La recherche sur l’antibiorésistance démarre sur les chapeaux de roue en ce début d’année 2020 ! L’équipe de recherche de Nathalie Balaban, implantée à l’Université de Jérusalem, a publié un excellent article dans l’édition de janvier du journal Science (1) : https://science.sciencemag.org/content/367/6474/200.abstract. Les résultats présentés dans cet article questionnent l’intérêt des combinaisons d’antibiotiques pour la prévention de l’apparition de résistance et l’impact de la tolérance aux antibiotiques sur ce phénomène. Mais qu’est-ce que la tolérance aux antibiotiques ?
En 2018, un groupe de chercheurs a débattu sur la question de la persistance et de la tolérance aux antibiotiques. Ils ont publié une déclaration de consensus en 2019 dans Nature Reviews Microbiology (2). A la différence d’une bactérie devenue résistante pour un certain antibiotique (où on observera une augmentation de la concentration minimale inhibitrice, CMI), une bactérie tolérante (aussi appelée « persister ») ne verra pas de modification au niveau de sa CMI. La tolérance aux antibiotiques correspond à l’augmentation du temps nécessaire pour l’élimination d’une population bactérienne. La persistance aux antibiotiques concerne une sous-population bactérienne qui est donc tolérante aux antibiotiques et va perdurer plus longtemps malgré la présence d’antibiotiques.
Revenons à notre article d’intérêt. Les auteurs se sont intéressés aux bactériémies persistantes dues à Staphylococcus aureus résistant à la méticilline (SARM). L’antibiothérapie reçue par le patient débutait par vancomycine en monothérapie, puis une combinaison vancomycine + rifampicine puis un changement pour daptomycine + rifampicine. Les auteurs ont travaillé avec des isolats bactériens issus d’hémocultures réalisées quasi quotidiennement chez le patient pendant 14 jours. En observant la croissance sur gélose de différents isolats bactériens obtenus tout au long de l’infection, les auteurs ont remarqué que les colonies issues des bactéries présentes dans l’hémoculture à J7 après le début de l’infection se développaient plus lentement que les colonies des bactéries présentes dans l’hémoculture prélevée à J1. Dans certaines hémocultures, des populations à croissance normale et à croissance retardée coexistaient. Des tests phénotypiques réalisés sur les différentes sous-populations ont montré que le phénotype de croissance retardée était associé à une tolérance à la vancomycine, sans augmentation de la CMI. Un séquençage du génome complet des différents isolats (ancestral à J1 en comparaison avec les isolats bactériens des hémocultures des jours suivants) a permis de mettre en évidence des polymorphismes sur un seul nucléotide dans différents gènes associés à la tolérance (rpoC, purR, clpX). Des expériences in vitro ont ensuite été réalisées afin de mimer l’apparition de la tolérance et/ou de la résistance aux antibiotiques. Dans un premier temps, les bactéries ont été exposées à la vancomycine et l’apparition de tolérance a été observée au bout de 5 jours. Puis la rifampicine a été combinée à la vancomycine. Malgré la combinaison d’antibiotiques, des mutations ont émergé au niveau du gène rpoB et une résistance à la rifampicine a été observée. De plus, les isolats tolérants à la vancomycine étaient aussi tolérants à la daptomycine conférant une tolérance à la daptomycine lors de la combinaison daptomycine + rifampicine. Afin d’observer si la rapide apparition de la résistance à la rifampicine était facilitée par le phénotype tolérant vancomycine/daptomycine lors d’un traitement daptomycine + rifampicine, les auteurs ont quantifié la survie aux antibiotiques de l’isolat ancestral et d’un isolat vancomycine/daptomycine tolérant. Les résultats obtenus révèlent i) que l’isolat vancomycine/daptomycine tolérant survit plus facilement en présence de daptomycine, ii) que le traitement à la rifampicine est aussi efficace sur l’isolat ancestral que sur l’isolat vancomycine/daptomycine tolérant et iii) que la combinaison daptomycine + rifampicine n’est pas plus efficace sur l’isolat ancestral que sur l’isolat vancomycine/daptomycine tolérant. Cependant, dans cette dernière condition, la résistance à la rifampicine apparait beaucoup plus rapidement avec l’isolat vancomycine/daptomycine tolérant qu’avec l’isolat ancestral. Alors pourquoi utiliser la combinaison daptomycine + rifampicine en clinique si celle-ci favorise l’apparition de résistance ? En fait, l’association de ces 2 antibiotiques est une association dite suppressive. C’est-à-dire que l’association est moins efficace que la daptomycine seule. L’ajout de rifampicine supprime l’effet bactéricide de la daptomycine. Cependant, avec des isolats résistants à la rifampicine, la rifampicine n’aura pas d’effet et la daptomycine pourra exercer son effet bactéricide pleinement contre des isolats de type ancestral (c’est-à-dire sans tolérance vancomycine/daptomycine).
A l’opposé, la tolérance à la vancomycine ou daptomycine va favoriser l’apparition de résistance à la rifampicine. En effet, grâce à la susceptibilité réduite à la daptomycine, la résistance à la rifampicine va pouvoir se développer en présence de la combinaison daptomycine + rifampicine. Les auteurs ont par la suite validé ce principe « la tolérance favorise la résistance avec des combinaisons d’antibiotiques suppressives » chez E. coli (1).
Ce travail met en évidence le lien entre tolérance et résistance et révèle l’intérêt de mettre en place des traitements antibiotiques en combinaison avant l’apparition de la tolérance. Détecter la tolérance lors des analyses en laboratoire de routine apparait donc nécessaire pour limiter l’apparition de résistance. Cependant, les méthodes actuellement disponibles dans les laboratoires de recherche pour détecter la tolérance paraissent difficilement adaptable aux laboratoires de routine (3).
Références :
-
Liu J, Gefen O, Ronin I, Bar-Meir M, Balaban NQ. 2020. Effect of tolerance on the evolution of antibiotic resistance under drug combinations. Science 367:200–204.
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Balaban NQ, Helaine S, Lewis K, Ackermann M, Aldridge B, Andersson DI, Brynildsen MP, Bumann D, Camilli A, Collins JJ, Dehio C, Fortune S, Ghigo J-M, Hardt W-D, Harms A, Heinemann M, Hung DT, Jenal U, Levin BR, Michiels J, Storz G, Tan M-W, Tenson T, Van Melderen L, Zinkernagel A. 2019. Definitions and guidelines for research on antibiotic persistence. Nat Rev Microbiol 17:441–448.
-
Berti AD, Hirsch EB. 2020. Tolerance to antibiotics affects response. Science 367:141–142.
Jérôme JOSSE
Maitre de Conférences
Institut des Sciences Pharmaceutiques et Biologiques de Lyon (ISPB)
CIRI – Centre International de Recherche en Infectiologie, Team “Staphylococcal Pathogenesis”
INSERM U1111 – CNRS UMR5308 – ENS Lyon – UCBL1
jerome.josse@univ-lyon1.fr
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