- Email: [email protected]
Antibiotic residues in food animals: Public health concern
CHNAES-00621; No of Pages 5 Acta Ecologica Sinica xxx (xxxx) xxx
Contents lists available at ScienceDirect
Acta Ecologica Sinica journal homepage: www.elsevier.com/locate/chnaes
Antibiotic residues in food animals: Public health concern Zeuko'o Elisabeth Menkem a,b,⁎, Bronhilda Lemalue Ngangom a, Stella Shinwin Ateim Tamunjoh a, Fekam Fabrice Boyom b a
School of Health and Medical Sciences, Catholic University of Cameroon, Bamenda, Cameroon Antimicrobial and Biocontrol agent units; Laboratory for Phytobiochemistry and Medicinal Plants Studies, Department of Biochemistry, Faculty of Science, P.O. Box 812, University of Yaoundé 1, Cameroon b
a r t i c l e
i n f o
Article history: Received 10 September 2018 Accepted 16 October 2018 Available online xxxx Keywords: Antibiotic residues Health hazards Food animals Public health
a b s t r a c t Antibiotics are used to treat disease and improve animal production. These antibiotics might result in deposition of residues in meat, milk and eggs which are not permitted in food intended for human consumption. This review report some health hazards of antibiotic residues in food. There are many factors influencing the occurrence of residues in animal products such as drug's properties and their pharmacokinetic characteristics, physicochemical or biological processes of animals and their products. The use of antibiotics is necessary in the prevention and treatment of animal diseases. Moreover, these antibiotics also improve the performance of growth and feed efficiency, synchronizing the reproductive cycle and breeding performance. These may also lead to harmful residual effects. For this to be minimized, withdrawal periods must be observed. This withholding periods makes the residues to be negligible or no longer detected in foods. However, withdrawal period is established to safeguard human from exposure of antibiotics added food. Failure to respect this period, could result in one which produces potential threat to direct toxicity in human. Moreover, low levels of antibiotic exposure would result in alteration of microflora, causing disease and the possible development of resistant strains causing failure of antibiotic therapy. The regulation of these residues in food of animal origin is necessary to prevent the health of humans. © 2018 Published by Elsevier B.V. on behalf of Ecological Society of China.
Contents 1. 2.
3.
4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Definition . . . . . . . . . . . . . . . . . . . . . 2.2. Major classes of antibiotics . . . . . . . . . . . . . 2.2.1. Beta lactams. . . . . . . . . . . . . . . . 2.2.2. Amphenicols . . . . . . . . . . . . . . . 2.2.3. Tetracyclines . . . . . . . . . . . . . . . 2.2.4. Macrolides . . . . . . . . . . . . . . . . 2.2.5. Aminoglycosides. . . . . . . . . . . . . . 2.2.6. Fluoroquinolones . . . . . . . . . . . . . 2.3. The use of antibiotics in food animals . . . . . . . . 2.3.1. Antibiotics as growth promoters . . . . . . 2.3.2. Antibiotics as therapy,and prophylaxis . . . . 2.4. Antibiotic residues . . . . . . . . . . . . . . . . . Health impacts . . . . . . . . . . . . . . . . . . . . . . 3.1. Antibiotic resistance . . . . . . . . . . . . . . . . 3.2. Chronic health effects . . . . . . . . . . . . . . . Regulation of the use of antibiotics . . . . . . . . . . . . . 4.1. The concept of MRL has replaced “zero residue” . . . . 4.2. Withdrawal times . . . . . . . . . . . . . . . . . 4.3. Techniques used in the detection of antibiotic residues
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
⁎ Corresponding author at: School of Health and Medical Sciences, Catholic University of Cameroon, Bamenda, Cameroon. E-mail addresses: [email protected], [email protected] (Z.E. Menkem).
https://doi.org/10.1016/j.chnaes.2018.10.004 1872-2032/© 2018 Published by Elsevier B.V. on behalf of Ecological Society of China.
Please cite this article as: Z.E. Menkem, B.L. Ngangom, S.S.A. Tamunjoh, et al., Antibiotic residues in food animals: Public health concern, Acta Ecologica Sinica, https://doi.org/10.1016/j.chnaes.2018.10.004
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
2
Z.E. Menkem et al. / Acta Ecologica Sinica xxx (xxxx) xxx
4.3.1. 4.3.2. 5. Conclusion . . Conflicts of Interest . - . . . . . . . . .
Qualitative test . Quantitative test . . . . . . . . . . . . . . . . . . . . . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
1. Introduction Antibiotics are naturally-occurring, semi-synthetic and synthetic compounds with antimicrobial activity that can be administered orally, parenterally or topically and are used in human and veterinary medicine to treat and prevent disease, and for growth promotion in food animals (Ian [24]). Huge quantities of antibiotics are used annually in livestock farming operations throughout the world, but the eventual fate of their residues and their potential damage to environmental health generally remains unknown [6,16]. Moreover, antibiotics are also used to improve performance in growth and feed efficiency, to synchronize or control the reproductive cycle and breeding performance also often lead to harmful residual effects. Nonetheless, their misuse has led to an increase in diseases in humans and domestic animals worldwide [19]. The use of antibiotics in animals can have direct and indirect effects on human health. The direct effects are those that can be causally linked to contact with antibiotic-resistant bacteria from food animals, and indirect effects are those that result from contact with resistant organisms that have been spread to various components of the ecosystem (e.g., water and soil) as a result of antibiotic use in food animals [35]. The concern over antibiotic residues in food of animal origin occurs in two situations; one which produces potential threat to direct toxicity in human, second is whether the low levels of antibiotic exposure would result in alteration of microflora, cause disease and the possible development of resistant strains which cause failure of antibiotic therapy [36]. This review explains the effects of antibiotic residues in food animals as a critical and important issue to be considered.
2. Antibiotics 2.1. Definition Antibiotics are medicines – therapeutically used to protect the health and welfare of humans and animals. It inhibits or abolishes the growth of microorganisms such as bacteria, fungi or protozoa. There are currently about 250 different chemical entities registered for use in medicine and veterinary medicine [37].
2.2. Major classes of antibiotics They are often complex molecules which may possess different functions within the same molecule. Therefore, under different pH conditions antibiotics can be neutral, cationic, anionic, or zwitterionic. Antibiotics can be grouped by either their chemical structure or mechanism of action. They are divided into different sub-groups such as β-lactams, amphenicols, tetracyclines, macrolides, aminoglycosides, fluoroquinolones and others [26,31].
