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“Molecular Bases of Antimicrobial Resistance in Acinetobacter Spp. Clinical Isolates.”

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“Molecular Bases of Antimicrobial Resistance in Acinetobacter Spp. Clinical Isolates.” Facultad de Medicina. Departamento de Anatomía Patológica, Farmacología y Microbiología. Programa 2003-2005 - Microbiología Médica. “Molecular bases of antimicrobial resistance in Acinetobacter spp. clinical isolates.” Proyecto de Tesis Doctoral para optar al grado de Doctor en Biología. Presentada por: Sara Martí Martí. Bajo la dirección del Dr. Jordi Vila Estapé. Jordi Vila Estapé, Catedrático del Departamento de Anatomía Patológica, Farmacología y Microbiología de la Universidad de Barcelona y Jefe de Bacteriología del Servicio de Microbiología del Hospital Clínic de Barcelona CERTIFICA: Que el trabajo de investigación titulado “MOLECULAR BASES OF ANTIMICROBIAL RESISTANCE IN ACINETOBACTER SPP. CLINICAL ISOLATES”, presentado por Sara Martí Martí, ha sido realizado en el Laboratorio de Microbiología del Hospital Clínic de Barcelona, bajo su dirección y cumple todos los requisitos necesarios para su tramitación y posterior defensa frente al Tribunal correspondiente. Firmada: Dr. Jordi Vila Estapé Director de la tesis doctoral Barcelona, Septiembre de 2008 AGRADECIMIENTOS Por fin!!! Parece mentira pero al final todo se acaba. Cuando llegué era “la de Londres” pero con el tiempo me hice un pequeño agujerito en este laboratorio. Ahora ya está, la tesis está escrita y hay que seguir adelante. Pero como Goethe dijo: “Si yo pudiera enumerar cuánto debo a mis grandes antecesores y contemporáneos, no me quedaría mucho en propiedad”. Así que me gustaría empezar agradeciendo a Jordi Vila toda su ayuda durante estos años de tesis. He aprendido mucho, pero lo más importante es que nos ha enseñado a pensar por nosotros mismos y a cuestionar los experimentos que estábamos realizando. Tengo más motivos para estar agradecida: cuando volví de Londres encontré una pesadilla de papeles para homologar mis estudios. Jordi, muchas gracias por ofrecerme la oportunidad de volver a trabajar en lo que a mí me gusta. Me gustaría ampliar este agradecimiento a la Dra. Jiménez de Anta y al resto de miembros del departamento de microbiología. A los técnicos del departamento, que me han ayudado muchísimo con las identificaciones bioquímicas (sí, sí, Alicia a ti también, ya sé que estas deseando leer la dedicatoria para ver si me acuerdo de ti). A todos los doctorandos que aún estáis ahí (tranquilos el final de la tesis siempre llega), y a los que habéis leído recientemente. A todos los de “la ciencia”, me acordaré un montón de todos vosotros. Hemos trabajado mucho, pero también hemos pasado muy buenos ratos; ahora nos separamos pero estoy segura que seguiremos en contacto. Roberto que ya ha seguido su camino y Josep que ha cambiado de departamento (gracias por toda tu ayuda y tus consejos). A Marc que decidió que la investigación no era lo suyo pero que nos alegró la vida mientras estaba aquí; gracias por tu inestimable colaboración en la realización de esta tesis. A Paula, te cedo todas mis cepas y mis cajones del congelador. Te deseo mucha suerte con tu tesis; sigue trabajando así de duro y seguro que acabarás muy pronto. Ya sabes que puedes contar conmigo para lo que sea. 7 AGRADECIMIENTOS Muy especialmente a Javi y a Vero. No sé que hubiera hecho sin ellos; me habéis ayudado mucho, tanto en el trabajo como fuera. Los cafés y las cervecitas; las charlas y toda la ayuda que me habéis dado cuando las cosas no salían bien. Ahora estaremos uno en cada punta de mundo, pero os seguiré machacando con mis cosas. Muchas gracias y….. ya sabéis que os quiero un montón. A todos mis amigos de Morella que han tenido que aguantar mis agobios cuando los experimentos no salían bien y mis subidas cuando salían bien. No os voy a nombrar, no quiero dejarme a nadie. Muchas gracias, habéis tenido mucha paciencia. A los amigos que desgraciadamente ya no están; pienso mucho en vosotros. A Manu et à toute l’équipe de Rouen qui m’ont accueillie et vraiment fait sentir comme si j’étais “chez moi”. Manu, tu transmets ton énergie et ton amour pour la science; durant ces trois mois, j’ai revécu mes débuts dans le monde de la microbiologie et compris pourquoi j’ai choisi cette vocation. A “Aguas” que me ha apoyado y ayudado durante toda mi vida. Has estado ahí en los momentos buenos pero también en los malos. Muchas gracias, tú sí que eres un fantástico amigo. A toda mi familia y a la familia Daburon. Brigitte, Robert et Richard, vous m’avez toujours soutenue comme si vous étiez ma propre famille. Merci beaucoup pour toute l’aide que vous m’avez apportée à Londres et durant ces trois mois à Rouen. A Susi que ha sido mi punto de apoyo desde que nací; me has ayudado a crecer y a ser como soy. No sólo eres mi hermana, eres una de mis mejores amigas. A mis padres que me dieron la oportunidad de hacer algo diferente. Con 19 años me fui a Londres y eso cambió mi vida. Muchas gracias, no hubiera podido hacer esto sin vuestra ayuda. To David, what can I say? Thank you for being always there and for your patience while I was writing this report. You have always been very proud of me and I really appreciate it. All your positive thoughts towards me have helped me to overcome the difficult moments. 