Resisting upto 99.9% antibiotics: India’s superbug war begins

When it comes to antibiotics, an over 10% resistance is almost too high.

Indians show resistance as high as 99.9% towards some antibiotics. This, as per a paper published in the Indian Journal of Medical Research (IJMR) on 3 June—the first paper that indisputably establishes that Indians are alarmingly antibiotic resistant. Not only are Indians resistant to older antibiotics like penicillin by over 90%, the resistance to newer antibiotics like ciprofloxacin is also over 40%. The World Health Organisation (WHO) classifies antibiotics into three categories—access, watch and reserve, with each category stronger than the last.

In India, the drugs in the watch category have long crossed the 10% resistance mark. Even worse, Indians are becoming more and more resistant to some of the precious few drugs in the reserve category as they enter the human body through meat. The reserve category drug, colistin, for instance, is used to fatten the chickens in poultry farms.

India is now starting to look deep into this problem. Starting with a government conference in Kerala’s capital Thiruvananthapuram on 11 June. One that the deputy director of the national health mission in Madhya Pradesh (MP), Dr Pankaj Shukla, attended.

Shukla returned to MP, and at a never-before-for-an-Indian-bureaucrat pace, he framed and executed an antimicrobial resistance (AMR) action plan. In six weeks. As you read this, he’s giving final touches to it. Other states have also swung into action. Assam hosted its first meeting last week. Delhi has started the process to frame its action plan. The bureaucrats plan to finalise it next month. Shukla is ahead of the pack and plans to launch MP’s action plan on July 25. 

The conference convinced Shukla that AMR, which is killing more and more Indians every day, can be controlled. By not feeding antibiotics to chicken in poultry farms. Shukla was astonished to learn that resistance to antibiotics could be so easily avoided. Moreover, the weight of the chicken and size of the egg remained the same, he says.

Finger lickin’ antibiotics

According to a bureau of investigative journalism report, animal pharmaceutical companies in India were openly advertising products containing colistin as growth promoters – including Venky’s, which supplies meat to fast food chains such as KFC, McDonald’s, Pizza Hut and Dominos.

This chicken-and-egg solution is a precedent to a larger drive—an ‘antibiotic stewardship’ programme. And as per Dr Sanjeev K Singh, who instituted the programme in Kerala five years ago, it has led to a significant reduction in the use of antibiotics.

Singh, medical superintendent at Amrita Institute of Medical Sciences in Kochi, narrates the story of a 3-year-old boy who was brought to Amrita with congenital heart disease. He caught an infection that resisted all antibiotics; he died after three weeks. Singh encounters at least one or two such pan-drug resistant cases every month. The only ray of hope for Indians are the preliminary results of the stewardship programme; Singh claims it’s brought down mortality by one-fourth.

Shukla, meanwhile, has commissioned the training of 100 doctors in antibiotics stewardship, who will then train other doctors.

What does the programme do that can save lives? It teaches doctors a combination of practices to rationalise antibiotic use through the “right dose, right drug, right duration, right frequency, right patient and right indication,” says Singh. The current practice in India is exactly the reverse. A combination of prescribing antibiotics to those who don’t need it and denying those who do has led to superbugs that are stronger than every antibiotic available. The country is now waking up to this reality.

Over the last few weeks, representatives of patients unable to fight tuberculosis due to drug resistance met in Delhi to discuss the lack of medicines stocked by government centres. Meanwhile, Dr Kamini Walia, head of the Indian Council of Medical Research on AMR, who co-authored the IJMR paper, wades deep into telling data. It has taken her over five years to build evidence from India for something the scientific community already saw coming since antibiotics were discovered. 

Chronicle of data foretold

Sir Alexander Fleming, who was one of the three scientists to be awarded the Nobel Prize in 1945 for the discovery of penicillin, the world’s first broad-spectrum antibiotic, had warned that this day would come, says Walia.

“The time may come when penicillin can be bought by anyone in the shops. Then 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,” Fleming had said in his Nobel Prize acceptance speech. AMR is not new, but the data from India is. As alarming as it looks with Indians showing such high resistance percentages, Walia says that this data is an indication, not a reflection of the community.

The data  has been collected via a network of 20 hospitals that form the AMR surveillance network that ICMR set up. The problem with this data, she says, is that it came from only tertiary care centres, where people come after being prescribed multiple rounds of antibiotics at the primary and secondary levels. The samples are collected from the sick. Still, she says, over 70% resistance is madness. And it is growing.

