Pharmacotherapeutic group:

Antibacterials for systemic use

Pleuromutilins

Tiamulin hydrogen fumarate is a semi-synthetic diterpene antibiotic. The mode of action is by inhibition of ribosomal protein synthesis. It is a bacteriostatic antibiotic and the spectrum of activity includes: porcine and avian Mycoplasma species as well as gram-positive aerobes (streptococci and staphylococci), anaerobes (clostridia), gram-negative anaerobes (Brachyspira hyodysenteriae, Brachyspira pilosicoli), and gram-negative aerobes (Actinobacillus pleuropneumoniae and Pasteurella multocida).

Tiamulin has been shown to act at the 70S ribosome. The primary binding site is on the 50S subunit and there is possibly a secondary site where the 50S and 30S subunits join. Tiamulin appears to inhibit microbial protein production by producing biochemically inactive initiation complexes, which prevent elongation of the polypeptide chain.

Bactericidal concentrations can be reached but vary according to the bacterium. It can be as little as two times the MIC for Brachyspira hyodysenteriae and Actinobacillus pleuropneumoniae but as high as 50 -100 times the bacteriostatic level for Staphylococcus aureus. The MIC distribution for tiamulin against Brachyspira hyodysenteriae is bimodal, suggesting reduced susceptibility of some strains to tiamulin. Due to technical constraints the susceptibility of Lawsonia intracellularis is difficult to test in vitro.

In vitro research has shown that resistant bacterial mutants can be created through multi step resistance. Development of resistance in mycoplasmas is slower. Resistance against B. hyodysenteriae has been seen, and can vary geographically.

Cross resistance between tiamulin and tylosin tartrate has been reported: micro-organisms that are resistant for tiamulin, are also resistant for tylosin tartrate, but not vice versa.

Resistance in Brachyspirae hyodysenteriae can be caused by a point mutation in the 23S rRNA gene.

Tiamulin is well absorbed from the gastrointestinal tract of chickens and turkeys.

Tiamulin hydrogen fumarate is well absorbed in chickens (70-95%) after oral administration and reaches peak concentrations in 2-4 hours (Tmax 2.85 hours). Following a 50 mg tiamulin hydrogen fumarate/kg body weight single dose the Cmax was 4.02 μg/ml in serum by microbiological assay and after a 25 mg/kg dose it was 1.86 μg/ml. In drinking water the 250 ppm (0.025%) tiamulin hydrogen fumarate concentration provided a rolling serum level over a 48 hour medication period of 0.78 μg/ml (range 1.4-0.45 μg/ml) and at 125 ppm (0.0125%), 0.38 μg/ml (range 0.65-0.2 μg/ml) in eight-week old chickens. Serum protein-binding was approximately 45%. It distributes widely through the body and has been shown to concentrate in the liver and kidney (sites of excretion) and in the lung (30 times serum level). Excretion is mainly via the bile (55-65%) and kidney (15-30%) as mainly microbiologically inactive metabolites and is quite rapid, 99% of the dose within 48 hours.

In turkeys serum levels of tiamulin hydrogen fumarate are lower with a 50 mg tiamulin hydrogen fumarate/kg body weight single dose giving a Cmax of 3.02 µg/ml in serum, and 25 mg/kg giving 1.46 μg/ml. These were achieved at about 2-4 hours after dosing. In breeders on 0.025% tiamulin hydrogen fumarate the average serum level was 0.36 μg/ml (range 0.22-0.5 μg/ml). Serum protein-binding was approximately 50%.

Tiamulin hydrogen fumarate is well absorbed in the pig (over 90%) following oral administration and widely distributed through the body. Following a single oral dose of 10 mg and 25 mg tiamulin hydrogen fumarate/kg body weight the Cmax was 1.03μg/ml and 1.82 μg/ml in serum respectively by microbiological assay and the Tmax was 2 hours for both. It has been shown to concentrate in the lung, polymorphonuclear leucocytes and also in liver, where it is metabolised and excreted (70-85%) in the bile, the remainder is excreted via the kidney (15-30%). Serum protein binding is approximately 30%. Tiamulin, which has not been absorbed or metabolised, passes down the intestines to the colon. Colon contents concentrations of tiamulin have been estimated at 3.41 μg/ml following administration of tiamulin hydrogen fumarate at 8.8 mg/kg body weight.

Tiamulin hydrogen fumarate is persistent in soils.