Abstract
Antibiotics are used in human medicine to treat infections, as prophylaxis to prevent infections post surgery/trauma and in food producing animals, to treat infections and at suboptimum dose level as performance promoters. Up to 50% of all the antibiotics prescribed in human medicine are not needed or are not optimally effective as prescribed. The microbes express ways of resisting the antibiotics used. The antibiotic residues in a small sample of broilers in New Delhi NCR are at much lower levels than prescribed by EU union. There is little to no evidence to support the claim that the use of antibiotic feed additives in animals feeds has contributed to the problem of antibiotic resistance in human medicine. The EU banned the use of various antibiotic feed additives at levels labeled for growth promotion. Almost immediately a surge of enteric disease problems in food-producing animals followed. Herbal antibiotic preparations are available (eg. Herbiotic FS – a poly herbal preparation, having antimicrobial activity). A bacterium multiresistant is called a superbug or super bacteria. The recently discovered antibiotic from the screening of uncultured bacteria, is the teixobactin.
Antibiotics misuse and over use have to be stopped to zero level in human medicine. Antibiotics are to be used in food producing animals for therapeutic purposes as are being used in human beings. Certain antibiotics may be identified which are not used in humans for therapeutic purposes, but may be used for performance promotion purposes. Herbal antibiotics with proven efficacy may be approved for performance improvement and therapeutic purposes in poultry.
Introduction
Antibiotics are being widely used in human and veterinary medicine since more than 65 years, with benefit to both human and animal health. Antibiotic is a drug, naturally occurring, semi-synthetic or synthetic, that inhibits the growth or destroy microorganisms that cause disease in humans, animals, or plants (IFT, 2006). Antibiotics are used in human medicine to treat infections and as prophylaxis to prevent infections post surgery/trauma. In food producing animals, antibiotics are used to treat infections as in human medicine and at suboptimum dose level as performance promoters. Several physiological, nutritional and metabolic effects are ascribed to antibiotic performance improvement additives (Table 1). A general feeling exists in the animal feed/food industry that the gains that have been made in food production would not have been possible without the use of antibiotics as growth promoters to contain the threat of disease to animals. With proper management and gut health maintenance, it is possible to maintain poultry on antibiotic free diets with the best performance possible. In experimental diets, more than 2.6 kg body weight with about 1.7 FCR and not more than 4% mortality was obtained in broilers 1-42 days age. The World Health Organization stated, “Antimicrobials are vital medicines for the treatment of bacterial infections in both humans and animals. Antimicrobials have also proved to be important for sustainable livestock production and for the control of animal infections that could be passed on to humans” (USFDA, 2014). The benefit to human health in the proper use of antibiotics in food animals is related to the ability for these drugs to combat infectious bacteria that can be transferred to humans by either direct contact with the sick animal, consumption of food contaminated with pathogens from animals, or proliferation into the environment.” As poultry veterinarians and scientists, our challenge is to help poultry producers to understand the issues and implement effective controls for the benefit of both the poultry industry and society.
Antibiotic Resistance
The microbes express ways of resisting the antibiotics used. Resistance may be defined as the temporary or permanent ability of a microorganism and its progeny to remain viable and/or multiply under conditions that would destroy or inhibit other members of the strain (Cloete, 2003). Microorganisms have been present on this planet for about 4 billion years, and for much of that time have been engaged in intensive interaction (including predation, competition, and cooperation) and antimicrobials are sometimes produced in the process. It is therefore entirely to be expected that resistance to various antimicrobials will occur in natural microbial populations without our intervention. Alexander Fleming (1945) in his noble prize lecture on 11 Dec 1945 warned of the danger of resistance: “It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them, and the same thing has occasionally happened in the body and by exposing the microbes to non-lethal quantities of the drug make them resistant” (See Tadvi 2012). For any antibiotic sooner or later after its invention, antibiotic resistance occurs (Table 2). It is difficult to treat the infections with resistant organisms, requiring costly and sometimes toxic alternatives. It is always essential to be aggressive in keeping resistance developing and to prevent the resistance developed from spreading (CDC, 2013). In India, national estimates of antibiotic resistance are not available (CSE, 2014), but for most of the common antibiotics, the % resistance of many organisms is high (The Table 3).
Antibiotic resistance is a worldwide problem. The use of antibiotics is the single most important factor leading to antibiotic resistance around the world. Antibiotics are among the most commonly prescribed drugs used in human medicine. However, up to 50% of all the antibiotics prescribed for people are not needed or are not optimally effective as prescribed CDC, 2013). Antibiotics are also commonly used in food animals to prevent, control, and treat disease, and to promote the growth of food-producing animals. The use of antibiotics for promoting growth is not necessary, and the practice should be phased out (CDC, 2013).
The antibiotic overuse and misuse in humans and animals is the single most important cause of emergence and spread of antibiotic resistance. In fact, globally more antibiotics are used in animals than humans; in the US 80% used in animals. In India, poultry and fishery industry consumes a significant proportion of total antibiotics used, but data is not available (CSE, 2014).
The bacteria of concern from a human health standpoint are Campylobacter spp., Salmonella spp., and Enterococcus spp. None of the bacteria are of significant clinical concern in poultry flocks (i.e., very few clinical diseases are caused by them). However, at any time the antibiotic treatment is performed, these organisms are exposed to the antibiotic, and resistance can develop as a consequence of this exposure. Antibiotic resistance is a natural phenomenon that occurs when bacteria are exposed to antibiotics but also occurs without antibiotic exposure in the case of inherent resistance. The use of antibiotics in animals and humans has accelerated the rate of resistance development by increasing selection pressure placed against both pathogenic and nonpathogenic bacteria. When poultry are treated with antibiotics, it affects both target and nontarget bacteria, and resistance in both classes of bacteria may develop. Resistance development occurs by the exchange of extra-chromosomal DNA called plasmids and through genetic or chromosomal changes within the bacteria. Plasmid-mediated resistance can occur within or between the same or different populations of bacteria. There are, essentially, 3 routes by which animal use of antimicrobials can affect public health (Guardabassi et al., 2008).
Increased prevalence of resistance genes in zoonotic bacterial pathogens with transfer directly (to farm visitors, farm staff and veterinarians) or, through inadequate food hygiene, to susceptible humans.
Increased prevalence of resistance genes in commensal bacteria, again with either direct or indirect transfer, via food, to humans, or subsequent transfer of these genes into pathogens.
Contamination of the environment with residues of antimicrobials through disposal of carcasses, or litter, such that pathogens or commensals are exposed to selection and reach the human population directly or indirectly through pets and farm animals.
Antibiotic Residues
Antibiotics given to food producing animals (eg poultry) are found in tissues. A withdrawal period is suggested to get the residues to a safe level, for human consumption. This is termed as maximum residue level (MRL). European Union prescribed stringent standards than many other countries (eg US) (Table 4).
CSE (2014) studied the antibiotic residues (oxytetracycline, chlortetracycline, doxycycline, enrofloxacine and ciprofloxacine) in the chicken samples in Delhi NCR (National capital region). Chicken from all the parts of NCR tested contained antibiotic residues in muscle, liver and kidney (Table 5). This is a serious issue. However, the antibiotic residues are at lower levels than prescribed by EU union. Yet the guide lines suggested may be followed for the antibiotics to be given for producing animals for performance improvement.
Maximum Residue Limits (MRLs) and Food Safety
Whether the antibiotics are used for therapeutic purpose or for growth promotion, the withdrawal period specified has to be followed and the MRLs permissible for these antibiotic growth promoters should not be exceeded at any time.
