Emergence of an MDR Klebsiella pneumoniae ST231 producing OXA-232 and RmtF in Switzerland

Emergence of an MDR Klebsiella pneumoniae ST231 producing OXA-232 and RmtF in Switzerland Sir, The increasing incidence of carbapenem-resistant Klebsiella pneumoniae is a major challenge to public health. Despite the fact that the prevalence of carbapenemases among carbapenem-resistant K. pneumoniae varies geographically, the incidence of OXA-48-like enzymes has soared in recent years and is particularly high in some European countries, such as Spain and France (74% and 78% among carbapenemase-producing K. pneumoniae, respectively).1 A significant number of OXA-48 variants have been reported in the last decade. This includes OXA-232, a carbapenemase firstly identified in France in 20112 and thereafter found in several countries.3,4 Recently, an MDR K. pneumoniae ST231 co-producing OXA-232, the ESBL CTX-M-15 and the 16S rRNA methyltransferase RmtF conferring broad-spectrum resistance to aminoglycosides has emerged as a successful epidemic clone in South-East Asia, with related outbreaks being reported in Singapore and in Brunei Darussalam between 2013 and 2015.5,6 Here, we report on a nosocomial spread of this emerging resistant strain in Switzerland. Six K. pneumoniae clinical isolates with reduced susceptibility or resistant to carbapenems were recovered from February to April 2017 from five different patients, namely three hospitalized in the medicine ward of a regional hospital in Western Switzerland, and two non-hospitalized at the private Ear, Nose and Throat (ENT) centre located near to the hospital (Table 1) and were sent to the Swiss National Reference Center for Emerging Antibiotic Resistance for further characterization. All the patients reported no recent travel abroad. Clinical and epidemiological analyses failed to detect any obvious route of transmission for those isolates. Table 1 Characteristics of the Klebsiella pneumoniae isolates under study Isolate  Ward  Specimen  Date of isolation  ST  β- Lactamases identified by PCR  Approximate sizes of plasmids (kb)  MIC (mg/L)   carbapenems   colistin  novel cephalosporin/β-lactamase inhibitor combinations   IPM  MEM  ETP  ceftolozane/ tazobactam  ceftazidime/ avibactam  Kp1  ENT  sinus swab  28/02/17  231  blaOXA-232, blaCTX-M-15, blaTEM-1b  3.6, 6.1, 9, 70, 160  2  8  >256  2  >256  2  Kp2  ENT  sinus swab  09/03/17  231  blaOXA-232, blaCTX-M-15, blaTEM-1b  3.6, 6.1, 9, 70, 160  2  8  >256  2  >256  2  Kp3  Medicine  urine  21/03/17  231  blaCTX-M-15, blaTEM-1b  3.6, 4.8, 9, 70, 160  0.38  0.25  2  2  >256  2  Kp4  Medicine  rectal swab  23/03/17  231  blaOXA-232, blaCTX-M-15, blaTEM-1b  3.6, 6.1, 9, 70, 160  2  8  >256  2  >256  2  Kp5  Medicine  rectal swab  29/03/17  231  blaCTX-M-15, blaTEM-1b  3.6, 4.8, 9, 70, 160  0.38  0.25  2  2  >256  2  Kp6  Medicine  rectal swab  10/04/17  231  blaOXA-232, blaCTX-M-15, blaTEM-1b  3.6, 6.1, 9, 70, 160  2  8  >256  2  >256  2  Isolate  Ward  Specimen  Date of isolation  ST  β- Lactamases identified by PCR  Approximate sizes of plasmids (kb)  MIC (mg/L)   carbapenems   colistin  novel cephalosporin/β-lactamase inhibitor combinations   IPM  MEM  ETP  ceftolozane/ tazobactam  ceftazidime/ avibactam  Kp1  ENT  sinus swab  28/02/17  231  blaOXA-232, blaCTX-M-15, blaTEM-1b  3.6, 6.1, 9, 70, 160  2  8  >256  2  >256  2  Kp2  ENT  sinus swab  09/03/17  231  blaOXA-232, blaCTX-M-15, blaTEM-1b  3.6, 6.1, 9, 70, 160  2  8  >256  2  >256  2  Kp3  Medicine  urine  21/03/17  231  blaCTX-M-15, blaTEM-1b  3.6, 4.8, 9, 70, 160  0.38  0.25  2  2  >256  2  Kp4  Medicine  rectal swab  23/03/17  231  