1. The prudent use of antibiotics in veterinary medicine: the right drug, the right time, the right dose & the right duration of treatment
P.L. Toutain
National Veterinary School ; Toulouse, France
The Bunge y Born foundation, 18th November 2011
Tandil, Argentina

2. The priorities of a sustainable veterinary antimicrobial therapy is related to public health issues, not to animal health issues: Why?

3. Medical consequences of antimicrobial resistance

4. The antibiotic ecosystem: One world, One health
Treatment & prophylaxis
Veterinary
medicine
Human medicine
Community
Animal feed additives
Hospital
Agriculture
Plant protection
Environment
Industry

5. Prevent emergence of resistance: but of what resistance?

6. Emergence of resistance for Salmonella typhimurium DT104 in UK to quinolones following the market autorisation of enrofloxacin
Stöhr & Wegener, Drug resistance Updates, 2000, 3:

7. Commensal bacteria: transmission of resistance genes from animal to man:

8. Horizontal genes exchanges (BLSE) in the gut
The gut is the main animal ecosystem in which veterinary antibiotics are able to promote resistance in man

9. Gut flora & antimicrobial resistance
G.I.T
Proximal
Distal
AB: oral route
1-F%
Gut flora
Zoonotic (salmonella, campylobacter
commensal ( enterococcus)
Résistance = public health concern
Food chain
Environmental exposure F%
Blood
Target biophase
Bug of vet interest
Résistance = lack of efficacy

10. Gut flora & antimicrobial resistance
Gastrointestinal tract
Proximal
Distal
Gut flora
Zoonotic (salmonella, campylobacter
commensal ( enterococcus)
Intestinal secretion
Bile
Quinolones
Macrolides
Tétracyclines
Food chain
Systemic Administration
Environment
Blood
Biophase
Target pathogen
Résistance =public health issue
Résistance = lack of efficacy

11. The aim was to assess the impact of 3 ampicillin dosage regimens on ampicillin resistance among Entrobacteriaceae recovered from swine feces and on the excretion in feces of the blaTEM gene

12. Result: Percent of ampicillin-resistant Enterobacteriaceae for each mode of administration

13. Hazard associated to the release of antibiotic in environment

14. Air, water & ground pollution
Fate of antibiotics, zoonotic pathogens and resistance genes: residence time in the different biotopes
Lagoon: few weeks
Digestive tract: 48h
Ex:T1/2 tiamuline=180 days
Bio-aérosol
Air, water & ground pollution
Air pollution

15. What are the solutions to these critical issues
No or few solution for the veterinarians
For mastistis, use local intramammary treatment, not systemic treatment
We need innovations from pharmaceutical companies

16. Innovation: PK selectivity of antibiotics
G.I.T
Proximal
Distal
AB: oral route 0%
Gut flora
Zoonotic (salmonella, campylobacter
commensal ( enterococcus)
100%
Food chain
environment
Blood
Kidney
Biophase
Résistance = public health concern
Animal health

17. Innovation: PK selectivity of antibiotics
G.I.T
Proximal
Distal
Gut flora
Zoonotic (salmonella, campylobacter
commensal ( enterococcus)
Food chain
AB: IMroute
Quinolones, macrolides
environment
Blood
Kidney
Biophase
Résistance = public health concern
Animal health

18. Judicious, prudent,responsible sustainable… use of antibiotics

19. 1- No misuse

20. An example of misuse: in ovo administration of ceftiofur

21. Correlation between the prévalence of chicken meat contaminated by E
Correlation between the prévalence of chicken meat contaminated by E.coli and Salmonella enterica résistant to ceftiofur and human infection to resistant Salmonella Heidelberg (r=0.91 pour Salmonella)
Salmonella Heidelberg
Salmonella
enterica
E Coli

