Elimination kinetics of ceftiofur hydrochloride after intramammary administration in lactating dairy cows

OBJECTIVE: To determine the elimination kinetics of ceftiofur hydrochloride in milk after intramammary administration in lactating dairy cows. DESIGN: Prospective study. ANIMALS: 5 lactating dairy cows. PROCEDURE: After collection of baseline milk samples, 300 mg (6 mL) of ceftiofur was infused into the left front and right rear mammary gland quarters of each cow. Approximately 12 hours later, an additional 300 mg of ceftiofur was administered into the same mammary gland quarters after milking. Milk samples were collected from each mammary gland quarter every 12 hours for 10 days. Concentrations of ceftiofur and its metabolites in each milk sample were determined to assess the rate of ceftiofur elimination. RESULTS: Although there were considerable variations among mammary gland quarters and individual cows, ceftiofur concentrations in milk from all treated mammary gland quarters were less than the tolerance (0.1 microg/mL) set by the FDA by 168 hours (7 days) after the last intramammary administration of ceftiofur. No drug concentrations were detected in milk samples beyond this period. Ceftiofur was not detected in any milk samples from nontreated mammary gland quarters throughout the study. CONCLUSIONS AND CLINICAL RELEVANCE: Ceftiofur administered by the intramammary route as an extra-label treatment for mastitis in dairy cows reaches concentrations in milk greater than the tolerance set by the FDA. Results indicated that milk from treated mammary gland quarters should be discarded for a minimum of 7 days after intramammary administration of ceftiofur. Elimination of ceftiofur may be correlated with milk production, and cows producing smaller volumes of milk may have prolonged withdrawal times.     

Posology and Field Efficacy Study with Novobiocin for Intramammary Infusion in Nonlactating Dairy Cows

Four dose levels of novobiocin (50, 200, 400, 600 mg) were compared with no drug for the intramammary treatment of Staphylococcus aureus, Streptococcus agalactiae and other streptococcal infections present in the udder of dairy cows at the initiation of the dry period. Treatment success was evaluated by comparing the microbiological status of duplicate pretreatment quarter milk samples collected at drying off with the microbiological status of duplicate quarter milk samples collected four to ten days postcalving. Infection status of 1318 cows in 75 herds in five geographic locations was determined. Treatment effects on infected cows were evaluated by least squares analysis of variance with treatment, herd, lactation number, days dry and milk production at drying off considered as variables. The dose of 400 mg novobiocin per quarter was demonstrated to be significantly more effective (P < 0.05) than no drug and significantly better than (P < 0.05) or equal to the other doses for curing infections caused by S. aureus, S. agalactiae and other streptococci. A significant reduction (P < 0.05) in the overall rate of new udder infections acquired during the dry period was observed in cows treated with ≥ 200 mg novobiocin at drying off. The data supported the conclusion that the cow rather than the quarter is the appropriate experimental unit in the evaluation of intramammary mastitis treatments. Herd and lactation number were the most significant variables affecting cures.     

奶牛乳房内灌注头孢噻呋钠的消除动力学研究

在奶牛乳房内灌注头孢噻呋钠后,采用超高效液相色谱一串联质谱法测定牛乳中头孢噻呋的浓度,对其消除动力学进行了研究。3头实验奶牛按每个乳房0．3g头孢噻呋灌注,牛乳中药物达到的最高浓度Cmax=107．89μg／mL,达峰时间Tmax=8h,药物半衰期T1/2=13．97h。在乳房内用药后的最初56h内,头孢噻呋浓度快速下降;最后一次给药88h后,所有乳腺中头孢噻呋的浓度都低于允许限量（0．1μg／mL）。故建议头孢噻呋在牛奶中的休药期为4d。     

Resistance mechanisms of the bovine udder: new implications for mastitis control at the teat end

