudintermedius. Hypothesis/ObjectivesThe aim of this study was to establish rational dosage recommendations for minocycline use in dogs. Specific objectives were to generate and analyse minocycline pharmacokinetic (PK) data on plasma and interstitial fluid (ISF) concentrations, plasma protein binding and pharmacodynamic (PD) data on antimicrobial activity against S.pseudintermedius. AnimalsSix healthy dogs from a research colony were used in this study. MethodsDogs were administered 5mg/kg intravenously and 10mg/kg orally (p.o.) of minocycline hydrochloride in separate crossover experiments. In vivo drug concentrations in plasma and in ISF collected by ultrafiltration were measured by high-performance liquid chromatography. Pharmacokinetic analysis was performed on plasma and ISF concentrations. PK/PD analysis was completed using in vitro data on plasma protein binding and minocycline susceptibility in 168 S.pseudintermedius isolates. ResultsMinocycline distributed to the ISF to a higher degree than predicted by the protein-unbound fraction in plasma. A large volume of distribution after oral administration, with plasma and ISF elimination half-lives of 4.1 and 7.4h, respectively, demonstrated that the ISF serves as a drug reservoir for sustained tissue concentrations. Monte Carlo simulation, used to assess target attainment at different drug dosages, indicated that p.o. administration of 5mg/kg twice daily is sufficient to inhibit S.pseudintermedius strains with minimal inhibitory concentrations 0.25g/mL. Conclusions and clinical importanceBesides dosage recommendations for therapy of meticillin-resistant Staphylococcus pseudintermedius infections in dogs, the study also provides PK/PD data necessary to consider species-specific clinical breakpoints for minocycline susceptibility testing. Resume ContexteLa minocycline n'est pas autorisee chez le chien et pourtant cette tetracycline a des effets therapeutiques contre les Staphylococcus pseudintermedius resistants a la meticilline. Hypotheses/objectifsLe but de cette etude etait de determiner les recommandations de dosage pour la minocycline chez le chien. Les objectifs specifiques etaient de generer et d'analyser les donnees pharmacocinetiques (PK) sur les concentrations plasmatiques et le fluide interstitiel (ISF), la liaison aux proteines plasmatiques et les donnees pharmacodynamiques (PD) sur l'activite antimicrobienne contre S.pseudintermedius. SujetsSix chiens sains d'une colonie de recherche ont ete inclus dans l'etude.