- Email: [email protected]
Global spread of New Delhi metallo-β-lactamase 1
Correspondence
Patient A
3
Patient B
MIC (mg/L)
Susceptibility*
MIC (mg/L)
Susceptibility*
Imipenem†
>32
R
>32
R
Meropenem†
>32
R
>32
R
Ertapenem†
>32
R
>32
R
Piperacillin–tazobactam
>32, 4
R
>32, 4
R
Cefuroxime
>64
R
>64
R
Cefotaxime
>8
R
>8
R
Ceftriaxone
>16
R
>16
R
Ceftazidim
>32
R
>32
R
Aztreonam
>32
R
>32
R
Ciprofloxacin
>4
R
>4
R
Gentamicin
>16
R
>16
R
Tobramycin
>4
R
>4
R
>16
R
>16
R
Cotrimoxazole
>8
R
>8
R
Nitrofurantoin
>64
R
>64
R
Amikacin
Tigecyclin
0·25
S
0·25
S
Colistin
≤1
S
≤1
S
Chloramphenicol
≤2
S
4
S
MIC=minimum inhibitory concentration. R=resistant. I=intermediate susceptible. S=susceptible *Susceptibility defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints. †Tested by Etest: carbapenem MICs were all more than 32 mg/L. Tested by microbroth dilution: the MICs of strain A and B were for imipenem 2 (S) and 8 (I), meropenem 8 (I) and 16 (R), and ertapenem 2 (R) and 8 (R), respectively.
Table: Antimicrobial susceptibilities for NDM-1-positive Klebsiella pneumoniae isolated in patients A and B
India and Pakistan, independent of admittance to health-care facilities. In many low-endemic countries, measures are taken to prevent the in-hospital spread of multiresistant strains by screening patients who received previous medical care in high-prevalence countries and subjecting them to barrier precautions awaiting the screening results. However, as shown in this study, travellers might also acquire carbapenemase-producing isolates with no history of medical care abroad; thus, this control strategy might fail. On admission, patients should therefore be asked whether they have recently travelled to India or Pakistan and, if positive, should be screened for NDM-1-positive enterobacteria. Additionally, because travel history is often unavailable, we advise screening of all enterobacteria isolated in the routine clinical laboratory for the
presence of carbapenemase genes using decreased susceptibility to meropenem as an indicator.5 We declare that we have no conflicts of interest.
*Maurine A Leverstein-Van Hall, James Cohen Stuart, Guido M Voets, Dik Versteeg, Thijs Tersmette, Ad C Fluit [email protected] University Medical Centre Utrecht, Medical Microbiology, Utrecht, 3584 CX Utrecht, Netherlands (MAL-vH, JCS, GMV, DV, TT, ACF); Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands (MALvH); and St Antonius Hospital, Medical Microbiology and Immunology, Nieuwegein, Netherlands (DV, TT) 1
2
www.thelancet.com/infection Vol 10 December 2010
Leverstein-van Hall MA, Stuart JC, Voets GM, Versteeg D, Roelofsen E, Fluit AC. Carbapenem-resistant Klebsiella pneumoniae following foreign travel. Ned Tijdschr Geneeskd 2010; 154: A2013 (in Dutch). Cohen Stuart J, Dierikx C, Al Naiemi N, et al. Rapid detection of TEM, SHV and CTX-M extended-spectrum beta-lactamases in Enterobacteriaceae using ligation mediated amplification with microarray analysis. J Antimicrob Chemother 2010; 65: 1377–81.
4
5
Kumarasamy KK, Toleman MA, Walsh TR, et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study. Lancet Infect Dis 2010; 10: 597–602. Tängdén T, Cars O, Melhus Ǻ, Löwdin E. Foreign travel is a major risk factor for colonization with Escherichia coli producing CTX-M-type extended-spectrum β-lactamases: a prospective study with Swedish volunteers. Antimicrob Agents Chemother 2010; 54: 3564–68. Cohen Stuart J, Leverstein-Van Hall MA, for the Dutch Working Party on the Detection of Highly Resistant Microorganisms. Guideline for phenotypic screening and confirmation of carbapenemases in Enterobacteriaceae. Int J Antimicrob Agents 2010; 36: 205–10.
