Quel$futur$pour$l’antibiothérapie? · - Stable vis-à-vis des β-lactamases: BLSE,...

Mai 2015, XVIIIème JRP

Quel futur pour l’antibiothérapie?J-‐P Bedos, Réanimation, CH Versailles

Pourquoi cette question?

-‐ Risque de disparition des antibiotiques?→ R&D en antibiotiques diminue +++ (temps; coût; risque; retour sur investissement ....)… pas de nouvelle classe d’antibiotique…

-‐ Risque d’inefficacité des antibiotiques? (Post-‐antibiotic era)→WEF 2013: ... « the greatest risk to human health comes in the form of antibiotic -‐resistant bacteria. »

-‐ « We live in a bacterial word... »!! → Guerre permanente entre bactéries et antibiotiques = SURVIE →Tout est « déjà » dans la nature... et intimement lié!!!: les bactéries -‐ les

antibiotiques -‐ la résistance

-‐ La résistance des bactéries aux antibiotiques existe depuis « toujours » dans la nature... et à des molécules non encore inventées !!!

-‐ L’homme = Antibiotiques sur de nouvelles cibles ... vies sauvées +++... Mais pression de sélection croissante ►« épuisement » des cibles ... = RESISTANCE ↑↑↑

3

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2,$3&,4&,+($56&-$7839:$;<=;>?&$@AB+C.-+$@0B+,-+$@+-&CA+$

B&-)$)0-$+-)+@/#+7,A&-.@&(.0-:$0-C0#04.+:$4,+%%+):$+(CD>

Peut-‐on donc réellement ‘sauver’ les antibiotiques ?

Pas sûr !!! : Trois idées fausses

ü Seul le mauvais usage des ATB expose à l’émergence de résistance

ü Certains ATB ne sont pas à risque d’émergence de résistances

ü La résistance aux ATB est un phénomène créé par l’Homme

Peut-‐on donc réellement ‘sauver’ les antibiotiques ?

ü Seul le mauvais usage des ATB expose à l’émergence de résistance

FAUX: Les bons usages ont le même impact sur les flores !

ü Certains ATB ne sont pas à risque d’émergence de résistances

FAUX: En détruisant les bactéries sensibles, on favorise de facto l’émergence de bactéries résistantes !

ü La résistance aux ATB est un phénomène créé par l’HommeFAUX: Les micro-organismes savent résister depuis l’ère des temps !

! Grotte Lechuguilla, Nouveau Mexique" zones isolées de la surface de la terre de 400 m" depuis > 4 M d’années" 4 visiteurs depuis la découverte

! Résistance aux ATBnaturelleATB de synthèsedaptomycine, B-lactamines.. !!!

Antibiotic Resistance Is Prevalent in an Isolated CaveMicrobiomeKirandeep Bhullar1, Nicholas Waglechner1, Andrew Pawlowski1, Kalinka Koteva1, Eric D. Banks2,

Michael D. Johnston2, Hazel A. Barton2, Gerard D. Wright1*

1 M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada,

2 Department of Biology, University of Akron, Akron, Ohio, United States of America

Abstract

Antibiotic resistance is a global challenge that impacts all pharmaceutically used antibiotics. The origin of the genesassociated with this resistance is of significant importance to our understanding of the evolution and dissemination ofantibiotic resistance in pathogens. A growing body of evidence implicates environmental organisms as reservoirs of theseresistance genes; however, the role of anthropogenic use of antibiotics in the emergence of these genes is controversial. Wereport a screen of a sample of the culturable microbiome of Lechuguilla Cave, New Mexico, in a region of the cave that hasbeen isolated for over 4 million years. We report that, like surface microbes, these bacteria were highly resistant toantibiotics; some strains were resistant to 14 different commercially available antibiotics. Resistance was detected to a widerange of structurally different antibiotics including daptomycin, an antibiotic of last resort in the treatment of drug resistantGram-positive pathogens. Enzyme-mediated mechanisms of resistance were also discovered for natural and semi-syntheticmacrolide antibiotics via glycosylation and through a kinase-mediated phosphorylation mechanism. Sequencing of thegenome of one of the resistant bacteria identified a macrolide kinase encoding gene and characterization of its productrevealed it to be related to a known family of kinases circulating in modern drug resistant pathogens. The implications ofthis study are significant to our understanding of the prevalence of resistance, even in microbiomes isolated from humanuse of antibiotics. This supports a growing understanding that antibiotic resistance is natural, ancient, and hard wired in themicrobial pangenome.

