How India became the antibiotics capital of the world and laid the wonder cure to waste
Lhendup G Bhutia | 20 Oct, 2015
“The time may come when penicillin can be bought by anyone in the shops. There is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant.”
– Alexander Fleming at his 1945 Nobel Prize lecture
In 2009, A 59-year-old Swede of Indian origin began visiting a hospital in Örebro, a small city about 160 km away from Stockholm. The patient, a diabetic male, needed treatment for bed sores and urinary tract infection. He had recently returned from India, where he had developed an abscess in his buttocks and had been hospitalised, first in Ludhiana and later in Delhi. He had undergone a surgery in Delhi, recovered and returned to Sweden.
So far, so good. The development of the abscess wasn’t particularly unique. Diabetics are known to be susceptible to it. The bed sores and the urinary tract infection, one could understand, he probably acquired from his stay in the Delhi hospital. But there was something odd about his infection. No antibiotic seemed to work on it. Not even carbapenems, the strongest class of antibiotics currently known to man.
A routine urine test threw up something extremely unusual. The bacterium causing the infection, as the doctors analysing the case wrote in the journal Antimicrobial Agents and Chemotherapy, was the familiar Klebsiella pneumonia, which is one of the most frequent causes of pneumonia and bloodstream infections in hospitalised patients. What was highly irregular, however, was a gene it carried. Hitherto unknown, this gene, later named NDM-1 (New Delhi Metallo-beta-lactamase-1), after the city where the patient was thought to have picked up the bug, made the bacteria resistant to almost all antibiotics. And it didn’t just make treatment difficult. It could also move quickly from one bacterium to another, rapidly boosting the infection’s resistance.
As events over the following year showed, the bacterial gene had probably emerged in India. NDM-1 began to be discovered in several other parts of the country. PD Hinduja Hospital, the well- known Mumbai multi-specialty hospital that gets transfer patients from various smaller hospitals, conducted a study in 2010 and discovered 22 patients carrying microbes with the NDM-1 gene in a span of just three months. Such patients were also found in hospitals in Chennai, Haryana, and several other parts in India and Pakistan. And it wasn’t just hospitals. It was discovered in New Delhi’s drinking water and in the upper reaches of the river Ganges, at Rishikesh and Haridwar, indicating the successful transition of the bacteria from hospitals, where it is believed to have developed, to the rest of the environment.
Antibiotic resistance is a worldwide problem. But experts feared that India’s excessive antibiotic usage was now leading to a powerful never-before-seen mutation within bacteria. Within a year’s time, patients with this bacterial gene were discovered in the US, UK, Canada, Japan and China. So far, cases in more than 70 countries have been reported. Some had travelled to the Indian Subcontinent and been exposed through medical treatment and hospital stays, but many had never been here, suggesting local transmission within those countries.
The Indian Government, however, dismissed the suggestion. Lawmakers and government healthcare professionals claimed that the naming of the bacterial gene was a plot against the country’s lucrative medical tourism industry. Strict new curbs on taking biological samples out of India were announced— aimed, it appeared, chiefly at British and Scandinavian researchers who had named the bacterial gene, and, after smuggling water samples out of the country, exposed its prevalence across India to the world at large. “It was a complete knee-jerk reaction,” says Ramanan Laxminarayan, a noted researcher in the field of antibiotic resistance. “Instead of dealing with this new healthcare issue, they got caught up in irrelevant details like the naming of NDM-1.”
Around the same time, 162 km away from New Delhi, in a small, unassuming private nursing home for newborns in the Uttar Pradesh town of Bijnor, baby after baby began to reel under the effect of an unusual infection. “I just didn’t know what was going on,” says Dr Vipin Vashishtha, the paediatrician who runs Mangla Hospital. “Nothing worked on them.” From 2009 to almost 2011, several babies, most of them born prematurely and referred to his hospital after their delivery in other hospitals, began to show resistance to antibiotics. “When they first came in, I thought they would be out in a few weeks. But they had to be kept here in the ICU for several months.”
