Drug residues in poultry meat: A literature review of commonly used veterinary antibacterials and anthelmintics used in poultry

2.1 Fluoroquinolones/Quinolones

Fluoroquinolones (ciprofloxacin, enrofloxacin, danofloxacin, sarafloxacin) are antimicrobial agents that exhibit broad spectrum activity, including activity against Pseudomonas spp. These bactericidal agents act by inhibiting DNA gyrase in bacterial cells. Studies have found a longer elimination half-life for poultry than in mammals (Abd El-Aziz, Aziz, Soliman, & Afify, 1997). Both enrofloxacin and sarafloxacin were historically labeled for use in chickens and turkeys. Attributed to the increase in human infections with antibacterial resistant Campylobacter spp. the FDA withdrew the use of fluoroquinolones in poultry (Cornejo et al., 2011). Sarafloxacin, the first fluoroquinolone approved for use in poultry in the United States was withdrawn in 2001 by the FDA (Federal Register, 2001). Additionally, enrofloxacin was withdrawn by the FDA in 2005 (Federal Register, 2005). However, in the USA, National Antimicrobial Resistance Monitoring System (NARMS) data has shown no change in resistance trends in Campylobacter jejuni isolates from either humans or chickens following the ban of enrofloxacin in poultry (NARMS, 2014).

Within this drug class, drug depletion times for these agents can be different for various reasons. In comparison to ciprofloxacin, danofloxacin shows greater bioavailability following oral and intramuscular administration and has a higher degree of protein binding. These variations may account for the difference in drug elimination for these two agents in broiler chickens (El-Gendi, El-Banna, Abo Norag, & Gaber, 2001). Active metabolites can also account for differences in withdrawal times. Enrofloxacin is metabolized into ciprofloxacin, a pharmacologically active metabolite. Both the parent and metabolites may be found in chicken muscle after treatment with enrofloxacin (Shim, Shen, Kim, Lee, & Kim, 2003). Some studies have found substantial concentrations of the metabolite ciprofloxacin for multiple days after termination of enrofloxacin treatment (Anadón et al., 1995).

The FDA has established muscle as target tissue for residue monitoring in chickens and turkeys, but the regulatory process does not differentiate between edible muscle types in poultry (Reyes-Herrera et al., 2005). There is some evidence that there can be significant differences in fluoroquinolone drug residue deposition between different muscle types (Reyes-Herrera & Donoghue, 2008). One study found that when using both the lowest and highest FDA approved enrofloxacin doses, breast tissue had consistently higher drug concentrations than thigh tissues during the dosing period (Reyes-Herrera et al., 2005). Although enrofloxacin residue concentrations were higher in breast versus thigh tissues in this study, another antibacterial medication may produce higher concentrations in thigh muscle. Therefore, it is important to determine which edible tissue contains the highest residue content when muscle is the target tissue (Reyes-Herrera et al., 2005).

Some studies suggest that fluoroquinolone residues are also found in feathers. This is of concern because feather meal could be a potential source of drug residue that can pass through the food chain when contaminated meal is fed to food-producing animals (San Martín, Cornejo, Iragüen, Hidalgo, & Anadón, 2007). Studies involving flumequine, enrofloxacin and ciprofloxacin showed drug concentrations that remained elevated during and after withdrawal time, which suggests that withdrawal times do not guarantee the absence of drug in chicken nonedible tissue such as feathers (Cornejo et al., 2011). Please refer to Table 1 for further information on fluoroquinolone drug residue studies.

2.2 Lincosamides

Lincosamides (lincomycin, clindamycin) are antimicrobial agents produced from Streptomyces lincolnensis and show exceptional activity against various gram positive organisms (Hornish, Gosline, & Nappier, 1987). They act by binding to the 50s subunit of bacterial ribosomes and inhibiting protein synthesis. Lincomycin is approved in the United States for broilers only and is used as a feed and water additive in broilers to aid in the prevention and control of coccidiosis, clinical and subclinical necrotic enteritis (Hornish et al., 1987). Based on the FDAs guidance for industry document (GFI #213; https://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM299624.pdf) the use of antimicrobial drugs with indications such as “increased rate of weight gain” or “improved feed efficiency” is no longer permissible.

