Intended for healthcare professionals

Analysis Antimicrobial Resistance in South East Asia

# Antibiotic resistance and its containment in India

BMJ 2017; 358 (Published 05 September 2017) Cite this as: BMJ 2017;358:j2687

1. Manish Kakkar, senior public health specialist1,
2. Kamini Walia, scientist2,
3. Sirenda Vong, regional technical lead, antimicrobial resistance3,
4. Pranab Chatterjee, senior research associate1,
5. Anuj Sharma, technical officer, antimicrobial resistance4
1. 1Public Health Foundation of India
2. 2Indian Council of Medical Research, New Delhi, India
3. 3World Health Organization Regional Office for South-East Asia, New Delhi, India
4. 4World Health Organization Country Office for India, New Delhi, India
1. Correspondence to: A Sharma sharmaan{at}who.int

Manish Kakkar and colleagues discuss factors contributing to antibiotic resistance in India, and examine policy initiatives to address it

Antibiotic resistance is a major public health threat in India. A high burden of infectious diseases, unregulated sale of antibiotics, financial incentives for healthcare providers to prescribe antibiotics, patient expectations, rising incomes, and limited public health response have helped drive the emergence of resistance.1 Resistance patterns in India in human samples are shown in box 1. Resistance to commonly used antibiotics is increasing. This complicates clinical management, and newer, more expensive antibiotics need to be used. Resistance to newer, broad spectrum drugs such as carbapenems, which are the antibiotics of last resort, has been seen in parallel with their increased use.4

#### Box 1: Patterns of antimicrobial resistance in isolates from humans23

##### Shigella
• High resistance (>50%) to nalidixic acid, norfloxacin, and ampicillin

• Presence of the blaCTX-M-15 gene with a risk of spreading cephalosporin resistance to Enterobacteriaceae

##### Salmonella typhi
• High resistance to fluoroquinolones, and cephalosporins

• Decreased multidrug resistance, and resistance to ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole

##### Pseudomonas spp
• Low resistance to imipenem (15%), amikacin (20%), and ciprofloxacin (20%)

• High resistance to piperacillin-tazobactam (42%), and meropenem (50%)

• 12% of samples carry the gene for New Delhi metallo-beta-lactamase-1 (NDM-1), the enzyme that confers resistance

##### Acinetobacter spp
• Maximum susceptibility to colistin (99%), followed by imipenem, and meropenem (53%)

• 13% of samples carry the NDM-1 gene

##### Rising trends
• Rise in meticillin resistant Staphylococcus aureus from 29% in 2008 to 47% in 2015

• Carbapenem resistant isolates of Escherichia coli increased from 10% in 2008 to 13% in 2013

• Carbapenem resistant isolates of Klebsiella pneumoniae increased from 29% in 2008 to 57% in 2014

• In S typhi isolates, resistance to fluoroquinolones has increased from 8% in 2008 to 28% in 2014. Resistance to antimicrobials that are not used commonly (trimethoprim-sulfamethoxazole, aminopenicillin) is decreasing

In April 2017, the government of India finalised the National Action Plan on Antimicrobial Resistance (AMR)5 in line with the strategic objectives of the global action plan on AMR.6 In addition, the Delhi Declaration on AMR,7 which aims to increase multisectoral actions to reduce AMR, was endorsed by 12 ministries, including health, environment, agriculture, and food.

We looked at the factors contributing to AMR in India, and the initiatives being taken to tackle it.

## Data sources

We used findings from a scoping review on AMR in India, and a background paper commissioned by the WHO Country Office for India.8 The review identified documents from both peer reviewed publications and other sources. Most studies were conducted in local areas, and lacked methodological rigor, and representative samples. These were, however, included in the assessment as they provide estimates of local resistance. Additional data were obtained from documents in the public domain including unpublished research from the National Dairy Research Institute, and the National Anti-Microbial Resistance Surveillance Network. Data on antibiotic consumption and resistance patterns were obtained from the resistance map project.9

## Drivers of antibiotic resistance 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

#### Box 2: Resistance patterns in livestock and aquaculture

• Vancomycin resistant Staphylococcus aureus reported in cow and goat milk20

• Milk samples from cows with mastitis contained E coli carrying the NDM-1, and extended spectrum β-lactamase genes21

• Resistance to streptomycin (75%), and erythromycin (57%) has been found in isolates from poultry. Resistance was over 40% for kanamycin, ampicillin, tobramycin, and rifampicin22

• Samples from backyard poultry have shown high rates of resistance to chloramphenicol, ciprofloxacin, gentamicin, levofloxacin, norfloxacin, and oxytetracycline in a wide variety of bacteria, including Staphylococcus spp (29.1%), Streptococcus spp (25%), E coli (12.5%), Salmonella spp (8.3%), and Aeromonas spp (4.1%) 23

• Multidrug resistant bacteria were isolated from over two thirds of 250 aquaculture samples24

• NDM-1 has been reported in community and hospital settings and found in environmental samples and water sources in India 25

### 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.

## Initiatives to prevent antibiotic resistance in India

### 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.

#### Box 3: Key initiatives to contain AMR in India3132

##### National Programme for the Containment of Antimicrobial Resistance (within the 12th Five Year Plan, 2012-17)

Objectives

• Establish a laboratory based AMR surveillance system of 30 network laboratories across the country, and generate high quality data on AMR for pathogens of public health importance

