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Gamithromycin
A new azalide antibiotic for the treatment and control of Bovine
Respiratory Disease
Andy Forbes, BVM&S PhD MRCVS
Merial, Lyon, France
OutlineProduct Profile
ChemistryPharmacokineticsAntibacterial activityChallenge studies
European Field trialsRegistration
TreatmentPrevention (metaphylaxis)
Post-launch experiencesItalyFrance
Closing remarks
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
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
Antibacterial potency
Species (European strains)
n
MIC50 MBC50 MIC90s MBC90s
µg/ml
Mannheimia haemolytica 96 0.25 0.5 0.5 1
Pasteurella multocida 120 0.5 1 1 2
Histophilus somni 39 0.5 1 1 2
Lung Pharmacokinetics and in vitro Antibacterial activity
MIC mcg/ml 0.5 1.0
T> MIC 15 days 12 days
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
+
+
Therapeutic efficacy
Depression
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
+
+
Day-10Zactran
Day-5Zactran
Day-1Zactran
Day+1Saline
0
10
20
30
40
50
60
70
80
Treatment
Lung
Les
ion
Sco
re
1,00E+00
1,00E+01
1,00E+02
1,00E+03
1,00E+04
Zactran - 10 Zactran - 5 Zactran - 1 Saline +1
Lung lesion scores
Lung bacterial counts
Post-mortem lung bacteriology and pathology
Day -10 -5 -1 controlDay -10 -5 -1 control
Score: 74 Score: 14
Control Zactran Day -10
Lung lesions
European registration trials
European treatment studies
Sites Locations Breeds Total numbers
19 BelgiumFranceGermanyItaly
Belgian BlueBrown SwissCharolaisHolsteinLimousinMontbelliardSalersSimmentalX-breds
528
Non-ruminating Ruminating
230 298
2-24 weeks old 10-88 weeks old
43-169 kg 55-495 kg
Single injection of gamithromycin @ 6 mg/kgPositive control
Therapeutic studiesBRD inclusion criteria
Depression Score ≥1 andRespiratory Score ≥1 andRectal Temperature ≥40.0°C
European prevention studies
Sites Locations Breeds Total numbers
5 FranceGermanyItaly
AubracBlonde d’AquitaineCharolaisFleckviehLimousinSalerX-breds
802
Non-ruminating Ruminating
246 556
2-13 weeks old 28-92 weeks old
54-139 kg 152-582 kg
Single injection of gamithromycin @ 6 mg/kgSaline control
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 caseAt least one of the main pathogens was present, confirmed through culture of nasal swabs– Mannheimia haemolytica– Pasteurella multocida– Mycoplasma bovis
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
European post-launch trials
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)
Microbiology of controls Day 14
Not present on Day 0
Responses in animals treated with gamithromycin for BRD
1,6
4 4
0,8
3,2
0,8
3,2
4,8
1,6
4
1,6
6,4
1,6 1,6
0
1
2
3
4
5
6
7
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Control GamithromycinDay
Mo
rbid
ity r
ate
Morbidity rateControl 34%Gamithromycin 5%
Growth rate to Day 30Control 1.1 kg/dayGamithromycin 1.9 kg/day
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
Number of animals requiring re-treatment
1 1 1 1 1
2
1
2
1 1 1
0
0,5
1
1,5
2
2,5
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Tulathromycin Gamithromycin
Days after arrival
n° o
f a
nim
als
wit
h r
es
pir
ato
ry
dis
ea
se
re
lap
se
s
Re-treatment rateTulathromycin 82%Gamithromycin 31%
Animals moved to hospital penTulathromycin 28%Gamithromycin 0%
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
Methodology
167 young cattle 8 different sourcesMales et females4,5 to 11 months old188 to 420 kgLimousin and Charolais
Start March 09On arrival– Weighed– Vaccinated
• Rispoval RSV/BVD• Iffavax IBR
– Parasiticide• Ivomec D
Start of the study
4 days after arrival 13 animals had clinical BRDAll 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
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 2Group 3
By Day 8 – 26 animals treated in Group 3
Pattern of clinical cases in Group 3
Arrival Day -4
73% of cases within 1 week of arrival
Microbiology (PCR deep nasal swabs)
Résultats PCR du lot 1 à J 0 et J 14
60%
0%
100%100%
25% 25%
50%
100%
50%
20%
60%
20%
0%
20%
40%
60%
80%
100%
120%
Pou
rcen
tag
e d
e p
ools
posit
ifs
J 0 0% 20% 60% 20% 60% 0% 100%
J14 100% 25% 25% 50% 100% 50%
BVDMannheimia haemolytica
Pasteurella multocida
RSV PI3Mycoplasma
bovis
Coronavirus respiratoire
bovin
ResultsBy 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
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 normBRD control is not easy and results may be inconsistentIn addition to Management & Vaccination, Antibiotics can provide powerful tools to control BRD and treat clinical casesThe 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