mobic and Mastitis--Bovine

Nonsteroidal anti-inflammatory drugs (NSAID) are commonly used in combination with antimicrobial mastitis treatments to reduce pain. Little is known about whether meloxicam, an NSAID designed for the preferential inhibition of cyclooxygenase-2 over cyclooxygenase-1, affects the mammary immune response. The objective of this study was to analyze the mammary immune response to intramammary (local) or intravenous (systemic) administration of meloxicam with or without immune activation by lipopolysaccharide (LPS). We challenged 108 quarters of 30 cows with or without a low or high dose of LPS from Escherichia coli (0.1 or 0.2 µg/quarter), with or without meloxicam via intramammary administration (50 mg/quarter) or intravenous injection (0.5 mg/kg of body weight; ~300 mg/cow). Intramammary administration of meloxicam alone did not trigger an acute inflammatory response, verified by unchanged somatic cell count (SCC) and lactate dehydrogenase (LDH), BSA, and IgG concentrations in milk, which are normally augmented during mastitis due to an opening of the blood-milk barrier. Similarly, intramammary meloxicam did not change the mRNA abundance of inflammatory factors in mammary gland tissue. As expected, quarters challenged with either dose of LPS showed increased leukocyte infiltration (SCC); increased LDH, BSA, IgG, Na, and Cl concentrations; and diminished K concentrations in milk. In contrast to our hypothesis, the addition of intramammary or intravenous meloxicam did not reduce these markers of mastitis in milk. Instead, intramammary meloxicam appeared to accelerate the SCC response to LPS, but only at the lower LPS dose. Moreover, the mRNA expression of inflammatory factors in mammary tissue was not modified by the intramammary application of meloxicam compared with the contralateral quarters that were challenged with LPS only. We demonstrated for the first time that intramammary meloxicam at a dose of 50 mg/quarter did not trigger an immune response in the mammary glands of dairy cows. At the doses we used, meloxicam (intramammary or systemic) did not lower inflammatory responses. The intramammary administration of meloxicam seemed to stimulate leukocyte recruitment into the milk in quarters challenged with a low dose of LPS. The integrity of the blood-milk barrier was not protected by meloxicam in LPS-stimulated quarters. This study provides the first indications that meloxicam does not limit the inflammatory response in the mammary gland, although it does

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cattle; Cell Count; Escherichia coli; Female; Inflammation; Lipopolysaccharides; Mammary Glands, Animal; Mastitis, Bovine; Meloxicam; Milk

Parturition is a painful event experienced by cows at the onset of lactation. This pain could lead to a reduced feed intake, altered metabolic and immunological status, and a host of other diseases that could seriously limit her productive herd lifespan. The objective of the current study was to assess the effect of administration of a single dose of oral meloxicam, a non-steroidal anti-inflammatory drug (NSAID), on the production and health status of cows during their lactation. A total of 2,653 (1,009 meloxicam-treated and 1,644 untreated control) cows were enrolled across 20 herds in the provinces of Ontario and Quebec, Canada. Relative to untreated controls, meloxicam-treated cows produced 0.64 kg/day (SE = 0.29. P = 0.03) more milk over the first 3 test days (90-120 days in lactation), had 0.75 times the odds of subclinical mastitis at first test (SE = 0.08, P = 0.01), and were culled or died at 0.46 times the rate (SE = 0.16, P = 0.03) before 60 days in milk. These results are consistent with previous research and lend support to the hypothesis that parturition is a painful event in cattle. Attempts to ameliorate such pain with analgesics is associated with a variety of positive health and production outcomes.

Topics: Administration, Oral; Animal Husbandry; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cattle; Cattle Diseases; Dairying; Female; Lactation; Mastitis, Bovine; Meloxicam; Parturition; Random Allocation; Treatment Outcome

