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   Overview of the ...
   Alternatives to ...
   Burden of Antibi...
   Global Burden of...
   Indian Scenario ...
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EDITORIAL
Year : 2019  |  Volume : 51  |  Issue : 4  |  Page : 231-235
 

Positive list of antibiotics and food products: Current perspective in India and across the globe


Department of Pharmacology, PGIMER, Chandigarh, India

Date of Submission27-Aug-2019
Date of Acceptance27-Aug-2019
Date of Web Publication13-Sep-2019

Correspondence Address:
Prof. Bikash Medhi
Department of Pharmacology, PGIMER, Chandigarh - 160 012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijp.IJP_548_19

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How to cite this article:
Mahalmani VM, Sarma P, Prakash A, Medhi B. Positive list of antibiotics and food products: Current perspective in India and across the globe. Indian J Pharmacol 2019;51:231-5

How to cite this URL:
Mahalmani VM, Sarma P, Prakash A, Medhi B. Positive list of antibiotics and food products: Current perspective in India and across the globe. Indian J Pharmacol [serial online] 2019 [cited 2019 Nov 13];51:231-5. Available from: http://www.ijp-online.com/text.asp?2019/51/4/231/266825




The word antibiotic means “against life.” Antibiotics, also known as antibacterials, are medicines that help in completely killing or slowing down the growth of bacteria. Regulatory authorities have laid down the positive list of antibiotics in livestock sector including poultry in food-producing animals. The discovery of antibiotics was a big boon to the humankind as they were helpful in preventing infectious diseases caused by bacteria in humans as well as in animals. However, rampant use of antibiotics has led to loss of efficacy of the antibiotics known as “Antibiotic Resistance.” Antibiotic resistance has been defined as “the capacity of an organism to resist the killing effects of an antibiotic to which it was earlier susceptible.” In simple terms, this means that infectious diseases which were once easily curable can now prove to be fatal. Since decades, antimicrobial resistance (AMR) has been a global issue of concern. Among the major health challenges faced in the 21st century, AMR is one of the major problems which can have devastating effects. For more than 50 years, antibiotics have been used in the poultry industries for the prevention/treatment of infectious (Avian) diseases, growth promotion, as well as improving the production in farm animals. In most of the developing countries like India, there is a widespread use of a large number of antimicrobials to raise the poultry. The indiscriminate use of antibiotics has caused rapid increase in the surge of AMR, subsequently leading to therapeutic failure, decline in economy, and as a source of resistant gene pool carried over to humans. The history of usage of antibiotics for increasing the poultry and livestock production dates back to the 1910s, where the workers across America started protests and riots due to shortage of meat products. As a result, scientists began searching for new methods for enhancing the production at comparatively cheaper rates and ended up in using antibiotics. Sweden was the first country to take up a major initiative to ban nontherapeutic use of antimicrobials, which was later followed by Denmark, the United Kingdom (UK), and various European Union (EU) countries. This major step was further strengthened by these countries in the year 2011 by banning all essential antibiotics for prophylactic use. However, it is estimated that out of all the antimicrobials synthesized, more than 60% of them are utilized in livestock production including poultry.[1]


  Burden of Antibiotic Overuse on Humans and Environment Top


Global antibiotics usage in animals producing food was 131,109 tons in 2013, is estimated to rise over 50% to 200,235 tons by the year 2030. India is one among the BRICS countries – Brazil, Russia, India, China and South Africa where consumption of antimicrobials is expected to double. Use of different antibiotics as feed supplements is quite common in livestock production. India's livestock sector accounts for 11.6% of world's livestock population, is one of the largest in the world.[2] Hence, problem of antibiotic resistance is quite high particularly in a developing country like India. Normally, antibiotics when used in animal production remove susceptible strains of bacteria, whereas the resistant ones remain in the body of animals. Later, these resistant strains multiply in number and transfer their resistant genes to other bacteria. The resistant bacteria are then transferred to human beings from poultry products while handling contaminated meat or upon consumption. These pathogenic organisms carrying resistant genes establish their colonies in human intestines and transfer the resistant genes to endogenous intestinal flora. Individuals being infected with such microorganisms will put themselves at risk of therapeutic failure, which is an alarming global threat. Antibiotic resistance is not only limited to poultry, but also poses a serious risk to the environment. Animals fed with large quantities of antimicrobials excrete them via urine and feces into the environment. Hence, sewage disposal is also one of the most common routes through which antimicrobials gain entry into the environment.