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
0 0 0 0 0
2.2.2. Amphenicols These are antibiotics with a phenylpropanoid structure. They function by blocking the enzyme peptidyl transferase on the 50S ribosome subunit of bacteria e.g. chloramphenicol, thiamphenicol, azidamphenicol and florfenicol [26,31]. 2.2.3. Tetracyclines They are antibiotics with four (“tetra-”) hydrocarbon rings (“-cycl-”) derivation (“-ine”) defined as “a subclass of polyketides having an octahydrotetracene-2-carboxamide skeleton”. They are used for treatment of bacterial blood diseases e.g. oxytetracycline, chlortetracycline and tetracycline [26,31]. 2.2.4. Macrolides They are basic and lipophilic antibiotics with a 14 membered macrocyclic lactone ring linked with glycosidic linkages and are potent against wide variety of gram positive and negative bacteria used for the treatment of infectious diseases in cattle, sheep, swine and poultry e.g. tylosine, erythromycin and lincomycin [26,31]. 2.2.5. Aminoglycosides They consist of an aminocyclitol ring connected to two or more amino sugars linked via a glycoside link. They act by inhibiting the bacterial protein synthesis by binding to the 50s ribosomal subunits e.g. streptomycin, gentamycin, neomycin, and spectinomycin [26,31]. 2.2.6. Fluoroquinolones They have a fluorine atom attached to the central ring system, typically at the 6-position and are used as growth promoters. They act by inhibiting nucleic acids synthesis e.g. ciprofloxacin, ernofloxacin, and norfloxacin [26,31]. 2.3. The use of antibiotics in food animals 2.3.1. Antibiotics as growth promoters The mechanism of action of antibiotics as growth promoters is related to interactions between the antibiotics and the gut microbiota [8]. The low doses of antibiotics are sometimes added to cattle, poultry and swine feed to increase their body size. Example includes Sulphonamides which is used as growth promoter in poultry [1]. 2.3.2. Antibiotics as therapy,and prophylaxis The use of antibiotics in specific conditions is justified because the role of microbial agents is mainly to kill or destroy the rapidly invading cells. These invading microorganisms sometimes damage the cells of the animals and reduce their growth performance. These antibiotics may either be administered to prevent disease or during an infection. 2.4. Antibiotic residues
2.2.1. Beta lactams They have a b-lactam ring nucleus with a heteroatomic ring structure, consisting of three carbon atoms and one nitrogen atom. They act by attacking the cell walls of bacteria. e.g penicillins, ampicillin, cloxacillin and amoxicillin [26,31].
Antibiotic residues are metabolites found in trace amounts in any edible portion of the animal product after the administration of the antibiotics. The antibiotic residues in food animal in excess of the acceptable maximum residue limit may contribute to the development of antibiotic resistances in animals or humans.
Please cite this article as: Z.E. Menkem, B.L. Ngangom, S.S.A. Tamunjoh, et al., Antibiotic residues in food animals: Public health concern, Acta Ecologica Sinica, https://doi.org/10.1016/j.chnaes.2018.10.004
Z.E. Menkem et al. / Acta Ecologica Sinica xxx (xxxx) xxx
3. Health impacts Antibiotics used in food animals can cause health hazards due to their secretion in edible animal tissues in trace amounts. Some drugs have the potential to produce toxic reactions in consumers directly while some other is able to produce allergic or hypersensitivity reactions [30]. For example, b-lactam antibiotics can cause cutaneous eruptions, dermatitis, gastro-intestinal symptoms and anaphylaxis at very low doses. Such drugs include the penicillin and cephalosporin groups of antibiotics [22]. These direct effects may include the induction of resistance in normal flora of the human gastrointestinal tract due to the consumption of antibiotic-containing meat products causing an outbreak of resistant diarrheal disease. Moreover, increased risk of resistant colonization or infection in humans due to their exposure to farm animals treated with antibiotics. The Indirect and long term hazards include microbiological effects, carcinogenicity, reproductive effects and teratogenicity. Microbiological effects are one of the major health hazards in human beings. The Resistant bacteria from animal waste used as fertilizer may cause contamination of water supply and alterations in human flora [35]. 3.1. Antibiotic resistance Antibiotic resistance is the ability of a microorganism to withstand the effects of an antibiotic. The low efficiency of an antibiotic in the treatment an infection may be considered as resistant to that antibiotic [11]. This antibiotic resistance is a global public health concern today. The U.S. Centers for Disease Control and Prevention [5] has described antibiotic resistance as “one of the world's most pressing health problems”, because “the number of bacteria resistant to antibiotics has increased in the last decade. Its primary cause is long-term overexposure to antibiotics through their use as medicines in humans, as well as in animals, horticulture and for food preservation. The factors influencing the development of resistance include drug concentration, duration of exposure, organism type, antimicrobial type and host immune status [32]. The organism and bacteria cell may react by three main mechanisms: The first is that, the organism can produce encoding enzymes that will degrade or inactive the antibiotics, secondly the bacteria may acquire efflux pumps that will extrude the antibiotics thereby deviating the antibiotic target site and lastly, the bacteria may acquire genes that will alter the metabolic pathway and altering the target site of the enzyme [39]. Nature has developed different systems for transfer of genes between bacteria (conjugation, transformation, transduction and transposition) and these mechanisms have proven effective in the promotion of resistant genes (Fig. 2). The resistant bacteria may be pathogenic and can transfer their resistance genes to pathogenic bacteria resulting in adverse health effects. The transfer of resistant pathogens to humans via direct contact with animals, or through the consumption of contaminated food or water. Also, there is an increase in the prevalence of resistant bacteria in animals. These resistance can be described in two ways: a) Intrinsic or natural whereby microorganisms naturally do not possess target sites for the drugs and therefore the drug does not affect them or they naturally have low permeability to those agents because of the differences in the chemical nature of the drug and the microbial membrane structures especially for those that require entry into the microbial cell in order to affect their action [34,41]. b) Acquired or active resistance is the major mechanism of antibiotic resistance which results in specific evolutionary pressure to develop a counterattack mechanism against an antibiotic so that bacterial populations previously sensitive to antibiotics become resistant. This type of resistance results from changes in the bacterial genome.
3
The resistance in bacteria may be acquired by a mutation and passed vertically by selection to daughter cells (Fig. 1). More commonly, resistance is acquired by horizontal transfer of resistance genes between strains and species. Exchange of genes is possible by transformation, transduction or conjugation [17,34]. Acquired resistance mechanisms can occur through various ways.
3.2. Chronic health effects The chronic health effects of some antibiotics detected in some studies include: Oxytetracycline (Class: Tetracycline) Oxytetracycline (OTC) is a broad-spectrum antibiotic used to treat a variety of infections and as a growth promoter in animals. The symptoms of chronic exposure to oxytetracycline include blood changes (leucocytosis, atypical lymphocytes, lung congestion, toxic granulation of granulocytes and thrombocytopenia purpura). It can damage calcium rich organs such as teeth and bones and sometimes causes nasal cavities to erode. Some other effects include increased sensitivity to the sun, wheezing and asthmatic attack. Toxicological studies indicate that this drug is not mutagenic, carcinogenic, or terratogenic. Erythromycin (Class: Macrolides) The exposure to erythromycin has been linked to an increased probability of pyloric stenosis in young infants a condition that causes severe vomiting in the first few months of life [20]. Erythromycin is a reproductive hazard (terratogen) with chronic exposure. Cardiac malformation was observed in infants of women who had taken erythromycin in their early pregnancy [14]. Enrofloxacin (Class: Fluoroquinolones) Enrofloxacin (ENR) a fluroquinolone antibiotic which acts by the inhibition of bacterial DNA gyrase Embryo lethality and terratogenicity of fluoroquinolone antibacterials in rats and rabbits [13]. Chromosomal aberrations evaluated in cultures of human peripheral lymphocytes from eight healthy donors, exposed to the antimicrobial enrofloxacin or to its major metabolite ciprofloxacin suggested a genotoxic effect of enrofloxacin and ciprofloxacin [12]. It is also associated with increased photosensitivity. The Food and Drug Administration's Center for Veterinary Medicine has proposed to withdraw approval for use of the fluoroquinolone antimicrobial, enrofloxacin, in poultry based not on drugs direct toxicity but on potential for increasing human pathogen resistance. http://www.fda.gov/cvm/Documents/baytrilDDL.pdf Chloramphenicol (Class: Amphenicol)
Fig. 1. The different mechanisms involved in the development of antibiotic resistance.
