How Indian scientists have been scrambling to contain antimicrobial resistance for years
Antibiotics of last-resort are routinely being used for common clinical infections in India, putting young lives at risk.
In 2017, the World Health Organization (WHO) came up with a new classification system for antibiotics on its essential medicines list: Access, Watch, and Reserve. Antibiotics on the Access list were narrow spectrum antibiotics — only effective against a small range of organisms — that would be recommended as first and second treatment options for common clinical infections. Those on the Watch list were broader spectrum, able to tackle a wider range of pathogens and therefore considered more important for human medicine. The Reserve list describes antibiotics of last-resort; only for use when all other antibiotics had failed.
As SARS-CoV-2 wreaks havoc around the world, antibiotics have fallen off the agenda; they are completely ineffective against a viral infection. But antibiotics do work against the disease-causing bacteria that are responsible for millions of deaths worldwide each year. Antibiotic resistance was a critical health issue long before COVID-19 exploded into hospitals and headlines, and it will continue to be one long after the pandemic has been brought under control.
Antibiotics on the Access list are the ones that should be the most widely available and the most widely used, and the WHO says by 2023, 60% of all antibiotics consumed should come from the Access group. Unfortunately in India, that trend is going in the opposite direction, says Jyotsna Singh, program officer at humanitarian organisation Medicins Sans Frontiers’ Access campaign in Delhi. One 2017 analysis found that while sales of key Access antibiotics had risen 20% since 2007-2008, sales of Watch group antibiotics had risen by 73% and sales of Reserve antibiotics increased by 174%.
“What we are seeing is that in the Access category there are medicines which are in shortage, which is becoming a huge problem,” Singh says. It means that instead of treating infections in a targeted fashion, with antibiotics specifically tailored to individual pathogens, doctors are using broader spectrum antibiotics from the Watch and Reserve categories. Not only are these antibiotics supposed to be used only for more difficult infections, but they are associated with a higher likelihood of resistance developing. “You have to save Watch and Reserve for certain infections which cannot be treated otherwise,” she says, “or in the long term patients’ health will be put at risk.”
This has already cost lives. Each year, more than 58,000 newborns in India are estimated to die from bacterial sepsis that is resistant to first-line antibiotics. Individuals in India infected with bacteria resistant to more than one antibiotic are two to three times more likely to die than those with non-resistant infections. Another study has found that 40 per cent of pregnant women and 60 per cent of schoolchildren are carrying strains of E. coli bacteria resistant to at least one antibiotic.
In 2019, India scored highest of 41 countries on the Drug Resistance Index — a measure combining both antibiotic use and resistance levels, and by 2050, antimicrobial resistance has been forecast to claim an additional two million lives per year in India.
But Satya Sivaraman, who develops communications strategies on antibiotic resistance with ReAct Asia Pacific — one arm of the global ReAct network created in 2005 to focus on antibiotic resistance — says many healthcare professionals face a bigger issue.
“If you talk to doctors on the ground about antimicrobial resistance, they’ll say ‘yes it’s a problem in some cases, but the bigger problem is that we don’t have antibiotics at all,’” says Sivaraman. In a country with such a high incidence of infectious disease, the lack of any treatment is killing more people than treatment resistance. It also means India is a huge reservoir of infectious pathogens: a “factory of disease production,” he adds.
At the same time, antibiotics are being overused and misused to such an extent that even India’s massive generic drug manufacturing industry can’t keep up with demand.
Singh says generic drug manufacturers — many of which produce copies of brand-name medications in India’s thriving pharmaceutical manufacturing sector — blame the shortage on the low price set for antibiotics by India’s price control mechanism, which limits what pharmaceutical companies can charge the government and consumers for essential medicines and makes them a far less attractive business.
Some state governments in India are taking matters into their own hands to ensure a supply of antibiotics. In 1974, for example, the state government of Kerala established its own, government-run pharmaceutical manufacturing operation — Kerala State Drugs and Pharmaceuticals — which supplies essential and life-saving medicines, including antibiotics, to government hospitals.
The other problem is that, around the world as well as in India, pharmaceutical companies are pulling out of research and development of new antibiotics, leaving it to governments to pick up the slack. Sidarth Chophra, microbiologist and professor at the Central Drug Research Institute (CSIR) in Lucknow, India, is hunting for new molecules specifically targeted at drug-resistant bacteria. One focus is the so-called ESKAPE pathogens which are responsible for the majority of hospital-acquired infections and which all show resistance to multiple existing antibiotics. CSIR is directly funded by the Indian government.
The speed with which bacteria evolve resistance to new antimicrobials presents a huge challenge, says Chopra. “I tell my students all the time, this is like playing chess with a grandmaster,” he says.
Chopra and colleagues are trying every trick in the book to gain the upper hand. First, they’re looking at existing drugs to see whether any might also show antimicrobial activity, because that can help speed up the drug development and testing process. One molecule showing antibiotic properties is disulfiram, which is normally used to treat chronic alcoholism.
They’re also looking at molecules that might otherwise not be considered potential candidates because they don’t meet the so-called Lipinski’s rule of five for predicting compounds that are likely to succeed as drug candidates. “We are more than happy to look at unconventional molecules which a normal medicinal chemist would not touch with a barge pole,” Chopra says.
Even if vital antibiotics become more widely available in India, there is still the problem of how, in a country with an overwhelmingly private healthcare system, many citizens could afford to access the doctors who prescribe them. A report published in April this year by the Center For Disease Dynamics, Economics & Policy, a public health research organisation based in Washington DC and New Delhi, found that 65% of health expenditure in India comes from the pockets of individual patients, compared to 13% in Germany. The cost of health care is estimated to drive 57 million Indian residents into poverty each year.