  Global Burden of Antimicrobial Resistance Top


In the 1960s, a rapid increase in multidrug-resistant  Salmonella More Details was noted in the UK. The UK published a “Swann Report” which reported that the chief cause for the development of resistance to infections was the use of antibiotic growth promoters (AGPs). It highlighted upon the ban of antibiotics for growth promotion, particularly those which were meant for human therapy.[3] However, usage of antibiotics such as avoparcin, bacitracin, virginiamycin, bambermycin, and tylosin continued as narrow-spectrum substitutes which had less impact on the wide range of gut flora. The most astonishing fact observed was that there existed structural relationship between these antimicrobials and the ones intended for clinical use in humans. Hence, the use of one antibiotic produced cross-resistance with the other. An example of cross-resistance was observable with avoparcin (AGP) and vancomycin (therapeutic drug in humans) which led to the development of vancomycin-resistant enterococci. Ribotyping methods revealed that there was resemblance between the patterns obtained from farms and sewage with that of Enterococci obtained in hospital.[4] Although the United States does not permit the use of gentamycin for growth promotion, it was most frequently used in broiler production for preventing early mortality in poultry animals. Price et al. in their study showed that the danger of carrying gentamicin-resistant  Escherichia More Details coli was 32 times more in pupils who worked in poultry compared to nonpoultry workers: 50% of workers in poultry were colonized with gentamicin-resistant E. coli, whereas it was just 3% in the general population.[5]

In China, samples obtained from gentamicin-resistant urinary tract infections and fecal E. coli isolates from humans and animal food disclosed that 84.1% of human samples and 75.5% of animal samples had aaaC2 gene responsible for resistance to gentamicin.[6] Clenbuterol, a beta agonist, is used to produce meat comprising of more protein and less fat. Bio-resistant bacteria (Staphylococcus xylosus) have been found in air in broiler farms. This airborne transmission may pose a risk of easy spread of epidemic diseases, a serious danger to public health. Currently, colistin is considered to be the last resort against multidrug-resistant pathogenic bacteria, particularly the ones resistant to carbapenems. Excessive utilization of colistin in farm animals in China has led to the development of resistance in E. coli through colistin-resistance mcr-1 gene. China has, therefore, banned colistin usage as an AGP and released a mandate to control its use in the therapy of animals. Recently, even India has banned the manufacture, sale, and use of colistin in food-producing animals in the year 2019 under the Drugs and Cosmetics Act, 1940.


  Indian Scenario of Antimicrobial Resistance Top


India is a developing country where factors such as poor nutrition, sanitation, and overcrowding are the major causes for the development of infections. The Center for Science and Environment (CSE) on performing a study in India have found considerable amounts of antibiotic residues in poultry and multidrug-resistant bacteria in nearby farms. The chicken litter or chicken litter-based organic fertilizers are often used in agriculture. The Center for Science and Environment (CSE) performed a study in India in the year 2017. It was found that considerable amount of antibiotic residues were present in poultry and multidrug resistant bacteria emerged in nearby farms as well. The chicken litter or chicken litter based organic fertilizers are often used in agriculture. So, samples of litter and soil was collected randomly from 12 poultry farms from four main poultry producing states in north India, namely Haryana, Uttar Pradesh, Punjab and Rajasthan where antibiotics were being used and the litter was being utilized as manure in nearby agricultural farms. 217 isolates of three types of bacteria, namely  E.coli Scientific Name Search , Klebsiella pneumoniae and Staphylococcus lentus were obtained and examined for resistance against 16 antibiotics. Out of these, ten antibiotics have been professed by the World Health Organization (WHO) as critically important ones. The study revealed that 100% of the E.coli, 92% of K. pneumoniae, and 78% of S. lentus isolated were found to be multidrug resistant. E. coli and K. pneumoniae exhibited very high resistance to antibiotics such as penicillins, fluoroquinolones, and third- and fourth-generation cephalosporins and carbapenems, which are the last resort antibiotics in hospitals. Summarizing, the study revealed high degree of resistance to all critically important antibiotics. Out of these critically important antibiotics utilized in the study, five fitted into the “highest priority” category and the remaining into the “high priority.” The study also found that there existed a strong resemblance in the pattern of resistance in E. coli isolated from litter and neighboring farms where litter was utilized as manure. This showed that multidrug-resistant E. coli produced in the poultry were gaining entry into the environment through litter.[7] Raw food samples were taken from different parts of a metropolitan city, Chennai, in India. Out of 110 samples in total, 46.4% of them had colistin resistance organisms.[8] Many more studies if conducted would definitely reveal the emergence of resistant pathogens in other parts of the country.

