title: Pharmacodynamics of oxytetracycline administered alone and in combination with carprofen in calves.
abstract: The pharmacodynamics (PD) of oxytetracycline was investigated against a strain of Mannheimia haemolytica. In vitro measurements, comprising minimum inhibitory concentration (MIC), minimum bactericidal concentration and time-kill curves, were conducted in five matrices; Mueller Hinton Broth (MHB), cation-adjusted MHB (CAMHB) and calf serum, exudate and transudate. MICs were much higher in the biological fluids than in MHB and CAMHB. Ratios of MIC were, serum: CAMHB 19 : 1; exudate:CAMHB 16.1; transudate:CAMHB 14 : 1. Ex vivo data, generated in the tissue cage model of inflammation, demonstrated that oxytetracycline, administered to calves intramuscularly at a dose rate of 20 mg/kg, did not inhibit the growth of M haemolytica in serum, exudate and transudate, even at peak concentration. However, using in vitro susceptibility in CAMHB and in vivo-determined pharmacokinetic (PK) variables, average and minimum oxytetracycline concentrations relative to MIC (C(av)/MIC and C(min)/MIC) predicted achievement of efficacy for approximately 48 hours after dosing. Similar C(av)/MIC and C(min)/MIC data were obtained when oxytetracycline was administered in the presence of carprofen. PK-PD integration of data for oxytetracycline, based on MICs determined in the three biological fluids, suggests that it possesses, at most, limited direct killing activity against M haemolytica. These data raise questions concerning the mechanism(s) of action of oxytetracycline, when administered at clinically recommended dose rates.
authors: Department of Veterinary Basic Sciences, The Royal Veterinary College, Hawskhead Campus, Hatfield, Hertfordshire AL9 7TA, UK.
authors: C
authors: C
authors: Brentnall
authors: Z
authors: Z
authors: Cheng
authors: Q A
authors: QA
authors: McKellar
authors: P
authors: P
authors: Lees
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D002227:Carbazoles / Q000493:pharmacokinetics / Q000494:pharmacology; D002417:Cattle / Q000378:metabolism*; D015169:Colony Count, Microbial / Q000662:veterinary; D004305:Dose-Response Relationship, Drug; D005122:Exudates and Transudates / Q000378:metabolism*; D007273:Injections, Intramuscular / Q000662:veterinary; D016978:Mannheimia haemolytica / Q000187:drug effects*; D008826:Microbial Sensitivity Tests / Q000662:veterinary*; D010118:Oxytetracycline / Q000493:pharmacokinetics / Q000494:pharmacology; D048089:Pneumonia of Calves, Enzootic / Q000188:drug therapy / Q000517:prevention & control; D014018:Tissue Distribution
chemical_list: D000890:Anti-Infective Agents; D002227:Carbazoles; C007005:carprofen; D010118:Oxytetracycline