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New Delhi metallo-beta-lactamase (NDM-1): towards a new pandemia?
EDITORIAL
10.1111/j.1469-0691.2010.03385.x
New Delhi metallo-beta-lactamase (NDM-1): towards a new pandemia? J. M. Rolain1, P. Parola1,2 and G. Cornaglia3 1) URMITE UMR CNRS-IRD 6236, IFR48, Faculte´ de Me´decine et de Pharmacie, Universite´ de la Me´diterrane´e, Marseille, France, 2) EuroTravNet, The ECDC Collaborative Network for Tropical and Travel Medicine, Marseille, France and 3) Department of Pathology and Diagnostics, University of Verona, Verona, Italy E-mail: [email protected]
Article published online: 27 September 2010
During the past decade the increase of antibiotic resistance in Enterobacteriaceae has become a major concern worldwide. Although beta-lactams have been widely used as the mainstay of treatment for severe infections due to these bacteria, with carbapenems often representing last-resource drugs, carbapenem resistance due to acquired carbapenemases has emerged and spread worldwide since the early 2000s, being even more worrisome for public health because these bacteria are a common source of hospital-acquired infections. Carbapenemases have been now studied in depth, and widely differ from one another, including enzymes from class B (metallo-beta-lactamases, MBLs), class A and class D (serine carbapenemases) [1]. The most prevalent carbapenemase so far in Enterobacteriaceae is the KPC-type class-A carbapenemase, which has been found in Klebsiella pneumonia, especially in the United States, Asia, the United Kingdom, Israel and southern Europe [2]. Interestingly, acquired carbapenemases have been mainly restricted to geographical areas and to specific bacterial species, and outbreaks as well as spread in other countries have been often associated with imported cases from countries where the bacteria are endemic. Population mobility is known to be a main factor in globalization and spreading of antimicrobial drug-resistant organisms [3]. For example, the emergence of KPC-producing Enterobacteriaceae in the United States in 2001 [2] could be later associated with the emergence of travel-related outbreaks in other countries [1,4]. The New Delhi metallo-beta-lactamase (NDM-1) is a novel type of MBL named after the city of origin, which has been recently criticized, following a common practice with transferable MBLs since VIM-1 was named after Verona, Italy [5]. NDM-1 was first reported in 2009 in a Swedish patient of Indian origin, who travelled to New Delhi and acquired a urinary tract infection due to a carbapenem-resistant K. pneumoniae strain resistant to all antibiotics tested except colistin [6]. Faecal samples collected from this patient during his stay at the nursing home yielded an NDM-1 positive E. coli as well [6]. The NDM-1 encoding gene is located on different large
plasmids (a 180-kb plasmid for K. pneumoniae and a 140-kb plasmid for E. coli) that are easily transferable to susceptible E. coli J53 at a high frequency [6]. These plasmids also harbour genes conferring resistance to almost all antibiotics, thus making their rapid dissemination in clinically relevant bacteria a serious threat for therapy. Following this first case, sporadic cases of infection due to NDM-1 positive bacteria have been detected, including an E. coli from blood cultures of a patient of Indian origin in the United Kingdom [7], three cases of Enterobacteriaceae isolates (one E. coli, one K. pneumoniae and one E. cloacae) in the United States from patients who received care in India [8], and three cases of Acinetobacter baumannii from New Delhi [9]. In the August issue of the journal The Lancet: Infectious Diseases, a multinational team reported the emergence and spread of 180 cases of patients infected by bacteria carrying the NDM-1, including 37 cases in the United Kingdom and 143 cases in various sites in Pakistan and India, thus suggesting a widespread dissemination [10]. Among these bacteria many different Enterobacteriaceae species were identified, including K. pneumonia, E. coli, E. cloacae, Proteus spp., Citrobacter freundii, K. oxytoca, M. morganii and Providencia spp. Most isolates remained susceptible to colistin and tigecycline, except those Enterobacteriaceae endowed with a natural resistance to these compounds such as M. morganii, Proteus spp. and Providencia spp. Most plasmids detected in these bacteria were easily transferable and capable of wide rearrangement, suggesting a widespread transmission and plasticity among bacterial populations. Interestingly, among the 25 patients detected in the UK, 17 patients had travelled to India or Pakistan within 1 year and 14 had been hospitalized in these countries showing a worldwide dissemination of a new ‘superbug’ from a local source in Asia [10]. Indeed, since August 2010, spreading and dissemination has occurred, with several cases being reported by national and international media from other countries in all continents, including the United States and Canada, Europe (Sweden, the United Kingdom, Austria, Belgium, France, Netherlands and Germany), Japan, Africa,
ª2010 The Authors Clinical Microbiology and Infection ª2010 European Society of Clinical Microbiology and Infectious Diseases
1700
Clinical Microbiology and Infection, Volume 16 Number 12, December 2010
CMI
FIG. 1. Global spread of the New Delhi metallo-beta-lactamase encoding gene (NDM-1).