Please cite this article as: Z.E. Menkem, B.L. Ngangom, S.S.A. Tamunjoh, et al., Antibiotic residues in food animals: Public health concern, Acta Ecologica Sinica, https://doi.org/10.1016/j.chnaes.2018.10.004
4
Z.E. Menkem et al. / Acta Ecologica Sinica xxx (xxxx) xxx Table 1 Maximum Residues Limit (MRL) (mg/kg) for antibiotics [36,40]. Antibiotics
Chicken
Pork
Beef
Ampicillin Amoxycillin Tetracycline Oxytetracycline Chlortetracycline Streptomycin Gentamycine Neomycin Spiramycin Tylosine Erythromycine
– – 0.25 0.1 1.0 N.D – 0.25 0.2 0.2 0.12
0.01 – 0.25 0.1 0.1 – 0.1 0.25 0.025 0.2 0.1
0.01 0.01 0.25 0.1 0.1 – 0.1 0.25 0.025 0.2 N.D
N.D: Not determined.
Fig. 2. The three main processes involved in antibiotic resistance transfer.
Chloramphenicol (CAP) a bacteriostatic antimicrobial used in veterinary medicine. It has been found to be potentially carcinogenic, which makes it an unacceptable substance for use with any food producing animals. The United States, Canada, and the European Union (EU), as well as many other countries, have completely banned the usage of CAP in the production of food. Chloramphenicol is anticipated to be a human carcinogen and genotoxic from studies in humans. It is toxic to blood, kidney and liver. The repeated or prolonged exposure to Chloramphenicol can lead to target organ damage and bone marrow toxicity. The most serious effect of chloramphenicol is aplastic anemia which is idiosyncratic (rare, unpredictable, and unrelated to dose) and generally fatal and could presumably be triggered by residues [23]. Ampicillin (Class: ß-lactam). Ampicillin (AMP) is a penicillin derivative b-lactam antibiotic is widely used in cattle, swine, honey bees and poultry to treat infections and as feed or drinking water additives to prevent some diseases. Workers from an antibiotic-producing factory developed asthma and eosinophilia on inhalation of ampicillin and related substance [7]. Ampicillin may cause recurrent cholestatic hepatitis [15]. The repeated contact may cause allergic reactions, asthmatic attack, exfoliative dermatitis, anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis. http://www.druglib.com/druginfo/ampicillin/side-effects_adversereactions/.
4. Regulation of the use of antibiotics 4.1. The concept of MRL has replaced “zero residue” The Maximum Residue Limit (MRL) is the maximum allowable concentration of a chemical in a feed or food (milk, meat, egg) at a specified time of slaughter or harvesting, processing, storage and marketing still the consumption by humans [18]. Below this limit, scientists and the authorities consider there to be no health hazard for the consumer and no effect on the manufacturing process. The concept of MRL is a balance between the consumers' expectations and the producers' constraints, allowing antibiotic use, without a ban, in complete safety. The MRL is calculated by taking into account both the toxicological risk as well as the possible effect of residues on the human digestive flora [4]. This MRL must not be exceeded for food products from animal origin
(Table 1). The MRL level is determined on the basis of three essential concepts: The No observable effect level (NOEL) is the concentration of a chemical that produces harmful effects on laboratory animals. The acceptable daily intake is established to provide a guide for maximum quantity that can be taken daily in food without risk in the health of the consumer. It is the amount of a substance that can be ingested daily over a lifetime without appreciable health risk [38]. 4.2. Withdrawal times A withdrawal time is the time needed after drug administration to a food animal to insure that drug residues of toxicological concern to reach safe concentration in edible target tissues or milk as defined by the tolerance. This interval is required to minimize or prevent harmful levels of residues in the products for consumption. During withdrawal studies, the target organ is determined and animals are sampled at various times after drug administration is stopped [2]. Moreover, these target tissues are most commonly the liver or kidney. As the primary organs of elimination, they will typically display a residue for the longest time [3]. Table 2 Some antibiotics and their withdrawal periods. Antibiotics
Withdrawal periods (days)
Oxytetracycline Erythromycine Ampicillin Tetracycline Gentamicine
15–35 2–14 6–15 5 0
4.3. Techniques used in the detection of antibiotic residues There are two main methods used in the detection of antibiotics in food animals. They include qualitative and quantitative test 4.3.1. Qualitative test The process of determining whether or not a particular chemical is present in a sample. Some types of business specialize in the service of performing qualitative testing of samples provided by customers who wish to know what is in them. This analysis process can often be done for solid samples by using an x-ray diffractometer. It only detects the presence of antibiotic residues in food animals. The methods used are Thin layer chromatography, rapid tests kits.The limit of this method is just to idenify the components in food. 4.3.2. Quantitative test It is the determination of the absolute or relative abundance (often expressed as a concentration) of one, several or all particular
Please cite this article as: Z.E. Menkem, B.L. Ngangom, S.S.A. Tamunjoh, et al., Antibiotic residues in food animals: Public health concern, Acta Ecologica Sinica, https://doi.org/10.1016/j.chnaes.2018.10.004
Z.E. Menkem et al. / Acta Ecologica Sinica xxx (xxxx) xxx
substance(s) present in a sample. Microbiological and immunological methods are used to detect antimicrobial residues in milk and muscle. Two types of microbiological test are employed: one using test tubes (Delvotest/DSM, Charm I/Charm II, Eclipse/Zeu-Inmunotec) and the other using combinations of Petri dishes [25]. Immunological techniques (enzyme-linked immunosorbent assay [ELISA], radioimmunoassay) and receptor-binding techniques are also used, with different instruments for measurement [9,10]. 5. Conclusion Antibiotics are extremely important class of drugs, as they represent a key component in the strategy used in the control of bacterial infections in both humans and animals. It is therefore important that their use in food animals be done with utmost care; antibiotics should be given at recommended doses and with appropriate supervision. Adequate holding period should be observed in all slaughter animals following therapeutic use of antibiotics. Ideally, the use of antibiotics in food animals by non-veterinarians should be discouraged. Also, genetic improvement and use of biologicals (including vaccines) to control diseases may replace the sub-therapeutic use of antibiotics in food animals. Conflicts of Interest The authors declare no conflict of interest. - References [1] A. Anadon, The EU the ban of antibiotics as feed additives: alternatives and consumer safety, in: Workshop III: 2006 EU ban on antibiotics as feed additives: consequences and perspectives, J. Vet. Pharmacol. Therapeutics 29 (2006) 41–46. [2] M. Apley, How do violative residues happen in swine? Pork Safety Sheet, National Pork Board, Iowa State University, USA, 2003. [3] T. Beyene, Veterinary Drug Residues in Food-animal Products: Its Risk Factors and Potential Effects on Public Health, J.Vet. Sci. Technol. 7 (2016) 285, https://doi.org/ 10.4172/2157-7579.1000285. [4] J. Boisseau, Basis for the evaluation of the microbiological risks due to veterinary drug residues in food, Vet. Microbiol. 35 (1993) 187–192. [5] CDC, Interagency Task Force on Antimicrobial Resistance. A Public Health Action Plan to Combat Antimicrobial Resistance, The Centers for Disease Control and Prevention, the Food and Drug Administration, and the National Institutes of Health, 2000 , Retrieved from http://www.cdc.gov/drugresistance/actionplan/aractionplan. pdf. [6] C.G. Daughton, T.A. Temes, Pharmaceutical and personal care products in the environment: Agents of subtle change? Environ. Health Perspect. 107 (1999) 907–938. [7] R.J. Davfes, D.J. Hendrick, J. Pepys, Asthma due to inhaled chemical agents: ampicillin, benzyl penicillin, 6 amino penicillanic acid and related substances, Clin. Exp. Allergy 4 (3) (1974) 227–247. [8] J.J. Dibner, J.D. Richard, Antibiotic growth promoters in agriculture: history and mode of action, Poult. Sci. 84 (2005) 634–643. [9] J.P. Ferguson, G.A. Baxter, J.D.G. McEvoy, S. Stead, E. Rawlings, M. Sharman, Detection of streptomycin and dihydrostreptomycin residues in milk, honey and meat samples using an optical biosensor, Analyst 127 (2002) 951–956. [10] V. Gaudin, N. Cadieu, P. Sanders, Results of a European profciency test for the detection of streptomycin/ dihydrostreptomycin, gentamicin and neomycin in milk by ELISA and biosensor methods, Anal. Chim. Acta 529 (2005) 273–283. [11] H. Goossens, M. Ferech, V.R. Stichele, M. Elseviers, Outpatient antibiotic use in Europe and association with resistance: a cross-national database study, Lancet 365 (9459) (2005) 579–587. [12] N. Gorla, H.G. Ovando, I. Larripa, Chromosomal aberrations in human lymphocytes exposed in vitro to enrofloxacin and ciprofloxacin, Toxicol. Lett. 104 (11) (1999) 43–48.