In chickens, liver and kidney tissue contained the highest total concentration of lincomycin drug residue, and liver metabolites were detected and identified as lincomycin sulfoxide, N-demethyl lincomycin, and N-demethyl lincomycin sulfoxide. The concentrations were so low, however, that authors have suggested they should be classified as safe, nontoxic residues, and of no toxicological concern (Hornish et al., 1987). Please refer to Table 2 for further information on lincosamide drug residue studies.

2.3 Macrolides

Macrolides (erythromycin, roxithromycin, spiramycin, tilmicosin, tylosin) are bacteriostatic antimicrobial agents produced by Streptomyces spp. and are characterized by a macrocyclic lactone ring attached to two or more sugar moieties. They act by binding to the 50s bacterial ribosome and inhibiting protein synthesis and they are particularly useful against intracellular bacterial infections due their lipophilic nature. In mammals, macrolides are metabolized in the liver and the highest tissue concentrations for chickens and turkeys are also found in the liver (Goudah, Abo El Sooud, & Abd El-Aty, 2004). In the United States, only tylosin is approved for use in poultry although licensed poultry veterinarians can use other macrolides as ELDU under the AMDUCA if they are willing to take full responsibility for residues.

The absorption of erythromycin in poultry is highly variable following oral administration (Vermeulen, De Backer, & Remon, 2002). There is literature that suggests that crop flora can impede the absorption of certain macrolide drugs, such as erythromycin (Devriese & Dutta, 1984; Vermeulen et al., 2002). Erythromycin should be given twice daily at a dosage of 30 mg/kg body weight with a 3 day withdrawal time to ensure that the drug is eliminated from the tissues (Goudah et al., 2004).

Roxithromycin can be more effective at lower doses than erythromycin and can be given less frequently, due to the drug's longer elimination half-life and higher plasma levels (Lim, Park, & Yun, 2003). Following oral administration in broilers, the liver was detected to have the highest residual concentration of drug and one study determined withdrawal time to be 7 days after treatment of roxithromycin (Lim et al., 2003). Although roxithromycin is not FDA approved for use in poultry, it can be used in an extralabel manner. Tilmicosin also exhibits a long elimination half-life and residues from the liver persist for up to 9 days in broilers (Zhang et al., 2004) and up to 20 days in turkeys (Fricke et al., 2008) following a 5 day oral course of treatment. Tylosin and spiramycin have been studied in growing chicks and results show that tylosin residues are not detected more rapidly from the liver than spiramycin residues. After withdrawal of dietary tylosin at a dose of 8000 mg kg⁻¹ day⁻¹ for 7 days, no residues were detected in the liver after 2 days while residues of spiramycin were detectable in the liver for up to 7 days (Yoshida, Hoshii, Yonezawa, Nakamura, & Yamaoka, 1972). In laying hens, residues from both spiramycin and tylosin are not detected after 7 days, although large individual variations have been observed among the liver content of spiramycin (Yoshida, Daisaku et al., 1972). Please refer to Table 3 for further information on macrolide drug residue studies.

2.4 Polymyxins

Polymyxins (colistin) are polypeptide antibacterials that are primarily effective against Gram-negative bacteria and are utilized in veterinary medicine as a drug or feed additive. Human exposure to colistin, via parenteral routes of administration, could result in nephrotoxicity, CNS dysfunction, drug fever, and anorexia.

Studies suggest that polymyxins are not absorbed to any extent from the GI tract when administered orally (Zeng et al., 2010). After oral administration in ducks, colistin was not detectable in plasma and tissues, except for the intestines. Following a single intramuscular dose in ducks, the highest colistin concentrations were observed in kidney and the lowest concentrations in muscle. In contrast, colistin was eliminated rapidly in plasma, kidney, and liver, but very slowly in muscle. Since high drug concentrations and a long elimination profile were observed in duck kidney and muscle, these sites could serve as representative tissues in duck for colistin residue monitoring (Zeng et al., 2010).