Oman and Australia [11–14] (Fig. 1). A K. pneumoniae NDM1 positive strain has been recently isolated from a patient repatriated in Marseille, France, in April 2010, after an accident in New Delhi (personal communication). To date there is only one reported death attributed to an infection with a bacterium carrying NDM-1, occurring in a Belgian man being repatriated in Belgium after a car accident during a trip in Pakistan. Because this carbapenemase is encoded by a genetic element found on different plasmids that may duplicate or jump from bacteria to bacteria easily, rapid dissemination and spread between different bacterial species by lateral gene transfer favoured by globalization and travel represent a high risk of a worldwide pandemia among Enterobacteriaceae. Moreover, the NDM-1 spread poses once again at least four major problems frequently highlighted when dealing with MBLs [1], namely: (i) the lack of a routine standardized phenotypic test for MBL detection; (ii) the consequent probable high prevalence of unrecognized asymptomatic carriers, allowing an international dissemination of such bacteria; (iii) the scarcity of available effective antibiotics so far, and (iv) the possibility to disseminate in many different Gramnegative bacteria. Molecular methods, especially real-time PCR, should be used for the detection of this specific carbapenemase-encoding gene, especially for patients returning from Asia, to limit the propagation and dissemination of these alarming ‘superbugs’. A systematic monitoring of both infected patients and possible asymptomatic carriers returning from Asia should be the rule to implement control strategy policies such as contact isolation procedures. However, both the rapidly growing number of potential contacts to isolate and the multiplicity of geographical areas at risk could make this approach problematic, if not virtually impossible, within a very short time. In conclusion, the NDM-1 gene spreading in Enterobacteriaceae is an alarming risk because these novel multidrug-
resistant bacteria (increasingly familiar even to the lay public as ‘superbugs’) could disseminate worldwide very quickly and originate a wide and uncontrollable spread of pandemic clones for which new and effective antibiotics are currently not available.
Transparency Declaration The authors declare no conflict of interest.
References 1. Miriagou V, Cornaglia G, Edelstein M et al. Acquired carbapenemases in Gram-negative bacterial pathogens: detection and surveillance issues. Clin Microbiol Infect 2010; 16: 112–122. 2. Nordmann P, Cuzon G, Naas T. The real threat of Klebsiella pneumoniae carbapenemase-producing bacteria. Lancet Infect Dis 2009; 9: 228–236. 3. Macpherson DW, Gushulak BD, Baine WB et al. Population mobility, globalization, and antimicrobial drug resistance. Emerg Infect Dis 2009; 15: 1727–1732. 4. Navon-Venezia S, Leavitt A, Schwaber MJ et al. First report on a hyperepidemic clone of KPC-3-producing Klebsiella pneumoniae in Israel genetically related to a strain causing outbreaks in the United States. Antimicrob Agents Chemother 2009; 53: 818–820. 5. Lauretti L, Riccio ML, Mazzariol A et al. Cloning and characterization of blaVIM, a new integron-borne metallo-beta-lactamase gene from a Pseudomonas aeruginosa clinical isolate. Antimicrob Agents Chemother 1999; 43: 1584–1590. 6. Yong D, Toleman MA, Giske CG et al. Characterization of a new metallo-beta-lactamase gene, bla(NDM-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: 5046–5054. 7. Muir A, Weinbren MJ. New Delhi metallo-beta-lactamase: a cautionary tale. J Hosp Infect 2010; 75: 239–240. 8. Detection of Enterobacteriaceae isolates carrying metallo-betalactamase – United States, 2010. MMWR Morb Mortal Wkly Rep 2010; 25: 59.