Going forward, ICMR intends to start collecting data from secondary care hospitals and nursing homes to get a better understanding of resistance to antibiotics among Indians. A clear answer would still be elusive as India does not have microbiology labs at the primary care level. Even if the surveillance network does build evidence from the ground to support nationwide policy intervention on AMR, the future seems exactly as Fleming had warned.

You see, India has almost no alternative to pumping people with antibiotics. 

Sneezed? Here’s an antibiotic

The flow of antibiotics, after being produced by drug manufacturers and before they reach the patients, can be checked at two points—at the pharmacist’s and the doctor’s. Except neither has reason to avoid sales or prescriptions, respectively. 

In 2015, Dr Singh started collecting evidence from the ground. His team interviewed 3,000 doctors, over 200 labs and over 100 pharmacists across Kerala. The data (that would eventually lead to Kerala’s AMR action plan) established that the doctors prescribed newer antibiotics without any knowledge of AMR, as medical representatives (hired by pharma companies to market antibiotics) never warned them about the risks associated with them. It also indicated that about 50% of the time, patients asked doctors to prescribe antibiotics in the hope that they would recover sooner. Finally, doctors did not have a choice but to prescribe antibiotics as they either didn’t have access to detailed diagnostic lab reports or they didn’t trust the labs.

Doctors don’t want to lose the patient and want to go all out to save them, says Singh. For instance, every patient in need of surgery requires just one dose of antibiotics pre-surgery, but doctors, as a precautionary measure, end up prescribing three doses a day for 5-7 days. This, says Singh, is an irrational but common practice. Another example of bad prescription practice, he notes, is dual prescription. For instance, in the case of typhoid, clinical protocols require starting with old-generation antibiotics like chloramphenicol (over six decades old), then moving on to the newer ciprofloxacin family (five decades old) and then trying the decade-old ceftriaxone, moxifloxacin and gatifloxacin. But doctors, explains Singh, usually prescribe two drugs that do the same thing together as a safety net. This doesn’t make any clinical difference in outcomes, but it increases the chances of resistance to the newest drugs available. 

Not only do Indian doctors prefer to prescribe newer antibiotics, they prefer broad-spectrum antibiotics over narrow-spectrum ones, says Walia. The former can be used to treat a variety of illnesses without diagnosing the underlying illness, while the latter requires proper diagnostics.

A doctor can prescribe a combination of antibiotics for immediate relief and order a test at the same time. This sort of thing happens the most with upper respiratory tract infection and diarrhoea. Both, Walia adds, are self-limiting and not always caused by bacteria. However, when the diagnosis of the disease is more expensive than the drug, drugs are prescribed. A blood culture costs between Rs 500 ($7.3) and Rs 1000 ($14.6) but drugs cost Rs 200 ($2.9) to 300 ($4.4). Taking a drug that is widely available is often easier than getting a test done that is not available everywhere, says Walia.

ICMR has recognised hospital-acquired infections as one of the primary reasons for mortality among patients who are resistant to antibiotics. Also, doctors don’t de-escalate dosage with hospitalised patients for they’re vulnerable to bacteria present in the environment. After seeing the results of diagnostics, they are supposed to de-escalate the therapy, but doctors often don’t to avoid the risk of patients deteriorating, says Walia.

Walia says that hospitals often see infection control as a resource-intensive exercise, involving cleaning AC shafts to prevent bacteria or fungal survival. Pills are cheaper, she says. “Overall, people see eating and prescribing medicines as easy but washing hands as difficult. This is precipitating AMR,” she adds.

Apart from hospital-acquired bacterial infections, Neonatal Sepsis and Tuberculosis are the leading causes of mortality from antibiotics resistance, she says. ICMR has framed guidelines on hospital-acquired infections, but these are not mandatory as government hospitals are overburdened and cash-strapped, while private hospitals are outside regulatory purview. 

And the government does not want to regulate pharmacists.

An antibiotic a day

Every time there has been a discussion to regulate the 800,000 pharmacies in India from selling antibiotics over the counter and making them prescription-only, the central government stops in its tracks. Because doctors who can prescribe drugs are not available in remote parts of the country but pharmacists are.

