Qnr Genes in Enterobacteriaceae

July 26, 2016 updated by: CHU de Reims

Prevalence, Characterization and Risk Factors of Acquiring Qnr Genes in Extended Spectrum Beta-lactamase Producing Enterobacteriaceae Isolated in East Inter-region.

Enterobacteriaceae are bacteria of the gastrointestinal tract which are also the most frequently involved in bacterial infections, especially urinary tract infections. Because of their presence in the gut, these bacteria are the most exposed to antibiotic treatment administered to patients.

Therefore, many antibiotic resistance mechanisms are observed in some of them. Quinolone antibiotics are often used because of their distribution in the body, of the great number of bacterial species that are sensitive to these antibiotics and the possibility to give oral treatments.

For a long time no transferable resistance gene to quinolones from one bacterium to another had been observed. This phenomenon has been demonstrated in 1998 in a bacterium of the Klebsiella pneumoniae species carrying a qnrA gene which encodes a protein that protects the target of the antibiotic in the bacteria. Since several genes have been observed. These genes reduce the sensitivity of the bacteria without ever reach detectable resistance levels on the tests commonly used in the laboratory. However, these genes are often found among enterobacteria in combination with other mechanisms of resistance to other classes of antibiotics including beta-lactam antibiotics that are widely used antibiotics.

Moreover, it is considered that quinolone administration to bacteria carrying these qnr genes could promote the emergence of mutants resistant to quinolones to a more high-level. That furthers multiresistance emergence when the bacteria is already resistant to beta-lactam antibiotics.

The aim of this study performed between April 2008 and March 2009 was to collect strains resistant to beta-lactams because of the production of enzymes, called extended-spectrum beta-lactamase to determine quinolone resistance gene frequency in these bacteria.

Meanwhile, control patients were selected to seek the emergence of these genes risk factors.

The clinical study failed to identify specific risk factors, however, the biological study enhanced the knowledge on this issue with the setting-up of a method for rapid detection of these plasmidic mediated quinolones resistance genes and the description a new plasmid containing a qnr gene, qnrD, whose study is still ongoing.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

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Intervention / Treatment

Intervention / Treatment

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Detailed Description

The multidrug resistance in Enterobacteriaceae is a recurring concern for the treatment of patients. Given their epidemic character, the bacteria that produce extended spectrum beta-lactamase (ESBLs) are subject to extensive and costly preventive measures. Gene location of the first described ESBL were plasmids which could transfer from one species to another often associated with resistance to aminoglycoside. Quinolone resistance was not transferable. In 1998, was discovered a Klebsiella pneumoniae carrying a qnr A plasmid gene encoding a protein protecting girases and topoisomerase IV against quinolones. Yet the levels of ciprofloxacin MIC achieved by strains harboring this gene without any other quinolones resistance mechanism associated, remain low. However, the ciprofloxacin MICs for Escherichia coli lacking any other quinolone resistance mechanism can go from 0.003 mg / L to 0.25 mg / L, depending on the type of qnr. Currently, three types of qnr genes have been described, encoding proteins having several variants (qnrA (n = 6), qnrB (n = 10) and qnrS (n = 2). The qnrA and qnrB genes are carried by plasmids of 54-180 kb. Gene environment on plasmid DNA is that of class 1 integron or Type sul1 called. However the sequenced plasmids carrying qnrS do not have integron-like structures. These genes are more common in the Enterobacteriaceae strains producing ESBL strains than in the others. The low prevalences observed up to date, are increasing in some studies. We have observed qnr in 9 of 138 (6.5%) strains isolated in Champagne-Ardenne in 2004, including 4 of 10 strains of Enterobacter cloacae. Furthermore it has been shown in vitro that the presence of qnrA gene facilitated mutant selection for high-level quinolone resistance. Therefore, given the increasing trend in the prevalence of this gene reported by some authors, it is necessary to establish a monitoring and identify factors favoring the emergence of these strains. The purpose of the study is to observe the evolution of the prevalence of qnr genes within ESBL-producing strains, to detect the emergence of an epidemic clonal strain, and look for the emergence of risk factors of these genes. Given the low prevalence of these genes that research involves a multicenter study which will be organized on 9 East region's inter hospitals from 1 April 2008 to 31 March 2009. It is therefore a descriptive study that clinicobiological aims to: - To collect a sufficient number of producer strains of these genes, - To characterize their different variants (CHU Reims), - To identify the clones possibly associated with these genes (Besançon University Hospital), - To study their genetic environment (CHU Dijon), - Seek clinical factors and antibiotic treatments favoring their presence. All ESBL-producing Enterobacteriaceae isolates, identified in the 5 CHU inter region and CH 4, Colmar, Vesoul, Troyes and Charleville for one year will be centralized at the Bacteriology Laboratory of the University Hospital of Reims. The non duplicate isolates will be included (one isolate per patient resistance phenotype, by species and by month). 600 ESBL-producing strains are expected in this period and among them 50 strains carrying the gene qnr. The clinical study is a retrospective record. For each patient with a isolate carrying qnr, 2 control patients from the same hospital with an age difference of less than 10 years with the "case" will be drawn in the list of patients who had a ESBL producing Enterobacteriaceae. And 150 patient records will be included in the study. Parallel sequencing of qnr genes will allow their precise identification and highlight variants. The quinolones MICs will be determined to detect any increase in the level of resistance. The rest of the study include ESBL identification by sequencing. The study of the genetic environment of qnr will be performed for one isolate by gene type and by species for detecting genetic factors promoting their dissemination (plasmid, integron), variabilities compared to the literature data and get additional epidemiological markers. Genotyping of the isolates will highlight a possible epidemic clone. For Escherichia coli phylogenetic group will be determined at the University Hospital of Besancon. The distribution of E. coli strains. coli carrying the qnr among different phylogenetic groups will be compared to that of a number of isolates of Escherichia coli drawn among the ESBL strains having no qnr (2 controls for 1 case). The major clinical parameters recorded from the files will be, among others, the reason for hospitalization, the main underlying disease, antibiotic treatment before and after the isolation of ESBL bacteria. It will determine if the strains carrying the gene qnr are statistically more resistant to certain molecules that stem not having.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
133

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
    • Reims
      • France, Reims, France, 51092
        • CHU Reims

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

For one year, plasmidic mediated quinolone resistance (PMQR) were detected all the Extended- Spectrum beta-lactamase producing Enterobacteriaceae isolated in the 5 teaching hospitals and 4 general hospitals of the french East inter region during the first nine months of 2009. A case-control study was performed. The cases were the 29 patients in whom a qnr gene was detected in an enterobacteriaceae. The controls were 104 patients hospitalized in the hospital with a age difference < 10 years with a case and having an Enterobacteriaceae without a qnr gene. At least, 2 control patients were selected. for each case

Description

Inclusion Criteria:

  • patients hospitalized

Exclusion Criteria:

  • <18 yo

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort

Group / Cohort

A group or subgroup of participants in an observational study that is assessed for biomedical or health outcomes.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Case group
patients with Extended-Spectrum Beta-lactamase producing Enterobacteriaceae carrying a qnr gene isolate
Other: collection of bacterial sample
control-group
patients with Enterobacteriaceae isolate without qnr gene
Other: collection of bacterial sample

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Time Frame
number of ESBL-producing strains
Time Frame: 22 months
22 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
CHU de Reims

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
January 1, 2009

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
September 1, 2009

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
October 1, 2009

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
July 13, 2016

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 13, 2016

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
July 15, 2016

Study Record Updates

Last Update Posted (Estimate)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
July 27, 2016

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 26, 2016

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
July 1, 2016

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 173IR08

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