By Arpit Agrawal :
Antimicrobial resistance (AMR), including Multidrug resistance (MDR), is increasing in our many healthcare institutions and the community. Reported data indicate that almost 2 million cases of infection with resistant bacteria have been reported each year in the United States, leading to incremental direct healthcare costs of $ 20 billion. Estimates from the European Medicines Agency (EMA) and European Center for Disease Prevention and Control (ECDC) stated a toll of 25,000 deaths per year as a direct result of MDR infection with a total cost of € 1.5 billion . In Canada, hospitalization due to resistant infections led to a increased economic burden with additional costs of $ 9- $ 14 million. Study by the Indian Network for Surveillance or Antimicrobial Resistance (INSAR) group, India reported a prevalence of 41% in specific cases. Increase of Gram-negative bacterial resistance has also been reported in India. World Health Organization (WHO) estimates that an estimated 3.7% of new cases and 20% of previously treated cases have MDR-Tuberculosis.
The path of antibiotic development is challenged at each step by the emerging microbial resistance. The emergence of MDR has already affected the most effective treatments. Recent reports have witnessed changing the sensitivity pattern and the trend break in AMR.
As a global issue, AMR is now well accepted by various stakeholders. In 2011, the WHO agenda was to combat antimicrobial resistance. It was one of the most important attempts to attract international attention and the need for combined efforts to reduce the problem of AMR.
Antimicrobial Resistance
Micro-organisms are called ‘antimicrobially-resistant’ or ‘drug-resistant’ if they are no longer inhibited by an antimicrobial for which they were previously sensitive. Such a resistance is called ‘acquired resistance’ and is encoded by resistance genes in the DNA of the microbe. Resistance genes can arise from spontaneous mutations in the microbial DNA, but some have evolved over the course of many years as a result of natural selection by natural antimicrobials in the environment. These genes can also transfer antimicrobial resistance from drug-resistant microbes to drug-sensitive microbes.
AMR refers to micro-organisms – bacteria, fungi, viruses, and parasites – that have acquired resistance to antimicrobial substances. While this phenomenon can occur naturally through microbial adaption to the environment, it has been exacerbated by inappropriate and excessive use of antimicrobials. Various factors are involved, such as:
- lack of regulation and oversight of use;
- poor therapy adherence;
- non-therapeutic use;
- over-the-counter or internet sales, and;
- availability of counterfeit or poor-quality antimicrobials.
The consequences of AMR include the failure to successfully treat infections, leading to increased mortality; more severe or prolonged illness; production losses; and reduced livelihoods and food security. The indirect impacts of AMR include higher costs for treatment and health care. The health consequences and economic costs of AMR are estimated at 10 million human fatalities annually and a 2 to 3.5 percent decrease in global Gross Domestic Product (GDP), or USD 100 trillion, by 2050. But the true cost of AMR is hard to predict.
Antimicrobial resistance occurs naturally in time, mostly due to genetic changes. However, the abuse and excessive use of antimicrobials accelerates this process. In many places, antibiotics are overused and abused by humans and animals and often without professional supervision. Examples of abuse are when they are taken by people with viral infections such as colds and flu, and when they are administered as growth promoters in animals or used to prevent diseases in healthy animals.
Antimicrobial resistant microbes are found in people, animals, food and the environment (in water, soil and air). They can spread between people and animals, also from food of animal origin, and from person to person. Poor infection control, inadequate hygienic conditions and inadequate food processing stimulate the spread of antimicrobial resistance.
International Measurers for preventing AMR and the role of International Organizations.
World Health Organization (WHO)
In 2011, the WHO theme was to combat antimicrobial resistance. It was one of the most important efforts to attract international consideration and the need for collective efforts to reduce the problem of AMR. The prominent approaches recommended by the WHO are:
- More cooperation between governments, non-governmental organizations, professional groups and international bodies
- New networks that monitor antimicrobial use and AMR
- International approach to controlling counterfeit antimicrobials
- Incentives for the research and development of new drugs and vaccines
- Forming new and strengthening existing programs to control AMR.
In 2015 the WHO adopted the Global Action Plan on Antimicrobial Resistance which listed five prong strategic objectives to ensure, for as long as possible, continuity of the ability to treat and prevent infectious diseases with effective and safe medicines that are quality assured, used in a responsible way, and accessible to all who need them.
Objective 1: Improve awareness and understanding of antimicrobial resistance through effective communication, education and training.
Immediate measures should be taken to increase awareness of antimicrobial resistance and to promote behavioral change, through public communication programs targeting different target groups in public health, animal health and farming practice, as well as consumers. Inclusion of the use of antimicrobials and resistance in school curricula will promote understanding and awareness from an early age. Making antimicrobial resistance a core component of vocational education, training, certification, continuing education and development in the health and veterinary sector and agricultural practice will contribute to a good understanding and awareness of professionals.
