Modelling the concentration-time relationship in milk from cattle administered an intramammary drug

Whittem, T., Whittem, J. H., Constable, P. D. Modelling the concentration–time relationship in milk from cattle administered an intramammary drug. J. vet. Pharmacol. Therap.  35 , 460–471. Antimicrobial drugs are often infused directly through the streak canal into the bovine udder for the treatment or prevention of mastitis. These infusions have two major problems: drug residues in milk and variable antimicrobial efficacy. Both problems are influenced by the pharmacokinetics of intramammary delivery and elimination of drugs. This pharmacokinetics does not conform to the assumptions of traditional first‐order mamillary pharmacokinetic models. To help understand drug delivery into and elimination from the udder, a new approach to pharmacokinetic modelling of the udder is proposed. This new model was used to predict the movement of drug within the udder and the concentrations of drug achieved within physiological compartments of the udder. These predictions were examined using computer modelling. The model was evaluated using data from in vivo intramammary infusion of cefuroxime. The model predicts that changes in milking efficiency (residual volume), milk productivity and milking frequency can impact both the drug residue persistence and the time that milk drug concentrations exceed the minimum inhibitory concentrations for pathogens. The model provides a new tool for future evaluation of intramammary dosing studies.     

Effect of prepartum intramammary treatment with pirlimycin hydrochloride on prevalence of early first-lactation mastitis in dairy heifers

OBJECTIVE: To determine whether prepartum intramammary treatment of dairy heifers with pirlimycin hydrochloride would reduce the prevalence of intramammary infection (IMI) and lower the somatic cell count (SCC) during early lactation or improve 305-day mature equivalent milk production. DESIGN: Prospective clinical trial. ANIMALS: 183 Holstein-Friesian heifers (663 quarters) from 2 dairy farms. PROCEDURE: Heifers were assigned to treatment and control groups. Treated heifers received a single 50-mg dose of pirlimycin in each mammary quarter approximately 10 to 14 days prior to parturition. Prepartum mammary gland secretions and postpartum milk samples were collected for bacterial culture. Postpartum milk samples were also collected for determination of SCC or California mastitis testing and were tested for pirlimycin residues. Mature equivalent 305-day milk production data were recorded. RESULTS: Treated heifers in herd A had a higher overall cure rate, higher cure rates for IMI caused by coagulase-negative staphylococci (CNS) and Staphylococcus aureus, lower SCC, and lower prevalence of chronic IMI, compared with control heifers. Treated heifers in herd B had a higher overall cure rate and cure rate for IMI caused by CNS, compared with control heifers, but postpartum California mastitis test scores and prevalence of chronic IMI did not differ between groups. Mature equivalent 305-day milk production did not differ between herds or treatment groups. No pirlimycin residues were detected in postpartum milk samples. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that prepartum treatment of dairy heifers with pirlimycin may reduce the prevalence of early lactation IMI, particularly IMI caused by CNS, without causing pirlimycin residues in milk.     

Factors associated with intersucking in Swiss dairy heifers

Intersucking is a problem that may lead to udder damage, mastitis, milk loss, and culling of breeding animals. To analyse the risk factors for intersucking in dairy heifers in Switzerland, we asked 130 randomly selected dairy farmers about a broad spectrum of environmental factors that might be associated with intersucking (such as housing conditions, management, and the feeding of calves and heifers). In total, 2768 heifers (Swiss Brown Cattle, Simmental and Holstein Friesian) were included of which 303 had ever performed intersucking. Data at the farm level were analysed using path analysis (linear and logistic regression). Two outcome variables were considered: the occurrence of intersucking on the farm and the proportion of intersucking heifers above the cut-off of 7.2%. Farms where calves had no access to barnyard or pasture, where calves were reared in pens in enclosed buildings, where heifers after weaning were not restrained while feeding, where heifers after weaning received <0.5 kg concentrate per day, and where heifers after weaning were fed ≥40% maize silage (dry-matter ratio) were most likely to have intersucking heifers.     

