Drug residues in milk after intrauterine injection of oxytetracycline, lincomycin-spectinomycin, and povidone-iodine in cows with metritis

A study was conducted to document the maximum retention times of antimicrobial residues in milk after their use in intrauterine treatment of metritis in lactating cows and to evaluate several risk factors hypothesized to influence the retention time of these drugs. Oxytetracycline (3 g), lincomycin-spectinomycin (2 g of one-third lincomycin and two-thirds spectinomycin), or povidone-iodine (6 g) were given to cows with metritis by intrauterine route. The Bacillus stearothermophilus var calidolactis disk assay was performed on each milk sample. Of the 61 cows treated with oxytetracycline, 30 had residues in their postinjection milk for variable periods (range, 12.5 to 44.0 hours; mean, 26.6 +/- 10.3). Of the 47 cows treated with lincomycin-spectinomycin, 17 had residues in their postinjection milk for various periods (range, 14.5 to 24 hours; mean, 19.5 +/- 8.9). Povidone-iodine was not detected in milk. Because a high number of cows (n = 61) were treated with oxytetracycline, only data from these cows were used in testing the influence of 3 factors (severity of metritis, time after parturition when cows with metritis were treated, and parity) on maximum retention of the drug in milk. Severity of metritis did not have a significant influence (P greater than or equal to 0.1) on the maximum retention time of the drug. The retention time decreased linearly with the increase of time after parturition when the cow with metritis was treated. First lactation cows had a significantly (P less than or equal to 0.01) shorter retention time than did older cows.     

Persistence of oxytetracycline residues in milk after the intrauterine treatment of lactating cows for endometritis

Milk samples were collected at one day intervals after the last dose from 31 cows that had received an intrauterine infusion of oxytetracycline once daily between one and five times. The tetrazolium chloride assay was used to determine whether there were significant residues of the antibiotic in the samples. A single treatment resulted in residues for between one and eight days, and the period tended to be longer in the cows that had received more than one dose. Of the 31 cows, six remained tetracycline-positive for more than five days after their last dose of the drug.     

Antibiotic residues in milk samples obtained from cows after treatment for papillomatous digital dermatitis.

OBJECTIVE: To determine whether there would be detectable antibiotic residues in milk obtained from dairy cattle with papillomatous digital dermatitis (PDD) after topical treatment with oxytetracycline. DESIGN: Randomized controlled clinical trial. ANIMALS: 28 lactating Holstein cows with PDD. PROCEDURE: Cows were assigned to 2 treatment groups. Treatment 1 (n = 16) consisted of spraying of PDD lesions with 15 ml of a solution containing 100 mg of oxytetracycline/ml; lesions were sprayed twice daily for 7 days, using a garden sprayer. Treatment 2 (n = 12) consisted of a one-time application of a bandage that consisted of cotton soaked with 20 ml of a solution containing 100 mg of oxytetracycline/ml. Milk samples were obtained before and after treatment and assayed for tetracycline content by use of high-performance liquid chromatography and a commercially available tetracycline screening test. RESULTS: None of the cows in either treatment group had violative residues of oxytetracycline in milk samples. CONCLUSIONS AND CLINICAL RELEVANCE: Producers treating lactating cows that have PDD, via topical application of oxytetracycline solution at the concentrations reported in this study, have a low risk of causing violative antibiotic residues in milk.     

Pharmacological aspects of chloramphenicol administration by the intramammary route to lactating dairy cows

Concentrations of chloramphenicol (C M) were determined, by microbiological assay, in the milk and blood serum of 17 culled dairy cows after intramammary infusion of an approved parenteral CM product (Gloveticol) and in the milk of 16 lactating cows after treatment with two approved CM products for intramammary infusion, at dosages ranging from 1 to 30 g/cow. C M was quickly absorbed from the udder into the blood circulation; the doses of 12.5 and 25 g/cow were almost completely absorbed within 20 hours. Absorption half-life (t1/2ab) from fully functioning quarters was 57+/-18 minutes, and the t1/2ab from partially functioning quarters was 125+/-37 minutes. Mean peak serum C M concentrations were 6.1, 16.2, and 37.4 microg/ml after the cows had been infused with 5, 12.5, and 25 g, respectively. These values were considerably higher than the corresponding peak serum C M concentrations reported following intramuscular injection of equivalent doses of the drug. C M residues were not detectible microbiologically in milk from treated quarters 20 hours after treatment with 5 g or 6.25 g, and 36 hours after treatment with 15 g. Drug concentrations in the milk from the non-treated quarters were approximately 70 per cent of the corresponding serum drug levels. Serum CM concentrations of potential therapeutic value in the treatment of gram-negative bacterial infections, i.e. > 5 microg/ml, were maintained for 8 hours after cows had been infused with 12.5 g, and for 12 hours after infusion with 25 g. The implications of the improved systemic availability of C M infused by the intramammary route over the intramuscular route are discussed in terms of potential therapeutic efficacy, local irritation, and duration of drug residues.     