Tuberculosis (TB) in India has also become one of the biggest health issues. On March 24, 2019, the World Tuberculosis Day, the Ministry of Health and Family Welfare of India reported that 2.15 million new TB cases have been discovered in 2018. The issue of drug-resistant TB began with multidrug-resistant TB and extensive drug-resistant TB. The most dangerous form of TB now in India is totally drug-resistant TB. A study conducted by Qumar et al. in Hyderabad on Helicobacter pullorum isolates found that free-range and broiler chickens were resistant to different antibiotics such as fluoroquinolones, cephalosporins, sulfonamides, and macrolides.[9] Hence, consumption of animal food containing such resistant bugs would definitely cause a hindrance in the therapy of TB as some of these drugs are second-line drugs in TB therapy.

Besides colistin, it is also important for us to reserve antibiotics such as fourth- and fifth-generation cephalosporins, polymyxins, carbapenems, linezolid, tigecycline, and daptomycin, exclusively for human use. Superbug New Delhi metallo β-lactamase 1 was named after the place where it was first isolated, in a Swedish patient of Indian origin in the year 2008. This gene is resistant even to carbapenems which are usually the last resort to treat bacterial infections. Resistance makes conditions such as pneumonia, urinary tract infections, and bloodstream infections difficult to treat. Prohibition of nontherapeutic use of antimicrobials would not only prevent further occurrence of damage but would also benefit by preserving the critical antibiotics for future as very few ones are in pipeline. Urgent interventions in the medical settings as well as in public are essential to preserve the usefulness of antibiotics.


  Overview of the Regulatory Framework Top


In the United States, the National Antimicrobial Resistance Monitoring System was framed for monitoring the trends in the emergence of resistant pathogens found in animal food and humans.[10] In order to control the rampant consumption of antibiotics in domestic sector in India, few regulations were framed. Unfortunately, none of the protocols were strictly implemented because of lack of stringent regulations, especially for nontherapeutic uses such as prevention of infections or for growth promotion which is one of the chief causes for misuse of antibiotics. There is also limited surveillance with respect to the usage of antibiotics in animal food sectors. In 2017, the National Action Plan (2017–2021) has been implemented by Indian health authorities, a plan that highlights several challenges that need to be overcome to address the problem of AMR. A major drawback of such plans is that there is no proper coordination between the human and animal health sectors with respect to collection of data regarding the usage of antimicrobials. In addition, the Food Safety and Standards Authority of India (FSSAI) established under the Food Safety and Standards Act, 2006, mainly looks after food safety and regulations in India. In the year 2017, after the amendment of the regulation, it was anticipated that the tolerance limits of the antimicrobials in food obtained from animals will be clearly stated. This was to ensure that antimicrobial residue in animal food does not affect human health. The amendment laid down the maximum permissible limits of 21 antibiotics and other 77 more drugs used in veterinary for animal food production. However, it is sad to know that none of the action plans were implemented strictly due to lack of awareness and proper knowledge of this “farm-to-fork” transmission process. In addition, there is lack of routine testing of animal food, which often makes the general population to consume foodstuffs containing antibiotic residues, which is more than the maximum permissible level. Lack of proper data regarding antibiotic usage in food of animal origin due to poor surveillance systems will ultimately lead to failure of appropriate designing and evaluation of interventions. There is lack of proper registries and surveillance systems for properly recording and reporting the usage of antibiotics in farm animals. Hence, there is an urgent need to establish Veterinary Pharmacovigilance Programme in India to monitor the usage of antimicrobials in animals as various countries have already established it.

