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Sound and fury over the ‘New Delhi superbug’

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The Government of India has decided on a matter of medical research to protest what it sees as an attack on India’s pride and reputation. In the process it is ignoring entirely the public health implications of the findings concerning the ‘New Delhi metallo-beta-lactamase 1 (NDM-1) positive Enterobacteriaceae‘ which a typically hair-trigger and chronically underinformed media have promptly labelled the ‘New Delhi superbug‘.

The Lancet study on 'New Delhi metallo-beta-lactamase 1'National politicians are notoriously quick to point out and rubbish any perceived stain on Mother India’s honour – never mind that 53 million children under five are malnourished and 456 million live in poverty. And so it is with the Lancet Infectious Diseases paper whose findings ought to be treated with the seriousness they deserve, rather than be rubbished out of hand as being an attempt to scuttle India’s ambitious medical tourism industry. The problem is seen as commercial, not health, which becomes clear given the non-partisan nature of the defenders.

India’s Union Health and Family Welfare Minister Ghulam Nabi Azad directed the ministry he heads to issue a statement which said: “While such organisms may be circulating more commonly in the world due to international travel but to link this with the safety of surgery hospitals in India and citing isolated examples to show that due to presence of such organism in Indian environment, India is not a safe place to visit is wrong.” The Indian health authorities also complained to the Indian media that several authors of the Lancet study had pharmaceutical ties. “After seeing the research paper I strongly refute that hospitals in India are the source of the strain and strongly condemn naming the bacteria after New Delhi,” said Director General of Health Services RK Srivastav.

Malnourished children under 5, MDGs map, World Bank

Malnourished children under 5, MDGs map, World Bank

Politician S S Ahluwalia, who is deputy leader of opposition in the Rajya Sabha (upper house), called the study a “sinister design” of foreign multinational companies to undermine India’s burgeoning medical tourism industry. He said in the Rajya Sabha that “the timing of the article was suspicious” as it came when “India is emerging as a global power in medical tourism”. However, being in the opposition, he also asked the government to “come out with a registry that will record infections when they are detected in hospitals, and also antibiotics for their treatment”. This demand was probably prompted by a report citing an official of the Indian Council of Medical Research as having said that India currently does not have any rules or registry to record hospital-acquired infections.

In all the expressions of outrage, what is clear is that the immediate concern of the Union Health Ministry and the assortment of politicians and health officials protesting is the impact of the Lancet study on India’s medical tourism industry, which is no doubt booming, of which a substantial portion is composed of medical visitors from Britain, and which is estimated by the healthcare industry to reach USD 2.3 billion in value by 2012. Perhaps the only rational response was from the Minister of State for Science and Technology and Parliamentary Affairs, Prithviraj Chavan, who told Parliament he would provide an answer “after consulting with the health ministry and department of biotechnology”.

What actually set off the outrage in India? As Nature Blogs explains, the ‘New Delhi metallo-beta-lactamase 1 (NDM-1) positive Enterobacteriaceae’ comprise a new breed of multidrug-resistant bacterium. Germs carrying the NDM-1 gene fend off almost every known antibiotic, including the carbapenem family of drugs reserved as a last resort. One such bug claimed its first known fatality in June, when a Belgian man infected while hospitalised in Pakistan died in Brussels. The Lancet paper found the NDM-1 gene in isolates of Escherichia coli and Klebsiella pneumoniae taken from sites in the United Kingdom, India, and Pakistan. Of the 29 UK patients found with NDM-1 germs, 17 had recently traveled to India or Pakistan, and several had been hospitalised while undergoing elective surgery.

The Lancet study on 'New Delhi metallo-beta-lactamase 1'What does the Lancet study actually say? Entitled ‘Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study’, the 31 collaborating authors say that “Gram-negative Enterobacteriaceae with resistance to carbapenem conferred by New Delhi metallo-beta-lactamase 1 (NDM-1) are potentially a major global health problem“. They say this because they investigated the prevalence of NDM-1, in multidrug-resistant Enterobacteriaceae in India, Pakistan, and the UK. Enterobacteriaceae isolates were studied from two major centres in India – Chennai (south India), Haryana (north India) – and those referred to the UK’s national reference laboratory.

Here is the short statement of findings: “We identified 44 isolates with NDM-1 in Chennai, 26 in Haryana, 37 in the UK, and 73 in other sites in India and Pakistan. NDM-1 was mostly found among Escherichia coli (36) and Klebsiella pneumoniae (111), which were highly resistant to all antibiotics except to tigecycline and colistin. K pneumoniae isolates from Haryana were clonal but NDM-1 producers from the UK and Chennai were clonally diverse. Most isolates carried the NDM-1 gene on plasmids: those from UK and Chennai were readily transferable whereas those from Haryana were not conjugative. Many of the UK NDM-1 positive patients had travelled to India or Pakistan within the past year, or had links with these countries.”

And this is the no-nonsense assessment: “The potential of NDM-1 to be a worldwide public health problem is great, and co-ordinated international surveillance is needed.” Who funded the research? The European Union, Wellcome Trust, and Wyeth. Does this pose conflicts of interest? According to the Indian government it does, for the Union Health Ministry has pointed out that one author “has received a travel grant from Wyeth” and another “has received
conference support from numerous pharmaceutical companies, and also holds shares in AstraZeneca, Merck, Pfizer, Dechra, and GlaxoSmithKline, and, as Enduring Attorney, manages further holdings in GlaxoSmithKline and Eco Animal Health”. However what was not mentioned is the statement that “all other authors declare that they have no conflicts of interest” which covers 29 out of 31.

