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1 Aix-Marseille Universite Faculte De Médecine De AIX-MARSEILLE UNIVERSITE FACULTE DE MÉDECINE DE MARSEILLE ECOLE DOCTORALE DES SCIENCES DE LA VIE ET DE LA SANTE T H È S E Présentée et publiquement soutenue devant LA FACULTÉ DE MÉDECINE DE MARSEILLE Le 21 Novembre 2019 Par Mr DIALLO Ousmane Oumou Né le 02 Février 1988 à Dalaba SURVEILLANCE DE LA RESISTANCE AUX ANTIBIOTIQUES DANS LA REGION PROVENCE ALPES COTE D’AZUR A PARTIR DES SYSTEMES DE SURVEILLANCE (MARSS et PACASURVE) Pour obtenir le grade de Doctorat d’Aix-Marseille Universités Spécialité Pathologie Humaine : Maladies infectieuses Membres du jury de Thèse Pr. Laurence Camoin Président du jury Pr. Jean Philippe Lavigne Rapporteur Pr. Max Maurin Rapporteur Pr. Jean-Marc Rolain Directeur de thèse MEPHI, Aix Marseille Université, IHU Méditerranée Infection, AP-HM, Marseille Faculté de Médecine, Marseille. 1 1 AVANT PROPOS Le format de présentation de cette thèse correspond à une recommandation de la spécialité Maladies Infectieuses et Microbiologie, à l’intérieur du Master des Sciences de la Vie et de la Santé qui dépend de l’École Doctorale des Sciences de la Vie de Marseille. Le candidat est amené à respecter des règles qui lui sont imposées et qui comportent un format de thèse utilisé dans le Nord de l’Europe et qui permet un meilleur rangement que les thèses traditionnelles. Par ailleurs, la partie introduction et bibliographie est remplacée par une revue envoyée dans un journal afin de permettre une évaluation extérieure de la qualité de la revue et de permettre à l’étudiant de commencer le plus tôt possible une bibliographie exhaustive sur le domaine de cette thèse. Par ailleurs, la thèse est présentée sur article publié, accepté ou soumis associé d’un bref commentaire donnant le sens général du travail. Cette forme de présentation a paru plus en adéquation avec les exigences de la compétition internationale et permet de se concentrer sur des travaux qui bénéficieront d’une diffusion internationale. Professeur Didier RAOULT 2 2 REMERCIEMENTS : Je remercie le Professeur Jean-Marc ROLAIN et le Docteur Hervé CHAUDET, ainsi que le Professeur Philippe COLSON pour avoir accepté de m’encadrer au cours de cette thèse. Je les remercie pour leur patience, leur disponibilité et leur aide dans la réalisation de ce travail. J’exprime également mes sincères remerciements au Professeur Didier Raoult qui m’a accepté dans son laboratoire et qui a participé activement à mon encadrement tout au long de ma thèse. Je remercie également les Professeurs Laurence Camoin et Jean Philippe Lavigne ainsi que le Professeur Max Maurin pour avoir accepté de participer à mon jury de thèse. J'aimerais exprimer mon amour le plus profond à ma famille, ma douce épouse Rabiatou Sow ; ce parcours fut difficile et jonché d’obstacles mais le succès de cette thèse de doctorat ne sera pas possible sans vous. Vous avez été un incroyable et, humblement, je vous exprime toute ma gratitude. A mon père, Abdoulaye Diallo, et ma mère Oumou Sadio Barry merci pour tous vos encouragements, vos conseils et vos bénédictions. Je tiens à remercier Dr Sophie Baron et Dr Cédric ABAT pour vos soutiens, vos conseils et votre encadrement. Enfin je tiens à remercier particulièrement Aïssatou Bailo Diallo, Mamadou Aliou Bah, Thierno Bassir Baldé, Edgarthe Ngaiganam, Thérèse Dieng, Audrey Giraud-Gatineau, Rajaonison Andriamiharimamy, David Lupande et tous les étudiants de l’équipe du Pr Rolain pour leur amitié, leurs encouragements et leur soutien. Je voudrais dédier cette thèse à mon père, ma mère, ma douce épouse, ma fille Yaya Goulo et mon fils Thierno Bassir ; je vous dois ce succès. Grand amour !!! 3 3 SOMMAIRE RESUME ......................................................................................................................... 5 ABSTRACT ...................................................................................................................... 6 INTRODUCTION ............................................................................................................ 7 PARTIE I : SYSTEMES DE SURVEILLANCE DE LA RESISTANCE AUX ANTIBIOTIQUES DANS LE MONDE ........................................................................... 16 Article 1: REVIEW. Antibiotic Resistance Surveillance Systems: A Review. ........................... 21 Conclusions et perspectives de la partie I ...................................................................................... 61 PARTIE II : ANALYSE EPIDEMIOLOGIQUE DE LA RESISTANCE AUX ANTIBIOTIQUES A PARTIR DES DONNÉES ISSUES DES DIFFERENTS SYSTEMES DE SURVEILLANCE AU SEIN DE L’INSTITUT HOSPITALO-UNIVERSITAIRE MEDITERRANEE INFECTION DE MARSEILLE. ....................................................... 