The doctor threw every antibiotic at them—cephalosporins, aminoglycosides, monobactams, quinolones, a piperacillin- tazobactum combination and even carbapenems. But nothing worked. In all, 14 infants were in a bad way and showing resistance to all antibiotics. “I called up experts everywhere. I sent their blood and urine samples to far off places. Nobody in Bijnor had ever faced anything like this,” Dr Vashishtha recounts.
The infants, however, responded to colistin and polymyxinB, two strong last-resort antibiotics that are avoided because they could harm kidneys beyond a point. Eventually, six babies died of their infections. Among the eight survivors, half of them developed complications like meningitis and arthritis.
When the results from the lab arrived, the culprit was identified as the recently- discovered NDM1 gene. Dr Vashishtha, who wrote about the experience in the journal Indian Pediatrics in 2011, says, “It was the most horrific period. I was losing babies at regular intervals. I knew we were dealing with something very new.”
Since then, Dr Vashishtha has built a separate section for infants in the ICU who show resistance, and tried to improve infection control. The nursing home is now fumigated every few weeks, repainted often, and hand-sanitising liquid are kept next to every bed and all over the hospital. “I try to control everything,” he says, “but I can’t control what’s happening outside.”
“What I found out what that there is a deadly epidemic going on. And very few of us have any clue,” he says. “The bacteria in our water, sewage, soil, even the bacteria within us—they are all immune to nearly all antibiotics.”
The discovery of penicillin by Alexander Fleming in 1928 transformed the world of medical science. Before its discovery, humans had for thousands of years been laid low or killed by minor infections. Even a single abrasion from a blade of grass could call for an amputation if not leave one dead. But, after its discovery, infections acquired even during complex surgeries could be treated with a simple dose of antibiotics. The new drugs revolutionised medicine, transformed human health and saved millions of lives.
But in a time blip of just around half a century, it now appears, we have exhausted and overused antibiotics. We have popped antibiotic pills on the smallest of pretexts, to deal with viral fevers and colds that cannot be treated with antibiotics, for instance. We have stuffed them into our livestock to fatten them and sprayed them on our crops to keep pests away.
In short, we have used them with impunity, assuming we would enjoy its advantage forever, and if a problem occurred, the pharmaceutical industry would simply fire up its labs to stay ahead of the game. But now, unsurprisingly, even the strongest antibiotics don’t appear to work. In the story of co-evolution and natural selection, bacteria have evolved to resist the threat posed by these drugs. We have now entered, as several experts point out, a post-antibiotic world.
Current estimates place the annual number of deaths from antibiotic resistant bacteria at around 700,000 worldwide. This figure is predicted to rise, according to one study, to 10 million by 2050.
Antibiotic resistance is a global phenomenon. But its epicentre is India. The country is afflicted by easy access to the strongest of antibiotics without prescriptions or diagnoses; by qualified doctors, not just quacks, who prescribe drugs with little thought; by hospitals where overuse has created colonies of these superbugs; by excessive usage on livestock; and by poor sanitation. All this has created a kind of perfect storm for these super-resistant microbes to menace our health.
Last year, a study published by researchers from Princeton University, which analysed global trends of antibiotic consumption between 2000 and 2010, discovered that India now consumes the most antibiotics in the world. In 2010, India is estimated to have consumed 12.9 billion antibiotic pills. In comparison, China consumed 10 billion pills and the US, 6.8 billion. While antibiotic usage worldwide in the first decade of the 21st century rose by 36 per cent, in India, the count went up by 62 per cent, from 8 billion pills in 2001 to 12.9 billion in 2010.
