PHARMACOLOGICAL PROPERTIES
Pharmacotherapeutic group
antibacterials for systemic use, amphenicols, combinations.
ATCvet code: QJ01BA99.
Pharmacodynamic properties
Florfenicol is a synthetic broad spectrum antibiotic effective against most Grampositive and Gram-negative bacteria isolated from domestic animals. Florfenicol acts by inhibiting bacterial protein synthesis at the ribosomal level and is bacteriostatic.
Laboratory tests have shown that florfenicol is active against the most commonly isolated bacterial pathogens involved in bovine respiratory disease which include Mycoplasma bovis, Mannheimia haemolytica, Pasteurella multocida and Histophilus somni.
Florfenicol is considered to be a bacteriostatic agent, but in vitro studies of florfenicol demonstrate bactericidal activity against Mannheimia haemolytica, Pasteurella multocida and Histophilus somni.
Florfenicol bactericidal activity was characterised as essentially time dependant against the three target pathogens with the possible exception of H. somni where a concentration dependency was observed.
Surveillance data of the susceptibility of target field isolates from cattle, collected between 2009 and 2012 across Europe, show consistent efficacy of florfenicol with no finding of resistant isolates. The in vitro Minimum Inhibitory Concentration (MIC) values for these field isolates are presented in the table below.
Species | MIC50 (μg/ml) | MIC90 (μg/ml) |
Mannheimia haemolytica (n=149) | 1.0 | 1.0 |
Pasteurella multocida (n=152) | 0.5 | 0.5 |
Histophilus somni (n=66) | 0.25 | 0.25 |
Breakpoints have been established by the Clinical and Laboratory Standard Institute (CLSI VET08 ED4: 2018) for bovine respiratory pathogens as follows:
Pathogen | Florfenicol Disk Concentration (μg) | Diameter (mm) | MIC (ug/ml) |
S | I | R | S | I | R |
M.haemolytica P.multocida H.somni | 30 | ≥19 | 15-18 | ≤14 | ≤2 | 4 | ≥8 |
There are no established breakpoints for Mycoplasma bovis nor have culture techniques been standardized by CLSI. Despite a reduction in Mycoplasma bovis pathogen load, Mycoplasma bovis may not be fully eliminated from the lungs after treatment with the veterinary medicinal product.
Resistance to florfenicol is mainly mediated by an efflux system due to a specific (Flo-R) or multidrug transporter (AcrAB-TolC). The genes corresponding to these mechanisms are coded on mobile genetic elements such as plasmids, transposon or genes cassettes. Resistance to florfenicol in the target pathogens has only been reported on rare occasions, and was associated with efflux pump and the presence of the floR gene. Cross resistance with the third-generation cephalosporins is possible and has been observed in respiratory and digestive E. coli.
Flunixin meglumine is a non-steroidal anti-inflammatory drug with analgesic and antipyretic activity. Flunixin meglumine acts as a reversible non-selective inhibitor of cyclo-oxygenase (both COX 1 and COX 2 forms), an important enzyme in the arachidonic acid cascade pathway which is responsible for converting arachidonic acid to cyclic endoperoxides. Consequently, synthesis of eicosanoids, important mediators of the inflammatory process involved in central pyresis, pain perception and tissue inflammation is inhibited. Through its effects on the arachidonic acid cascade, flunixin also inhibits the production of thromboxane, a potent platelet pro-aggregator and vasoconstrictor which is released during blood clotting. Flunixin exerts its antipyretic effect by inhibiting prostaglandin E2 synthesis in the hypothalamus. Although flunixin has no direct effect on endotoxins after they have been produced, it reduces prostaglandin production and hence reduces the many effects of the prostaglandin cascade. Prostaglandins are part of the complex processes involved in the development of endotoxic shock.
Pharmacokinetic particulars
The administration of the product by the subcutaneous route at the recommended dosage of 40 mg/kg florfenicol maintained efficacious plasma levels in cattle above a MIC90 of 1 μg/mL for approximately 50 hours and above a MIC90 of 2 μg/mL for approximately 36 hours. Maximum plasma concentration (Cmax) of approximately 9.9 μg/mL occurred approximately 8 hours (Tmax) after dosing.
After administration of the product by the subcutaneous route at the recommended dosage of 2.2 mg/kg flunixin, peak plasma concentrations of 2.8 μg/mL were achieved after 1 hour.
The binding of florfenicol on proteins is approximately 20 % and for flunixin > 99 %. The degree of elimination of florfenicol residues in urine is approximately 68 % and in faeces approximately 8 %. The degree of elimination of flunixin residues in urine is approximately 34 % and for faeces approximately 57 %.