Evaluation of certification in the Milk and Dairy Beef Quality Assurance Program and associated factors on the risk of having violative antibiotic residues in milk from dairy farms in Michigan

OBJECTIVE: To determine whether certification in a Milk and Dairy Beef Quality Assurance Program (MDBQAP) was associated with a reduced risk of having antibiotic residues in milk and to define specific management factors that may have predisposed dairy farms to having violative antibiotic residues in milk. SAMPLE POPULATION: 124 dairy farms in Michigan that had > 1 violative residue in milk during 1993 and 248 randomly selected control farms in Michigan that did not have violative residues in milk during 1993. PROCEDURE: A pretested structured questionnaire was mailed to case and control farms. A conditional multivariate logistic regression model was developed to determine risk factors associated with having a violative antibiotic residue in milk. RESULTS: Certification in the MDBQAP did not significantly reduce the risk of having a violative antibiotic residue. Annual treatment of > 10% of a herd for metritis was associated with a reduced risk of having a violative residue. Evidence suggested that a routine request for a milk processor to perform residue testing was associated with a decreased risk of having had a violative antibiotic residue, but routine on-farm residue testing was associated with an increased risk of having had a residue. CONCLUSIONS AND CLINICAL RELEVANCE: MDBQAP certification was associated, although not significantly, with a reduced risk of having violative antibiotic residues in milk. Risk factors significantly associated with violative antibiotic residues are addressed by various critical control points in the MDBQAP and may be indicators for strengths and weaknesses of MDBQAP.     

牛奶中抗生素残留及其检测方法研究

随着抗生素在乳畜饲养业中的广泛应用,牛奶中抗生素残留问题日趋受到国际社会的重视。对此,检测技术也迅速发展,以寻求简便、快速、准确、敏感性高的检测方法满足日趋严格的残留限量的要求,保障人们饮用牛奶的卫生和安全。1牛奶中抗生素残留的来源及其危害1.1牛奶中抗生素残留的来源一般认为,对泌乳牛用药不当或不注意安全时间是牛乳中抗生素残留的重要因素,尤其是使用乳房灌注法治疗乳腺炎时,易造成牛乳中抗生素残留。随着畜牧业的发展,在牛饲料中添加饲料添加剂已十分广泛,其中含有一定比例的抗生素,主要作用是预防疾病的发生,这也是牛乳…     

Impact of intramammary infections in dairy heifers on future udder health, milk production, and culling

Dairy heifers represent the future of a dairy herd, and are expected to freshen with a healthy and well-developed udder, capable of producing an optimal amount of high quality milk. A high proportion of heifers have infected mammary quarters at calving, with coagulase-negative staphylococci (CNS) being the most common cause. Staphylococcus aureus and environmental pathogens are also found. The aim of this paper is to summarize how intramammary infections during (late) gestation and early lactation impair the development of the mammary gland and negatively affect future udder health and milk production. Heifers calving with either subclinical or clinical mastitis are also at a higher risk to be culled in first lactation. The magnitude of the effect is most likely related to the virulence of the causative pathogen, the persistence of the infection when milk production has started, and the time of onset of infection. Histological changes in udder tissue from quarters infected with S. aureus are more pronounced than those in udder tissue from CNS-infected quarters. The longer the infections exist and the longer they persist into lactation, the larger the impact on heifers' future udder health and milk production will be. In general, CNS infections are cleared early in lactation and some studies show that CNS do not have a large impact on future milk production and udder health. Future research should elucidate to what extent pathogen-specific as well as host-related factors affect the persistence of IMI in early lactating heifers.     

Effect of precalving intramammary treatment with pirlimycin in nulliparous Holstein heifers

A clinical trial was conducted to determine whether prepartum intramammary pirlimycin reduces the proportion of nulliparous heifers with intramammary infection (IMI) during early lactation and improves milk production. Quarter milk samples were collected from 428 heifers, systematically allocated to treatment and control groups, 6 to 12 d before the expected calving date and 2 to 8 d after calving. At the prepartum visit, heifers in the treatment group (n = 219) received an infusion of pirlimycin hydrochloride in all 4 quarters; the control heifers (n = 209) received no infusions. Intramammary infection was detected in 69% of the heifers and 33% of the quarters before calving. After calving, the proportion of treated heifers with IMI was significantly lower than the proportion of control heifers (31% versus 45%). Staphylococcus aureus was isolated from 10% of the heifers and 3% of the quarters before calving. After calving, the proportion of IMIs due to S. aureus was significantly lower in the treated heifers than in the control heifers (5.6% versus 10%). Antibiotic treatment increased the percentage of cures and prevented new IMIs caused by gram-positive bacteria after calving. The incidence of new IMIs caused by gram-negative bacteria and yeast was higher among treated heifers than among control heifers. There was no overall effect of treatment on milk production, but there was a significant interaction effect of treatment and the interval between treatment and calving. An increase of 302 kg of milk was observed when antibiotic treatment was applied more than 1 wk before calving. Treatment did not affect the milk somatic cell count on the 1st 3 test days after calving.     