Citation: Bhullar K, Waglechner N, Pawlowski A, Koteva K, Banks ED, et al. (2012) Antibiotic Resistance Is Prevalent in an Isolated Cave Microbiome. PLoS ONE 7(4):e34953. doi:10.1371/journal.pone.0034953

Editor: Ramy K. Aziz, Cairo University, Egypt

Received December 13, 2011; Accepted March 8, 2012; Published April 11, 2012

Copyright: ! 2012 Bhullar et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permitsunrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This research was supported by the Canada Research Chairs program (GDW), a Canadian Institutes of Health Research Operating Grant (MT-13536 toGDW), the National Science Foundation Microbial interactions and Processes Program (NSF0643462 to HAB) and a Canadian Institutes of Health ResearchFrederick Banting and Charles Best Canada Graduate Scholarship to KB. The funders had no role in study design, data collection and analysis, decision to publish,or preparation of the manuscript.

Competing Interests: The authors have declared that no competing interests exist.

* E-mail: [email protected]

Introduction

The question of whether the extensive presence of resistanceelements in microbes is primarily the result of human activity iscontroversial. Investigation of antibiotic resistance in bacteria fromthe Galapagos, a remote environment with limited humanoccupation and presumably low anthropogenic antibiotic expo-sure, revealed that acquired antibiotic resistance genes were absentin bacteria isolated from terrestrial animals [1]. Similarly, plasmidsfrom bacterial collections that predate the antibiotic era are largelydevoid of resistance elements [2,3]. This suggests that the presenceof antibiotics is an important selective force in evolution andspread of antibiotic resistance genes and can contribute signifi-cantly in altering the natural microbiota. In a survey of soilsamples from the Netherlands spanning the pre-and post-antibioticeras (1940–2008), an increase in the relative abundance ofantibiotic resistance genes for major antibiotic families (ß-lactams,tetracyclines and macrolides) was observed in contemporary soilsamples in comparison to pre-antibiotic era samples [4]. This bodyof evidence is consistent with the hypothesis that widespreadresistance is a modern phenomenon linked to human use ofantibiotics.

On the other hand, antibiotics and antibiotic biosyntheticpathways are believed to have evolved over millions of yearssuggesting that antibiotic resistance is an equally ancientphenomenon [5,6,7]. Indeed, we have recently shown thatantibiotic resistance elements were abundant and diverse inancient DNA dating from the Pleistocene (30,000 years ago) [8].The concept of the antibiotic resistome predicts that resistance isthe result of dynamic and competitive microbial interactions thatpre-date human use of antibiotics [9,10]. Consistent with thisnotion is our survey of contemporary soil actinomycetes thatreported widespread multidrug resistance even in the absence ofobvious human sources of antibiotics [11]. There have also beenreports of antibiotic resistance in microorganisms isolated fromextreme natural habitats including the deep terrestrial subsurface[12] and the deep ocean [13]; environments presumably largelyabsent of human influence. These studies support a hypothesis thatresistance is an ancient and genetically rich natural phenomenon,deeply embedded in the microbial pangenome.

One of the challenges in measuring contemporary environ-mental resistance is rigorously ensuring the absence of anthropo-genic sources of antibiotics as a selective pressure for theacquisition of ‘modern’ resistance genes. A survey of a diverse

PLoS ONE | www.plosone.org 1 April 2012 | Volume 7 | Issue 4 | e34953

Antibiotic Inactivation by Gram-negative isolatesWe observed little enzyme-mediated antibiotic inactivation in

Gram-negative isolates (Table 2), suggesting that there are othermolecular mechanisms of resistance at play such as efflux, targetmodification, or barriers to entry. Three strains belonging to thegenera Agrobacterium and Ochoromobactrum displayed chloramphen-icol inactivation, which we determined by LC/MS to be themodification by acetylation (Table S5); a well-established resis-tance mechanism both in Gram-positive and Gram-negativebacteria [33].