Milk residues and performance of lactating dairy cows administered high doses of monensin

Milk residues and performance were evaluated in lactating cows that were fed up to 10 times the recommended dose of monensin. Following an acclimatization period of 14 d, during which cows were fed a standard lactating cow total mixed ration containing 24 ppm monensin, 18 lactating Holstein dairy cows were grouped according to the level of feed intake and then randomly assigned within each group to 1 of 3 challenge rations delivering 72, 144, and 240 ppm monensin. Outcome measurements included individual cow daily feed intakes, daily milk production, body weights, and monensin residues in composite milk samples from each cow. There were no detectable monensin residues (< 0.005 microg/mL) in any of the milk samples collected. Lactating cows receiving a dose of 72 ppm monensin exhibited up to a 20% reduction in dry matter intake, and a 5% to 15% drop in milk production from the pre-challenge period. Cows receiving doses of 144 and 240 ppm monensin exhibited rapid decreases in feed intake of up to 50% by the 2nd d and milk production losses of up to 20% and 30%, respectively, within 4 d. Lactating cows receiving up to 4865 mg monensin per day had no detectable monensin residues (< 0.005 microg/mL) in any of the milk samples collected. Results of this study confirm that food products derived from lactating dairy cattle receiving monensin at recommended levels are safe for human consumption.     

Dexamethasone and flumethasone residues in milk of intramuscularly dosed cows

A field study was performed to assess the level of drug residues in milk after therapeutic application of highly potent synthetic glucocorticoids. Dexamethasone was tested either as a crystalline suspension or as a combination of sodium phosphate and phenylpropionate esters. Intramuscular injection of these preparations in lactating dairy cows (60 μg dexamethasone/kg body wt) yielded drug residues in milk of up to 8.4 ng/mL 12 h after treatment. These dexamethasone residues fell to below 1.0 ng/mL within 3 days after treatment. Intramuscular injection of an aqueous flumethasone preparation (13.5 μg/kg body wt) produced drug residues in milk in the range of 0.7-1.2 ng/mL 12 h after treatment, whereas flumethasone was below the detection limit of 0.23 ng/mL 2 days after administration. These results indicate that toxicologically significant residues may arise transiently in the milk during the first 2-3 days after intramuscular injection of synthetic glucocorticoids. Urine from the same animals contained 5- to 50-fold higher glucocorticoid concentrations than the corresponding milk samples. Thus, urine analysis appears to be an effective method to monitor the use of synthetic glucocorticoids in food producing animals.     

Tissue disposition and depletion of penicillin G after oral administration with milk in unweaned dairy calves

OBJECTIVE: To determine tissue depletion of penicillin G in calves after oral ingestion with milk replacer and estimate a withdrawal period. DESIGN: Longitudinal controlled trial. ANIMALS: 26 Holstein calves. PROCEDURE: Once daily, 24 calves were fed milk replacer containing procaine penicillin G (0.68 mg/kg [0.31 mg/lb] of body weight); 2 calves served as controls. After 1 feeding, 12 calves were euthanatized in groups of 3 each 4, 6.5, 9.5, and 13 hours after feeding. After 14 days, 12 calves were euthanatized in groups of 3 each 4, 6.5, 9.5, and 13 hours after the final feeding. Concentrations of penicillin G were determined in tissues, blood, and urine by use of high-performance liquid chromatography. RESULTS: Penicillin G was not detected in muscle samples of treated calves. The highest concentrations of penicillin G in plasma, kidney, and liver were 13 ng/ml, 92 ng/g, and 142 ng/g, respectively. Thirteen carcasses had violative drug residues; 12 had violative residues in the liver only, and 1 had violative residues in the liver and kidney. A 21-hour withdrawal period was estimated. CONCLUSIONS AND CLINICAL RELEVANCE: Liver had the highest concentration of penicillin G and was most likely to have violative residues. Feeding calves milk containing penicillin G has the potential to cause violative drug residues in tissues. It is recommended to observe an appropriate withdrawal time prior to slaughter if calves are fed milk from cows treated with penicillin G.     