blaOXA-232, blaCTX-M-15, blaTEM-1b  3.6, 6.1, 9, 70, 160  2  8  >256  2  >256  2  Kp5  Medicine  rectal swab  29/03/17  231  blaCTX-M-15, blaTEM-1b  3.6, 4.8, 9, 70, 160  0.38  0.25  2  2  >256  2  Kp6  Medicine  rectal swab  10/04/17  231  blaOXA-232, blaCTX-M-15, blaTEM-1b  3.6, 6.1, 9, 70, 160  2  8  >256  2  >256  2  IPM, imipenem; MEM, meropenem; ETP, ertapenem. Antimicrobial susceptibility testing was performed by disc diffusion assay (Sanofi-diagnostic Pasteur, France) and MICs were determined using Etest (bioMérieux, France) and broth microdilution techniques, with susceptibility defined according to CLSI breakpoints (https://clsi.org/standards/products/microbiology/documents/m100/). Four isolates were resistant to penicillins, broad-spectrum cephalosporins, meropenem and ertapenem and showed intermediate resistance to imipenem. The remaining two isolates displayed a typical ESBL phenotype, with resistance towards all penicillins, to expanded-spectrum cephalosporins (antagonized by β-lactamase inhibitors) and to ertapenem, and susceptibility to imipenem and meropenem. Interestingly, one isolate presenting carbapenemase activity and one exhibiting an ESBL phenotype had been recovered from a single patient (Table 1). All six K. pneumoniae isolates also exhibited broad-spectrum resistance to aminoglycosides and were additionally resistant to sulphonamides, fluoroquinolones, trimethoprim/sulfamethoxazole, chloramphenicol, tetracycline and to the recently developed ceftolozane/tazobactam combination. Notably, all six clinical isolates were susceptible to colistin and to the ceftazidime/avibactam combination. Multiplex PCRs performed to detect Ambler class A, B and D carbapenemases and 16S rRNA aminoglycoside resistance genes7,8 followed by sequencing revealed that all six isolates possessed the rmtF 16S rRNA methyltransferase gene, and that the four carbapenem-resistant isolates possessed the blaOXA-232 carbapenemase gene. In addition, all the isolates possessed the ESBL blaCTX-M-15 and the blaTEM-1 gene (Table 1). Transferability of the blaOXA-232, blaCTX-M-15 and rmtF genes was attempted by mating-out assays using the azide-resistant Escherichia coli J53 as a recipient strain. Transconjugants were obtained on azide (100 mg/L) and either amikacin/gentamicin (50 mg/L each) or ceftazidime (1 mg/L), but not imipenem (1 mg/L), indicating the transferability of the plasmids harbouring the rmtF and blaCTX-M-15, but not that one carrying the blaOXA-232 gene. Analysis of the plasmid content by using the Kieser technique revealed the presence of several plasmids in all isolates. The blaOXA-232 was carried on a 6141 bp plasmid identical to that identified by Potron et al.,2 as further supported by sequence analysis performed as previously reported.6 Noticeably, the rmtF and blaCTX-M-15 genes were located on the same 160 kb plasmid. PFGE of the SpeI-digested genomic DNA obtained from the six K. pneumoniae isolates revealed that they were clonally related. MLST showed that they belonged to ST231 (https://cge.cbs.dtu.dk/services/MLST/). In an attempt to unravel the genetic factors contributing to the emergence and spread of this multiresistant pathogen, WGS of genomic DNA from isolate Kp1 (KP06–2017) was performed using a MiniSeq system (Illumina, USA), generating a total of 13 078 950 reads with an average length of 145.8 bp. Reads were de novo assembled using CLC Genomics Workbench version 7.5.1 (Qiagen, France). The draft genome revealed a size of 6 015 778 bp, with an average GC content of approximately 57%. The antimicrobial resistome was identified using ResFinder9 and comprises genes