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