Sound and fury over the ‘New Delhi Superbug’
The Indian government has been quick to rubbish the Lancet study on the NDM-1 bacterium, choosing to see this as a commercial problem that will impact our growing medical tourism industry, rather than as a health care problem that could seriously impact a country where antibiotics are overused and where scant attention is paid to infection control in hospitals.
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 an impatient and under-informed media have promptly labelled the “New Delhi superbug”.
Quite aside from the clumsy label given to the new bacterium, 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 450 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 an attempt to scuttle India’s ambitious medical tourism industry. It is unfortunate that amidst the sound and fury, the problem is seen as a commercial one, not a health one.
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, 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,” was the reaction of the Director General of Health Services, RK Srivastav.
SS Ahluwalia, who is deputy leader of the Opposition in the Rajya Sabha, called the study a “sinister design” of foreign multinational companies to undermine India’s fast-expanding 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.
Behind 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 is the impact of the Lancet study on India’s medical tourism industry. A substantial portion of medical visitors are from Britain, and the medical tourism industry is reported to be valued at USD 2.3 billion by 2012. Perhaps the only rational official response thus far has been that of 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? 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 travelled to India or Pakistan, and several had been hospitalised while undergoing elective surgery.
What does the Lancet study in fact 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 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 press has reported statements apparently made by two of the several Indian authors of the Lancet study, both in effect saying that the conclusions pertaining to India are not necessarily shared by them. This partial dissent may have to do with new pressures being brought upon the authors but again do little to inform the public and health policymakers about the realities of antibiotic resistance, which is the subject at the heart of this matter. Infection control practices in government and private hospitals alike in South Asia are far from satisfactory and tend to be reactive rather than anticipatory. In India, usually, a hospital’s infection control committee exists only on paper, and will commence work only in the wake of a serious outbreak of infection within
the hospital. The excessive use of antibiotics has long been researched as a major cause of resistance in industrialised countries, and we have for several years seen concerns voiced about the increasing emergence of resistant micro-organisms in developing countries. There are other circumstances which confound the matter. Overcrowding in hospitals, the burdens of poverty, dreadful sanitation in urban zones, inappropriate use of antibiotics and the availability of antibiotics without prescription are also contributing factors. Add to this the generally poor level of health care infrastructure, inadequate hospital hygiene and the absence of reliable diagnostic tools—these worsen the problem. It is in this context that the Lancet paper makes several observations which have implications for public health in India, Pakistan, Bangladesh and South Asia and these are:
“NDM-1-positive bacteria from Mumbai (32 isolates), Varanasi (13), and Guwahati (3) 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 non-prescription use of antibiotics in India, 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. Generally, there is little control on the use of antibiotics (it is commonly known in the Konkan for example that antibiotics are also sprayed on crops in an effort to boost per hectare yield). Community awareness of the issues involved in antibiotic therapy is poor and this is compounded by over-the-counter availability. Coupled with primitive infection control in hospitals and weak or deficient sanitation, the conditions are conducive to transmission and acquisition of antibiotic resistance. The facility with which enteric pathogens spread widely in India illustrates this point.
New Delhi and other India metropolises and cities have witnessed repeated surges in the incidence of dengue and, especially in monsoon months, malaria, which the city authorities of Mumbai are currently battling in a haphazard manner; this only illustrates how the deficiency in disease anticipation at the hospital level is evidence of a system-wide malaise. 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 K.”
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.”
Is this a novel concern? Here are the institutes to which the authors of the Lancet study belong (number of authors in parenthesis): Department of Microbiology, Dr ALM PG IBMS, University of Madras, Chennai (2); Department of Infection, Immunity and Biochemistry, School of Medicine, Cardiff University, UK (2); Health Protection Agency Centre for Infections, London, UK (16); Department of Microbiology, Shaukat Khanum Cancer Hospital, Lahore, Pakistan (1); Department of Microbiology, Pandit BD Sharma, PG Institute of Medical Sciences, Haryana (2); Department of Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden (1); Department of Pathology and Microbiology, The Aga Khan University, Karachi, Pakistan (1); Department of Microbiology, Amrita Institute of Medical Sciences, Kerala (1); University of Queensland Centre for Clinical Research, University of Brisbane, Australia (1); Department of Microbiology, Apollo Gleneagles Hospital, Kolkata (1); Department of Medical Microbiology, Northumbria Healthcare NHS Foundation Trust, Tyne and Wear, UK (1); Department of Microbiology, Apollo Hospitals, Chennai (1); and Department of Microbiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi (1).
With 16 authors, the Health Protection Agency Centre for Infections, London, UK, and its concerns become clear. Its reasons for making its concerns clear have also been dealt with by research literature in the past. For instance, in his article “Emerging antibiotic resistance in bacteria with special reference to India”, D Raghunath of the Sir Dorabji Tata Centre for Research in Tropical Diseases, Innovation Centre, at the Indian Institute of Science Campus, Bangalore, wrote, “Apart from the medical consequences of antibiotic resistance there is a direct cost to society. Newer antibiotics come with a higher cost, implementing hospital practices to control spread of resistant bacteria and investigation of outbreaks add to the cost of health care. On a national scale the burden is considerable amounting to about £ (GBP) 1,000 million per annum in the UK and corresponding figures in other countries that have computed their costs” (Journal of Biosciences, 2008 November).
It is precisely the widespread and persistent problem of antibiotic resistance that has led to the creation of organisations such as the Global Antibiotic Resistance Partnership (www.resistancestrategies.org). Current regulation and enforcement mechanisms do not prevent over-the-counter purchases of antibiotics. A Delhi Society for Promotion of Rational Use of Drugs study of pharmacies in New Delhi found that a third of people who bought antibiotics did so without a prescription, despite laws requiring one. The study found that the most common antibiotics purchased without a prescription were fluoroquinolones, while cephalosporins were the most common antibiotic purchased with a prescription. Moreover, a WHO study found that private hospitals prescribe fluoroquinolones and expensive antibiotics more than public hospitals.
For these reasons—and for the circumstances that surround public health practice and responses in India—there have been repeated calls for the central government and state governments to (1) increase prescription auditing, (2) partner with pharmaceutical industry to increase drug regulation, (3) set up national surveillance networks to track the evolution and spread of resistant pathogens, and (4) increase the number of certified laboratories. The actual measures and how they may be applied deserve to be a subject of public debate. There is no justification for the Ministry of Health, Government of India, delaying recognition of the need for debate and action on widespread antibiotic resistance by invoking hollow notions of pride and reputation.
By Rahul Goswami