Pharmacokinetics and residues in milk of oxytetracyclines administered parenterally to dairy goats

OBJECTIVE: To determine for two commercial preparations of oxytetracycline (OTC) the pharmacokinetic behaviour, the presence of detectable milk residues and the penetration in milk of OTC administered by intravenous (IV) (conventional formulation [CF]) and intramuscular (IM) routes (CF and long-acting [LA] formulations) in goats producing milk. The effects of these formulations on plasma activity values of creatine kinase (CK) and lactate dehydrogenase (LDH) were also determined as indicators of tissue damage. PROCEDURE: Five healthy lactating goats producing 1.5+/-0.5 L/d milk and weighing 56.0+/-4.8 kg were used. Single doses of OTC chlorhydrate (CF) were administered (20 mg OTC/kg) by IV (Trial 1 IV) and IM (Trial 1 IM) routes and OTC dehydrate (LA) by the IM route. The same goats were first given IV CF, then IM CF followed by IM LA with 3 weeks between each treatment. Blood and milk samples were taken. The quantification of OTC was performed by HPLC and the plasma activities of CK and LDH enzymes were determined by spectrophotometry. The presence of OTC residues in milk was determined by a commercial reagent. The plasma pharmacokinetic parameters were calculated using a two-compartment model. RESULTS: Estimates of kinetic variables following IV administration were: Vss= 400.0+/-120.0 mL/kg and CL= 110.0+/-14.0 (mL/h)/kg. The t(fi) for IV= 3.0+/-0.3 h; IM, CF = 10.5+/-2.1 h and IM, LA = 15.1+/-3.1 h. The concentration of OTC in milk at 48 h was: IV= 0.6+/-0.4; IM CF= 1.1+/-0.2 and at 72 h (IM LA)= 0.6+/-0.1 microg/mL and the penetration in milk of OTC was: IV= 70.0+/-18.0; IM CF= 79.0+/-14.0 and IM LA= 66.0+/-6.0%. The areas under the curve of CK and LDH activities in plasma were calculated by the trapezoidal method. Values of CK and LDH IM, LA were greater (P < 0.05) than those observed for IM, CF at 2 and 3 days after administration of the antibiotic. Finally, the bioavailability of OTC CF = 92.0+/-22.0 and LA= 78.0+/-23.0% was suitable for its usage by the IM route in lactating goats. CONCLUSION: Plasma concentration-time values of OTC administered parenterally in production dairy goats showed similar bioavailability for the two pharmaceutical preaprations. The presence of detectable residues in milk indicates that milk should not be used for human consumption for 2 and 3 days after administration of conventional and long-acting formulations, respectively. The increments in CK and LDH activities after the IM administration of LA are consistent with the presence of tissue damage provoked by the pharmaceutical preparations at the injection site.     

Efficacy of intramammary treatment in unbred and primigravid dairy heifers

A total of 73 breeding-age and primigravid Jersey heifers in 4 herds was randomly allotted to treatment and control groups according to expected calving date. Thirty-five heifers were injected intramammarily with a nonlactating cow product containing penicillin/streptomycin. Thirty-eight heifers served as untreated controls. Of the 35 treated heifers, 34 (97.1%) were infected at time of treatment. In the untreated control group, all 38 heifers (100%) were infected at treatment time. At parturition, prevalence of intramammary infection in treated heifers decreased to 40%, whereas in the control group, prevalence remained about the same (97.4% of heifers). Prevalence of Staphylococcus aureus mastitis in treated heifers was reduced from 17.1% to 2.9% after treatment. In the control group, prevalence of S aureus mastitis decreased from 26.3% to 15.8%. Heifers treated during the second trimester of pregnancy had the greatest reduction in prevalence of mastitis and in somatic cell count at parturition, compared with controls. Findings indicated that intramammary treatment during pregnancy in primigravid heifers was effective in reducing prevalence of mastitis and somatic cell counts at parturition.     