Media has also reported that few world's largest animal drug companies have been accused for supplying antibiotics to Indian farmers although the practice was banned worldwide by the WHO. They claimed to advertise that “antibiotics will make the animals grow bigger and faster,” thus supplying the antibiotics to Indian farmers, and also reported that antibiotics, when used properly for approved indications and under the supervision of a veterinarian, do not pose a threat to public health. Even, over-the-counter prescriptions is a common practice in India which could be dangerous. It was found that veterinary drug stores in India were selling antibiotics to fatten the animals without a prescription. In addition, Neftin-T which has been in sale in India contains an antibiotic tylosin. This is believed to enhance weight and feed conversion ratio. Tylosin as a growth promoter was banned by the EU in 1998 because of the fear of erythromycin resistance. The WHO classifies erythromycin as critically important as it is commonly used to treat chest infections. Media has also reported cases where few pharmaceutical companies have been found supplying colistin to farmers for making the chickens grow faster without a prescription. Furthermore, in India, at few places, the shopkeepers were found to sell the antibiotics loosely in a polythene bag without any details such as date of manufacture, date of expiry, or cost.

India has been under severe international pressure, with the reason being a drastic increase in the emergence of superbugs. Keeping in mind the current scenario and challenges faced, the FSSAI in the year 2018 decided to fix “tolerance limits” for antibiotic use in animal food such as meat, eggs, seafoods, and milk. Apart from the medical fraternity, proposed regulations involve participation of veterinarians and animal handlers to make sure that the products produced by them are drug free before marketing them for consumption. The FSSAI also highlights the imposition of drug withdrawal period for the animals or the products treated with antibiotics before they are marketed for human consumption. Drug withdrawal period ensures that the antibiotic residues are swept away from the animal body, making it fit for human consumption. The new regulation will also involve surprise inspections and sampling at random intervals to ensure that the products do not contain residues of antibiotics beyond the permissible level. The FSSAI also insists on maintaining a manual of the antibiotics and identification of a list of chemicals that are found in animal products as residues. This will help in proper designing of interventions to overcome the challenges faced in the current scenario. There is a need to control the usage of antibiotics in animal food sectors and aquaculture and prevent pollution of environment. The measures mainly include establishment of nationwide surveillance systems with close monitoring of antibiotic usage; adequate allocation of funds in implementing such measures; educating farmers, veterinarians, and consumers regarding the threat of misuse of antibiotics and subsequent consequences; avoiding nontherapeutic use of antimicrobials in animals; maintenance of proper hygiene and sanitation; prohibition of usage of critically vital antibiotics in animal food sectors; and promotion of usage of alternative growth promoters wherever necessary.


  Alternatives to the Usage of Antimicrobials Top


The main focus of alternatives is to retain low mortality rate, obtain better animal yield, and protect both the environment and humans from the devastating effects arising from the inadvertent use of antibiotics. Scientists are working hard to search for substitutes to the antibiotics, which include natural agents such as prebiotics, probiotics, organic acids, enzymes, bacteriophages, bacteriocins, nanoparticles, essential oils, and phytogenic feed additives (PFAs) derived from various plants, herbs, and spices. Toghyani et al. in their study showed that PFAs had a positive effect on growth and improvement in immune system and promoted broiler chicken's growth. Beneficial effects were also seen with cinnamon oil.[11] Few nanoparticles such as silver, copper, and oxidized metals were shown to exhibit antimicrobial action, which could be beneficial when used in animal feeds.[12] Further research regarding the combinations of various alternatives so as to obtain maximum yield with minimal risk of infections is lacking. Recent advancement in the field of biotechnology has led to the development of CRISPR/Cas gene-editing technology. With the help of this technology, virulence factors and drug-resistant genes can be specifically targeted, and thus there is capability to kill a bacterium based on genetic sequence. The prime benefit is that commensals would be spared, thus maintaining an ecological balance and preventing the emergence of resistant strains.[13]

Other methods include antibiotic conjugates which are used along with antibiotics to enhance their activity, as antimicrobials in natural form have drawbacks associated with their bioavailability and efficacy.[14] Vaccinating humans as well as animals is also an effective approach to avoid them from infections, and thus the need for antibiotics. Extensive research is being carried out on the use of DNA and RNA vaccines. These advances in vaccine technology have helped in producing high and sustained antibody titers in animals. However, further studies are essential to evaluate the safety and efficacy of such vaccines before they are employed in livestock production and poultry. The burden of AMR can be compared to a “tip of iceberg” where a major submerged portion still remains unexplored due to lack of adequate monitoring systems and inadequate data. Therefore, it is our duty to join hands together to say no to antibiotics unless indicated and use them within their permissible levels. Because if not done today, our future generation would be in a “World without Antibiotics” where treating even common conditions would become difficult.



