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Gamithromycin

Gamithromycin. A new azalide antibiotic for the treatment and control of Bovine Respiratory Disease. Andy Forbes, BVM&S PhD MRCVS Merial, Lyon, France. Outline. Product Profile Chemistry Pharmacokinetics Antibacterial activity Challenge studies European Field trials Registration

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Gamithromycin

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  1. Gamithromycin A new azalide antibiotic for the treatment and control of Bovine Respiratory Disease Andy Forbes, BVM&S PhD MRCVSMerial, Lyon, France

  2. Outline • Product Profile • Chemistry • Pharmacokinetics • Antibacterial activity • Challenge studies • European Field trials • Registration • Treatment • Prevention (metaphylaxis) • Post-launch experiences • Italy • France • Closing remarks

  3. Gamithromycin is an Azalide • Azalides have a core 15-membered nitrogen-containing lactone ring • Azalide chemistry • Marked tissue affinity • Extensive uptake by cells • Broad antibacterial spectrum

  4. Pharmacokinetics Gamithromycin is rapidly absorbed from the injection site and is re-distributed to tissues and cells, where it persists for many days at effective concentrations • Gamithromycin is present in the bronchioalar macrophages at concentrations >60x those in plasma within 6 hours of administration • Gamithromycin is present in the lungs at concentrations >100x those in plasma for >20 days after administration

  5. Antibacterial potency

  6. Lung Pharmacokinetics and in vitro Antibacterial activity

  7. Therapeutic efficacy M.haemolytica challenge • Cattle ~8 months old, mixed breed & sex • Challenge Day 0 • Mannheimia haemolytica • MIC 0.5 mcg/ml • 3.03 x 1010 cfu • Treatment on Day 1 • Saline • Gamithromycin @ 6 mg/kg + +

  8. Therapeutic efficacy Depression

  9. Preventive efficacy M.haemolytica challenge • Dairy calves <3 months old, mixed breed & sex • Treatment Days -10, -5 & -1 • Gamithromycin @ 6 mg/kg • Challenge Day 0 • Mannheimia haemolytica • MIC 1.0 mcg/ml • 1.0 x 108 cfu • Treatment on Day +1 • Saline + +

  10. Post-mortem lung bacteriology and pathology Lung bacterial counts Day -10 -5 -1 control Day -10 -5 -1 control Lung lesion scores

  11. Lung lesions Control Zactran Day -10 Score: 14 Score: 74

  12. European registration trials

  13. European treatment studies • Single injection of gamithromycin @ 6 mg/kg • Positive control

  14. Therapeutic studiesBRD inclusion criteria • Depression Score ≥1 and • Respiratory Score ≥1 and • Rectal Temperature ≥40.0°C

  15. European prevention studies • Single injection of gamithromycin @ 6 mg/kg • Saline control

  16. Prevention studiesBRD inclusion criteria • Cattle sharing an air-space where ≤10 animals had BRD • >5% of cattle sharing an air-space had BRD within 3 days of the first case • At least one of the main pathogens was present, confirmed through culture of nasal swabs • Mannheimia haemolytica • Pasteurella multocida • Mycoplasma bovis

  17. European Field Trials on Undifferentiated BRD • Bacteria present • Mannheimia haemolytica • Pasteurella multocida • Histophilus somni • Mycoplasma bovis • Viral status • Not identified • Some farms had used viral vaccines • Response to singles/c injection of gamithromycin at 6 mg/kg) • Therapeutic • 82% Success Rate • Control (metaphylactic) • 86%Success Rate Treatment Success • Depression Score <1 • Respiratory Score <1 • Rectal Temperature <40.0°C Prevention Success • Depression Score 0 • Respiratory Score 0 • Rectal Temperature >40.0°C

  18. European post-launch trials

  19. Italian prevention trial • Animals: 250 Charolais males • Zactran group • 125 animals - 349 Kg • Control group(no treatment) • 125 animals – 353 Kg • Arrival date: October 29 • Respiratory vaccination on arrival • IBR/PI3+RSV+M. haemolytica • Start of the trial: October 30 • Microbiology • Single treatment with gamithromycin 6mg/kg (1ml/25kg)

  20. Microbiology of controls Day 14 Not present on Day 0

  21. Responses in animals treated with gamithromycin for BRD Morbidity rate Control 34% Gamithromycin 5% Growth rate to Day 30 Control 1.1 kg/day Gamithromycin 1.9 kg/day

  22. Italian therapeutic trial • Animals: 24 Limousin females with severe respiratory disease • Gamithromycin group • 13 animals – 258±32 Kg • Tulathromycin group • 11 animals – 259±33 Kg • Arrival date: December 1 • Respiratory vaccination on arrival • IBR+PI3+BVD+RSV

  23. Number of animals requiring re-treatment Re-treatment rate Tulathromycin 82% Gamithromycin 31% Animals moved to hospital pen Tulathromycin 28% Gamithromycin 0%

  24. Practical ‘System’ approach, France • Objective • Evaluate the therapeutic efficacy and the practicality & profitability of group metaphylaxis and individual treatments with gamithromycin. • Economic factors included • Costs of treatment • Costs of handling • Growth rate

  25. Methodology • 167 young cattle • 8 different sources • Males et females • 4,5 to 11 months old • 188 to 420 kg • Limousin and Charolais • Start March 09 • On arrival • Weighed • Vaccinated • Rispoval RSV/BVD • Iffavax IBR • Parasiticide • Ivomec D

  26. Start of the study • 4 days after arrival 13 animals had clinical BRD • All animals were then divided into 3 groups • Group 1 : 13 sick • Day 0: Gamithromycin + ketoprofen • Group 2 : 62 animals* metaphylaxis • Day 0: Gamithromycin • Group 3 : 92 animals treated on a case-by-case basis • Day n: Gamithromycin + ketoprofen *high risk, lower live weight, mainly Limousin heifers

  27. Allocation • 16 pens, 8 each side of the central passage • One side • Group 1: 2 pens for sick animals (13) • Group 2: 6 pens for metaphylactic group (62) • Other side • Group 3: 8 pens for case-by-case treatment (92) Group 1 Group 3 Group 2

  28. By Day 8 – 26 animals treated in Group 3

  29. Pattern of clinical cases in Group 3 Arrival Day -4 73% of cases within 1 week of arrival

  30. Microbiology (PCR deep nasal swabs)

  31. Results • By Day 14 all animals in all groups were clinically normal • No animals in any group required re-treatment • BRD challenge appeared high • 28% new cases within 8 days in untreated animals • Mixture of common BRD pathogens • Mannheimia haemolytica and Mycoplasma bovis predominated by Day 14 • Growth performance and full economic analysis to follow

  32. Concluding Remarks • BRD remains a common disease • Bovine Lung anatomy & physiology, breed & genetics • Pathogens are numerous, diverse and ubiquitous • Predisposing factors are part of normal cattle husbandry • Moving, mixing, crowding • BRD is a complex disease because it is multifactorial, in every sense of the word & variability is the norm • BRD control is not easy and results may be inconsistent • In addition to Management & Vaccination, Antibiotics can provide powerful tools to control BRD and treat clinical cases • The introduction of a dual-purpose antibiotic that provides good therapeutic activity and prolonged protective efficacy after a single treatment can deliver obvious benefits to the animal, the farmer and the veterinarian

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