|Year : 2012 | Volume
| Issue : 4 | Page : 437-441
First characterisation of plasmid-mediated quinolone resistance-qnrS1 co-expressed bla CTX-M-15 and bla DHA-1 genes in clinical strain of Morganella morganii recovered from a Tunisian Intensive Care Unit
S Mahrouki1, A Bourouis1, H Chihi1, R Ouertani1, M Ferjani2, MB Moussa3, F Barguellil3, O Belhadj1
1 Department of Biology, Laboratory of Biochemistry and Biotechnology, Faculty of Sciences of Tunis, Campus Universitaire, 2092 El-Manar II, Tunis, Tunisia
2 Intensive Care Unit Ward, Military Hospital of Tunis, 1089 Monfleury, (MF), Tunis, Tunisia
3 Laboratory of Microbiology, Military Hospital of Tunis, 1089 Monfleury, Tunis, Tunisia
|Date of Submission||04-Jan-2012|
|Date of Acceptance||30-May-2012|
|Date of Web Publication||24-Nov-2012|
Department of Biology, Laboratory of Biochemistry and Biotechnology, Faculty of Sciences of Tunis, Campus Universitaire, 2092 El-Manar II, Tunis
Source of Support: Tunisian Ministry of Higher Education and Scientific Research., Conflict of Interest: None
Purpose: Aim of this study was to show the emergence of the qnr genes among fluoroquinolone-resistant, AMPC and ESBL (extended-spectrum-beta-lactamase) co-producing Morganella morganii isolate. Materials and Methods: A multi resistant Morganella morganii SM12012 isolate was recovered from pus from a patient hospitalized in the intensive care unit at the Military hospital, Tunisia. Antibiotic susceptibility was tested with the agar disk diffusion method according to Clinical and Laboratory Standards Institute guidelines. ESBLs were detected using a standard double-disk synergy test. The characterization of beta-lactamases and associated resistance genes were performed by isoelectric focusing, polymerase chain reaction and nucleotide sequencing. Results: The antimicrobial susceptibility testing showed the high resistance to penicillins, cephalosporins (MICs: 64-512 μg/ml) and fluoroquinolones (MICs: 32-512 μg/ml). But M. morganii SM12012 isolate remained susceptible to carbapenems (MICs: 4-<0.25 μg/ml). The double-disk synergy test confirmed the phenotype of extended-spectrum β-lactamases (ESBLs). Three identical β-lactamases with pI values of 6.5, 7.8 and superior to 8.6 were detected after isoelectric focusing analysis. These β-lactamases genes can be successfully transferred by the conjugative plasmid. Molecular analysis demonstrated the co-production of bla DHA-1, bla CTX-M-15 and qnrS1 genes on the same plasmid. The detection of an associated chromosomal quinolone resistance revealed the presence of a parC mutation at codon 80 (Ser80-lle80). Conclusion: This is the first report in Tunisia of nosocomial infection due to the production of CTX-M-15 and DHA-1 β-lactamases in M. morganii isolate with the association of quinolone plasmid resistance. The incidence of these strains invites continuous monitoring of such multidrug-resistant strains and the further study of their epidemiologic evolution.
Keywords: AmpC, Extended-spectrum β-lactamase, M. morganii, Nosocomial infection, Resistance
|How to cite this article:|
Mahrouki S, Bourouis A, Chihi H, Ouertani R, Ferjani M, Moussa M B, Barguellil F, Belhadj O. First characterisation of plasmid-mediated quinolone resistance-qnrS1 co-expressed bla CTX-M-15 and bla DHA-1 genes in clinical strain of Morganella morganii recovered from a Tunisian Intensive Care Unit. Indian J Med Microbiol 2012;30:437-41
|How to cite this URL:|
Mahrouki S, Bourouis A, Chihi H, Ouertani R, Ferjani M, Moussa M B, Barguellil F, Belhadj O. First characterisation of plasmid-mediated quinolone resistance-qnrS1 co-expressed bla CTX-M-15 and bla DHA-1 genes in clinical strain of Morganella morganii recovered from a Tunisian Intensive Care Unit. Indian J Med Microbiol [serial online] 2012 [cited 2019 Jun 27];30:437-41. Available from: http://www.ijmm.org/text.asp?2012/30/4/437/103765
| ~ Introduction|| |
Recently, the CTX-M β-lactamases are the most widespread enzymes with a growing prevalence. CTX-M-15 (belonging to CTX-M-1 group) was the most commonly encountered CTX-M enzymes produced in Escherichia More Details coli and Klebsiella pneumoniae isolates that was responsible for outbreaks in France, the United Kingdom, Sweden, Canada and India as previously described. ,,,, In Tunisia, more recent studies revealed the outbreaks of CTX-M-15 extended-spectrum β-lactamases producing E. coli and K. pneumoniae isolates recovered in Charles Nicolle Hospital from March 2000 to June 2003. 
