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

TY - JOUR

T1 - Minocycline pharmacokinetics and pharmacodynamics in dogs

T2 - dosage recommendations for treatment of meticillin-resistant Staphylococcus pseudintermedius infections

AU - Maaland, Marit Gaastra

AU - Guardabassi, Luca

AU - Papich, Mark G.

N1 - © 2014 ESVD and ACVD.

PY - 2014/6

Y1 - 2014/6

N2 - BACKGROUND: Although minocycline is not licensed for use in dogs, this tetracycline has therapeutic potential against meticillin-resistant Staphylococcus pseudintermedius.HYPOTHESIS/OBJECTIVES: The 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.ANIMALS: Six healthy dogs from a research colony were used in this study.METHODS: Dogs were administered 5 mg/kg intravenously and 10 mg/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.RESULTS: Minocycline 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 7.4 h, 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 5 mg/kg twice daily is sufficient to inhibit S. pseudintermedius strains with minimal inhibitory concentrations ≤0.25 μg/mL.CONCLUSIONS AND CLINICAL IMPORTANCE: Besides 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.

AB - BACKGROUND: Although minocycline is not licensed for use in dogs, this tetracycline has therapeutic potential against meticillin-resistant Staphylococcus pseudintermedius.HYPOTHESIS/OBJECTIVES: The 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.ANIMALS: Six healthy dogs from a research colony were used in this study.METHODS: Dogs were administered 5 mg/kg intravenously and 10 mg/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.RESULTS: Minocycline 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 7.4 h, 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 5 mg/kg twice daily is sufficient to inhibit S. pseudintermedius strains with minimal inhibitory concentrations ≤0.25 μg/mL.CONCLUSIONS AND CLINICAL IMPORTANCE: Besides 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.

U2 - 10.1111/vde.12130

DO - 10.1111/vde.12130

M3 - Journal article

C2 - 24840325

SN - 0959-4493

VL - 25

SP - 182-190, e46-47

JO - Veterinary Dermatology

JF - Veterinary Dermatology

IS - 3

ER -