Extralabel Drug Use Research Articles

Review on effect of antimicrobial residual on human health

Human beings can get protein-rich foods from animal as by product (milk, meat, and eggs), to fulfill their nutritional requirements, and the quality and nature of this animal origin food may be directly or indirectly associated with the health human that consumed this animal origin food. “Veterinary drug” means any substance or mixture of substances that are essential for treatment of diseased animal (as therapeutic purpose), prevention of diseases (prophylaxis), modification of physiological functions (such as tranquilizers, anesthetic drugs), improvement of growth and productivity (growth promoters) as well as for ensuring food safety or restoring, correcting or modifying any physical, mental or organic function in an animal. However, the benefits of drug utilization to farm animals used for food production are also accompanied by the risks associated with drug residues in the edible parts of treated animals. The drug itself and their metabolites left over in the body after their administration for longer time are termed as residues. Residues are defined as chemical substances or metabolites of medicinal products that may accumulate within the tissues or edible parts of treated animals. These residues may result from failure to observe the proper withholding period following treatment, failure to maintain treatment records, overdose, or using prohibited drugs for economic animal treatment. Age of animal, disease statues, Extra-label drug use and Improper Withdrawal Time are the major risk factor for drug residues. The major potential effect of veterinary drug residues on public health are development of drug resistance, hypersensitive reaction, mutagenicity, carcinogenic disruption of intestinal micro flora and microbial drug resistance. Drug residue control and prevention responsible organs not only lie on within a governmental agency; rather the responsibility must be shared by all responsible bodies which includes, the government, producers, animal health practitioner and academicians, marketing associations, livestock producers, farmers and other interested parties, who must strive for both healthy and efficiently grown animals as well as a safe food supply. Proper maintenance of treatment records and identification of treated animals; institute a workable health record for each animal to record all health related events, including administration of medication, this for all about mentioned above points are the way of prevention and control strategies of drug residues.

Integration of Food Animal Residue Avoidance Databank (FARAD) empirical methods for drug withdrawal interval determination with a mechanistic population-based interactive physiologically based pharmacokinetic (iPBPK) modeling platform: example for flunixin meglumine administration.

Violative chemical residues in animal-derived food products affect food safety globally and have impact on the trade of international agricultural products. The Food Animal Residue Avoidance Databank program has been developing scientific tools to provide appropriate withdrawal interval (WDI) estimations after extralabel drug use in food animals for the past three decades. One of the tools is physiologically based pharmacokinetic (PBPK) modeling, which is a mechanistic-based approach that can be used to predict tissue residues and WDIs. However, PBPK models are complicated and difficult to use by non-modelers. Therefore, a user-friendly PBPK modeling framework is needed to move this field forward. Flunixin was one of the top five violative drug residues identified in the United States from 2010 to 2016. The objective of this study was to establish a web-based user-friendly framework for the development of new PBPK models for drugs administered to food animals. Specifically, a new PBPK model for both cattle and swine after administration of flunixin meglumine was developed. Population analysis using Monte Carlo simulations was incorporated into the model to predict WDIs following extralabel administration of flunixin meglumine. The population PBPK model was converted to a web-based interactive PBPK (iPBPK) framework to facilitate its application. This iPBPK framework serves as a proof-of-concept for further improvements in the future and it can be applied to develop new models for other drugs in other food animal species, thereby facilitating the application of PBPK modeling in WDI estimation and food safety assessment.

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

Poultry meat is widely consumed throughout the world and production practices often include the administration of pharmaceutical products. When appropriate, extra-label drug use of medications is necessary, but scientifically derived drug withdrawal intervals must be observed so that poultry meat is not contaminated with drug residues which could pose health risks to consumers. Over the past decade, there has been increased advocacy for judicious use of antimicrobial drugs for treating food animals. Judicious use of medications is commonly referred to as practices that reduce antibiotic resistance, but also includes residue avoidance. In that light, many investigators have performed scientific studies and have published estimated pharmacokinetic parameters for veterinary medications used in commercial avian species. This manuscript is a review of medication classes that have been studied in poultry (mostly chickens) with an emphasis on drug residue depletion in poultry meat.

