Impact of the Choice of 3rd Generation Cephalosporins on the Emergence of Resistance in the Microbiota Intestinal.
Condition: Emergence of Bacterial Resistance to Antibiotics
Study type: Interventional
Phase: Phase 3

Summary: 
      CEREMI is an open, randomised prospective study in parallel groups in healthy volunteers.
      This study compare the effect of a monotherapy by ceftriaxone or cefotaxime on the emergence
      of resistance of enterobacteria to 3rd-generation cephalosporins within the intestinal
      microbiota. Each volunteer will be treated for 3 days by either ceftriaxone (1 gram per day)
      or cefotaxime (1 gram every 8 hours).
    

Detailed description: 
      Selection of resistant bacteria within the microbiota constitutes the main mechanism for the
      emergence and the diffusion of bacterial resistance to antibiotics. Ceftriaxone is a 3rd
      generation cephalosporin that exposes the intestinal microbiota to an important selecting
      pressure, due to its high biliary clearance. It is thereby suspected to have an important
      role in the emergence of resistance of enterobacteria to 3rd generation cephalosporins. Its
      pharmacokinetics features allow a once daily administration, and it is more largely used than
      cefotaxime, which requires ter in die injections but whose mainly urinary elimination suggest
      a lower impact on the intestinal microbiota.

      Our hypothesis is that ceftriaxone exerts a higher selecting pressure on the intestinal
      microbiota than cefotaxime.

      Our main objective is to compare the effect of a monotherapy by ceftriaxone or cefotaxime on
      the emergence of resistance of enterobacteria to 3rd-generation cephalosporins within the
      intestinal microbiota.

      Secondary objectives include :

        -  Comparison of the effect of ceftriaxone and cefotaxime on the counts of (i) total
           enterobacteria, (ii) 3rd generation cephalosporins resistant enterobacteria according to
           the resistance mechanism, (iii) colonisation resistance in the intestinal microbiota

        -  Pharmacokinetic analysis of cefotaxime and ceftriaxone at steady-state, and link between
           plasma and fecal expositions to each antimicrobial

        -  Analysis of the association between individual exposition to ceftriaxone and cefotaxime
           and their impact on the intestinal microbiota.

      The main evaluation criteria is the area under the curve of the 3rd generation cephalosporins
      resistant enterobacteria in the intestinal microbiota between D0 and D7.

      Secondary evaluation criteria include :

        -  Bacterial and fungal AUC (area under the curve) in the intestinal microbiota between D0
           and D7 and between D0 and D15. Proportion of patients with 3rd generation cephalosporins
           resistant enterobacteria and proportion of patients with non commensal bacteria and
           fungi in the intestinal microbiota at D30, at D90 and at D180.

        -  Studied pharmacokinetic parameters : total bocy clearance, volume of distribution, half
           life. Studied plasma exposition parameters : AUC, maximal and minimal concentration at
           steady-state. Studied fecal exposition parameter : AUC between D0 and D7.

        -  Association between plasma and fecal exposure and AUC of bacterial and fungal counts
           between D0 and D7.

      Methodology :

      Open, randomised prospective study in parallel groups in healthy volunteers. Each volunteer
      will be treated for 3 days by either ceftriaxone (1 gram per day) or cefotaxime (1 gram every
      8 hours). Fecal samples will be collected before (3 samples, D-14, D-7 and D-1) and after the
      first administration of the antibiotic (D1, D2, D3, D4, D7, D10, D15, D30, D90, D180).

      Bacterial analysis of the fecal samples will be performed blindly from the treatment group.
      Drug plasma concentration will be determined at steady-state (T0, T0.5h, T1h, T2h, T4, T6h
      for cefotaxime and T0, T0.5h, T1h, T2h, T4, T8h for ceftriaxone). Drug concentration in the
      feces will be measured on the samples obtained between D0 and D7.

      Pharmacokinetic analysis will be performed using the population approach. All statistical
      analysis will be performed using non parametric tests.
    

Intervention name(s): ceftriaxone; Cefotaxime
Intervention type(s): Drug; Drug
Intervention description(s): ceftriaxone (1 gram per day); cefotaxime (1 gram every 8 hours)
Other intervention name(s): cephalosporin 3rd generation; cephalosporin 3rd generation
Intervention MeSH terms: Ceftriaxone; Cephalosporins; Cefotaxime; Cefoxitin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: microbiota; resistant bacteria