Antibiotic Use And Resistance In Food Animals Biology Essay

Executive Summary

This report contains an introduction to veterinary antibiotic use, resistance and why we should be concerned. It reviews the most recent literature discussing veterinary antibiotic use and resistance patterns in India. Following this is an overview of the current laws in India, the United States and the European Union with regard to the antibiotic use in food animals. The report concludes with a series of recommendations for reducing inappropriate use of veterinary antibiotics and the spread of antibiotic resistance.

This report was written at the request of the Ministry of Heath & Family Welfare, Government of India, as order number X.19029/07/2011-DFQC. The goal of this report is to summarize the available information on antibiotic use and resistance in food animals, review the current laws on animal antibiotic use in India and other countries, and to suggest policies that could be adopted by the government of India.

Antibiotic Use and Resistance

India is the world’s largest exporter of beef and milk, and the third largest producer of eggs and fish. In 2009-10, livestock and fishery industries were valued at Rs. 4,08,386 crore, of this export earnings from livestock and poultry totaled Rs. 19,036 crore. In 2009, 1.6 lakh livestock animals were reported to have been affected by bacterial infections including salmonellosis and mastitis.

Antibiotics are used to treat bacterial infections in both humans and animals. Antibiotics in food animals are used for prophylactic, therapeutic purposes as well as growth promotion (at sub-therapeutic levels). While all antibiotic use contributes to the development of resistance, inappropriate use by farmers contributes to the problem while reaping no benefit. Resistant bacteria in animals can spread to the human population mainly through the consumption of animal products. There is also weak evidence for the entry of un-metabolized antibiotics into the environment contributing to the spread.

There is little information on antibiotic use and few studies describe antibiotic resistance in India. Most research shows high levels of resistance in all veterinary sectors. More studies are required to determine veterinary antibiotic usage patterns.

Laws

Currently, only few laws exist pertaining to antibiotic use in food animals. The two laws for internal meat, chicken and fish consumption refer to withdrawal periods and maximum residue limits of certain antibiotics for seafood. As India is a major exporter of animals and animal products, there are more laws pertaining to antibiotic use in food animals for export. The creation of new and enforcement of existing laws, could slow down the spread of antibiotic resistance in both animal and consequently human populations.

Policy Recommendations

The report suggests that changes be made through improving animal hygiene and living conditions, monitoring antibiotic use and resistance patterns through the setting up of a surveillance system and educating veterinarians and farmers on appropriate use of antibiotics. Subsidies and alternatives to antibiotics can help provide an incentive for farmers to lower their use of antibiotics. As little is known about the situation in India, more research is needed to paint a full picture. Funding for research and development on veterinary specific drugs that are not used in humans could also help reduce the spread of antibiotic resistance in humans. Lastly, but perhaps most importantly without new appropriate laws, and the enforcement of current laws, little progress will be made.

CHAPTER 1: Antibiotic Use and Resistance

A little more than seventy years ago, the first human infection was cured by penicillin. In the ensuing decades, antibiotics have tamed many bacterial illnesses that were once deadly to humans. The same is true with respect to agricultural animals: antibiotics have been a boon for treating and preventing their diseases.

Unfortunately, the story does not end there. Antibiotic use – both life-saving and unnecessary, and in humans and animals alike – has led bacteria through a natural course of evolution whereby they become resistant to the drugs that were developed to fight them. These antibiotic-resistant bacteria can infect both humans and animals, sometimes traveling from one to the other, both within and across national borders.

Antibiotic resistance is a global problem, but actions at the national and local levels can slow and even reverse the spread of antibiotic-resistant bacteria, thereby slowing the loss of antibiotic effectiveness over time. Although antibiotic use in humans contributes to the problem of resistance, a significant proportion of antibiotic use, hence resistance, is due to use in animals both for treating illnesses and for the purpose of "growth promotion" – the addition of a very low dose of antibiotics to animal feed, which makes animals put on weight more quickly than they would without the antibiotics. Countries in Europe and elsewhere in the world have regulated the use of antibiotics for growth promotion, and forces in the United States are pushing toward this goal. However, in much of the developing world, antibiotic use for growth promotion in farm animals is rising and threatens the effectiveness of the most affordable first-line drugs.

The Use of Antibiotics in Food Animals

No reliable estimates of the amount of antibiotics used in livestock in India are available, but it may be more than the amount used in humans, judging from practices in other countries. The main uses of antibiotics in animal are for prevention and treatment of disease. Therapeutic use is defined as the use of antibiotics to treat an infection caused by pathogenic bacteria. Non-therapeutic use includes prophylaxis (also referred to as "metaphylaxis") and growth promotion.

Antibiotics are used prophylactically, often continually, to prevent disease in herds or flocks. In crowded, dirty conditions, disease outbreaks can occur quickly and become deadly. Farmers may use antibiotics in place of improving sanitation and to allow more animals to be kept in smaller spaces. Antibiotic prophylaxis is also used pre- and post-surgery, prior to transportation, and at other times when animals are under stress, to prevent respiratory and intestinal ailments, and as "dry cow therapy" (antibiotic treatment between lactation periods to reduce the high risk of infection) (Michigan State University, 2011a). In aquaculture, antibiotics are used therapeutically and prophylactically—often in high concentrations due to the ease with which bacteria travel in water—but not for growth promotion

In livestock and poultry, antibiotics used for growth promotion are added to animal feed in low, sub-therapeutic doses. The observation that small doses of antibiotics could increase the rate of weight gain was first noted in the 1940s and the practice gained widespread use beginning in the early 1950s. The reason why antibiotics work to promote growth is not well understood, but a number of hypotheses have been put forward (Hughes & Heritage, 2004).