Probabilistic Physiologically Based Pharmacokinetic Model for Penicillin G in Milk From Dairy Cows Following Intramammary or Intramuscular Administrations.

Penicillin remains one of the most frequently identified violative drug residues in food-producing animals. The predominant violations of penicillin were found in cull dairy cows. In the United States, procaine penicillin G is approved to be used in dairy cows through intramuscular (IM) and intramammary (IMM) administrations. Physiologically based pharmacokinetic (PBPK) models are useful tools to predict withdrawal intervals and tissue residues of drugs in food animals to ensure food safety, especially for extralabel drug use due to the scarcity of experimental data after extralabel administrations. Currently, no PBPK model is available to predict penicillin concentrations in milk. A population PBPK model with a physiologically based compartment for the mammary gland was established for penicillin G in dairy cows. The model predicted the tissue and milk residues well based on comparison with data from previous pharmacokinetic studies. The predicted milk discard interval of procaine penicillin G administered at 10 times the label dose for 3 repeated IM administrations was 182 h, and 122 h at 4 times the label dose after 3 repeated IMM infusions. Predicted results showed that even 4 times label dose did not lead to violative tissue residues in healthy dairy cows with IMM infusions. The predominant violations found in cull dairy cows may be caused by altered pharmacokinetics due to mastitis, other diseases, and/or interactions with other drugs, which have impacts on penicillin distribution and elimination. The current PBPK model can help predict milk discard interval for penicillin following extralabel use through IM and IMM administrations.

Automation and applications of the tolerance limit method in estimating meat withdrawal periods for veterinary drugs

A program was written in R to facilitate the implementation of the tolerance limit method (TLM) for establishing regulatory withdrawal times for limiting drug residues in meat, milk, and eggs. The developed computer source code can use pharmacokinetic and regulatory data to calculate the drug withdrawal period according to United States Food and Drug Administration (U.S. FDA) guidelines. The code called the “Withdrawal Time Calculator (WTC)” applied this TLM method to meat samples. The program was tested with the data provided by the U.S. FDA guidance and other published data collected from in vivo studies. Additional algorithm validation data were flunixin and sulfamethazine liver concentration data from peer-reviewed publications generated by our laboratory. This manuscript reports the withdrawal period results from testing the developed WTC code. Moreover, the source code for the WTC contains a data removal algorithm, constructed according to U.S. FDA data elimination recommendations if the user chooses. The power of the WTC is that it bypasses the use of multiple platforms typically required to perform the TLM, including standard commercial spreadsheet software (i.e., Microsoft Excel) and Statistical Analysis System (SAS) while providing speed and usability. This novel program provides a platform to calculate a withdrawal period recommendation for any drug in any class of animal for various regulatory body standards and could be very helpful in cases of extra-label drug use in food animals.

Extra–Label Drug Use in Wildlife Rehabilitation Medicine

Wildlife rehabilitators work with licensed veterinarians to use prescribed drugs in wildlife. Since most of these drugs are not labeled for use in wild species, their use is considered extra–label. Veterinarians and rehabilitators should take care to follow rules and regulations surrounding extra–label drug use in wildlife. Additionally, certain drugs, such as enrofloxacin, are illegal to use in any species that has a hunting season in the area. Finally, withdrawal times must be adhered to for specific drugs in hunted species.

Extended withdrawal time (EWDT) of drugs to prevent residues in food following extra label use

Safety of food originated from animals is an emerging global health problem, and ensuring food safety is a challenge for the producers and governments who deal with protecting the food supply chain from contamination with hazardous microbes, chemicals and/or drugs. In the United States (US), the Food Animal Residue Avoidance Databank (FARAD) program is a unique consortium of scientific experts who help maintain a proper balance among animal health, food safety, and regulatory policies. Veterinarians must often use drugs in an extra-label manner to treat food animals due to limited availability of Food and Drug Administration (FDA) approved drugs. Extra-label drug use (ELDU) is allowable under the Animal Medicinal Drug Use Clarification Act (AMDUCA). Following ELDU, and before products derived from the treated animal can be sold and marketed, an extended withdrawal time (EWDT) needs to be established, based on appropriate scientific data. The objective of this paper is to discuss the scientific basis for determination of EWDT of drugs used in food animals using kinetic modeling approach.