Investigations on bovine teat-end defenses and their role in mastitis control were reviewed. Alteration of teat canal keratin by method of intramammary drug infusion through the teat canal influenced the number of new infections. At the beginning of the nonlactating period, 2 methods of administering antibiotic were studied: full insertion of treatment syringe cannulas into teat cisterns and expelling contents and partial insertion of cannulas into the distal 2 to 3 mm of teat canals and slowly infusing contents. Partial cannula insertion reduced new infections by 50% and is an easily adopted management tool to reduce prevalence of mastitis. Intramammary devices used during lactation and the nonlactating period increased leukocyte concentrations in mammary secretions. An abraded polyethylene coil device reduced clinical mastitis and increased milk yield. Staphylococci colonize teat canal keratin and lacteal secretions of dairy heifers as early as 9 months of age, leading to intramammary infection at time of calving and persisting into lactation. Subsequent somatic cell counts are associated with milk production losses. Previously, such infections were shown to be associated only with older, mature animals.     

Assessment of antimicrobial transfer from treated to untreated mammary gland quarters by use of high-pressure liquid chromatography for detection of cloxacillin in milk samples from nonlactating dairy cows

OBJECTIVE: To determine whether half-udder intramammary infusion of cloxacillin results in transfer of cloxacillin from treated to untreated mammary gland quarters within nonlactating cows, and, if so, at what concentrations, and to determine whether selection of ipsilateral versus diagonal-contralateral quarters for treatment affects cloxacillin transfer among quarters. ANIMALS: 20 Holstein-Friesian cows from a dairy herd. PROCEDURES: A within-cow half-udder comparison trial was used in which 2 of 4 mammary gland quarters (ipsilaterally or diagonally) received an intramammary infusion of cloxacillin on day 1 of the nonlactating period. Three days later, milk samples were taken from all untreated quarters and high-pressure liquid chromatography was used to detect and quantify milk cloxacillin concentrations. RESULTS: Cloxacillin was detected in 25% of all untreated mammary gland quarters. Mean cloxacillin concentration in untreated quarters was below minimum inhibitory concentrations for targeted mastitis pathogens. No significant difference in cloxacillin concentrations was found in the ipsilateral or diagonal treatment groups. CONCLUSIONS AND CLINICAL RELEVANCE: Within-cow half-udder comparison trials are valid for antimicrobial trials in nonlactating cows, although transfer of antimicrobials does occur in trace concentrations. Ipsilateral or diagonal-contralateral treatment designs perform similarly. This type of design is economical for researchers, although care must be taken to account for within-cow clustering of mammary gland quarter data.     

Persistence of antibiotics in bovine mammary secretions following intramammary infusion at cessation of milking

A study was conducted to determine the persistence of antibiotic preparations for use in nonlactating cows in bovine mammary secretions following intramammary infusion at cessation of milking. Five commercially available antibiotic formulations were evaluated using 311 cows. All quarters of each cow were sampled once only during the nonlactating period and most cows were sampled at or near parturition. Antibiotic residues were detected qualitatively by the Bacillus stearothermophilus disc assay. Great variation between different antibiotics in persistence in mammary secretion was observed. In general, mammary secretions from most mammary glands infused with cloxacillin or penicillin-dihydrostreptomycin were positive at 28–35 days after infusion and some were positive at 42–49 days after infusion. On the other hand, <13% of mammary secretions at 7 days after infusion of novobiocin and 50% of mammary secretions at 14 days after infusion of penicillin-novobiocin were positive for antibiotics. Cephapirin benzathine persisted for about 21 days after infusion. Some samples that were positive for antibiotics after initial testing were negative following heating of samples, suggesting that component(s) of dry secretion can inhibit growth of B. stearothermophilus and influence the interpretation of results. Colostrum samples from all quarters except one were negative for antibiotics. These data suggest that nonlactating-cow antibiotic formulations persist primarily during the early to mid-nonlactating period. Based upon present methods of formulation, it would appear that antibiotic preparations for use in nonlactating cows most likely provide little protection during the periparturient period, at a time when mammary glands are highly susceptible to new intramammary infections.     