Residues of veterinary medicinal products are “pharmacologically active substances and their metabolites which remain in foodstuffs obtained from animals to which the veterinary medicinal product in question has been administered”. An MRL is the maximum concentration of residue following administration of a veterinary medicine which is legally permitted or acceptable in food. The responsibility for keeping residues under the MRL lies with veterinarians and farmers, using licensed animal medicines. Use of animal medicines is strictly controlled by law, and requires observance of the withdrawal period. This is the time which passes between the last dose given to the animal and the time when the level of residues in the tissues (muscle, liver, kidney, skin/fat) or products (milk, eggs, honey) is lower than or equal to the MRL. Until the withdrawal period has elapsed, the animal or its products must not be used for human consumption.
Withdrawal periods exist so that MRLs are not exceeded and to ensure consumer safety. Accordingly, safety is of paramount importance when both MRLs and withdrawal periods are established. As a result, although residues above the MRL should not occur, even if they do, they generally present no risk to the consumer because of the very large safety margins used in setting the MRL. For example, the calculation of the MRL value is based on the acceptable daily intake (ADI) for the drug in question. The calculation of the ADI includes an extremely large safety factor. In addition, the MRL calculation assumes an average intake per person of 500g of meat, 1.5 litres of milk, 2 eggs and 20g of honey.
Maximum Residue Limits are set considering the safety and residues data. The safety data contains all the pharmacology and toxicology studies carried out with the medicine in laboratory animals. These studies examine what happens to the substance in the body and assess how much can be given safely, without inducing any unwanted adverse effects. The safety data also includes the calculation of the ADI. This is based on results in laboratory animals and particularly on the so-called No-Observed-Effect Level, the dose with no observable effect is the most sensitive test used. The residues data contains all the data concerning the formation, nature, behavior and disappearance of residues after a medicine has been given to a farm animal. Together, the results from the residues data on the quantities and behavior of residues in farm animals, with the ADI derived from the safety data and the theoretical food intakes (500 g meat, 1.5 litres of milk etc) are used to calculate the MRL(s), on the assumption that consumers get the maximum level every day of their lives. The MRLs set by the EU/USA depend on the per capita meat consumption of the concerned countries. The same MRLs will be of little importance in Indian context since the per capita meat consumption in our country is still far below as compared to EU/USA (EMA, FDA 2001, CAC 2012).
EU Ban on Feed Additives in Food producing animals
Cervantes (2005) concluded that “There is little to no evidence to support the claim that the use of antibiotic feed additives in animals feeds has contributed to the problem of antibiotic resistance in human medicine”.
The EU banned the use of various antibiotic feed additives at levels labeled for growth promotion. Almost immediately a surge of enteric disease problems in food-producing animals followed. The surge in enteric diseases of food-producing animals was followed by a surge in antibiotic use in food-producing animals for therapeutic purposes. The antibiotics used to treat food-producing animals belong to the various classes of antibiotics most frequently used in human medicine, this might have actually had a more adverse effect on the creation of antibiotic resistance in people than the use of the antibiotic feed additives. The surge in use of antibiotics for therapeutic purposes in food-producing animals has clearly proven that the prior use of antibiotic feed additives had a health promotional and disease prevention effect in food-producing animals even when used at concentrations labeled for “growth promotion”. Although the antibiotic feed additive bans implemented by the EU achieved the objective of reducing the incidence of resistance on indicator bacteria in raw food products of animal origin, this has not resulted in any measurable improvement on the problem related to antibiotic resistance in human patients or human hospitals. This may be explained by the fact that monitoring of antibiotic resistance in raw meat products is not representative of the bacteria that may actually reach the consumer. Proper cooking of foods of animal origin destroys any bacteria that might have contaminated them, and dead bacteria cannot transmit antibiotic resistance to people. While the incidence of food borne diseases in the USA population has continued to decline, in the EU it has continued to increase, at least for certain bacteria like salmonella, campylobacter and C. perfringens. Therefore, it is becoming increasingly apparent that the bans on antibiotic feed additives have not resulted in a safer food supply (Cervantes, 2005).
