Détermination de nouvelles modalités d'utilisation des bêta-lactamines en médecine vétérinaire par des approches PK/PD en vue de la protection de la santé publique: impIication de la taille de la charge bactérienne pathogène.

Au cours des dernières années, le microbiote intestinal de l'Homme et des animaux a été identifié comme étant le principal réservoir potentiel de gènes de résistance aux antibiotiques pouvant potentiellement être transmis aux pathogènes humains. Dans ce contexte, nous avons voulu déterminer, par des approches PK/PD, des outils et de nouvelles modalités d'utilisation des antibiotiques en médecine vétérinaire dans le but de réduire leur consommation mais également leur impact sur la flore digestive des animaux afin de réduire le phénomène d'antibiorésistance. Pour ce faire, nous avons développé, par des approches in vitro un indice pharmacodynamique permettant d'évaluer la sélectivité des antibiotiques, c'est-à-dire leur impact à la fois sur la flore pathogène et sur le microbiote intestinal. Nous avons également développé des modèles d'infection rongeurs qui nous ont permis de tester l'impact de traitements antibiotiques à l'amoxicilline et à la cefquinome, utilisant de faibles doses, initiés durant les phases précoces de l'infection et ciblant de faibles inocula pathogènes sur la guérison des animaux et sur l'émergence de bactéries résistantes au sein du microbiote intestinal. Enfin, nous avons testé l'impact de ce type de traitement sur l'émergence de bactéries résistantes au sein de la flore digestive de porcs, espèce cible potentielle. Nos résultats combinés nous ont permis de voir que cette modalité d'utilisation des antibiotiques pourrait se révéler très intéressante en médecine vétérinaire, notamment dans le cadre de la métaphylaxie

Infection-stage adjusted dose of beta-lactams for parsimonious and efficient antibiotic treatments: A Pasteurella multocida experimental pneumonia in mice

In this study, the impact of infection stage on clinically and microbiologically efficacious doses and on antibiotic consumption was assessed during a naturally evolving infectious disease, using an original mouse model of pulmonary infection produced by air-borne contamination. When Pasteurella multocida was administered as pathogenic agent to immunocompetent mice, 60% of the animals exhibited clinical symptoms of pneumonia 2 to 4 days after bacterial contamination of the lungs. Two beta-lactam antibiotics were evaluated: amoxicillin and cefquinome, a fourth generation cephalosporin developed for food animals. First, a pharmacokinetic study was performed in infected mice to determine the exposure to amoxicillin or cefquinome required to treat clinically affected animals, based on the targeted values of PK/PD indices for beta-lactams. We then confirmed that these doses resulted in a 100% clinical cure rate in animals exhibiting clinical signs of infection and harboring a high pathogenic inoculum. More interestingly, we also showed that the same 100% clinical cure could be obtained in our model with 10-fold lower doses in animals at pre-patent stages of infection i.e. when harboring a low pathogenic inoculum. At the group level, antimicrobial drug consumption was reduced by treating animals at an early stage of the infection course with a pre-patent tailored dose. These results suggest that early treatment with a dose suitably adjusted to the stage of infection might help to reduce both overall antibiotic consumption and resistance selection pressure in the animals and in the environment

Clinical and microbiological cure rates with amoxicillin.

<p>Clinical (dark bars) and microbiological (light bars) cure rates of mice after no treatment (grey/black), early (green) or late (red) treatments with different doses of amoxicillin (2.5, 5, 25, or 50 mg/kg). Rates were calculated for all the mice of the group in control and early treatments (as all the mice in a given group were subjected to the same protocol) whereas cure rates for the late treatments were only calculated from the 60 to 70% of mice treated with amoxicillin NA: not assessed.</p

Amoxicillin and cefquinome pharmacokinetics in mice.

<p>Observed (○) and predicted (-) plasma antibiotic concentrations <i>versus</i> time in mice (n = 3 at each time point) after a single subcutaneous administration. A) Amoxicillin, 50 mg/kg. B) Cefquinome, 5 mg/kg. Cefquinome concentrations were below the LOQ for one mouse at 4 h, 2 mice at 6, 8 and 24 h and 3 mice at 12 h.</p

Values of the PK/PD index T_>MIC for different dosing regimens of amoxicillin and cefquinome.

<p>Values of the PK/PD index T_>MIC for different dosing regimens of amoxicillin and cefquinome.</p

Pharmacokinetic and pharmacodynamic parameters of amoxicillin and cefquinome in mice after subcutaneous injection.

<p>Pharmacokinetic and pharmacodynamic parameters of amoxicillin and cefquinome in mice after subcutaneous injection.</p

Growth of <i>Pasteurella multocida</i> inocula <i>versus</i> time (h) in mouse lungs after an aerial challenge.

<p>Symbols represent pathophysiological status of mice: asymptomatic mouse (empty circle), sick mouse (full square), severely sick mouse (full diamond).</p

Clinical and microbiological cure rates with cefquinome.

<p>Clinical (dark bars) and microbiological (light bars) cure rates of mice after no treatment (grey/black), early (green) or late (red) treatments with different doses of cefquinome (0.5, 1, 5, or 10 mg/kg). Rates were calculated for all the mice of the group in control and early treatments (as all the mice in a given group were subjected to the same protocol) whereas cure rates for the late treatments were only calculated from the 60 to 70% of mice treated with cefquinome NA: not assessed.</p