conferring resistance to aminoglycosides (rmtF, aadB, aadA2 and aacA4), β-lactams (blaOXA-232, blaCTX-M-15, blaTEM-1b), fluoroquinolones [aac(6′)Ib-cr], macrolides, lincosamides and streptogramin B (MLS) [erm(B) and mph(A)], phenicols (catA1 and catB4), sulphonamides (sul1), trimethoprim (dfrA12) and rifampicin (arr-2) (Table 1). Plasmid finder10 revealed the presence of IncFIB(pQil), IncFII(K), IncFII(pRSB107), IncFIA and ColKP3 replicons; the latter two present in the plasmids carrying the rmtF/blaCTX-M-15 and blaOXA-232 genes, respectively. Overall, to our knowledge, we report here the first occurrence in Europe of an MDR K. pneumoniae ST231 clone, so far geographically confined in South-East Asia. This represents an important and worrying step toward the rise of another epidemic clone as a global public threat. Accession number The draft genome sequence of the K. pneumoniae KP06–2017 has been deposited in GenBank under accession number NTFP00000000. Funding This work was funded by the University of Fribourg, by the Swiss National Reference Center for Emerging Antibiotic Resistance (NARA) and by the Swiss National Science Foundation (project FNS-31003A_163432). Transparency declarations None to declare. References 1 Lee CR, Lee JH, Park KS et al.   Global dissemination of carbapenemase-producing Klebsiella pneumoniae: epidemiology, genetic context, treatment options, and detection methods. Front Microbiol  2016; 7: 895. Google Scholar PubMed  2 Potron A, Rondinaud E, Poirel L et al.   Genetic and biochemical characterisation of OXA-232, a carbapenem-hydrolysing class D β-lactamase from Enterobacteriaceae. Int J Antimicrob Agents  2013; 41: 325– 9. Google Scholar CrossRef Search ADS PubMed  3 Lahlaoui H, Bonnin RA, Moussa MB et al.   First report of OXA-232-producing Klebsiella pneumoniae strains in Tunisia. Diagn Microbiol Infect Dis  2017; 88: 195– 7. Google Scholar CrossRef Search ADS PubMed  4 Yin D, Dong D, Li K et al.   Clonal dissemination of OXA-232 carbapenemase-producing Klebsiella pneumoniae in neonates. Antimicrob Agents Chemother  2017; 61: e00385– 17. Google Scholar CrossRef Search ADS PubMed  5 Abdul Momin MHF, Liakopoulos A, Phee LM et al.   Emergence and nosocomial spread of carbapenem-resistant OXA-232-producing Klebsiella pneumoniae in Brunei Darussalam. J Glob Antimicrob Resist  2017; 9: 96– 9. Google Scholar CrossRef Search ADS PubMed  6 Teo JW, Kurup A, Lin RT et al.   Emergence of clinical Klebsiella pneumoniae producing OXA-232 carbapenemase in Singapore. New Microbes New Infect  2013; 1: 13– 5. Google Scholar CrossRef Search ADS PubMed  7 Bercot B, Poirel L, Nordmann P. Updated multiplex polymerase chain reaction for detection of 16S rRNA methylases: high prevalence among NDM-1 producers. Diagn Microbiol Infect Dis  2011; 71: 442– 5. Google Scholar CrossRef Search ADS PubMed  8 Poirel L, Walsh TR, Cuvillier V et al.   Multiplex PCR for detection of acquired carbapenemase genes. Diagn Microbiol Infect Dis  2011; 70: 119– 23. Google Scholar CrossRef Search ADS PubMed  9 Zankari E, Hasman H, Cosentino S et al.   Identification of acquired antimicrobial resistance genes. J Antimicrob Chemother  2012; 67: 2640– 4. Google Scholar CrossRef Search ADS PubMed  10 Carattoli A, Zankari E, García-Fernández A et al.   In silico detection and typing of plasmids using PlasmidFinder and plasmid multilocus sequence typing. Antimicrob Agents Chemother  2014; 58: 3895– 903. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

Emergence of an MDR Klebsiella pneumoniae ST231 producing OXA-232 and RmtF in Switzerland

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Oxford University Press
