Pharmacotherapeutic group: antibacterials for systemic use/pleuromutilins/tiamulin

ATC Vet code: QJ01XQ01

Tiamulin is a bacteriostatic semi-synthetic antibiotic belonging to the pleuromutilin group of antibiotics and acts at the ribosomal level to inhibit bacterial protein synthesis.

Tiamulin has shown a high level of in vitro activity against 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 (Pasteurella multocida).

Tiamulin has been shown to act at the 70S ribosome level and the primary binding sites are on the 50S subunit. It appears to inhibit microbial protein production by producing biochemically inactive initiation complexes, which prevent elongation of the polypeptide chain.

In European isolates of Brachyspira hyodysenteriae collected between 1990 and 2012 the minimum inhibitory concentration (MICs) ranged from ≤0.016 µg/ml to >16 µg/ml, with MIC50 of ≤0.063 µg/ml to 4 µg/ml and MIC90 of ≤0.016 µg/ml to >16 µg/ml.

In European isolates of Brachyspira pilosicoli the MICs ranged from (citation from 2006-2008-2012) ≤0.008-64 µg/ml, with MIC50s of ≤0.062 µg/ml up to 0.125 µg/ml and MIC90s of 0.25 µg/ml up to 8 µg/ml.

Susceptibility testing of Lawsonia intracellularis is challenging since this is an obligate intracellular organism. The tiamulin MIC data determined for the available EU Lawsonia strains were (citation from 2017) all below the estimated ileal tiamulin contents of 0.63 μg/ml.

In European isolates tiamulin was highly active against Mycoplasma hyopneumoniae, with MIC50 of 0.016 µg/ml, MIC90 of 0.062 µg/ml, and a MIC range of 0.002-0.125 µg/ml (citation from 2014).

In newer European strains (2005-2013) and older global isolates (before 1997) MIC ranges were similar for Mycoplasma gallisepticum ranging from 0.001 – 0.037 µg/ml with MIC50s of 0.001 and 0.008 µg/ml and MIC90s of 0.025 and 0.031 µg/ml. No resistant strains were found. For Mycoplasma synoviae MICs ranged from 0.05 to 0.5 µg/ml with MIC50s of 0.1 µg/ml and a MIC90 of 0.25 µg/ml.

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 1.03 µg/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 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.

Tiamulin only degrades slowly in soils and may accumulate over years.