Efficacy of extended pirlimycin hydrochloride therapy for treatment of environmental Streptococcus spp and Staphylococcus aureus intramammary infections in lactating dairy cows

Fifty-one chronically infected lactating dairy cows were used to evaluate the efficacy of extended pirlimycin therapy regimens for treatment of intramammary infections by environmental Streptococcus spp and Staphylococcus aureus. Cows (n = 47) with one or more infected mammary quarters were blocked by parity and randomly allocated to one of three groups for treatment with pirlimycin (50 mg/mammary quarter) as follows: one treatment per day for 2 days (n = 36 infected mammary quarters); one treatment per day for 5 days (n = 36 infected mammary quarters); and one treatment per day for 8 days (n = 20 infected mammary quarters). Four cows with nine infected mammary quarters were included as untreated controls. Milk samples from each mammary quarter were collected 7 days before treatment, immediately before treatment, and weekly for 4 weeks after the final treatment for microbiological evaluation. A bacteriologic cure was defined as a treated, infected quarter that was bacteriologically negative for the presence of previously identified bacteria at weekly intervals after treatment. Efficacy of pirlimycin therapy against intramammary infections caused by environmental Streptococcus spp and S. aureus was 44.4%, 61.1%, and 95.0% for the 2-, 5-, and 8-day treatment regimens, respectively. None of the infections in the untreated control quarters was cured. Significant differences in efficacy were detected between all pirlimycin groups and the untreated control group, between the 8- and 2-day treatment regimens, and between the 8-day and 5-day treatment regimens (P < or = .05). Results of this study indicate that extended pirlimycin therapy was effective in eliminating intramammary infections caused by environmental streptococci and S. aureus in lactating dairy cows.     

Milk and serum concentration of ceftiofur following intramammary infusion in goats

Five dairy goats were used to determine the milk and serum concentrations along with elimination characteristics of ceftiofur following intramammary administration. One udder half of each goat was infused twice with 125 mg ceftiofur with a 24‐h interval between infusions. Milk samples were collected at 1, 2, 8, and 12 h after the last infusion and then every 12 h for a total of 7 days. Blood was collected from each animal at 3, 8, 12, and 24 h after infusion and then every 24 h for 6 days. Following a washout period of 1 week, the experiment was repeated using the opposite udder half. The elimination half‐life of ceftiofur from the mammary gland was 4.7 h. The concentration of ceftiofur was greater than published MIC₉₀ values for Staphylococcus spp. bacteria for 24 h. Ceftiofur was absorbed into systemic circulation from the mammary gland. The maximum concentration was 552 ng/mL at 3 h after infusion, and the serum elimination half‐life was 10 h. Intramammary infusion of 125 mg ceftiofur every 24 h can be expected to maintain drug concentration in milk above published MIC₉₀ for Staphylococcus spp.     

Acute coliform mastitis in buffaloes (Bubalus bubalis): Clinical findings and treatment outcomes

This report was delineated to study the clinical, bacteriological and therapeutic aspects concerned with acute coliform mastitis in buffaloes. Bacteriological examination of 80 quarter milk samples obtained aseptically from 56 buffaloes with acute mastitis revealed that coliform bacteria was the most common pathogen (45 cases) followed by Staphylococcus aureus (seven cases) then Streptococcus uberis (three cases), and Streptococcus agalactiae (one case). Clinically, hotness, swelling and painful reaction with serous excretion containing clots was recorded in buffaloes with coliform mastitis. The efficacy of ceftiofur was evaluated in the treatment of buffaloes with acute coliform mastitis. Parenteral ceftiofur neither improved clinical signs nor returned milk to pre-infection production level, whereas intramammary ceftiofur and combination of intramammary with parenteral ceftiofur improved the clinical signs in 10/15 and 12/15 buffaloes, respectively. On quarter level, 3/17, 12/17 and 15/21 quarters recovered in groups received parenteral, intramammary and combination therapy, respectively. This study demonstrates that systemic ceftofur is not effective in the treatment of clinical coliform mastitis in buffaloes.     