Objective 2: Strengthen the knowledge and evidence base through surveillance and research.
Actions and investments to address antimicrobial resistance must be supported by clear reasons for their benefit and cost-effectiveness. National governments, intergovernmental organizations, agencies, professional organizations, non-governmental organizations, industry and academia have an important role in generating such knowledge and translate it into practice.
Insight into how resistance develops and spreads, including how resistance circulates in and between man and man and through food, water and the environment, is important for the development of new instruments, policies and regulations for counter-antimicrobial resistance.
Objective 3: Reduce the incidence of infection through effective sanitation, hygiene and infection prevention measures.
Better measures for hygiene and infection prevention are essential to limit the development and spread of antimicrobial-resistant infections and multi-resistant bacteria. Effective prevention of infections transmitted by means of sex or medication injection, as well as better sanitation, hand washing and food and water safety must also be components of the prevention of infectious diseases. Vaccination, where appropriate as a means of preventing infection, should be encouraged.
Much antibiotic use is linked to animal production. Antibiotics are sometimes used to prevent infections, to prevent the spread of diseases within a herd when the infection occurs, and as a growth stimulant, and are often administered via feed and water. Sustainable grassland practices, including the use of vaccines, can reduce infection rates and dependence on antibiotics, as well as the risk that antibiotic-resistant organisms will develop and spread through the food chain.
Objective 4: Optimize the use of antimicrobial medicines in human and animal health.
Evidence that antimicrobial resistance is increasing by the use of antimicrobial substances is conclusive. High antibiotic use may indicate over-prescription, easy access through free sales, and more recently internet sales that are widespread in many countries. Despite measures taken by some Member States, the use of antibiotics in humans, animals and agriculture is still increasing worldwide. The expected increase in the demand for animal food products may lead to a further increase in antibiotic use. There is a need to strengthen the regulation of their distribution, quality and use and to encourage investment in research and development.
Regulation of the use of antimicrobials is inadequate or poorly applied in many areas, such as over-the-counter and internet sales. Related weaknesses contributing to the development of antimicrobial resistance include poor patient adherence, the prevalence of non-compliant drugs, both for human and veterinary use, and inappropriate or unregulated use of antimicrobials in agriculture.
Objective 5: Develop the economic case for sustainable investment that takes account of the needs of all countries, and increase investment in new medicines, diagnostic tools, vaccines and other interventions.
The economic case should reflect the need for capacity development, including training in low-resource settings, and the need for evidence-based use of interventions in human and animal health care systems, including medicines, diagnostic tools and vaccines.
Antibiotics should also be supplemented with affordable, point-of-care diagnostic tools to inform health professionals and veterinarians about the pathogen’s susceptibility to available antibiotics. The applicability and affordability of these techniques in low and middle-income countries should be considered.
Food and Agriculture Organization of the UN (FAO)
FAO contributes to international efforts to address the issue of AMR. It supports governments, producers, traders and other stakeholders in taking measures to minimize the use of antimicrobials and reduce AMR while being sensitive for the needs of the food and agriculture sectors worldwide. The organization has a wide range of expertise in a variety of disciplines and is present at national, regional and global level. It also supports the standard setting in the field of scientific advice as the basis for sound international standards and promotes the implementation of these standards by offering support to countries.
As a multidisciplinary organization, the FAO plays a key role in providing integrated and coherent support to countries in the regulation and monitoring of the use of antimicrobial agents and in preventing and minimizing the development of resistance in all sectors. FAO encourages countries to identify and involve all stakeholders including policy makers and government agencies, retailers, agricultural and animal producers, the food and feed industry and the general public, etc. in order to ensure that they are involved at an early stage and to secure their current activities, cooperation and their quick action.
In addition, the FAO’s extensive experience in capacity development enables it to respond to requests for support from countries regarding the use of antimicrobials and the prevention and control of AMR, among other issues. This is particularly important for countries where the risk of AMR may be particularly high due to weak or inadequate legislation, supervisory arrangements and / or monitoring systems.
India’s approach to prevent spread of AMR
In 2011 a National Policy for Containment of Anti-Microbial Resistance was introduced. The policy is aimed at understanding the emergence, spread and factors that influence AMR, the setting up of antimicrobial programs, the rationalization of the use of antimicrobial drugs and the stimulation of the innovation of newer effective antimicrobial agents. Moreover, some important action points were identified in national policy; setting up an AMR surveillance system, strengthening infection prevention and control measures and training, training and motivating all stakeholders in the rational use of antimicrobial agents. The WHO estimates that less than 50% of all countries implement a basic policy for the appropriate use of medicines.