• Strengthen infection control guidelines and practices, and promotion of rational use of antibiotics

• Raise awareness among healthcare providers, and the community about rational use of antibiotics

Stage of implementation: Ten laboratories are included in the network; surveillance covers four pathogens of public health importance—Klebsiella spp, E coli, Staph aureus, and Enterococcus spp; resistance in Salmonella typhi (and paratyphi), Pseudomonas aeruginosa, and Acinetobacter spp is being added this year

Activities: AMR surveillance in various geographical regions; promotion of the rational use of antibiotics; development and implementation of national infection control guidelines; training and capacity building of professionals in relevant sectors; dissemination of information about rational use of antibiotics; development of a national repository of bacterial strains and cultures; monitoring quality control checks, audits, feedback to advisory body, and annual review of action plan

Responsibility: National Centre for Disease Control

##### Antimicrobial Resistance Surveillance Research Network

Objectives

• Compile national data of AMR at different levels of the healthcare system

• Provide a detailed understanding of the underlying mechanisms of resistance, clonality, transmission dynamics, and genetic molecular studies

Stage of implementation: All the six proposed national centres at four institutions are functional; of the 20-25 medical colleges proposed as regional centres, 15 have started reporting; a web-based portal has been developed for participating institutions for real time data collection, monitoring, and analysis; diagnostic protocols, and reporting formats are standardised

Activities: Standard operating procedures for diagnostic methods, and criteria in bacteriology and mycology have been developed; over 20 000 samples have been tested; each national centre will be the reference centre for one pathogenic group: bacterial organisms that cause diarrhoea, enteric fever pathogens, Enterobacteriaceae that cause sepsis, Gram negative non-fermenting bacteria, Gram positive bacteria including MRSA, fungal infections, and respiratory pathogens; national centres will share samples for the reference centre to carry out genetic, and advanced testing; regional centres will report to the national centre; the network will be expanded to include animal and food samples

Responsibility: Indian Council of Medical Research

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.

## Conclusion

Antibiotic resistance has not received adequate attention in India. However, recent policy moves show growing political commitment at the highest levels to strong action on AMR, and support for nationwide surveillance, and stewardship to contain resistance. Box 4 outlines the actions needed to reduce AMR in India based on the strategic objectives of the national action plan.5

#### Box 4: Actions to tackle AMR in India based on the strategic priorities of the National Action Plan on AMR5

##### Improve awareness and understanding of AMR through effective communication, education, and training
• Develop information, education, and communication programmes based on identified knowledge gaps

• Train physicians, veterinarians, and other professionals in essential medicines, stewardship, infection prevention and control, and surveillance

• Implement and monitor the effect of the Red Line campaign40

##### Strengthen knowledge and evidence through surveillance
• Harmonise and expand the scope of the National Programme on the Containment of Antimicrobial Resistance and the AMR surveillance network to include samples from clinical and community settings, and from food, animal, and environmental sources

• Strengthen microbiology laboratories for culture and sensitivity testing to identify AMR and mainstream surveillance of AMR

##### Reduce the incidence of infection through effective infection prevention and control
• Develop implementation strategies for infection prevention and control in human and animal health, and the environment

• Implement the swachh bharat abhiyan (clean India campaign) to improve sanitation and reduce infectious diseases

##### Optimise the use of antimicrobial agents in health, animals and food
• Review and revise the national essential list of medicines to ensure access to antibiotics at reasonable prices and to tackle incentives to providers to overprescribe antibiotics

• Establish national patterns of antibiotic consumption in humans and animals

• Strengthen the antimicrobial stewardship programme based on the identified gaps3538 and increase compliance with treatment guidelines for common infectious diseases

##### Promote investments in AMR activities, research, and innovations
• Develop funding strategies to support innovations to tackle AMR43

• Invest in research to develop new interventions (diagnostics, drugs, vaccines, and alternatives to antibiotics), and models to help guide policy interventions

##### Strengthen India’s leadership in AMR
• Maintain India’s contribution to global efforts to contain AMR through international collaborations

• Facilitate collaboration between vertical disease control programmes and national stakeholders

• Support action at the local level against AMR through state level collaboration

#### Key messages

• Antibiotic resistance has not received adequate attention in India in the past, but recent government initiatives show commitment to tackle this global challenge

• The National Action Plan on AMR, which is aligned with the global action plan on AMR, is a strategic plan for effective action against AMR in India

• The Delhi Declaration on AMR highlights the commitment of 12 Indian ministries to tackle AMR with a One Health approach

## Footnotes

• This article is one of a series commissioned by The BMJ based on an idea from WHO SEARO. The BMJ retained full editorial control over external peer review, editing, and publication. Open access fees are funded by the WHO SEARO.

• Contributors and sources: This paper is based on a background paper commissioned by the WHO Country Office for India to help the development of the National Action Plan on AMR. AS and SV conceived the outline and scope of the paper. MK and PC conducted the literature searches and drafted the manuscript, which was critically reviewed by AS, KW and SV. AS is the guarantor.

• Competing interests: All authors have read and understood BMJ policy on declaration of interests and have no relevant interests to declare.

• Provenance and peer review: Commissioned; externally peer reviewed.

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