Herbal Antibiotics
Herbal antibiotic preparations are available. One such preparation is Herbiotic FS, a poly herbal preparation, having antimicrobial activity (Table6 and 7).
Super bugs
Bacterial genes can be transferred between bacteria in horizontal fashion by conjugation, transduction or transformation. A gene for antibiotic resistance which had evolved via natural selection may be shared. Many antibiotic resistance genes reside on plasmids, facilitating their transfer. If a bacterium carries several antibiotic resistance genes it is called multiresistant or informally a superbug or super bacteria (Gaikwad, 2010). New Delhi Metallo-beta-lactamase-1 (NDM-1) is an enzyme that makes bacteria resistant to a broad range of beta-lactam antibiotics. These include the antibiotics of the carbapenem family, which are a mainstay for the treatment of antibiotic-resistant bacterial infections. The gene for NDM-1 is one member of a large gene family that encodes beta-lactamase enzymes called carbapenemases. Bacteria that produce carbapenemases are often referred to in the news media as “superbugs” because infections caused by them are difficult to treat. Such bacteria are usually susceptible only to polymyxins and tigecycline. NDM-1 was first detected in a Klebsiella pneumoniae isolate from a Swedish patient of Indian origin in 2008. It was later detected in bacteria in India, Pakistan, the United Kingdom, the United States, Canada and Japan. The most common bacteria that make this enzyme are Gram-negative such as Escherichia coli and Klebsiella pneumoniae, but the gene for NDM-1 can spread from one strain of bacteria to another by horizontal gene transfer (See wikipedia.org/wiki/New_Delhi_metallo-beta-lactamase_1).
A recent discovery of a new antibiotic from the screening of uncultured bacteria, after a long time, is the teixobactin. The teixobactin inhibits cell wall synthesis by binding to a highly conserved motif of lipid II (precursor of peptidoglycan) and lipid III (precursor of cell wall teichoic acid). The mutants of Staphylococcus aureus or Mycobacterium tuberculosis resistant to teixobactin were not obtained. The properties of this compound suggest a path towards developing antibiotics that are likely to avoid development of resistance (Ling et al., 2015).
Strategies to reduce or minimize antibiotics in food producing animals
The serious nature of antibiotic residues concerns us to have strategies to reduce the antibiotic residues in food producing animals. Several strategies are possible. The following may be considered for discussion.
1. Antibiotic misuse and over use has to be stopped to zero level in human medicine.
2. Antibiotics are to be used in food producing animals for therapeutic purposes as are being used in human beings.
3. Certain antibiotics may be identified which are not used in humans for therapeutic purposes may be used for performance promotion purposes. A list of such products approved by FDA is given in Table 8.
4. Herbal antibiotics with proven efficacy may be approved for performance improvement and therapeutic purposes in poultry.
5. Water quality and management practices have to be improved to reduce microbial burden.
Several additives (Antioxidants, Vitamins, Trace minerals (organic), acidifiers, enzymes, immunostimulants, pre and probiotics, herbal additives, essential oils) may be considered for improving the well being and immune status of poultry.
Possibility of Implementation
The restriction of the antibiotic types for poultry if carried with all the strategies may yield good results. Can we implement it effectively? Pesticides in bottled water, in blood of punjab farmers, transfats in edible oils, antibiotics in honey, high salt, sugar and transfats in junk food, were reported in our country (CSE, 2014). Artificial milk (prepared with urea, animal fat) and vegetable oils mixed with animal fats extracted from dead animals are being marketed? How many organizations/persons have been prosecuted for these?
*References are available on request.
*V R Reddy, Retired Professor, Agricultural University, Rajendranagar, Hyderabad
**M R Reddy, Principal Scientist, Project Directorate n Poultry (ICAR), Rajendranagar, Hyderabad
