The ideal antimicrobial in veterinary medicine PierreLouis Toutain

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 (T 1, T 2 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 (1 kg) 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 24 h 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 ED 50 Emax 1 1 Emax 2 2 1 G+ vs G 2 ED 501 ED 502 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/m. L) 32 R 2 = 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. 00 E+00 4. 00 E+00 2. 00 E+00 R 2 = 0. 3719 MIC µg/m. L 1. 00 E+00 5. 00 E-01 2. 50 E-01 1. 25 E-01 MI E coli 6. 25 E-02 Expon. (MI E coli) 3. 13 E-02 1. 56 E-02 7. 81 E-03 3. 91 E-03 1. 95 E-03 9. 77 E-04 -0. 5 0 0. 5 1 1. 5 Hydrophobicity (Clog-P) Takenouchi et al AAC 1996 2 2. 5

Fluoroquinolones: XLog-P 3 vs. impact on gut flora Impact gut microbiome 3. 50 Major impact 3. 00 2. 50 R 2 = 0. 4597 2. 00 1. 50 1. 00 Minimal impact 0. 50 0. 00 Veterinary FQ -2 -1 0 1 2 Hydrophobicity (Xlog-P) 3

Impact gut microbiome Cephalosporins XLog-P vs. impact on gut flora 3. 5 3 R 2 = 0. 3397 2. 5 2 1. 5 1 0. 5 0 -0. 5 -4 -3 -2 -1 -1 -1. 5 0 1 2 -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% F=100% =lower dose • 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 Administration Biliary & intestinal clearance=0 Food chain 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 (e. g. old AMD) Substance (new AMD) High clearance Slow absorption Local tolerance; residues; Low clearance Renal Metabolic Active Betalactams/sulfamides Large volume of distribution Intestinal, Bile Inactive Macrolides/FQ

Is there a successful antibiotic development complying with Eco. Evo 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 39