Emergence of Bacterial Resistance to AntibioticsPhase 3CEREMINCT02659033
Impact of the Choice of 3rd Generation Cephalosporins on the Emergence of Resistance in the Microbiota Intestinal.
A Phase 3 study testing ceftriaxone and Cefotaxime in people with Emergence of Bacterial Resistance to Antibiotics, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 65 yearsHealthy volunteers can take part
- Conditions the study is for
- Emergence of Bacterial Resistance to Antibiotics
- What is being tested?
- ceftriaxone and Cefotaxime
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 22 participants
- Where
- 1 siteFrance
- Study dates
- Mar 2016to Dec 2017
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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
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- 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
Trial locations and contacts
1 site in 1 country.
About this study
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).
Read the 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.
- Being tested
- ceftriaxone, Cefotaxime
- Keywords
- microbiota, resistant bacteria
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ceftriaxoneDrug
Also called cephalosporin 3rd generation
ceftriaxone (1 gram per day)
CefotaximeDrug
Also called cephalosporin 3rd generation
cefotaxime (1 gram every 8 hours)
| Study group | Role | What they receive |
|---|---|---|
| ceftriaxone | Active comparator | healthy volunteer who receive ceftriaxone Receives: Drug: ceftriaxone |
| cefotaxime | Active comparator | healthy volunteer who receive cefotaxime Receives: Drug: Cefotaxime |
What is being measured
The primary outcome is the main question the study is designed to answer.
The area under the curve of the 3rd generation cephalosporins resistant enterobacteria in the intestinal microbiota between D0 and D7.
Measured: within the first 7 days
Secondary outcomes (9)
The area under the curve of enterobacteriaceae resistant to C3G accounts (regardless of the resistance mechanism) from D0 to D15 in each treatment group.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: within the first 15 days
Proportion of patients with β-lactamase activity in the stools at D30, D90 and D180 in each treatment group.
Measured: D30, D90 and D 180
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Jan 2016 (estimated)
- Study startMar 2016
- Primary completionMar 2016
- Study completionDec 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Emergence of Bacterial Resistance to AntibioticsStudies of the same condition, open and under way.
- More trials run by Assistance Publique - Hôpitaux de ParisThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 22 participants (actual)
Sponsor and investigators
- Lead sponsor
- Assistance Publique - Hôpitaux de Paris
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Xavier Duval, Profesor, Principal investigator, Assistance Publique - Hôpitaux de Paris
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02659033
- Sponsor's protocol ID
- CRC13-179 / P140904
- Other IDs
- 2014-005485-30, 2014
- Acronym
- CEREMI
- Status last verified
- May 2018
- First submitted
- 5 Jan 2016
- Last updated
- 21 May 2018
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- Undecided
Publications
Burdet C, Grall N, Linard M, Bridier-Nahmias A, Benhayoun M, Bourabha K, Magnan M, Clermont O, d'Humieres C, Tenaillon O, Denamur E, Massias L, Tubiana S, Alavoine L, Andremont A, Mentre 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):e02244-18. doi: 10.1128/AAC.02244-18. Print 2019 Jun.
PubMed 30936104
Study at a glance
From the registry record, last updated by the sponsor on 21 May 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Impact of the Choice of 3rd Generation Cephalosporins on the Emergence of Resistance in the Microbiota Intestinal.
- ClinicalTrials.gov ID
- NCT02659033
- Acronym / sponsor ID
- CEREMI / CRC13-179 / P140904
- Keywords
- microbiota, resistant bacteria
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 22 participants (actual)
- Lead sponsor
- Assistance Publique - Hôpitaux de ParisUniversity, hospital or other
- Study start
- Mar 2016
- Primary completion
- Mar 2016 (actual)
- Study completion
- Dec 2017 (actual)
- First posted
- 20 Jan 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| ceftriaxone | Active comparator | Drug: ceftriaxonehealthy volunteer who receive ceftriaxone |
| cefotaxime | Active comparator | Drug: Cefotaximehealthy volunteer who receive cefotaxime |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- 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)
Key exclusion criteria (16 listed)
- Antibiotic therapy in the previous 6 months
- Hospitalisation in the previous 12 months;
- Active infection
- Ongoing treatment
- Any chronic disease
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ceftriaxoneAlso: cephalosporin 3rd generationceftriaxone (1 gram per day) | Drug | ceftriaxone |
| CefotaximeAlso: cephalosporin 3rd generationcefotaxime (1 gram every 8 hours) | Drug | cefotaxime |
Primary outcome
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
9 secondary outcomes
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
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 May 2018.
- Derived from this study: PubMed 30936104Burdet C, Grall N, Linard M, Bridier-Nahmias A, Benhayoun M, Bourabha K, Magnan M, Clermont O, d'Humieres C, Tenaillon O, Denamur E, Massias L, Tubiana S, Alavoine L, Andremont A, Mentre 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):e02244-18. doi: 10.1128/AAC.02244-18. Print 2019 Jun.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Xavier Duval, Profesor principal investigator
Assistance Publique - Hôpitaux de Paris
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing ceftriaxone and Cefotaxime in people with Emergence of Bacterial Resistance to Antibiotics, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 21 May 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02659033, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 May 2018.