A blinded, negative controlled, randomized intervention study was undertaken to test the hypothesis that addition of meloxicam, a nonsteroidal anti-inflammatory drug, to antimicrobial treatment of mild to moderate clinical mastitis would improve fertility and reduce the risk of removal from the herd. Cows (n=509) from 61 herds in 8 regions (sites) in 6 European countries were enrolled. Following herd-owner diagnosis of mild to moderate clinical mastitis within the first 120 d of lactation in a single gland, the rectal temperature, milk appearance, and California Mastitis Test score were assessed. Cows were randomly assigned within each site to be treated either with meloxicam or a placebo (control). All cows were additionally treated with 1 to 4 intramammary infusions of cephalexin and kanamycin at 24-h intervals. Prior to treatment and at 14 and 21 d posttreatment, milk samples were collected for bacteriology and somatic cell count. Cows were bred by artificial insemination and pregnancy status was subsequently defined. General estimating equations were used to determine the effect of treatment (meloxicam versus control) on bacteriological cure, somatic cell count, the probability of being inseminated by 21 d after the voluntary waiting period, the probability of conception to first artificial insemination, the number of artificial insemination/conception, the probability of pregnancy by 120 or 200 d postcalving, and the risk of removal by 300 d after treatment. Cox's proportional hazards models were used to test the effect of treatment on the calving to first insemination and calving to conception intervals. Groups did not differ in terms of age, clot score, California Mastitis Test score, rectal temperature, number of antimicrobial treatments given or bacteria present at the time of enrollment, but cows treated with meloxicam had greater days in milk at enrollment. Cows treated with meloxicam had a higher bacteriological cure proportion than those treated with the placebo [0.66 (standard error=0.04) versus 0.50 (standard error=0.06), respectively], although the proportion of glands from which no bacteria were isolated posttreatment did not differ between groups. No difference was observed in the somatic cell count between groups pre- or posttreatment. The proportion of cows that underwent artificial insemination by 21 d after the voluntary waiting period was unaffected by treatment. Treatment with meloxicam was associated with a higher proportion of co

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Bacteria; Cattle; Cell Count; Cephalexin; Drug Therapy, Combination; Europe; Female; Fertility; Fertilization; Insemination, Artificial; Kanamycin; Lactation; Mastitis; Mastitis, Bovine; Meloxicam; Milk; Pregnancy; Reproduction; Thiazines; Thiazoles

The current study was designed to characterize methicillin-resistant Staphylococcus aureus (MRSA) isolated from bovine milk, along with its response to antibiotics, and ultimately reverse its mechanism of resistance by modulation with non-antibiotics. The synergistic combination of antibiotics with NSAIDs were tested in-vivo by giving MRSA challenge to rabbits. The current study reported an overall 23.79% prevalence of MRSA. The BLAST alignment of current study sequences revealed 99% similarity with mecA gene of MRSA from NCBI database. The current study isolates were more similar to each other and also with reference sequences as compared to other mecA gene sequences from Turkey, India, and Russia. Antibiogram of MRSA isolates showed a highly resistant response to cefoxitin, amoxicillin, and gentamicin. Amoxicillin, gentamicin, tylosin, vancomycin, and ciprofloxacin elicited a significant response (p < 0.05) in combination with non-antibiotics against tested MRSA isolates. The highest zone of inhibition (ZOI) increase was noted for vancomycin in combination with flunixin meglumine (145.45%) and meloxicam (139.36%); gentamicin with flunixin meglumine (85.71%) and ciprofloxacin with ivermectin (71.13%). Synergistic behavior was observed in the combination of gentamicin with ketoprofen; sulfamethoxazole and oxytetracycline with meloxicam. Hematological analysis showed significant differences (p < 0.05) among lymphocyte count and bilirubin. On histopathological examination of skin tissue, hyperplasia of epithelium, sloughed off epidermis, hyperkeratosis, infiltration of inflammatory cells, and hemorrhages were observed. The highest cure rate was observed in case of gentamicin in combination with ketoprofen as compared to other treatment groups. The current study concluded antibiotics in combination with non-antibiotics as potential therapeutic agents for resistance modulation against MRSA. This study will help to devise treatment and control strategies against bovine mastitis. Although the prospect of using NSAIDs to manage infections caused by MRSA appears to be a promising direction, further studies should be conducted to test these medications using suitable in-vivo models in controlled clinical trials to justify their repurposing as a treatment for MRSA infections.

