Antibacterials for systemic use

Florfenicol is a synthetic broad-spectrum antibiotic effective against most Gram-positive and Gram-negative bacteria isolated from domestic animals. Florfenicol acts by inhibiting protein synthesis at the ribosomal level and is bacteriostatic and time-dependent. Laboratory tests have shown that florfenicol is active against the most commonly isolated bacterial pathogens involved in bovine respiratory disease which include 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.

For Mannheimia haemolytica, Pasteurella multocida and Histophilus somni the following breakpoints have been determined for florfenicol in bovine respiratory disease: susceptible: ≤2 µg/ml, intermediate: 4 µg/ml, resistant: ≥8 µg/ml.

Resistance to florfenicol is mainly mediated by an efflux system due to specific (flo-R) or multidrug transporters (AcrAB-TolC). The genes corresponding to these mechanisms are coded on mobile genetic elements such as plasmids, transposons or genes cassettes.

Surveillance data of the susceptibility of target field isolates from cattle collected between 1995 and 2009 across Europe show a constant activity of florfenicol with no finding of resistant isolates. In the recent literature, one resistant isolate of P. multocida was reported from a calf in Germany in 2007 harbouring a plasmid mediated flo-R. No co-resistance to other antibiotic families was observed. Cross-resistance with chloramphenicol can occur.

Resistance to florfenicol and other antimicrobials has been identified in the food-borne pathogen Salmonella typhimurium and co-resistance with the third-generation cephalosporins has been observed in respiratory and digestive Escherichia Coli. This has not been observed for the target pathogens.

After parenteral application florfenicol is mainly excreted via urine and to a small extent via faeces, mainly as parent compound but also followed by florfenicol amine and florfenicol oxamic acid.

The administration of the product by the subcutaneous route at the recommended dose of 40 mg/kg maintained efficacious plasma levels of florfenicol in cattle above the MIC90 of 0.5 µg/ml and 1.0 µg/ml for 90.7 hours and 33.8 hours, respectively. Maximum mean serum concentration (Cmax) of 1.8 µg/ml occurred 7 hours (Tmax) after dosing.

The administration of the product by the intramuscular route at the recommended dose of 20 mg/kg maintained efficacious plasma levels of florfenicol in cattle above the MIC90 of 0.5 µg/ml and 1.0 µg/ml for 48.7 hours and 30.3 hours, respectively. Maximum mean serum concentration (Cmax) of 3.0 µg/ml occurred 6 hours (Tmax) after dosing.