牛奶中抗生素残留及其检测方法研究进展

抗生素在畜牧业中的广泛应用，不可避免地造成牛奶中残留抗生素。抗生素残留不仅危害人类健康，同时也影响牛奶的品质，造成经济损失。本文综述牛奶中抗生素残留的来源和危害、现状以及残留的检测方法。     

Factors associated with shortened estrous cycles after abortion in beef heifers

Forty-six crossbred Hereford heifers were allotted into five experimental groups. Fenprotalene, a prostaglandin analogue, was administered to induce abortion and (or) to regress the corpus luteum (CL) in four groups of heifers about 75 d after conception. The four groups were 1) pregnant heifers, 2) pregnant heifers with the ovary contralateral to the gravid uterine horn removed 24 h after fenprostalene injection, 3) same as Group 2 but with the ipsilateral, rather than the contralateral, ovary removed and 4) heifers with uterus removed (ovaries intact) about 35 d after conception. A fifth group of nonpregnant heifers received implants containing norgestomet from 10 to 76 d after estrus and were given fenprostalene 24 h before removal of the implant. Average length of the first estrous cycle after the fenprostalene injection was 11.2, 8.3, 9.7 and 19.1 for Groups 1, 2, 3 and 5, respectively. Estrous cycles were longer (P less than .05) in norgestomet-treated heifers. Hysterectomized heifers (Group 4) did not exhibit a second estrus by 50 d after fenprostalene treatment; otherwise, all first estrous cycles after the fenprostalene injection were either "short" (7 to 13 d) or "normal" (17 to 23 d). Twenty-two of 24 heifers that aborted had short estrous cycles and two had normal estrous cycles. Short estrous cycles occurred after abortion regardless of whether the ovary ipsilateral or contralateral to the previously gravid uterine horn ovulated. Early regression of the CL (short luteal phase) did not occur in nonpregnant heifers after long-term progestogen stimulation or after hysterectomy, but it did occur in heifers with a previously gravid uterus.(ABSTRACT TRUNCATED AT 250 WORDS)     

Field trials on the prophylaxis of intramammary infections in pregnant heifers

The study was carried out in 5 farms on 174 pregnant heifers. Clinical examination of the udder and bacteriological tests of quarter secretion were performed between the 8th and 3rd week before parturition, and then the animals were divided into a control group (64 heifers) and 3 experimental groups and immediately treated. A group of 32 experimental heifers was injected once with antioxidants (Vitamin A--600,000 i.u.; Vitamin D3--200,000 i.u.; Vitamin E--1.5 mg/kg b.w., Selenium--0.022 mg/kg b.w., i.m.). The next group (26 heads) was intramammary infused with antibiotic DC product (cloxacillin). Heifers from last experimental group (52) were injected with lysosyme dimer in a single dose of 0.02 mg/kg b.w. Clinical and bacteriological examinations were made during the first week after calving. The presence of bacteria was found in secretion of 22.6-38.9% udder quarters in 56.2-71.2% of pregnant heifers. The number of infected quarters (cows) did not change distinctly in the first week after calving except the lysozyme dimer group, where a decrease by 30% was noted. The percentage of quarters with elevated somatic cell count was higher in antibiotic DC group and closely similar in the other groups. None of examined methods showed an acceptable prophylactic effect. Clinical mastitis cases during first week after parturition were mostly caused by Escherichia coli, Staph. chromogenes, Staph. simulans, Staph. aureus, Staph. hyicus, Str. uberis, Str. acidominimus and Enterococcus faecalis.     

Clinical features of consecutive intramammary infections with Streptococcus agalactiae in vaccinated and non-vaccinated heifers

The clinical, haematological and functional changes which followed three consecutive intramammary infections of Streptococcus agalactiae in the first lactation of eight heifers, four of which were systemically hyperimmune to the organism, are described. Irrespective of whether it was a vaccinated or non-vaccinated heifer or first, second or third infection the clinical features during the first 24 hours were characterised by elevated temperatures with hard, swollen and painful infected quarters. First infections were almost all of short duration because of self cure, while second or third infections were prolonged, with intermittent excretion of bacteria and low cell counts. Milk yields of infected quarters were depressed, ranging from 8 per cent in short infections to 31 per cent in chronic infections. All blood parameters remained within normal limits with the exception of total and differential white cell counts, which showed a change from a quantitative to a qualitative response by the third infection. The most significant finding was the absence of any real difference between the systemically hyperimmune and the non-vaccinated heifers, suggesting that circulating antibody has little effect against intramammary infection.     

