ATCvet code: QJ01FA96.
Pharmacotherapeutic group
Antibacterials for systemic use, macrolides.
Pharmacodynamic properties
Tildipirosin is a 16-membered semi-synthetic macrolide antimicrobial agent. Three amine substituents at the macrocyclic lactone ring result in a tri-basic character of the molecule. The product has a long duration of action, however, the exact clinical effect duration after a single injection is unknown.
Macrolides in general are bacteriostatic antibiotics but for certain pathogens can be bactericidal. They inhibit essential protein biosynthesis by virtue of their selective binding to bacterial ribosomal RNA and act by blocking the prolongation of the peptide chain. The effect is generally time-dependent. The antimicrobial activity spectrum of tildipirosin includes:
Histophilus somni, Mannheimia haemolytica and Pasteurella multocida, the bacterial pathogens most commonly associated with bovine respiratory disease (BRD). In vitro, the effect of tildipirosin is bactericidal against H. somni and M. haemolytica and bacteriostatic against P. multocida.
Minimum inhibitory concentration (MIC) data for the target pathogens (wild type distribution) are presented in the table below.
Species | Range (µg/ml) | MIC50 (µg/ml) | MIC90 (µg/ml) |
M. haemolytica (n=88) | 0.125 - >64 | 0.5 | 1 |
P. multocida (n=105) | 0.125 - 2 | 0.5 | 0.5 |
H. somni (n=63) | 0.5 - 4 | 2 | 4 |
The following tildipirosin breakpoints have been established for bovine respiratory disease (according to CLSI Guideline VET02 A3):
Disease Species | Disk content | Zone Diameter (mm) | MIC breakpoint ( µg/ml) |
S | I | R | S | I | R |
Bovine respiratory disease | 60 µg | | | | | | |
M. haemolytica | ≥ 20 | 17–19 | ≤ 16 | 4 | 8 | 16 |
P. multocida | ≥ 21 | 18–20 | ≤ 17 | 8 | 16 | 32 |
H. somni | ≥ 17 | 14–16 | ≤ 13 | 8 | 16 | 32 |
S: susceptible; I: intermediate; R: resistant
Resistance to macrolides generally results from three mechanisms: (1) the alteration of the ribosomal target site (methylation), often referred to as MLSB resistance as it affects macrolides, lincosamides and group B streptogramins; (2) the utilisation of active efflux mechanism; (3) the production of inactivating enzymes. Generally, cross-resistance between tildipirosin and other macrolides, lincosamides or streptogramins is to be expected. Data were collected on zoonotic bacteria and commensals. MIC values for Salmonella were reported to be in the range of 4-16 µg/ml, and all strains were wild type. For E. coli, Campylobacter and Enterococci, both wild type and non-wild type phenotypes were observed (MIC range 1 - >64 µg/ml).
Pharmacokinetic properties
Tildipirosin administered subcutaneously to cattle at a single dose of 4 mg/kg body weight resulted in rapid absorption with average peak plasma concentration of 0.7 µg/ml within 23 minutes (Tmax) and high absolute bioavailability (78.9 %). Macrolides are characterised by their extensive partitioning into tissues. Accumulation at the site of respiratory tract infection is demonstrated by high and sustained tildipirosin concentrations in lung and bronchial fluid, which far exceed those in blood plasma. The mean terminal half life is approximately 9 days. In vitro binding of tildipirosin to bovine plasma and bronchial fluid proteins is limited with approximately 30 %. In cattle, it is postulated that metabolism of tildipirosin proceeds by cleavage of the mycaminose sugar moiety, by reduction and sulphate conjugation with subsequent hydration (or ring opening), by demethylation, by mono- or dihydroxylation with subsequent dehydration and by S-cysteine and S-glutathione conjugation. The mean total excretion of the total dose administered within 14 days was about 24 % in urine and 40 % in faeces.