New metallo [beta]-lactamase NDM-1
Indian Journal of Medical Research, Nov, 2010 by D. Raghunath

Antimicrobial resistance has been recognized since the beginning of the antibiotic era in mid 20th century. The availability of newer agents minimized the clinical threats, however, depleting reserves and "the relentless and Dizzying Rise of antimicrobial Resistance" (1) have raised the spectre of a post-antibiotic scene with untreatable infections. Bacteria have countered the introduction of successive classes of antibiotics by developing a variety of resistance mechanisms. The versatility of the bacterial genomic pool and our incomplete knowledge of the modifying process have been demonstrated (2). The history of [beta]-lactamases starting from the discovery of the TEM in 1965 has demonstrated how the microbial world keeps pace with technical advances (3). At the top of the pyramid are the carbapenemases. The metallo [beta]-lactamases (MBL) are the more versatile enzymes that can convert the host bacteria into almost total [beta]-lactam insusceptibily (4). Infections by such organisms are practically untreatable by [beta]-lactam antibiotics, which are the most favoured agents used in Gram negative sepsis.

[beta]-lactamases capable of hydrolysing carbapenems are either serine enzymes or metallo--[beta]-lactamases that have a divalent cation (usually zinc) regulating the active site. The first bacterial isolate carrying the MBL later designated [bla.sub.NDM-1] was a Klebsiella pneumoniae urinary isolate from a patient with insignificant bacteria along with other multiresistant bacteria from wound swabs. Faecal cultures done to identify the reservoir of infections yielded a strain of Escherichia coli carrying a similar resistance factor suggesting the possibility of conjugational transfer in the gut. However, there are differences in the molecular properties in the two bacteria indicating in vivo rearrangement. The properties, biological characters and phylogenetic relationship to other MBLs have been reported (5). Briefly, [bla.sub.NDM-1] is a novel MBL with ability to confer resistance to almost all the [beta] lactams. The NDM-1 gene is normally carried on a variety of plasmids along with other resistance factors. The bacteria also showed broad antibiotic resistance to all classes except colistin and ciprofloxacin. Rarely the gene was integrated into the chromosome. The sequencing of the gene showed that it was a new enzyme unrelated to hitherto known MBLs. The closest known type was VIM-1/ VIM-2 sharing a 32.4 per cent identity. The NDM-1 has an unique additional sequence. The properties of the protein, kinetic characteristics etc are reported in detail5. In summary, NDM1 confers on its host bacteria almost all [beta] lactam resistance and is accompanied by extensive antibiotic resistance. Such bacteria would be difficult to eliminate in clinical situations.

Karthikeyan et al (6) presented the result of a larger study including the epidemiology of the resistance mechanism. Two sites at Chennai and Haryana covering 3521 and 198 isolates respectively showed 1 and 13 per cent prevalence ofNDM1 carrying Enterobacteriaceae. The Chennai isolates included different species whereas all the Haryana isolates were K. pneumoniae. The sources of the isolates were community acquired urinary tract infections, pneumonia and blood stream infections. In the UK starting from 2008, isolates with NDM1 enzymes became the "dominant carbapenemase-producing Enterobacteriaceae". A number of isolates from nine locations in India, eight cities in Pakistan and Dhaka, Bangladesh have been confirmed to carry NDM1 (by PCR) (6) indicating that the plasmid is perhaps quite widely distributed in the subcontinent. While this fact leads credence to the 'Indian' origin, it may not be necessarily so. The widespread prevalence of multidrug resistant Salmonella Typhimurium DT104 in India was traced to trans border induction and rapid dissemination thereafter7. Likewise, the now widely prevalent penicillin resistant Streptococcus pneumoniae was from Spain (8). However, the statement [bla.sub.NDM-1] is widespread in the Indian environment is true. In fact, National Institute of Cholera and Enteric Diseases (NICED), Koltaka, has demonstrated the plasmid in nine surveillance rectal isolates and four cases of neonatal sepsis from a remote area (Birbhum District) [personal communication : Sulagna Basu (NICED) and Arun Singh (Institute of Post Graduate Medical Educaction & Research and SSKM Hospital, Kolkata)]. Our experience of a fulminant fatal multiple antibiotic resistant Pseudomonas aeruginosa speticaemia in a 34 yr old woman being prepared for bone marrow transplant, brings the issue to the fore (9). Septicaemia caused by a bacterium carrying NDM-1 would be well nigh impossible to treat if it has the accompanying resistances. However, the mere presence of the organism in the environment would not translate to infection if control measures are in position, as they would be, in the major corporate hospitals that cater to medical tourism.

The study of antibiotic resistance, a major field of scientific endeavour is hardly noticed by lay media. However, the paper by Karthikeyan et al (6) has generated heated discussion in professional circles as well as the print and electronic media in India. Two aspects of the publication have provoked the discussions. One has been the designation of the new enzyme as NDM-1 ascribing the origin of the resistance factors to New Delhi, the capital of India. Essentially, this is in line with the current practice of naming carbapenemases by adopting the initials of the city/locality of origin of the first isolate carrying the enzyme, e.g. SPM-1 has been named after Sao Paulo (10). In the present case, the enzyme was first detected in Sweden in a urinary isolate. The K. pneumoniae strain carrying the enzyme was colonizing the patient's urinary tract. The patient had travelled from New Delhi, hence, the designation (5). The patient's travel history and prior hospitalization within India raises the possibility of the organism having been acquired outside New Delhi. Nevertheless, the designation as NDM-1 is not really objectionable but questionable as the origin was not proven conclusively. The second aspect that has generated a heated debate in Indian professional and media circles is the assertion of the authors that patients from the West who would travel to the Indian sub-continent for elective surgery are at risk of post-operative infections due to bacteria carrying NDM-1 resulting in higher treatment costs. This would negate any economy that would accrue to the NHS from contracted outsourcing of elective surgery to "countries such as India" (11). Kartikeyan et al (6) mention about 17 of 29 UK patients yielding isolates with NDM-1 having travelled to India or Pakistan within a year and that 14 of them had been admitted to hospitals in the region. However, except in two pairs, the K. pneumoniae and E. coli isolates were unrelated to each others. Making a putative policy modifying statement based on the evidence points to suscipicous non-scientific agenda. Strangely, the National (UK) Resistance Alert in vol 3 (4) of the Health Protection Report (referred to 28) (12) in this paper warns about carbapenemases but does not mention about the MBL [bla.sub.NDM-1]. However, a fresh alert specifically mentioning [bla.sub.NDM-1] has been issued on July 3, 2009 (12). It is seen from the Alerts that importation of carbapenemase (other than NDM-1) carrying organisms occurs from a number of sites in the Eastern Mediterranean too. In fact, the initial paper describing NDM-1 (5) with the same corresponding author hints at such a preconception. This should have been addressed during peer review of the Lancet Infections Disease paper. Notably, 'medical tourism' is a rapidly growing field in India and is attracting a number of patients from the West. The private medical care 'industry' in India is looking forward to significant growth in the near future (13). Any adverse reports on the safety of such patients who came to India for elective surgery without substantive evidence is likely to impact hospitals catering to such patients in India.


Full paper available (free) at;