5
[13] A. Guzman, C. Garcia, A.P. Marin, C. Willoughby, I. Demestre, Developmental toxicity studies of the quinolone antibacterial agent irloxacin in rats and rabbits, Arzneimittelforschung 53 (2003) 121–125. [14] JECFA (Joint Expert Committee on Food Additives), Toxicological evaluation of certain veterinary drug residues in food, WHO Food Additives Ser. 39 (1997). [15] S. Koklu, O. Yuksel, L. Filik, O. Uskudar, K. Altundag, E. Altiparmak, Recurrent cholestasis due to ampicillin, Ann. Pharmacother. 37 (3) (2003) 395–397. [16] D.W. Kolpin, E.T. Furlong, M.T. Meyer, E.M. Thurman, S.D. Zaugg, L.B. Barber, et al., Pharmaceuticals, hormones, and other organic wastewater contaminants in U.S. streams, 1999–2000: a national reconnaissance, Environ. Sci. Technol. 36 (2002) 1202–1211. [17] K.P. Langton, P.J. Henderson, R.B. Herbert, Antibiotic resistance: multidrug efflux proteins, a common transport mechanism, Nat. Prod. Rep. 22 (2005) 439–451. [18] H.J. Lee, M.H. Lee, P.D. Ruy, Public health risks: chemical and antibiotic residues, Asian. J. Anim. Sci. 14 (2001) 402–413. [19] S.B. Levy, The Antibiotic Paradox: How the Misuse of Antibiotics Destroys their Curative Powers, HarperCollins Publishers, Cambridge, 2002 (296 p). [20] N. Maheshwai, Are young infants treated with erythromycin at risk for developing hypertrophic pyloric stenosis, Arch. Dis. Child. 92 (3) (2007) 271–273. [22] J.C. Paige, L. Tollefson, M. Miller, Public health impact on drug residues in animal tissues, Vet. Hum. Toxicol. 9 (1997) 1–27. [23] M.A. Payne, R.E. Baynes, S.F. Sundolf, A. Craigmill, A.I. Webb, J. Riviere, E drugs prohibited from extra label use in food animals, J. Am. Vet. Med. Assoc. 215 (1) (1 Jul 1999) 28–32. [24] Ian Phillips, Mark Casewell, Tony Cox, Brad De Groot, Christian Friis, Ron Jones, Charles Nightingale, Rodney Preston, John Waddell, Does the use of antibiotics in food animals pose a risk to human health? A critical review of published data, J. Antimicrob. Chemother. 53 (2004) 28–52. [25] M.G. Pikkemaat, M.L.B.A. Rapallini, S. Oostra-Van Dijk, J.W.A. Elferink, Comparison of three microbial screening methods for antibiotics using routine monitoring samples, Anal. Chim. Acta 637 (2009) 298–304. [26] Sapna, Johnson and Nimisha, Jadon (2010). [30] C.M. Velicer, S. Heckbert, W. Johanna, R.D. Lampe, J.D. Potter, C.A. Robertson, H. Stephen, R. Wise, A review of the mechanisms of action and resistance of antimicrobial agents, Can. Respir. J. 6 (1999) S20–S22. [31] C. Walsh, T. Wencewicz, Major classes of antibiotics and their modes of action, Antibiotics: Challenges, Mechanisms, Opportunities, ASM Press, Washington, DC 2016, pp. 16–32, https://doi.org/10.1128/9781555819316.ch2. [32] WHO, The Medical Impact of the Use of Antimicrobials in Food Animals, World Health Organization, 1997 , Retrieved from http://whqlibdoc.who.int/hq/1997/ WHO_EMC_ZOO_97.4.pdf. [34] H. Yoneyama, R. Katsumata, Antibiotic resistance in bacteria and its future for novel antibiotic development, Biosci. Biotechnol. Biochem. 70 (2006) 1060–1075. [35] T.F. Landers, B. Cohen, T.E. Wittum, E.L. Larson, A review of antibiotic use in food animals: perspective, policy, and potential, Public Health Rep. 127 (1) (2012) 4–22. [36] A.R. Nisha, Antibiotics residues-A global health hazard, Vet World 1 (2008) 375–377. [37] K. Kümmerer, A. Henninger, Promoting resistance by the emission of antibiotics from hospitals and households into effluent, Clin. Microbiol. Infect. 9 (12) (2003) 1203–1214. [38] Takele Beyene, Abdulkaf Kemal, Tariku Jibat, Fanos Tadese, Dinka Ayana, Ashenafi Feyisa, Assessment on Chemicals and Drugs Residue in Dairy and Poultry Products in Bishoftu and Modjo, Central Ethiopia, J. Nutr. Food Sci. (2015) S13:003. [39] C. Fred, F.C. Tenover, Mechanisms of antimicrobial resistance in bacteria, Am. J. Med. 119 (6 Suppl 1) (2006) S3–S10 (discussion S62-70). [40] M.H. Lee, H.J. Lee, P.D. Ryu, Public Health Risks: Chemical and Antibiotics Residues, 2000 (Review). [41] R. Wise, Antimicrobial resistance_priorities for action, Journal of Antimicrobial Chemotherapy 49 (2002) (585-6).
Further Reading [33] WHO, Report of the 1st Meeting of the WHO Advisory Group on Integrated Surveillance of Antimicrobial Resistance, World Health Organization, Copenhagen, 2009 , 15–19 June 2009. Retrieved from http://apps.who.int/medicinedocs/index/ assoc/s16735e/s16735e.pdf.
