Antibiotic resistance and its containment in India

High burden of infectious diseases

According to World Health Organization estimates, the age standardised mortality from infectious diseases in India in 2008 was 377 per 100 000 persons, one of the highest in South Asia.10 An estimated 3.6 million cases of severe pneumonia occurred in India in 2010.11 Nearly 300 000 children under five years died from pneumonia and diarrhoea in 2016—the highest figure globally.12 In 2010, India had the highest consumption of antibiotics in humans, although per capita consumption (10.7 units/person) was lower than many other countries— for example, the United States with 22 units/person.4

Incomes have risen in India, and antibiotics are cheap, so the threat of infections may lead to their inappropriate use, and precipitate resistance.1314 A WHO pilot study in New Delhi found high antibiotic consumption: 43 390 defined daily doses (DDD) per 1000 patients in the public sector, 125 544 DDD per 1000 patients in private pharmacies, and 81 467 DDD per 1000 patients in private clinics.15 Prescription audits show widespread use of cephalosporins, penicillins, and fluoroquinolones in tertiary care hospitals.14 However, studies of drug use have been fragmented and are limited to local areas.

Antibiotic use for growth promotion in livestock

Although meat consumption in India is low, the trade in poultry has grown greatly. Estimates from the Food and Agricultural Organization16 indicate that net trade increased almost 40 times between 1990 ($79m; £61m; €69m) and 2014 ($3145m). To keep up production rates in this sector, where infectious diseases are common, non-therapeutic use of antibiotics is high.

In the US, antibiotic consumption in the livestock sector accounted for almost 80% of all antibiotics sold or distributed.17 A system for estimating consumption of antibiotics in pets or livestock is not available in India.18 In 2010, India was estimated to account for 3% of global antibiotic consumption in livestock, the fourth highest in the world, after China (23%), US (13%), and Brazil (9%).19

Box 2 shows resistance patterns found in dairy, poultry, and aquaculture sectors in India. In the absence of strong surveillance, it is difficult to assess the extent of the non-therapeutic use of antibiotics. Compared with the poultry and dairy sectors, antibiotic resistance has been studied closely in aquaculture because of stricter laws that limit antibiotic residues in fish, and aquatic products.26

Low awareness of antibiotic resistance

Without a national surveillance programme for antibiotic resistance, we had to rely on smaller studies that examined resistance patterns and antibiotic consumption in local or institutional settings. These do not provide a full understanding of the scale of the problem, what drives resistance, and effective interventions. Systematic surveillance needs to be combined with efforts to increase awareness among professionals in healthcare facilities, and livestock and aquaculture sectors, and the general public to reduce the misuse of antibiotics.

The medical curriculum does not adequately focus on rational antibiotic prescribing. Physicians have been reported to over prescribe antibiotics because of financial incentives and patient expectations.27 Despite being costly, the consumption of antibiotics like carbapenems is increasing, possibly because of inappropriate prescribing and non-prescription sales.28 Evidence from China shows that eliminating financial incentives leads to an immediate reduction in the prescription of antibiotics.29 Self administration of antibiotics bought without a prescription is also a serious concern.

Surveillance of antibiotic resistance

Surveillance for drug resistance in HIV/AIDS, tuberculosis, and malaria is in place,30 but a cross-cutting programme for multiple pathogens is lacking.

Two main initiatives for comprehensive surveillance were introduced in 2012 (box 3). The National Programme on Containment of Antimicrobial Resistance sets out a plan for a laboratory based AMR surveillance system for human, animal, and environmental sources, and for monitoring prescription patterns to improve the use of antibiotics. The Antimicrobial Resistance Surveillance Research Network aims to compile national data on AMR at all levels of healthcare, and build understanding of the mechanisms of resistance. The network has outlined diagnostic methods, and criteria for defining resistance profiles.

However, surveillance has largely been restricted to samples from tertiary care centres. These are likely to provide skewed estimates of resistant microbes, and miss resistant organisms circulating in the community. Non-hospital sources need to be included as well. This will require investment in capacity building and infrastructure for sample collection, transport, and testing at primary and secondary level health centres and in the community.

Infection prevention and control

Infection prevention and control is essential to reduce healthcare associated infections and antibiotic consumption. The Indian Council of Medical Research has published guidelines on infection prevention and control in hospitals which can be implemented locally.33 Hospitals should establish an infection control committee, with clinical staff as focal points, to direct initiatives to control healthcare associated infections, and monitor resistance.

Infection prevention and control guidelines developed by the National Centre for Disease Control provide broad principles for prevention and control of healthcare associated infections including cleaning, disinfection, and sterilisation practices; isolation procedures; antibiotic policies and stewardship; hospital outbreak management; and biomedical waste management.34

These guidelines need to be supplemented with a stronger implementation plan, and possibly legislation to ensure compliance. The National Centre for Disease Control is also finalising a national infection control policy which will include implementation plans.