Philip Mathew, a public health consultant with ReAct, says that universal health coverage might help enable many poorer patients to access essential medicines such as antibiotics. “A universal health care system in developing countries can solve many, many issues associated with access to essential antibiotics,” he says.
The Indian government is moving in that direction. In 2018, it announced the creation of the ‘Ayushman Bharat — National Health Protection Mission’ to provide health coverage worth up to 500,000 rupees (US$7,000) per family for 100 million poor and vulnerable families. The plan also includes ‘health and wellness centres’, which are intended to provide primary care, free diagnostic services and essential drugs. But there are questions about how the government of India will pay for the scheme, given its spending on public health is one of the lowest among low-middle income countries.
Another challenge is ensuring that clinicians in that healthcare system prescribe antibiotics appropriately. Because of their seemingly miraculous curative powers, antibiotics have become a victim of their own success. Patients — not just in India but around the world — have come to view antibiotics as a magic bullet for all ailments, and expect them from their doctor. “They are paying some fee to the private doctor for the consultation, and they want to know that they’ve actually taken some strong medicine back with them, so this whole cycle, the patient-doctor cycle, is completely skewed,” Sivaraman says.
This situation is further exacerbated by climate change, which is changing patterns of infectious disease outbreaks, and contributing to the emergence of new diseases for which there are no or only recently developed vaccines, such as dengue and chikungunya. The latter re-emerged in India in 2005 after a twenty-year hiatus and since then, over one million cases of the mosquito-borne viral infection have been reported. A vaccine is now available, but has limited efficacy.
“These viral fevers get confused with bacterial infections and then people tend to use antibiotics, so that contributes to the problem,” says Jyoti Joshi, head of South Asia at the Center for Disease Dynamics, Economics & Policy in New Delhi.
Changing the minds of doctors is one thing; changing the expectations of patients is another, says Ramanan Laxminarayan, director of the Center for Disease Dynamics, Economics & Policy in Washington DC. “Here you’re saying ‘don’t take an antibiotic, not because it will necessarily harm you but because you’re ruining the chances for someone else to be treated with that antibiotic. Human beings tend to work in selfish ways and in this instance it doesn’t work out so well for us.”
Cost of resistance
Every year in India, 1 million children die in the first four weeks of life. 190,000 of these deaths are attributable to neonatal sepsis, and just over 30% of those sepsis deaths are attributable to antibiotic resistance.
But the true scale of the antibiotic resistance is concealed by a lack of data, because when someone dies in hospital from infection, it’s rarely recorded as a death from antibiotic resistance. “It’s not something that the common man observes to say, ‘oh my God: people are dying of drug resistance’,” Laxminarayan says.
It is clear, at least, that antibiotic resistance rates continue to increase. Since 2008, the proportion of pathogenic bacteria found to be resistant to important antibiotics has risen significantly; in some cases, tripled or even quadruped.
In 2017, the Indian government released its National Action Plan on Antimicrobial Resistance. This identified six strategic priorities including improved awareness, better surveillance, reducing infection rates, and improved antibiotic stewardship. The priorities were aligned with global action plans on antibiotic resistance, but Joshi says this approach is not a magic bullet for all developing countries.
“The models that have worked in the ‘developed’ world cannot be copied back and implanted here … so you can't copy and paste,” she says. While India now has an action plan, she says it’s going to take some time for that cookie-cut plan to adapt to the Indian way of doing things.
“We need to really dirty our hands and get models that work for us in our settings with all the resource limitation and competing priorities, and try them out to control the scourge of antimicrobial resistance,” she says. While there are likely to be successes and failures, she believes the country will learn from those experiences, “and then come out and say, ‘yes, this is what can be done, and this is how it should be done.’”
Bianca Nogrady is a freelance science writer in Sydney, Australia.
Antibiotics in agriculture
Studies show that India’s booming poultry industry is a potential danger to health.
While antibiotic use in agriculture has caused headaches in many western countries, India’s primarily vegetarian diet has meant the problem of agricultural antibiotic use is much less severe. But, thanks in part to a booming poultry industry, it’s becoming a bigger issue. Poultry samples have found resistance rates to streptomycin as high as 75%. Resistance rates to other antibiotics including ampicillin and rifampicin were over 40%.
“You have these huge poultry farms where there’s a huge amount of overcrowding, and antibiotics are used to cover up your hygiene and biosecurity practices,” says Robin Paul, Quality Manager in the State Laboratory of Kerala’s State Veterinary Department in Kochi. A 2019 study identified India and China as the largest low-middle income global hotspots of antimicrobial resistance in animals, and singled out the antibiotic colistin — an antibiotic that the WHO recommends be reserved to treat multi-drug-resistant human infections — as a particular source of resistance and public health concern.
In July 2019, India followed China and banned the sale and use of colistin in the agricultural industry, because of the risk to human health. But Paul says more needs to be done to help farmers better manage their farms without resorting to antibiotics.
“The crux of animal health is to manage the health of animals so that they don’t need to go on antibiotics,” he says. But that can be challenging in a nation such as India, where there is widespread malnutrition and rising demand for protein, and Paul says farmers are likely to oppose any restrictions that could impact production. BN
Image: “Women queue at a medical centre in New Delhi, India, during a dengue and chikungunya outbreak in September 2016. (Photo by Saumya Khandelwal/Hindustan Times via Getty Images)"