When 59-year-old Kuldip Chatwal (name changed) came to Ludhiana from his home in Sweden in November 2007, little did he know what was in store for him. A seemingly innocuous urinary tract infection took him to a Ludhiana hospital. A few days later, he was shifted to a hospital in Delhi where he was operated on and developed a decubital ulcer. On January 8, 2008, he was referred to a hospital in Orbero, Sweden. The next day researchers isolated a drug-resistant bacterial gene from a urinary culture and named it New Delhi Metallo beta lactamase-1 (NDM-1), which was responsible for his continuing illness.
Three years after NDM-1 was discovered, it has spread to not just India but several other countries. NDM-1 is a gene carried by bacteria that causes gastric problems, enters the bloodstream and can cause multiple organ failure, leading to death. Doctors warn that the last line of treatment against the gene, the powerful antibiotic carbapenem, is also showing signs of giving up.
Worse still, its inappropriate and indiscriminate use in tandem with other powerful antibiotics holds the threat of developing more such strains of drug-resistant bacterial genes like NDM-1. Independent studies reported in the Journal of Association of Physicians of India (JAPI) in March this year and in The Lancet Infectious Diseases Journal in August have rung alarm bells. They say that the overuse of carbapenem is leading to a new antibiotic-resistant mechanism in which only a few drugs are left with which threatening infections can be treated.
For many years, researchers and doctors have been grappling with the resistance to the genre of extended spectrum beta lactamases (ESBL), drugs which, like antibiotics, have encountered resistance in E. coli and K. pneumoniae, exactly the same elements in which the so-called ’superbug’ NDM-1 has been detected. Liberal use of ESBL has led to increased resistance. Resistance to ESBL drugs like third-generation cephalsporins is 60 per cent higher in India compared to 15 per cent in developed countries. The most common way of treating severe forms of ESBL infections is carbapenem as it has the lowest resistance rate and the broadest action against infections.
NDM-1 infected patients also develop an increased resistance to carbapenem. Another worry is that the prevalence can increase within a relatively short time since the NDM-1 gene is carried in the plasmids of bacteria, which can move from one bacterium to another and even to different species.
The way forward to check the growth of ESBL resistance is to formulate a national antibiotic policy that restricts the use of carbapenem and other higher-end antibiotics to hospitals and only for patients with severe infections. Another measure is to find ways to curb hospital-acquired infections (HAI) that contribute to the development of newer strains and increasing drug resistance.
A study paper from Lancet has sent an ominous warning. It says that "several of the UK source patients had undergone elective, including cosmetic surgery, while visiting India or Pakistan (for cosmetic surgery)... The potential for wider international spread of producers and for NDM-1 encoding plasmids to become endemic worldwide are clear and frightening". The Lancet feature’s lead author Karthikeyan Kumaraswamy, a Ph.D. student at the Dr. A.L. Mudaliar Post-Graduate Institute of Basic Medical Sciences, Chennai, adds a new dimension to incipient alarmism by saying that patients from the Indian subcontinent have higher susceptibility to NDM-1. This has come in handy for the Union Ministry for Health and Family Welfare to describe the Lancet report as alarmist and having an ulterior motive of hitting India’s booming medical tourism.
"Whether the gene originated in India or not is irrelevant. But we can conclude that NDM-1 has been transmitted from India." Timothy R. Walsh, co-author of the Lancet report and professor of Medical Microbiology and Anti-microbial Resistance, Cardiff University
India has a variety of factors that will contribute to the rapid dissemination of NDM-1 positive bacteria. "Some of the infections presented by Indian patients were community-acquired, such as urinary tract infections and therefore we are concerned about the level of NDM-1," says Timothy R. Walsh, co-author of the Lancet report and professor of Medical Microbiology and Antimicrobial Resistance, School of Medicine, Cardiff University, UK. "The resistance genes found on bacteria from Israel, US, Greece and Turkey, due to their molecular scaffolds, don’t spread so quickly or so widely. Besides the UK, NDM-1 positive bacteria have now been found in the US, Canada, Netherlands, Australia and Belgium. In all cases there is evidence of admission in Indian or Pakistani hospitals," Walsh told India Today. His student Kumaraswamy disagrees. He says, "That the NDM-1 gene was transmitted from India is hypothetical. Unless we analyse samples from across the world to confirm its presence, we can only speculate."
NDM-1 is being monitored by researchers and scientists in India, Russia, China and South America. The gene has been found only from patients who have been to India and has spread from here over several years. "Whether the gene itself originated in India or not is irrelevant, but from available information, it is reasonable to conclude that NDM-1 has been transmitted from India," says Walsh. But in trying to pick holes in what Lancet reported, the primordial issues of tackling overuse of antibiotics and HAI are being glossed over by the health ministry. Claims of HAI going down in recent years are truer for urban and private hospitals that invest more in preventive measures. But even the modest estimate of incidence is that the prevalence of HAI is about 25 per cent, though largely in semi-urban and rural health facilities. Most private hospitals and leading Government facilities have a structured infection control policy in place in keeping with the norms for NABH accreditation. A proper drug administration policy is required to check indiscriminate use of antibiotics and its sale without prescriptions to curtail irrational use of drugs, monitor and increase surveillance at hospitals and implement guidelines for infection control.
"That the NDM-1 gene spread from india is hypothetical. unless we analyse samples from across the world, we can only speculate."Karthikeyan Kumaraswamy, Lancet report’s co-author and Ph.D. student at the Dr. A.L. Mudaliar Post-Graduate Institute of Basic Medical Sciences, Chennai.
Indians are the leaders in antibiotic resistance. Many multi-drug resistant superbugs are from bacterial cultures taken at the time of admission to a hospital. By the time a patient is being admitted to a tertiary care centre, he/she has already been to other hospitals and has received multiple courses of antibiotics. These patients are literally walking culture plates of superbugs.
After the initial hysterical response making accusations and questioning motives of the study published in Lancet, the health ministry is finally waking up to the NDM-1 threat. India has an enormous antibiotic consumption load where antibiotics are bought freely in "self-medication" that ultimately leads to those taking it becoming antibiotic resistant. This has to be checked. "The Government will establish a structure of drug monitoring and surveillance for proper use of antibiotics and advisories will also be sent to hospitals," says Dr.V.M. Katoch, director general, Indian Council of Medical Research. Further, as the organisms (like E. coli) that can carry NDM-1 spread easily, good sanitation facilities and clean water are as much an issue as the overuse of antibiotics. It is a major challenge for India to ban non-prescribed antibiotics and use permissible antibiotics with professional consultations.
Researchers agree on a need for a national surveillance programme using sophisticated molecular techniques to analyse these plasmids and determine their relatedness. This surveillance should also include strain typing. However, sampling hospitals is only addressing part of the problem as this does not address the issue of NDM-1 in the community. Environmental sampling-including hospital waste and water supplies and stricter examination of people-has to be incorporated into such a programme. Even as these are tackled, the way forward is in creating a worldwide molecular surveillance system. Health concerns cannot be addressed and resolved in isolation by individual countries but collectively by the medical comity.