2.5 Sulfonamides

Sulfonamides (sulfadimethoxine, sulfaquinoxaline, sulfamethoxazole, sulfachlorpyrazine) are bacteriostatic antibacterial agents that are active against Gram-negative and Gram-positive organisms, as well as protozoa, such as coccidia. They interfere with synthesis of folic acid by competing with para-aminobenzoic acid (PABA) and prevent cellular replication in bacteria (Lebkowska-Wieruszewska & Kowalski, 2010). These agents are approved for use in food-producing animals, but human consumption of sulfonamide contaminated products can cause central nervous system effects, gastrointestinal disturbances, and hypersensitivity reactions (Lebkowska-Wieruszewska & Kowalski, 2010). Sulfonamides exhibit high protein binding in tissues and blood and some sulfonamides are known to have active metabolites. Sulfadimethoxine is metabolized by acetylation and hydroxylation (Furusawa, 1999). Hydroxylation has been suggested as the main metabolic pathway (Nagata & Fukuda, 1994). Hydroxylated metabolites have antibacterial properties, but <40% activity of the parent drug and pharmacological effects seem to be low (Nagata & Fukuda, 1994). Sulfonamide medications are used very rarely in US broiler production because of the high potential for residues. On rare occasions, a sulfadimethoxine + ormethoprim combination is used in a “prestarter feed” for birds under 16 weeks of age to prevent mortality from coccidiosis and bacterial infections with a 5 day meat withdrawal (United States Food and Drug Administration, 2016).

Many studies have found high drug residues in broiler skin and turkey skin and this is an important public health concern because broiler skin is considered an edible tissue and comprises >10% carcass weight (Righter, Lakata, & Mercer, 1973; Takahashi, Hashizume, Said, & Kido, 1993; Takahashi, Said, Hashizume, & Kido, 1991). Some authors suggest a two compartment model within the skin which could explain the slow drug elimination rates from the skin (Takahashi et al., 1993). Please refer to Table 4 for further information on sulfonamide drug residue studies.

2.6 Tetracyclines

Tetracyclines (oxytetracycline, chlortetracycline, doxycycline, tetracycline) are broad spectrum antibacterial agents that act by inhibiting the 30s bacterial ribosomal subunits and inhibiting protein synthesis. This class of antibacterials is often used in the treatment of avian infectious diseases, especially in bacterial respiratory tract diseases (Croubels et al., 1998). Tetracycline antibacterials can be administered orally, in medicated feed or water, or by injection. Doxycycline is highly lipophilic and would be expected to distribute widely in the chicken; however, one chicken study found a lower apparent volume of distribution than expected and this may be attributed to higher plasma protein binding, as well as lower gut reabsorption of drug (Anadón et al., 1994). Studies have demonstrated that oxytetracycline displays greater oral bioavailability than doxycycline and tetracycline and oral administration of this drug is acceptable as a feasible route of administration to avoid irritation and tissue damages at the injection site in chickens (Anadón et al., 1993, 1994; Atef, El-Gendi, Youssef, & Amer, 1986). Multiple studies have demonstrated that drug residues from the tetracycline class are completely eliminated upon cooking the meat. Studies have found that cooking meat contaminated with chlortetracycline residues will destroy the residues completely (Yoshida, Yonezawa et al., 1971). One study found that simmering the muscle tissue for one hour destroyed all traces of oxytetracycline activity in the tissue (Katz, Fassbender, & Dowling, 1973).

Some differences in oxytetracycline drug compartments have been found between chicks and adults. Findings suggest that a part of dietary oxytetracycline is deposited in some storage site in the chick's body and authors suggest the most possible storage site may be bone (Yoshida et al., 1975). In contrast, studies in laying hens found that there were no reservoirs of antibacterial activity or release from bone tissue that could be measured by analytical methods used (Katz et al., 1973). Potential drug reservoirs could lead to a difference in withdrawal times between chicks and adults.