Antibiotic Resistance and its Spread

The development of bacterial resistance arises in two ways: (i) intrinsic resistance, which occurs when the bacterial species is able to innately resist the activity of an antibacterial agent (by preventing either the entry or binding of the antibacterial agent); and (ii) acquired resistance, which occurs when once susceptible bacterial species mutate or obtain genes from other bacteria, to acquire resistance (Figure 1). The speed at which bacteria multiply, as well as their exposure to a continuously changing environment, results in the development of naturally occurring mutations that reduce their sensitivity to antibiotics. Bacteria are also able to adapt to their environment by acquiring genetic material through plasmids and transposable elements from other species of bacteria. This is known as horizontal gene transfer (Serrano, 2005).

The use of antibiotics can lead to the development and spread of antibiotic resistance. Selection pressure on a bacterial population, such as that from antibiotics, can result in few surviving members who carry resistant genes (Figure 2). These bacteria then multiply, contributing to a growing population of bacteria with antibiotic resistant genes. Bacteria resistant to one type of antibiotic may exhibit resistance to related antibiotics. If robust enough, these bacteria can spread through a human population. "Antibiotic resistance cannot be prevented. Every time antibiotics are used, whether they save a life or are used to no effect (to treat viral rather than bacterial infections, for example), the effective lifespan of that antibiotic and perhaps related drugs is shortened

Multidrug resistant bacteria are resistant to more than two types of antibiotics. An example of this is methicillin-resistant Staphylococcus aureus (MRSA), which is resistant to all ß-lactam antibiotics including the penicillin and cephalosporin classes. Livestock are known to harbour MRSA, and these bacteria move easily to humans in close contact with infected or colonised animals. As animals infected by MRSA are often asymptomatic, the transfer of Livestock-Associated MRSA (LA-MRSA) to humans can go unnoticed

An instructive example of how using one antibiotic in animals can have a dramatic effect in humans involves the drugs avoparcin and vancomycin. Vancomycin is a last resort antibiotic, reserved for treating MRSA and other resistant infections. Avorparcin, an animal antibiotic related to vancomycin, was used for growth promotion in Europe. In the years following the introduction of avoparcin as a growth promoter, the increased use of avoparcin led to an increase in vancomycin-resistant enterococci (VRE) in humans. As a result, avoparcin is now banned in the European Union

Widespread resistance to antibiotics means that infections that were once easily treatable can become deadly (e.g., just over 30 percent of neonatal sepsis deaths in India are attributable to antibiotic resistance. This is of special concern to India, where the burden of infectious diseases is high and health care spending is low. In addition to causing increased morbidity and mortality, resistant infections are more expensive to treat than sensitive ones, often requiring longer hospital stays and pricier

Perhaps the most infamous antibiotic resistance gene is New Delhi metallo-ß-lactamase-1 (NDM-1). NDM-1 was first isolated from Klebsiella pneumoniae from a patient in 2008. The patient’s infection was resistant to all available antibiotics, including carbapenems, a class of antibiotics used as a last resort for highly-resistant infections The NDM-1 gene is carried on plasmids and can be transferred among a wide variety of bacterial species. It confers broad resistance to most antibiotics, including carbapenems (Deshpande et al., 2010). Since its discovery, NDM-1 has been found around the world, including major cities in India.

Uses of Antibiotics in Humans and Animals

The World Health Organization (WHO) defines three categories of antibiotic for human use: critically important, highly important and important (WHO, 2011). The criteria used by the WHO to classify antibiotics are:

An antimicrobial agent which is the sole, or one of limited available therapy, to treat serious human disease.

Antimicrobial agent is used to treat diseases caused by either: (1) organisms that may be transmitted to humans from non-human sources or, (2) human diseases caused by organisms that may acquire resistance genes from non-human sources.

Antibiotics classified as critically important meet both criteria, highly important antibiotics meet either criterion 1 or 2, and important antibiotics meet neither but are considered essential. Tables 1-3 list these antibiotics, noting their use in humans and in animals for therapy, prophylaxis and growth promotion. The tables (are not inclusive of all antibiotics, but provide examples in each class.

Reservoirs

Antibiotic resistance genes can be transferred from animals to humans through contaminated soil and water, and through animal food products, such as milk and meat (figure 3)

Food Animals

Antibiotic use in animals, as in humans, creates selective pressure for resistant bacteria in the animal gut. In some cases, drug-resistant strains can move directly between humans and animals. In a recent example, an emerging strain of MRSA (clonal complex 398) originated in humans, was transmitted to pigs (where resistance emerged), and then transferred back to humans who were in close contact with the animals. Other cases in which farmers have acquired strains of bacteria resistant to the antibiotics used in their animals are reviewed by Van den Bogard and Stobberingh .

Consumption of animal food products and exposure to bacteria through animal-contaminated soil and water are also routes by which humans acquire antibiotic resistance genes.

Terracumulation and Antibiotics in Water

Terracumulation refers to the buildup of pollutants (including antibiotics) in soil over time and can happen as a result of the excretion of unmetabolized antibiotics given to animals (Rooklidge, 2004). Feces of antibiotic-fed livestock can contain unmetabolized antibiotics, which are then introduced to the soil and water. A study by Subbiah et al. found that ceftiofur used in animal feed can be responsible for selection of resistant Escherichia coli in contaminated soil .