Karthikeyan Kumarasamy and colleagues1 show the threat of multidrug-resistant enterobacteria harbouring New Dehli metallo-βlactamase (NDM-1)2 and caused great concern in the scientific community and in the public. Although most reports emphasised the close link between NDM-1 and the Indian subcontinent, the extent and geographical distribution of NDM-1 remains unknown. The exact incidence of NDM-1 might be underestimated by both nondetection of isolates that express NDM-1, and by underestimating the extent of the geographical distribution of this resistance mechanism. In Belgium, a national alert was issued in June, 2010, after a patient from Pakistan with diabetes died from uncontrolled sepsis due to an NDM-1-producing Escherichia coli.3 3 weeks later, a second case of NDM-1-carbapenemase-producing enterobacteria was detected when a mentally disabled patient with epilepsy had a seizure while swimming in the pool of a hotel in Montenegro. He was hospitalised in Podgorica, had to be mechanically ventilated in the intensive-care unit, and was treated with many antibiotics in 3 weeks before being repatriated to Belgium. On admission, microbiological analysis of endobronchial aspirates 831
Correspondence
showed the presence of several multidrug-resistant organisms including Klebsiella pneumoniae and Pseudomonas aeruginosa. The clinical microbiologist was initially concerned by the P aeruginosa isolate, which proved to be carbapenemresistant by OprD porin deficiency only. At the request of the reference laboratory, the K pneumoniae isolate was sent and finally identified as a panresistant NDM-1-producing strain (susceptible to colistin only). That isolates of NDM-1-producing enterobacteria could be identified in a patient who did not travel to the Indian subcontinent, or to the UK, shows the threat of neglecting to screen patients who are transferred from countries thought not to be at risk for multidrug resistance. Moreover, that the NDM-1 K pneumoniae originating from Montenegro was initially not sent to the reference laboratory shows that more of these isolates could be disseminating in the community. Screening for the carriage of multidrug-resistant organisms, including carbapenem-resistant enterobacteria is mandatory upon hospital admission irrespective of the country of origin, and suspected isolates have to be sent to the reference laboratory.
*Pierre Bogaerts, Alexia Verroken, Beatrice Jans, Olivier Denis, Youri Glupczynski [email protected] Université Catholique de Louvain, Cliniques Universitaires UCL Mont-Godinne, Laboratory of Bacteriology, Yvoir 5530, Belgium (PB, AV, YG); Scientific Institute of Public Health, Public Health and Surveillance Unit, Brussels, Belgium (BJ); and Université Libre de Bruxelles, Erasme Hospital, Laboratory of Bacteriology, Brussels, Belgium (OD) 1
2
832
Kumarasamy KK, Toleman MA, Walsh TR, et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study. Lancet Infect Dis 2010; 10: 597–602. Yong D, Toleman MA, Giske CG, et al. Characterization of a new metallo-β-lactamase gene, blaNDM-1, and a novel erythromycin esterase gene carried on a unique genetic structure in Klebsiella pneumoniae sequence type 14 from India. Antimicrob Agents Chemother 2009; 53: 5046–54.
3
Institut Scientifique de la Santé Publique. Guidelines for control of infections in case of cross-border transfer of patients hospitalized in countries with high endemicity of carbapenenemase-producing Enterobacteriaceae. Surveillance de germes multi-résistants dans les hôpitaux belges. Sept 23, 2010. http://www. nsih.be/download/MDR/NewDelhi_fiche_ alert_V5_FR.pdf (in French) (accessed Nov 8, 2010).
The plasmid-mediated blaNDM-1 gene that encodes a powerful carbapenemase was first identified in Escherichia coli and in Klebsiella pneumoniae in Sweden from a patient who was transferred from India.1 It was then identified from many patients in the UK, India, and Pakistan in different enterobacterial species.2 Here we report a woman aged 60 years who was admitted to hospital in April, 2009, for treatment of a breast cancer. The patient came from Darjeeling, India, where she had lived for several years and had never been hospitalised. Upon her admission in France, bacterial cultures from the surface of her breast tumour were grown. The cultures were of the E coli isolate GUE that was resistant to most β-lactams (remaining susceptible to aztreonam) and that had reduced susceptibility to carbapenems (minimum inhibitory concentrations of imipenem 3 μg/mL, ertapenem 3 μg/mL, and meropenem 2 μg/mL).3 This isolate was also resistant to gentamicin, kanamycin, tobramycin, sulfonamides, tetracycline, and fluoroquinolones, but remained susceptible to amikacin, chloramphenicol, rifampicin, and colistin. PCR and sequencing revealed that E coli GUE harboured the blaNDM-1 gene. Mating-out assays4 allowed the blaNDM-1 gene to be identified on a 110 kb plasmid, with markers for kanamycin, gentamicin, tobramycin, trimethoprim, and sulfonamide resistance. Multilocus sequence typing5 identified E coli GUE as an ST131-type strain, which corresponds to a genetic background that is also responsible for the worldwide diffusion of another
common resistance determinant, CTX-M-15. This case is the first identification of an NDM-1-producing E coli isolate in France, and corresponds again to an imported case from India. This example confirms the recent data suggesting that the Indian subcontinent might represent an important reservoir, and therefore a source, of NDM-producing isolates. The patient had not been hospitalised in India; therefore, the multidrugresistant isolate had likely been community acquired. Worringly, this resistance gene has been identified here in an E coli strain belonging to a genotype that has proved its ability to disseminate widely in the community. We declare that we have no conflicts of interest. This study was mostly funded by the INSERM (U914), France, and by grants from the Ministère de l’Education Nationale et de la Recherche (UPRES-EA3539), Université Paris XI, France, and from the European Community (TEMPOtest-QC, HEALTH-2009-241742).