Characterization of a B. paraconglomeratum macrolidekinase

Phosphorylation of macrolides in pathogenic bacteria is agrowing clinical problem [38] catalyzed by a family of macrolide

phosphotransferases (MPHs) [36,39]. In order to probe for thepresence of possible mph genes in macrolide inactivating B.paraconglomeratum, we prepared a draft genome sequence usingRoche 454 and Illumina platforms. A gene encoding a predictedmacrolide kinase, mphE, was identified (Figure 6). We expressedthe gene product in E. coli, purified the enzyme and determined itsactivity and specificity using steady state kinetics (Table 3). Theenzyme efficiently modified 14-, 15-, and 16-membered macrolideantibiotics aligning this enzyme with known type II MPHs (basedon previous characterization of these enzymes in E. coli isolates)[40,41]. The regiospecificity of phosphorylation of telithromycinwas determined by multidimensional and multinuclear magneticresonance analysis to be at the 29-hydroxyl group of thedesosamine sugar (Figures S3 and S4, Tables S6 and S7).

The genome of another Brachybacterium species has beenreported, Brachybacterium faecium DSM 4810, a terrestrial soil isolate

Figure 2. Resistance levels of Lechuguilla cave bacteria at 20 mg/ml against various antibiotics: (top) Gram-positive strains (bottom)Gram-negative strains. Antibiotics are grouped according to their mode of action/target, where each color represents a different target.doi:10.1371/journal.pone.0034953.g002

Antibiotic Resistance in Cave Bacteria

PLoS ONE | www.plosone.org 4 April 2012 | Volume 7 | Issue 4 | e34953

J$27'8

Nature, Sept 2011

CID May 2013

L’industrie ne développe plus de nouveaux antibiotiques intéressants??....

CID, June 2013

►« New incentives »...: GAIN Act ( 10 ans d’exclusivité....) , BARDA (Biomed Adv Resand Dev Authority) → Argent +++; « Facilitations » et ...Start-‐up)

Il y a de « nouveaux » antibiotiques anti Gram – (BLSE et carbapénémases) très intéressants... now and in the future !!

-Dérivé semi-synthétique 6-α-méthoxy de la ticarcilline

- Molécule « orpheline », Belgique, Royaume Uni, AMM européenne en décembre 2014

- Spectre étroit: entérobactéries, Burkholderia cepacia,H. influenzae, M. catarrhalis, N. gonorrhoeae

- Stable vis-à-vis des β-lactamases: BLSE, céphalosprinases déréprimées

- Efficace in vitro sur 92% des entérobactéries BLSE +

-Liaison protéique élevée: 70-80%

- Demi-vie 4-5h, 2 injections de 2g par jour (IM, IV) (ou en REA: 2g x 3 ou 6g IVSE)

- Elimination rénale, pas de métabolisme hépatique

- Indications: BLSE +++ dans infections urinaires hautes, respiratoires, bactériémies

→ Now : La témocilline (Negaban®), Laboratoire Eumedica

Quelles différences et apports du CEFTOBIPROLE (Mabelio®) Laboratoire Basilea ( AMM européenne récente!!!) versus la

CEFTAROLINE?

• Spectre d’activité plus large du ceftobiprole: – Activité et spectre proche sur CG+ dont SDMR ET SBMR, Sprésistant aux CIIIG, E.faecalis et faecium sensible à l’amoxicilline, E.faecalis résistant à la vancomycine

– Spectre plus large +++ sur les BG- proche de celui de la ceftazidime, avec en particulier une activité sur P. aeruginosamais réduite sur Proteus indol +, Enterobacter sp, Serratiamarcescens

– Activité limitée sur B.cepacia, S.maltophilia et Acinetobacter– Pas d’activité sur EBLSE ou D-Amp C– Pas d’activité sur Bacteroides sp et Lactobacillus, Cl .difficile

► AMM pour Pneumonies nosocomiales non ventilées et PACà 500 mg en 2h toutes les 8h

A brève échéance...