Pathogen group specific risk factors at herd, heifer and quarter levels for intramammary infections in early lactating dairy heifers

Risk factors for intramammary infections caused by coagulase-negative staphylococci, contagious major pathogens and environmental major pathogens in early lactating heifers were evaluated at the herd, heifer and quarter levels. In total, 764 quarters of 191 dairy heifers in 20 randomly selected farms in Flanders (Belgium) were sampled. Quarter milk samples were collected between 1 and 4 days in milk and between 5 and 8 days in milk for bacteriological culture. Data were analyzed using multivariable, multilevel logistic regression analysis. Higher average herd milk somatic cell count (>200,000 cells/mL), not having an effective fly control strategy, contact with lactating cows prior to calving and moderate to severe udder edema prior to calving increased the odds of intramammary infections caused by contagious major pathogens. Poor heifer hygiene and lack of mineral/vitamin supplementation prior to calving were risk factors for intramammary infection caused by environmental major pathogens. Teat apex colonization with coagulase-negative staphylococci prior to calving seemed to protect quarters against intramammary infections caused by major pathogens. Poor heifer hygiene before calving, a non-clipped udder and not practicing of teat dipping prior to calving increased the odds of intramammary infection with coagulase-negative staphylococci. Although management is important in the prevention and control of intramammary infections in early lactating heifers, most variation in the prevalence of intramammary infections resided at the heifer and quarter levels, indicating that the susceptibility for intramammary infections around calving is mainly determined by heifer and quarter characteristics.     

Gram-negative bacterial infections of the mammary gland in cows

Naturally acquired gram-negative bacterial intramammary infections (n = 160) were studied in 99 cows over a 2-year period. Escherichia coli, Klebsiella spp, Serratia spp, Enterobacter spp, and unidentified gram-negative bacteria were isolated from 28.8, 39.4, 9.4, 5.0, and 11.2%, respectively, of infected mammary glands. A majority (61%) of intramammary infections were first detected during the nonlactating period. Gram-negative bacteria isolated during the first half of the nonlactating period were predominantly Klebsiella spp, Serratia spp, and Enterobacter spp. Onset of E coli intramammary infections was more prevalent during the second half of the nonlactating period and during the first 7 days of lactation. The majority (59%) of infections were less than 28 days in duration, but Klebsiella spp and Serratia spp infections were of significantly (P less than 0.05) greater duration than infections with E coli. The greatest percentage (47%) of gram-negative bacterial intramammary infections were first detected during the summer.     

Efficacy of using an internal teat sealer to prevent new intramammary infections in nonlactating dairy cattle

OBJECTIVE: To determine whether insertion of an internal teat sealer (ITS) at the end of lactation would prevent development of new intramammary infections (IMIs) during the nonlactating period. DESIGN: Controlled clinical trial. ANIMALS: 939 Holstein-Friesian dairy cows from 16 herds. PROCEDURES: Results of bacteriologic culture of milk samples collected 14 days prior to the end of lactation were used to assign cows to groups (group 1 = negative results for all quarters; group 2 = positive results for > or = 1 quarter). Quarters of cows in group 1 were treated with an ITS or a single intramammary dose of cloxacillin; quarters of cows in group 2 were treated with cloxacillin in conjunction with an ITS or with cloxacillin alone. Milk samples were collected at the end of lactation and within 8 days after calving. RESULTS: Regardless of whether the outcome of interest was new IMIs caused by any pathogens, major pathogens, environmental pathogens, or streptococci other than Streptococcus agalactiae, quarters in group 2 treated with both cloxacillin and an ITS were less likely to develop a new IMI than were quarters treated with cloxacillin alone. For cows in group 1, no significant difference in risk of new IMIs was found between treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that for dairy cattle with an IMI late in the lactation period, intramammary administration of cloxacillin at the end of lactation followed by insertion of an ITS enhanced protection against development of new IMIs, compared with use of cloxacillin alone.     

Experimental intramammary infection of the dairy cow with Escherichia coli during the nonlactating period

The nonlactating mammary gland was experimentally inoculated with Escherichia coli. During the first half of the nonlactating period, 32% of 34 inoculated glands were temporarily infected. All intramammary infections were eradicated by the cow without therapy and no signs of mastitis were observed. During the 30 days before parturition occurred, 88% of 42 inoculated glands in the cows became infected. Twenty-three intramammary infections were eradicated by the cow and infection in 14 glands persisted after parturition occurred. Peracute toxic mastitis occurred in those cows with infected glands.     