 
  References Top

1.
Van Boeckel TP, Brower C, Gilbert M, Grenfell BT, Levin SA, Robinson TP, et al. Global trends in antimicrobial use in food animals. Proc Natl Acad Sci U S A 2015;112:5649-54.  Back to cited text no. 1
    
2.
Islam MM, Anjum S, Modi RJ, Wadhwani KN, Husbandry A, Vidyanagar V. Scenario of livestock and poultry in India and their contribution to national economy. Int J Sci Environ Technol 2016;5:956-65.  Back to cited text no. 2
    
3.
Swann M. Report of the Joint Committee on the Use of Antibiotics in Animal Husbandry and Veterinary Medicine. London, United Kingdom: Her Majesty's Stationery Office; 1969.  Back to cited text no. 3
    
4.
Bates J, Jordens JZ, Griffiths DT. Farm animals as a putative reservoir for vancomycin-resistant enterococcal infection in man. J Antimicrob Chemother 1994;34:507-14.  Back to cited text no. 4
    
5.
Price LB, Graham JP, Lackey LG, Roess A, Vailes R, Silbergeld E. Elevated risk of carrying gentamicin-resistant Escherichia coli among U.S. poultry workers. Environ Health Perspect 2007;115:1738-42.  Back to cited text no. 5
    
6.
Ho PL, Wong RC, Lo SW, Chow KH, Wong SS, Que TL. Genetic identity of aminoglycoside-resistance genes in Escherichia coli isolates from human and animal sources. J Med Microbiol 2010;59:702-7.  Back to cited text no. 6
    
7.
Khurana A, Sinha R, Mouna N. Antibiotic resistance in poultry spread of resistance from poultry farm to agricultural field. Cent Sci Environ 2017; p. 1-36.  Back to cited text no. 7
    
8.
Ghafur A, Shankar C, GnanaSoundari P, Venkatesan M, Mani D, Thirunarayanan MA, et al. Detection of chromosomal and plasmid-mediated mechanisms of colistin resistance in Escherichia coli and Klebsiella pneumoniae from Indian food samples. J Glob Antimicrob Resist 2019;16:48-52.  Back to cited text no. 8
    
9.
Qumar S, Majid M, Kumar N, Tiwari SK, Semmler T, Devi S, et al. Genome dynamics and molecular infection epidemiology of multidrug-resistant Helicobacter pullorum isolates obtained from broiler and free-range chickens in India. Appl Environ Microbiol 2017;83. pii: e02305-16.  Back to cited text no. 9
    
10.
Gilbert JM, White DG, McDermott PF. The US national antimicrobial resistance monitoring system. Future Microbiol 2007;2:493-500.  Back to cited text no. 10
    
11.
Toghyani M, Toghyani M, Gheisari A. Evaluation of cinnamon and garlic as antibiotic growth promoter substitutions on performance, immune responses, serum biochemical and haematological parameters in broiler chicks. Livest Sci 2011;138:167-73.  Back to cited text no. 11
    
12.
Gangadoo S, Stanley D, Hughes RJ, Moore RJ, Chapman J. Nanoparticles in feed: Progress and prospects in poultry research. Trends Food Sci Technol 2016. [doi.org/10.1016/j.tifs. 2016.10.013].  Back to cited text no. 12
    
13.
Bikard D, Barrangou R. Sciencedirect using CRISPR-Cas systems as antimicrobials. Curr Opin Microbiol 2017;37:155-60.  Back to cited text no. 13
    
14.
Walsh TR, Wu Y. China bans colistin as a feed additive for animals A hepatitis B-free generation in China: From dream to reality. Lancet Infect Dis 2016;16:1102-3.  Back to cited text no. 14
    




 

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