Antibiotics and resistant bacteria entering water are also a concern, as the aquatic environment is thought to be the largest reservoir for antibiotic resistant genes (The Norwegian School of Veterinary Science, 2012). A recent study found antibiotic-resistant bacteria in fish that had not been subjected to treatment with antibiotics. The authors proposed that antibiotic residues from domestic farm and poultry waste are responsible for the presence of resistant bacteria.

Furthermore, antibiotics that enter soil and water can have damaging effects on the environment by killing off beneficial soil and water microbes. This shift in ecological contamination often goes unmonitored, and may not be realized until important aspects of the ecosystem are already damaged.

Some Aspects of Indian Livestock and Aquaculture Farming

Scale of Food Animal Farming

India is a top producer and exporter of animal meat and products. The Food and Agricultural Organization of the United Nations estimates that in 2011 there were 32.3 crore cattle and buffalo and 96.8 crore poultry birds in India. India was the world’s top beef exporter in 2012 and India’s share of the world’s beef exports is expected to rise from 20 percent to almost a quarter in 2013. Almost 4.2 lakh tonnes of beef are predicted to be produced in India in 2013, of which less than half will be consumed in India.

In 2006-2007, 10 crore tonnes of milk were produced, making India the largest producer of milk in the world (Ministry of Agriculture [Department of Animal Husbandry, Dairying & Fisheries], 2011). India was the third largest producer of eggs in 2009-2010 with production of 5980 crore eggs per year (Ministry of Agriculture [Department of Animal Husbandry Dairying & Fisheries], 2011). 34 lakh tonnes of broiler meat is produced, almost of all of which is consumed domestically (USDA, 2012). Fish production has almost doubled in the last 10 years, and India is now the third largest producer of fish, producing 78 lakh tonnes of fish per year rying &ndof Paleontology Understanding Science Website. Retrieved Dec 15, 2013.

Economically, the livestock and fisheries department contributes to almost 30 percent of the annual earnings of the agriculture and allied sector. The fishery industry provides jobs for 14 million Indians. The value of the livestock and fisheries component during the 2009-10 fiscal year was Rs.4,08,386 crore. Of this, Rs. 3,40,473 crore came from the livestock sector and Rs.67,913 crore from fisheries. From livestock and poultry products alone, the total export earnings were Rs.19,036 crore rying &ndof Paleontology Understanding Science Website. Retrieved Dec 15, 2013. (Ministry of Agriculture [Department of Animal Husbandry, Dairying & Fisheries], 2011).

The latest livestock and poultry census conducted in 2007 reveals that Tamil Nadu and Andhra Pradesh had the most poultry and Madhya Pradesh, Uttar Pradesh and West Bengal had the most beef cattle, while Uttar Pradesh was home to the largest number of buffalo. In 2007, there were 59,826 poultry farms in India, of which more than 90 percent were in rural areas. Tamil Nadu and Andhra Pradesh had the most fowl, followed by West Bengal and Maharashtra. There were about 4.1 crore dairy cattle in 2007, most of which were in rural areas. States with the most dairy cattle were Uttar Pradesh, Rajasthan, West Bengal and Tamil Nadu. In 2009-10 Andhra Pradesh and West Bengal had the greatest fish production and the most fishing villages were in Orissa and Tamil Nadu followed by Andhra Pradesh and Maharashtra. (Ministry of Agriculture [Department of Animal Husbandry, Dairying & Fisheries], 2011).

Though there are a large number of food animals in India, most are raised on small farms with a handful of livestock each. Most of the farms are in rural and peri-urban areas (Shah Hossain, personal communication, January 11, 2013). While some commercial poultry farms, dairy, goat and pig farms exist, the majority of farming in India does not occur industrially. The most common types of livestock rearing are either mixed crop-livestock or pastoralism, neither of which are high volume operations.

Animal Health and Government Initiatives

Bacterial infections make up a significant proportion of animal illnesses. The reported number of bacterial infections in Indian livestock is summarized in the 2010-2011 report by the Department of Animal Husbandry, Dairying & Fisheries. In 2009, 120,923 Indian livestock animals had salmonellosis (7,129 died), 26,333 were affected by mastitis, 3,729 suffered from haemorrhagic septicaemia (1,595 died), 1109 were affected by black quarter (481 died) and 94 fell ill from brucellosis. In addition, enterotoxemia caused by Clostridium perfringens killed 533 animals and affected 2,167. These numbers may be underestimated, as reporting levels are unknown. (Ministry of Agriculture [Department of Animal Husbandry, Dairying & Fisheries], 2011).

In order to mitigate the loss that farmers can incur as a result of a disease outbreak, the government has taken several initiatives. In 2008, they began offering livestock insurance in 300 districts to compensate against animal deaths. In addition, the government set up six quarantine centers. Imported animals found to be diseased are moved to one of six quarantine stations, located in New Delhi, Chennai, Mumbai, Kolkatta and airports in Hyderabad and Bangalore (Ministry of Agriculture [Department of Animal Husbandry, Dairying & Fisheries], 2011).

In 2010, the government expanded the Centrally Sponsored Scheme to involve:

Assistance to States for Control of Animal Diseases (ASCAD) – an organization responsible for immunizations, strengthening existing state run biological production units and diagnostic laboratories, and providing training to veterinarians and para-veterinarians. The organization is also responsible for reporting incidence rates of livestock and poultry diseases to the World Animal Health Organization (OIE) twice a year.