Please cite this article as: Z.E. Menkem, B.L. Ngangom, S.S.A. Tamunjoh, et al., Antibiotic residues in food animals: Public health concern, Acta Ecologica Sinica, https://doi.org/10.1016/j.chnaes.2018.10.004
Contents lists available at ScienceDirect
Acta Ecologica Sinica journal homepage: www.elsevier.com/locate/chnaes
Antibiotic residues in food animals: Public health concern Zeuko'o Elisabeth Menkem a,b,⁎, Bronhilda Lemalue Ngangom a, Stella Shinwin Ateim Tamunjoh a, Fekam Fabrice Boyom b a
School of Health and Medical Sciences, Catholic University of Cameroon, Bamenda, Cameroon Antimicrobial and Biocontrol agent units; Laboratory for Phytobiochemistry and Medicinal Plants Studies, Department of Biochemistry, Faculty of Science, P.O. Box 812, University of Yaoundé 1, Cameroon b
a r t i c l e
i n f o
Article history: Received 10 September 2018 Accepted 16 October 2018 Available online xxxx Keywords: Antibiotic residues Health hazards Food animals Public health
a b s t r a c t Antibiotics are used to treat disease and improve animal production. These antibiotics might result in deposition of residues in meat, milk and eggs which are not permitted in food intended for human consumption. This review report some health hazards of antibiotic residues in food. There are many factors influencing the occurrence of residues in animal products such as drug's properties and their pharmacokinetic characteristics, physicochemical or biological processes of animals and their products. The use of antibiotics is necessary in the prevention and treatment of animal diseases. Moreover, these antibiotics also improve the performance of growth and feed efficiency, synchronizing the reproductive cycle and breeding performance. These may also lead to harmful residual effects. For this to be minimized, withdrawal periods must be observed. This withholding periods makes the residues to be negligible or no longer detected in foods. However, withdrawal period is established to safeguard human from exposure of antibiotics added food. Failure to respect this period, could result in one which produces potential threat to direct toxicity in human. Moreover, low levels of antibiotic exposure would result in alteration of microflora, causing disease and the possible development of resistant strains causing failure of antibiotic therapy. The regulation of these residues in food of animal origin is necessary to prevent the health of humans. © 2018 Published by Elsevier B.V. on behalf of Ecological Society of China.
Contents 1. 2.
3.
4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Definition . . . . . . . . . . . . . . . . . . . . . 2.2. Major classes of antibiotics . . . . . . . . . . . . . 2.2.1. Beta lactams. . . . . . . . . . . . . . . . 2.2.2. Amphenicols . . . . . . . . . . . . . . . 2.2.3. Tetracyclines . . . . . . . . . . . . . . . 2.2.4. Macrolides . . . . . . . . . . . . . . . . 2.2.5. Aminoglycosides. . . . . . . . . . . . . . 2.2.6. Fluoroquinolones . . . . . . . . . . . . . 2.3. The use of antibiotics in food animals . . . . . . . . 2.3.1. Antibiotics as growth promoters . . . . . . 2.3.2. Antibiotics as therapy,and prophylaxis . . . . 2.4. Antibiotic residues . . . . . . . . . . . . . . . . . Health impacts . . . . . . . . . . . . . . . . . . . . . . 3.1. Antibiotic resistance . . . . . . . . . . . . . . . . 3.2. Chronic health effects . . . . . . . . . . . . . . . Regulation of the use of antibiotics . . . . . . . . . . . . . 4.1. The concept of MRL has replaced “zero residue” . . . . 4.2. Withdrawal times . . . . . . . . . . . . . . . . . 4.3. Techniques used in the detection of antibiotic residues
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . .
⁎ Corresponding author at: School of Health and Medical Sciences, Catholic University of Cameroon, Bamenda, Cameroon. E-mail addresses: [email protected], [email protected] (Z.E. Menkem).
https://doi.org/10.1016/j.chnaes.2018.10.004 1872-2032/© 2018 Published by Elsevier B.V. on behalf of Ecological Society of China.
Please cite this article as: Z.E. Menkem, B.L. Ngangom, S.S.A. Tamunjoh, et al., Antibiotic residues in food animals: Public health concern, Acta Ecologica Sinica, https://doi.org/10.1016/j.chnaes.2018.10.004
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
2
Z.E. Menkem et al. / Acta Ecologica Sinica xxx (xxxx) xxx
4.3.1. 4.3.2. 5. Conclusion . . Conflicts of Interest . - . . . . . . . . .
Qualitative test . Quantitative test . . . . . . . . . . . . . . . . . . . . . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
1. Introduction Antibiotics are naturally-occurring, semi-synthetic and synthetic compounds with antimicrobial activity that can be administered orally, parenterally or topically and are used in human and veterinary medicine to treat and prevent disease, and for growth promotion in food animals (Ian [24]). Huge quantities of antibiotics are used annually in livestock farming operations throughout the world, but the eventual fate of their residues and their potential damage to environmental health generally remains unknown [6,16]. Moreover, antibiotics are also used to improve performance in growth and feed efficiency, to synchronize or control the reproductive cycle and breeding performance also often lead to harmful residual effects. Nonetheless, their misuse has led to an increase in diseases in humans and domestic animals worldwide [19]. The use of antibiotics in animals can have direct and indirect effects on human health. The direct effects are those that can be causally linked to contact with antibiotic-resistant bacteria from food animals, and indirect effects are those that result from contact with resistant organisms that have been spread to various components of the ecosystem (e.g., water and soil) as a result of antibiotic use in food animals [35]. The concern over antibiotic residues in food of animal origin occurs in two situations; one which produces potential threat to direct toxicity in human, second is whether the low levels of antibiotic exposure would result in alteration of microflora, cause disease and the possible development of resistant strains which cause failure of antibiotic therapy [36]. This review explains the effects of antibiotic residues in food animals as a critical and important issue to be considered.
2. Antibiotics 2.1. Definition Antibiotics are medicines – therapeutically used to protect the health and welfare of humans and animals. It inhibits or abolishes the growth of microorganisms such as bacteria, fungi or protozoa. There are currently about 250 different chemical entities registered for use in medicine and veterinary medicine [37].
2.2. Major classes of antibiotics They are often complex molecules which may possess different functions within the same molecule. Therefore, under different pH conditions antibiotics can be neutral, cationic, anionic, or zwitterionic. Antibiotics can be grouped by either their chemical structure or mechanism of action. They are divided into different sub-groups such as β-lactams, amphenicols, tetracyclines, macrolides, aminoglycosides, fluoroquinolones and others [26,31].
