Influence of experimental pasteurella haemolytica pneumonia in goats on the pharmacokinetics of doxycycline
This study was undertaken to investigate the effect of respiratory tract disease on the serum concentrations and disposition kinetics of doxycycline (DOTC) in goats. In addition, the in vitro sensitivity of Pasteurella haemolytica to doxycycline was determined. The effect of experimentally induced Pasteurella haemolytica pneumonia on the pharmacokinetics of doxycycline (Doxycen Retard ®, Cenevisa, S.A. Spain) administered intramuscularly was studied in small East African goats (n=7). The study was conducted in two consecutive trials in a cross-over design separated by a wash¬out period of four weeks. The experimental infection was induced in six goats by intratracheal administration of infectious doses ranging from 107 to 109 colony forming units (cfu) of Pasteurella haemolytica .. One goat served as a control. Clinical signs and haematologtcal parameters were monitored following challenge. The in vitro minimum inhibitory concentration (MIC) of doxycycline for the P. haemolytica used in this study was determined by the broth dilution technique. Following intramuscular administration of doxycycline at the recommended dosage rate of 20 mg/kg before and after infection blood samples of 5 ml each were collected by jugular venipuncture at 0, 0.25, 0.5, 1, 2, 4, 8, 12, 24, 36, 48, 72, and 96 hours after DOTe administration. Serum concentrations of doxycycline were determined by a quantitative microbiological assay using an agar-gel diffusion method employing Bacillus cereus Var mycoides (ATCC 11 778) as the test organism with a limit of detection of approximately 0.05 Jlg/ml . All the goats that were infected developed pneumonia characterized by a temperature rise. depression and laboured breathing within six to? twelve days post inoculation. White blood cell counts (WBC) were significantly increased while total protein concentration (TP) apparently decreased following infection. The serum concentration - time curve of doxycycline (DOTC) after intramuscular injection before and after experimental infection. was best described by a two¬compartment open model with first order absorption. Maximum serum concentrations (Cmax) of doxycycline were apparently lower (p > 0.05) in pneumonic goats than in healthy goats (5.56 ± 0.58 and 3.87 ± 0.52 Jlg/ml. respectively). suggesting an increased distribution volume of the peripheral compartment. The elimination half-life t i /2J3 (24.51 ± 0.02 h) after infection was significantly increased (p < 0.05). while the corresponding rate constant (.13) decreased (p < 0.01). The absorption half-life. t1/2abs (0.137 ± 0.03 h) significantly decreased (p< 0.01) after infection. The distribution volume. Vd~) after infection (8.24 ± 0.72 L/kg) significantly increased (p < 0.05) . which explains lower initial serum concentrations in disease state. The MIC. defined as the lowest concentration of DOTe at which there was no bacterial growth. was found to be approximately 0.4 Jlg/ ml. The results of the present study indicate a longer sojourn of doxycycline in goats suffering from respiratory disease. It is concluded that although experimental infection had an effect on the disposition kinetics of doxycycline, this effect is not so pronouced to necessitate alteration of dosage during disease. Changes int drug concentration at the site of infection remain to be determined. In addition, antibiotic sensitivity tests (MIC) carried out on the infecting organism displayed an in vitro sensitivity to doxycycline. On this basis however, serum concentrations of DOTC obtained in this study would only be effective within the first 36 hours following intramuscular administration.