A frequent association of quinolone resistance with the production of extended-spectrum β-lactamases (ESBLs) has been noticed and was explained by the selective pressures of multiple antibiotics and plasmid mediated qnr.  A recent investigation showed the prevalence of plasmid-mediated quinolone resistance determinants in Enterobacteriaceae from Tunisia and described the wide spread of qnr-like determinants with an association with the ESBL CTX-M-15.  A new emerging class of plasmid-borne β-lactamases derived from chromosomal ampC genes, was increasingly reported. Association of acquired AmpC cephalosporinases and ESBL is difficult to detect in daily practice.  As our knowledge, no publications reported the Enterobacteriaceae co-producing DHA-1 and extended-spectrum β-lactamases (ESBLs) in Tunisia. Here, we describe a multidrug resistant Morganella morganii isolated from Military Hospital in Tunisia with reduced susceptibility to oxyimino-cephalosporins, coproducing DHA-1, CTX-M-15 β-lactamases and qnrS1 .
| ~ Materials and Methods|| |
On April 4 th , 2008, a 48-year-old man was hospitalized in the intensive care unit at a Tunisian Hospital, for grave cranial traumatism. On May 31, 2008, M. morganii SM12012 isolate was recovered from pus. It was identified using the API 20 E identification system (bioMιrieux, Marcy l'Etoile, France). This isolate showed resistance or decreased susceptibility to penicillins, cephalosporins but remained susceptible to carbapenem and rifampicin. The patient had received a course of imipenem (Sigma, USA) (3 g per day during 15 days) and a course of rifampicin (Sigma, USA) (140 mg daily for 4 days). The patient showed clinical improvement and treatment was completed after 14 days. The same antibiotic resistance pattern was observed in blood culture of M. morganii 6019 strain producing CTX-M-15 enzyme isolated on March 2008 in the intensive care unit at a Tunisian Hospital. The clonal relationship between the strains was studied by Pulsed Filed Gel Electrophoresis (PFGE) using SpeI as a restriction enzyme (Bio-rad® , laboratories, France). Restriction fragments of DNA were separated by electrophoresis in agarose gels at 6V/cm for 20 h with CHEF-DRII system (Bio-Rad® , Laboratories, Richmond, CA, France). The results were analysed according to established criteria.  Susceptibilities to various antimicrobial agents [Table 1] were tested, and potential ESBL-producing isolates were confirmed by the disk diffusion method on Mueller-Hinton agar (Diagnostics Pasteur, France).  Antibiotics disks were purchased from Bio-Rad®, Marnes La Coquette, France. The double-disk synergy test (DDST) for confirmation of ESBL activity was carried out as described previously  in presence of cloxacillin (Sigma, USA) at 250 μg/ mL in Mueller-Hinton agar. The minimum inhibitory concentrations (MICs) of various β-lactam agents (Sigma, USA) were determined by dilution method on Mueller-Hinton agar. Interpretation of antibiogram and MICs results was determined according to Clinical and Laboratory Standards Institute recommendations. 
|Table 1: MICs of various antimicrobial agents obtained for the clinical isolate M. morganii SM12012, trans conjugant and the E. coli HB101 recipient|
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Conjugation experiments were carried out in liquid Luria Broth (LB) (Diagnostics Pasteur, France) medium with E. coli HB101 (F -, Δ(gpt-proA) 62, leuB6, supE44, ara-14, galK2, lac Y1, Δ(mcrc-mrr), rps, L26, Xyl-rmtl 1, thi-1, IncFI, rec AB, strr ) as the recipient, as described previously.  Trans conjugants were selected on LB agar containing ampicillin (100 μg/ml) (Sigma, USA) and streptomycin (256 μg/ml) (Sigma, USA). Crude β-lactamases extracts of the strain SM12012 and its trans conjugants were subjected to analytical isoelectric focusing on a pH-3 to 10 ampholine polyacrylamide (Bio-rad®, France) gel containing starch 0.5% at a voltage of 100 to 300 in a 111 Mini IEF Cell (Bio-Rad® , France ). β-lactamases with known pIs were used as standards: TEM- 1(pI 5.4), TEM-2 (pI 5.6), TEM-3 (pI 6.3) and SHV- 1(pI 7.6).  Plasmid DNA was extracted from M. morganii SM12012 strain and its trans conjugant by the rapid alkaline lysis procedure  and was used as DNA template for PCR experiments.
The presence of bla TEM, bla CTX-M were detected by PCR and DNA sequencing was performed with the Big-Dye® Terminator v.3.1 Cycle sequence Kit with Ampli Taq DNA polymerase (Promega, USA) and ABI PRISM 310 automatic sequencer (Applied Biosystems, USA) with appropriated oligonucleotide primers (TEM24-F, TEM24-R ) (Eurogentec, Belgium) as previously described  and the four primer sets which were used in reactions with plasmid preparations from M. morganii SM12012 to amplify bla CTX-M sequences and were designated CTX-M-1, CTX-M-2, CTX-M-8 and CTX-M-9 (targeting sequences encoding β-lactamases of CTX-M-1, CTX-M-2, CTX-M-8 and CTX-M-9 groups, respectively) (Eurogentec, Belgium).
The detection of qnr genes (qnrA, qnrB, and qnrS) and plasmid-mediated AmpC β-lactamases (CMY/LAT, DHA, CMY/MOX, FOX, ACT/MIR and ACC) was performed by multiplex PCR using respectively these appropriate primers: QnrAM, QnrBM and QnrSM; MOXM, CITM, DHAM, AACM, EBCM and FOXM (Eurogentec, Belgium) as previously described. , M. morganii SM12012 isolate (DHA + , qnrS + ) was subjected to further PCR analysis using respectively (DHA-1/A; DHA-1/B) Eurogentec, Belgium) and (QnrSm/F; QnrSm/R) (Eurogentec, Belgium) as specific primers; amplification was carried out under the PCR conditions as described previously. , Nucleotide and amino acid sequence analysis were performed using NCBI analysis tools (http://www.ncbi.nlm.nih.gov/), and by comparison with data available in GenBank at http://www.lahey.org/studies/webt.html.
A search for additional chromosome-encoded quinolone resistance determinants (gyrA, gyrB, parC, and parE genes) was performed by PCR using the flowing primers (GyrA, GyrB, ParC, ParE) (Eurogentec, Belgium) under the conditions as previously.  The genomic DNA was extracted from the clinical isolate by a genomic extraction kit illustra Bacteria Genomic Prep Mini Spin Kit (Amersham-Biosciences, Germany). PCR products were sequenced to detect mutations.
| ~ Results|| |
This isolate showed resistance or decreased susceptibility to penicillin's, cephalosporins but remained susceptible to carbapenem. The MICs for SM12012 indicated that this strain was resistant to amoxicillin, ticarcillin, cefoxitin, and reduced susceptibility to cefotaxime, ceftriaxone and ceftazidime. The strain co- resistant to chloramphenicol, tetracycline and ofloxacin but it remained susceptible to ertapenem and imipenem [Table 1]. After addition of cloxacillin, M. morganii SM12012 strain was susceptible to 3 rd -generation cephalosporin's with a positive synergy test (cefotaxime), suggesting an acquired AmpC β-lactamase and ESBL co-expression.
A large plasmid DNA (>70 kb) was transferred from parental strain to E. coli HB101 recipient strain with a frequency of conjugational transfer equal to 0.6 10 -5 /donors. The E. coli trans conjugants were resistant to penicillin and expanded-spectrum cephalosporin [Table 1]. These results confirmed the plasmid-mediated co-production ESBLs and ampC β-lactamases enzymes which exhibit notable activity against ceftazidime, cefotaxime and cefoxitine. Resistance to quinolones was also co-transferred with the ESBL phenotype [Table 1]. A protein extract from a culture of SM12012 strain showed three β-lactamases with pI values of 6.5, 7.8 and superior to 8.6 after isoelectric focusing analysis.
A positive CTX-M-1 and TEM-24 PCR amplicons were obtained in SM12012 strain and its trans conjugant and, after sequencing; the bla CTX-M-15 and bla TEM-24 genes were identified.
With the aim of investigating an association between CTX-M, AMPC β-lactamases production and resistance to quinolones, we screened for plasmid-mediated AMPC β-lactamases and qnr genes by multiplex PCR. Amplification products of the expected size of about 428 bp and 405 bp were observed with the use respectively of qnrS and DHA-1 specific primers. Sequencing of the PCR products, followed by comparative analysis with published sequences, revealed the presence of qnrS1 and DHA-1 in M. morganii SM12012 isolate and its trans conjugant. MICs of nalidixic acid, ofloxacin and ciproflaxacin ranged between 32 and 512 μg/ml, these results confirmed the quinolone resistance phenotype [Table 1]. The resistance to nalidixic acid was co-transferred with the ESBL-type resistance phenotype [Table 1]. The detection of an associated chromosomal quinolone resistance does not revealed the presence of GyrA, GyrB and parE but we detect a parC mutation at codon 80 (Ser-lle).
| ~ Discussion|| |
In our study, we have reported the association of quinolone plasmid resistance with the production of ESBL and Amp-C β-lactamase in M. morganii isolate. This is the first report of nosocomial infection due to DHA-1 and CTX-M-15 coproducing M. morganii clinical isolate harbouring plasmid-mediated quinolone resistance gene in Tunisia.
