Download metaphylaxis - Physiologie et Thérapeutique Ecole Véto Toulouse

ECOLE
NATIONALE
VETERINAIRE
TOULOUSE
Prophylaxis & Metaphylaxis in
Veterinary Antimicrobial
Therapy
Alain Bousquet-Mélou
National Veterinary School, Toulouse, France
Tel Aviv May 2010
AAVM-2010 1
Antimicrobial resistance : from animals to humans
Treatment & prophylaxis
Human medicine
Community
Hospital
Veterinary
medicine
Animal feed additives
Agriculture
Plant protection
Environment
Industry
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
AAVM-2010 3
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
GROWTH
prophylaxis
PREVENTION
Metaphylaxis
CONTROL
Therapeutics
THERAPY
(Ban in EU)
AAVM-2010 4
Are prophylaxis and metaphylaxis the same
type of use ?
Prophylaxis
– 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
AAVM-2010 5
Are prophylaxis and metaphylaxis the same
type of use ?
Metaphylaxis
– 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
AAVM-2010 6
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
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The time course of the bacterial disease
Health
Start
of the
infectious disease
Disease
No symptoms
Symptoms
Bacterial contamination / Host defenses
Growth of the initial inoculum
AAVM-2010 8
The time course of the bacterial disease
Health
Start
of the
infectious disease
No symptoms
Disease
Symptoms
PROPHYLAXIS
PREVENTIVE
AAVM-2010 9
The time course of the bacterial disease
Health
Start
of the
infectious disease
Disease
No symptoms
Symptoms
METAPHYLAXIS
(few)
EARLY
conventional
(few ?)
PREVENTIVE
CURATIVE TREATMENT
AAVM-2010 10
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
AAVM-2010 11
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
AAVM-2010 12
Early versus later (conventional) treatments
1. Clinical and microbiological cure ?
1. In vitro evidences of the effect of inoculum size on
antimicrobial activity
2. In vivo evidences
2. Resistance selection/prevention at the infection site ?
3. Resistance selection/prevention in the gut flora ?
AAVM-2010 13
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
AAVM-2010 14
Inoculum size and antimicrobial activity
• Ciprofloxacin and imipenem against Staphylococcus aureus
(Mizunaga et al. JAC 2005)
Bactericidal effect (%)
• Marbofloxacin against Escherichia coli (Ferran et al. unpublished)
100%
80%
Low
105
Interm.
High
60%
109
40%
20%
0%
0.001
0.01
0.1
Concentrations (µg/mL)
AAVM-2010 15
Early versus later (conventional) treatments
1. Clinical and microbiological cure ?
1. In vitro evidences of the effect of inoculum size on
antimicrobial activity
2. In vivo evidences
2. Resistance selection/prevention at the infection site ?
3. Resistance selection/prevention in the gut flora ?
AAVM-2010 16
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
AAVM-2010 17
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
AAVM-2010 18
Inoculum size and clinical or microbiological cure
• Marbofloxacin against klebsiella pneumoniae
(Kesteman et al. AAC
2009)
Log10 CFU / Lung
10
Early treatment
lung infection
105 CFU – 4h after
Later treatment
lung infection
109 CFU – 24h after
8
6
4
2
Fractionated
Single
16 mg/kg
Fractionated
64 mg/kg
100 mg/kg
Single
AAVM-2010 19
Early versus later (conventional) treatments
1. Clinical and microbiological cure ?
1. In vitro evidences of the effect of inoculum size on
antimicrobial activity
2. In vivo evidences
2. Resistance selection/prevention at the infection
site ?
3. Resistance selection/prevention in the gut flora ?
AAVM-2010 20
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)
AAVM-2010 21
Percentages of rats with resistant* K. pneumoniae in their
lungs 96h after the start of marbofloxacin treatment
* Growth in the presence of half MPC
Early treatment
105 CFU – 4h after
100%
Later treatment
109 CFU – 24h after
80%
70%
60%
55%
50%
40%
27%
20%
0%
0%
0%
Fractionated
16 mg/kg
0%
Single
Fractionated
64 mg/kg
0%
Single
100 mg/kg
AAVM-2010 22
Early versus later (conventional) treatments
1. Clinical and microbiological cure ?
1. In vitro evidences of the effect of inoculum size on
antimicrobial activity
2. In vivo evidences
2. 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
AAVM-2010 23
Early versus later (conventional) treatments
1. Clinical and microbiological cure ?
1. In vitro evidences of the effect of inoculum size on
antimicrobial activity
2. In vivo evidences
2. Resistance selection/prevention at the infection site ?
3. Resistance selection/prevention in the gut flora ?
AAVM-2010 24
Critical bacterial flora for antimicrobial resistance
AB: Oral route
Proximal
Digestive tract
Distal
• Resistant zoonotic pathogens (salmonella,
campylobacter spp)
• Commensal flora (resistance genes)
AB: Parenteral route
Blood
Food chain
Contact
Environment
genes flux
Infectious site
Pathogens of veterinary interest
ANIMAL HEALTH
HUMAN
Resistance
Therapeutic
failures
PUBLIC HEALTH
AAVM-2010 25
Critical bacterial flora for antimicrobial resistance
AB: Oral route
Proximal
Digestive tract
Distal
• Resistant zoonotic pathogens (salmonella,
campylobacter spp)
• Commensal flora (resistance genes)
AB: Parenteral route
Blood
Infectious site
Pathogens of veterinary interest
Effects of early vs later
treatments ?
• Dose levels ?
• Treatment duration ?
ANIMAL HEALTH
AAVM-2010 26
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
AAVM-2010 27
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
Marbofloxacin (µg/mL)
•
10
1
0.1
0.01
High inoculum
0.001
0.0001
Low inoculum
0
6
12
Time (h)
18
24
AAVM-2010 28
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
AAVM-2010 29
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
AAVM-2010 30
AAVM-2010 31
Inoculum size and resistant mutant selection
Low bacterial load
High bacterial load
(size < mutation rate)
(size >> mutation rate)
susceptible
population
The same
dosage regimen
resistant mutants
population
Resistant mutants prevention
susceptible
population
resistant mutants
population
Resistant mutants selection
AAVM-2010 32