Laurent Poirel, Cécile Hombrouck-Alet, Claire Freneaux, Sandrine Bernabeu, *Patrice Nordmann [email protected] Hôpital de Bicêtre, Department of BacteriologyVirology, Le Kremlin Bicêtre, Paris 94275, France 1
2
3
4
5
Yong D, Toleman MA, Giske CG, et al. Characterization of a new metallo-βlactamase gene, blaNDM-1, and a novel erythromycin esterase gene carried on a unique genetic structure in Klebsiella pneumoniae sequence type 14 from India. Antimicrob Agents Chemother 2009; 53: 5046–54. Kumarasamy KK, Toleman MA, Walsh TR, et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study. Lancet Infect Dis 2010; 10: 597–602. Clinical and Laboratory Standards Institute. 2010. Performance standards for antimicrobial susceptibility testing; twentieth informational supplement. Jan, 2010. http://www.clsi.org/source/orders/ free/m100-s20.pdf (accessed Nov 6, 2010). Rodriguez-Martinez JM, Nordmann P, Fortineau N, Poirel L. VIM-19, a metallo-βlactamase with increased carbapenemase activity from Escherichia coli and Klebsiella pneumoniae. Antimicrob Agents Chemother 2010; 54: 471–76. Tartof SY, Solberg OD, Manges AR, Riley LW. Analysis of a uropathogenic Escherichia coli clonal group by multilocus sequence typing. J Clin Microbiol 2005; 43: 5860–64.
www.thelancet.com/infection Vol 10 December 2010
Patient A
3
Patient B
MIC (mg/L)
Susceptibility*
MIC (mg/L)
Susceptibility*
Imipenem†
>32
R
>32
R
Meropenem†
>32
R
>32
R
Ertapenem†
>32
R
>32
R
Piperacillin–tazobactam
>32, 4
R
>32, 4
R
Cefuroxime
>64
R
>64
R
Cefotaxime
>8
R
>8
R
Ceftriaxone
>16
R
>16
R
Ceftazidim
>32
R
>32
R
Aztreonam
>32
R
>32
R
Ciprofloxacin
>4
R
>4
R
Gentamicin
>16
R
>16
R
Tobramycin
>4
R
>4
R
>16
R
>16
R
Cotrimoxazole
>8
R
>8
R
Nitrofurantoin
>64
R
>64
R
Amikacin
Tigecyclin
0·25
S
0·25
S
Colistin
≤1
S
≤1
S
Chloramphenicol
≤2
S
4
S
MIC=minimum inhibitory concentration. R=resistant. I=intermediate susceptible. S=susceptible *Susceptibility defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints. †Tested by Etest: carbapenem MICs were all more than 32 mg/L. Tested by microbroth dilution: the MICs of strain A and B were for imipenem 2 (S) and 8 (I), meropenem 8 (I) and 16 (R), and ertapenem 2 (R) and 8 (R), respectively.
Table: Antimicrobial susceptibilities for NDM-1-positive Klebsiella pneumoniae isolated in patients A and B
India and Pakistan, independent of admittance to health-care facilities. In many low-endemic countries, measures are taken to prevent the in-hospital spread of multiresistant strains by screening patients who received previous medical care in high-prevalence countries and subjecting them to barrier precautions awaiting the screening results. However, as shown in this study, travellers might also acquire carbapenemase-producing isolates with no history of medical care abroad; thus, this control strategy might fail. On admission, patients should therefore be asked whether they have recently travelled to India or Pakistan and, if positive, should be screened for NDM-1-positive enterobacteria. Additionally, because travel history is often unavailable, we advise screening of all enterobacteria isolated in the routine clinical laboratory for the
presence of carbapenemase genes using decreased susceptibility to meropenem as an indicator.5 We declare that we have no conflicts of interest.