Intramammary antibiotic treatment at the end of lactation for prophylaxis and treatment of intramammary infections in ewes

Ewes treated by intramammary infusion of cephapirin benzathine at the end of lactation were less likely to develop new intramammary infections by early in the next lactation. A controlled clinical trial involving 135 treated ewes and 145 untreated control ewes evaluated the prophylactic and treatment efficacy of intramammary antibiotic treatment of ewes at the time of weaning lambs. Milk samples for bacteriologic examination and identification of intramammary infections were collected at weaning of lambs and 1 to 3 weeks into the subsequent lactation. Untreated ewes were 2.6 times more likely than treated ewes to develop new intramammary infections between sampling times. Existence of an intramammary infection in one mammary gland significantly increased the risk of the other mammary gland becoming infected. Treatment also appeared to be associated with a higher cure rate of existing infections.     

Efficacy of extended pirlimycin therapy for treatment of experimentally induced Streptococcus uberis intramammary infections in lactating dairy cattle

Streptococcus uberis is an important cause of mastitis in dairy cows throughout the world, particularly during the dry period, around the time of calving, and during early lactation. Strategies for controlling S. uberis mastitis have not received adequate research attention and are therefore poorly defined and inadequate. Objectives of the present study were to evaluate the efficacy of extended therapy regimens with pirlimycin for treatment of experimentally induced S. uberis intramammary infections in lactating dairy cows during early lactation and to evaluate the usefulness of the S. uberis experimental infection model for evaluating antimicrobial efficacy in dairy cows. The efficacy of extended pirlimycin intramammary therapy regimens was investigated in 103 mammary glands of 68 dairy cows that became infected following experimental challenge with S. uberis during early lactation. Cows infected with S. uberis in one or both experimentally challenged mammary glands were randomly allocated to three groups, representing three different treatment regimens with pirlimycin, including 2-day (n = 21 cows, 31 mammary quarters), 5-day (n = 21 cows, 32 quarters), and 8-day (n = 26 cows, 40 quarters). For all groups, pirlimycin was administered at a rate of 50 mg of pirlimycin hydrochloride via intramammary infusion. A cure was defined as an experimentally infected mammary gland that was treated with pirlimycin and was bacteriologically negative for the presence of S. uberis at 7, 14, 21, and 28 days after treatment. Experimental S. uberis intramammary infections were eliminated in 58.1% of the infected quarters treated with the pirlimycin 2-day regimen, 68.8% for the 5-day regimen, and 80.0% for the 8-day regimen. Significant differences (P <.05) in efficacy were observed between the 2-day and 8-day treatment regimens. The number of somatic cells in milk decreased significantly following therapy in quarters for which treatment was successful in eliminating S. uberis. However, there was no evidence to suggest that extended therapy with pirlimycin resulted in a greater reduction in somatic cell counts in milk than the 2-day treatment. The S. uberis experimental infection model was a rapid and effective means of evaluating antimicrobial efficacy during early lactation at a time when mammary glands are highly susceptible to S. uberis intramammary infection.     

Growth of Staphylococcus aureus and Streptococcus species in bovine mammary secretions during the nonlactating and peripartum periods following intramammary infusion of lipopolysaccharide at cessation of milking.

The objective was to determine if induced mammary inflammation at cessation of milking influenced growth of gram-positive mastitis pathogens in mammary secretions, particularly during early involution. Growth of all mastitis pathogens evaluated was similar in cell-free fat-free mammary secretions from LPS-infused and control glands. These data indicate that intramammary infusion of LPS at cessation of milking did not alter growth of gram-positive mastitis pathogens in mammary secretion during the nonlactating period. Stage of lactation and the nonlactating period influenced bacterial growth and marked differences between bacteria and among strains of a bacterial species were observed. Staphylococcus aureus grew well in secretions collected during late lactation, but growth decreased during early- and mid-involution and increased again in secretions obtained near parturition. Streptococcus agalactiae and Strep. uberis grew better in mammary secretion obtained during involution than in secretions collected during late or early lactation. Streptococcus dysgalactiae grew well in mammary secretions at all time periods. These data demonstrate the variability of mastitis pathogen growth during physiologic transitions of the bovine udder.     

