Forcyl (Canada)

MICROBIOLOGY

The marbofloxacin mode of action is similar to that of other fluoroquinolones. Marbofloxacin acts directly on the bacterial DNA gyrase and topoisomerase IV by penetrating the bacterium by simple diffusion. Through irreversible and specific inhibition of the DNA supercoiling and replication, marbofloxacin causes death of the bacteria. Marbofloxacin has demonstrated in vitro and in vivo activity against Mannheimia haemolytica and Pasteurella multocida, and in vitro activity against Histophilus somni, the three major pathogenic bacteria associated with BRD. Marbofloxacin susceptibility has been demonstrated in Gram-negative aerobic bacteria (Enterobacteriaceae and Pasteurellaceae), including fastidious Gram-negative bacteria (Bordetella spp.). Enterobacteriaceae, such as Escherichia coli, Klebsiella spp., Proteus spp. and Salmonella spp., and Pseudomonaceae, such as Pseudomonas aeruginosa, have shown susceptibility. Gram-positive bacteria such as Staphylococcus aureus, Staphylococcus intermedius or other coagulase positive or negative bacteria have shown susceptibility. The clinical significance of these findings is not known.

Minimum inhibitory concentration (MIC) values of marbofloxacin for cattle respiratory disease bacterial pathogens isolated in 2014 during a Canadian clinical field trial were obtained. For Mannheimia haemolytica isolates (n=190), 78 (41%) and 110 (58%) of the isolates had an MIC of 0.02 µg/mL and 0.2 µg/mL, respectively (with two isolates that showed an MIC of 1 µg/mL and >2 µg/mL, respectively). For Pasteurella multocida isolates (n=72), 57 (79%) and 15 (21%) isolates had an MIC of 0.02 µg/mL and of 0.2 µg/mL, respectively.

ANIMAL SAFETY

The tolerance of Forcyl (160 mg/mL marbofloxacin solution for injection) was evaluated in young ruminant calves after intramuscular administrations at the recommended dose (10 mg/kg) or 3-fold the recommended dose (30 mg/kg) for an increased duration (3 days). The general tolerance of the 160 mg/mL marbofloxacin solution for injection administered at 3 times the recommended dose for an extended duration was good but induced some local injection site reactions. Following marbofloxacin administration whatever the dosage, tumefaction and gross lesions, but no heat or redness, were observed at injection sites in some animals. Pain was sometimes observed at the time of injection.

Cartilage necrosis with matrix lysis and subsequent erosion, ulceration, and fibrocartilage formation are well-documented changes associated with this class of compounds in juvenile animals of other species, such as dogs. At the proposed therapeutic dosage, 10 mg/kg in a single intramuscular injection, there was evidence of microscopic changes in cartilage, however there was no expression of clinical signs.

EFFICACY STUDIES

In order to assess the efficacy and the safety of Forcyl for the treatment of BRD under Canadian field conditions, 300 cattle were enrolled in a 2-site feedlot study taking place in Alberta and Quebec. 150 heads were enrolled at each site and evenly divided between (75 animals/site) the treatment and the negative control group.

To be included in the trial, the animals had to be ruminant cattle having at inclusion, signs of abnormal respiration AND general depression AND hyperthermia, i.e. rectal temperature ≥ 40°C.

In this randomized, blinded multi-centre trial, it was demonstrated that a single intramuscular injection of Forcyl (10 mg/kg of marbofloxacin) was significantly more effective than a negative control product (saline) in the treatment of BRD (associated with M. haemolytica and P. multocida) in Canadian bovine feedlots. Seven days post-treatment, 92% of the animals in the Forcyl group compared to 52% of the negative control group were deemed a treatment success (P < 0.05). Fourteen days post-treatment the animals treated with Forcyl continued to have a higher successful treatment rate (77%) than the animals in the negative control group (44%; P <0.05). Furthermore, Forcyl was well tolerated at injection site and during injection. Thus, Forcyl showed satisfactory efficacy and safety, in field conditions.

A European non-inferiority study was conducted with 231 ruminant cattle separated into two treatment groups, one receiving a single dose of 10 mg/kg of Forcyl by the intramuscular route and the other receiving the reference product, florfenicol (300 mg/mL) as a single 40 mg/kg subcutaneous dose. The animals were clinically monitored in parallel for 21 days. The success rates were high in both groups demonstrating acceptable efficacy in both treatment groups (success rate > 80%).