*Maurine A Leverstein-Van Hall, James Cohen Stuart, Guido M Voets, Dik Versteeg, Thijs Tersmette, Ad C Fluit [email protected] University Medical Centre Utrecht, Medical Microbiology, Utrecht, 3584 CX Utrecht, Netherlands (MAL-vH, JCS, GMV, DV, TT, ACF); Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands (MALvH); and St Antonius Hospital, Medical Microbiology and Immunology, Nieuwegein, Netherlands (DV, TT) 1
2
www.thelancet.com/infection Vol 10 December 2010
Leverstein-van Hall MA, Stuart JC, Voets GM, Versteeg D, Roelofsen E, Fluit AC. Carbapenem-resistant Klebsiella pneumoniae following foreign travel. Ned Tijdschr Geneeskd 2010; 154: A2013 (in Dutch). Cohen Stuart J, Dierikx C, Al Naiemi N, et al. Rapid detection of TEM, SHV and CTX-M extended-spectrum beta-lactamases in Enterobacteriaceae using ligation mediated amplification with microarray analysis. J Antimicrob Chemother 2010; 65: 1377–81.
4
5
Kumarasamy KK, Toleman MA, Walsh TR, et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study. Lancet Infect Dis 2010; 10: 597–602. Tängdén T, Cars O, Melhus Ǻ, Löwdin E. Foreign travel is a major risk factor for colonization with Escherichia coli producing CTX-M-type extended-spectrum β-lactamases: a prospective study with Swedish volunteers. Antimicrob Agents Chemother 2010; 54: 3564–68. Cohen Stuart J, Leverstein-Van Hall MA, for the Dutch Working Party on the Detection of Highly Resistant Microorganisms. Guideline for phenotypic screening and confirmation of carbapenemases in Enterobacteriaceae. Int J Antimicrob Agents 2010; 36: 205–10.
Karthikeyan Kumarasamy and colleagues1 show the threat of multidrug-resistant enterobacteria harbouring New Dehli metallo-βlactamase (NDM-1)2 and caused great concern in the scientific community and in the public. Although most reports emphasised the close link between NDM-1 and the Indian subcontinent, the extent and geographical distribution of NDM-1 remains unknown. The exact incidence of NDM-1 might be underestimated by both nondetection of isolates that express NDM-1, and by underestimating the extent of the geographical distribution of this resistance mechanism. In Belgium, a national alert was issued in June, 2010, after a patient from Pakistan with diabetes died from uncontrolled sepsis due to an NDM-1-producing Escherichia coli.3 3 weeks later, a second case of NDM-1-carbapenemase-producing enterobacteria was detected when a mentally disabled patient with epilepsy had a seizure while swimming in the pool of a hotel in Montenegro. He was hospitalised in Podgorica, had to be mechanically ventilated in the intensive-care unit, and was treated with many antibiotics in 3 weeks before being repatriated to Belgium. On admission, microbiological analysis of endobronchial aspirates 831
Correspondence
showed the presence of several multidrug-resistant organisms including Klebsiella pneumoniae and Pseudomonas aeruginosa. The clinical microbiologist was initially concerned by the P aeruginosa isolate, which proved to be carbapenemresistant by OprD porin deficiency only. At the request of the reference laboratory, the K pneumoniae isolate was sent and finally identified as a panresistant NDM-1-producing strain (susceptible to colistin only). That isolates of NDM-1-producing enterobacteria could be identified in a patient who did not travel to the Indian subcontinent, or to the UK, shows the threat of neglecting to screen patients who are transferred from countries thought not to be at risk for multidrug resistance. Moreover, that the NDM-1 K pneumoniae originating from Montenegro was initially not sent to the reference laboratory shows that more of these isolates could be disseminating in the community. Screening for the carriage of multidrug-resistant organisms, including carbapenem-resistant enterobacteria is mandatory upon hospital admission irrespective of the country of origin, and suspected isolates have to be sent to the reference laboratory.
*Pierre Bogaerts, Alexia Verroken, Beatrice Jans, Olivier Denis, Youri Glupczynski [email protected] Université Catholique de Louvain, Cliniques Universitaires UCL Mont-Godinne, Laboratory of Bacteriology, Yvoir 5530, Belgium (PB, AV, YG); Scientific Institute of Public Health, Public Health and Surveillance Unit, Brussels, Belgium (BJ); and Université Libre de Bruxelles, Erasme Hospital, Laboratory of Bacteriology, Brussels, Belgium (OD) 1
2
832
Kumarasamy KK, Toleman MA, Walsh TR, et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study. Lancet Infect Dis 2010; 10: 597–602. Yong D, Toleman MA, Giske CG, et al. Characterization of a new metallo-β-lactamase gene, blaNDM-1, and a novel erythromycin esterase gene carried on a unique genetic structure in Klebsiella pneumoniae sequence type 14 from India. Antimicrob Agents Chemother 2009; 53: 5046–54.