63 Article 2: Major discrepancy between factual antibiotic resistance and consumption in South of France: analysis of 539,037 bacterial strains. ........................................................................... 70 Article 3: Hospital mortality and positive blood culture with Difficult-to threat (DTR) bacterial infections, Marseille, France ......................................................................................... 123 Conclusions et perspectives de la partie II .................................................................................. 205 PARTIE III : INVESTIGATIONS MENEES AU SEIN DE L'EQUIPE DE SURVEILLANCE EPIDEMIOLOGIQUE. ................................................................... 209 Article 4: Epidemiology of Aerococcus urinae based on clinical isolates using data from 212 public and private laboratories performing clinical microbiological analyses in the French Provence-Alpes-Côte d'Azur region, 2014-2018 ......................................................................... 215 Article 5: Increasing trend Enterococcus gallinarum and Enterococcus avium in the French Provence-Alpes-Côte d'Azur region (PACA),France ................................................................. 235 Conclusion et perspectives de la partie III .................................................................................. 248 CONCLUSIONS ET PERSPECTIVES ......................................................................... 250 POSTERS…………………………………………………………………………………255 ANNEXES………………………………………………………………………………256 Article 6: Tobacco Smoking Affects the Salivary Gram-Positive Bacterial Population ….257 4 RESUME La résistance aux antibiotiques est un sujet d’actualité qui intéresse autant le monde scientifique que les médias. L’impact de la résistance sur la prise en charge et la mortalité sont généralement estimés par des modèles prédictifs et non des modèles factuels. Ces modèles prédictifs permettent de réaliser des estimations qui ne reflètent pas forcement la réalité. Ainsi, l’une des dernières grandes études publiées est celle de Cassini et al. qui estime le coût de la résistance aux antibiotiques en Europe à 33,000 morts par an. En outre selon le rapport de l’OCDE, la résistance aux antibiotiques pourrait couter 3.5 milliards de dollars US par an. Cependant depuis plusieurs années au sein de l’institut hospitalo-universitaire, des études ont été effectuées pour estimer le poids réel de la résistance aux antibiotiques et la mortalité associée. L’objectif de cette thèse est d’évaluer la prévalence de la résistance aux antibiotiques et d’évaluer le coût humain de cette résistance en utilisant des données issues des systèmes de surveillance développés au sein de l’Institut Hospitalo-Universitaire de Marseille. Cette thèse a été divisé en trois objectifs : i) évaluer les capacités actuelles de récupération des données réelles par une revue de la littérature recensant les systèmes de surveillance de la résistance aux antibiotiques dans le monde afin de définir les besoins et les améliorations à réaliser de ces systèmes de surveillance ; ii) établir la prévalence de la résistance aux antibiotiques clés dans la région PACA et évaluer l’impact sur la mortalité de cette résistance lors de sepsis à l’AP-HM, iii) montrer l’intérêt des systèmes de surveillance mis en place à l’IHU et les améliorations réalisées pour mieux détecter des évènements anormaux concernant la résistance aux antibiotiques. Mots clés : Résistance aux antibiotiques, surveillance épidémiologique, Bactéries difficile- à-traité, Mortalité 5 5 ABSTRACT Antibiotic resistance is a topical issue of interest to both the scientific community and the media. The impact of resistance on management and mortality is generally estimated by predictive models and not by factual models. These predictive models allow estimates to be made, but they are false and do not reflect reality. For example, one of the latest major studies published is that of Cassini et al., which estimates the cost of antibiotic resistance in Europe at 33,000 deaths per year. In addition, according to the OECD report, antibiotic resistance could cost US$3.5 billion per year. The objective of this thesis is to evaluate the prevalence of antibiotic resistance and to evaluate the human cost of this resistance using data from surveillance systems developed at the Institut Hospitalo-Universitaire de Marseille. This thesis has been divided into three objectives: i) assess current capacities for recovering actual data through a review of the literature identifying antibiotic resistance surveillance systems worldwide to define the needs and improvements to be made in these surveillance systems; ii) establish the prevalence of key antibiotic resistance in the PACA region and assess the impact on mortality of this resistance during AP-HM sepsis; iii) demonstrate the value of
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