What should India do to control antimicrobial resistance

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Although often viewed as a medical problem, antibiotic resistance is really one of managing a shared resource to maintain antibiotic effectiveness.

Any conservation effort to protect this global resource would also necessarily need to be global. India — with its combination of large population, rising incomes that facilitate purchase of antibiotics, high burden of infectious diseases and easy over-the-counter access to antibiotics — is an important locus for the generation of resistance genes.

The multi-drug resistance determinant, New Delhi Metallo-beta-lactamase-1 (NDM-1), emerged from this region to spread globally. Africa, Europe and other parts of Asia have also been affected by multi-drug resistant typhoid originating from South Asia.

The containment of antimicrobial resistance (AMR) in India is, therefore, central to the global effort to address this threat. In India, over 56,000 newborn deaths each year due to sepsis are caused by organisms that are resistant to first line antibiotics.

Also, an estimated 170,000 deaths from pneumonia in children under five can be averted with timely access to effective antibiotics. While rising rates of resistant infections are a threat, many deaths are attributable to the lack of access to basic antibiotics.

We need to balance excessive and inappropriate use, a key driver of antibiotic resistance, while ensuring live-saving medicines are available to those who need them.

Clean up first

Beyond access to effective antibiotics, reductions in India’s mortality from infectious diseases will be brought about by improvements in vaccination coverage, access to clean water, adequate sanitation and improved hygiene.

Half of the south Asian population lacked access to basic sanitation in 2018. The Swachh Bharat Mission in India has improved access to toilets in many areas.

However, efforts must be made to bring about behavioural changes so that people use these toilets.

One estimate found that improvements to the infrastructure required for and access to clean water, adequate sanitation and quality hygiene in India could result in a reduction of 590 million diarrheal cases by 2020 that would have been treated with antibiotics.

Vaccination has been shown to reduce the transmission of AMR infections and the volume of antibiotics consumed due to both, appropriate treatment of bacterial infections and inappropriate treatment of viral infections.

India has undertaken many activities like Mission Indradhanush — to address low vaccination coverage — strengthened micro-planning and additional mechanisms to improve monitoring and accountability.

Yet improvements in coverage are still needed; coverage of the DTP3 vaccine against diphtheria, tetanus and pertussis is 89 per cent, for the measles vaccine, the first dose, MCV1, has coverage of 90 per cent and the second dose, MCV2, of 80 per cent, the Hepatitis B vaccine, HepBB, has coverage of 54 per cent, and for HepB3, it is 89 per cent.

As antibiotics are commonly given to patients presenting with a fever, any vaccine that reduces the incidence of febrile patients will lower antibiotic consumption.

In many countries, the introduction of the vaccine against Haemophilis influenza, eliminated Hib meningitis, bacteremia, pneumonia, and epiglottitis, including drug-resistant infections — Hib3 coverage is 89 per cent in India.

Rotavirus is the most common cause of severe diarrheal disease in young children worldwide and a cause of inappropriate antibiotic use, yet coverage of the vaccine, RotaC, is just 35 per cent in India.

When the pneumococcal conjugate vaccine (PCV) was rolled out in South Africa, it was related to an 82 per cent reduction in the rate of penicillin-resistant pneumococcal disease in children.

PCV coverage in India is currently six per cent, as many states are yet to adopt it into immunisation schedules.

Trials are currently underway for vaccines at different stages of development against typhoid, dengue and malaria which have the potential to reduce antibiotic prescribing and the incidence of drug resistant infections in India.

Flaws in medical fraternity

Consumption of antibiotics is the key driver of resistance. Effective management of this limited resource will ensure antibiotics are only used when appropriate and necessary.

Many medical practitioners lack formal training in India and 70 per cent of primary healthcare is delivered by such individuals. Sales companies target both doctors as well as those acting in a medical capacity without required qualifications.

They may be given gifts, such as medical equipment, televisions, travel or cash not to switch to competitors or to incentivise the sale of antibiotics to dispensers.

