1. The ideal antimicrobial in veterinary medicine Pierre-Louis Toutain Ecole Nationale Vétérinaire de Toulouse & INRA, Toulouse, France SEPTEMBER 30 - 2 OCTOBER 2015, COPENHAGEN DENMARK

2. 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

3. The 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

4. A major review Nature Drug Discovery 2013 What is an ideal antibiotics

5. 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.

6. 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

7. EU guidelines against combinations for veterinary medicine (Sep 2015)

8. 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

9. The prudent use of antibiotics Most recommendations are copy and paste from human medicine Doing that we may inflate the public health issues

10. 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 No impact on gut flora No release of active substances in the environment

11. « 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

12. 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 (zoonotic pathogens) Commensal flora Environment Food chain

13. 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

14. Where are manufactured genes of resistance having a public health impact

15. Bacterial load exposed to antibiotics during a treatment Infected Lungs Digestive tract mgKg Manure waste Food chain Tons Soil, plant…. 1µg Test tube

16. Duration 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

17. An ideal AMD in veterinary medicine should not be release in its active form in the environment

18. Principles of solution

19. What could be the ideal pharmacodynamic pharmacokinetic & profile for a veterinary antibiotic to minimize the public health issues

20. The 3 PD parameters Emax ED 50 G+ vs G- ED 50 2 Emax 1 EfficacyPotency Selectivity Emax 2 1 2 1 2 ED 50 1

21. A major misconception: To develop in veterinary medicine antibiotics with the highest as possible potency

22. Potency of Fluoroquinolones Hydrophobicity vs MIC for S aureus Hydrophobicity (Clog-P) MIC (µg/mL) Takenouchi et al AAC 1996

23. Potency of fluoroquinolones Hydrophobicity vs MIC for E coli Hydrophobicity (Clog-P) MIC µg/mL Takenouchi et al AAC 1996

24. Fluoroquinolones: XLog-P3 vs. impact on gut flora Hydrophobicity (Xlog-P) Impact gut microbiome Minimal impact Major impact

25. Cephalosporins XLog-P vs. impact on gut flora Xlog-P Impact gut microbiome

26. Selectivity of antimicrobial drugs Selectivity PD Large vs Narrow spectrum PK Selective distribution of the AB to its biophase

27. PK 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)

28. Objective : Improve the oral bioavailability for oral antibiotics

29. 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

30. 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.

31. Desirable pharmacokinetic properties for antibiotic administered by the non-oral route in food producing animals

32. PK selectivity: systemic route Trapping, inactivation Proximal Distal Target pathogen Blood Food chain Environment Administration Biliary & intestinal clearance=0 microbiome Zoonotics commensal Renal elimination =100%

33. 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.

34. How to get a long Half-life a Long HL Formulation (e.g. old AMD) High clearance Slow absorption Local tolerance; residues; Substance (new AMD) Low clearance RenalMetabolicActiveInactive Intestinal, Bile Large volume of distribution Macrolides/FQ Betalactams/sulfamides

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

36. Ecological impact of some new AMD Ceftobiprole Ceftaroline Telavancin Ceftobiprole Ceftaroline Telavancin

37. 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 …

38. 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

39. Veterinary medicine needs green antibiotics 39