Frontline, September 10, 2010

by Praful Bidwai

“SHOCKING”. “Unscientific”. “MNC-pharma Conspiracy”. “More Hype than Substance”. Driven by “Ulterior Motives” and “Conflict of Interest”. The way Health Ministry and private medical establishment went ballistic over an article in The Lancet Infectious Diseases on the isolation in Indian hospitals of a gene called New Delhi metallo-beta-lactamase-1 (NDM-1) associated with antibiotic resistance is without precedent.

It is as if the very foundations of our health system and the integrity of Indian doctors were questioned; “Western” researchers had conspired, with multinational companies, to undermine India's rapidly growing medical tourism business. Health Minister Ghulam Nabi Azad questioned the researchers' motive: “They were funded by one pharmaceutical company …. The company itself makes antibiotics.” He forgot that eight of the 31 researchers were Indians.

Apollo Hospitals chairman Prathap C. Reddy asserted that India has “very strict quality control standards”, with results equalling “some of the best in the world”: “It is atrocious to have named a bug over a country/city. Infections are everywhere.” Ironically, the first professional comment about NDM-1 came from Dr Abdul Ghafur K, an infectious diseases consultant at Apollo Hospital, Chennai, who wrote an acerbic editorial, “An Obituary — Death of Antibiotics!” in the Journal of the Association of the Physicians of India (JAPI) in March. Two of The Lancet authors are from Apollo Hospitals.

What is so special about NDM-1? The gene, which is easily transmitted between bacteria called Enterobacteriaceae such as E. coli and Klebsiella pneumoniae (which cause urinary infections and pneumonia) makes them resistant to numerous classes of antibiotics, including the newest called carbapenems.

Carbapenems are the last line of defence against multi-drug-resistant bugs. This has horrific implications. If such genes spread, the world will have no means left to fight bacterial diseases. We could return to the pre-penicillin era, in which millions perished like flies.

Since penicillin was industrially produced in 1942, the world has created more than a dozen kinds/classes of powerful antibiotics, including, recently, three new classes called 4-quinolones (for instance, ciprofloxacin), cephalosporins (for instance, cephalexin) and carbapenems (for instance, colistin). Antibiotics are indispensable in major surgical procedures and treatment of infectious diseases, which remain among the biggest killers in poor countries. Rampant antibiotic resistance will disarm humanity against bugs.

So, the NDM-1 disclosure should deeply worry the establishment and trigger critical introspection and corrective steps. Instead, it has reacted hysterically while denying the gravity of the situation – in a manner reminiscent of the plague outbreak in 1994, where the government was more preoccupied with maintaining India's image as an investment destination than with saving its citizens' lives.


At the core of this profoundly irrational response is a paranoid self-assumption of victimhood (“They are jealous of our medical tourism”); a desperate desire to “externalise” the issue (as if NDM-1-induced resistance would only affect foreign tourists); and a sick variety of nationalism.

There is also a commercial angle: minting money by selling health care to foreigners at a fraction of the cost in the West, while sustaining the utmost callousness towards the Indian people, who have abysmal health indices and little access even to primary health care. As citizens, we are naturally inclined to welcome the whistle-blowing on NDM-1. Equally, the corporate health-care industry is inclined to condemn it. There could be no sharper divergence of interests.

Three criticisms have been levelled against The Lancet article: that it is alarmist and reaches conclusions that go beyond the scientific findings; that it involves an unethical conflict of interest related to funding; and that it is wrong and unprecedented in science to name a bacterium/gene after a particular place. The criticisms are all misplaced.

The Lancet study says the NDM-1 gene was identified in 37 people who returned to the United Kingdom after undergoing surgery in India/Pakistan. Six Indian institutes, including Banaras Hindu University's Institute of Medical Sciences and the University of Madras Microbiology Department, participated in it with Cardiff University, U.K., Stockholm's prestigious Karolinska Institute and a laboratory of the U.K.-based Health Protection Agency.

There is evidence that NDM-1 has spread to Chennai, Mumbai, Varanasi, Guwahati, Bangalore, Pune, Kolkata, Hyderabad, Rohtak and Port Blair. It has been found in Pakistan and Bangladesh. It has also spread to the U.K., the United States, the Netherlands, Australia and Canada.