Pharmaceutical sales representatives are a key source of updates and information for prescribers, but the information they provide may be biased and motivated by commercial considerations to promote antibiotic sales.

Efforts in India to address the high levels of unqualified health workers by offering training courses will need to be monitored closely for success.

Even trained doctors worry that patients may not return if they are not prescribed antibiotics. Trainee doctors need more training on antimicrobial resistance (AMR). Standard treatment guidelines are either lacking or may have been developed by different authorities for the same conditions.

These guidelines only partially fulfil the World Health Organization (WHO) recommendations. Consensus on treatment recommendations, tailored to local environments, is the need of the hour.

The sale of antibiotics without a prescription is prohibited under Schedule H1, which has been supported by the red line campaign. But it is not widely enforced.

Antibiotics continue to be easily accessible and self-medication rates are 73 per cent in some parts of India. The lack of access, due to geographical distance or affordability, to medical professionals and prescribers, in rural areas of India, leads 50 per cent of people to buy antibiotics directly from the pharmacy as a first choice.

Fixed dose combinations (FDCs) of two or more antibiotics, which have not been proven to be of greater benefit and may have a greater risk of harm than therapies containing a single antibiotic.

Between 2011 and 2012, 34 per cent of the total antibiotics sold in India were FDCs. More than a third of FDCs sold in the same year were of unapproved formulations and 64 per cent of the 118 systemic antibiotic FDC formulations for sale in India were unapproved.

In 2018, 328 FDC products were banned by the Central Drugs Standard Control Organization, though in the past such bans have been challenged by the industry. This has shown the ability of the government to effectively regulate antibiotics and reduce the risk posed by AMR.

Selection of antibiotics

Not only the quantity of antibiotic prescribed, but the selection of which antibiotic has a role to play in promoting drug resistance. Broad spectrum antibiotics target a larger range of bacteria and are more likely to select for resistance.

WHO has categorised antibiotics into “Access”, which should be widely available; “Watch”, to be limited to specific indications; and, “Reserve”, to be used as a last-resort. In 2015, India had the highest consumption rate worldwide for oxazolidinones, which have been defined by WHO as “Reserve” antibiotics.

Consumption of carbapenems, also “Reserve” antibiotics, has increased in some hospitals. Between 2010 and 2014, consumption of faropenem, a carbapenem antibiotic, increased by 150 per cent. In some facilities, “Watch” and “Reserve” antibiotics are more commonly in stock than “Access” antibiotics.

Evidence of hospital antimicrobial stewardship campaigns being effective in reducing consumption is encouraging. However, it also suggests some hospital prescriptions are inappropriate.

Hospital drugs and therapeutics committees should be strengthened and healthcare providers should be trained in stewardship. Evidence from New Delhi suggests that private clinics prescribe antibiotics more often than public primary care settings.

Given that 70 per cent of disease episodes are treated in the private sector, it is important to address inappropriate prescriptions in this sector.

When facilities run out of essential antibiotics, patients are forced to purchase them from uncertified vendors, which often charge higher prices and may have poorer quality stock.

Falsified, substandard or counterfeit antimicrobials exacerbate AMR in several ways. They can leave patients under-dosed and bacteria that are only partially suppressed may be more likely to evolve resistance.

This also prolongs the time during which the infection may be transmitted, facilitating the spread of resistant strains and leading to further antibiotic use. When drugs don’t work, physicians prescribe the next line of antimicrobials, making resistance more likely to emerge to second-line drugs.

Multidrug-resistant tuberculosis affecting Tibetan refugees in India has been associated with the administration of counterfeit medicines and delayed treatment.

Ciprofloxacin resistance is also related to low-quality ciprofloxacin. Half of the 10 per cent of medications worldwide that are falsified are antimicrobials and 78 per cent of falsified medications are found in Asia or Africa.

More than three per cent of drugs tested at the Indian National Drug Survey (2016–2018) were not of standard quality and 0.0245 per cent were spurious.

To effectively manage the use of antibiotics and mitigate the emergence of resistance, surveillance data on antibiotic consumption and resistance are needed.