Evidence in support of veterinary involvement in antimicrobial stewardship training programs in the dairy industry

The recent emergence of antimicrobial resistance has triggered initiatives aimed at conveying antimicrobial stewardship in human and veterinary medicine. The importance of effective education and training programs has been highlighted as a key area of expansion for championing judicious use of antimicrobial agents. In order to provide data that would aid in design of interventions encouraging prudent antimicrobial use, Illinois dairy farmers (n=Z0) were surveyed using a probability cluster sampling technique. Survey responses were analyzed and examined for significant trends based upon potential knowledge, attitudinal, and behavioral indices of antimicrobial stewardship. The key areas of training needs that were identified from the survey responses include appropriate antimicrobial selection, the use of protocols, improved on-farm record keeping, and understanding of the factors that constitute extra-label drug use. The results from this preliminary study highlight the need for additional antimicrobial stewardship training in this sector of the livestock industry, and may be used to guide veterinarians in developing producer-focused education and training programs aimed at encouraging best practices surrounding the practical antimicrobial stewardship necessary to foster high-health animal care systems.

Considerations for extralabel drug use in calves.

Considerations for extralabel drug use in calves.

Veterinary Feed Directive

In 1996, the Animal Drug Availability Act created a new category of products called veterinary feed directive (VFD) drugs. These are livestock antibacterial drugs (medically important) intended for use in or on animal feed. Any animal feed containing a VFD drug to be used in animals will be required to have a veterinarian issue an order, called a veterinary feed directive (VFD), providing for such use. The purpose of this rule is to limit the use of medically important antibiotics in livestock to those considered necessary for assuring animal health, and only for treatment, control and prevention of disease. The VFD is an authorization granted by a licensed veterinarian who is familiar with the client's operation and provides health, management, and treatment recommendations. This type of professional relationship is known as a veterinary-client-patient/producer relationship (VCPR). Medicated feed articles have a number of approved claims and uses; however, the use of VFD drugs does not permit any extra-label drug use.
 Whenever antibiotics are used, resistance by susceptible bacterial populations is likely to occur. However, our stewardship responsibility is to use all of these products in a judicious manner and to demonstrate a greater awareness and accountability in this arena.

Making antibiotic choices in bovine medicine

Selection of therapeutic antibiotics for use in bovine patients can be a difficult decision, particularly when clinical experience is limited. A limited number of antimicrobial drugs are available to the bovine practitioner, and extra-label drug use is restricted in food animal medicine. Factors of the target infectious agent, the host and management scheme, as well as the drug must be considered when prescribing or administering antibiotics. The goal of this presentation is to review the major antibiotics available to the bovine practitioner, and provide a brief outline of the restrictions of extra-label drug use in cattle with the aim of applying this knowledge to selection of antibiotics for use in beef or dairy cattle.

Evaluation of risks of violative milk residues following extra-label topical administration of tetracycline for digital dermatitis in dairy cattle

Digital dermatitis (DD) is a commonly found foot lesion in cattle at the time of hoof trimming. At this point in time there are no licensed antimicrobials available for DD in North America, and DD is commonly treated with topical tetracycline antimicrobials at varying doses. This usage of topical tetracycline is extra-label drug use, and limited data is available to evaluate the risk of violative milk residues following treatment. Previous work that has evaluated the risk of violative milk residues only looked at one dosing regimen and used a tetracycline formulation that is currently not widely used by professional hoof trimmers or veterinarians. The objective of this project was to determine if various application methods or tetracycline dosages would result in tetracycline residue levels in milk.

Pharmaceuticals and personal care products in chicken meat and other food animal products: A market-basket pilot study

