The ideal antimicrobial in veterinary medicine

Pierre-Louis ToutainEcole 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

Treatment & prophylaxis

Human medicineCommunity

Veterinary medicine Animal feed additives

Environment

Hospital Agriculture

Plant protection

Industry

New antibiotics

A major review

Nature Drug Discovery 2013

What is an ideal antibiotics

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 floraNo release of active substances in the environment

« New » natural history of bacterial infections

Commensal flora of a future patient (1kg)

Colonization/carriageGene of resistanceESBL, 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

Link Man/AnimalAMR 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(zoonotic pathogens)

Commensal flora

Environment

Food chain

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

Infected Lungs

Digestive tract

mg Kg

Manurewaste

Food chain

Tons

Soil, plant….

1µg

Test tube

Duration of exposure of bacteria exposed to antibiotics

Infected Lungs

Digestive tract

few days

ManureSludgewaste

Food chain

Several weeks/months

Soil, plant….

24h

Test tube

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

Emax ED50 G+ vs G-

ED502

Emax 1

Efficacy Potency • Selectivity

Emax 2

12

12

ED501

A major misconception: To develop in veterinary

medicine antibiotics with the highest as possible potency

Potency of FluoroquinolonesHydrophobicity vs MIC for S aureus

-0.5 0 0.5 1 1.5 2 2.5 30.1

1

10

100

f(x) = 26.7571017466184 exp( − 2.29705488725533 x )R² = 0.676387169322196

MIC SAExponential (MIC SA)

Hydrophobicity (Clog-P)

MIC

(µg/

mL)

Takenouchi et al AAC 1996

Potency of fluoroquinolonesHydrophobicity vs MIC for E coli

-0.5 0 0.5 1 1.5 2 2.5 31.00E-03

1.00E-02

1.00E-01

1.00E+00

1.00E+01

f(x) = 1.15399838853637 exp( − 2.00272117999116 x )R² = 0.37191398509997

MI E coliExponential (MI E coli)

Hydrophobicity (Clog-P)

MIC

µg/

mL

Takenouchi et al AAC 1996

Fluoroquinolones:XLog-P3 vs. impact on gut flora

Hydrophobicity (Xlog-P)

Impa

ct g

ut m

icro

biom

e

Minimal impact

Major impact

-1.5 -1 -0.5 0 0.5 1 1.5 2 2.50.00

0.50

1.00

1.50

2.00

2.50

3.00

3.50f(x) = 0.670772865339183 x + 1.91275734053324R² = 0.459710713745388

Veterinary FQ

CephalosporinsXLog-P vs. impact on gut flora

-4 -3 -2 -1 0 1 2

-1.5

-1

-0.5

0

0.5

1

1.5

2

2.5

3

3.5

-1

f(x) = 0.497202877040758 x + 2.15432697796552R² = 0.339657808550981

Veterinary cephalosporins

Xlog-P

Impa

ct g

ut m

icro

biom

e

Selectivity of antimicrobial drugs

Selectivity

PD

Large vs Narrow spectrum

PK

Selective distribution of the AB to its biophase

PK selectivity : oral route

Proximal Distal1-F=0%

BiophaseTarget pathogen

Blood

Food chain Environment

microbiome• Zoonotics • commensal

F=100%=lower dose

AB: oral route

Renal elimination

=100%

Trapping , inactivation

(betalactamase)

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, inactivationProximal Distal

Target pathogen

Blood

Food chain

EnvironmentAdministration

Biliary & intestinal clearance=0

microbiome• Zoonotics

• commensal

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(e.g. old AMD)

High clearanceSlow absorption

Local tolerance; residues;

Substance(new AMD)

Low clearance

Renal Metabolic

Active Inactive

Intestinal, Bile

Large volume of distribution

Macrolides/FQBetalactams/sulfamides

Is there a successful antibiotic development complying with Eco-Evo concept i.e green antibiotics?

Ecological impact of some new AMD

CeftobiproleCeftarolineTelavancin

The ideal antibiotics: PD properties1. Full efficacy

• including against persisters, biofilms..2. Rather low potency

• especially in acidic condition (no activity in gut)3. Microbiological selectivity: rather narrow spectrum4. No effect on procaryote cells

• safety issue; e.g. action on bacterial wall rather intracellular proteins

5. Prodrugs converted by an hepatic first-pass effect6. Non specific intracellular mechanism of action or dual

mechanism of action or combination7. Others properties:

• immunostimulation, anti-inflammatory, quorum sensing …

The ideal antibiotics: PK1. 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 binding4. Small volume of distribution5. Slow metabolic clearance

• giving hydrophilic inactive metabolites6. Renal clearance (substance & inactive metabolites)7. No bile and/or intestinal clearance8. Rapid degradation in the environment

Veterinary medicine needs green antibiotics

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