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© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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Abstract

Sir, The increasing incidence of carbapenem-resistant Klebsiella pneumoniae is a major challenge to public health. Despite the fact that the prevalence of carbapenemases among carbapenem-resistant K. pneumoniae varies geographically, the incidence of OXA-48-like enzymes has soared in recent years and is particularly high in some European countries, such as Spain and France (74% and 78% among carbapenemase-producing K. pneumoniae, respectively).1 A significant number of OXA-48 variants have been reported in the last decade. This includes OXA-232, a carbapenemase firstly identified in France in 20112 and thereafter found in several countries.3,4 Recently, an MDR K. pneumoniae ST231 co-producing OXA-232, the ESBL CTX-M-15 and the 16S rRNA methyltransferase RmtF conferring broad-spectrum resistance to aminoglycosides has emerged as a successful epidemic clone in South-East Asia, with related outbreaks being reported in Singapore and in Brunei Darussalam between 2013 and 2015.5,6 Here, we report on a nosocomial spread of this emerging resistant strain in Switzerland. Six K. pneumoniae clinical isolates with reduced susceptibility or resistant to carbapenems were recovered from February to April 2017 from five different patients, namely three hospitalized in the medicine ward of a regional hospital in Western Switzerland, and two non-hospitalized at the private Ear, Nose and Throat (ENT) centre located near to the hospital (Table 1) and were sent to the Swiss National Reference Center for Emerging Antibiotic Resistance for further characterization. All the patients reported no recent travel abroad. Clinical and epidemiological analyses failed to detect any obvious route of transmission for those isolates. Table 1 Characteristics of the Klebsiella pneumoniae isolates under study Isolate  Ward  Specimen  Date of isolation  ST  β- Lactamases identified by PCR  Approximate sizes of plasmids (kb)  MIC (mg/L)   carbapenems   colistin  novel cephalosporin/β-lactamase inhibitor combinations   IPM  MEM  ETP  ceftolozane/ tazobactam  ceftazidime/ avibactam  Kp1  ENT  sinus swab  28/02/17  231  blaOXA-232, blaCTX-M-15, blaTEM-1b  3.6, 6.1, 9, 70, 160  2  8  >256  2  >256  2  Kp2  ENT  sinus swab  09/03/17  231  blaOXA-232, blaCTX-M-15, blaTEM-1b  3.6, 6.1, 9, 70, 160  2  8  >256  2  >256  2  Kp3  Medicine  urine  21/03/17  231  blaCTX-M-15, blaTEM-1b  3.6, 4.8, 9, 70, 160  0.38  0.25  2  2  >256  2  Kp4  Medicine  rectal swab  23/03/17  231  blaOXA-232, blaCTX-M-15, blaTEM-1b  3.6, 6.1, 9, 70, 160  2  8  >256  2  >256  2  Kp5  Medicine  rectal swab  29/03/17  231  blaCTX-M-15, blaTEM-1b  3.6, 4.8, 9, 70, 160  0.38  0.25  2  2  >256  2  Kp6  Medicine  rectal swab  10/04/17  231  blaOXA-232, blaCTX-M-15, blaTEM-1b  3.6, 6.1, 9, 70, 160  2  8  >256  2  >256  2  Isolate  Ward  Specimen  Date of isolation  ST  β- Lactamases identified by PCR  Approximate sizes of plasmids (kb)  MIC (mg/L)   carbapenems   colistin  novel cephalosporin/β-lactamase inhibitor combinations   IPM  MEM  ETP  ceftolozane/ tazobactam  ceftazidime/ avibactam  Kp1  ENT  sinus swab  28/02/17  231  blaOXA-232, blaCTX-M-15, blaTEM-1b  3.6, 6.1, 9, 70, 160  2  8  >256  2  >256  2  Kp2  ENT  sinus swab  09/03/17  231  blaOXA-232, blaCTX-M-15, blaTEM-1b  3.6, 6.1, 9, 70, 160  2  8  >256  2  >256  2  Kp3  Medicine  urine  21/03/17  231  blaCTX-M-15, blaTEM-1b  3.6, 4.8, 9, 70, 160  0.38  0.25  2  2  >256  2  Kp4  Medicine  rectal swab  23/03/17  231  