Pharmacodynamic properties
Doxycycline is a bacteriostatic antibiotic that acts by interfering with the bacterial protein synthesis of sensitive species.
Doxycycline is a semi-synthetic tetracycline derived from oxytetracycline. It acts on the subunit 30 S of the bacterial ribosome, to which is bound reversibly, blocking the union between aminoacyl-tRNA(transfer RNA) to the mRNA-ribosome complex, preventing the addition of new aminoacids into the growing peptide chain and thus interfering with protein synthesis.
Doxycycline is active against Mycoplasma spp. (chickens) and Pasteurella multocida (fattening pigs).
Sensitivity of Doxycycline against Pasteurella multocida strains isolated from fattening pigs in 2004 has been determined, by means of agar dilution method. MIC90 values found are shown in next table (source of breakpoints: NCCLS 2000).The concentration range used is 0.065 - 16µg/ml.
| Pasteurella multocida |
MIC 90 | 0.25 |
Breakpoints | Sensitive ≤4 µg/ml |
MIC90 of micro-organisms involved in porcine respiratory complex. |
There are at least two mechanisms of resistance to tetracyclines:
One mechanism is evidenced by decreased ribosome affinity for the tetracycline-Mg2+ complex owing to chromosomal mutations. It is a ribosomal protection mechanism, in which protein synthesis is resistant to inhibition through a cytoplasmic protein (Prescott et al., 2000).
The most important mechanism of acquired resistance to tetracyclines is plasmid mediated, and is evidenced by a decrease in the cellular accumulation of the drug. The basis of this decrease is a reduction of the active transport of tetracyclines into the cell due to alterations of the external cellular membrane and increased efflux (or active pump elimination) by acquisition of new transport systems of cytoplasmic membrane. (Prescott et al., 2000). The alteration in the transport system is produced by inducible proteins codified in plasmids and transposones. Because the action mechanism of all tetracyclines has the same base, when resistance occurs, normally there is cross-resistance and complete within its group.
Resistance to tetracyclines may not only be the result of therapy with tetracyclines, but may also be caused by therapy with other antibiotics leading to selection of multi-resistant strains including tetracyclines. although minimal inhibitory concentrations (MIC) tend to be lower for doxycycline than for older generation tetracyclines, pathogens resistant to one tetracycline are generally also resistant to doxycycline (cross resistance). Both long term treatment and treating for an insufficient length of time and/or sub-therapeutic dosages can select for antimicrobial resistance and should be avoided.
Pharmacokinetic properties
Doxycycline is bio-available after oral administration. When orally administered, it reaches values greater than 70% in most species.
Feeding can modify the oral bioavailability of Doxycycline. In fasting conditions bioavailability is around 10 – 15% greater than when the animal is fed. Doxycycline is well distributed through the body as it is highly lipid soluble. It reaches well irrigated tissues as well as peripheral ones. It accumulates in liver, kidney, bones and intestine; enterohepatic recycling occurs. In lungs it always reaches higher concentrations than in plasma. Therapeutic concentrations have been detected in aqueous humour, myocardium, reproductive tissues, brain and mammary gland.
Plasma protein binding is 90 – 92%.
40% of drug is metabolized and largely excreted through faeces (biliary and intestinal route), mainly as microbiologically inactive conjugates.
CHICKENS
After oral administration, doxycycline is quickly absorbed, achieving maximum concentrations (Cmax) around 1.5 h. Bioavailability is 75%. Absorption is decreased in the presence of feed in the gastrointestinal tract, bioavailability is then around 60% and the time to achieve the maximum concentration peak is significantly prolonged, (Tmax) 3.3 h.
FATTENING PIGS
Treatment with the recommended dosage, maximum blood concentration in steady state (Cmax-ss) was 0.83 μg/ml (SD = 0.29) , minimum blood concentration in steady state (Cmin–ss) was 0.22 (SD = 0.07) and Cave-ss= 0.49 (SD= 0.14)
After oral administration of 10 mg doxycycline /kg bw in pigs the bioavailability was 24.8 ± 4.6%. The elimination half-life (t1/2) was 4.6 h; plasmatic clearance was 0.15 l/h.kg and apparent distribution volume was 0.89 l/kg.