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Requirement for a next generation of green antibiotics

This article explores the requirements for a new generation of green antibiotics that address the link between the human and veterinary resistomes. It discusses the shortcomings of the current paradigm for antibiotic use in veterinary medicine and highlights the need for eco-evolutionary drugs and strategies to minimize the impact on gut flora and the environment.

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Requirement for a next generation of green antibiotics

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  1. Requirement for a next generation of green antibiotics Pierre-Louis Toutain Ecole Nationale Vétérinaire de Toulouse & INRA, Toulouse, France August 23-26 ,2016

  2. Do we need “new” antibiotics in veterinary medicine? • From an animal health perspective: No • Currently, no major animal health issues • From a public health perspective: Yes • Currently, a major public health issue for vets • to manage the link between the human and the veterinary resistome by decreasing our contribution to the overall pool of genes of resistance

  3. One world, one health, one resistome Treatment & prophylaxis Veterinary medicine Human medicine Community Animal feed additives Hospital Agriculture Plant protection Environment Industry

  4. The prudent use of antibiotics Commensal flora Most recommendations are copy and paste from human medicine May be counterproductive Target pathogens

  5. The shortcomings of the paradigm of a prudent use of antibiotics in veterinary medicine • Selected examples • Revision (increase) of dosage regimen • Ignore the inoculum effect for metaphylaxis • Local route of administration at drying off • Systematic recourse to Antimicrobial Susceptibility Testing (AST) • Few or lack of clinical breakpoint • Promotion of generics • Local route of administration at drying off • ……

  6. The shortcomings of the paradigm of a prudent use of antibiotics in veterinary medicine • Selected examples • Local route of administration at drying off • 93% of respondents used antibiotic intramammary tubes to treat mastitis • 83% per cent of respondents (413) fed waste milk to calves

  7. WHO and critical AMDs • it is recommended by the WHO, to reserve to human medicine the most critical antibiotics keeping for veterinary medicine the most outdated substances.

  8. Tetracyclines • Tetracyclines: half the amount of veterinary antibiotic used worldwide • Extensively excreted in environment • Soils may be hot spots for gene transfer,

  9. Q1: But of what resistance are we speaking?

  10. The three types of AMR faced by vetmedicine Target pathogen Zoonotic Commensal Global ecological problem Efficacy in animal Efficacy in man Farm Environment Food chain Animal health Issue Human health issue Public health Issue

  11. Q2: what is the pathways for transmission between animal and human resistomes

  12. “Classical” natural history of bacterial infections (at hospital) Disease Specific pathogen Andremont et al, The lancet infection 2011 11 6-8

  13. « New » natural history of bacterial infections(in the community) Commensal flora of a future patient Colonization/carriage Gene of resistance ESBL, CTX-M… Disease Specific pathogen Disselmination of gene of resistance Dissemination of genes of resistance Adapted from Andremont et al, The lancet infection 2011 11 6-8

  14. Link man/Animals Environment Food chain Most of the prudent use recommandations do not address this question

  15. Intestinal microbiota is the turnstile between the two medicine To have a clean commensal microbiota is public health issue

  16. 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

  17. Q3: Where are manufactured genes of resistance having a public health impact

  18. Bacterial load & duration of exposition to antibiotics during treatment Manure Sludge Waste Infected Lungs Test tube Digestive tract Tons Months Kg Weeks µg Hours mg Days Food chain Environment

  19. Elimination of antibiotics into the environment • As much as 75% of the antibiotics administered to food producing animals are directly excreted into the environment without any benefit for the animal

  20. Rate of antibiotic degradation in manure, soil, waste…

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

  22. Q5: Why veterinary antibiotic treatments are able to alter the resistome of the animal gut microbiota.

  23. AMD: oral route Oral route of administration Gastro-intestinal tract Proximal Distal Microbiota • Zoonotics (salmonella, campylobacter • commensal ( enterococcus) 1-F% F% Food chain Blood Environment Biophase Target pathogen

