title: Comparison of Active Drug Concentrations in the Pulmonary Epithelial Lining Fluid and Interstitial Fluid of Calves Injected with Enrofloxacin, Florfenicol, Ceftiofur, or Tulathromycin.
abstract: Bacterial pneumonia is the most common reason for parenteral antimicrobial administration to beef cattle in the United States. Yet there is little information describing the antimicrobial concentrations at the site of action. The objective of this study was to compare the active drug concentrations in the pulmonary epithelial lining fluid and interstitial fluid of four antimicrobials commonly used in cattle. After injection, plasma, interstitial fluid, and pulmonary epithelial lining fluid concentrations and protein binding were measured to determine the plasma pharmacokinetics of each drug. A cross-over design with six calves per drug was used. Following sample collection and drug analysis, pharmacokinetic calculations were performed. For enrofloxacin and metabolite ciprofloxacin, the interstitial fluid concentration was 52% and 78% of the plasma concentration, while pulmonary fluid concentrations was 24% and 40% of the plasma concentration, respectively. The pulmonary concentrations (enrofloxacin + ciprofloxacin combined) exceeded the MIC90 of 0.06 μg/mL at 48 hours after administration. For florfenicol, the interstitial fluid concentration was almost 98% of the plasma concentration, and the pulmonary concentrations were over 200% of the plasma concentrations, exceeding the breakpoint (≤ 2 μg/mL), and the MIC90 for Mannheimia haemolytica (1.0 μg/mL) for the duration of the study. For ceftiofur, penetration to the interstitial fluid was only 5% of the plasma concentration. Pulmonary epithelial lining fluid concentration represented 40% of the plasma concentration. Airway concentrations exceeded the MIC breakpoint for susceptible respiratory pathogens (≤ 2 μg/mL) for a short time at 48 hours after administration. The plasma and interstitial fluid concentrations of tulathromcyin were lower than the concentrations in pulmonary fluid throughout the study. The bronchial concentrations were higher than the plasma or interstitial concentrations, with over 900% penetration to the airways. Despite high diffusion into the bronchi, the tulathromycin concentrations achieved were lower than the MIC of susceptible bacteria at most time points.
authors.affiliation: Department of Population Health and Pathobiology, College of Veterinary Medicine, NC State University, Raleigh, NC, United States of America.
authors.forename: Derek M
authors.initials: DM
authors.lastname: Foster
authors.affiliation: Department of Population Health and Pathobiology, College of Veterinary Medicine, NC State University, Raleigh, NC, United States of America.
authors.forename: Luke G
authors.initials: LG
authors.lastname: Martin
authors.affiliation: Department of Molecular and Biomedical Sciences, College of Veterinary Medicine, NC State University, Raleigh, NC, United States of America.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Papich
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D002417:Cattle; D002511:Cephalosporins / Q000097:blood / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D004187:Disaccharides / Q000097:blood / Q000493:pharmacokinetics; D000077422:Enrofloxacin; D004847:Epithelial Cells / Q000378:metabolism*; D045604:Extracellular Fluid / Q000737:chemistry / Q000378:metabolism*; D024841:Fluoroquinolones / Q000097:blood / Q000493:pharmacokinetics; D006571:Heterocyclic Compounds / Q000097:blood / Q000493:pharmacokinetics; D008168:Lung / Q000378:metabolism; D008297:Male; D016978:Mannheimia haemolytica / Q000187:drug effects / Q000254:growth & development; D008826:Microbial Sensitivity Tests; D020545:Respiratory Mucosa / Q000378:metabolism*; D013839:Thiamphenicol / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics; D019155:Veterinary Drugs / Q000097:blood / Q000493:pharmacokinetics; D018942:Macrolides
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D004187:Disaccharides; D000077422:Enrofloxacin; D024841:Fluoroquinolones; D006571:Heterocyclic Compounds; D013839:Thiamphenicol; D019155:Veterinary Drugs; C053503:ceftiofur; C035534:florfenicol; C485204:tulathromycin; D018942:Macrolides