3
Institut Scientifique de la Santé Publique. Guidelines for control of infections in case of cross-border transfer of patients hospitalized in countries with high endemicity of carbapenenemase-producing Enterobacteriaceae. Surveillance de germes multi-résistants dans les hôpitaux belges. Sept 23, 2010. http://www. nsih.be/download/MDR/NewDelhi_fiche_ alert_V5_FR.pdf (in French) (accessed Nov 8, 2010).
The plasmid-mediated blaNDM-1 gene that encodes a powerful carbapenemase was first identified in Escherichia coli and in Klebsiella pneumoniae in Sweden from a patient who was transferred from India.1 It was then identified from many patients in the UK, India, and Pakistan in different enterobacterial species.2 Here we report a woman aged 60 years who was admitted to hospital in April, 2009, for treatment of a breast cancer. The patient came from Darjeeling, India, where she had lived for several years and had never been hospitalised. Upon her admission in France, bacterial cultures from the surface of her breast tumour were grown. The cultures were of the E coli isolate GUE that was resistant to most β-lactams (remaining susceptible to aztreonam) and that had reduced susceptibility to carbapenems (minimum inhibitory concentrations of imipenem 3 μg/mL, ertapenem 3 μg/mL, and meropenem 2 μg/mL).3 This isolate was also resistant to gentamicin, kanamycin, tobramycin, sulfonamides, tetracycline, and fluoroquinolones, but remained susceptible to amikacin, chloramphenicol, rifampicin, and colistin. PCR and sequencing revealed that E coli GUE harboured the blaNDM-1 gene. Mating-out assays4 allowed the blaNDM-1 gene to be identified on a 110 kb plasmid, with markers for kanamycin, gentamicin, tobramycin, trimethoprim, and sulfonamide resistance. Multilocus sequence typing5 identified E coli GUE as an ST131-type strain, which corresponds to a genetic background that is also responsible for the worldwide diffusion of another
common resistance determinant, CTX-M-15. This case is the first identification of an NDM-1-producing E coli isolate in France, and corresponds again to an imported case from India. This example confirms the recent data suggesting that the Indian subcontinent might represent an important reservoir, and therefore a source, of NDM-producing isolates. The patient had not been hospitalised in India; therefore, the multidrugresistant isolate had likely been community acquired. Worringly, this resistance gene has been identified here in an E coli strain belonging to a genotype that has proved its ability to disseminate widely in the community. We declare that we have no conflicts of interest. This study was mostly funded by the INSERM (U914), France, and by grants from the Ministère de l’Education Nationale et de la Recherche (UPRES-EA3539), Université Paris XI, France, and from the European Community (TEMPOtest-QC, HEALTH-2009-241742).
Laurent Poirel, Cécile Hombrouck-Alet, Claire Freneaux, Sandrine Bernabeu, *Patrice Nordmann [email protected] Hôpital de Bicêtre, Department of BacteriologyVirology, Le Kremlin Bicêtre, Paris 94275, France 1
2
3
4
5
Yong D, Toleman MA, Giske CG, et al. Characterization of a new metallo-βlactamase gene, blaNDM-1, and a novel erythromycin esterase gene carried on a unique genetic structure in Klebsiella pneumoniae sequence type 14 from India. Antimicrob Agents Chemother 2009; 53: 5046–54. Kumarasamy KK, Toleman MA, Walsh TR, et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study. Lancet Infect Dis 2010; 10: 597–602. Clinical and Laboratory Standards Institute. 2010. Performance standards for antimicrobial susceptibility testing; twentieth informational supplement. Jan, 2010. http://www.clsi.org/source/orders/ free/m100-s20.pdf (accessed Nov 6, 2010). Rodriguez-Martinez JM, Nordmann P, Fortineau N, Poirel L. VIM-19, a metallo-βlactamase with increased carbapenemase activity from Escherichia coli and Klebsiella pneumoniae. Antimicrob Agents Chemother 2010; 54: 471–76. Tartof SY, Solberg OD, Manges AR, Riley LW. Analysis of a uropathogenic Escherichia coli clonal group by multilocus sequence typing. J Clin Microbiol 2005; 43: 5860–64.
www.thelancet.com/infection Vol 10 December 2010