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The ideal antimicrobial in
veterinary medicine
Pierre-Louis Toutain
Ecole Nationale Vétérinaire de Toulouse &
INRA,
Toulouse, France
SEPTEMBER 30 - 2 OCTOBER 2015, COPENHAGEN DENMARK
Do we need “new” antibiotics in
veterinary medicine?
• From an animal health perspective: No
– Currently, no major animal health issues
• But with exception (e.g. persisters, biofilm… for chronic
infection in pets)
– Cascade is possible
• From a public health perspective: Yes
– We urgently need new antibiotic to manage the
link between the human and the veterinary
resistome by decreasing our contribution to the
overall pool of genes of resistance
The antibiotic ecosystem:
one world, one health, one resistome
New antibiotics
Treatment & prophylaxis
Veterinary
medicine
Human medicine
Community
Hospital
Animal feed additives
Agriculture
Plant protection
Environment
Industry
A major review
What is an ideal antibiotics
Nature Drug Discovery 2013
The ideal antibiotic
1. A prodrug enters the cell, where it is converted into a reactive compound
by a bacteria-specific enzyme (E).
2. The reactive moiety covalently attaches to unrelated targets (T1, T2 to Tx),
killing both actively dividing and dormant cells, thus sterilizing an infection.
3. Covalent binding to targets provides an irreversible sink, leading to
effective accumulation of the active drug over time and ensuring a broad
specificity of action. MDR, multidrug-resistant.
Using multiple agents with differing modes
of action is necessary for intractable
infections such as TB and HIV, and we now
turn this approach on bacterial infections
Not to extent the spectrum or to increase
efficacy but to prevent emergence of resistance
EU guidelines against combinations
for veterinary medicine (Sep 2015)
The priority for the rationale development of
new AMDs in vet medicine is to take into
account public health issues,
Because the concept of prudent use
of AMD has many shortcomings
The prudent use of antibiotics
Most
recommendations
are copy and paste
from human
medicine
Doing that we
may inflate the
public health
issues
New Eco-Evo drugs and strategies should
be considered when developing new AMD
No impact on gut flora
No release of active substances in the environment
« New » natural history of bacterial infections
Commensal flora of a
future patient (1kg)
Disease
Colonization/carriage
Gene of resistance
ESBL, CTX-M…
Dissemination of gene of resistance
Dissemination of
genes of resistance
Adapted from Andremont et al, The lancet infection 2011 11 6-8
Specific pathogen
Link Man/Animal
AMR slould be viewed as an ecological problem with the animal
and human commensal flora as the turntable of the system
Commensal flora
Genes of resistance
Environment
(zoonotic pathogens)
Food chain
Commensal
flora
Although there are many other potential routes of
human exposure to antimicrobial-resistant bacteria
(e.g. via general environmental contamination) it is
currently difficult to attribute the resistance to use of
VMPs and these routes are not within scope of this
guidance
Where are manufactured genes
of resistance having a public
health impact
Bacterial load exposed to antibiotics
during a treatment
Test
tube
1µg
Infected
Lungs
mg
Digestive
tract
Kg
Food chain
Manure
waste
Tons
Soil, plant….
Duration of exposure of bacteria exposed to
antibiotics
Manure
Digestive
Infected
Test
Sludge
tract
Lungs
tube
waste
24h
few days
Several weeks/months
Food chain
Soil, plant….