ª2010 The Authors Clinical Microbiology and Infection ª2010 European Society of Clinical Microbiology and Infectious Diseases, CMI, 16, 1699–1701
Editorial
CMI
9. Karthikeyan K, Thirunarayan MA, Krishnan P. Coexistence of blaOXA23 with blaNDM-1 and armA in clinical isolates of Acinetobacter baumannii from India. J Antimicrob Chemother 2010; 65: 2253–2254. 10. 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. 11. Poirel L, Lagrutta E, Taylor P, Pham J, Nordmann P. Emergence of metallo-beta-lactamase NDM-1-producing multidrug resistant Escherichia coli in Australia. Antimicrob Agents Chemother 2010 (in press).
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12. Poirel L, Revathi G, Bernabeu S, Nordmann P. Emergence of MetalloBeta-Lactamase NDM-1 producing Klebsiella pneumoniae in Kenya. Abstracts 50th ICAAC, Boston, 12–15 September 2010; C1-1334. 13. Limbago BPHD, Rasheed JK, Anderson KF, Zhu W, Kallen AJ. Recognition of NDM-1 among Enterobacteriaceae in the United States. Abstracts 50th ICAAC, Boston, 12–15 September 2010; C1-675d. 14. Peirano G, Ahmed-Bentley J, Woodford N, Pitout JDD. The characteristics of a metallo-beta-lactamase-producing Escherichia coli isolated in Canada from a patient with recent travel to India. Abstracts 50th ICAAC, Boston, 12–15 September 2010; C1-675a.
ª2010 The Authors Clinical Microbiology and Infection ª2010 European Society of Clinical Microbiology and Infectious Diseases, CMI, 16, 1699–1701
10.1111/j.1469-0691.2010.03385.x
New Delhi metallo-beta-lactamase (NDM-1): towards a new pandemia? J. M. Rolain1, P. Parola1,2 and G. Cornaglia3 1) URMITE UMR CNRS-IRD 6236, IFR48, Faculte´ de Me´decine et de Pharmacie, Universite´ de la Me´diterrane´e, Marseille, France, 2) EuroTravNet, The ECDC Collaborative Network for Tropical and Travel Medicine, Marseille, France and 3) Department of Pathology and Diagnostics, University of Verona, Verona, Italy E-mail: [email protected]
Article published online: 27 September 2010
During the past decade the increase of antibiotic resistance in Enterobacteriaceae has become a major concern worldwide. Although beta-lactams have been widely used as the mainstay of treatment for severe infections due to these bacteria, with carbapenems often representing last-resource drugs, carbapenem resistance due to acquired carbapenemases has emerged and spread worldwide since the early 2000s, being even more worrisome for public health because these bacteria are a common source of hospital-acquired infections. Carbapenemases have been now studied in depth, and widely differ from one another, including enzymes from class B (metallo-beta-lactamases, MBLs), class A and class D (serine carbapenemases) [1]. The most prevalent carbapenemase so far in Enterobacteriaceae is the KPC-type class-A carbapenemase, which has been found in Klebsiella pneumonia, especially in the United States, Asia, the United Kingdom, Israel and southern Europe [2]. Interestingly, acquired carbapenemases have been mainly restricted to geographical areas and to specific bacterial species, and outbreaks as well as spread in other countries have been often associated with imported cases from countries where the bacteria are endemic. Population mobility is known to be a main factor in globalization and spreading of antimicrobial drug-resistant organisms [3]. For example, the emergence of KPC-producing Enterobacteriaceae in the United States in 2001 [2] could be later associated with the emergence of travel-related outbreaks in other countries [1,4]. The New Delhi metallo-beta-lactamase (NDM-1) is a novel type of MBL named after the city of origin, which has been recently criticized, following a common practice with transferable MBLs since VIM-1 was named after Verona, Italy [5]. NDM-1 was first reported in 2009 in a Swedish patient of Indian origin, who travelled to New Delhi and acquired a urinary tract infection due to a carbapenem-resistant K. pneumoniae strain resistant to all antibiotics tested except colistin [6]. Faecal samples collected from this patient during his stay at the nursing home yielded an NDM-1 positive E. coli as well [6]. The NDM-1 encoding gene is located on different large
