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Background: Bovine respiratory disease (BRD) is an economically important disease in the beef industry, and a major driver of therapeutic antibiotic use. Pharmacokinetic data of these drugs is relatively limited in diseased animals., Hypothesis/objective: To determine the concentrations of pradofloxacin, florfenicol, and tulathromycin in the airways, plasma, and interstitial fluid (ISF) of steers with a clinically relevant model of bacterial respiratory disease., Animals: Twenty-four Holstein and Holstein/Jersey cross steers ranging in age from 6 to 15 months., Methods: A randomized, blinded clinical trial was performed. After transport stress, steers were inoculated with Mannheimia hemolytica to induce BRD. Upon onset of clinical disease, steers were treated with pradofloxacin, florfenicol or tulathromycin. Blood, ISF, and pulmonary epithelial lining fluid (PELF) samples were obtained for drug concentration determination. Clinical exams and thoracic ultrasound examinations were conducted daily. Animals were euthanized at the end of the study period to assess lung lesions., Results: Pradofloxacin C max in PELF was 0.81 μg/mL (CV = 49.02%) and penetration into the PELF was 203.58% (72%). Florfenicol C max in PELF was 2.94 μg/mL (42.1%) and penetration was 230.08% (78.82%). Tulathromycin PELF C max was 0.9 μg/mL (45.03%) and PELF penetration was 518.97% (56.59%)., Conclusions and Clinical Importance: There are differences in penetration of the drugs into the ISF and PELF compared to one another and previous data from healthy steers demonstrating the effect of disease on the PK of these drugs., (© 2024 The Author(s). Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)