22. Effect of the withdrawal of ceftiofur in hatchery
Salmonella Heidelberg
Salmonella
E Coli

23. 2- No overuse

24. Human and veterinary antibiotic usage: US vs EU
Source: UCS 2000
Source: FEDESA 2001

25. No overuse means no antibiotics as growth promotor

26. we have evidence that market introduction of generics or of “me-too’ drugs has influence on antibiotic consumption;

27. Generics for antibiotics (quinolones) : conclusions

28. Generics and antibiotic consumption

29. Use of fluoroquinolones in veterinary medicine: Germany, DK, UK
From Hellmann: Assoc Vet Consult. SAGAM 2005

30. From Hellmann: Assoc Vet Consult. SAGAM 2005
Use of fluoroquinolones in veterinary medicine: Eastern EU, Spain, Portugal
From Hellmann: Assoc Vet Consult. SAGAM 2005

31. Issues associated to ‘generics’ that are not bioequivalence

32. Non-bioequivalence of various trademarks of enrofloxacin in cow
Sumano & al 2001 Dtsch tierärztl Wschr

33. 3-The right drug

34. Old or more recent drugs?
Many recommendations to establish list of essential antibiotics for human medicine
Where is the science demonstrating the benefit in terms or resistance to only use old antibiotics in veterinary medicine?

35. For three antibiotic classes (quinolones, cephalosporins and carbapenems), it was observed that the less active drugs could be worse at hastening the spread of resistance than more active drugs in the same class.
This led the authors to qualify the (WHO) stratagem of recommending the use of old antibiotics as part of microbiological folklore.

36. How a vet can select the best drug amongst competitors (the so-called me-too) for pulmonary infection?

37. Tulathromycine,Draxxin (Pfizer) Tilmicosine, Micotil (Elanco)
Amongst the different macrolides marketed for treatment and prevention of bovine respiratory disease (BRD) associated with Mannheimia haemolytica, Pasteurella multocida, Histophilus somni diseases, what is the best one?
Tulathromycine,Draxxin (Pfizer)
Tilmicosine, Micotil (Elanco)
Gamithromycine, Zactran (Merial)
Tildipirosin, Zuprevo (Intervet)

38. The need of comparative clinical trials for the newest antibiotics

39. Currently, antibiotics are compared only by non-inferiority trials

40. Draxxin vs. Micotil by Pfizer
Micotil vs . Draxxin by Elanco

41. Draxxin vs Micotil by Pfizer
Take home message:
Draxxin superior to Micotil P<0.00x
Micotil vs . Draxxin by Elanco
Take home message:
Micotil not significantly different of Draxxin for most endpoints (P>0.05) but Micotil is more cost-effective (CAN$8/animal) and the lower initial BRD treatment costs in the DRAX group did not offset the higher metaphylactic cost of DRAX

42. 4-The right time to start a treatment

43. The different modalities of antimicrobial therapy
Disease
health
Antibiotic consumption
Metaphylaxis
(Control)
Prophylaxis
(prévention)
Growth promotion
Therapy
High
Pathogen load
Only a risk factor No
Small NA

45. A mouse model to compare metaphylaxis and curative treatment
anorexia lethargy dehydration
no clinical signs of infection
100
102
104
106
108
1010
Progression of infection
Bacteria counts per lung (CFU/lung)
Inoculation of Pasteurella multocida
1500 CFU/lung 10 20 30 40 50
Time (h)
Late (32h)
Administration
early (10h)
Administration

46. Early administrations were more favourable than late administrations
What we demonstrated
For a same dose of marbofloxacin, early treatments (10 hours after the infection) were associated to
more frequent clinical cure
more frequent bacteriological cure
less frequent selection of resistant bacteria
than late treatments (32 hours after the infection)
Early administrations were more favourable than late administrations

47. 5-The right dose for efficacy

48. Why to optimize dosage regimen for antibiotics
To optimize efficacy
Reduce the emergence and selection of resistance

49. How to find and confirm a dose (dosage regimen)
Dose titration
Animal infectious model
PK/PD
Clinical trials

50. Dose titration for antibiotic using infectious model
Response
clinical
Black box
Dose titration for antibiotic using infectious model
PK/PD PK PD
Body
pathogen
Dose
response
Plasma
concentration