• Ceftazidime – avibactam (ATU puis AMM en 2016)

• Ceftolozane – tazobactam (phase III, IUc, VAP, IIA)

• Ceftaroline – avibactam (Phase II, IUc et IIA)

A plus longue échéance (phase I et II ... III)► Eravacycline► Plazomicine►Imipénème + MK-7655►Brilacidine►Carbavance►BAL 300372►Delafloxacine►Amikacine inhalé►Pleuromutilines........ …………………….Et d’autres encore !!

n engl j med 368;4 nejm.org january 24, 2013

PERSPECTIVE

299

tation, like many of the resource constraints that affect progress, is blamed on the long-standing U.S. economic embargo, but there may be other forces in the cen-tral government working against rapid, easy communication among Cubans and with the United States.

As a result of the strict eco-nomic embargo, Cuba has devel-oped its own pharmaceutical industry and now not only man-ufactures most of the medications in its basic pharmacopeia, but also fuels an export industry. Re-sources have been invested in de-veloping biotechnology expertise to become competitive with ad-vanced countries. There are Cuban academic medical journals in all the major specialties, and the med-ical leadership is strongly encour-aging research, publication, and stronger ties to medicine in other Latin American countries. Cuba' s medical faculties, of which there are now 22, remain steadily fo-cused on primary care, with fam-ily medicine required as the first

residency for all physicians, even though Cuba now has more than twice as many physicians per cap-ita as the United States.4 Many of those physicians work outside the country, volunteering for two or more years of service, for which they receive special compensation. In 2008, there were 37,000 Cuban health care providers working in 70 countries around the world.5 Most are in needy areas where their work is part of Cuban for-eign aid, but some are in more developed areas where their work brings financial benefit to the Cuban government (e.g., oil sub-sidies from Venezuela).

Any visitor can see that Cuba remains far from a developed country in basic infrastructure such as roads, housing, plumb-ing, and sanitation. Nonetheless, Cubans are beginning to face the same health problems the devel-oped world faces, with increas-ing rates of coronary disease and obesity and an aging population (11.7% of Cubans are now 65

years of age or older). Their un-usual health care system ad-dresses those problems in ways that grew out of Cuba' s peculiar political and economic history, but the system they have created ó with a physician for everyone, an early focus on prevention, and clear attention to community health ó may inform progress in other countries as well.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

1. Keck CW, Reed GA. The curious case of Cuba. Am J Public Health 2012;102(8):e13-e22.2. Drain PK, Barry M. Fifty years of U.S. em-bargo: Cubaí s health outcomes and lessons. Science 2010;328:572-3.3. World population prospects, 2011 revision. New York: United Nations (http://esa.un.org/ unpd/wpp/Excel-Data/mortality.htm).4. The world factbook. Washington, DC: Central Intelligence Agency, 2012 (https://www.cia.gov/library/publications/the-world- factbook).5. Gorry C. Cuban health cooperation turns 45. MEDICC Rev 2008;10:44-7.

DOI: 10.1056/NEJMp1215226Copyright © 2013 Massachusetts Medical Society.

A Different Model ó Medical Care in Cuba

The Future of Antibiotics and ResistanceBrad Spellberg, M.D., John G. Bartlett, M.D., and David N. Gilbert, M.D.

In its recent annual report on global risks, the World Eco-

nomic Forum (WEF) concluded that ì arguably the greatest risk . . . to human health comes in the form of antibiotic-resistant bacteria. We live in a bacterial world where we will never be able to stay ahead of the mutation curve. A test of our resilience is how far behind the curve we al-low ourselves to fall.î 1

Traditional practices in infec-tion control, antibiotic steward-ship, and new antibiotic develop-

ment are cornerstones of society' s approach to combating resistance and must be continued. But the WEF report underscores the facts that antibiotic resistance and the collapse of the antibiotic research-and-development pipeline continue to worsen despite our ongoing efforts on all these fronts. If we' re to develop countermeasures that have lasting effects, new ideas that complement traditional ap-proaches will be needed.