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
0 0 0 0 0
2.2.2. Amphenicols These are antibiotics with a phenylpropanoid structure. They function by blocking the enzyme peptidyl transferase on the 50S ribosome subunit of bacteria e.g. chloramphenicol, thiamphenicol, azidamphenicol and florfenicol [26,31]. 2.2.3. Tetracyclines They are antibiotics with four (“tetra-”) hydrocarbon rings (“-cycl-”) derivation (“-ine”) defined as “a subclass of polyketides having an octahydrotetracene-2-carboxamide skeleton”. They are used for treatment of bacterial blood diseases e.g. oxytetracycline, chlortetracycline and tetracycline [26,31]. 2.2.4. Macrolides They are basic and lipophilic antibiotics with a 14 membered macrocyclic lactone ring linked with glycosidic linkages and are potent against wide variety of gram positive and negative bacteria used for the treatment of infectious diseases in cattle, sheep, swine and poultry e.g. tylosine, erythromycin and lincomycin [26,31]. 2.2.5. Aminoglycosides They consist of an aminocyclitol ring connected to two or more amino sugars linked via a glycoside link. They act by inhibiting the bacterial protein synthesis by binding to the 50s ribosomal subunits e.g. streptomycin, gentamycin, neomycin, and spectinomycin [26,31]. 2.2.6. Fluoroquinolones They have a fluorine atom attached to the central ring system, typically at the 6-position and are used as growth promoters. They act by inhibiting nucleic acids synthesis e.g. ciprofloxacin, ernofloxacin, and norfloxacin [26,31]. 2.3. The use of antibiotics in food animals 2.3.1. Antibiotics as growth promoters The mechanism of action of antibiotics as growth promoters is related to interactions between the antibiotics and the gut microbiota [8]. The low doses of antibiotics are sometimes added to cattle, poultry and swine feed to increase their body size. Example includes Sulphonamides which is used as growth promoter in poultry [1]. 2.3.2. Antibiotics as therapy,and prophylaxis The use of antibiotics in specific conditions is justified because the role of microbial agents is mainly to kill or destroy the rapidly invading cells. These invading microorganisms sometimes damage the cells of the animals and reduce their growth performance. These antibiotics may either be administered to prevent disease or during an infection. 2.4. Antibiotic residues
2.2.1. Beta lactams They have a b-lactam ring nucleus with a heteroatomic ring structure, consisting of three carbon atoms and one nitrogen atom. They act by attacking the cell walls of bacteria. e.g penicillins, ampicillin, cloxacillin and amoxicillin [26,31].
Antibiotic residues are metabolites found in trace amounts in any edible portion of the animal product after the administration of the antibiotics. The antibiotic residues in food animal in excess of the acceptable maximum residue limit may contribute to the development of antibiotic resistances in animals or humans.
Please cite this article as: Z.E. Menkem, B.L. Ngangom, S.S.A. Tamunjoh, et al., Antibiotic residues in food animals: Public health concern, Acta Ecologica Sinica, https://doi.org/10.1016/j.chnaes.2018.10.004
Z.E. Menkem et al. / Acta Ecologica Sinica xxx (xxxx) xxx
3. Health impacts Antibiotics used in food animals can cause health hazards due to their secretion in edible animal tissues in trace amounts. Some drugs have the potential to produce toxic reactions in consumers directly while some other is able to produce allergic or hypersensitivity reactions [30]. For example, b-lactam antibiotics can cause cutaneous eruptions, dermatitis, gastro-intestinal symptoms and anaphylaxis at very low doses. Such drugs include the penicillin and cephalosporin groups of antibiotics [22]. These direct effects may include the induction of resistance in normal flora of the human gastrointestinal tract due to the consumption of antibiotic-containing meat products causing an outbreak of resistant diarrheal disease. Moreover, increased risk of resistant colonization or infection in humans due to their exposure to farm animals treated with antibiotics. The Indirect and long term hazards include microbiological effects, carcinogenicity, reproductive effects and teratogenicity. Microbiological effects are one of the major health hazards in human beings. The Resistant bacteria from animal waste used as fertilizer may cause contamination of water supply and alterations in human flora [35]. 3.1. Antibiotic resistance Antibiotic resistance is the ability of a microorganism to withstand the effects of an antibiotic. The low efficiency of an antibiotic in the treatment an infection may be considered as resistant to that antibiotic [11]. This antibiotic resistance is a global public health concern today. The U.S. Centers for Disease Control and Prevention [5] has described antibiotic resistance as “one of the world's most pressing health problems”, because “the number of bacteria resistant to antibiotics has increased in the last decade. Its primary cause is long-term overexposure to antibiotics through their use as medicines in humans, as well as in animals, horticulture and for food preservation. The factors influencing the development of resistance include drug concentration, duration of exposure, organism type, antimicrobial type and host immune status [32]. The organism and bacteria cell may react by three main mechanisms: The first is that, the organism can produce encoding enzymes that will degrade or inactive the antibiotics, secondly the bacteria may acquire efflux pumps that will extrude the antibiotics thereby deviating the antibiotic target site and lastly, the bacteria may acquire genes that will alter the metabolic pathway and altering the target site of the enzyme [39]. Nature has developed different systems for transfer of genes between bacteria (conjugation, transformation, transduction and transposition) and these mechanisms have proven effective in the promotion of resistant genes (Fig. 2). The resistant bacteria may be pathogenic and can transfer their resistance genes to pathogenic bacteria resulting in adverse health effects. The transfer of resistant pathogens to humans via direct contact with animals, or through the consumption of contaminated food or water. Also, there is an increase in the prevalence of resistant bacteria in animals. These resistance can be described in two ways: a) Intrinsic or natural whereby microorganisms naturally do not possess target sites for the drugs and therefore the drug does not affect them or they naturally have low permeability to those agents because of the differences in the chemical nature of the drug and the microbial membrane structures especially for those that require entry into the microbial cell in order to affect their action [34,41]. b) Acquired or active resistance is the major mechanism of antibiotic resistance which results in specific evolutionary pressure to develop a counterattack mechanism against an antibiotic so that bacterial populations previously sensitive to antibiotics become resistant. This type of resistance results from changes in the bacterial genome.
3
The resistance in bacteria may be acquired by a mutation and passed vertically by selection to daughter cells (Fig. 1). More commonly, resistance is acquired by horizontal transfer of resistance genes between strains and species. Exchange of genes is possible by transformation, transduction or conjugation [17,34]. Acquired resistance mechanisms can occur through various ways.
3.2. Chronic health effects The chronic health effects of some antibiotics detected in some studies include: Oxytetracycline (Class: Tetracycline) Oxytetracycline (OTC) is a broad-spectrum antibiotic used to treat a variety of infections and as a growth promoter in animals. The symptoms of chronic exposure to oxytetracycline include blood changes (leucocytosis, atypical lymphocytes, lung congestion, toxic granulation of granulocytes and thrombocytopenia purpura). It can damage calcium rich organs such as teeth and bones and sometimes causes nasal cavities to erode. Some other effects include increased sensitivity to the sun, wheezing and asthmatic attack. Toxicological studies indicate that this drug is not mutagenic, carcinogenic, or terratogenic. Erythromycin (Class: Macrolides) The exposure to erythromycin has been linked to an increased probability of pyloric stenosis in young infants a condition that causes severe vomiting in the first few months of life [20]. Erythromycin is a reproductive hazard (terratogen) with chronic exposure. Cardiac malformation was observed in infants of women who had taken erythromycin in their early pregnancy [14]. Enrofloxacin (Class: Fluoroquinolones) Enrofloxacin (ENR) a fluroquinolone antibiotic which acts by the inhibition of bacterial DNA gyrase Embryo lethality and terratogenicity of fluoroquinolone antibacterials in rats and rabbits [13]. Chromosomal aberrations evaluated in cultures of human peripheral lymphocytes from eight healthy donors, exposed to the antimicrobial enrofloxacin or to its major metabolite ciprofloxacin suggested a genotoxic effect of enrofloxacin and ciprofloxacin [12]. It is also associated with increased photosensitivity. The Food and Drug Administration's Center for Veterinary Medicine has proposed to withdraw approval for use of the fluoroquinolone antimicrobial, enrofloxacin, in poultry based not on drugs direct toxicity but on potential for increasing human pathogen resistance. http://www.fda.gov/cvm/Documents/baytrilDDL.pdf Chloramphenicol (Class: Amphenicol)
Fig. 1. The different mechanisms involved in the development of antibiotic resistance.