National Project on Rinderpest Eradication (NPRE)

Professional Efficiency Development (PED), a regulatory organization for veterinary practitioners

Foot and Mouth Disease Control Programme (FMD-CP)

National Animal Disease Reporting System (NADRS) –a new computerized reporting system.

National Control Programme on Peste des Petits Ruminants (NCPPPR)

National Control Programme on Brucellosis (NCPB) – mass vaccination program completely funded by the government.

Establishment and Strengthening of Veterinary Hospitals and Dispensaries (ESVHD) (responsible for improving the current infrastructure of veterinary clinics and hospitals)

(Department of Animal Husbandry, Dairying and Fisheries, 2011)

Furthermore, the government invested Rs. 28.2 crore in veterinary vaccines from 2009 – 2010, issued by the ASCAD. Most vaccines are manufactured within India, with 21 public veterinary vaccine production units and 7 private producers. The government has recently given the responsibility for ensuring vaccine quality to the Choudhary Charan Singh National Institute of Animal Health. In addition, there are currently 250 disease diagnostic laboratories in place for microbiological testing (Ministry of Agriculture [Department of Animal Husbandry, Dairying & Fisheries], 2011).

In 2011, the Ministry of Health and Family Welfare released the National Policy for Containment of Antimicrobial Resistance. This policy encourages the development of regulations for antibiotic use in food animals, appropriate food labeling, and banning non-therapeutic uses of antibiotics in animals. The development of an inter-sectoral committee and the creation of this report were also recommended. (Directorate General of Health Services, 2011)

 

The 2012 Chennai Declaration – a roadmap to tackle the challenge of antimicrobial resistance, was developed at the annual conference of the Clinical Infectious Disease Society and outlined the following needs:

to evaluate the extent of antibiotic usage in the veterinary practice and the indications of use (Prophylaxis, treatment, or growth promoter)

to regulate antibiotic usage in the veterinary practice

to ascertain and monitor the prevalence of resistant bacteria, especially important zoonotic food-borne bacteria in animals and food of animal origin to quantify the rate of transfer of medically-relevant resistance genes and resistant bacteria from animals to humans.

to regulate monitoring of residues of antibiotics in food of animal origin and study the role of antibiotic residues in food towards development of resistance.

to formulate/implement proper regulations for observance of withholding or withdrawal periods between the use of antibiotics and animal slaughter or milking to avoid residues of antibiotics in milk and meat.

 

An international effort by the Global Antibiotic Resistance Partnership was made through the New Delhi Call to Action on Preserving the Power of Antibiotics in 2011, and signed by the governments of Ghana, Kenya, Mozambique, South Africa and Vietnam. It emphasized the need for a multi-sectorial approach to (Global Antibiotic Resistance Partnership, 2011):

 

prevent bacterial infections and their spread

ensure access to appropriate drug prescribing, dispensing and use

strengthen and enforce regulation to ensure drug quality

implement surveillance for resistance bacteria and for antibiotic use patterns

stimulate R&D for new antibiotics

discourage sub-therapeutic use of antibiotics in animal feed for growth promotion. 

Veterinary Services

There are too few veterinary hospitals/polyclinics (8,732) and dispensaries (18,830) in India to meet the needs of the food industry (Ministry of Agriculture [Department of Animal Husbandry, Dairying & Fisheries], 2011). There are currently no trained veterinary practitioners specializing in aquaculture or fish in the country.

Veterinary hospitals and dispensaries are staffed with veterinarians or para-veterinarians. It takes five years training to become a veterinarian and subsequent registration with the Veterinary Council of India. Becoming a para-veterinarian or a village-based livestock service provider (VLSP) require shorter training periods. VLSPs are usually located in villages and provide basic care including preventative health services. They serve as liaisons between livestock owners and veterinarians

Antibiotic Use

Animal feed containing antibiotics are available over the counter and are also produced by local farmers using their own recipes and formulas. The proportions of store-bought and homemade preparations are unknown. There are no restrictions on the production or distribution of feed containing antibiotics (Nadeem Fairoze, Shah Hossain and JPS Gill, personal communication, January 11 and 17, 2013). Because most cattle are raised on small farms, there are no feed-lots (mass cattle feeding operations that often involve regular feeding of antibiotics) in India.

The situation in aquafarming is slightly different from that in livestock. Antibiotics used in aquaculture are available throughout the country and can be purchased without a prescription. Some laws are in place to control antibiotic production and distribution, but enforcement is inadequate. There are no effective controls on the production, distribution and marketing of antibiotics used in aquaculture. In general feed for aquaculture is not manufactured with antibiotics, but antibiotics are added to feed the farmers based on recommendations from unqualified aquaculture consultants (VI George, personal communication, January 30, 2013).

Conclusion

Continued use of veterinary antibiotics for growth promotion (and other unnecessary uses), given the expected increases in production of animal products, could make untreatable bacterial diseases more common among animals. An even greater concern is the contribution of antibiotic resistant bacteria in animals to increased resistance in humans.

CHAPTER 2: A Review of the Literature on Antibiotic Use and Antibiotic-Resistant Bacteria in Food Animals

The published reports of antibiotic use and bacterial resistance in agriculture in India are summarized in this chapter. The literature covers a number of settings, antibiotics, and bacterial species, but the body of evidence is small in comparison to the size of the agricultural enterprise in India, and in light of the seriousness of the resistance problem. From our review, however, the sum of the evidence suggests high and increasing levels of bacterial resistance in all veterinary sectors. Basic information from all the studies included in this review can be found in Annex tables 4 and 5.