plasmids (a 180-kb plasmid for K. pneumoniae and a 140-kb plasmid for E. coli) that are easily transferable to susceptible E. coli J53 at a high frequency [6]. These plasmids also harbour genes conferring resistance to almost all antibiotics, thus making their rapid dissemination in clinically relevant bacteria a serious threat for therapy. Following this first case, sporadic cases of infection due to NDM-1 positive bacteria have been detected, including an E. coli from blood cultures of a patient of Indian origin in the United Kingdom [7], three cases of Enterobacteriaceae isolates (one E. coli, one K. pneumoniae and one E. cloacae) in the United States from patients who received care in India [8], and three cases of Acinetobacter baumannii from New Delhi [9]. In the August issue of the journal The Lancet: Infectious Diseases, a multinational team reported the emergence and spread of 180 cases of patients infected by bacteria carrying the NDM-1, including 37 cases in the United Kingdom and 143 cases in various sites in Pakistan and India, thus suggesting a widespread dissemination [10]. Among these bacteria many different Enterobacteriaceae species were identified, including K. pneumonia, E. coli, E. cloacae, Proteus spp., Citrobacter freundii, K. oxytoca, M. morganii and Providencia spp. Most isolates remained susceptible to colistin and tigecycline, except those Enterobacteriaceae endowed with a natural resistance to these compounds such as M. morganii, Proteus spp. and Providencia spp. Most plasmids detected in these bacteria were easily transferable and capable of wide rearrangement, suggesting a widespread transmission and plasticity among bacterial populations. Interestingly, among the 25 patients detected in the UK, 17 patients had travelled to India or Pakistan within 1 year and 14 had been hospitalized in these countries showing a worldwide dissemination of a new ‘superbug’ from a local source in Asia [10]. Indeed, since August 2010, spreading and dissemination has occurred, with several cases being reported by national and international media from other countries in all continents, including the United States and Canada, Europe (Sweden, the United Kingdom, Austria, Belgium, France, Netherlands and Germany), Japan, Africa,
ª2010 The Authors Clinical Microbiology and Infection ª2010 European Society of Clinical Microbiology and Infectious Diseases
1700
Clinical Microbiology and Infection, Volume 16 Number 12, December 2010
CMI
FIG. 1. Global spread of the New Delhi metallo-beta-lactamase encoding gene (NDM-1).
Oman and Australia [11–14] (Fig. 1). A K. pneumoniae NDM1 positive strain has been recently isolated from a patient repatriated in Marseille, France, in April 2010, after an accident in New Delhi (personal communication). To date there is only one reported death attributed to an infection with a bacterium carrying NDM-1, occurring in a Belgian man being repatriated in Belgium after a car accident during a trip in Pakistan. Because this carbapenemase is encoded by a genetic element found on different plasmids that may duplicate or jump from bacteria to bacteria easily, rapid dissemination and spread between different bacterial species by lateral gene transfer favoured by globalization and travel represent a high risk of a worldwide pandemia among Enterobacteriaceae. Moreover, the NDM-1 spread poses once again at least four major problems frequently highlighted when dealing with MBLs [1], namely: (i) the lack of a routine standardized phenotypic test for MBL detection; (ii) the consequent probable high prevalence of unrecognized asymptomatic carriers, allowing an international dissemination of such bacteria; (iii) the scarcity of available effective antibiotics so far, and (iv) the possibility to disseminate in many different Gramnegative bacteria. Molecular methods, especially real-time PCR, should be used for the detection of this specific carbapenemase-encoding gene, especially for patients returning from Asia, to limit the propagation and dissemination of these alarming ‘superbugs’. A systematic monitoring of both infected patients and possible asymptomatic carriers returning from Asia should be the rule to implement control strategy policies such as contact isolation procedures. However, both the rapidly growing number of potential contacts to isolate and the multiplicity of geographical areas at risk could make this approach problematic, if not virtually impossible, within a very short time. In conclusion, the NDM-1 gene spreading in Enterobacteriaceae is an alarming risk because these novel multidrug-
resistant bacteria (increasingly familiar even to the lay public as ‘superbugs’) could disseminate worldwide very quickly and originate a wide and uncontrollable spread of pandemic clones for which new and effective antibiotics are currently not available.