  24. Bioavailability of tetracyclins by oral route • Chlortetracycline: • about 20% • Doxycycline: • About 20% • Oxytetracycline: • Pigs:4.8% • Piglets, weaned, 10 weeks of age: by drench: 9%; • in medicated feed for 3 days: 3.7% . • Tetracycline: • Pigs fasted:23% . • Most of the administered dose is lost for the animal and is only spill in the environment

  25. Non-oral route of adminsitration Gastro-intestinal tract Proximal Distal Microbiota • Zoonotics (salmonella, campylobacter ) • commensal ( enterococcus) Intestinal efflux Bile Quinolones Macrolides Tetracyclines Food chain Non oral route Blood Environment Biophase Target pathogen

  26. Genotypic evaluation of ampicillin resistance:copy of blaTEM genes per gram of feces A significant effect of route of administration on blaTEM fecal elimination (p<0.001).

  27. Enrofloxacin (SQ, 7.5mg/kg) • AUC (enro+cipro) • Plasma=19 (total) • ISF=25 (free) • Ileum=21 (free) • Spiral colon =36 (free) Messenger et al JVPT 2011

  28. Principles of solution • Green AMDs: • “no” ecological impact: • on gut microbiome • on environmental microbiome

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

  30. PharmacodynamyA major misconception: To develop in veterinary medicine antibiotics with the highest possible potency

  31. The 3 PD parameters ED50 Emax 1 1 Emax 1 2 2 Emax 2 ED501 ED502 Efficacy Potency

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

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

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

  35. CephalosporinsXLog-P vs. impact on gut flora Impact gut microbiome Xlog-P

  36. Wat is the situation of veterinarydrugs in terms of lipophilicity

  37. Relationship between lipophilicity and pharmacokinetic parameters for the 10 most used antimicrobial in cattle. The terminal half-life is positively correlated to the degree of lipophilicity with a coefficient of determination (R2) between lipophilicity and duration of half-of 0.37. • MW=371.6 • ClogP = -0.18.

  38. Why Veterinary AM%D are more lipophilic The terminal half-life is positively correlated to the degree of lipophilicity with a coefficient of determination (R2) between lipophilicity and duration of half-of 0.37.

  39. Selectivity of antimicrobial drugs

  40. AB: oral route PK selectivity : oral route Trapping , inactivation (betalactamase) Proximal Distal microbiome • Zoonotics • commensal 1-F=0% F=100% =lower dose Food chain Environment Blood Biophase Target pathogen Renal elimination =100%

  41. Objective 1: Improve the oral bioavailability for oral antibiotics

  42. PK Variability Doxycycline F≈20% n = 215

  43. Social rank vs. fosfomycin exposure AUC Fosfomycin in feed Social rank Soraci et al 2014 :Research Vet Science

  44. How to get a high BioavailabilityPrecisionmedicine • Metaphylaxis should not be longer synonym of mass medication Radio Frequency Identification (RFID)

  45. Ideal AMD: oral route • A high oral bioavailability is required: • To minimize or suppress a uselessly impact of the gut microbiota • To decrease the dose • To decrease the intersubject variability

  46. Intestinal vs Bacterial membrane Intestine Lipinskirule LogP=2 Gram-negative Gram-positive Aquaporin MDR system Efflux pump Outer membrane Murein/peptidoglycan Cell Wall Betalactams: Site of action Cytoplasmic membrane Intracellular site of action

  47. How to get a high Bioavailability • Appropriate logP: Lipinskyrule • optimization of formulation (including in water as micellar formulations) • No interference with food (binding to cellulosis) • No taste (no influence on feeding behavior) • No active transport (as for peptides like AMDs) • No PGP… substrate • No first-pass effect (but prodrugs)

  48. Bioavailability: prodrugs • Bioavailability of a too hydrophilic compound can be lower as it is the case of aminoglycosides, colistine etc and a strategy consisting to administrate a lipophilic prodrug extensively absorbed in the digestive tract and then immediately metabolised to a hydrophilic active moiety a by a first-pass effect could be a attractive option.

  49. The produgapproach Intestine Lipophilic prodrug Gram-negative First passeffect Aquaporin MDR system Efflux pump Liver Outer membrane Cell Wall Hydrophilicdrug Intracellular site of action

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