Antibiotic Use

While a number of studies have examined the resistance profiles of bacteria isolated from livestock, poultry, and aquaculture, the frequency of antibiotic use and reasons for use during animal rearing are poorly represented in the published literature. Several researchers have measured antibiotic residues in animals or animal products as a proxy for the level of antibiotic usage, though few have directly administered questionnaires to farmers concerning antibiotic use.

Dairy

Most of the published literature concerns antibiotic use in dairy farming and residues in milk.

In an early study (1985), Ramakrishna and Singh tested raw milk samples in markets in Haryana for streptomycin, which was found in approximately 6 percent of samples (Ramakrishna & Singh, 1985).One decade later, dairy farmers in Hyderabad, Secunderabad, and surrounding villages were surveyed on antibiotic use practices. Among 38 dairy farmers, about half used oxytetracycline to treat diseases such as mastisis and fever. Oxytetracycline residues were found in samples from markets (9 percent) and individual animals (73 percent), while no resides were found in government dairy samples. From interviews with 155 urban and rural farmers, Sudershan and Bhat found that antibiotic use was lower among the farmers in rural areas (20 percent) compared to those in urban areas (55 percent). In addition, these interviews revealed that 87 percent of urban and 38 percent of rural farmers treated their animals without consulting a veterinarian.

A survey completed by the National Dairy Research Institute near Bangalore in 2000 reported that tetracyclines, gentamycin, ampicillin, amoxicillin, cloxacillin, and penicillin were commonly used to treat dairy animals. Mastitis was treated with β-lactams or streptomycin. None of the above studies mentioned antibiotic use for the purpose of growth promotion in dairy farming.

The prevalence of antibiotic residues in milk samples has been reported to be higher in silo and tanker samples than in market and commercial pasteurized milk samples. Two of the five pooled milk samples collected from public milk booths in Assam contained antibiotic residues at high levels (at least 5 μg/ml equivalent of penicillin) and two to six percent of milk samples collected from individual cows, tankers and organized and unorganized farms in southern states were reported to contain antibiotics

In 2010, 11 percent of raw milk samples collected from Delhi and villages surrounding Delhi contained β-lactams and 2 percent contained streptomycin. Other antibiotics, including gentamycin, tetracycline, and erythromycin were not detected (National Dairy Research Institute, 2011). The presence of antibiotic residues in milk is evidence that antibiotics are used in dairy animals from these regions, though details of the frequency, duration, and reasons for use are unknown.

Fisheries

A survey of freshwater fish hatcheries in West Bengal in 2006-2007 reported that oxytetracycline, althrocin, ampicillin, sparfloxacin, and enrofloxacin were used commonly in fish farms both for prophylaxis and treatment. The aquaculturists also reported using ciprofloxacin, enrofloxacin, and other drugs in a few hatcheries to improve larval survival. The authors report that responsible use of antibiotics in the hatcheries is lacking and suggest that the observed usage patterns may contribute to the development of drug resistance.

Poultry

In many countries, antibiotics are commonly added to commercial feed for growth promotion in chickens. Often the amount of antibiotics given is not under the direct control of the farmers, due to premixed antibiotics contained in the feed they purchase. Dr. Mohamed Nadeem Fairoze from the Veterinary College of KVAFS University estimates that in Karnataka, 70 percent of antibiotics used in poultry are for growth promotion, while the remaining 30 percent is for therapeutic use However, we were unable to find documentation of the level of antibiotic use in the poultry sector, either for growth promotion, prophylaxis or treatment.

Antibiotic Resistance

A number of researchers have isolated bacteria from animals or seafood and tested them for resistance to common antibiotics. The levels of resistance reported are consistently high in food animals including livestock, poultry, and fish, and shellfish.

Bovines

Several studies have reported resistance profiles of bacteria isolated from sick cattle and buffalo. In 2003, Escherichia coli 0157 was isolated from stool samples collected from adult cattle after slaughter and from diarrhoeic calves in West Bengal. Of the 14 strains isolated, resistance was most frequent against antibiotics commonly used in the region such as nitrofurantoin (57 percent), co-trimoxazole (29 percent), tetracycline (21 percent) and ampicillin (21 percent). Nearly three-quarters of the isolates were resistant to at least one antibiotic, and more than half were multi-drug resistant.

Similarly, a high level of antimicrobial resistance was reported from shiga toxin-producing E. coli isolated from calves with diarrhoea in Gujarat and the Kashmir valley. All of the strains from Gujarat were resistant to at least three antibiotics and almost half were resistant to eight or more of the 11 antibiotics tested. Resistance was ubiquitous for kanamycin and cephalexin and was above 50 percent for seven of the antibiotics.

Isolates of Staphylococcus aureus from milk samples of cows with mastitis were also resistant to a variety of antibiotics. Between 20 percent and 30 percent of isolates from mastitic buffalo were resistant to tetracycline, gentamicin, erythromycin and lincomycin. Similarly, S. aureus isolates from milk samples of mastitic Sahiwal cattle were resistant to streptomycin (36 percent), oxytetracycline (34 percent), and gentamicin (30 percent). Thirteen percent were methicillin-resistant, and these MRSA isolates were significantly more resistant to other antibiotics than methicillin-susceptible isolates. All isolates from the mastitic Sahiwal cattle remained susceptible to vancomycin. Another study on mastitic cattle found that resistance to ampicillin, carbenicillin and oxacillin was near 100 percent for all bacteria tested. Analysis of milk samples and milk products from shops in Mizoram showed similar resistance patterns, with complete resistance against ampicillin as well as high resistance to penicillin (87 percent) and cefotaxime (59 percent) (Tiwari et al., 2011).