New ideas are often based on the recognition of old truths. Pro-

karyotes (bacteria) ì inventedî anti-biotics billions of years ago, and resistance is primarily the result of bacterial adaptation to eons of antibiotic exposure. What are the fundamental implications of this reality? First, in addition to antibiotics' curative power, their use naturally selects for preexist-ing resistant populations of bac-teria in nature. Second, it is not just ì inappropriateî antibiotic use that selects for resistance. Rath-er, the speed with which resis-tance spreads is driven by micro-

The New England Journal of Medicine Downloaded from nejm.org at INSERM DISC DOC on January 8, 2014. For personal use only. No other uses without permission.

Copyright © 2013 Massachusetts Medical Society. All rights reserved.

PERSPECTIVE


bial exposure to all antibiotics, whether appropriately prescribed or not. Thus, even if all inappro-priate antibiotic use were elimi-nated, antibiotic-resistant infec-tions would still occur (albeit at lower frequency).

Third, after billions of years of evolution, microbes have most likely invented antibiotics against

every biochemical target that can be attacked ó and, of necessity, developed resistance mechanisms to protect all those biochemical targets. Indeed, widespread anti-biotic resistance was recently dis-covered among bacteria found in underground caves that had been geologically isolated from the sur-face of the planet for 4 million

years.2 Remarkably, resistance was found even to synthetic antibiot-ics that did not exist on earth until the 20th century. These re-sults underscore a critical reality: antibiotic resistance already exists, widely disseminated in nature, to drugs we have not yet invented.

Thus, from the microbial per-spective, all antibiotic targets are

The Future of Antibiotics and Resistance

New Interventions to Address the Antibiotic-Resistance Crisis.*

Intervention Status

Preventing infection and resistance

ì Self-cleaningî hospital rooms; automated disinfectant application through misting, vapor, radiation, etc.

Some commercially available but require clinical validation; more needed

Novel drug-delivery systems to replace IV catheters; regenerative-tissue tech-nology to replace prosthetics; superior, non invasive ventilation strategies

Basic science and conceptual stages

Improvement of population health and health care systems to reduce ad-missions to hospitals and skilled nursing facilities

Implementation research stage

Niche vaccines to prevent resistant bacterial infections Basic and clinical development stage

Refilling antibiotic pipeline by aligning economic and regulatory approaches

Government or nonprofit grants and contracts to defray up-front R&D costs and establish nonprofits to develop antibiotics

Models in place, expansion needed in number and scope; new nonprofit corporations needed

Institution of novel approval pathways (e.g., Limited Population Antibiotic Drug proposal)

Proposed, legislative and regulatory action needed

Preserving available antibiotics, slowing resistance

Public reporting of antibiotic-use data as a basis for benchmarking and re-imbursement

Policy action needed to develop and implement

Development of and reimbursement for rapid diagnostic and biomarker tests to enable appropriate use of antibiotics

Basic and applied research and policy action needed

Elimination of use of antibiotics to promote livestock growth Legislation proposed

New waste-treatment strategies; targeted chemical or biologic degradation of antibiotics in waste

One strategy approaching clinical trials

Studies to define shortest effective courses of antibiotics for infections Some trials completed

Developing microbe-attacking treatments with diminished potential to drive resistance

Preclinical, proof-of-principle stage

Immune-based therapies, such as infusion of monoclonal antibodies and white cells that kill microbes

Antibiotics or biologic agents that doní t kill bacteria but alter their ability to trigger inflammation or cause disease

Developing treatments attacking host targets rather than microbial targets to avoid selective pressure driving resistance


Direct moderation of host inflammation in response to infection (e.g., cyto-kine agonists or antagonists, PAMP receptor agonists)

Sequestration of host nutrients to prevent microbial access to nutrients

Probiotics that compete with microbial growth

* IV denotes intravenous, PAMP pathogen-associated molecular pattern, and R&D research and development.