Risk factors associated with the presence of viable Listeria monocytogenes in bulk tank milk from US dairies

The objective of the study was to screen a large number of herd management practices and herd characteristics from US dairies to identify herd-level risk factors associated with the presence of Listeria monocytogenes in bulk tank milk (BTM). A total of 71 variables was univariately evaluated for their association with the presence of L. monocytogenes in BTM. Results from the univariate analysis indicated that using automatic take offs and having an open herd management increased the risk of BTM contamination with L. monocytogenes, while storing manure in outside pens not accessible to cattle decreased the risk. These variables, however, were not sustained in the multivariable model, which indicated that the presence of L. monocytogenes in BTM was significantly associated with region of the country (farms in the southeast and northeast were six and four times more likely respectively, to have BTM contamination than farms in the west) and number of milking cows (herds with >500 milking cows were five times more likely to have BTM contamination than herds with <100 milking cows). In conclusion, our results suggest that risk factors associated with BTM contamination are different depending on the geographical region and herd size of the operation.     

Factors associated with the determination of antibiotic activity in bovine semen.

Rosaramicin, an agent shown to be effective in vitro against ureaplasma of bovine origin was tested as an additive to bovine semen extender. Although some reduction in semen quality occurred it was still deemed satisfactory for use. In a test involving 41 cows inseminated once at estrus with rosaramicin-treated semen (162 mcg/mL) the nonreturn rate was 24% compared to a calculated average for this semen of 63% (n = 3310). The effect of centrifugation, time and temperature was examined in vitro using a combination of 150 mcg of lincomycin, 300 mcg of spectinomycin and 450 mcg of tylosin against ten strains of bovine ureaplasma. This combination has ureaplasmacidal activity and is suggested as an additive to semen extenders for the control of ureaplasma.     

Bacteriological survey of mammary secretions from prepartum heifers in a dairy herd with a high prevalence of Staphylococcus aureus infection

This study was performed to examine the bacteriological findings in 58 mammary secretions from 15 heifers at 4-5 weeks before parturition, and to evaluate whether a high prevalence of S. aureus infection in lactating cows affects the occurrence of S. aureus infection in prepartum heifers in the dairy herd. A total of 86.7%(13/15) of the heifers and 60.3%(35/58) of quarter milk samples from the heifers were bacteriologically positive. No S. aureus isolate was detected in mammary secretions from the heifers. Coagulase-negative staphylococcus (CNS) species were predominantly detected in 54.3%(19/35) and Streptococci other than Streptococcus agalactiae were isolated from 22.9%(8/35) of the quarters. A high S. aureus prevalence in the herd may not necessarily be a decisive factor for S. aureus infection in heifers.     

Association between measures of milk quality and risk of violative antimicrobial residues in grade-A raw milk

OBJECTIVE: To determine whether bulk-tank standard plate counts or plate loop counts and bulk-tank somatic cell counts (SCC) were associated with detection of violative antimicrobial residues in milk from dairy cattle. DESIGN: Longitudinal study. PROCEDURE: Information for 1994 through 1997 was obtained from a large milk marketing cooperative that operated in multiple states throughout the northeastern and midwestern United States (16,831 herd-years of information from 6,546 farms) and from the Ohio Department of Agriculture Grade-A Milk Certification Program (12,042 herd-years of information from 4,022 farms). Data were analyzed by use of multivariate logistic regression. RESULTS: For both data sets, odds that a violative antibiotic residue would be detected increased as mean SCC for the herd-year increased. Standard plate counts and plate loop counts were not associated with odds that a violative antibiotic residue would be detected. CONCLUSIONS AND CLINICAL RELEVANCE: Results of this study suggested that the odds that a violative antibiotic residue would be found in bulk-tank milk increased as mean SCC for the herd-year increased. This suggests that management practices that would be expected to influence SCC may also influence the risk of antibiotic residue violations.     

Factors associated with the effectiveness of antibiotic treatment for ovine virulent footrot

Factors associated with the proportion of sheep cured of virulent footrot after antibiotic treatment were studied in a field trial under dry environmental conditions. From 2 similar flocks, 1091 Merino sheep weighing about 50 kg and infected with virulent footrot received an intramuscular injection of either 12 mL of a mixture of penicillin (250 mg/mL) and streptomycin (250 mg/mL), 6 mL of long acting oxytetracycline (200 mg/mL) or 6 mL of a mixture of lincomycin (50 mg/mL) and spectinomycin (100 mg/mL). Variables that were significantly associated with the proportion of sheep cured were: the type of antibiotic used, the number of feet infected and the flock from which the sheep came. There was an interaction between antibiotic type and number of feet infected and between antibiotic type and flock in association with the proportion of sheep cured. The extent of paring and the occurrence of blowfly strike in footrot lesions treated with diazinon had no significant association with the proportion of sheep cured.