8 If we knew what it was we were doing, it would not be called research, would it? Albert Einstein A person who never made a mistake, never tried anything new. Albert Einstein All truths are easy to understand once they are discovered; the point is to discover them. Galileo Galilei The most exciting phrase to hear in science, the one that heralds new discoveries, is not “Eureka!” but “That’s funny…” Isaac Asimov TABLE OF CONTENTS I. INTRODUCTION ................................................................ 17 1. CHARACTERISTICS OF THE GENUS ACINETOBACTER ....................................... 21 1.1 TAXONOMIC CHARACTERISTICS ......................................................................................... 21 1.2 IDENTIFICATION IN THE LABORATORY .............................................................................. 25 1.2.1 Identification to the genus level .................................................................................................. 25 1.2.2 Identification to the genomic species level.................................................................................. 28 1.3 CLINICALLY IMPORTANT ACINETOBACTER SPP.. ............................................................... 30 1.4 NATURAL AND CLINICAL RESERVOIRS ............................................................................... 31 1.4.1 Reservoirs ................................................................................................................................... 31 1.4.2 Survival in the environment ........................................................................................................ 32 2. EMERGENCE OF A. BAUMANNII AS A NOSOCOMIAL PATHOGEN .................. 34 2.1 EPIDEMIOLOGY .................................................................................................................... 34 2.2 INFECTIONS CAUSED BY A. BAUMANNII .............................................................................. 35 - Nosocomial pneumonia ................................................................................................................... 36 - Nosocomial bloodstream infections ................................................................................................ 36 - Meningitis ........................................................................................................................................ 37 - Urinary Tract Infection ................................................................................................................... 37 2.3 RISK FACTORS FOR INFECTIONS WITH A. BAUMANNII ....................................................... 38 2.4 CLINICAL IMPACT OF ACINETOBACTER SPP.. ..................................................................... 38 2.5 VIRULENCE AND PATHOGENICITY ...................................................................................... 40 - Lipopolysaccharide (LPS) ............................................................................................................... 40 - Quorum-sensing .............................................................................................................................. 41 - Genetic exchange ............................................................................................................................ 41 - Biofilm formation ............................................................................................................................ 41 - Outer Membrane Proteins (OMPs) ................................................................................................. 42 - Stress-response mechanisms ........................................................................................................... 42 2.6 MULTIDRUG RESISTANCE .................................................................................................... 42 2.7 TREATMENT. ........................................................................................................................ 44 - Treatment of pneumonia caused by carbapenem susceptible A. baumannii ................................... 46 - Treatment of pneumonia caused by carbapenem resistant A. baumannii ....................................... 46 - Treatment of bacteraemia ............................................................................................................... 47 2.8 PREVENTION, MONITORING AND CONTROL MEASURES. ..................................................
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