medicine PierreLouis Toutain Ecole Nationale Vétérinaire de Toulouse amp INRA Toulouse France SEPTEMBER 30 2 OCTOBER 2015 COPENHAGEN DENMARK Do we need new antibiotics in veterinary medicine ID: 919238
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Slide1
The ideal antimicrobial in veterinary medicine
Pierre-Louis ToutainEcole Nationale Vétérinaire de Toulouse & INRA,Toulouse, FranceSEPTEMBER 30 - 2 OCTOBER 2015, COPENHAGEN DENMARK
Slide2Do we need “new” antibiotics in veterinary medicine?
From an animal health perspective: NoCurrently, no major animal health issuesBut with exception (e.g. persisters, biofilm… for chronic infection in pets)Cascade is possibleFrom a public health perspective: YesWe 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
Slide3The antibiotic ecosystem:
one world, one health,
one resistome
Treatment & prophylaxis
Human medicine
Community
Veterinary
medicine
Animal feed additives
Environment
Hospital
Agriculture
Plant protection
Industry
New antibiotics
Slide4A major review
Nature Drug Discovery 2013
What is an ideal antibiotics
Slide5The ideal antibiotic
A prodrug enters the cell, where it is converted into a reactive compound by a bacteria-specific enzyme (E).
The reactive moiety covalently attaches to unrelated targets (T1, T2 to Tx), killing both actively dividing and dormant cells, thus sterilizing an infection. 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.
Slide6Using 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
Slide7EU guidelines against combinations for veterinary medicine (Sep 2015)
Slide8The 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
Slide9The prudent use of antibiotics
Commensal flora
Public health
Target pathogens
Animal health
Most recommendations are copy and paste from human medicine
Doing that we may inflate the public health issues
Slide10New Eco-
Evo drugs and strategies should be considered when developing new AMDNo impact on gut floraNo release of active substances in the environment
Slide11« New » natural history of bacterial infections
Commensal flora of a future patient (1kg)
Colonization/carriage
Gene of resistance
ESBL, CTX-M…
Dissemination of genes of resistance
Disease
Specific pathogen
Adapted from
Andremont
et al, The lancet infection 2011 11 6-8
Dissemination of gene of resistance
Slide12Link Man/Animal
AMR slould be viewed as an ecological problem with the animal and human commensal flora as the turntable of the system
Environment
Food chain
Slide13Although 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
Slide14Where are manufactured genes of resistance having a public health impact
Slide15Bacterial load exposed to antibiotics during a treatment
Infected
Lungs
Digestive
tract
mg
Kg
Manure
waste
Food chain
Tons
Soil, plant
….
1µg
Test
tube
Slide16Duration of exposure of bacteria exposed to antibiotics
Infected
Lungs
Digestive
tract
few
days
Manure
Sludge
waste
Food chain
Several weeks/months
Soil, plant
….
24h
Test
tube
Slide17An ideal AMD in veterinary medicine should not be release in its active form in the environment
Slide18Principles of solution
Slide19What could be the ideal pharmacodynamic
pharmacokinetic & profile for a veterinary antibiotic to minimize the public health issues
Slide20The 3 PD
parameters
Emax
ED
50
G+
vs G-
ED
50
2
Emax 1
Efficacy
Potency
Selectivity
Emax 2
1
2
1
2
ED
50
1
Slide21A major misconception:
To develop in veterinary medicine antibiotics with the highest as possible potency
Slide22Potency of FluoroquinolonesHydrophobicity vs MIC for S aureus
Hydrophobicity (Clog-P)
MIC (µg/mL)Takenouchi et al AAC 1996
Slide23Potency of fluoroquinolonesHydrophobicity vs MIC
for E coliHydrophobicity (Clog-P)
MIC µg/mLTakenouchi et al AAC 1996
Slide24Fluoroquinolones:XLog-P3 vs. impact on gut flora
Hydrophobicity (Xlog-P)Impact gut microbiome
Minimal impactMajor impact
Slide25CephalosporinsXLog-P
vs. impact on gut flora
Xlog
-P
Impact gut microbiome
Slide26Selectivity of antimicrobial drugs
Slide27PK
selectivity : oral route
Proximal
Distal
1-F=0%
Biophase
Target
pathogen
Blood
Food
chain
Environment
microbiome
Zoonotics
commensal
F=100%
=lower dose
AB: oral route
Renal
elimination
=100%
Trapping
, inactivation
(
betalactamase
)
Slide28Objective :
Improve the oral bioavailability for oral antibiotics
Slide29How 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 antibioticsThe prodrug approach
Slide30The 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.
Slide31Desirable pharmacokinetic properties for antibiotic administered by the non-oral route in food producing animals
Slide32PK
selectivity: systemic route
Trapping
, inactivation
Proximal
Distal
Target
pathogen
Blood
Food
chain
Environment
Administration
Biliary
& intestinal clearance=0
microbiome
Zoonotics
commensal
Renal
elimination
=100
%
Slide33The % of urinary excretion decreased or fecal excretion increased with increasing
octanol±water partition coeffcient, especially for the drugs with C log P>0The more hydrophobic is a drug, the more likely it is to be excreted in
the feces.
Slide34How to get a long Half-life
Macrolides/FQ
Betalactams
/
sulfamides
Slide35Is there a successful antibiotic development complying with Eco-Evo
concept i.e green antibiotics?
Slide36Ecological impact of some new AMD
CeftobiproleCeftaroline
Telavancin
Slide37The ideal antibiotics: PD properties
Full efficacy including against persisters, biofilms.. Rather low potency especially in acidic
condition (no activity in gut) Microbiological selectivity: rather narrow spectrum No effect on procaryote cells
safety issue;
e.g. action on bacterial wall rather intracellular
proteins
Prodrugs
converted
by an hepatic first-pass effect
Non specific intracellular mechanism of action or dual mechanism of action or combination Others properties:
immunostimulation, anti-inflammatory, quorum sensing …
Slide38The ideal antibiotics: PK
Oral: High oral bioavailabilityno first pass effect but prodrugs; no affinity for efflux pumps, no interference with diet; No influence on feeding behaviorNon oral: slow absorption
LA formulations> LA substancesPro & Cons for a low plasma protein bindingSmall volume of distributionSlow metabolic clearance
giving
hydrophilic inactive
metabolites
Renal
clearance
(substance &
inactive metabolites) No bile and/or intestinal clearance Rapid degradation in the environment
Slide39Veterinary medicine needs green antibiotics
39