Occurrence of chlormequat (CCC) in wheat straw and its excretion in milk following feeding of straw pellets containing chlormequat]

When the herbicide chlormequat (chlorocholine chloride or CCC) was correctly used at 2 kg per hectare at the five-leaf stage of growth, the residues in wheat straw did not exceed 3 ppm. Such residual amounts remained unchanged after storage and pelleting. However, the feeding of contaminated straw pellets to cows did not result in contaimination of the milk detectable by a method which was capable of determining concentrations down to 0.05 ppm.     

Infectious bovine rhinotracheitis virus: studies on the venereal carrier status in range cattle.

Genital samples collected at autopsy from 193 beef cows representing 22 different herds in Northern Australia yielded only one isolate of infectious bovine rhinotracheitis (IBR) virus. Serological evidence showed 59 per cent of similar cows had prior infection with this virus and of 19 sero-positive cows tested, 11 (58-2 per cent) shed detectable IBR virus from the vagina after treatment with corticosteroids. Transitory lesions of the vagina and vulva developed in five of the treated cows. Twenty-six (65 per cent) of 40 sero-positive bulls shed detectable IBR virus into the prepuce after corticosteroid treatment. Except for one bull, virus was not isolated after corticosteroid treatment of sero-negative animals. IBR virus and mucosal disease (MD) virus were not isolated from nasal swabs before or after corticosteroid administration. No correlation was observed between initial circulating antiboyd titre and virus excretion after treatment. There were no significant changes in levels of serum antibody during the virus excretion period.     

Reproductive performance of dairy cows not detected in oestrus but with a detectable corpus luteum, in response to treatment with progesterone, oestradiol benzoate and prostaglandin F2alpha

AIM: To determine if the reproductive performance of dairy cows not previously detected in oestrus but with a detectable corpus luteum before the planned start of mating (PSM), could be improved by treatment with progesterone, oestradiol benzoate (ODB) and prostaglandin F2alpha (PGF). METHODS: Cows in 18 herds which had not been detected in oestrus, but which had a detectable corpus luteum present at veterinary examination 7 days prior to the PSM (Day -7), were allocated to 1 of 2 groups. Treated cows (n=232) received an injection of 2 mg ODB and an intravaginal progesterone releasing device (CIDR insert) on Day -7, and an injection of PGF on the day of insert removal 7 days later (Treated group). The Control group (n=243) remained untreated. Cows were mated to detected oestrus from Day 0, and conception dates confirmed by manual palpation or transrectal ultrasonography. RESULTS: During the first 7 days of mating, 37.4% of Control cows and 65.9% of Treated cows were inseminated on detection of oestrus (p<0.001). Pregnancy rates for this period were 20.4% and 36.3%, respectively (p=0.001). Conception rates to first insemination, pregnancy rates after 21 days of mating and at the end of the mating period were similar between groups (p>0.1). Median interval from the PSM to conception did not differ between treatment groups (24 and 23 days for Control and Treated, respectively, p>0.1). CONCLUSION: Treating postpartum dairy cows which had not previously been detected in oestrus but which had a detectable corpus luteum, with progesterone, ODB and PGF did not significantly improve their reproductive performance compared with no hormonal intervention. KEY WORDS: dairy cattle, postpartum, anoestrous, reproduction, progesterone treatment.     

Pharmacokinetics of veterinary drugs in laying hens and residues in eggs: a review of the literature

Poultry treated with pharmaceutical products can produce eggs contaminated with drug residues. Such residues could pose a risk to consumer health. The following is a review of the information available in the literature regarding drug pharmacokinetics in laying hens, and the deposition of drugs into eggs of poultry species, primarily chickens. The available data suggest that, when administered to laying hens, a wide variety of drugs leave detectable residues in eggs laid days to weeks after the cessation of treatment.     

The national milk safety program and drug residues in milk.

There are a number of factors that must be considered in any attempt to control animal drug residues in milk and milk products. Dairy herds vary greatly in number of cows. Milk from individual cows and farms is pooled, diluting drug residues that may be present in the milk from a single treated cow. Management techniques, including the handling, administration, and record keeping of animal drugs, vary greatly from one dairy to another. It is important that both veterinarians and nonveterinarians adhere to adequate milk discard times for animal drugs used to treat dairy animals. Observance of appropriate safeguards at the farm level, such as record keeping and clearly identifying treated animals, is critical for controlling and preventing the presence of illegal animal drug residues. Within the framework of the Federal Food, Drug, and Cosmetic Act and the Public Health Service Act, the FDA is working with state and other regulatory agencies and industry to better ensure the absence of illegal animal drug residues in milk and milk products. Preventive measures concentrate on minimizing the need to administer animal drugs to lactating cows, and diverting milk containing drug residues from the human food supply. Monitoring programs concentrate on screening milk and tracing violations to the individual producer. Minimizing illegal drug residues in milk and milk products requires close cooperation between farmers, veterinarians, the dairy industry, the pharmaceutical industry, and regulators.     