Transparency Declaration The authors declare no conflict of interest.
References 1. Miriagou V, Cornaglia G, Edelstein M et al. Acquired carbapenemases in Gram-negative bacterial pathogens: detection and surveillance issues. Clin Microbiol Infect 2010; 16: 112–122. 2. Nordmann P, Cuzon G, Naas T. The real threat of Klebsiella pneumoniae carbapenemase-producing bacteria. Lancet Infect Dis 2009; 9: 228–236. 3. Macpherson DW, Gushulak BD, Baine WB et al. Population mobility, globalization, and antimicrobial drug resistance. Emerg Infect Dis 2009; 15: 1727–1732. 4. Navon-Venezia S, Leavitt A, Schwaber MJ et al. First report on a hyperepidemic clone of KPC-3-producing Klebsiella pneumoniae in Israel genetically related to a strain causing outbreaks in the United States. Antimicrob Agents Chemother 2009; 53: 818–820. 5. Lauretti L, Riccio ML, Mazzariol A et al. Cloning and characterization of blaVIM, a new integron-borne metallo-beta-lactamase gene from a Pseudomonas aeruginosa clinical isolate. Antimicrob Agents Chemother 1999; 43: 1584–1590. 6. Yong D, Toleman MA, Giske CG et al. Characterization of a new metallo-beta-lactamase gene, bla(NDM-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: 5046–5054. 7. Muir A, Weinbren MJ. New Delhi metallo-beta-lactamase: a cautionary tale. J Hosp Infect 2010; 75: 239–240. 8. Detection of Enterobacteriaceae isolates carrying metallo-betalactamase – United States, 2010. MMWR Morb Mortal Wkly Rep 2010; 25: 59.
ª2010 The Authors Clinical Microbiology and Infection ª2010 European Society of Clinical Microbiology and Infectious Diseases, CMI, 16, 1699–1701
Editorial
CMI
9. Karthikeyan K, Thirunarayan MA, Krishnan P. Coexistence of blaOXA23 with blaNDM-1 and armA in clinical isolates of Acinetobacter baumannii from India. J Antimicrob Chemother 2010; 65: 2253–2254. 10. 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. 11. Poirel L, Lagrutta E, Taylor P, Pham J, Nordmann P. Emergence of metallo-beta-lactamase NDM-1-producing multidrug resistant Escherichia coli in Australia. Antimicrob Agents Chemother 2010 (in press).
1701
12. Poirel L, Revathi G, Bernabeu S, Nordmann P. Emergence of MetalloBeta-Lactamase NDM-1 producing Klebsiella pneumoniae in Kenya. Abstracts 50th ICAAC, Boston, 12–15 September 2010; C1-1334. 13. Limbago BPHD, Rasheed JK, Anderson KF, Zhu W, Kallen AJ. Recognition of NDM-1 among Enterobacteriaceae in the United States. Abstracts 50th ICAAC, Boston, 12–15 September 2010; C1-675d. 14. Peirano G, Ahmed-Bentley J, Woodford N, Pitout JDD. The characteristics of a metallo-beta-lactamase-producing Escherichia coli isolated in Canada from a patient with recent travel to India. Abstracts 50th ICAAC, Boston, 12–15 September 2010; C1-675a.
ª2010 The Authors Clinical Microbiology and Infection ª2010 European Society of Clinical Microbiology and Infectious Diseases, CMI, 16, 1699–1701