The Lancet paper follows the standard scientific format in blandly describing samples, methods of analysis and inferences. Its discussion ends with an opinion: “Several of the U.K. 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 U.K. patients to opt for corrective surgery in India with the aim of saving the NHS National Health Service money. … 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 … NDM-1 is … clear and frightening.”


Biologist Sandip Basu, former Director of the National Institute of Immunology, says the study appears competent and the conclusions “innocuous”: “One might take exception to the sermonising tone of the last paragraph. But that is not particularly unreasonable given the grave implications for the global public. Besides, we shouldn't pretend, ostrich-like, that all is well with India's healthcare system. There is rampant overuse of antibiotics. Many doctors and hospitals cut corners on safety ….”

The Lancet paper is not the first study on NDM-1. The first case was identified last year in a Swedish patient of Indian origin admitted to an Indian hospital. The gene was “officially” named last December. The first systematic NDM-1 study in India was conducted by researchers from the Hinduja National Hospital, Mumbai, reporting the isolation of 22 NDM-1-producing bacteria in just three months, and published in JAPI in March.

That issue carried Ghafur's editorial, which said: “If a single hospital can isolate such a significant number of bacteria with a new resistant gene in a short period of time, the data from all the Indian hospitals, if available, would potentially be more interesting and shocking than the human genome project data ….”

“The easiest way of tackling the superbug problem,” wrote Ghafur, “is to use the notorious ostrich strategy, which denies the existence of the problem – stop looking for these bugs, stop looking for the hidden resistance mechanisms and closing your eyes even if you find them. … It is an Indian tradition. Why should we Indians worry? We can always depend on honey, yogurt and cow's urine.”

As for the The Lancet study's funding, the paper mentions the sources as the European Union, the Wellcome Trust, and pharmaceutical multinational Wyeth. Wyeth provided travel grants to two researchers. Now, the Wellcome Trust is a well-known international funding agency for biomedical research, which has donated to numerous Indian laboratories. Department of Biotechnology Secretary M.K. Bhan is on record as saying: “They (Wellcome) have outstanding standards. They are very India-centric and have helped India build its own biomedical science. We value their partnership and they do everything in partnership with the government.”

As for Wyeth, it is not unusual for pharmaceutical companies to fund genuine research projects – although many also do questionable promotional funding by sponsoring doctors' jaunts abroad or giving them expensive gifts. Unfortunate though corporate funding may be, that in itself is not an argument for rejecting the paper's conclusions.

Finally, it is standard practice in the biomedical sciences to name genes or bacterial strains after places/people. Some strains of the metallo-beta-lactamase gene were named after Verona and Sao Paulo. Similar genes were named after Dusseldorf and Seoul. Indian place names have been used in the past, for example, Pseudomonas delhiensis and Methanolobus bombayensis. Similarly, bugs have also been named after places such as Adelaide, Beijing, Berlin, Moscow, Singapore, Texas, Washington and Zurich. The name does not necessarily mean the organism originated there. “NDM-1” does not insinuate that the gene is endemic to New Delhi. It may have been transmitted from elsewhere.

Antibiotic resistance is growing the world over as bacteria mutate to adapt themselves to their environment. Until recently, resistance used to be overcome through the invention of new and powerful antibiotics. “But today almost all the known antibiotics have been matched by resistant bacteria; this is a menacing phenomenon,” says Professor Otto Cars, an infectious diseases specialist at Uppsala University, Sweden, who also heads Action on Antibiotic Resistance or ReAct, a global grouping that hopes to find innovative ways of tackling the problem.


Among the most notorious early instances of resistance is methicillin-resistant Staphylococcus aureus (MRSA). MRSA causes over 5,000 deaths in the U.S. among 126,000 hospitalised patients. The U.K. death toll is 1,200 or more. This writer has also been a victim of MRSA caused through medical negligence in surgery in 1988 in Delhi. He spent two years in hospitals in India and abroad and underwent 18 major operations before the infection subsided in 1993.

One reason why resistance is growing is that Big Pharma is not investing much in antibiotics research. Drug companies invented 16 new antibiotics in 1983-87, but only seven in 1998-2002. Currently, antibacterial drugs constitute only 1.6 per cent of all new molecules being developed. New-generation antibiotics are exorbitantly costly. For instance, carbapenems treatment costs Rs.6,900 a day.