Effects on cattle and their calves of tansy ragwort (Senecio jacobaea) fed in early gestation

Tansy ragwort (Senecio jacobaea) fed to pregnant cows on gestation days 15 through 30 in lethal and near-lethal doses did not cause detectable damage to 100-day-old or to full-term fetuses as determined by gross examinations, serum enzyme tests chosen to detect hepatic changes, and by histopathologic examinations. Some cows that appeared normal during gestation expired soon after parturition from typical seneciosis apparently triggered by parturition stress. Pregnant cows fed 12% smaller tansy ragwort doses on gestation days 30 through 45 had only minimal serum enzyme changes and gave birth to normal calves that had normal serum enzymes up to 64 days after parturition.     

Determination of trimethoprim and sulphadoxine residues in porcine tissues and plasma.

Healthy gilts and market-ready hogs were administered a single intramuscular (IM) injection of Borgal, a commercial formulation of trimethoprim-sulfadoxine (TMP-SDX), once or twice daily. The objectives were to determine if a newly-developed high-performance liquid chromatographic (HPLC) method would be suitable for measuring the residual concentrations of TMP in the plasma of these live animals, and to determine if the administration of this veterinary drug would leave measurable residues in their plasma and tissues at slaughter. Plasma and tissue concentrations of SDX and TMP from these animals were determined over a period of 14 d using thin-layer chromatography/densitometry (TLCD), and the newly-developed HPLC method, respectively. The lowest detectable limit (LDL) for SDX in plasma and tissue was 20 ppb by TLCD. The HPLC method had a LDL of 5 ppb for TMP in plasma and tissue. Both methods were then used to provide baseline data on the absorption and depletion of TMP and SDX from these healthy animals. It was observed that both TMP and SDX were readily absorbed into the blood and tissues, but TMP was eliminated much faster than SDX. No TMP residues were detected in the plasma of any of the gilts at and beyond 21 h after drug administration. Also, no TMP residues were detected in the plasma of any of the market-ready hogs 24 h after drug administration at either the label dose or twice the label dose. Sulfadoxine residues at concentrations above the maximum residue limit (MRL) of 100 ppb were, however, detected in the plasma, muscle, kidney, liver, and injection sites of hogs slaughtered 1 and 3 d after a single IM administration at the label dose. Although SDX residues were still detectable in the lungs, kidney, liver and plasma of some hogs 10 d after administration of the label dose and twice the label dose, these were below the MRL. Postmortem examination revealed necrosis and inflammation at the injection sites, but no visible deposits of the injected drug.     

Antibiotic residues (bacterial inhibitory substances) in the milk of cows treated under label and extra-label conditions

The objectives of this study were to describe the depletion pattern of antibiotic residues (microbial inhibitory substances) from the milk of cows treated under field conditions of clinical disease and antibiotic administration, including both label and extra-label use, and to determine if the type of extra-label use, the route of administration, and the drug used were factors associated with prolonged shedding of residues in milk.

Milk samples from 138 cows, treated with a variety of antibiotic products on farms in southwestern Ontario in 1989 and 1990, were collected before treatment and for six days after cessation of treatment. Samples were tested for antibiotic residues with the Brilliant Black reduction test (BR-test) and the Bacillus stearothermophilus var calidolactis disc assay. In 13/138 (9.4%) of cow treatments, at least one milk sample was positive on both antibiotic residue tests after the label milk withholding time for the drug(s) used. In ten of these instances, the antibiotics were administered in extra-label fashion and in three the drugs were reportedly used according to label instructions. Extra-label use of antibiotics was significantly associated with increased risk of antibiotic residues in milk beyond the label withholding time. No significant differences in risk were observed among the various antibiotic products used in the study.

The farms involved in this study were selected on the basis of their proximity to our laboratory; therefore, the frequency of antibiotic residue detection after withholding times may not be indicative of the provincial or national situation. If farmers and veterinarians find themselves in a situation where extra-label use of an antibiotic is necessary, use of an alternative antibiotic that can be used at label dose and with a known withdrawal time may avoid a problem with residues.