A few weeks ago, a public health research organisation with offices in Washington and New Delhi, the Center for Disease Dynamics, Economics & Policy (CDDEP), published an in-depth report detailing antibiotic use and resistance across the world. It too had found India a hotbed for antibiotic resistance. The resistance of Klebsiella pneumonia to carbapenems, the antibiotic of last resort, for instance, was 57 per cent compared to just below 5 per cent across Europe. Resistance to other bacteria like E Coli, MRSA (Methicillin-resistant Staphylococcus aureus), and ESBL- producing bacteria (Extended-spectrum beta-lactamases) was just as bad as in other countries. The most vulnerable, of course, are newborns. According to a Lancet study last year, 58,000 infants in India are estimated to have died from bacterial infections in 2013.
“India really has the perfect storm,” says Laxminarayan, the director of CDDEP and the Vice-President for Research and Policy at the Public Health Foundation of India, who co-authored both the Princeton and CDDEP studies. “A large pharmaceutical industry, high background rates of infectious diseases and an affluent population that can afford antibiotics. You put all the things together and you get high pathogenic strains.”
As Laxminarayan explains, every individual is at the mercy of others, rich or poor. “Antibiotics are different from other drugs. If I were to take a statin, for instance, it’s not going to diminish the statin’s effectiveness for you. But with antibiotics, you can get an infection that is drug-resistant even if you’ve never misused antibiotics in your life.”
Last September, Anand Gharad, a 42-year-old healthy-if-diabetic police constable in Thane’s crime branch, was returning home with his family after immersing a Ganapati idol in a nearby creek, when he dashed against a wooden structure on the road. As he was turning into bed that night, he felt a slight discomfort in his abdomen, around the area of the impact. By the next morning, a fever of around 104° Fahrenheit had consumed him. He was in deep pain and couldn’t move.
After spending about a week in several hospitals, he was wheeled into Mumbai’s multi-specialty Fortis Hospital. It turned out that he had developed an abscess with huge quantities of pus, although no one could understand why.
Gharad, his doctors realised, had developed an E Coli infection that was resistant to almost all antibiotics. “The moment the [bacteria] culture report came in, we knew we were in trouble,” says Dr Ramesh Punjani, a laparoscopic surgeon with Fortis. “We began giving him high dosages of colistin, although the antibiotic is known to be harmful. Because, otherwise, we really had nothing else,” he says. Gharad spent over three months in the ICU. “When I was discharged from the hospital, everyone was telling me how lucky I was. Nobody thought I would make it.”
Another of Dr Punjani’s patients, however, wasn’t as lucky. Earlier this year, a 50-year-old diabetic woman was admitted under his care after a gallstone had caused a blockage in the common bile duct, leading to several abscesses in the liver. She had spent about a week with little improvement in a private nursing home before this. To make matters worse, the woman had developed an infection with an antibiotic resistant bacterium, E Coli, during that period. The patient spent about 18 days under Dr Punjani’s care, before being transferred to another hospital, both of which gave her the strongest of antibiotics, from carbapenem to colistin. Dr Punjani continued to interact with the patient’s doctors in the other hospital. After a week of her admission to the second hospital, she succumbed to the infection. “Maybe I can fault the previous doctors for not being able to extract the gallstone earlier,” Dr Punjani says. “But the truth is no person should die from an infection. But you increasingly see this now.”
Dr Om Shrivastav, one of Mumbai’s top infectious disease consultants, recalls the case of a man, aged over 60, who almost lost an arm to an antibiotic-resistant bug. The patient had been advised an amputation after a shoulder operation led to an antibiotic-resistant infection. Dr Shrivastav, however, was able to treat the patient without having to let go of a limb. “The difficulty with the assessment of antibiotic resistance [in India] is that while it starts at multiple levels, it is recorded only at the final stages. Commencing from veterinary practice of feeding antibiotics to poultry to free access over the counter, the abuse of access is almost incalculable. But reporting is done only at the tertiary hospital, which is a poor reflection of the magnitude,” he says. “Unsurprisingly the number of effective antibiotics has dwindled in less than five years… Antibiotic therapy is a crisis strategy… [with the] desperate hope that an antibiotic regimen will work.”
