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  • 1 Department of Medical Microbiology, Faculty of Medicine, Hacettepe University, 06100, Ankara, Turkey
  • 2 Department of Microbiology, Faculty of Molecular Biology and Genetics, Usak University, 64200, Usak, Turkey

Abstract

Carbapenemase-producing and colistin resistant Klebsiella pneumoniae has become a worldwide healthcare problem. This study describes molecular characterization of carbapenemase-producing and colistin resistant clinical K. pneumoniae isolates.

A total of 93 non-replicate carbapenem and colistin resistant K. pneumoniae were recovered from clinical specimens in a university hospital during 2017–2019. Detection of blaOXA-48, blaKPC, blaNDM-1, blaIMP, blaVIM-1 and mcr-1, -2, -3, -4, -5, -6, -7, and -8 genes was performed by PCR. The bacterial isolates were assigned to clonal lineages by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST).

All isolates harbored blaOXA-48 and only two isolates harbored blaOXA-48, and blaNDM-1 genes together. In colistin resistant K. pneumoniae, mcr-1 was detected in two (2.1%) isolates. Ninety three isolates of K. pneumoniae were categorized into three clusters and five pulsotypes. MLST revealed two different sequence types, ST101 (89/93) and ST147 (4/93).

In our study ST101 was found to be a significantly dominant clone carrying blaOXA-48 and among our strains a low frequency of mcr-1 gene was determined. The emergence of colistin resistance was observed in K. pneumoniae ST101 isolates. ST101 may become a global threat in the dissemination of carbapenem and colistin resistance.

Abstract

Carbapenemase-producing and colistin resistant Klebsiella pneumoniae has become a worldwide healthcare problem. This study describes molecular characterization of carbapenemase-producing and colistin resistant clinical K. pneumoniae isolates.

A total of 93 non-replicate carbapenem and colistin resistant K. pneumoniae were recovered from clinical specimens in a university hospital during 2017–2019. Detection of blaOXA-48, blaKPC, blaNDM-1, blaIMP, blaVIM-1 and mcr-1, -2, -3, -4, -5, -6, -7, and -8 genes was performed by PCR. The bacterial isolates were assigned to clonal lineages by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST).

All isolates harbored blaOXA-48 and only two isolates harbored blaOXA-48, and blaNDM-1 genes together. In colistin resistant K. pneumoniae, mcr-1 was detected in two (2.1%) isolates. Ninety three isolates of K. pneumoniae were categorized into three clusters and five pulsotypes. MLST revealed two different sequence types, ST101 (89/93) and ST147 (4/93).

In our study ST101 was found to be a significantly dominant clone carrying blaOXA-48 and among our strains a low frequency of mcr-1 gene was determined. The emergence of colistin resistance was observed in K. pneumoniae ST101 isolates. ST101 may become a global threat in the dissemination of carbapenem and colistin resistance.

Introduction

Klebsiella pneumoniae is an opportunistic pathogen which can cause different types of healthcare-associated infections. Enhanced use of carbapenems in clinical practice, promoted emergence of carbapenem-resistant K. pneumoniae (CRKP) worldwide in recent years [1]. CRKP has mainly been link to K. pneumoniae carbapenemase (KPC), oxacillinase-48 (OXA-48), and metallo-β-lactamases (MBLs), such as NDM, IMP, and VIM type carbapenemases. While these plasmid-encoded carbapenemases have been increasingly reported worldwide, their prevalence varies geographically [2]. The first identified OXA-48 producer was a K. pneumoniae strain isolated in Turkey in 2003 [3]. Since then, OXA-48 producers have been extensively reported from Turkey as a source of nosocomial outbreaks [4–8]. Worldwide distribution of OXA-48 now includes countries in Europe, in the southern and eastern part of the Mediterranean Sea, and Africa [3–8].

Treatment of infected patients with CRKP is always problematic due to their multidrug resistance phenotype, and several therapeutic options have been considered. Colistin is one of these therapeutic options. However, colistin resistance had been observed in CRKP isolates, and rapid dissemination of colistin resistant isolates has been recently reported [9]. Colistin resistance mechanisms are presumed to be linked to chromosomal mutation untransferable via horizontal gene transfer [10]. Recently, several plasmid-mediated colistin resistance genes, named mcr, encoding pEtN transferases, have also been reported in K. pneumoniae [11].

Dissemination of CRKP is mainly caused by the spread of a few successful clones. Major representatives of these high-risk clonal lineages include sequence type (ST) 11, ST15, ST307, ST17, ST37, ST101, and ST147 strains [1]. ST258 strains are major players in the worldwide spread of KPC-type carbapenemases, and are responsible for 68% of the CRKP outbreaks [12]. ST101 strains harbor different clinically-relevant resistance determinants, such as carbapenemases of the KPC, OXA-48, VIM, and NDM types [1].

In this study, carbapenemase producing and colistin resistant clinical K.pneumoniae isolates were characterized to evaluate genetic differences and relationships, and prevalence of carbapenem resistance determinants, as well as to determine plasmid-mediated colistin resistance mechanism.

Material and methods

Bacterial isolates and susceptibility testing

We retrospectively analyzed ninety-three carbapenem and colistin resistant K. pneumoniae isolates consecutively isolated from patients who were hospitalized at the Hacettepe University Hospitals between October 2017 and December 2019. The Hacettepe University Hospitals are tertiary care hospitals of 1,040 beds that provides specialized attention to a population size of ∼5.504 million habitants in the capital of Turkey. In the period between October 2017 and December 2019, altogether 8624 K. pneumoniae isolates were obtained from routine microbiological cultures of clinical samples. In total, 93 carbapenem and colistin resistant K. pneumoniae isolates were obtained. These isolates were detected from blood (n = 34), urine (n = 26), abscess (n = 13), tracheal aspirate (n = 11), peritoneal fluid (n = 4), cerebrospinal fluid (n = 2), synovial fluid (n = 1), pleural fluid (n = 1), and pericardial fluid (n = 1). Isolates were identified with conventional tests (Gram staining, catalase and oxidase tests), and matrix assisted lazer desorption ionization time of flight mass spectrometry (MALDI-TOF MS, Bruker Daltonics, Germany). All isolates were identified with a score ≥2.0; accurate identification to the species level by MALDI-TOF MS. Antibiotic susceptibility profiles of isolates were determined by BD Phoenix™ automated susceptibility testing system (Becton Dickinson and Company BD, USA). Isolates non-susceptible to at least one carbapenem (ertapenem, meropenem, and imipenem) were also tested for carbapenem resistance by gradient test (bioMérieux, France) according to manufacturer's instructions. CRKP was defined when the isolate was resistant to ertapenem, meropenem or imipenem by gradient test. Colistin MICs were determined for 93 CRKP isolates using the Sensititre™ plate (Thermo Fisher, UK). Results were interpreted according to the European Committee on Antimicrobial Susceptibility Testing breakpoints [13]. Escherichia coli ATCC 25922 and E. coli NCTC 13846 (mcr-1 positive) was used for quality control. The isolates were stored in tryptic soy broth containing 10% (v/v) glycerol at −80 °C until use.

Molecular analysis of carbapenem and colistin resistance

Genomic DNA was isolated using the QIAsymphony DSP Virus/Pathogen kit in the QIAsymphony system according to the manufacturer's instructions (Qiagen, USA). OXA-48, KPC, NDM-1, IMP, and VIM-1 carbapenemases were identified by PCR amplification and sequencing as described previously [14]. The colistin resistant isolates were screened by simplex PCRs for the presence of mcr-1, mcr-2, mcr-3, mcr-4, mcr-5, mcr-6, mcr-7, and mcr-8 genes [15–21] (Supplementary Table S1).

PFGE

Pulsed-field gel electrophoresis (PFGE) was performed as per a method described in a previous study [22]. A thin slice of plug was digested overnight at 37 °C with 50 U of the XbaI restriction enzyme according to the manufacturer's instructions. The restriction fragments were separated through PFGE in 1% agarose gel (Bio-Rad, USA) with 0.5x TBE buffer (45 mM Tris, 45 mM boric acid, and 1.0 mM EDTA [pH 8.0]) for 22 h at 200 V and 14 °C, with ramp times of 2 s-40 s using the CHEF Mapper apparatus (Bio-Rad, USA). The gels were stained in ethidium bromide (1 mg/mL), were viewed under an ultra-violet transillumination. Digital images were stored electronically. PFGE banding patterns were analysed with the BioNumerics Software (Applied Maths, Belgium) using the dice coefficient and unweighted pair group method with arithmetic averages algorithm. PFGE patterns were compared and analysed according to the criteria mentioned by Tenover et al. [23].

MLST

Multilocus sequence typing (MLST) was performed on K. pneumoniae isolates according to the protocol described on the K. pneumoniae MLST website (https://bigsdb.pasteur.fr/klebsiella/klebsiella.html). Seven conserved housekeeping genes (gapA, infB, mdh, pgi, phoE, rpoB, and tonB) were used [24]. MLST results were typed according to the updated international K. pneumoniae MLST database at the Pasteur Institute in Paris, France.

Results

Bacterial isolates and susceptibility testing

In the period between October 2017 and December 2019, a total of 8,624 clinical isolates of K. pneumoniae were isolated from patients admitted to Hacettepe University Hospitals. Among those, 2,259 isolates (26.2%) were non-susceptible to at least one carbapenem by gradient test and were tested for colistin resistance. A total of 93 isolates (4.1%) out of this subset showed a colistin resistant phenotype by Sensititre with minimum inhibitory concentrations (MIC) that ranged between 4 and 128 µg/m. Carbapenem and colistin MIC ranges, MIC50 and MIC90 profiles of the isolates are summarized in Table 1. Overall carbapenem and colistin resistance rates are shown in Supplementary Table S2.

Table 1.

MIC (µg/mL) profiles of carbapenem and colistin resistant K. pneumoniae isolates

2017 (n = 18)2018 (n = 38)2019 (n = 37)
Colistin
MIC range4–644–1284–64
MIC50444
MIC90163264
Meropenem
MIC range16–12816–12816–256
MIC50161616
MIC903264128
Imipenem
MIC range16–6416–1288–64
MIC5016168
MIC90326432
Ertapenem
MIC range2–642–1282–64
MIC5021616
MIC90323232

Molecular analysis of carbapenem and colistin resistance

The PCR results indicated that blaOXA-48 gene was detected in all K. pneumoniae isolates (100%), and 2.1% (n = 2) of the isolates co-produced blaOXA-48, and blaNDM-1. Other tested carbapenemase genes, such as blaKPC, blaIMP, and blaVIM-1 could not detected in any of the isolates. Detection of mcr 1-8 genes using PCR technique revealed that two (2.1%) isolates were positive for mcr-1. No mcr-2, -3, 4, -5, -6, -7, and -8 were detected among all tested isolates.

PFGE

The characteristics of the molecular epidemiology of the 93 carbapenem and colistin resistant K. pneumoniae isolates are displayed in Fig. 1. All the 93 carbapenem and colistin resistant K. pneumoniae isolates were grouped into three cluster and five pulsotypes. Cluster three is the largest cluster that possesses 71 isolates. Fourteen isolates belonged to cluster one and eight isolates belong to cluster two. PFGE discriminatory power was of 96%, as calculated by Simpson's Index of Diversity [25].

Fig. 1.
Fig. 1.

Dendrogram based on pulsed-field gel electrophoresis pattern analysis (PFGE) of 93 colistin and carbapenem resistant K. pneumoniae isolates from different wardss and their ST determined via multilocus sequence typing (MLST)

Citation: Acta Microbiologica et Immunologica Hungarica AMicr 67, 4; 10.1556/030.2020.01275

MLST

Ninety-three carbapenem and colistin resistant K. pneumoniae isolates were analysed by MLST, and two ST types were detected. ST101(95.6%, 89/93) was the dominant ST type followed by ST147 (4.4%, 4/93). Among four isolates of ST147, two isolates carried both blaOXA-48 and blaNDM-1 genes, and the other two ST147 clones coproduce blaOXA-48 and mcr-1 genes (Fig. 1).

Discussion

Multidrug resistant pathogens have become a global problem recently [12]. K. pneumoniae is an important nosocomial multidrug resistant pathogen that can cause high morbidity and mortality [26]. After widespread dissemination of carbapenemase producing K. pneumoniae isolates; colistin resistance has emerged in K. pneumoniae isolates and caused problems in treatment modalities [9, 26, 27]. CRKP isolates that produce carbapenemases such as the OXA-48, KPC, VIM-1, NDM-1, and IMP, have been reported worldwide [1, 3, 5–7, 9, 10, 26]. KPCs are the most clinically common enzymes, and have been detected in North America (especially the United States), South America (Colombia, Argentina), Europe (Greece, Italy, Poland), Asia (China), and the Middle East (Israel) [28–30]. Turkey is a country with a specific epidemiology, where OXA-48 carbapenemase has been extensively identified. However, first KPC-2-positive K. pneumoniae have been identified in Turkey, in 2014 [31]. Since then, sporadic KPC-producing K. pneumoniae was reported [32, 33]. In the present study, we didn't detect blaKPC gene among tested carbapenem and colistin resistant K. pneumoniae isolates.

MBLs identified in K. pneumoniae mainly reported from Japan (IMP), Taiwan (IMP), Indian subcontinent (NDM), Balkan states (NDM), and Greece (VIM) [33]. Recent findings suggest that the Balkan states and the Middle East may act as secondary reservoirs of NDM-1 producers. In the European Survey of Carbapenemase-Producing Enterobacteriaceae (EuSCAPE) study, Turkey was classified as a stage 3 country on a scale of 1–5 (1: no reported case; 5: endemic situation) for the existence of NDM carbapenemases. Among CRKP, NDM-1 carbapenemases detected between 6.3% and 52.9% in our country [34, 35]. Moreover, the coproduction of both OXA-48 and NDM-1carbapenemases has been frequently reported. We detected two (2.1%) NDM-1-producing isolates, which have already been found to harbour OXA-48 carbapenemases. Interestingly, NDM-1 carbapenemase detected in a very low rate compared to our country results. Our hospital setting is not an endemic region for blaNDM-1 positive K. pneumoniae. The carbapenemase genes blaIMP and blaVIM were reported in a low but notable incidence in Turkey like other countries [27, 35–38]. In our study, blaIMP and blaVIM genes were not detected in any of the isolates.

OXA-48-producing K. pneumoniae was first reported from Turkey and it is endemic for our country [30, 32, 36, 37]. The emergence of the OXA-48 enzyme is mediated by the rapid spread of a broad host-range conjugative plasmid harboring the blaOXA-48 gene. Plasmid harboring blaOXA-48 with the Tn1999.2 transposon detected from a K. pneumoniae isolate in Turkey [39]. OXA-48-producing K. pneumoniae is also endemic in certain North African and European countries (Morocco, Tunisia, Spain, Belgium) [40]. OXA-48-producing K. pneumoniae remain relatively uncommon in the United States and Canada [41]. As it was expected, we detected blaOXA-48 gene in all tested CRKP isolates. However, two of these isolates were positive for both blaNDM-1 and blaOXA-48 genes.

Multilocus sequence typing is an excellent method in evolutionary studies for exploring the common ancestral lineages of bacterial isolates [20]. Various ST types (ST11, ST14, ST101, ST147, and ST258) and resistance mechanisms can be related to carbapenem and colistin resistance in K. pneumoniae [41]. A single K. pneumoniae clone ST258 was identified extensively worldwide, indicating that it may have contributed to the spread of the blaKPC genes [26]. On the other hand, KPC-producing K. pneumoniae remains rare for our country [31, 32]. Among all tested isolates, we didn't detect KPC-producing K. pneumoniae and also its emerging high-risk clone ST258. We found that the epidemic Klebsiella pneumonia isolate in our hospital was in ST101 type. ST101 was previously accepted as a high-risk epidemic clone, and it was reported that the ST101 clone was associated with various β-lactamases, including NDM-1, OXA-48, and CTX-M-15 [38]. Nevertheless, CRKP assigned to ST101 are carbapenem resistant frequently because of the production OXA-48. David et al., analysed the genome sequences of K. pneumoniae strains, isolated from patients in 244 hospitals in 32 countries during the European Survey of Carbapenemase-Producing Enterobacteriaceae. CRKP are concentrated in four clonal lineages, ST11, ST15, ST101, ST258/512, and authors identified OXA-48-producing ST101 clones in Romania, Spain, and Turkey [39]. Also, the emergence of colistin resistance has been observed in CRKP isolates, and colistin resistance was shown to be associated with the ST101 clone. Detection of carbapenem and colistin resistant K. pneumoniae ST101 was reported from Italy and Serbia [42, 43]. A large multicentre cohort study, describe the molecular characteristics of clinical colistin and carbapenem resistant K. pneumoniae isolates. Researchers observed a significant association between ST101, OXA-48, and colistin resistance [44]. Our study reports the clonal expansion of emerging ST101 clone associated with OXA-48 producing and colistin resistance in our hospital settings.

K. pneumoniae ST147 is an emerging high-risk clone that was first identified in Greece and has been associated with VIM and KPC carbapenemases in that country [45]. This global ST has also been associated with NDM and OXA-181 carbapenemases in various countries, including Switzerland, Iraq, Canada, United Kingdom, India, and Italy [26, 46]. In the current study, two isolates of ST147 were detected which co-harbored blaNDM-1 and blaOXA-48 genes.

Carbapenem-resistance among K. pneumoniae isolates makes colistin the last therapeutic option for the treatment. With the rise in consumption of colistin, cases of colistin resistant CRKP isolates are reported globally [1, 9, 11]. Chromosomal mutations in phoP/phoQ, pmrA/pmrB, mgrB and plasmid-borne mobile colistin resistance genes (mcr-1 to mcr-9) positivity have an important role in increasing colistin resistance in K. pneumoniae [47, 10, 11]. The highest colistin resistance rate was reported in Asia (especially Korea and Singapore), followed by Europe (especially Greece) and America, where colistin resistance rates are continually increasing [48]. Nowadays, all known mcr genes have been detected in various K. pneumoniae isolates, whereas a small number of studies have shown the presence of mcr genes in clinical K. pneumoniae isolates [49]. Several studies suggested that chromosomal mutations rather than mcr genes positivity might have an important role in colistin resistance [47, 44, 50]. Different STs such as ST274, ST461, ST15, ST16, ST416, ST1890, ST37, ST1942, ST101, ST147, ST258, ST152, and ST15 were detected in carbapenem and colistin resistant K. pneumoniae [42, 50, 51]. We detected two ST types, ST101 (95.6%) and ST147 (4.4%) in carbapenem and colistin resistant K. pneumoniae. In Turkey, a few study investigated mcr-1 to -3 genes among carbapenem and colistin resistant K. pneumoniae isolates and only Arabacı et al., determined mcr-1 positive KRCP (5.2%) [44, 51–53]. In this study, we investigated mcr-1 to -8 genes in colistin and carbapenem resistant K. pneumoniae and reported the molecular characteristics of mcr-1 positive CRKP. To our knowledge, this is the first report of mcr-1 positive K. pneumoniae isolates that produce both NDM-1 and OXA-48 while also belonging to the one of the emerging clones ST147 from Turkey.

Conclusion

We identified two different STs, namely, ST101 and ST147 among the carbapenem and colistin resistant K. pneumoniae isolates identified during 2017 and 2019. ST101 is a epidemic ST and has been associated with OXA-48. Our results show that this ST also has the ability to develop colistin resistance. Early detection and surveillance can prevent the spread of carbapenem and colistin resistant K. pneumoniae isolates.

Ethical committee approval

Not required.

Conflict of interest

The authors declare no competing interests.

Acknowledgements

None.

Supplementary material

Supplementary data to this article can be found online at https://doi.org/10.1556/030.2020.01275.

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    Borsa BA, Demirci M, Gungordu-Dalar Z, Karabiyik G, Aygun G, Kucukbasmaci O. Molecular mechanisms of colistin resistance among Klebsiella pneumoniae strains. Clin Lab 2019;65:112530.

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    Arabacı Ç, Dal T, Başyiğit T, Genişel N, Durmaz R. Investigation of carbapenemase and mcr-1 genes in carbapenem-resistant Klebsiella pneumoniae isolates. J Infect Dev Ctries 2019;30:5049.

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    Poirel L, Potron A, Nordmann P. OXA-48-like carbapenemases: the phantom menace. J Antimicrob Chemother 2012;67:1597606.

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    David S, Reuter S, Harris SR, Glasner C, Feltwell T, Argimon S, Epidemic of carbapenem-resistant Klebsiella pneumoniae in Europe is driven by nosocomial spread. Nat Microbiol 2019;4:191929.

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    Nordmann P, Naas T, Poirel L. Global spread of carbapenemase-producing enterobacteriaceae. Emerg Infect Dis 2011;17:17918.

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    Novovic K, Trudic A, Brkic S, Vasiljević Z, Kojić M, Medić D, Molecular epidemiology of colistin resistant, carbapenemase-producing Klebsiella pneumoniae in Serbia from 2013 to 2016. Antimicrob Agents Chemother 2017;61:e0255016.

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    Del Franco M, Paone L, Novati R, Giacomazzi CG, Bagattini M, Galotto C, Molecular epidemiology of carbapenem resistant Enterobacteriaceae in Valle d'Aosta region, Italy, shows the emergence of KPC-2 producing Klebsiella pneumoniae clonal complex 101 (ST101 and ST1789). BMC Microbiol 2015;15:260.

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    Can F, Menekse S, Ispir P, Atac N, Albayrak O, Demir T, Impact of the ST101 clone on fatality among patients with colistin-resistant Klebsiella pneumoniae infection. J Antimicrob Chemother 2018;73:123541.

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    Giakkoupi P, Papagiannitsis CC, Miriagou V, Pappa O, Polemis M, Tryfinopoulou K, An update evolving epidemic of blaKPC-2-carrying Klebsiella pneumoniae in Greece (2009–10). J Antimicrob Chemother 2011;66:151013.

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    Lascols C, Peirano G, Hackel M, Laupland KB, Pitout JD. Surveillance and molecular epidemiology of Klebsiella pneumoniae isolates that produce carbapenemases: first report of OXA-48-like enzymesin North America. Antimicrob Agents Chemother 2016;57:1306.

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    Jayol A, Poirel L, Brink A, Villegas MV, Yilmaz M, Nordmann P. Resistance to colistin associated with a single amino acid change in protein PmrB among Klebsiella pneumoniae isolates of worldwide origin. Antimicrob Agents Chemother 2014;58:47626.

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    • Search Google Scholar
    • Export Citation
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    Bialvaei AZ, Samadi Kafil H. Colistin, mechanisms and prevalence of resistance. Curr Med Res Opin 2015;31:70721.

  • 49.

    Wang Y, Liu F, Hu Y, Zhang G, Zhu B, Gao GF. Detection of mobile colistin resistance gene mcr-9 in carbapenem-resistant Klebsiella pneumoniae strains of human origin in Europe. J Infect 2020;80:578606.

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  • 50.

    Longo LGA, de Sousa VS, Kraychete GB, Justo-da-Silva LH, Rocha JA, Superti SV, Colistin resistance emerges in pandrug-resistant Klebsiella pneumoniae epidemic clones in Rio de Janeiro, Brazil. Int J Antimicrob Agents 2019;54:57986.

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    Guducuoglu H, Gursoy NC, Yakupogullari Y, Parlak M, Karasin G, Sunnetcioglu M, Hospital outbreak of a colistin-resistant, NDM-1- and OXA-48-producing Klebsiella pneumoniae: high mortality from pandrug resistance. Microb Drug Resist 2018;24:96672.

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    • Export Citation
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    Borsa BA, Demirci M, Gungordu-Dalar Z, Karabiyik G, Aygun G, Kucukbasmaci O. Molecular mechanisms of colistin resistance among Klebsiella pneumoniae strains. Clin Lab 2019;65:112530.

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    • Search Google Scholar
    • Export Citation
  • 53.

    Arabacı Ç, Dal T, Başyiğit T, Genişel N, Durmaz R. Investigation of carbapenemase and mcr-1 genes in carbapenem-resistant Klebsiella pneumoniae isolates. J Infect Dev Ctries 2019;30:5049.

    • Crossref
    • Search Google Scholar
    • Export Citation

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