     

Study of enrofloxacin and flumequine residues depletion in eggs of laying hens after oral administration

Two groups of laying hens (each n=12) were administered 10 mg/kg enrofloxacin (ENRO) (group A) or 26.6 mg/kg flumequine (FLU) (group B) by gastric catheter daily for five consecutive days. A third group (n=6) was untreated controls. Eggs were collected from day one of treatment and up to 30 days after withdrawal of the drug. Egg white and yolk from each egg were separated, and ENRO, its metabolite ciprofloxacin (CIP) and FLU residues were analysed by a high-performance liquid chromatography method with fluorescence detection. The sum of ENRO and CIP was detectable in egg white on the first day of treatment in high-level concentrations (2007.7 μg/kg) and remained steady during administration. In egg yolk, residues were detectable at day one in lower concentrations (324.4 μg/kg), increasing to the end of treatment. After treatment, these residues decreased and were detectable up to day 8 in egg white, and day 10 in yolk. FLU residues during drug administration in white were detectable in high concentrations from day one to five (6788.4-6525.9 μg/kg), and in yolk, concentrations were lower during administration (629.6-853.9 μg/kg). After drug withdrawal, FLU residues remained longer in egg white (30 days) than in yolk (26 days). For both drugs, differences of concentrations between matrices were significant.     

Fenbendazole-related drug residues in milk from treated dairy cows

Oral administration of [¹⁴C] fenbendazole (FBZ) at a dose of 5.Omg/kg leads to the presence of radiolabel in the milk of lactating dairy cows. However, the maximum mean concentration of total FBZ equivalents quantitated to one-third of the recommended safe concentration in milk (1.67 μg/mL). The label is equally distributed to the fat and aqueous portions of the milk. The maximum level, in general, is attained approximately 24-36 h after drug administration, with the highest levels ranging from 24 to 48 h after administration. The residues rapidly deplete, attaining levels of 10-20ng/mL by day 5, and are essentially undetectable by radiolabel monitoring by day 6. Extraction of the milk by matrix solid phase dispersion indicated that the label was distributed between traces of the parent drug, FBZ, and predominantly, the FBZ sulphoxide (SO) and sulphone (SO₂) metabolites. No other radiolabelled peaks were observed. Based on these data the metabolites of FBZ, FBZ-sulphone and FBZ-sulphoxide, could be used as marker residues for monitoring the administration of FBZ to lactating dairy cows.     

Compliance with recommended drug withdrawal requirements for dairy cows sent to market in Michigan

By examination of computerized individual cow records from January 1981 through June 1985, compliance with premarketing drug withdrawal times was investigated in 23 dairy herds. During this period, 877 cows were culled from 23 herds; 33 cows from 12 herds were in violation of premarketing drug withdrawal times. Six herds had 1 violation, 2 herds had 2 violations, 2 herds had 3 and 4 violations, and 2 herds had 7 and 9 violations. Fifty drugs had been used; 15 drugs were used in violation of drug withdrawal times before cows were sent to market. The most commonly used drugs in violation were oxytetracycline, gentamicin, chloramphenicol, and a combination of lincomycin/spectinomycin. Significant differences between cows in violation and cows not in violation were not observed for age, lactation number, milk production, herd size, or month of culling. However, the 12 herds in violation of premarket drug withdrawal times had significantly (P less than 0.05) more cows culled within 30 days for retained placenta and milk fever, and more cows culled within 30 and 100 days for mastitis, metritis, and displaced abomasum. Although not significant, the 2 herds with 7 and 9 violations had more hired vs family labor than did the other herds with violations.     

Postpartum toll-like receptors and β-defensin 5 mRNA levels in the endometrium of Holstein cows

Toll-like receptors (TLRs) and β-defensins are important components of the innate immune system. This study aimed to evaluate endometrial mRNA levels of TLRs (1/6, 2, 4, and 5) and β-defensin 5 in Holstein cows by quantitative real time RT-PCR. Uterine biopsies were performed from 6 to 12 h after parturition, and cows were divided into two groups: (i) cows with placental retention and clinical signs of uterine infection until 45 days postpartum (n=10) or (ii) cows with normal puerperium (n=10). All cows had detectable levels of TLRs and β-defensin 5 mRNAs, but these levels did not differ between groups (P>0.05). Levels of TLR4 mRNA had a positive and significant correlation with the time required for uterine involution in both groups.     

Role of ketoprofen in the modulation of hyperalgesia associated with lameness in dairy cattle

Forty lame dairy cows were randomly assigned to receive a course of either the non-steroidal anti-inflammatory drug ketoprofen, or sterile saline, together with conventional treatment for lameness. The effect of the ketoprofen was measured by using locomotion scoring and by testing the cows' nociceptive threshold over a period of 28 days. The locomotion score of all the cows improved but ketoprofen had no significant effect on this change. However, in the cows that received ketoprofen the hyperalgesia associated with lameness, recorded using a nociceptive threshold test, was significantly modulated on days 3, 8 and 28 after their initial examination, drug administration and treatment of lesions.