Pharmaceutical drugs are extensively used in industrial food animal production. We examined whether residues of veterinary antibiotics and other pharmaceuticals and personal care products (PPCPs) were detectable in a small market-basket sample of retail chicken (n=39), ground beef (n=3) and milk (n=3) samples. High-performance liquid chromatography and tandem mass spectrometry were used to assess the concentration of 59 PPCPs and their residues in animal products. All samples of ground beef, milk, and 14 chickens were analyzed individually, while an additional 25 chicken samples were pooled and analyzed in groups of five. The majority of PPCPs were not detected in meat and milk samples. Caffeine was detected in two of three milk samples (0.4ng/mL, 2.0ng/mL) and in 10 of 19 individual and pooled chicken samples (median: 18.6ng/g, range: 6.1–28.8ng/g). Acetaminophen was detected in three of three milk samples (median: 1.5ng/mL, range: 1.4–2.1ng/mL). Antibiotics in the tetracycline class were detected in two of three milk samples (median: 1.0ng/mL, range: 0.1–2.0ng/mL) and did not exceed regulatory residue tolerances of 300ng/mL. There are no regulatory residue tolerances for caffeine or acetaminophen in animal products. The acetaminophen detections in milk, however, raise questions about extra-label and unapproved use of pharmaceutical drugs in food animal production, as this drug is not approved for use in lactating dairy cattle or any other type of food animal production. Additional studies are needed to confirm our finding of PPCPs in meat and dairy products.

Animal Medicinal Drug Use Clarification Act, extralabel drug use, and residue avoidance

Increased scrutiny of drug use by regulatory agencies and the general public requires dairy animal owners and dairy veterinarians to examine their drug decision-making processes and drug use policies. This presentation will review relevant legislation, regulations, and drug use guidelines to aid practitioners in making good decisions that maximize drug efficacy while maintaining a safe food supply. In addition, the ethical and professional issues underlying many drug selection and use issues will be considered.

Efficacy of cyclo‐oxygenase inhibition by two commercially available firocoxib products in horses

Two firocoxib preparations for oral use are approved for use in animals in many countries: a chewable canine tablet and an equine paste. In order to reduce costs, many veterinarians use the canine product in horses even though this is an off-label use of the preparation. To determine the relative efficacy of 2 commercially available firocoxib products to inhibit prostaglandin E₂ (PGE2) synthesis after oral dosing in horses. A crossover design using 8 adult horses (n = 4 for each preparation during each treatment period). Body weight range 532-614 kg. Horses received 57 mg of the assigned firocoxib preparation orally once daily for 7 days, with a 14 day washout period between drug crossover. Ten healthy adult light breed horses were used as no-treatment controls. During each treatment period, blood was taken before dosing on Days 0 and 7 and on Day 7 1 h after dosing for ex vivo lipopolysaccharide (LPS) stimulation to induce (PGE₂ ) synthesis. Heparinised plasma was also collected on Day 7 immediately prior to and 1 h after dosing to determine plasma firocoxib concentrations. In the control group, there was no significant change in LPS-induced PGE2 over time. In contrast, immediately prior to and 1 h after treatment on Day 7, the mean LPS-induced PGE₂ concentration decreased significantly compared to Day 0 values in all treated horses. There was no difference in PGE₂ or plasma firocoxib concentrations between firocoxib treatment groups. In this model, the canine chewable preparation of firocoxib was as effective as the equine paste formulation at reducing LPS-induced PGE₂ synthesis. The canine chewable preparation of firocoxib may be a suitable alternative to the paste formulation in horses for situations where extra-label drug use can be legally justified. The Summary is available in Chinese - see Supporting information.

欧米における動物用医薬品の適用外使用の方針と延長すべき休薬期間の計算法

欧米における動物用医薬品の適用外使用の方針と延長すべき休薬期間の計算法

Retrospective study of cattle poisonings in California: recognition, diagnosis, and treatment.

In this retrospective study all suspect bovine intoxications submitted to the California Animal Health and Food Safety Laboratory between January 1, 2000 and December 31, 2011 were reviewed. A total of 1199 cases were submitted, but a diagnosis of intoxication was only established in 13.5% of cases. In these cases, overexposures to minerals, metals, and poisonous plants were determined as the most commonly diagnosed poisonings in cattle in California. Nitrate/nitrite poisoning was the most commonly diagnosed plant-associated intoxication, followed by gossypol and oleander. This study details the diagnostic challenges and treatment options for the most commonly diagnosed intoxications. To ensure proper treatment and prevention of new cases, accurate diagnosis is necessary, and therefore this review provides an essential tool for the food animal practitioner. Available toxicological analyses are offered at select laboratories, which can be time consuming and expensive, yet the potential for residues in consumed animal products and implications for human health necessitate testing and consultation. Any potential exposure to a toxicant in cattle should be reviewed to determine whether a residue hazard exists. Therapy focuses on immediate removal of the toxicant from the environment and from the gastrointestinal tract. With few antidotes available, most are cost prohibitive to treat numerous affected cattle. In addition, most antidotes will require extra-label drug use and establishment of meat and milk withdrawal times.

A review of pain assessment techniques and pharmacological approaches to pain relief after bovine castration: Practical implications for cattle production within the United States

Castration of male calves destined for beef production is a common livestock management practice in the United States amounting to approximately 7 million procedures per year. Recently there has been renewed interest in identifying methods to reduce pain associated with dehorning and castration. Although several studies have reported that analgesic drug administration prior to castration attenuates plasma cortisol response, there are currently no compounds specifically approved for pain relief in livestock in the U.S. Validated pain assessment tools are needed to support regulatory approval of analgesic compounds. This may include use of accelerometers, videography, heart rate variability determination, electroencephalography, thermography and plasma neuropeptide measurement to assess behavioral, physiological and neuroendocrine changes associated with a pain response. Extra-label drug use (ELDU) for pain relief is regulated under the Animal Medicinal Drug Use Clarification Act (AMDUCA) and requires that drugs be administered by or under the supervision of a veterinarian. Agents that may provide preemptive analgesia include local anesthetics, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, α2-agonists, and N-methyl d-aspartate (NMDA) receptor antagonists. A review of the published literature suggests that a significant decrease in plasma cortisol concentration after castration was associated with preemptive administration of a NSAID and local anesthesia. Local anesthesia alone tended to decrease peak plasma cortisol concentrations more than NSAIDs. However NSAIDs alone tended to decrease the area under the plasma cortisol–time curve more than local anesthesia alone. These findings suggest that multimodal analgesic regimens that extend into the post-operative period are more effective at mitigating pain and distress associated with castration than a single drug modality. Regulatory approval of safe and cost effective analgesic compounds with convenient routes of administration is needed for routine use of pain relieving drugs to be considered as standard practice at the time of castration.

Review of AMDUCA and Extra-Label Drug Use in Food Animals

This presentation will review the Animal Medicinal Drug Use Clarification Act (AMDUCA) of 1994 and how the Food Animal Residue Avoidance Databank (FARAD) provides scientifically-based residue withholding information within the context of extra-label drug use guidelines. Several beef and dairy cases will be presented to demonstrate FARAD’s successes and challenges to minimize violative drug residues in animal-derived food products. Finally, several of the research initiatives developed by FARAD scientists that have improved withdrawal time estimation will be reviewed within the context of extra-label drug use in food animals.

The use of sedatives, analgesic and anaesthetic drugs in the horse: An electronic survey of members of the American Association of Equine Practitioners (AAEP)

To determine the sedative, analgesic and anaesthetic drugs and techniques that are used by equine veterinarians. HYPOTHESIS OR OBJECTIVES: To provide equine veterinarians with information concerning veterinary use of anaesthetic techniques, a reflection of the collective experiences of the profession. A survey was conducted of those members of the American Association of Equine Practitioners (AAEP) with an electronic mail address on file with the organisation using proprietary, web-based software. The survey was comprised of 30 questions divided into 8 sections: nonsteroidal anti-inflammatory drugs; local anaesthesia; alternative techniques; standing chemical restraint; epidural anaesthesia; short-term anaesthesia; long-term anaesthesia; and a place for the respondent to make comments. The response rate was 13.8% (952/6911) AAEP member veterinarians primarily use phenylbutazone and flunixin as anti-inflammatory drugs, and lidocaine and mepivacaine for local anaesthesia. Combinations of drugs are preferred for standing chemical restraint. While many veterinarians frequently utilise short-term anaesthesia, longer anaesthesia is less frequently performed. Most AAEP member veterinarians use sedatives in combination to provide standing chemical restraint. Extra-label use of drugs is a core component of current equine sedation and anaesthetic practice. Equine veterinarians can compare their choices of anaesthetic drugs with others practising equine medicine and surgery and may be stimulated to investigate alternative methods of providing comfort to horses.