“Five years ago, we hardly ever saw these kinds of infections,” says Dr Preeti Mehta, head of the microbiology department at King Edward Memorial (KEM) Hospital in Mumbai, one of the largest government healthcare facilities in the city. “Now, almost every other patient, adult or newborn, has multi-drug resistant infections. It’s really very scary.”
So far in India, as carpabenems show increasing antibiotic resistance, several hospitals and doctors have begun to turn to colistin and polymyxin B as last- recourse lines of treatment, both of them powerful but also toxic. Colistin, which is known to harm kidneys, was brought back from a 40-year-old exile in 2005 to deal with the increasing cases of resistance to other high-end antibiotics. But, as a study published by a group of doctors from Chennai last year shows, several bugs are now also showing signs of resistance to colistin. The study, published last year in Journal of Microbiology and Infectious Diseases, maps 13 pan-drug resistant cases, including to the antibiotic colistin, in the span of 18 months. “Colistin resistance is still rare. It is used to treat cases that are resistant even to carbapenem,” says Dr Abdul Ghafur, a well-known infectious diseases specialist in Chennai. “But as this study shows, there is a problem emerging here too.”
In a scenario where the misuse of antibiotics is rampant, regulations to tackle the problem are too lax to be effective. As strong strains of multi-drug resistant microbes have emerged, however, several healthcare professionals and hospitals have begun to establish strict antibiotic policies. The microbiology department at Fortis, for instance, issues new guidelines every few months on what antibiotics can be used, in what dosages, and for what ailments. Every time there is an emergency and the doctor believes a stronger dose is essential, he has to fill a form justifying the action, appended with an approval signature from another physician. KEM Hospital has enforced a strict antibiotic policy, with audits every few months to check whether drugs are being given out too loosely.
“But these are being done by only a few hospitals,” says Dr Mehta. “Most hospitals are hardly bothered by the issue of resistance. And they will prescribe antibiotics, whether required or not, just to be safe that no infections occur.” According to Dr Ghafur, private practitioners and hospitals are breeding grounds for resistance. “There are very few hospitals in India with infectious diseases and infection control specialists. The majority of hospitals are in denial, either purposefully or due to ignorance.”
In August 2012, several medical bodies and organisations came together to develop a plan to tackle resistance. Their action, co-ordinated by Dr Ghafur, led to a five-year-plan, named the Chennai Declaration, after the city where the meeting was held, to control the misuse of antibiotics. Some healthcare institutions across the country have begun to adopt its recommendations, which are aimed at gradually restricting access to powerful antibiotics. It has also been shared with the Government to help it draft an antibiotic policy.
One solution to this crisis is to develop newer and stronger antibiotics. No new class of antibiotics has been developed for several years, since, as experts point out, it is not as profitable as producing other more expensive drugs (for instance, those to treat HIV). “But you don’t want to be throwing money at this problem. Inventing new antibiotics alone will only perpetuate the cycle of bacteria developing resistance to every new drug,” Dr Laxminarayan says. “This is a race we just can’t win.”
As Dr Punjani says, patients in India often consult doctors convinced that they have infections and are unwilling to leave without a prescription. “There is an extremely powerful urge to please a patient and to alleviate his or her anxieties,” he says. “So doctors think, ‘It can’t hurt’. But it can. And we need to curb this practice.”
According to Dr Ghafur, however, all is almost lost. We are already living in a post-antibiotic world. “With increasing drug-resistant bacteria, we will be forced to stop organ transplantation, chemotherapy, or even the smallest surgeries. We will face this situation not in a decade or so, but within a few years.”
As we ride a motorbike on a dark patch of Thane’s streets, Gharad in front, and me on pillion, with the quietness of the mangrove swamp only occasionally interrupted by the sound of distant speeding trucks, Gharad begins to discuss the politics within the police department and the importance of having ‘godfathers’ within its upper echelons. And then he suddenly and dangerously lets go of the handle of his bike, points to the dark sky, and tells me what he learnt from his experience with antibiotic resistance. “Mera godfather upar hai” (My godfather is up there).