Function of phagocytes obtained from lacteal secretions of lactating and nonlactating cows

Phagocytes, macrophages and neutrophils, were obtained from lacteal secretions of lactating (n = 13) and nonlactating cows (n = 14). Secretions from nonlactating cows were collected at 7 and 14 days after cessation of lactation. Phagocytes were incubated in vitro with Staphylococcus aureus or Escherichia coli, and function was assessed by fluorescent microscopy of cell suspensions stained with acridine orange and crystal violet. A greater percentage of macrophages from nonlactating cow secretions collected on day 14 phagocytized bacteria than did those collected on day 7. A greater percentage of macrophages from nonlactating cow secretions collected on days 7 and 14 phagocytized bacteria than did neutrophils obtained from the same secretions. A similar percentage of phagocytes from nonlactating cow secretions phagocytized bacteria, compared with phagocytes from lactating cow secretions. Results indicated that the intramammary macrophage may be most important in defense of the mammary gland during the early nonlactating period, because it was more phagocytic than the neutrophil and was more active at 14 days than at 7 days into the nonlactating period.     

Efficacy of extended intramammary ceftiofur therapy against mild to moderate clinical mastitis in Holstein dairy cows: A randomized clinical trial

Few studies have investigated the efficacy of extended ceftiofur therapy and none have focused on extended therapy for naturally occurring clinical mastitis. The objective of this study was to compare the efficacy of extended intramammary ceftiofur therapy of 8 d duration with a standard 2-day regimen for the treatment of naturally occurring mild to moderate clinical mastitis in lactating dairy cows. Holstein cows from 22 dairy herds (n = 241) were randomly allocated to the 2 treatment groups. For each case of mastitis, 125 mg of ceftiofur hydrochloride was administered intramammary once a day for 2 or 8 d. Clinical cure, 21 d after the last treatment, was 89% (98/110) in each group. Bacteriological cure 21 d after the last treatment for the 2- and 8-day regimens were 32% (15/47) and 61% (25/41), respectively, for all bacteria (P = 0.007), 64% (9/14) and 82% (9/11), respectively, for streptococci (P = 0.50), and 0% (0/20) and 47% (9/19), respectively, for Staphylococcus aureus (P = 0.0004). There were no statistical differences between groups for new intramammary infections. Overall, ceftiofur extended therapy increased cure when compared to a 2-day regimen for the treatment of naturally occurring mild to moderate clinical mastitis in lactating dairy cows.     

Experimental infection of bovine mammary glands with Streptococcus agalactiae during the nonlactating period

Two experiments were done to determine the rate of intramammary infection (IMI) in dairy cows during the nonlactating period. In experiment 1, all glands were equally exposed to Klebsiella pneumoniae and Streptococcus agalactiae for the first 3 weeks after the start of the nonlactating period. Nearly all new IMI was caused by S agalactiae. In experiment 2, the susceptibility of nonlactating mammary glands to new IMI by S agalactiae after direct inoculation into the lactiferous sinus was determined. During the 1st month of the nonlactating period, 30% of inoculated glands became infected. During the last month of the nonlactating period, 90% of inoculated glands became infected.     

Effects of temporary cessation of milking following intramammary cefazolin sodium infusion on residual antibiotic in lactating dairy cows

The aims of studies were to estimate the withdrawal period of antibiotic from milk after the intramammary infusion of cefazolin sodium (CEZ) in cows with difficulties in frequent milk discharge due to disease such as teat injury. The period was compared among cows milked twice a day after 150 or 450 mg of CEZ were administered to all quarters (Study 1, 2) and the cows in which milking of front-right quarter was ceased for five days after administration of these infusions to only that quarter (Study 3). In Studies 1 and 2, the median of 17.66 µg/ml and 83.18 µg/ml of CEZ were detected in the samples of first milking after intramammary administration, respectively; however, there was no residual antibiotic by 72 hr in all cows. In Study 3, the median of 1.96 µg/ml of CEZ was detected in the sample after the resumption of milking at 120 hr, and the residual was eliminated by 174 hr. The withdrawal period may be prolonged by the cessation of milking after administration, and the period is the total time from cessation to 72 hr after the resumption of milking.