Resistance and consumption vary at the hospital and community levels and the data required needs to be at the level at which prescribing occurs to be informative.

Though WHO collects data on consumption and resistance through the Global Antimicrobial Surveillance System (GLASS), consumption data for India was unavailable in the last report.

Resistance data is now being collected. To inform prescribing, local hospital level data is needed. However, the lab facilities are often not available.

Even with access to surveillance data, clinicians need access to affordable, rapid and accurate diagnostics to guide appropriate prescription. C-reactive protein, procalcitonin and film array assays are used as indicators of bacterial infections, for which antibiotics are likely to be an appropriate treatment in cases where bacterial cultures are not available.

However, particularly in rural areas, diagnostic facilities are often lacking. Diagnostic tests often cost more than the empirical treatment and trained lab staff, facilities and consumables may not be available.

Rapid diagnostic tests for malaria have proven effective in reducing the inappropriate consumption of antimalarials, but have been associated with increased consumption of antibiotics.

Further research is needed to understand how to mitigate such knock-on effects. Innovative technical solutions are required to meet the need for new diagnostics — the longitude prize is one initiative rising to this challenge.

Antibiotics in the environment

Opportunities for the appropriate management of antibiotics occur throughout the supply chain — from manufacture through to consumption. About 80 per cent of antibiotics sold by multinational pharmaceutical companies have been manufactured in India or China.

Effluents from this process contain active antibiotics, resistant bacteria and resistant genes. They contaminate rivers, streams and wells, including waters which are used for drinking and bathing. This increases both the emergence of resistant bacteria in local populations and also their spread.

In addition, even at the low levels present in wastewater, antibiotics select for resistant bacteria. Contamination in areas where the antibiotic manufacturing industry operates has shown to increase selection for bacteria that are highly resistant, even to last-resort antibiotics, such as the carbapenems.

At present, the Central Pollution Control Board does not have maximum residual limits for antibiotic residues in pharmaceutical effluents. However, this has been addressed and limits may be released soon.

One objective of the Indian National Action Plan (NAP) on AMR is to develop such standards, however these are yet to be announced. To ensure that access to effective antibiotics is maintained, sustainable antibiotic production methods need to be developed and adopted by manufacturers.

Another source of environmental contamination is contaminated hospital waste. At 44 per cent, the Southeast Asia region has the lowest levels for safe health waste disposal.

Untreated hospital waste may contain antibiotics and resistant bacteria. Where disposal mechanisms are inadequate, such waste puts staff and patients at increased risk from AMR.

Water sources that become contaminated may cause infections to increase and the associated antibiotic use is also likely to select for AMR. Investment in the infrastructure associated with appropriate waste disposal and the training of personnel are urgently needed.

The use of antibiotics for growth promotion in otherwise healthy animals is a common practice in India, as is across the world. In 2010, India was the fifth largest consumer of antibiotics in livestock (poultry, cattle, and pigs).

It is projected that antibiotic use in this sector will grow by 312 per cent by 2030.

Antimicrobial residues have been found in chicken meat and shrimp being sold for human consumption. The use of Colistin in food-producing animals was recently banned in India.

However, it remains to be seen how this will be enforced. A one health approach that incorporates diverse stakeholders from farming, veterinary, medical, and environmental sectors is essential to mount an effective response to AMR.

India, home to 17 per cent of the world population, has an important role to play in addressing AMR both in the South Asia region and on the global stage.

At present, many more still die worldwide due to a lack of access to antibiotics than from resistant infections. However, in the long-term, for these drugs to remain effective, measures are needed to prevent the spread of resistance.

As India rolls out the universal health coverage, in the form of Ayushman Bharat, it will be important for access to be balanced with excessive and inappropriate use.

In particular, where the administration of antibiotics appears to be a cheap alternative to investing in the infrastructure required for adequate infection prevention, which played a key role in the dramatic reductions in incidence of infectious diseases seen in the developed world.

This was first published in Body Burden: Antibiotic Resistance — State of India’s Health

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