“The government worries that antibiotics can save lives where a doctor is not there to write prescription,” said a senior bureaucrat with a body associated with the ministry of health. He requested anonymity as he did not want to criticise the government policy on what he sees as a sensitive issue. “Pharma companies have reached every village, but the government has not been able to ensure that the doctor reaches every village,” he said. 

In 2013, under the Drugs and Cosmetics Act, the health ministry had put certain 3rd and 4th generation antibiotics in a Schedule H1—they can be sold under certain conditions. While drugs under the Schedule H and Schedule X can only be retailed to a buyer with a prescription from a registered medical practitioner, the drugs under the Schedule H1, when sold, need to be recorded in a separate register (with the name and address of the prescriber, the name of the patient, the name of the drug and the quantity supplied, and such records shall be maintained for three years and be open to inspection). But this is not effectively implemented. 

The bureaucrat acknowledged the central government’s failure in regulating pharmacies and building healthcare infrastructure at the primary and secondary level. When Singh had surveyed Kerala, he had found that 76% pharmacists admitted to selling antibiotics over the counter even when they were prescription drugs. 

Shukla, in MP, intends to enforce the law at the state level. “We are making software to ensure every H1 antibiotic will be uploaded in the software. We can see who were the prescribing doctors, patient and the pharmacist,” says Shukla. Last year, he had found that most of the antibiotics were prescribed in excess for diarrhoea and pneumonia, both of which may not need antibiotics at all. 

The problem, however, doesn’t end at the lack of regulation in sale. The governments (both centre and states) are also unable to ensure the sale of newer antibiotics at government centres for those suffering from drug-resistant tuberculosis (DR-TB). A form of drug-resistant disease that leads to mortality.

Missing drugs

According to a government’s survey conducted between 2014 and 2016, 2.84% of about 2.79 million TB patients added annually have multi-drug resistant TB. The highest in the world.

And yet, it’s all too common for government-funded TB centres to run out of life-saving DR-TB drugs. This was the topic of discussion at the Delhi meet on 1 July, where representatives of patient groups, DR-TB survivors and public health activists came together to “assess the extent of the shortages and find out why they were happening,” says Blessina Kumar, CEO of the Global Coalition of TB Activists. 

An activist from Jharkhand, who did not want to be named, reported a stock-out of levofloxacin, cycloserine, ethionamide and pyrazinamide in his state for over three months now. A DR-TB survivor, who lost her hearing during the treatment, reported a stock-out of pyridoxine, a supplement used for DR-TB treatment, in Maharashtra government centers.

Bio and antibiotics

In 2016, researchers at IIT, Hyderabad reported high levels of antibiotics (fluoroquinolone) residues in water and sediment samples of the Musi river. Another study, published in Infection, shows that water samples from the direct environment of bulk drug manufacturing facilities were contaminated with antimicrobial pharmaceuticals and resistance genes.

“Community representatives have been reporting shortages and stock-outs of TB and DR-TB drugs for months,” says Leena Menghaney, an HIV and TB treatment activist. She also manages the access campaign at nobel laureate not-for-profit Médecins Sans Frontières (MSF). “It could be for a variety of reasons, like delay in finalising tenders, supply chain inefficiency, or just red tapism,” she explains. When one of the activists wrote to the government TB department in Delhi, they said that the drugs were available in the central government warehouses and blamed the states for not ensuring access in district centers. Menghaney says the solution lies in supply chain reforms recommended by the World Health Organisation. Reforms, she says, can bring transparency, show which warehouse holds which medicine and ensure access. However, without transparency, the central government can blame state governments, states can blame the district TB officers, and no one knows the reason for the shortage of a crucial antibiotic at the government centre. An opaque supply chain for drugs where stock-outs are common can lead to even more drug resistance, she adds.

With every dose missed in the treatment regimen of a patient suffering due to drug-resistance, the chances are that the bacteria has become more resistant. Similarly, every misuse of last-resort drugs by patients who never needed them ruins their chances of getting better should they ever need a newer drug.

The result is fear. Fear that patients, doctors and bureaucrats feel for the future of AMR in India. 

MSF has recommended that linezolid—a higher-end antibiotic categorised as reserve by the WHO but sold over the counter in India—be withdrawn from the private market to prevent AMR. Meanwhile. the Delhi based not-for-profit Center for Science and Environment  is lobbying to ban colistin in chicken feed. 

States can do their part, but the clock is ticking. If the national government does not wake up to the dangers of AMR, soon there won’t be any drugs left that Indians wouldn’t be resistant to.

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