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Impact of the Choice of 3rd Generation Cephalosporins on the Emergence of Resistance in the Microbiota Intestinal. (CEREMI)

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ClinicalTrials.gov Identifier: NCT02659033
Recruitment Status : Completed
First Posted : January 20, 2016
Last Update Posted : May 21, 2018
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Tracking Information
First Submitted Date  ICMJE January 5, 2016
First Posted Date  ICMJE January 20, 2016
Last Update Posted Date May 21, 2018
Study Start Date  ICMJE March 2016
Actual Primary Completion Date March 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 14, 2016)
The area under the curve of the 3rd generation cephalosporins resistant enterobacteria in the intestinal microbiota between D0 and D7. [ Time Frame: within the first 7 days ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 14, 2016)
  • The area under the curve of enterobacteriaceae resistant to C3G accounts (regardless of the resistance mechanism) from D0 to D15 in each treatment group. [ Time Frame: within the first 15 days ]
  • Proportion of patients with 3rd generation cephalosporins resistant enterobacteria in the intestinal microbiota (regardless of the resistance mechanism) at D30 at D90 and at D180 in each treatment group. [ Time Frame: D30, D90 and D180 ]
  • Area under the curve of enterobacteriaceae resistant to C3G accounts distinguishing the resistance mechanism (B lactamase,plasmid cephalosporinase or cephalosporinase) from D0 to D15 in each treatment group. [ Time Frame: within the first 15 days ]
  • Proportion of patients with 3rd generation cephalosporins resistant enterobacteria in the intestinal microbiota (distinguishing the resistance mechanism) at D30 at D90 and at D180 in each treatment group. [ Time Frame: D30, D90 and D180 ]
  • Area under the curve of total coliform accounts from D0 to D 7 and D0 to D15 in each treatment group. [ Time Frame: within the first 15 days ]
  • Change in total coliform accounts between D0 and D30 between D0 and D90 and between D0 and D180 in each treatment group. [ Time Frame: D30, D90 and D180 ]
  • The area under the curve of aeruginosa accounts, S. aureus, Enterococcus spp., Clostridium difficile and yeasts from D0 to D7 and D0 to D15 in each treatment group. [ Time Frame: within the first 15 days ]
  • The area under the curve of β-lactamase activity of the intestinal microbiota from D0 to D7 and D0 to D15 in each treatment group. [ Time Frame: within the first 15 days ]
  • Proportion of patients with β-lactamase activity in the stools at D30, D90 and D180 in each treatment group. [ Time Frame: D30, D90 and D 180 ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Impact of the Choice of 3rd Generation Cephalosporins on the Emergence of Resistance in the Microbiota Intestinal.
Official Title  ICMJE Impact of the Choice of 3rd Generation Cephalosporins on the Emergence of Resistance in the Microbiota Intestinal.
Brief 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Emergence of Bacterial Resistance to Antibiotics
Intervention  ICMJE
  • Drug: ceftriaxone
    ceftriaxone (1 gram per day)
    Other Name: cephalosporin 3rd generation
  • Drug: Cefotaxime
    cefotaxime (1 gram every 8 hours)
    Other Name: cephalosporin 3rd generation
Study Arms  ICMJE
  • Active Comparator: ceftriaxone
    healthy volunteer who receive ceftriaxone
    Intervention: Drug: ceftriaxone
  • Active Comparator: cefotaxime
    healthy volunteer who receive cefotaxime
    Intervention: Drug: Cefotaxime
Publications * Burdet C, Grall N, Linard M, Bridier-Nahmias A, Benhayoun M, Bourabha K, Magnan M, Clermont O, d'Humières C, Tenaillon O, Denamur E, Massias L, Tubiana S, Alavoine L, Andremont A, Mentré F, Duval X; CEREMI Group. Ceftriaxone and Cefotaxime Have Similar Effects on the Intestinal Microbiota in Human Volunteers Treated by Standard-Dose Regimens. Antimicrob Agents Chemother. 2019 May 24;63(6). pii: e02244-18. doi: 10.1128/AAC.02244-18. Print 2019 Jun.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 22, 2017)
22
Original Estimated Enrollment  ICMJE
 (submitted: January 14, 2016)
24
Actual Study Completion Date  ICMJE December 2017
Actual Primary Completion Date March 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Age between 18 and 65 years
  • Volunteer regarded as healthy after detailed examination
  • Subject whose entourage (person living under the same roof) does not present any chronic disease throughout the course and did not receive antibiotics within 15 days.
  • Effective contraception for women in reproductive age and negative pregnancy test before inclusion
  • Normal intestinal passage (one stool per day)
  • Negative urinalysis for toxic substances
  • Normal blood test (including blood and platelets counts, prothrombin, ionograms, Liver function tests)
  • Negative HIV and HCV (hepatitis C virus) test, no HBV (hepatitis B virus)chronic infection
  • Normal weight (BMI comprised between 19 and 29 kg/m²)
  • Freely obtained consent
  • Health insurance beneficiary

Exclusion Criteria:

  • Antibiotic therapy in the previous 6 months
  • Hospitalisation in the previous 12 months;
  • Active infection
  • Ongoing treatment
  • Any chronic disease
  • Allergy to one of the study drugs
  • Any contraindications to β-lactam therapy in particular to penicillins or cephalosporins
  • Pregnancy or no effective contraception, suckling women
  • Subject, as determined by the investigating physician, could not observing during the study, or unable to communicate because of language or mental disorders barrier;
  • Subject participating simultaneously in another biomedical research
  • Subject can not be contacted in case of emergency;
  • Subject about legally protected under tutorship or curators;
  • Subject deprived of freedom under judicial or administrative constraints

Secondary exclusion criteria

  • No pre-treatment stool sample obtained
  • More than one stool sample missing from D1 to D7
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02659033
Other Study ID Numbers  ICMJE CRC13-179 / P140904
2014-005485-30 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Assistance Publique - Hôpitaux de Paris
Study Sponsor  ICMJE Assistance Publique - Hôpitaux de Paris
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Xavier Duval, Profesor Assistance Publique - Hôpitaux de Paris
PRS Account Assistance Publique - Hôpitaux de Paris
Verification Date May 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP