Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02834910 |
| Other study ID # |
173IR08 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
July 13, 2016 |
| Last updated |
July 26, 2016 |
| Start date |
January 2009 |
| Est. completion date |
October 2009 |
Study information
| Verified date |
July 2016 |
| Source |
CHU de Reims |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
France: Comité consultatif sur le traitement de l'information en matière de recherche dans le domaine de la santé |
| Study type |
Observational
|
Clinical Trial Summary
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.
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.
