Effect of Imipenem and Meropenem on the Digestive Microbiota and the Emergence and Carriage of Multidrug-resistant Bacteria

Study Overview
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Brief Summary
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Among enterobacteria, ESBL production is the leading cause of multidrug resistance. The first cases of ESBL-producing Enterobacteriaceae (EBLSE) infections were described in the 1980s and subsequently spread worldwide. Since the turn of the century, the prevalence of EBLSE infections, particularly among E. coli and K. pneumoniae, has increased dramatically. The emergence of multidrug-resistant enteric bacteria (MRE) is currently a real public health problem. The European network for monitoring antibiotic resistance in cooperation with Santé Publique France evaluated the rate of resistance to third generation cephalosporins (C3G) among clinical strains at 10.2% for Escherichia coli and 28.8% for Klebsiella pneumoniae. The consequences of infections with multi-resistant enteric bacteria, mainly represented by ESBL, are currently well known, both from an individual point of view (increased mortality and length of hospitalization) and from a collective point of view (increased costs of care). The current reference treatment for ESBL-producing Enterobacteriaceae infections is based on carbapenems. Imipenem and meropenem are the two most commonly used carbapenems in clinical practice. Despite their similar spectrum of action, these two molecules have different pharmacokinetic properties, notably concerning their half-life and their elimination routes (mainly urinary for imipenem, mixed: biliary and urinary for meropenem). Some studies have suggested that imipenem has a low impact on the digestive microbiota. However, no studies comparing the impact of imipenem and meropenem have been conducted. Woerther et coll. explained in their work that the digestive microbiota confers resistance to colonization by MREs. The impact of antibiotics on the microbiota probably leads to a breakdown of this barrier and a loss of this resistance to colonization. Moreover, each antibiotic therapy does not impact the digestive microbiota in the same way and it seems that antibiotics with a high activity against strict anaerobic species and/or a high biliary elimination are the most impacting. It is therefore essential, in the era of multidrug resistance, to look at the influence of antibiotics on the digestive microbiota and on the emergence and carriage of MRE. In a context where the incidence of multi-resistant bacteria is constantly increasing, it seems relevant to conduct a study aiming at comparing the respective impact of the use of imipenem and meropenem on the emergence of MRE and on the digestive microbiota at the individual level. This study aims at comparing the microbiological impact (in terms of emergence of bacterial resistance and in terms of impact on the diversity of cultivable digestive bacteria). It will be a comparative study with matching of patients according to age, service and previous duration of hospitalization. Indeed, the usual management of patients with an infection requiring treatment with a carbapenem is different between the 2 participating centers. Thus, according to the usual management of patients in these 2 participating centers, patients at Avicenne Hospital are treated with meropenem and patients at the Paris Saint-Joseph Hospital Group with imipenem, except in the case of a need for a high daily dose (osteoarticular infection, for example) due to the neurological toxicity of imipenem at high dosage. In the case of high-dose use, meropenem will be the preferred molecule.

Official Title
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Effect of Imipenem and Meropenem on the Digestive Microbiota and the Emergence and Carriage of Multidrug-resistant Bacteria

Conditions
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Enterobacteriaceae Infections

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient ≥ 18 years old Patient hospitalized in the intensive care unit of the Groupe Hospitalier Paris Saint-Joseph or the Avicenne Hospital Patient with an infection requiring probabilistic or documented treatment with a carbapenem (imipenem or meropenem) French speaking patient Patient or relative able to give his or her non-objection Exclusion Criteria: Patients with a carbapenem allergy Pregnant or breastfeeding woman Patient under guardianship or curatorship Patient deprived of liberty Patient under court protection

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Imipenem<br>Prescribing rules differ from one department to another: Imipenem is the preferred drug at Saint-Joseph Hospital. | |
| Meropenem<br>Prescribing rules differ from one department to another: Meropenem is the preferred carbapenem at Avicenne Hospital. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ecological impact of imipenem and meropenem on the microbiota (modification of bacterial diversity) | This outcome corresponds to the rate of modification in bacterial diversity judged by the loss of at least one bacterial species in the microbiota after initiation of antibiotic therapy. | Month 1 | 
| Ecological impact of imipenem and meropenem on the microbiota (abundance) | This outcome corresponds to the rate of diminution in bacterial abundance within the microbiota, defined as a decrease of at least 2 logs in abundance. | Month 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the change in bacterial diversity | This outcome corresponds to the rate of loss of at least one bacterial species in the microbiota after initiation of antibiotic therapy. | Month 1 | 
| Change in bacterial abundance | This outcome corresponds to the rate of loos corresponding to at least 2 log decrease in bacterial abundance. | Month 1 |