ATCvet code: QJ01FA99.

Tulathromycin is a semi-synthetic macrolide antimicrobial agent, which originates from a fermentation product. It differs from many other macrolides in that it has a long duration of action that is, in part, due to its three amine groups; therefore, it has been given the chemical subclass designation of triamilide.

Macrolides are bacteriostatic acting antibiotics and inhibit essential protein biosynthesis by virtue of their selective binding to bacterial ribosomal RNA. They act by stimulating the dissociation of peptidyl-tRNA from the ribosome during the translocation process.

Tulathromycin possesses in vitro activity against Mannheimia haemolytica, Pasteurella multocida, Histophilus somni and Mycoplasma bovis the bacterial pathogens most commonly associated with bovine respiratory disease. Increased minimum inhibitory concentration (MIC) values have been found in some isolates of Histophilus somni.

The Clinical and Laboratory Standards Institute CLSI has set the MIC clinical breakpoints for tulathromycin against M. haemolytica, P. multocida, and H. somni of bovine respiratory origin, as ≤16 μg/ml susceptible and ≥ 64 μg/ml resistant. CLSI has also published clinical breakpoints for tulathromycin based on a disk diffusion method (CLSI document VET08,4th ed, 2018). Neither EUCAST nor CLSI have developed standard methods for testing antibacterial agents against veterinary Mycoplasma species and thus no interpretative criteria have been set.

Resistance to macrolides can develop by mutations in genes encoding ribosomal RNA (rRNA) or some ribosomal proteins; by enzymatic modification (methylation) of the 23S rRNA target site, generally giving rise to cross-resistance with lincosamides and group B streptogramins (MLSB resistance); by enzymatic inactivation; or by macrolide efflux. MLSB resistance may be constitutive or inducible. Resistance among the BRD pathogens may be chromosomal or plasmid-encoded and may be transferable if associated with transposons, plasmids, integrative and conjugative elements. Additionally, the genomic plasticity of Mycoplasma is enhanced by the horizontal transfer or large chromosomal fragments.

In addition to its antimicrobial properties, tulathromycin demonstrates immune-modulating and anti-inflammatory actions in experimental studies. In bovine polymorphonuclear cells (PMNs; neutrophils), tulathromycin promotes apoptosis (programmed cell death) and the clearance of apoptotic cells by macrophages. It lowers the production of the pro-inflammatory mediators leukotriene B4 and CXCL-8 and induces the production of anti-inflammatory and pro-resolving lipid lipoxin A4.

Ketoprofen is a substance belonging to the group non-steroidal anti-inflammatory drugs (NSAIDs). Ketoprofen has anti-inflammatory, analgesic and antipyretic properties. Not all aspects of its mechanism of action are known. Effects are obtained partially by the inhibition of prostaglandin and leukotriene synthesis by ketoprofen, acting on cyclooxygenase and lipoxygenase respectively. The formation of bradykinin is also inhibited. Ketoprofen inhibits thrombocyte aggregation.

When subcutaneously co-administered in the combination formulation, at 2.5 mg tulathromycin/kg body weight, the maximum concentration (Cmax) in plasma was approximately 0.4 μg/ml, this was achieved approximately 3 hours post-dosing (Tmax). Peak concentrations were followed by a slow decline in systemic exposure with an apparent elimination half-life (t1/2) of 85 hours in plasma.

Furthermore, after subcutaneous injection of the tulathromycin-ketoprofen combination, the AUC(0-t) of tulathromycin has been shown to be bioequivalent to the AUC(0-t) after subcutaneous injection of tulathromycin 100 mg/ml for cattle. The combination had a slightly lower tulathromycin Cmax and the rate of absorption was decreased in comparison with the administration of the compounds separately.

Regarding ketoprofen, following administration of the combination product, at 3 mg ketoprofen/kg body weight, the pharmacokinetics of ketoprofen are driven by flip-flop kinetics. The mean Cmax in plasma was 2 μg/ml, which was achieved at 4 hours on average. The terminal half-life of ketoprofen is dominated by the slow absorption and was estimated at 6.8 hours.

Furthermore, after subcutaneous injection of the tulathromycin-ketoprofen combination, there was a delay in the absorption, with a lower ketoprofen peak concentration, and a longer elimination half-life, as compared with the compound alone.

Ketoprofen in the combination product is a racemic mixture of two enantiomers, S(+) and R (-). In-vitro models suggest that the S(+) enantiomer is 250 times more potent than the R(-) enantiomer. Inversion of R-ketoprofen to S-ketoprofen has been reported in cattle to be 31% following intravenous dosing of R-ketoprofen.