Le taux de mortalité due au sepsis reste plus que jamais des enjeux cruciaux en santé publique. Les patients hospitalisés en réanimation pour syndromes septiques sont sujets à d’importantes modifications physiopathologiques conduisant à une importante variabilité pharmacocinétique. Cette variabilité induit chez les patients atteints de sepsis des risques de sous-dosage et de toxicité non négligeables par rapport à la population générale. Il est donc nécessaire qu’un travail d’optimisation posologique soit effectué pour pouvoir contrôler l’infection mise en cause et ainsi, faire perdurer l’utilisation des antibiotiques actuels en limitant l’émergence de résistances tout en réduisant la morbi-mortalité d’une large proportion de patients hospitalisés en réanimation.
Par la mesure et l’étude des concentrations en antibiotiques, ce travail a permis de caractériser cette variabilité pharmacocinétique parmi deux classes d’antibiotiques : bêta-lactamines et aminosides qui, lorsqu’ils sont associés, permettent de couvrir une large gamme d’espèces bactériennes pathogènes. Via une approche de data-mining, ce travail a également permis d’identifier les facteurs de risques de sous exposition lors de la première administration d’amikacine. Par le biais de la modélisation pharmacocinétique de population et de simulations, ce travail a abouti en un algorithme posologique optimisation les cibles PK/PD de l’amikacine. Concernant la tobramycine, la modélisation pharmacocinétique a été capable de décrire son comportement au niveau pulmonaire chez un modèle animal sous ventilation mécanique sous deux modalités : la voie intraveineuse et la voie inhalée.
L’ensemble de ce travail suggère que pour atteindre les cibles PK/PD d’efficacité, les anti-infectieux doivent être utilisés à des posologies différentes, en moyenne bien plus importante, par rapport à la population générale. Pour l’amikacine en IV, les doses initiales doivent être fortement majorées ce qui pourrait induire une toxicité rénale. En cas d’infection pulmonaire, la voie inhalée semblerait être une alternative intéressante pour la tobramycine car elle possède un profil de diffusion pulmonaire plus intéressant que la voie intraveineuse tout en limitant son exposition systémique à risque de néphrotoxicité. Ce travail souligne la faiblesse des pratiques actuelles d’utilisation des anti-infectieux en réanimation, avec des schémas posologiques très peu individualisés, peu à même de gérer de façon optimale les multiples
sources de variabilité PK/PD. Les pratiques de suivi thérapeutique pharmacologique apparaissent également insuffisantes en termes de disponibilité, de performance et d’interprétation.
Ce travail propose quelques avancées dans l’optimisation et la modélisation des anti-infectieux. Mais les études pharmacocinétique en réanimation sont souvent soumises à de nombreuses contraintes pratiques : faible effectif de patients, méthodes de dosages peu accessibles en routine, imprécision des méthodes microbiologiques évaluant le degré de résistance des germes pathogènes. De plus, des incertitudes subsistent concernant les cibles PK/PD d’efficacité concernant les aminosides et trop peu de données sont disponibles quant à la toxicité des anti-infectieux de façon général. Pour finir, la diversité qu’offre les patients hospitalisés en réanimation peut également amener à remettre en cause certaines aspect statistiques suggérant d’utiliser de nouvelles approches permettant de mieux expliquer la physiopathologie du sepsis et permettant la détection de nouvelles covariables de façon à mieux évaluer la pharmacocinétique des anti-infectieux.
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