blaOXA-232, blaCTX-M-15, blaTEM-1b  3.6, 6.1, 9, 70, 160  2  8  >256  2  >256  2  Kp5  Medicine  rectal swab  29/03/17  231  blaCTX-M-15, blaTEM-1b  3.6, 4.8, 9, 70, 160  0.38  0.25  2  2  >256  2  Kp6  Medicine  rectal swab  10/04/17  231  blaOXA-232, blaCTX-M-15, blaTEM-1b  3.6, 6.1, 9, 70, 160  2  8  >256  2  >256  2  IPM, imipenem; MEM, meropenem; ETP, ertapenem. Antimicrobial susceptibility testing was performed by disc diffusion assay (Sanofi-diagnostic Pasteur, France) and MICs were determined using Etest (bioMérieux, France) and broth microdilution techniques, with susceptibility defined according to CLSI breakpoints (https://clsi.org/standards/products/microbiology/documents/m100/). Four isolates were resistant to penicillins, broad-spectrum cephalosporins, meropenem and ertapenem and showed intermediate resistance to imipenem. The remaining two isolates displayed a typical ESBL phenotype, with resistance towards all penicillins, to expanded-spectrum cephalosporins (antagonized by β-lactamase inhibitors) and to ertapenem, and susceptibility to imipenem and meropenem. Interestingly, one isolate presenting carbapenemase activity and one exhibiting an ESBL phenotype had been recovered from a single patient (Table 1). All six K. pneumoniae isolates also exhibited broad-spectrum resistance to aminoglycosides and were additionally resistant to sulphonamides, fluoroquinolones, trimethoprim/sulfamethoxazole, chloramphenicol, tetracycline and to the recently developed ceftolozane/tazobactam combination. Notably, all six clinical isolates were susceptible to colistin and to the ceftazidime/avibactam combination. Multiplex PCRs performed to detect Ambler class A, B and D carbapenemases and 16S rRNA aminoglycoside resistance genes7,8 followed by sequencing revealed that all six isolates possessed the rmtF 16S rRNA methyltransferase gene, and that the four carbapenem-resistant isolates possessed the blaOXA-232 carbapenemase gene. In addition, all the isolates possessed the ESBL blaCTX-M-15 and the blaTEM-1 gene (Table 1). Transferability of the blaOXA-232, blaCTX-M-15 and rmtF genes was attempted by mating-out assays using the azide-resistant Escherichia coli J53 as a recipient strain. Transconjugants were obtained on azide (100 mg/L) and either amikacin/gentamicin (50 mg/L each) or ceftazidime (1 mg/L), but not imipenem (1 mg/L), indicating the transferability of the plasmids harbouring the rmtF and blaCTX-M-15, but not that one carrying the blaOXA-232 gene. Analysis of the plasmid content by using the Kieser technique revealed the presence of several plasmids in all isolates. The blaOXA-232 was carried on a 6141 bp plasmid identical to that identified by Potron et al.,2 as further supported by sequence analysis performed as previously reported.6 Noticeably, the rmtF and blaCTX-M-15 genes were located on the same 160 kb plasmid. PFGE of the SpeI-digested genomic DNA obtained from the six K. pneumoniae isolates revealed that they were clonally related. MLST showed that they belonged to ST231 (https://cge.cbs.dtu.dk/services/MLST/). In an attempt to unravel the genetic factors contributing to the emergence and spread of this multiresistant pathogen, WGS of genomic DNA from isolate Kp1 (KP06–2017) was performed using a MiniSeq system (Illumina, USA), generating a total of 13 078 950 reads with an average length of 145.8 bp. Reads were de novo assembled using CLC Genomics Workbench version 7.5.1 (Qiagen, France). The draft genome revealed a size of 6 015 778 bp, with an average GC content of approximately 57%. The antimicrobial resistome was identified using ResFinder9 and comprises genes