title: Standard PK/PD concepts can be applied to determine a dosage regimen for a macrolide: the case of tulathromycin in the calf.
abstract: The pharmacokinetic (PK) profile of tulathromycin, administered to calves subcutaneously at the dosage of 2.5 mg/kg, was established in serum, inflamed (exudate), and noninflamed (transudate) fluids in a tissue cage model. The PK profile of tulathromycin was also established in pneumonic calves. For Mannheimia haemolytica and Pasteurella multocida, tulathromycin minimum inhibitory concentrations (MIC) were approximately 50 times lower in calf serum than in Mueller-Hinton broth. The breakpoint value of the PK/pharmacodynamic (PD) index (AUC(0-24 h)/MIC) to achieve a bactericidal effect was estimated from in vitro time-kill studies to be approximately 24 h for M. haemolytica and P. multocida. A population model was developed from healthy and pneumonic calves and, using Monte Carlo simulations, PK/PD cutoffs required for the development of antimicrobial susceptibility testing (AST) were determined. The population distributions of tulathromycin doses were established by Monte Carlo computation (MCC). The computation predicted a target attainment rate (TAR) for a tulathromycin dosage of 2.5 mg/kg of 66% for M. haemolytica and 87% for P. multocida. The findings indicate that free tulathromycin concentrations in serum suffice to explain the efficacy of single-dose tulathromycin in clinical use, and that a dosage regimen can be computed for tulathromycin using classical PK/PD concepts.
authors: UMR 1331 Toxalim INRA, École Nationale Vétérinaire de Toulouse, Toulouse Cedex 03, France.
authors: P-L
authors: PL
authors: Toutain
authors: The Royal Veterinary College, Hatfield, Hertfordshire, UK.
authors: T
authors: T
authors: Potter
authors: The Royal Veterinary College, Hatfield, Hertfordshire, UK.
authors: L
authors: L
authors: Pelligand
authors: UMR 1331 Toxalim INRA, École Nationale Vétérinaire de Toulouse, Toulouse Cedex 03, France.
authors: M
authors: M
authors: Lacroix
authors: The Royal Veterinary College, Hatfield, Hertfordshire, UK.
authors: J
authors: J
authors: Illambas
authors: The Royal Veterinary College, Hatfield, Hertfordshire, UK.
authors: P
authors: P
authors: Lees
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000032:analysis / Q000493:pharmacokinetics / Q000627:therapeutic use; D001424:Bacterial Infections / Q000188:drug therapy / Q000662:veterinary; D002417:Cattle; D002418:Cattle Diseases / Q000188:drug therapy; D004187:Disaccharides / Q000008:administration & dosage* / Q000032:analysis / Q000493:pharmacokinetics / Q000627:therapeutic use; D005122:Exudates and Transudates / Q000737:chemistry; D005260:Female; D006571:Heterocyclic Compounds / Q000008:administration & dosage* / Q000032:analysis / Q000493:pharmacokinetics / Q000627:therapeutic use; D007279:Injections, Subcutaneous / Q000662:veterinary; D018942:Macrolides
chemical_list: D000900:Anti-Bacterial Agents; D004187:Disaccharides; D006571:Heterocyclic Compounds; C485204:tulathromycin; D018942:Macrolides