Pharmacotherapeutic group: Tetracyclines
ATCvet code: QJ01AA 02
Pharmacodynamics
Doxycycline is a semisynthetic tetracycline derivative. It acts by inhibiting protein synthesis at the ribosomal level, predominantly by binding to the 30S ribosomal subunits of bacteria. Doxycycline is a broad-spectrum antibiotic. It exhibits a wide range of activity against Gram-positive and Gram-negative, aerobic and anaerobic pathogens, especially against Pasteurella multocida and Mycoplasma hyopneumoniae isolated from pig respiratory infections and Mycoplasma gallisepticum associated with clinical respiratory infections in chickens and turkeys.
Four resistance mechanisms acquired by micro-organisms against tetracyclines in general have been reported: decreased accumulation of tetracyclines (decreased permeability of the bacterial cell wall and active efflux), protein protection of the bacterial ribosome, enzymatic inactivation of the antibiotic and rRNA mutations (preventing the tetracycline binding to ribosome). Tetracycline resistance is usually acquired by means of plasmids or other mobile elements (e.g. conjugative transposons). Cross-resistance between tetracyclines is common but depends on the mechanism conferring resistance. Due to the greater liposolubility and greater ability to pass through cell membranes (in comparison to tetracycline), doxycycline retains a certain degree of efficacy against micro-organisms with acquired resistance to tetracyclines via efflux pumps. However, resistance mediated by ribosomal protection proteins confer cross-resistance to doxycycline.
Pharmacokinetics
In general, doxycycline is quite rapidly and extensively absorbed from the gastrointestinal tract, widely distributed in the organism, not metabolised to any significant extent and excreted primarily in faeces, mostly in a microbiologically inactive form.
After oral administration to pigs, doxycycline is substantially absorbed from the gastrointestinal tract. The binding rate to plasma proteins is 93%. It is widely distributed in the organisms; at the steady state, the volume of distribution (VSS) is 1.2 L/kg. The elimination half-life was reported to be 4-4.2 hours in pigs. The steady-state plasma concentrations of doxycycline after repeated oral administrations of the veterinary medicinal product at a dose of 20 mg/kg body weight for 5 days ranged from 1.0 and 1.5 µg/ml. Both the lung and nasal mucosa concentrations at steady-state were higher than the plasma level. The ratio between tissue- and plasma concentration was found to be 1.3 for lung and 3.4 for nasal mucosa. The doxycycline concentrations both in the lung and the nasal mucosa exceeded the MIC90 of the drug against the target respiratory pathogens.
Pharmacokinetics of doxycycline after single oral administration to chickens and turkeys is characterised by a quite rapid and substantial absorption from the gastrointestinal tract providing peak plasma concentrations between 0.4 and 3.3 hours in chickens and 1.5 to 7.5 hours in turkeys, depending on age and the presence of food. The drug is widely distributed in the organism with Vd values close to or greater than 1, and exhibits a shorter elimination half-life in chickens (4.8 to 9.4 hours) than in turkeys (7.9 to 10.8 hours). The protein binding ratio at therapeutic plasma concentrations is in the range of 70-85%. The bioavailability in chickens and turkeys may vary between 41 and 73%, and 25 and 64%, respectively also depending on the age and feeding. The presence of food in the gastrointestinal tract determines a lower bioavailability compared to that obtained in the fasted state.
After continuous in-water administration of the veterinary medicinal product at doses of 20 mg doxycycline/kg (chickens) and 25 mg doxycycline/kg (turkeys) for 5 days the average plasma concentrations over the whole treatment period were reported as 1.86 ± 0.71 µg/ml in chickens and 2.24 ± 1.02 µg/ml in turkeys. In both avian species the PK/PD analysis of ƒAUC/MIC90 data resulted in > 24 h values that meet the requirements for tetracyclines.