The Lancet paper makes several observations which have implications for public health in India, Pakistan, Bangladesh and South Asia and these are:

Population living in poverty, MDGs map, World Bank

Population living in poverty, MDGs map, World Bank

“NDM-1-positive bacteria from Mumbai (32 isolates), Varanasi (13), and Guwahati (three) in India, and 25 isolates from eight cities in Pakistan (Charsadda, Faisalabad, Gujrat, Hafizabad, Karachi, Lahore, Rahim Yar Khan, and Sheikhupura) were also analysed in exactly the same manner but in laboratories in India and Pakistan. These isolates were from a range of infections including bacteraemia, ventilator-associated pneumonia, and community-acquired urinary tract infections.”

“In addition to the collections of isolates from Chennai and Haryana detailed above, we have confirmed by PCR alone the presence of genes encoding NDM-1 in carbapenem-resistant Enterobacteriaceae isolated from Guwahati, Mumbai, Varanasi, Bangalore, Pune, Kolkata, Hyderabad, Port Blair, and Delhi in India, eight cities (Charsadda, Faisalabad, Gujrat, Hafizabad, Karachi, Lahore, Rahim Yar Khan, and Sheikhupura) in Pakistan, and Dhaka in Bangladesh suggesting widespread dissemination.”

The concern is that there is widespread nonprescription use of antibiotics in India, leading to huge selection pressure, which led the study authors to predict that the NDM-1 problem is likely to get substantially worse in the foreseeable future. “This scenario is of great concern because there are few new anti-Gram-negative antibiotics in the pharmaceutical pipeline and none that are active against NDM-1 producers.” Even more disturbing, the authors have said, is that most of the Indian isolates from Chennai and Haryana were from community-acquired infections, suggesting that NDM-1 is widespread in the environment.

New Delhi and other India metropolises and cities have witnessed repeated surges in the incidents of dengue and, especially in monsoon months, malaria, which the city authorities of Mumbai (Bombay) are currently battling in a haphazard and quite ineffectual manner. The conclusions of the Lancet study on NDM-1 naturally also raise question about the ability of a worn out public health system to identify and respond to new threats, and it is this aspect which ought to be exercising the Union Health Ministry rather than the perceived slur on five-star medical tourism facilities. Moreover, as the affiliations of the study authors show, this is a South Asian effort concerning what ought to be viewed as a South Asian health issue, and the Indian Government’s nationalistic response ignores the regional dimension entirely (and typically).

“The introduction of NDM-1 into the UK is also very worrying and has prompted the release of a National Resistance Alert 3 notice by the Department of Health on the advice of the Health Protection Agency,” the study has said in conclusion. “Given the historical links between India and the UK, that the UK is the first western country to register the widespread presence of NDM-1-positive bacteria is unsurprising. However, it is not the only country affected. In addition to the first isolate from Sweden, a NDM-1-positive K pneumoniae isolate was recovered from a patient who was an Australian resident of Indian origin and had visited Punjab in late 2009. The isolate was highly resistant and carried NDM-1 on an incompatibility A/C type plasmid similar to those in India and the UK.”

Several of the UK source patients had undergone elective, including cosmetic, surgery while visiting India or Pakistan. India also provides cosmetic surgery for other Europeans and Americans, and NDM-1 will likely spread worldwide. It is disturbing, in context, to read calls in the popular press for UK patients to opt for corrective surgery in India with the aim of saving the NHS money. As our data show, such a proposal might ultimately cost the NHS substantially more than the short-term saving and we would strongly advise against such proposals. The potential for wider international spread of producers and for NDM-1-encoding plasmids to become endemic worldwide, are clear and frightening.”

The authors of the Lancet study and their institutional affiliations are: Department of Microbiology, Dr ALM PG IBMS, University of Madras, Chennai, India (K K Kumarasamy MPhil, P Krishnan PhD); Department of Infection, Immunity and Biochemistry, School of Medicine, Cardiff University, Cardiff , UK (M A Toleman PhD, Prof T R Walsh PhD, the lead author); Health Protection Agency Centre for Infections, London, UK (J Bagaria MD, R Balakrishnan MD, M Doumith PhD, S Maharjan MD, S Mushtaq MD, T Noorie MD, A Pearson PhD, C Perry PhD, R Pike PhD, B Rao MD, E Sheridan PhD, J Turton PhD, M Warner PhD, W Welfare PhD, D M Livermore PhD, N Woodford PhD); Department of Microbiology, Shaukat Khanum Cancer Hospital, Lahore, Pakistan (F Butt MD); Department of Microbiology, Pandit B D Sharma PG Institute of Medical Sciences, Haryana, India (U Chaudhary MD, M Sharma MD); Department of Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden (C G Giske MD); Department of Pathology and Microbiology, The Aga Khan University, Karachi, Pakistan (S Irfan MD); Department of Microbiology, Amrita Institute of Medical Sciences, Kerala, India (A V Kumar MD); University of Queensland Centre for Clinical Research, University of Brisbane, Herston, QLD, Australia (D L Paterson MD); Department of Microbiology, Apollo Gleneagles Hospital, Kolkata, India (U Ray MD); Department of Medical Microbiology, Northumbria Healthcare NHS Foundation Trust, Tyne and Wear, UK (J B Sarma MD); Department of Microbiology, Apollo Hospitals, Chennai, India (M A Thirunarayan MD); and Department of Microbiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India (S Upadhyay PhD).

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