Rational Dosing of Antimicrobial Agents for Bovine Respiratory Disease: The Use of Plasma Versus Tissue Concentrations in Predicting Efficacy

Factors associated with identifying an appropriate dose and dosing regimen for the treatment of bovine respiratory disease include the activity of a given drug against common respiratory bacterial pathogens and the ability of the drug to gain access to the site of infection. Although randomized prospective field trials are the best means of determining the relative efficacy of antimicrobial agents for the treatment of bovine respiratory disease, it is impossible to conduct such trials for every possible dose and dosing interval. Based on limited data in cattle, traditional pharmacokinetic/pharmacodynamic models focused strictly on plasma concentrations appear to be adequate surrogate markers of efficacy for the treatment of susceptible extracellular bacterial respiratory pathogens with β-lactams and fluoroquinolones. However, plasma concentrations of macrolides and azalides, such as gamithromycin, tilmicosin, and tulathromycin in cattle, are considerably lower than their respective minimum inhibitory concentrations (MIC) against the pathogens for which they are approved. Nonetheless, multiple studies have demonstrated the efficacy of these drugs in the treatment of bovine respiratory disease, indicating that drug concentrations at the site of infection provide more clinically relevant information than simple reliance on plasma concentrations. Measurement of drug concentration in lung tissue homogenates does not distinguish between free drug available for bacterial killing and drug bound to various extra- or intracellular biological material. For macrolides and azalides, recent findings suggest that measurement of drug concentrations in pulmonary epithelial lining fluid is a better predictor of efficacy than either lung or plasma concentrations for the treatment of pulmonary infections caused by extracellular pathogens.