conferring resistance to aminoglycosides (rmtF, aadB, aadA2 and aacA4), β-lactams (blaOXA-232, blaCTX-M-15, blaTEM-1b), fluoroquinolones [aac(6′)Ib-cr], macrolides, lincosamides and streptogramin B (MLS) [erm(B) and mph(A)], phenicols (catA1 and catB4), sulphonamides (sul1), trimethoprim (dfrA12) and rifampicin (arr-2) (Table 1). Plasmid finder10 revealed the presence of IncFIB(pQil), IncFII(K), IncFII(pRSB107), IncFIA and ColKP3 replicons; the latter two present in the plasmids carrying the rmtF/blaCTX-M-15 and blaOXA-232 genes, respectively. Overall, to our knowledge, we report here the first occurrence in Europe of an MDR K. pneumoniae ST231 clone, so far geographically confined in South-East Asia. This represents an important and worrying step toward the rise of another epidemic clone as a global public threat. Accession number The draft genome sequence of the K. pneumoniae KP06–2017 has been deposited in GenBank under accession number NTFP00000000. Funding This work was funded by the University of Fribourg, by the Swiss National Reference Center for Emerging Antibiotic Resistance (NARA) and by the Swiss National Science Foundation (project FNS-31003A_163432). Transparency declarations None to declare. References 1 Lee CR, Lee JH, Park KS et al.   Global dissemination of carbapenemase-producing Klebsiella pneumoniae: epidemiology, genetic context, treatment options, and detection methods. Front Microbiol  2016; 7: 895. Google Scholar PubMed  2 Potron A, Rondinaud E, Poirel L et al.   Genetic and biochemical characterisation of OXA-232, a carbapenem-hydrolysing class D β-lactamase from Enterobacteriaceae. Int J Antimicrob Agents  2013; 41: 325– 9. Google Scholar CrossRef Search ADS PubMed  3 Lahlaoui H, Bonnin RA, Moussa MB et al.   First report of OXA-232-producing Klebsiella pneumoniae strains in Tunisia. Diagn Microbiol Infect Dis  2017; 88: 195– 7. Google Scholar CrossRef Search ADS PubMed  4 Yin D, Dong D, Li K et al.   Clonal dissemination of OXA-232 carbapenemase-producing Klebsiella pneumoniae in neonates. Antimicrob Agents Chemother  2017; 61: e00385– 17. Google Scholar CrossRef Search ADS PubMed  5 Abdul Momin MHF, Liakopoulos A, Phee LM et al.   Emergence and nosocomial spread of carbapenem-resistant OXA-232-producing Klebsiella pneumoniae in Brunei Darussalam. J Glob Antimicrob Resist  2017; 9: 96– 9. Google Scholar CrossRef Search ADS PubMed  6 Teo JW, Kurup A, Lin RT et al.   Emergence of clinical Klebsiella pneumoniae producing OXA-232 carbapenemase in Singapore. New Microbes New Infect  2013; 1: 13– 5. Google Scholar CrossRef Search ADS PubMed  7 Bercot B, Poirel L, Nordmann P. Updated multiplex polymerase chain reaction for detection of 16S rRNA methylases: high prevalence among NDM-1 producers. Diagn Microbiol Infect Dis  2011; 71: 442– 5. Google Scholar CrossRef Search ADS PubMed  8 Poirel L, Walsh TR, Cuvillier V et al.   Multiplex PCR for detection of acquired carbapenemase genes. Diagn Microbiol Infect Dis  2011; 70: 119– 23. Google Scholar CrossRef Search ADS PubMed  9 Zankari E, Hasman H, Cosentino S et al.   Identification of acquired antimicrobial resistance genes. J Antimicrob Chemother  2012; 67: 2640– 4. Google Scholar CrossRef Search ADS PubMed  10 Carattoli A, Zankari E, García-Fernández A et al.   In silico detection and typing of plasmids using PlasmidFinder and plasmid multilocus sequence typing. Antimicrob Agents Chemother  2014; 58: 3895– 903. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Journal

Journal of Antimicrobial ChemotherapyOxford University Press

Published: Mar 1, 2018

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