The vigil for multidrug-resistant bugs is tight at the Holy Family Hospital, a charitable institution in the Indian capital known for its dedication to neonatal care.

“We cannot afford to have newborns falling prey to difficult-to-treat bugs,” says Sumbul Warsi, medical director of the 345-bed hospital and leading paediatrician. “We have infection control nurses collecting data daily – hand-washing is observed and audited, swabs are taken from the nursery and equipment and decontamination carried out when warranted.”

Despite the vigilance, drug-resistant microbes pop up frequently at the hospital, as they do in health facilities across India. When these microbes infect newborns less than 28-days old, there is a high risk of potentially fatal neonatal sepsis, where the body’s own response to infection can cause organs to shut down.

The condition affects 16 per thousand live births in India. A third of those babies die for lack of working antibiotics, according to a review of scientific literature from South Asia on the subject, published in January in the British Medical Journal by researchers at the All India Institute of Medical Sciences in New Delhi.

Warsi blames the situation squarely on “irrational and inappropriate” use of antibiotics. “Overuse of antibiotics in intensive care units due to decreased immunity of patients, frequent resort to invasive procedures, free availability of antibiotics over the counter and misuse [in] agricultural – all contribute to antibiotic resistance and rising instances of neonatal sepsis,” she says.

In March, a newborn at Warsi’s hospital developed breathing difficulty and was given medicines that allow the lungs to inflate more easily and placed on ventilation. But, the baby ended up being infected with Pseudomonas aeruginosa, a multidrug-resistant bacterium.

“We then resorted to colistin, a reserve antibiotic used exclusively for multidrug-resistant gram-negative bacteria,” explains Dinesh Raj, a paediatrician who works with Warsi. “But the baby died because it took several days before a positive culture of P. aeruginosa could be developed in the lab.”

Colistin has been used successfully in similar neonatal sepsis cases, though. In February, a newborn became infected with Klebsiella pneumoniae, a common drug-resistant bacterium. “In this case, the baby responded well,” says Raj. Colistin has been around since 1960, but it is rarely used because of its toxicity. Now, because of the resurgence of drug-resistant pathogens, it is being used as a drug of last resort.

Lax laws

The question troubling Raj is how long colistin will remain effective, given that poultry farmers freely use it and other antibiotics to boost chickens’ growth. While India’s Drugs Technical Advisory Board, part of the Ministry of Health and Family Welfare, has recommended that colistin and other antimicrobials should not be used in agriculture, there is no formal ban.

India’s agricultural ministry also recognises the dangers of widespread misuse of antibiotics in animal feed and supplements. An advisory notice issued in 2014 named Oxytetracycline, Doxycycline, Ciprofloxacin and Neomycin as antibiotics detected in tissues of marketed poultry. But little has been done by way of enforcement.

The most comprehensive action taken by the government to curb misuse of antibiotics was the adoption in 2017 of the national action plan on antimicrobial resistance which focuses on strengthening surveillance and encouraging rational use of antibiotics in hospitals and the community.

But an Antimicrobial Resistance Surveillance and Research Network set up in India in 2013 has so far been confined to 20 top medical colleges and hospitals and the study of selected drug-resistant bacteria.


Superbug surveillance

Chief among the microbes under surveillance is methicillin-resistant Staphylococcus aureus, which is commonly found in hospitals and in patients who have undergone procedures involving invasive devices such as catheters.

Methicillin-resistant Staphylococcus aureus infections began in hospitals but are now caught in the community from other people and livestock, which underscores the steady spreading of the bacteria. The superbug is resistant to beta-lactam antibiotics, a broad-spectrum group which includes methicillin as well as oxacillin and the cephalosporins. It is now endemic in India, surveys show.

According to the AIIMS scientific literature review – which included 109 studies, 69 of them from India – the most common multidrug-resistant organisms present in South Asian hospitals other than methicillin-resistant Staphylococcus aureus are species of Klebsiella, Acinetobacter, and E. coli.

The review suggests that the source of infection in neonatal sepsis is likely to be unhygienic practices in labour rooms and neonatal intensive care units rather than vertical transmission from mothers, as commonly believed. It found common pathogens isolated in hospitals exhibited far higher resistance to WHO-recommended first-line drugs – the go-to choice for doctors – than those isolated in community-based studies, pointing to overuse of antibiotics and poor diagnostics.

Over-the-counter drugs

Adding to the calls for state intervention, the AIIMS review says misuse of antibiotics in agriculture should be stopped and there should be tighter restrictions on over-the-counter sale of antibiotics.

But doctors and patients also need to shoulder some responsibility, according to Warsi. “It is important to educate the community about the importance of rational use of antibiotics,” she says. “Simultaneously, doctors need to be taught not to bow to pressures from pharmaceutical companies to push their products and also resist demands by patients for quick satisfaction.”

Counter sales of antibiotics have been restricted by India’s Central Drugs Standard Control Organisation since 2014 when 24 antibiotics were brought under the Schedule H1 list of antibiotics. These Schedule H1 drugs can be sold only against prescriptions, with dispensing pharmacists required to register details such as the patient’s name and the quantity of medicines dispensed. The register is subject to audit and authorities have cancelled the retail licenses of hundreds of violators.

However, no penalties are imposed on pharmaceutical companies offering doctors incentives like paid holidays to push particular brands of antibiotics. In 2015, the government introduced a code of practice for pharmaceutical marketing, but it is not enforceable by law.

Scary sanitation

Poor sanitation combined with medical waste disposal is another major contributor to antimicrobial resistance. It is common to find effluent from hospitals and drug manufacturing plants entering water courses, creating conditions that foster the growth of multidrug-resistant bacteria.

Of particular worry is horizontal gene transfer, where genetic material moves directly from one organism to another without any reproduction. “Horizontal gene transfer is the primary mechanism by which antibiotic resistance spreads across bacterial species,” says pathologist Sudhir Kulkarni at Batra Hospital in New Delhi.

Now the dangers of horizontal gene transfer in India are being felt globally. In 2008 bacteria containing an enzyme known as NDM-1 were found in a Swedish patient who had been to India. The enzyme makes bacteria resistant to several antibiotics and is capable of moving across species by horizontal gene transfer.

In May 2010, a man who had had dialysis in India was found to have E. coli expressing NDM-1. The following year, a study published by Lancet Infectious Diseases showed NDM-1 positive bacteria present not just in hospitals but also in the environment in a 12-km radius around central New Delhi – even in drinking water samples.

“It’s scary how fast India is slipping back into the pre-antibiotic era, only because nothing smart is being done to stop smart bugs developing multidrug resistance,” says Kulkarni.

This article was first published on SciDev.