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Developing microbe-attacking treatments with diminished potential to driveresistance




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Developing treatments attacking host targets rather than microbial targetsto avoid selective pressure driving resistance




Z[6'WXYi

Bactériophages = virus qui parasitent les bactéries => usage thérapeutique! Peptidoglycane hydrolase

Principes de la phagothérapie (1)

ü Spécificité d’actionoSpectre très étroit (lysotype)

• nécessité de tester activité sur la souche visée• impact très limité sur les flores

oTolérance supposée excellente (aucune action sur cellules mammifères)

ü Agent biologique vivantoSimplifie le choix des doses et des duréesoMais complique beaucoup:

• la partie ‘règlementaire’• la production et la conservation

Kutaledadze M et al. Trends Biotechnology 2010

28#<P#9/D$C/$5"$9>"T:7>?8"9#/$U%V

! Sélectionner phages avec cycle lytique exclusif

! Mettre en place un test prédictif d’efficacitéo isolement du pathogène pour screening de phages candidats…oou ‘cocktail’ de phages

Deresinski S et al. Clin Infect Dis 2009

Applications chez l’Homme en 2014 (1)

ü Usage topique +++oOtite chronique à P. aeruginosa (randomisée, double aveugle, 24 patients)

• Cocktail de 6 phages, 24 patients• Efficacité clinique et microbio• Tolérance parfaite et disparition des phages au décours

oTraitement ulcères de jambe (randomisée, double aveugle, 40 patients)• Cocktail phages anti P. aeruginosa, E. coli & S. aureus

Prévention diarrhées bactérienneso Industrie alimentaire (décontamination)

• ListShield, EcoShield, SalmoFresh = autorisation FDA

oVibriophages pour mettre fin aux épidémies de choléra (en cours)

Knoll BM et al. Clin Infect Dis 2014

Applications chez l’Homme en 2014 (2)

ü Traitement des diarrhées bactériennesoPlusieurs essais cliniques avec T4 phages (anti E. coli)

oEpidémie SHU Allemagne 2011: Sélection + caractérisation génétique de

phages candidats actifs sur Shiga toxin-producing E. coli O104:H4 (STEC) en72 h Merabishvili M et al. PLoS One 2012

ü BiofilmsoPrévention colonisation sondes urinaires à P. aeruginosa

• Monophages => sélection résistances en 24 h…• Cocktails phages ou combinaison phage + ATB => efficacité microbio

oTraitement infections osseuses sur matériel (modèle rat)• Phage + teicoplanine = synergie sur SARM

JID 2010

-‐ Pneumonie exp à Pyo 107 intra-‐nasal puis instillation de bacteriophages : survie +++

-‐ Et effet preventif de l’infection si Ttr par phages, 24h avant l’infection

B"P7?8#:P#</D

! Petits peptides antimicrobiens produits par des bactérieso Tolérance excellente par voie orale (produits de fermentation dans aliments)o Actifs préférentiellement sur bactéries Gram positifo Spectre variableo Manipulation génétique simple

! Deux principaux modes d’actiono Membrane bactérienneo Répression de gènes et de synthèse protéique

Cotter PD et al. Nature Rev Microbiol 2013

Bactériocines: Modes d’action

Thuricine CD

ü Bactériocine de classe I

ü 2 peptides synthétisés par Bacillus thuringiensis

ü Efficacité comparable à métronidazole sur Clostridium difficile

ü Pas d’impact sur la floreintestinale

ABP118

Bactériocine de classe IIB

ü Peptide synthétisé par Lactobacillus salivarius

ü Prévient la listériose dans un modèle expérimental murin

Cotter PD et al. Nature Rev Microbiol 2013

Oligonucléotides anti-‐sens: les principes

ü Extinction gène(s) délétère(s) par appariement spécifique

ü Forte spécificité

ü Synthèse relativement simple

ü Mais difficultés pour la diffusion à travers la paroi bactérienne…

ü Potentiel thérapeutique fort quand ce souci sera résolu ?