Poultry

The level of resistance in Indian poultry is reported to be high for many antibiotics, however resistance to chloramphenicol remains low.

In 1981, a study of fowl from the area around Ludhiana reported that almost all E. coli strains from apparently healthy fowl and about 80 percent from diseased fowl were resistant to chlortetracycline, tetracycline, oxytetracycline, and triple sulphas (Sarma, Sambyal, & Baxi, 1981). In 1995, isolates of Enterococcus from State Duck Farms in Assam showed total resistance to oxytetracycline, chlortetracycline, erythromycin, oleandomycin, lincomycin, and clindamycin. Some strains were also resistant to streptomycin and nitrofurantoin, and high sensitivity remained only for chloramphenicol.

Similarly, all 123 strains of Pasteurella multocida isolated from chicken and other birds (duck, quail, turkey, and goose) from 11 states across India were resistant to sulfadiazine. A majority of isolates were also resistant to amikacin, carbenicillin, erythromycin, and penicillin, with sensitivity to chloramphenicol at 74 percent (Shivachandra et al., 2004). In contrast, only a minority of Campylobacter jejuni strains isolated from healthy chickens in northern India showed resistance to ampicillin and tetracycline (7 percent and 13 percent respectively).

In 2009, several species of bacteria in poultry litter from a farm in Tamil Nadu were screened for resistance to a variety of antibiotics. A majority of isolates were resistant to at least one antibiotic, and resistance was highest to streptomycin (75 percent) and erythromycin (57 percent). Resistance was also greater than 40 percent for kanamycin, ampicillin, tobramycin, and rifampicin. The authors speculate that the high levels of resistance may be due to antibiotic use for growth promotion.

Finally, a study of Salmonella from eggs in South India reported that all strains isolated were resistant to ampicillin, neomycin, polymyxin-B and tetracycline. Lower levels of resistance were recorded for ciprofloxacin, kanamycin, nalidixic acid, and sulphamethoxazole. Multidrug resistance was also reported in Salmonella isolated from poultry in Haryana.

Studies including other livestock

Resistance patterns in Salmonella isolated from livestock have been reported in India since the 1970s, when resistance to streptomycin and tetracycline was substantial, but sensitivity to ampicillin, chloramphenicol, erythromycin, and nitrofurans remained high. In the years since, more studies have investigated the levels of resistance in livestock across the country. A quarter of the E. coli strains isolated from livestock near Lucknow in 1984-1986 were resistant to at least one antibiotic among the nine that were tested, and almost half of these isolates were multidrug resistant. Resistance was most frequent in isolates from sheep and goat diarrhea (82 percent and 100 percent respectively). Similarly, a majority of E. coli strains isolated from bovines, sheep, and poultry in 1992 at the Veterinary Hospital in Lucknow were resistant to one or more of the seven antibiotics tested (M. Singh, Sanyal, & Yadav, 1992). Two recent studies of bacteria from pigs in North East India reported a high prevalence of resistance to many antibiotics in Pasteurella and E. coli isolates.

Singh and colleagues have published several papers reporting drug resistance patterns in Salmonella and Enterococcus isolated from equines (hoofed mammals, such as horses). Almost all Salmonella isolates from horses, donkeys, and mules kept by low-income individuals and from equine farms were resistant to three or more antibiotics. The highest frequencies of resistance were to sulfamethoxazole (91 percent), tetracycline (71 percent), doxycycline (68 percent), furazolidone (66 percent) and colistin (55 percent). Widespread resistance was found in Salmonella isolates from equids in Izatnagar: 100 percent were resistant to at least one antibiotic and 89 percent were resistant to more than one. Resistance was highest to furazolidone (87 percent), sulphamethoxazole (82 percent), and tetracycline (43 percent). Finally, Singh showed that resistance levels of Enterococci isolates from equids were higher in North India than have been seen in the United States and many countries in the EU. Eighty percent of the isolates from the equids studied were resistant to vancomycin and over 99 percent were resistant to at least five of the 19 antibiotics for which resistance was tested. Resistance was highest to cefdinir (97 percent), oxacillin (91 percent), cefotaxime (89 percent), ampicillin (88 percent), cloxacillin (88 percent), cotrimazine (87 percent) and vancomycin (80 percent).

Seafood

Antibiotic resistance in the marine sector has been closely studied in India in comparison with other agriculture sectors. Several studies of Salmonella isolates from fish and other seafood have been conducted. One study from Tamil Nadu found that over 90 percent of Salmonella isolates from fish and crustacean samples from retail outlets were resistant to bacitracin, penicillin, and novobiocin. This study found that many of the antibiotic-resistant isolates originated from poultry, livestock and humans, suggesting transmission of antibiotic-resistant bacteria

In a study conducted in Cochin from 2003 to 2007, half of the Salmonella isolates from seafood were resistant to sulfamethizol. Resistance to carbenicillin and oxytetracycline was also prevalent. Multidrug resistance was detected in two-thirds of isolates, with four out of 256 samples resistant to five drugs.

In 2012, Salmonella isolates from fish and shellfish from markets and fish landing centers in Mangalore were tested for nine antibiotics. Two-thirds were resistant to at least two antibiotics, and a quarter of the isolates were resistant to three drugs or more. A study of Salmonella isolates from fresh water prawns and cuttlefish found no resistance to the 16 antibiotics tested.