The increase of consumption of cefotaxime and ceftazidime could have contributed to the emergence of CTX-M enzymes encoding genes among E. coli and K. pneumoniae strains.  Between March 2000 and June 2003, the first discovery of CTX-M-15-type-lactamases has been reported among E. coli and K. pneumoniae clinical strains in Tunis  and on May to July 2005 in the Hospital of Sfax, Tunisia.  A retrospective survey of ESBL-producing K. pneumoniae and E. coli clinical isolates was carried out in Tunis from December 1998 to September 2007. All strains harboured the bla CTX-M-15 gene. 
In this study, Macro-restriction analysis using SpeI restriction endonuclease identified one genotype profile [Figure 1], showing that both strains (SM12012 and 6019) were clonally related. The current finding showed the dissemination of specific clone of the CTX-M-15-producing M. morganii isolates within the same ward [Figure 1], where this enzyme was widespread in E. coli in other Tunisian hospital. This fact could explain the presence of the ESBL determinants in this unusual host following co-infection with E. coli strains carrying conjugative plasmids encoding CTX-M-15. More recent investigations showed the absolute association between qnrB4 and DHA-1 determinants with the production of CTX-M-14 in K. pneumoniae isolates recovered from the blood isolate collection at the Korean Hospital.  In Tunisia, early studies reported the first detection of a plasmid-encoded cephalosporinase CMY-4 in a single isolate of Proteus mirabilis.  Later, a phenotypic detection of ACC-1 type AmpC β-lactamase with the association of ESBL production was found in Salmonella More Details Livingstone and K. pneumoniae clinical isolates in the Hospital of Sfax, Tunisia. 
|Figure 1: Pulsed-field electrophoresis pattern of the CTX-M-15- producing M. morganii isolates. Phage lambda was used as size markers (Bio-rad® laboratories); Molecular sizes (in kb) are indicated in the right|
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The qnr genes are often located on transferable plasmids and co-transmitted with other important resistance genes, especially genes encoding resistance to cephalosporins.  The qnrS1 gene was previously identified for the first time on pAH0376 from Shigella flexneri strain.  In Europe, qnrS gene has been detected recently in ESBL positive M. morganii strain isolated from patient in Bolzano, a town in Northern Italy between January 2005 and April 2007.  In Tunisia, a recent investigation described the characterization of a multi-drug resistance Enterobacter cloacae strain isolated from patient, harboured plasmid mediated quinolone resistance determinant qnrS1 (accession number GQ336885.1)  and other studies reported the presence of qnrS1 gene in two clinical human isolates recovered at the Hospital of Sousse, with an association with the ESBL CTX-M-15.  These results suggested the dissemination of plasmid carried qnrS1 and bla CTX-M-15 in our hospitals. Frequently, quinolone resistance is associated with the production of extended-spectrum β-lactamases (ESBLs), which can be due to the plasmid-mediated ESBL and qnr genes, often associated with mobile elements such as integrons and ISCR transposons. In daily practice, it required a detailed analysis of the mechanisms underlying a multidrug resistance phenotype. Phenotypic techniques and molecular analysis are key approaches to determine the co-resistance. 
In conclusion, we were able, by molecular analysis, to identify the simultaneous presence of qnrS1, bla CTX-M-15, bla DHA-1 and bla TEM-24 in M. morganii SM12012 clinical isolate. The emergence of multi-resistant Enterobacteriaceae isolates harboring different β-lactamases represents a significant threat for the management of nosocomial infections, so it is important for laboratories to rapidly and accurately identify ESBL-producing isolates for successful therapeutic management to prevent the misuse of antibiotics by clinicians. ,, The presence of strains producing CTX-M-15 and qnr in the hospital environment could be linked to insufficient measures in room's surface cleaning,  so continued surveillance is essential to control the spread of this resistance parallel a further investigations are necessary to understand the genetic background of these enzymes.
| ~ Acknowledgments|| |
This work was funded and supported by grants from the Tunisian Ministry of Higher Education and Scientific Research.
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