Please cite this article as: Z.E. Menkem, B.L. Ngangom, S.S.A. Tamunjoh, et al., Antibiotic residues in food animals: Public health concern, Acta Ecologica Sinica, https://doi.org/10.1016/j.chnaes.2018.10.004
4
Z.E. Menkem et al. / Acta Ecologica Sinica xxx (xxxx) xxx Table 1 Maximum Residues Limit (MRL) (mg/kg) for antibiotics [36,40]. Antibiotics
Chicken
Pork
Beef
Ampicillin Amoxycillin Tetracycline Oxytetracycline Chlortetracycline Streptomycin Gentamycine Neomycin Spiramycin Tylosine Erythromycine
– – 0.25 0.1 1.0 N.D – 0.25 0.2 0.2 0.12
0.01 – 0.25 0.1 0.1 – 0.1 0.25 0.025 0.2 0.1
0.01 0.01 0.25 0.1 0.1 – 0.1 0.25 0.025 0.2 N.D
N.D: Not determined.
Fig. 2. The three main processes involved in antibiotic resistance transfer.
Chloramphenicol (CAP) a bacteriostatic antimicrobial used in veterinary medicine. It has been found to be potentially carcinogenic, which makes it an unacceptable substance for use with any food producing animals. The United States, Canada, and the European Union (EU), as well as many other countries, have completely banned the usage of CAP in the production of food. Chloramphenicol is anticipated to be a human carcinogen and genotoxic from studies in humans. It is toxic to blood, kidney and liver. The repeated or prolonged exposure to Chloramphenicol can lead to target organ damage and bone marrow toxicity. The most serious effect of chloramphenicol is aplastic anemia which is idiosyncratic (rare, unpredictable, and unrelated to dose) and generally fatal and could presumably be triggered by residues [23]. Ampicillin (Class: ß-lactam). Ampicillin (AMP) is a penicillin derivative b-lactam antibiotic is widely used in cattle, swine, honey bees and poultry to treat infections and as feed or drinking water additives to prevent some diseases. Workers from an antibiotic-producing factory developed asthma and eosinophilia on inhalation of ampicillin and related substance [7]. Ampicillin may cause recurrent cholestatic hepatitis [15]. The repeated contact may cause allergic reactions, asthmatic attack, exfoliative dermatitis, anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis. http://www.druglib.com/druginfo/ampicillin/side-effects_adversereactions/.
4. Regulation of the use of antibiotics 4.1. The concept of MRL has replaced “zero residue” The Maximum Residue Limit (MRL) is the maximum allowable concentration of a chemical in a feed or food (milk, meat, egg) at a specified time of slaughter or harvesting, processing, storage and marketing still the consumption by humans [18]. Below this limit, scientists and the authorities consider there to be no health hazard for the consumer and no effect on the manufacturing process. The concept of MRL is a balance between the consumers' expectations and the producers' constraints, allowing antibiotic use, without a ban, in complete safety. The MRL is calculated by taking into account both the toxicological risk as well as the possible effect of residues on the human digestive flora [4]. This MRL must not be exceeded for food products from animal origin
(Table 1). The MRL level is determined on the basis of three essential concepts: The No observable effect level (NOEL) is the concentration of a chemical that produces harmful effects on laboratory animals. The acceptable daily intake is established to provide a guide for maximum quantity that can be taken daily in food without risk in the health of the consumer. It is the amount of a substance that can be ingested daily over a lifetime without appreciable health risk [38]. 4.2. Withdrawal times A withdrawal time is the time needed after drug administration to a food animal to insure that drug residues of toxicological concern to reach safe concentration in edible target tissues or milk as defined by the tolerance. This interval is required to minimize or prevent harmful levels of residues in the products for consumption. During withdrawal studies, the target organ is determined and animals are sampled at various times after drug administration is stopped [2]. Moreover, these target tissues are most commonly the liver or kidney. As the primary organs of elimination, they will typically display a residue for the longest time [3]. Table 2 Some antibiotics and their withdrawal periods. Antibiotics
Withdrawal periods (days)
Oxytetracycline Erythromycine Ampicillin Tetracycline Gentamicine
15–35 2–14 6–15 5 0
4.3. Techniques used in the detection of antibiotic residues There are two main methods used in the detection of antibiotics in food animals. They include qualitative and quantitative test 4.3.1. Qualitative test The process of determining whether or not a particular chemical is present in a sample. Some types of business specialize in the service of performing qualitative testing of samples provided by customers who wish to know what is in them. This analysis process can often be done for solid samples by using an x-ray diffractometer. It only detects the presence of antibiotic residues in food animals. The methods used are Thin layer chromatography, rapid tests kits.The limit of this method is just to idenify the components in food. 4.3.2. Quantitative test It is the determination of the absolute or relative abundance (often expressed as a concentration) of one, several or all particular
Please cite this article as: Z.E. Menkem, B.L. Ngangom, S.S.A. Tamunjoh, et al., Antibiotic residues in food animals: Public health concern, Acta Ecologica Sinica, https://doi.org/10.1016/j.chnaes.2018.10.004
Z.E. Menkem et al. / Acta Ecologica Sinica xxx (xxxx) xxx
substance(s) present in a sample. Microbiological and immunological methods are used to detect antimicrobial residues in milk and muscle. Two types of microbiological test are employed: one using test tubes (Delvotest/DSM, Charm I/Charm II, Eclipse/Zeu-Inmunotec) and the other using combinations of Petri dishes [25]. Immunological techniques (enzyme-linked immunosorbent assay [ELISA], radioimmunoassay) and receptor-binding techniques are also used, with different instruments for measurement [9,10]. 5. Conclusion Antibiotics are extremely important class of drugs, as they represent a key component in the strategy used in the control of bacterial infections in both humans and animals. It is therefore important that their use in food animals be done with utmost care; antibiotics should be given at recommended doses and with appropriate supervision. Adequate holding period should be observed in all slaughter animals following therapeutic use of antibiotics. Ideally, the use of antibiotics in food animals by non-veterinarians should be discouraged. Also, genetic improvement and use of biologicals (including vaccines) to control diseases may replace the sub-therapeutic use of antibiotics in food animals. Conflicts of Interest The authors declare no conflict of interest. - References [1] A. Anadon, The EU the ban of antibiotics as feed additives: alternatives and consumer safety, in: Workshop III: 2006 EU ban on antibiotics as feed additives: consequences and perspectives, J. Vet. Pharmacol. Therapeutics 29 (2006) 41–46. [2] M. Apley, How do violative residues happen in swine? Pork Safety Sheet, National Pork Board, Iowa State University, USA, 2003. [3] T. Beyene, Veterinary Drug Residues in Food-animal Products: Its Risk Factors and Potential Effects on Public Health, J.Vet. Sci. Technol. 7 (2016) 285, https://doi.org/ 10.4172/2157-7579.1000285. [4] J. Boisseau, Basis for the evaluation of the microbiological risks due to veterinary drug residues in food, Vet. Microbiol. 35 (1993) 187–192. [5] CDC, Interagency Task Force on Antimicrobial Resistance. A Public Health Action Plan to Combat Antimicrobial Resistance, The Centers for Disease Control and Prevention, the Food and Drug Administration, and the National Institutes of Health, 2000 , Retrieved from http://www.cdc.gov/drugresistance/actionplan/aractionplan. pdf. [6] C.G. Daughton, T.A. Temes, Pharmaceutical and personal care products in the environment: Agents of subtle change? Environ. Health Perspect. 107 (1999) 907–938. [7] R.J. Davfes, D.J. Hendrick, J. Pepys, Asthma due to inhaled chemical agents: ampicillin, benzyl penicillin, 6 amino penicillanic acid and related substances, Clin. Exp. Allergy 4 (3) (1974) 227–247. [8] J.J. Dibner, J.D. Richard, Antibiotic growth promoters in agriculture: history and mode of action, Poult. Sci. 84 (2005) 634–643. [9] J.P. Ferguson, G.A. Baxter, J.D.G. McEvoy, S. Stead, E. Rawlings, M. Sharman, Detection of streptomycin and dihydrostreptomycin residues in milk, honey and meat samples using an optical biosensor, Analyst 127 (2002) 951–956. [10] V. Gaudin, N. Cadieu, P. Sanders, Results of a European profciency test for the detection of streptomycin/ dihydrostreptomycin, gentamicin and neomycin in milk by ELISA and biosensor methods, Anal. Chim. Acta 529 (2005) 273–283. [11] H. Goossens, M. Ferech, V.R. Stichele, M. Elseviers, Outpatient antibiotic use in Europe and association with resistance: a cross-national database study, Lancet 365 (9459) (2005) 579–587. [12] N. Gorla, H.G. Ovando, I. Larripa, Chromosomal aberrations in human lymphocytes exposed in vitro to enrofloxacin and ciprofloxacin, Toxicol. Lett. 104 (11) (1999) 43–48.