Examinations of Vibrio species isolated from seafood have also revealed high levels of antibiotic resistance. In 1988-1989 V. cholerae isolates from finfish, shellfish and crustaceans in southeast India were resistant to 10 of the 13 antibiotics tested. Among the antibiotics tested, the highest levels of resistance were found against tetracycline (50 percent) and sulphadiazine (43 percent).

More recently, V. cholerae isolated from seafood in the same region has showed higher levels of resistance. In a study completed in 2009, resistance to ampicillin, penicillin, streptomycin and bacitracin was 88 percent, 84 percent, 85 percent and 64 percent respectively, while resistance to other antibiotics was present at lower levels (P. A. Kumar et al., 2009).

Similarly, V. parahaemolyticus isolated from finfish in Cochin showed a high level of resistance to ampicillin (89 percent) and streptomycin (89 percent). More than half were also resistant to carbenicillin, cefpodoxime, cephalothin, colistin, and amoxycillin. Most isolates remained susceptible to tetracycline, nalidixic acid, and tetracycline.

Finally, a study of Aeromonas, Pseudomonas, and other bacteria isolated from freshwater fish hatcheries in West Bengal showed high prevalence of resistance to oxytetracycline, nitrofurantoin, and co-trimoxazole. Resistance to multiple antibiotics was observed in 90 percent of the bacteria isolated from catfish hatcheries and 30 percent of the bacteria present in carp hatcheries.

Resistance was widespread in farmed shrimp from the east coast of India between 1999 and 2002. All Vibrio and Aeromonas isolates were resistant to ampicillin and a large proportion were also resistant to chlortetracycline (66 percent) and erythromycin (53 percent). Similarly, E. coli O157:H7 isolates from shrimp collected from retail markets in Cochin were resistant to bacitracin and polymyxin B.

Several other studies of antibiotic resistance in bacteria isolated from the marine sector are similar to the studies summarized here.

CHAPTER 3: Laws Affecting the Use of Antibiotics in Livestock

National and supranational legislative bodies around the world have enacted laws to regulate the use of antibiotics in agriculture. Existing laws in India and for comparison, the European Union (EU) and the United States are reviewed in this chapter.  

Laws aim to limit the amount of antibiotic residue ingested by consumers, to ban the use of certain antibiotics in animals (mainly because they are important for use in humans), and, in more recent laws (particularly those of the EU), to reduce antibiotic use with the aim of slowing the evolution and spread of antibiotic resistant bacteria. In the EU, a critical step in this process was the banning of antibiotic use for growth promotion. India has no such ban.

In addition to laws, the Codex Alimentarius, developed by FAO and the WHO specifies a series of recommendations to "ensure safety and quality in international food trade." The Maximum Residue Limits for Veterinary Drugs in Foods updated in July 2012, recommends maximum residue limits (MRLs) for commonly used veterinary drugs, including antibiotics (Codex Alimentarius Commission, 2012). It includes detailed recommendations for MRLs in specific types of animal tissue for countries to consider when adopting national MRLs.

Laws in India

India has few laws affecting antibiotic use in food animals. Most are concerned with exports and aquaculture. In 2002, S.O. 722(E) amended an order from 1995 to include restrictions for antibiotics in fresh, frozen and processed fish and fishery products intended for export (see annex 3). The amendment includes maximum residue limits for tetracycline oxytetracycline, trimethoprim, and oxolinic acid, and it prohibits the use of certain antibiotics (table 6) in units processing all types of seafood (Ministry of Commerce and Industry [Department of Commerce], 2002).

In 2003, order S.O. 1227(E) prohibited the use of "antibacterial substances, including quinolones" from the culture of, or in any hatchery for producing the juveniles or lavae or nauplii of, or any unit manufacturing feed for, or in any stage of the production and growth of shrimps, prawns or any other variety of fish and fishery products (Ministry of Commerce and Industry [Department of Commerce], 2003a)

In addition to laws restricting antibiotic use in aquaculture for export, the export inspection council of India has requirements for the establishments to process fish & fishery products meant for export. These requirements include procedures for testing for antibiotic residues (Export Inspection Council of India, 2005).

In January 2012, G.S.R. 28(E) required that medicine for treatment of animals state a withdrawal period in the labeling (Ministry of Health and Family Welfare [Department of Health], 2012). The withdrawal period is defined as the time between last administration of the medicine and the entrance of the animal or animal product into the food chain. For medicines with no defined withdrawal period, withdrawal periods in meat/poultry and marine products should be 28 days and 500 degree-days (respectively).

In addition to veterinary specific regulations with respect to antibiotic use, the 2nd amendment of the Drugs and Cosmetics rules (2006), contains a list of 536 drugs that fall under Schedule H. These drugs, which include antibiotics, require by law a prescription for their use (Ministry of Health and Family Welfare [Department of Health], 2006).