51. Why plasma concentrations rather than the dose for an antibiotic ?

52. Most of our pathogens are located in extracellular fluids
(in phagocytic cell most often)
mycoplasma (some)
chlamydiae
Cryptosporidiosis
Salmonella
Rhodococcus equi
Extra Cellular Fluid
Most bacteria of clinical interest
- respiratory infection
- wound infection
- digestive tract inf.
Bug
Free plasma concentration is equal to free extracellular concentration

53. Do not confuse science, marketing and and propaganda

54. PK/PD indices as indicator of antibiotic efficacy

55. AUC/MIC: quinolones; macrolides
It has been developed surrogates indices (predictors) of antibiotic efficacy taking into account MIC (PD) and exposure antibiotic metrics (PK)
Practically, 3 indices cover all situations:
AUC/MIC: quinolones; macrolides
Time>MIC: Penicillins, cephalosporins
Cmax/MIC: aminoglycosies
We know the average critical values to achieve for theses indices to cure animals and we can compute the appropriate doses

56. To compute a dose, we have to take into account inter-animal variability using population approaches

57. PK Variability
Doxycycline
n = 215

58. PD variability: MIC distribution Pasteurella multocida (n=205)40 35 30
Pathogens % 25 20 15 10
SUSCEPTIBLE 5
0.0625
0.125
0.25
0.5 1 2 4
MIC ( m
g/mL)

59. Monte Carlo simulations
The goal of population kinetics is to document sources of variability to determine a dosage regimen controlling a given quantile (e.g. 90%) of a population and not an average dosage regimen
Monte Carlo simulations

60. 6-The right dose to prevent resistance

61. Traditional explanation for enrichment of mutants
Concentration
MIC
Selective Pressure
Time

62. Mutant Prevention Concentration (MPC) and the Selection Window (SW) hypothesis
This lecture was prepared on April 5, Literature cited is listed as a note to the last slide.

63. Blocking Growth of Single Mutants Forces Cells to Have a Double Mutation to Overcome Drug
Without antibiotics
10-8
single mutant population
10-8
Wild pop
With antibiotics
10-8
single mutant population
Wild population éradication
sensible
single mutant
Double mutant

64. The selection window hypothesis
Mutant prevention concentration (MPC)
(to inhibit growth of the least susceptible, single step mutant)
MIC
Selective concentration (SC)
to block wild-type bacteria
Plasma concentrations
Mutant selection window
All bacteria inhibited
Growth of only the most resistant subpopulation
Growth of all bacteria

65. Mutants are not selected at concentrations below MIC or above the MPC
For emphasis we restate that as a rule mutants are not selectively enriched at drug concentrations below MIC. As an aside, we note some selective pressure exists at concentrations below the standard MIC because it measures inhibition of growth of a large number of cells (100,000). Indeed, some enrichment of mutants does occur upon repeated serial passage of a strain (6). These data stress that the bottom boundary of the window can be fuzzy. That is why we define it to be MIC(99), the minimal concentration that blocks growth of 99% of the cells in a culture. MIC(50) would be a more precise lower boundary, but it is more difficult to determine experimentally.

66. 7-The right duration of a treatment

67. Duration of treatment The shortest as possible
Many epidemiological evidences that the likelihood of resistance increase with the duration of treatment

68. Conclusion: for a rational antibiotic use, what is the priority?
Environmental safety
operator safety
consumer safety
resistance in non-target pathogens (salmonella, campylobacters)
Transfer of resistance genes
target animal safety
efficacy
resistance in target pathogens

69. Bourgelat & the first veterinary school in the world at Lyon

70. Toulouse & El Francesito
Born here on the 11th Dec 1890

71. Toulouse: Rugby, Vet School and Airbus
Vet School campus