An ideal AMD in veterinary medicine
should not be release in its active
form in the environment
Principles of solution
What could be the ideal
pharmacodynamic
pharmacokinetic & profile for a
veterinary antibiotic to minimize
the public health issues
The 3 PD parameters
ED50
Emax
Emax 1
Emax 2
1
G+ vs G-
1
2
2
ED501 ED502
Efficacy
Potency
• Selectivity
A major misconception:
To develop in veterinary
medicine antibiotics with the
highest as possible potency
Potency of Fluoroquinolones
Hydrophobicity vs MIC for S aureus
128
64
MIC (µg/mL)
32
y = 26.757e-2.297x
R² = 0.6764
16
8
4
MIC SA
2
Expon. (MIC SA)
1
0.5
0.25
0.125
0.0625
-0.5
0
Takenouchi et al AAC 1996
0.5
1
1.5
Hydrophobicity (Clog-P)
2
2.5
Potency of fluoroquinolones
Hydrophobicity vs MIC for E coli
8.00E+00
4.00E+00
y = 1.154e-2.003x
R² = 0.3719
2.00E+00
MIC µg/mL
1.00E+00
5.00E-01
2.50E-01
1.25E-01
MI E coli
6.25E-02
Expon. (MI E coli)
3.13E-02
1.56E-02
7.81E-03
3.91E-03
1.95E-03
9.77E-04
-0.5
0
0.5
1
1.5
Hydrophobicity (Clog-P)
Takenouchi et al AAC 1996
2
2.5
Fluoroquinolones:
XLog-P3 vs. impact on gut flora
Impact gut microbiome
3.50
Major impact
3.00
2.50
y = 0.6708x + 1.9128
R² = 0.4597
2.00
1.50
1.00
Minimal impact
0.50
Veterinary FQ
0.00
-2
-1
0
1
2
Hydrophobicity (Xlog-P)
3
Impact gut microbiome
Cephalosporins
XLog-P vs. impact on gut flora
3.5
3
y = 0.4972x + 2.1543
R² = 0.3397
2.5
2
1.5
1
0.5
0
-4
-3
-2
-1
0
1
2
-0.5
-1
-1.5
-1
Xlog-P
Veterinary
cephalosporins
Selectivity of antimicrobial drugs
Selectivity
PD
PK
Large vs Narrow
spectrum
Selective distribution of
the AB to its biophase
PK selectivity : oral route
Trapping ,
inactivation
(betalactamase)
AB: oral route
Proximal
Distal
microbiome
1-F=0%
•Zoonotics
•commensal
Food chain
Environment
Blood
Biophase
Target pathogen
Renal
elimination
=100%
Objective :
Improve the oral bioavailability for
oral antibiotics
How to increase bioavailability
• A conflict of interest between factor favoring a
high bioavailability (rather lipophilic) and
penetration in a bacteria (rather hydrophilic)
• The Lipinski’s ‘rule of five’, does not apply for
antibiotics
• The prodrug approach
The prodrug approach
• Prodrug antibiotics which are not active
against the bacteria in the mouth and the
intestine (before absorption) and which are
not excreted to a significant degree via the
intestine, saliva or skin are therefore
preferred.
– Prodrugs such as pivampicillin, bacampicillin,
pivmecillinam and cefuroxime axetil are
favourable from an ecological point of view.
Desirable pharmacokinetic
properties for antibiotic
administered by the non-oral
route in food producing animals
PK selectivity: systemic route
Trapping, inactivation
Proximal
Distal
microbiome
•Zoonotics
•commensal
Biliary & intestinal
clearance=0
Food chain
Administration
Environment
Blood
Target pathogen
Renal
elimination
=100%
The % of urinary excretion decreased or fecal excretion
increased with increasing octanol±water partition coeffcient,
especially for the drugs with C log P>0
• The more hydrophobic is a drug, the more
likely it is to be excreted in the feces.
How to get a long Half-life
a Long HL
Formulation
Substance
(e.g. old AMD)
(new AMD)
High clearance
Low
clearance
Slow absorption
Local
tolerance;
residues;
Renal
Metabolic
Active
Betalactams/sulfamides
Large volume of
distribution
Intestinal, Bile
Inactive
Macrolides/FQ
Is there a successful antibiotic
development complying with EcoEvo concept i.e green antibiotics?
Ecological impact of some new AMD
Ceftobiprole
Ceftaroline
Telavancin
The ideal antibiotics: PD properties
1. Full efficacy
• including against persisters, biofilms..
2. Rather low potency
• especially in acidic condition (no activity in gut)
3. Microbiological selectivity: rather narrow spectrum
4. No effect on procaryote cells
• safety issue; e.g. action on bacterial wall rather
intracellular proteins
5. Prodrugs converted by an hepatic first-pass effect
6. Non specific intracellular mechanism of action or dual
mechanism of action or combination
7. Others properties:
•
immunostimulation, anti-inflammatory, quorum sensing
…
The ideal antibiotics: PK
1. Oral: High oral bioavailability
• no first pass effect but prodrugs; no affinity for efflux
pumps, no interference with diet; No influence on feeding
behavior
2. Non oral: slow absorption
• LA formulations> LA substances
3. Pro & Cons for a low plasma protein binding
4. Small volume of distribution
5. Slow metabolic clearance
• giving hydrophilic inactive metabolites
6. Renal clearance (substance & inactive metabolites)
7. No bile and/or intestinal clearance
8. Rapid degradation in the environment
Veterinary medicine needs green
antibiotics
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