Aims of the National Policy for Containment of Anti-Microbial Resistance are:
- Establish government commitment and support for a national antimicrobial program and policy and establish a national contact point for collaborations and compilation.
- Establish a national alliance for prevention and control of antimicrobial resistance.
- Establish a monitoring system that captures the emerging resistance, looks for and provides for trends in its distribution and correlates with the use of antimicrobials in the community as health care institutions.
- Promote rational use of antimicrobial agents.
- Strengthening infection prevention and management measures – health-related and community-based.
- Support research in developing newer antimicrobial agents and improving the use of available resources based on pharmacological properties.
- Develop, train and motivate all stakeholders in the rational and appropriate use of antimicrobial substances and their regulation.
- Establish a quality system and a national registry for antimicrobial resistance to bacteria, fungi and viruses at the national focal point.
- Co-develop antimicrobials with medicines and leave the distribution, sales and promotion to the government.
Though the policy has introduced many recommendations the current situation regarding manufacture, use and misuse of antibiotics in the country is still not in compliance with the WHO Global Action plan on Antimicrobial resistance.
The quality of the drugs imported, manufactured and sold in the country is regulated in the provisions of the Drugs and Cosmetics Act of 1940. The law visualizes the legal control over the drugs that are imported into the country by the central government, while the production, sale and distribution of medicines is mainly regulated by the state control authorities designated by the state governments. The production and sale of the medicines is regulated by a system of permits and inspection by the licensing authorities.
The Central Drugs Standard Control Organization (CDSCO), under the leadership of the Drugs Controller General (India) in the Directorate General of Health Services, is engaged in the regulatory control of the quality of medicines, cosmetics and certain reporting devices according to the Drugs and Cosmetics Act, 1940 and rules made there.
The manufacture and sale of medicines is a licensed activity under the Drugs and Cosmetics Act of 1940 and the licensees must comply with the provisions of the law and the terms of the license. The law specifies violations and penalties for violations of the provisions of the law. Licenses for the sale of drugs (wholesale or retail) are granted by the licensing authorities. The permits must comply with the permit conditions as stipulated in Rule 65 of the Drugs and Cosmetics Rules. Some of the striking conditions are as below:
The delivery, other than by way of wholesale treatment of any medicine supplied on the instructions of a Registered Physician, should only be carried out by or under the personal supervision of a registered pharmacist.
Schedule H of the drug provide a list of the drug which are required to be sold on the prescription of a registered medical practitioner and the manufacturer is required to label the drug with the symbol Rx and with the following words:
‘Schedule H drug – warning: To be sold by retail on the prescription of a Registered Medical Practitioner only’.
The Drug and Cosmetics Act provides for fine for the manufacture, sale, etc. of drug in continence with the law or the rule issued there. Drug Inspector appointed under the act is authorized to prosecute with regard to breaches of the law and Rules thereunder.
Schedule M of the Drugs and Cosmetics Rules provides requirements for Good Manufacturing Practices and requirements for equipment and equipment for making medicines. It specifies in detail the requirements of buildings, environment, personnel, sanitary facilities, storage of raw materials, documentation and records, self-inspections and quality control systems and site master files etc. The manufacturer must meet the requirements of scheme M under the conditions of the license.
Conclusion
Antimicrobial resistance is a global problem that needs to be addressed in all countries, due to the import of resistant micro-organisms through international travel and trade. The World Health Organization (WHO) had chosen to combat antimicrobial resistance as the theme for World Health Day 2011, which takes place on 7 April.
Infections caused by antimicrobial-resistant microbes often do not respond to standard drug therapy. This leads to long-term illness and longer periods of infectivity. When infections are resistant to front-line antimicrobials, second-line or third-line drugs are administered, which are usually more expensive and sometimes more toxic. For example, the combination of drugs necessary for the treatment of multidrug-resistant forms of tuberculosis (MDR-TB) is more than 100 times more expensive than the combination of first-line drugs used to treat non-resistant forms of TB. Longer hospital admission periods for patients also increase the financial burden for health authorities. Drug-resistant infections also compromise the success of treatments, such as organ transplantation, cancer chemotherapy and major surgery.
Despite the global call for action little or no action is observed on part of the global community as whole or if considering India specifically. Most of the strategies are not adequate and the recommendations are yet to be implemented. This is true in the case of India as the recommendations of the National Policy for Containment of Anti-Microbial Resistance to prevent the proliferation of antibiotics through much needed regulation such as implementation of Schedule H1 were not implemented.