PHARMACOLOGICAL PROPERTIES
Pharmacotherapeutic group:
Antibacterials for systemic use, macrolides, tilmicosin
ATC Vet code: QJ01FA91
Pharmacodynamic properties
Tilmicosin is a mainly bactericidal semi-synthetic antibiotic of the macrolide group. It is believed to affect protein synthesis. It has bacteriostatic action but at high concentrations it may be bactericidal. This antibacterial activity is predominantly against Gram-positive microorganism with activity against certain Gram-negative ones and Mycoplasma of a bovine and ovine origin. In particular its activity has been demonstrated against the following micro-organism:
Mannheimia, Pasteurella, Actinomyces (Corynebacterium), Fusobacterium, Dichelobacter, Staphylococcus, and Mycoplasma organisms of bovine and ovine origin.
Minimum inhibition concentration measured in recently (2009-2012) isolated European field strains, derived from respiratory bovine disease.
Bacteria spp | MIC (μg/ml) range | MIC50 (μg/ml) | MIC90 (μg/ml) |
P. multocida | 0.5- > 64 | 4 | 8 |
M. haemolytica | 1 - 64 | 8 | 16 |
The Clinical and Laboratory Standards Institute (CLSI) has set the interpretive criteria for tilmicosin against M. haemolyica of bovine origin and specifically for bovine respiratory disease, as ≤8μg/ml = susceptible, 16 μg/ml = intermediate and ≥ 32 μg/ml = resistant. The CLSI at the present time have no interpretive criteria for P. multocida of bovine origin, however they have interpretive criteria for P. multocida of swine origin, specifically swine respiratory disease, as ≤16 μg/ml = susceptible and ≥ 32 μg/ml = resistant.
Scientific evidence suggests that macrolides act synergistically with the host immune system. Macrolides appear to enhance phagocyte killing of bacteria.
Following oral or parenteral administration of tilmicosin the main target organ for toxicity is the heart. The primary cardiac effects are increased heart rate (tachycardia) and decreased contractility (negative inotrophy). Cardiovascular toxicity may be due to calcium channel blockade.
In dogs, CaCl2 treatment showed a positive effect on the left ventricular inotrophic state after tilmicosin administration and some changes in vascular blood pressure and heart rate.
Dobutamine partially offset the negative inotropic effects induced by tilmicosin in dogs. Beta adrenergic antagonists such as propanolol exacerbated the negative inotrophy of tilmicosin in dogs.
In pigs, intramuscular injection of 10 mg tilmicosin/kg body weight caused increased respiration, emesis and convulsions; 20 mg/kg body weight resulted in mortality in 3 of 4 pigs, and 30 mg/kg body weight caused the death of all 4 pigs tested. Intravenous injection of 4.5 to 5.6 mg tilmicosin/kg body weight followed by intravenous injection of 1 ml epinephrine (1/1000) 2 to 6 times resulted in death of all 6 injected pigs. Pigs given 4.5 to 5.6 mg tilmicosin/kg body weight intravenously with no epinephrine all survived. These results suggest that intravenous epinephrine may be contraindicated.
Cross resistance between tilmicosin and other macrolides and lincomycin has been observed.
Macrolides inhibit protein synthesis by reversibly binding to the 50S ribosomal subunit. Bacterial growth is inhibited by induction of the separation of peptidyl transfer RNA from the ribosome during the elongation phase.
Ribosomal methylase, encoded by the erm gene, can precipitate resistance to macrolides by alteration of the ribosomal binding site.
The gene that encodes for an efflux mechanism, mef, also brings about a moderate degree of resistance.
Resistance is also brought about by an efflux pump that actively rids the cells of the macrolide. This efflux pump is chromosomally mediated by genes referred to as acrAB genes.
Pharmacokinetic particulars
Absorption: Several studies have been conducted. The results show that, when administered as recommended to calves and sheep by subcutaneous injection over the dorso-lateral chest, the main parameters are:
| Dose Rate | Tmax | Cmax |
Cattle: Neonatal calves Feedlot cattle | 10 mg/kg body weight 10 mg/kg body weight | 1 hour 1 hour | 1.55 µg/ml 0.97 µg/ml |
Sheep: 40 kg animals 28-50 kg animals | 10 mg/kg body weight 10 mg/kg body weight | 8 hours 8 hours | 0.44 µg/ml 1.18 µg/ml |
Distribution: Following subcutaneous injection, tilmicosin is distributed throughout the body, but especially high levels are found in the lung.
Biotransformation: Several metabolites are formed, the predominant one being identified as T1 (N-demethyl tilmicosin). However the bulk of the tilmicosin is excreted unchanged.
Elimination: Following subcutaneous injection, tilmicosin is excreted mainly via the bile into the faeces, but a small proportion is excreted via the urine. The half-life following subcutaneous injection in cattle is 2-3 days.
PHARMACEUTICAL PARTICULARS
List of excipients
Propylene glycol (E1520)
Phosphoric acid, concentrated (for pH adjustment)Water for injections
Major incompatibilities
In the absence of compatibility studies, this veterinary medicinal product must not be mixed with other veterinary medicinal products.