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, Oman and Australia [11–14] (Fig. 1). A K. pneumoniae NDM-1 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 Gram-negative 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.


Figure 1.  Global spread of the New Delhi metallo-beta-lactamase encoding gene (NDM-1).

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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.

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The authors declare no conflict of interest.


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