Developing countries are especially vulnerable to antibiotic resistance. South Asia does not generate accurate data on resistance. But it is estimated that a large proportion of the one million-plus children dying of respiratory diseases every year succumb to bacterial resistance. In the 1980s, over 1,000 died in West Bengal owing to resistance to common antibiotics against the diarrhoea-causing Shigella. Recently, up to 89 per cent of some Shigella strains in Karachi were found resistant to commonly used cotrimoxazole and ampicillin. Shigella is a major public health problem in developing countries, accounting for a majority of diarrhoea deaths among children under five.


India has an extremely high incidence of antibiotic resistance – according to Ghafur, the highest in the world. Resistance is pervasive. Particularly alarming is the spread of drug-resistant tuberculosis (TB). This is partly because of the high incidence of infections, thanks to poor-quality water, air pollution, general lack of hygiene, and above all, poor nutrition. We are still struggling against water-borne dysenteries and respiratory problems from exposure to polluting cooking stoves.

Thus, even dirt-poor tribal regions in Central India, with meagre health care and extremely low exposure to antibiotics, exhibit high resistance to antibiotics. A study by Jan Swasthya Sahyog or People's Health Support Group, Bilaspur, shows that resistance to cotrimoxazole and ciprofloxacin is as high as 62 and 41 per cent among women in Chhattisgarh with uncomplicated urinary infections. The proportion rises to 73 and 69 per cent among those who used antibiotics in the preceding six months. Among hospitalised patients, resistance ranges from 72 to 94 per cent for most antibiotics.

Several factors explain high antibiotic resistance in India. The most important is the heavy promotion of expensive broad-spectrum antibiotics by drug companies. Antibiotics are the single largest class of medicines sold in India. Many companies – the principal source of information on pharmaceuticals for doctors – unethically and aggressively promote high-end antibiotics to treat simple diseases. For instance, the extremely toxic drug chloramphenicol, to be only used in life-threatening meningitis and typhoid, was for long years prescribed for colds and coughs. The result was scores of deaths in Kerala when typhoid broke out in the 1970s.

Secondly, the medical profession overprescribes antibiotics. Says Dr C.M. Gulati, editor of Monthly Index of Medical Specialities: “Doctors who charge between Rs.300 and Rs.1,200 for a consultation hesitate to prescribe effective but inexpensive drugs, opting for new-generation antibiotics – sometimes, many, when one will do.”

Ayurvedic doctors, homeopaths and dentists can all prescribe them. According to Ghafur, the Indian medical curriculum gives a low priority to infectious diseases. A general medicine candidate can clear the examination without reading the chapter on infectious diseases. Even worse, there is rampant unprescribed and self-prescribed antibiotics use. Most pharmacists in India sell them without prescription. Often, patients seek the advice of illiterate assistants in pharmacies on what drugs to take: the presumption is, the dispenser “knows”.

Antibiotics are powerful molecules, which act in complex, imperfectly understood, and unintended ways. Thus, successfully targeting a Shigella infection with a broad-spectrum antibiotic might breed Staph aureas resistance to that whole antibiotics class. The situation is alarming in hospitals, which concentrate bacteria and antibiotics. Hospital infections are especially stubborn.

This makes it imperative that all hospitals scrupulously practise an antibiotics policy, under which no doctor freely prescribes antibiotics but follows a protocol drawn up with infectious diseases specialists so that some drugs are kept in reserve to fight exceptionally severe infections or resistant strains. In India's dangerous laissez faire regime, anyone can prescribe anything, leading to galloping resistance.

Rectifying this situation demands a series of measures, including curbs on corporate drug promotion, with stiff penalties, public education on the rational use of drugs, re-education of doctors, mandatory antibiotics policies, proper recording of institutional antibiotics use, including resistance episodes, surveillance of vulnerable populations such as patients with drug-resistant TB, and not least, systematic surveys of new forms of resistance, including NDM-1. Antibiotic resistance is too serious a problem to be left to the mercy of a compromised medical profession, an overly privatised medical infrastructure, and an indifferent government.