Pharmacokinetic differences have been noted between healthy and diseased birds. Aflatoxin B1 experimentally intoxicated birds administered doxycycline via intramuscular and oral routes, had smaller systemic bioavailability percentages compared to nonintoxicated birds (Atef, Youssef, El-Eanna, & El-Maaz, 2002). Results show that distribution values are higher and clearance rates are faster in aflatoxin B1 experimentally intoxicated birds compared with healthy chickens. The authors suggest that the drug could penetrate diseased tissues more efficiently and hypoproteinemia could lead to decreased protein binding in broilers (Atef et al., 2002). In turkeys infected with Pasteurella multocida, the addition of citric acid significantly increased the fraction of drug absorbed and the rate of absorption (Pollet, Glatz, & Dyer, 1985). It is hypothesized that the ions in tap water may have the ability to inhibit absorption of tetracyclines (Pollet, Glatz, Dyer, & Barnes, 1983; Pollet et al., 1985). Organic acids, such as citric acid, have the ability to bind to divalent cations and prevents the cations from interfering with tetracycline absorption (Pollet et al., 1985). Citric acid has the ability to chelate multivalent cations such as Ca2 +  and Mg2 +  and inhibit the formation of insoluble complexes (Boling, Webel, Mavromichalis, Parsons, & Baker, 2000; Maenz, Engele-Schaan, Newkirk, & Classen, 1999; Woyengo, Slominski, & Jones, 2010). By binding the divalent cations the absorption of tetracycline is improved with citric acid and prevents chelation of the drug (Pollet et al., 1983, 1985). The diseased state of turkeys also appeared to increase plasma concentration of chlortetracycline by increasing intestinal permeability and lowering the hepatic and or renal clearance (Pollet et al., 1985).

Potentiation of tetracycline in poultry feeds is commonly achieved by reducing calcium concentration in the feed to prevent chelation of tetracycline and improve drug absorption (Price, Zolli, Atkinson, Collins, & Luther, 1959; Sebree & Roberts, 1957; Waldroup et al., 1981). Tetracycline's are often used in poultry starter diets, therefore reducing the concentration of calcium in diets should only be used for short periods since calcium is essential for growth (Waldroup et al., 1981). Please refer to Table 5 for further information on tetracycline drug residue studies.

2.7 Anthelmintics

Anthelmintics are a class of agents that exert their effects by either stunning or killing helminthes. Examples of some anthelmintics classes include benzimidazoles, macrocyclic lactones, and imidazothiazoles.

Benzimidazoles (mebendazole, fenbendazole) exert their effects by inhibiting tubulin polymerization and progressively depleting energy reserves and inhibiting excretion of waste products and protective factors from parasite cells (Vercruysse, 2018). In the United States, fenbendazole is the only benzimidazole specifically approved by the FDA for the treatment of helminthiasis (Ascaridia dissimilis and Heterakis gallinarum) in turkeys. Mebendazole appears to be slowly absorbed and peak plasma concentrations are not measurable until 24–48 hr after drug administration (Benard, Burgat-Sacaze, Massat, & Rico, 1986). Studies have found that as long as 15 days after dosing of mebendazole, residues were still measureable in the liver and kidneys (Benard et al., 1986). In contrast, fenbendazole appears to be eliminated more rapidly from the body. A depletion study performed in chickens found that fenbendazole residues were undetectable in plasma 36 hr after cessation of drug administration (Taylor et al., 1993). Metabolites of fenbendazole could be present as residues in meat with sulfoxide and sulfone present 48 and 96 hr after cessation of drug administration (Taylor et al., 1993). One depletion study found that there is a difference in fenbendazole metabolism between chickens and turkeys. The study found that chickens had a higher rate of metabolite production and elimination than turkeys (Short et al., 1988). Please refer to Table 6 for further information on drug residue studies.