1. Prophylaxis & Metaphylaxis in Veterinary Antimicrobial Therapy
ECOLE
NATIONALE
VETERINAIRE
T O U L O U S E
Prophylaxis & Metaphylaxis in Veterinary Antimicrobial Therapy
Alain Bousquet-Mélou
National Veterinary School, Toulouse, France
Tel Aviv May 2010

2. Antimicrobial resistance : from animals to humans
Treatment & prophylaxis
Veterinary
medicine
Human medicine
Community
Animal feed additives
Hospital
Agriculture
Plant protection
Environment
Industry

3. Antimicrobial resistance : from animals to humans
Antimicrobial resistance is an ineluctable adverse effect of antibiotics use
The association between the consumption of an antimicrobial agent and the occurrence of antimicrobial resistance is well established
The prudent use of antibiotics requires to reduce the overall consumption

4. Prudent use in relation with antimicrobial resistance
To target the major uses contributing to antibiotics consumption
Massive and collective administrations in food animals
Oral routes
Growth factor
prophylaxis
Metaphylaxis
Therapeutics
Prophylaxis and metaphylaxis are criticized
The use pf prophylaxis to counteract unhygienic routines or bad management is imprudent, and in some countries illegal
Metaphylaxis, where clinically healthy animals are treated along with their diseased “neighbours”, should be avoided
Ideally, only diseased animals should be treated and the treatment should be as individual as possible
GROWTH
(Ban in EU)
PREVENTION
CONTROL
THERAPY

5. Are prophylaxis and metaphylaxis the same type of use ?
when antibiotics are administered to a herd or flock of animals at risk of a disease outbreak
A measure taken to maintain health and prevent disease
A measure to protect against infection

6. Are prophylaxis and metaphylaxis the same type of use ?
when antimicrobials are administered to clinically healthy animals belonging to the same flock or pen as animals with clinical signs
infections are treated before their clinical appearance
“… a form of prophylaxis called metaphylaxis …”
“… the use of the term metaphylaxis is controversial …”
refers to situations where antimicrobials are used for both therapeutic and prophylactic purposes
refers to a particular form of prophylaxis in the presence of the pathogen with a high likelihood of disease

7. Are prophylaxis and metaphylaxis the same type of use ?
Phylaxis = PROTECTION
From phylax = guard, watchman
Arctophylaxis (Boote)
the « bear-driver »
(Ursus Minor, Ursus Major)
In relation with the start of the aggression
Pro - : before the aggression begins
Meta - : after the aggression begins

8. The time course of the bacterial disease
Start
of the
infectious disease
Health
Disease
No symptoms
Symptoms
Bacterial contamination / Host defenses
Growth of the initial inoculum

9. The time course of the bacterial disease
Start
of the
infectious disease
Health
Disease
No symptoms
Symptoms
PROPHYLAXIS
PREVENTIVE

10. The time course of the bacterial disease
Start
of the
infectious disease
Health
Disease
No symptoms
Symptoms
METAPHYLAXIS
(few)
EARLY
conventional
(few ?)
CURATIVE TREATMENT
PREVENTIVE

11. The time course of the bacterial disease
Metaphylaxis
“Metaphylaxis is treatment given to animals experiencing any level of (viral or) bacterial disease before overt disease occurs” (Young, 1995)
Metaphylaxis is an early curative treatment launched after the start of the disease (pathogen contamination, host defenses alteration) but before clinical expression with the goal of the bacteriological cure of the infected animals, which subsequently warrants the final protection against infection outbreaks
Metaphylaxis should be compared to “conventional” (later) curative treatments of sick animals, not to prophylaxis

12. Early versus later (conventional) treatments
Bacterial load at the infection site and pathophysiological status of the host are at the origin of differences in the responses to the drugs, at both pharmacodynamic and pharmacokinetic levels
Pharmacodynamics : bug-drug interactions
Inoculum size impacts both antimicrobial activity (bacteriological cure) and resistant bacteria selection

13. Early versus later (conventional) treatments
Clinical and microbiological cure ?
In vitro evidences of the effect of inoculum size on antimicrobial activity
In vivo evidences
Resistance selection/prevention at the infection site ?
Resistance selection/prevention in the gut flora ?

14. Inoculum size and antimicrobial activity
Inoculum effect on in vitro bacterial susceptibility assessment
Description in the literature since more than 40 years
Higher MICs when using high density bacterial inocula compared to the standard 105 CFU inocula (beta-lactams, fluoroquinolones …)
“Antibiotics with inoculum effects … administered empirically in clinical practice at a higher dose than the microbiological and pharmacokinetic data would indicate” Soriano et al. JAC 1990
Inoculum effect on in vitro antibacterial activity
Higher antibacterial activity against low versus high bacterial inoculum
Mizunaga et al. JAC 2005 ; Ferran et al. AAC 2007

15. Inoculum size and antimicrobial activity
Ciprofloxacin and imipenem against Staphylococcus aureus (Mizunaga et al. JAC 2005)
Marbofloxacin against Escherichia coli (Ferran et al. unpublished) 0%
20%
40%
60%
80%
100%
0.001
0.01
0.1
Concentrations (µg/mL)
Bactericidal effect (%)
Low
High
Interm.
105
109

16. Early versus later (conventional) treatments
Clinical and microbiological cure ?
In vitro evidences of the effect of inoculum size on antimicrobial activity
In vivo evidences
Resistance selection/prevention at the infection site ?
Resistance selection/prevention in the gut flora ?