Laws that Apply to Exported Animal Products

In 2003, order S.O. 1037(E) amended a 1997 law regulating antibiotic residues in eggs and egg products. Maximum residue limits (MRLs) for antibiotics in food products consider an acceptable daily intake, based on an assumed average daily intake, with a margin of safety. The amendment lists the following MRLs for the indicated antibiotics in egg powder for export (table 7). (Ministry of Commerce and Industry [Department of Commerce], 2003b)

MRLs in exported egg products as of September 9th 2003

Antibiotic

Maximum Residue Limit

Erythromycin

150 μg/kg

Tylosin

200 μg/kg

Lincomycin

50 μg/kg

Neomyciin

500 μg/kg

Colistin

300 μg/kg

Chlortetracycline

200 μg/kg

Tetracycline

200 μg/kg

Spectinomycin

200 μg/kg

Tiamulin

100 μg/kg

Josamycin

200μg/kg

Oxalinic Acid

50 μg/kg

Table 7: The MRLs in exported egg products as of September 9th 2003 (S.O. 1037(E))

In addition to MRLs, this order bans the following antibiotics from feed, treatment or in any stage of production of egg powder for export: chloramphenicol, dimetridazole, metronidazole, nitrofurans (including metabolites of furazolidone (AOZ) and nitrofurazone (SEM)).

Tables 8 and 9 in Annex 3 shows the list of antibiotics prohibited for use in food animals. The minimum required performance limit (MRPL) of the laboratory testing equipment for these antimicrobials is also indicated. India has adopted EU MRLs for antimicrobials in food animal products for export.

The European Commission Decision 2002/657/EC describes detailed rules for method validation within the framework of residue monitoring programs for countries exporting to the EU. National analytical surveillance testing to meet regulatory standards for export is undertaken in public sector laboratories and institutions that export products to the EU (MPEDA, 2012).

Government Agencies Responsible for Antibiotic Use

The Global Antibiotic Resistance Partnership draft report by the Center for Disease Dynamics, Economics & Policy describes government agencies responsible for antibiotic use in India:

Within the Ministry of Agriculture, the Directorate of Marketing & Inspection runs the Agricultural Marketing Information Network (AGMARK). This organisation certifies manufacturers of selected products, including eggs and chilled or frozen raw meat. In the early 2000s, AGMARK began upgrading some of its laboratories to measure antibiotic residues in animal products However, limits on antibiotic residues in animal products are not yet widely established as a part of AGMARK certification

The Drug Controller General of India has responsibility for enforcing regulations related to the use of antibiotics for both humans and animals in India. State Drug Controllers also have some responsibilities . However, the absence of uniform regulations dairy and poultry farming in India poses a serious challenge to the enforcement of rational use of antibiotics. Anecdotal evidence also suggests a general lack of awareness in India about regulations for antibiotic use and an absence of routine testing, making it likely that consumers are receiving products with more than the maximum permissible level of antibiotic residues

Laws in the European Union

In 2006, the EU banned all antibiotic growth promoters. Since the ban of avilamycin, erythromycin, vancomycin and virginiamycin as antibiotic growth promoters in Denmark, antibiotic resistance levels in humans have decreased, suggesting that the agriculture ban has had the desired effect. For example, following the ban on virginiamycin as a growth promoter in 1998, virginiamycin resistance decreased by one-third by 2000 erent ways.. if. In Great Britain the percent of S. typhimurium isolates from calves resistant to tetracycline dropped from 60 percent to 8 percent in the seven years after banning tetracycline for growth promotion

Based on the council regulation established in 1990, (EEC) No. 2377/90, the commission regulation (EU) 37/2010 outlines maximum levels of antibiotics in foodstuffs of animal origin. This commission regulation also includes a list of several antimicrobials that are banned from use in food products because safe levels have not been determined. They are chloramphenicol, dapsone, dimetridazole, metronidazole, nitrofurans (including furazolidone) and ronidazole

In November 2011, the EU put forward a five-year plan to fight against antimicrobial resistance. The plan included 12 recommendations to restrict veterinary use of antibiotics, both new antibiotics and antibiotics that are considered critically important to humans. Other recommendations focused on the "promotion of appropriate use of antimicrobials" and the strengthening of "regulatory frameworks on veterinary medicines." In addition, the commission suggested a new animal health law pertaining to good farming practices to avoid infections and the reduction of antimicrobials in aquaculture, to be implemented shortly

Laws in the United States

The U.S. Food and Drug Administration (FDA) prohibits the extra-label (off-label) use of certain antibiotics in food-producing animals (table 10). Extra-label use in livestock includes using the drug at unapproved dosage levels, as growth promoters, or for disease prevention, and using drugs meant for one species on another (for example, using cephalosporins meant to treat humans on chickens). The use of chloramphenicol for any reason is prohibited.

FDA Prohibited Antibiotics for Extra-Label Use in Food Animals

Chloramphenicol

Nitroimidazoles

Furazolidone, nitrofurazone, other nitrofurans

Sulfonamide drugs in lactating dairy cows (except approved use of sulfadimethoxine, sulfabromomethazine, and sulfaethoxypyridazine)

Fluoroquinolones

Glycopeptides (example: vancomycin)

Cephalosporin (excluding cephapirin) in cattle, swine, chickens, or turkeys

Table 10: Antibiotics prohibited for extra-label use by the FDA as of April 2012

The FDA’s Judicious Use of Medically Important Antimicrobial Drugs in Food-Producing Animals, a new set of usage guidelines for industry, has two specific recommendations. The first urges that antibiotics in animals be used for disease control only, and that large farms should voluntarily stop using antibiotics for growth promotion. The second recommendation states that the use of over-the-counter antibiotics in animals should be limited to use with oversight or consultation of a veterinarian

The FDA has approved only a few antibiotics for use in aquaculture: florfenicol, sulfadimethoxine, ormetoprim, oxytetracycline hydrochloride and oxytetracycline dehydrate