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

5. Antibacterial potency Species (European strains) n MIC 50 MBC 50 MIC 90s MBC 90s µg/ml Mannheimia haemolytica 96 0.250.5 1 Pasteurella multocida1200.5112 Histophilus somni390.5112

6. Lung Pharmacokinetics and in vitro Antibacterial activity MIC mcg/ml0.51.0 T> MIC15 days12 days

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 10 10 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 10 8 cfu Treatment on Day +1 –Saline + +

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

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

12. European registration trials

13. European treatment studies SitesLocationsBreedsTotal numbers 19Belgium France Germany Italy Belgian Blue Brown Swiss Charolais Holstein Limousin Montbelliard Salers Simmental X-breds 528 Non-ruminatingRuminating 230298 2-24 weeks old10-88 weeks old 43-169 kg55-495 kg Single injection of gamithromycin @ 6 mg/kg Positive control

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

15. European prevention studies SitesLocationsBreedsTotal numbers 5France Germany Italy Aubrac Blonde d’Aquitaine Charolais Fleckvieh Limousin Saler X-breds 802 Non-ruminatingRuminating 246556 2-13 weeks old28-92 weeks old 54-139 kg152-582 kg Single injection of gamithromycin @ 6 mg/kg Saline control

16. Prevention studies BRD 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 single s/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 Control34% Gamithromycin5% Growth rate to Day 30 Control1.1 kg/day Gamithromycin1.9 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 Tulathromycin82% Gamithromycin31% Animals moved to hospital pen Tulathromycin28% 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 2 Group 3

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