5
[13] A. Guzman, C. Garcia, A.P. Marin, C. Willoughby, I. Demestre, Developmental toxicity studies of the quinolone antibacterial agent irloxacin in rats and rabbits, Arzneimittelforschung 53 (2003) 121–125. [14] JECFA (Joint Expert Committee on Food Additives), Toxicological evaluation of certain veterinary drug residues in food, WHO Food Additives Ser. 39 (1997). [15] S. Koklu, O. Yuksel, L. Filik, O. Uskudar, K. Altundag, E. Altiparmak, Recurrent cholestasis due to ampicillin, Ann. Pharmacother. 37 (3) (2003) 395–397. [16] D.W. Kolpin, E.T. Furlong, M.T. Meyer, E.M. Thurman, S.D. Zaugg, L.B. Barber, et al., Pharmaceuticals, hormones, and other organic wastewater contaminants in U.S. streams, 1999–2000: a national reconnaissance, Environ. Sci. Technol. 36 (2002) 1202–1211. [17] K.P. Langton, P.J. Henderson, R.B. Herbert, Antibiotic resistance: multidrug efflux proteins, a common transport mechanism, Nat. Prod. Rep. 22 (2005) 439–451. [18] H.J. Lee, M.H. Lee, P.D. Ruy, Public health risks: chemical and antibiotic residues, Asian. J. Anim. Sci. 14 (2001) 402–413. [19] S.B. Levy, The Antibiotic Paradox: How the Misuse of Antibiotics Destroys their Curative Powers, HarperCollins Publishers, Cambridge, 2002 (296 p). [20] N. Maheshwai, Are young infants treated with erythromycin at risk for developing hypertrophic pyloric stenosis, Arch. Dis. Child. 92 (3) (2007) 271–273. [22] J.C. Paige, L. Tollefson, M. Miller, Public health impact on drug residues in animal tissues, Vet. Hum. Toxicol. 9 (1997) 1–27. [23] M.A. Payne, R.E. Baynes, S.F. Sundolf, A. Craigmill, A.I. Webb, J. Riviere, E drugs prohibited from extra label use in food animals, J. Am. Vet. Med. Assoc. 215 (1) (1 Jul 1999) 28–32. [24] Ian Phillips, Mark Casewell, Tony Cox, Brad De Groot, Christian Friis, Ron Jones, Charles Nightingale, Rodney Preston, John Waddell, Does the use of antibiotics in food animals pose a risk to human health? A critical review of published data, J. Antimicrob. Chemother. 53 (2004) 28–52. [25] M.G. Pikkemaat, M.L.B.A. Rapallini, S. Oostra-Van Dijk, J.W.A. Elferink, Comparison of three microbial screening methods for antibiotics using routine monitoring samples, Anal. Chim. Acta 637 (2009) 298–304. [26] Sapna, Johnson and Nimisha, Jadon (2010). [30] C.M. Velicer, S. Heckbert, W. Johanna, R.D. Lampe, J.D. Potter, C.A. Robertson, H. Stephen, R. Wise, A review of the mechanisms of action and resistance of antimicrobial agents, Can. Respir. J. 6 (1999) S20–S22. [31] C. Walsh, T. Wencewicz, Major classes of antibiotics and their modes of action, Antibiotics: Challenges, Mechanisms, Opportunities, ASM Press, Washington, DC 2016, pp. 16–32, https://doi.org/10.1128/9781555819316.ch2. [32] WHO, The Medical Impact of the Use of Antimicrobials in Food Animals, World Health Organization, 1997 , Retrieved from http://whqlibdoc.who.int/hq/1997/ WHO_EMC_ZOO_97.4.pdf. [34] H. Yoneyama, R. Katsumata, Antibiotic resistance in bacteria and its future for novel antibiotic development, Biosci. Biotechnol. Biochem. 70 (2006) 1060–1075. [35] T.F. Landers, B. Cohen, T.E. Wittum, E.L. Larson, A review of antibiotic use in food animals: perspective, policy, and potential, Public Health Rep. 127 (1) (2012) 4–22. [36] A.R. Nisha, Antibiotics residues-A global health hazard, Vet World 1 (2008) 375–377. [37] K. Kümmerer, A. Henninger, Promoting resistance by the emission of antibiotics from hospitals and households into effluent, Clin. Microbiol. Infect. 9 (12) (2003) 1203–1214. [38] Takele Beyene, Abdulkaf Kemal, Tariku Jibat, Fanos Tadese, Dinka Ayana, Ashenafi Feyisa, Assessment on Chemicals and Drugs Residue in Dairy and Poultry Products in Bishoftu and Modjo, Central Ethiopia, J. Nutr. Food Sci. (2015) S13:003. [39] C. Fred, F.C. Tenover, Mechanisms of antimicrobial resistance in bacteria, Am. J. Med. 119 (6 Suppl 1) (2006) S3–S10 (discussion S62-70). [40] M.H. Lee, H.J. Lee, P.D. Ryu, Public Health Risks: Chemical and Antibiotics Residues, 2000 (Review). [41] R. Wise, Antimicrobial resistance_priorities for action, Journal of Antimicrobial Chemotherapy 49 (2002) (585-6).
Further Reading [33] WHO, Report of the 1st Meeting of the WHO Advisory Group on Integrated Surveillance of Antimicrobial Resistance, World Health Organization, Copenhagen, 2009 , 15–19 June 2009. Retrieved from http://apps.who.int/medicinedocs/index/ assoc/s16735e/s16735e.pdf.
Please cite this article as: Z.E. Menkem, B.L. Ngangom, S.S.A. Tamunjoh, et al., Antibiotic residues in food animals: Public health concern, Acta Ecologica Sinica, https://doi.org/10.1016/j.chnaes.2018.10.004