Antimicrobial stewardship programmes include hospital based initiatives to improve antibiotic use. The Indian Council of Medical Research launched the Antimicrobial Stewardship, Prevention of Infection and Control Programme in 2013, which brings together staff from clinical pharmacology, microbiology, and other disciplines from 20 healthcare centres across the country. The objective is to build capacity and enable collaborative action to improve antibiotic stewardship and reduce healthcare associated infections through feasible infection control practices.35

Improving the use of antibiotics

Standard treatment guidelines are important to inform healthcare providers about appropriate treatment and prescribing practices for common infections. Treatment guidelines for antimicrobial use have been published by the National Centre for Disease Control and the Indian Council of Medical Research.3637 These guidelines can help individual healthcare facilities develop antibiotic policies based on local resistance profiles.

A survey conducted by the Indian Council of Medical Research on antimicrobial stewardship in eight private, and 12 government healthcare institutions in 2013 found good compliance with local guidelines on healthcare associated infections or hospital infection control measures. However, compliance with other aspects of antibiotic stewardship, such as analysis of antibiotic use, prescription audits and feedback, and monitoring implementation of stewardship programmes, was poor.38 Private institutions were better prepared to respond to antibiotic resistance or outbreaks of healthcare associated infections as they had policies on detection and response. The survey showed weak implementation of some core strategies of antimicrobial stewardship programmes, including restriction of certain classes of drug and rotation policies for drugs based on current resistance patterns.38

Stewardship programmes and enforcement vary considerably by institution. The national action plan provides a means to develop uniform requirements for prevention and control of infection and stewardship programmes for healthcare institutions at different levels, and to ensure adherence to these guidelines.

In 2013, a new restriction was introduced under the Drugs and Cosmetics Act and Rules to regulate non-prescription (over the counter) sale of third and fourth generation antibiotics, and first and second line antituberculosis drugs.39 These drugs can only be sold with a valid prescription, and details of the sale must be recorded by the pharmacist and the records kept for three years. A further amendment in 2015 prohibited advertisement of the listed drugs.26

To make this policy stronger, it should be extended to include more than the 46 drugs currently listed and have a clear implementation and monitoring plan, provision for online verification of sales or purchase records, and strict penalties to deter non-compliance. The effect of this regulation on antimicrobial consumption must be measured. It does not discourage physicians from overprescribing these drugs. Integrating this policy in essential drug lists and standard treatment guidelines, and a recent announcement by the Medical Council of India to encourage prescribing generic medicines can support appropriate use.

In February 2016, the Red Line Campaign was launched, and all antibiotics are marked with a prominent red line on the package (fig 1).40 The campaign aimed to raise public awareness about antibiotics and their risks and reduce their use outside of tertiary care settings. It received support in August 2016 from the Indian prime minister, Shri Narendra Modi, in the radio programme mann ki baat, in which he urged everyone to avoid self medication and take medicines only as prescribed.

Restrictions on the sale of these antibiotics apply to the animal industry as well. In 2015, the Food Safety and Standards Authority of India issued a directive to limit the use of antibiotics as growth promoters in animal feed.41 However, it did not indicate how this will be monitored. Furthermore, a directive from the Ministry of Health in 2012 requires that livestock labels must include the withdrawal period of medicines used for treatment (minimum of time from giving the last dose and use of the animal product for food), and these animal products should not be used before the withdrawal period of the drug is over.26 For fishery products, also, the use of some antibiotics is prohibited and maximum residue limits have been set.26

Research and innovation

In 2004, only 1.6% of drugs in development were antibiotics and none was new.42 Pharmaceutical companies are reluctant to invest in research and development for new antibiotics possibly because the market is small, as proper use of antibiotics results in complete cure. In addition, the emergence of resistant strains makes a drug ineffective and no longer needed. Furthermore, truly new antibiotics are likely to be kept in reserve to prevent the emergence of resistance, thereby limiting their potential profit.

The Open Source Drug Discovery initiative, launched by the Council of Scientific and Industrial Research, India, in 2008, aimed to share risks and rewards through collaborative research.43 The initiative had 7600 registered participants from 130 countries, and 240 projects. It resulted in the development of the drug PA-824 for treating drug resistant tuberculosis. However, the initiative has lost momentum. Investment in the development of new antibiotics, and point of care testing to confirm bacterial infection and susceptibility is urgently needed.

Cross-sectoral surveillance

Surveillance of AMR for specific diseases under vertical programmes duplicates efforts and does not show the complex drivers of AMR; cross-sectoral surveillance is needed for this. To ensure a One Health approach,44 surveillance systems must use the principles and standards of globally accepted frameworks such as the Global Antimicrobial Resistance Surveillance System.8 The national action plan provides the strategic framework for surveillance not only for human health, but also for food, animals, and the environment.

Locally relevant guidelines for infection prevention, and rational prescribing have been developed. Healthcare authorities must encourage their use, and develop a plan to monitor compliance.