Kole R et al. Nature Rev 2012

Traitement curatif des infections par immunoglobulines

ü Multiples usages théoriques / efficacité selon modèlesanimaux

ü Aucune indication validée …

ü Principaux écueilso Coûtso Maladies rares => pas d’essai randomisé de taille suffisanteo Intervention nécessairement précoce, voire préventiveo Combinée à d’autres interventions (ATB)

Ferrara G et al. Am J Med 2012

Action anti-‐toxinique des IgIV polyvalentes

ü Action anti-PVL démontrée

Gauduchon V et al. J Infect Dis 2004

ü Effet spectaculaire dans le modèle de pneumopathie du lapin à SARM communautaire PVL+

Duong et al. ICAAC 2012

ü Toxines super-antigèniqueso Chocs toxiniques strepto- et

staphylococciqueso Syndrome de Kawasaki

Anticorps monoclonaux

ü Ac anti-toxines A et B en prévention des rechutes de colites à Clostridium difficileaprès guérison par vancomycine

Lowy F et al. N Engl J Med 2010

ü Ac bi-spécifique en prévention des infections sévères à P. aeruginosa

üAc anti-hémolysine alpha enprévention/traitement des infections sévères à S. aureus

ND4BB, Combacte 2014

Traitements anti-‐virulence (1)

→ Cibler la virulence au lieu de la croissance peut potentiellement diminuer la résistance ...→Inhibiteurs du « Quorum – Sensing »:

(Plos One, Aout 2014)

(CCM, 2009)

Traitements anti-‐virulence (2)

Traitements anti-‐virulence (3)→ Cibler la virulence au lieu de la croissance peut potentiellement diminuer la résistance ...→Autres possibles facteurs de virulence cible de P.aeruginosa:

(Plos One, Aout 2014)

(CCM, 2009)

«Drug repurposing for antibacterial or anti-‐virulent effects » Front Microbiol, April 2015

«Drug repurposing for antibacterial or anti-‐virulent effects »

►Towards repositioning niclosamide for anti-‐virulence therapy of Pseudomonas aeruginosa lung infections: development of inhalable formulations throughnanosuspensiontechnology. (Mol Pharm 2015, May 14)

Front Microbiol, April 2015

La médecine « naturelle »

ü Transplantation fécale pour colite à Clostridium difficileréfractaire et/ou sévère => Révolutionnaire !

van Nood E et al. N Engl J Med 2013

a"$.?C/P#</$<"748/55/

! Asticothérapie (Maggot)o Ambroise Paré, 1557, etc…o des essais randomisés ! o disponibilité ATU depuis 2006 en France

Bourlioux P et al. Annales Pharmaceutiques Françaises 2013

!Apithérapie (miel)o pas celui du commerce (irradiation préalable pour destruction pathogènes)o effet antibactérieno raccourcit la cicatrisation des brûlures

Cochrane database Syst Review 2008

! Sérothérapie (sérum équin)o indiquée pour diphtérie, botulisme, tétanos en 2014

« Biospleen »...

Nature Medicine, sept 2014

Nature Medicine, sept 2014

Capture efficiency in vitro Epuration sanguine E.coli in vitro Epuration sanguine E.coli in vivoModèle de bactériémie rat

Modèle de bactériémie E.coli rat Modèle de choc endotoxinique LPS rat

Conclusions-‐ Les antibiotiques ne sont pas « en voie de disparition »...même moins nombreux

-‐ Le développement de nouveaux antibiotiques est toujours « poussé » par la diffusion de

nouveaux mécanismes de résistance

-‐ L’augmentation des résistances est inéluctable car une nécessité pour la survie bactérienne...

et nous vivons dans un monde bactérien « protecteur »

-‐ Les antibiotiques sont qqle part une idée réductrice et à « double effet » ...

-‐ Il faut changer les concepts !

-‐ Trouver de nouvelles cibles thérapeutiques pour ne pas « tuer » les bactéries

-‐ Il n’y a pas de bactéries « pathogènes ou non – pathogènes »

-‐ Il faut repenser l’infection dans une approche complexe de l’interaction hôte (immunité innée

et acquise)-‐pathogène(« facteurs de virulence »)

-‐ Il faut apprendre à « moduler » cette relation hôte-‐pathogène en jouant « à la fois et selon »

sur des facteurs hôte et/ou bactérie en préventif et en curatif

-‐ La montée en puissance de la génomique et des nano et biotechnologies vont nous aider dans

cette nouvelle approche

Quel$futur$pour$l’antibiothérapie? · - Stable vis-à-vis des β-lactamases: BLSE,...

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Transcript of Quel$futur$pour$l’antibiothérapie? · - Stable vis-à-vis des β-lactamases: BLSE,...