Clinical trial NCT01703299: Emergence of Resistance in Intestinal Microflora During Carbapenem Treatments
Official title: Emergence of Resistance in Intestinal Microflora During Carbapenem Treatments
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Carbapenem-induced Resistance
Keywords: imipenem
ertapenem
resistance
commensal flora
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2012-10-10
Enrollment: 35
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: hospitalized patients initiating a carbapenem treatment

Brief summary: The use of carbapenems, very broad spectrum antibiotics of last resort, is becoming more common due to the increased prevalence in the hospital and community of extended spectrum β-lactamase (ESBL) producing gram-negative bacilli (GNB), including CTX-M type, which are resistant to all other β-lactam antibiotics. Meanwhile, it creates a selective pressure towards emergence of strains which are also resistant to carbapenems, placing patients in a catastrophic situation of therapeutic dead-end. A better understanding of the mechanisms of emergence of BGN resistant to carbapenems is necessary to optimize their use and undertake preventive measures to preserve their effectiveness. The aim of the study is to evaluate and describe the emergence of carbapenem-induced resistant GNB in patient intestinal microflora.

Detailed description: The use of carbapenems, very broad spectrum antibiotics of last resort, is becoming more common due to the increased prevalence in the hospital and community of extended spectrum β-lactamase (ESBL) producing gram-negative bacilli (GNB), including CTX-M type, which are resistant to all other β-lactam antibiotics. Meanwhile, it creates a selective pressure towards emergence of strains which are also resistant to carbapenems, placing patients in a catastrophic situation of therapeutic dead-end. A better understanding of the mechanisms of emergence of BGN resistant to carbapenems is necessary to optimize their use and undertake preventive measures to preserve their effectiveness.

Hypotheses: Carbapenems induce in treated patients the emergence of resistant GNB in intestinal flora and have an impact on colonization resistance of the gut microbiota.

Primary objective: To determine the frequency of emergence of carbapenems resistant GNB in the intestinal flora at the end of a treatment by imipenem or ertapenem.

Secondary objective(s):

* Assess the presence of carbapenem resistant GNB in the intestinal flora before treatment.
* Evaluate the presence and / or persistence of carbapenem resistant GNB in the intestinal flora on day 3 of treatment, and 15 days and 1 month after the end of treatment.
* Determine the molecular mechanisms of resistance of strains of interest.
* Describe the gastrointestinal tract colonization by non-commensal microorganisms before and after treatment (impact on colonization resistance).
* Describe the characteristics of patients with emergence of resistance compared to patients who do not.
* Proper conservation of stool of 10 patients for metagenomic and/or metatranscriptomic analysis of changes in the intestinal flora.

Primary endpoint: Presence of carbapenem resistant GNB in the stool at the end of treatment in patients who did not before, after culture on selective media.

Secondary endpoints:

* Presence of carbapenem resistant GNB in stools before treatment, at day 3 and 15 days and 1 month after stopping treatment, after culture on selective media.
* PCR and sequencing of resistance genes from strains of interest.
* Colonization of the digestive tract by non-commensal microorganisms before and after treatment.
* Characteristics of patients with or without emergence of resistance.

Eligibility criteria: Inclusion Criteria:

* age\> or = 18 years old
* hospitalized
* initiating a treatment by imipenem or ertapenem-
* faeces harvested before the beginning of treatment
* written informed consent from the patient or from a relative if the patient is incapable of expressing his/her consent
* reachable by phone after hospitalization (only for patients able to express their consent).

Exclusion Criteria :

* hospitalized in intensive care unit
* concomitant antibiotic treatment (except aminosid or vancomycin for less than 4 days).

Secondary exclusion criteria :

* introduction of other antibiotics during carbapenem treatment (except vancomycin or aminosid)
* vancomycin treatment for more than 4 days during carbapenem treatment.

Primary outcomes:
measure: presence of carbapenem-resistant gram-negative bacteria at the end of carbapenem treatment in faeces of patients who were free of carbapenem-resistant gram-negative bacteria before the beginning of treatment
timeFrame: at the end of carbapenem treatment period which usually lasts between 2 and 15 days
Secondary outcomes:
measure: presence of carbapenem-resistant gram-negative bacteria in patient faeces before carbapenem treatment, at day 3 of carbapenem treatment and at day 15 et day 30 after the end of carbapenem treatment
timeFrame: before, at day 3 of carbapenem treatment and at day 15 and day 30 after the end of carbapenem treatment
Other outcomes:
Locations:
city: Clichy
country: France
facility: Hôpital Beaujon
city: Colombes
country: France
facility: Hôpital Louis Mourier
city: Paris
country: France
facility: Hôpital Bichat-Claude Bernard
city: Paris
country: France
facility: Hôpital Saint-Louis
city: Villejuif
country: France
facility: Hôpital Paul Brousse
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Antoine Andremont, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Grall N, Lazarevic V, Gaia N, Couffignal C, Laouenan C, Ilic-Habensus E, Wieder I, Plesiat P, Angebault C, Bougnoux ME, Armand-Lefevre L, Andremont A, Duval X, Schrenzel J. Unexpected persistence of extended-spectrum beta-lactamase-producing Enterobacteriaceae in the faecal microbiota of hospitalised patients treated with imipenem. Int J Antimicrob Agents. 2017 Jul;50(1):81-87. doi: 10.1016/j.ijantimicag.2017.02.018. Epub 2017 May 10.