17. Inoculum size and clinical or microbiological cure
Fluoroquinolones and beta-lactams against Staphylococcus aureus and Pseudomonas aeruginosa (Mizunaga et al. JAC 2005)
Intraperitoneal infection in mice
Doses associated with survival
Low
High
Low
High

18. Inoculum size and clinical or microbiological cure
Fluoroquinolone against Pseudomonas aeruginosa (Jumbe et al. JCI 2003)
Thigh infection in mice
Doses associated with log10 CFU reduction
Low
High
28 mg/kg
180 mg/kg

19. Inoculum size and clinical or microbiological cure
Marbofloxacin against klebsiella pneumoniae (Kesteman et al. AAC 2009)
Fractionated
Single
Early treatment
lung infection
105 CFU – 4h after
64 mg/kg
100 mg/kg
Fractionated
Single
Later treatment
lung infection
109 CFU – 24h after 2 4 6 8 10
Log10 CFU / Lung
16 mg/kg

20. Early versus later (conventional) treatments
Clinical and microbiological cure ?
In vitro evidences of the effect of inoculum size on antimicrobial activity
In vivo evidences
Resistance selection/prevention at the infection site ?
Resistance selection/prevention in the gut flora ?

21. Inoculum size and resistant mutant selection
In vitro evidence:
For the same exposure, the likelihood of resistant mutant selection is lower with a small inoculum: 105 versus 109 CFU/mL
Marbofloxacin against Escherichia coli: Ferran et al. AAC 2007
In vivo evidences:
Thigh infection in mice : marbofloxacin against Escherichia coli (Ferran et al. AAC 2009)
Lung infection in rats : marbofloxacin against Klebsiella pneumoniae (Kesteman et al. AAC 2009)

22. Percentages of rats with resistant. K
Percentages of rats with resistant* K. pneumoniae in their lungs 96h after the start of marbofloxacin treatment
* Growth in the presence of half MPC 0%
Fractionated
Single
Early treatment
105 CFU – 4h after
16 mg/kg
64 mg/kg
100 mg/kg
55%
70%
27%
50% 0%
Fractionated
Single
Later treatment
109 CFU – 24h after
100%
80%
60%
40%
20% 0%

23. Early versus later (conventional) treatments
Clinical and microbiological cure ?
In vitro evidences of the effect of inoculum size on antimicrobial activity
In vivo evidences
Resistance selection/prevention at the infection site ?
The same dose provides much better results for items 1 & 2 when given early before clinical signs
To reach “optimal” outcomes for items 1 and 2, (much more ?) lower doses are needed when given early to animals without clinical signs compared to sick animals
Reinforced by the work presented by A. Ferran

24. Early versus later (conventional) treatments
Clinical and microbiological cure ?
In vitro evidences of the effect of inoculum size on antimicrobial activity
In vivo evidences
Resistance selection/prevention at the infection site ?
Resistance selection/prevention in the gut flora ?

25. Critical bacterial flora for antimicrobial resistance
Digestive tract
AB: Oral route
Proximal
Distal
Resistant zoonotic pathogens (salmonella, campylobacter spp)
Commensal flora (resistance genes)
AB: Parenteral route
Food chain
Environment
PUBLIC HEALTH
HUMAN
Contact
genes flux
Infectious site
Pathogens of veterinary interest
ANIMAL HEALTH
Blood
Resistance
Therapeutic
failures

26. Critical bacterial flora for antimicrobial resistance
Digestive tract
AB: Oral route
Proximal
Distal
Resistant zoonotic pathogens (salmonella, campylobacter spp)
Commensal flora (resistance genes)
AB: Parenteral route
Infectious site
Pathogens of veterinary interest
ANIMAL HEALTH
Blood
Effects of early vs later treatments ?
Dose levels ?
Treatment duration ?

27. Early versus later (conventional) treatments
Bacterial load at the infectious site and pathophysiological status of the host are at the origin of differences in the responses to the drugs, at both pharmacodynamics and pharmacokinetics levels
Pharmacodynamics : bug-drug interactions
Inoculum size impacts both antimicrobial activity (bacteriological cure) and resistant bacteria selection
Pharmacokinetics : drug exposure
The disease impacts the relation between the dose and systemic exposure and is a source of variability of exposure between animals

28. Effects of infection on dose-exposure relation
Healthy versus sick animals
Review by Martinez & Modric JVPT 2010
Higher inter-individual variability in sick animals, increasing the likelihood of occurrence of under-exposure (Peyrou et al. JVPT 2004)
Low versus high inoculum
Ferran et al. AAC 2009
E. coli thigh infection in mice
Time (h)
Marbofloxacin (µg/mL)
0.0001
0.001
0.01
0.1 1 10 6 12 18 24
High inoculum
Low inoculum

29. To conclude
Favorables features of early treatments at the individual level
Higher antimicrobial activity and prevention of resistance : different doses
Probably more predictable dose-exposure relationships
Currently all regulatory PK, including for antibiotics, are obtained in healthy animals, which is irrelevant for severe infections but probably not for early treatments
Important questions to address when moving from early treatment to metaphylaxis
Heterogeneity of the treated group : effect of inter-individual variability ?
Bacterial load : what is the risk to under-expose high inocula ?
Collective (oral) treatments : influence of inter-individual variability of drug intake
Finally, whether metaphylactic setting (intervention at the group level) should really benefit to the potential advantages of early curative treatment (at the individual level) remains to be investigated, ideally in controlled clinical trials with special attention for dose levels and duration of treatments

30. Last remark
In term of risk communication it is probably better to promote the concept of early curative treatment in place of the misleading word of metaphylaxis

32. (size < mutation rate) (size >> mutation rate)
Inoculum size and resistant mutant selection
Low bacterial load
(size < mutation rate)
High bacterial load
(size >> mutation rate)
The same
dosage regimen
susceptible
population
resistant mutants
susceptible
population
resistant mutants
Resistant mutants prevention
Resistant mutants selection