title: Pharmacokinetics (PK), pharmacodynamics (PD), and PK-PD integration of ceftiofur after a single intravenous, subcutaneous and subcutaneous-LA administration in lactating goats.
abstract: BACKGROUND
  Bacterial pneumonia in goats is usually caused by Mannheimia haemolytica and Pasteurella multocida. Another important infection disease in lactating goats is intramammary infection producing mastitis, usually associated with coagulase-negative Staphylococcus spp. However, treatment of bacterial pneumonia in goats not affected by mastitis problems should be restricted to antimicrobials with scant penetration to milk in order to avoid long withdrawal times. Ceftiofur is a third-generation cephalosporin antimicrobial with activity against various gram-positive and gram-negative, aerobic and anaerobic bacteria encountered by domestic animals. The objectives of the present study were to establish the serum concentration-time profile for ceftiofur in lactating goats after intravenous, subcutaneous and a SC-long-acting ceftiofur formulation; to determine ceftiofur penetration into milk; to determine in vitro and ex vivo activity of ceftiofur establishing MIC, MBC, MPC and time-kill profiles against field strains of M. haemolytica and finally to calculate the main surrogate markers of efficacy.
  
  
  RESULTS
  The pharmacokinetics studies revealed an optimal PK properties for the SC-LA formulation tested. Ceftiofur was well absorbed following SC and SC-LA administration, with absolute bioavailabilities (F) of 85.16 and 84.43 %, respectively. After ceftiofur analysis from milk samples, no concentrations were found at any sampling time. The MIC, MBC and MPC data of ceftiofur against five M. haemolytica strains isolated from goats affected by pneumonia were tested showing excelent sensitivity of ceftiofur against this pathogen. For PK-PD analysis, ratios were calculated suggesting a high level of bacterial kill against the five strains of M. haemolytica tested.
  
  
  CONCLUSIONS
  The systemic ceftiofur exposure achieved in lactating goats following IV, SC and especially with the SC-LA administration is consistent with the predicted PK-PD ratios needed for a positive therapeutic outcome for M. haemolytica. Subcutaneous administration of the long-acting formulation showed safety and tolerance for all the animals used. Ceftiofur concentrations exceeded the MIC and MBC for up to 72 h and MPC for up 32 h in serum. Thus, this drug could be effective in treating infectious diseases of goats caused by M. haemolytica at a dose of 6 mg/kg with the SC-LA formulation.
authors.affiliation: Department of Pharmacology, Faculty of Veterinary Medicine, University of Murcia, Campus de Espinardo, 30.071, Murcia, Spain. emiliofv@um.es.
authors.forename: Emilio
authors.initials: E
authors.lastname: Fernández-Varón
authors.affiliation: Department of Pharmacology, Faculty of Veterinary Medicine, University of Murcia, Campus de Espinardo, 30.071, Murcia, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cárceles-García
authors.affiliation: Department of Pharmacology, Toxicology and Legal and Forensic Medicine, Faculty of Veterinary Medicine, University of Cordoba, Campus de Rabanales, 14.071, Córdoba, Spain.
authors.forename: Juan Manuel
authors.initials: JM
authors.lastname: Serrano-Rodríguez
authors.affiliation: Department of Pharmacology, Faculty of Veterinary Medicine, University of Murcia, Campus de Espinardo, 30.071, Murcia, Spain.
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Cárceles-Rodríguez
mesh_terms: D061605:Administration, Intravenous / Q000662:veterinary*; D000818:Animals; D001682:Biological Availability; D002511:Cephalosporins / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics* / Q000494:pharmacology; D015511:Goat Diseases / Q000188:drug therapy; D006041:Goats; D055104:Infusions, Subcutaneous / Q000662:veterinary*; D007774:Lactation; D016978:Mannheimia haemolytica / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D008892:Milk / Q000737:chemistry; D016871:Pasteurellaceae Infections / Q000188:drug therapy / Q000662:veterinary
chemical_list: D002511:Cephalosporins; C053503:ceftiofur
keywords: Ceftiofur; Lactating goats; Long-acting formulation; Pharmacokinetic/Pharmacodynamic