Topics: Amoxicillin; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Bilirubin; Cattle; Cefoxitin; Ciprofloxacin; Drug Repositioning; Female; Gentamicins; Ivermectin; Ketoprofen; Mastitis, Bovine; Meloxicam; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Oxytetracycline; Rabbits; Staphylococcal Infections; Sulfamethoxazole; Tylosin; Vancomycin

During inflammation of the mammary gland, the blood-milk barrier, which is predominantly composed of mammary epithelial cells, loses its integrity and gradients between blood and milk cannot be maintained. Nonsteroidal anti-inflammatory drugs (NSAID) are commonly used systemically in combination with local administration of antimicrobials in mastitis treatments of dairy cows to improve the well-being of the cow during the disease. However, the knowledge about their effects on the blood-milk barrier is low. This study aimed to investigate effects of different NSAID, with different selectivity of cyclooxygenase-inhibition, on the transepithelial electrical resistance (TEER) and capacitance, cell viability, and expression of tumor necrosis factor α of bovine mammary epithelial barriers in vitro. Primary mammary epithelial cells of 3 different cows were challenged with lipopolysaccharide (LPS) from Escherichia coli with or without addition of ketoprofen (1.25 mg/mL or 4 mM), flunixin meglumine (1.0 mg/mL or 4 mM), meloxicam (0.25 mg/mL, 0.75 mg/mL, or 4 mM), diclofenac (0.75 mg/mL or 4 mM) or celecoxib (0.05 mg/mL) for 6 h. Concentrations were adapted to comparable relations of the recommended dosage for systemic application. Additionally, a similar molar concentration of all NSAID was used. Lipopolysaccharide with or without NSAID induced a decrease in TEER within 5 h, which returned to control level within 14 h. Viability of cells challenged with LPS only was not affected. However, the cell viability was decreased with increasing concentrations of NSAID and this effect was amplified with simultaneous LPS challenge. Ketoprofen at both dosages, flunixin meglumine at 1.0 mg/mL, and meloxicam at 0.75 mg/mL accelerated the recovery of TEER in comparison to LPS only (return to control level within 9 h). The comparison of NSAID effects at the same molecular quantity of 4 mM showed different effect on the barrier in which ketoprofen accelerated the recovery after LPS-induced barrier opening, whereas meloxicam and diclofenac slowed down the recovery (return to control level after 24 h). In conclusion, NSAID do not prevent the mammary epithelial barrier opening by LPS; however, ketoprofen, flunixin meglumine, and meloxicam obviously support the re-establishment of the barrier integrity. Used in mastitis therapy at an optimized dosage the tested NSAID would likely support the recovery of milk composition. However, an overdose of NSAID would likely cause tissue irritat

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cattle; Cell Count; Clonixin; Cyclooxygenase Inhibitors; Epithelial Cells; Escherichia coli; Female; Inflammation; Ketoprofen; Lipopolysaccharides; Mammary Glands, Animal; Mastitis, Bovine; Meloxicam; Milk; Tumor Necrosis Factor-alpha

Nonsteroidal anti-inflammatory drugs are used as supportive therapy with antimicrobial treatments for mastitis in cows to alleviate pain of the inflamed mammary gland. They act mainly by inhibition of cyclooxygenases. Meloxicam (MEL) is a drug designed for cyclooxygenase-2 selectivity, which is upregulated upon inflammation, acting as a key enzyme for the conversion of arachidonic acid to prostaglandins. Although some studies in dairy cows showed positive results in recovery from mastitis when MEL was added to the treatments, direct effects of MEL on the immune system of mastitic cows are unknown. The aim of this study was to investigate effects of MEL on the immune response of bovine mammary epithelial cells (MEC) with or without simultaneous immune stimulation by pathogen-associated molecular patterns of common mastitis pathogens. Mammary epithelial cells from 4 cows were isolated and cultured. To evaluate dose effects of MEL, MEC were challenged with or without 0.2 µg/mL lipopolysaccharide (LPS; serotype O26:B6 from Escherichia coli) with addition of increasing concentrations of MEL (0, 0.25, 0.5, 1.0, 1.5, or 2.0 mg/mL). The addition of MEL prevented the increase of mRNA expression of key inflammatory factors in LPS-challenged MEC in a dose-dependent manner. To investigate the effects of MEL on pathogen-specific immune responses of MEC, treatments included challenges with LPS from E. coli and lipoteichoic acid from Staphylococcus aureus with or without 1.5 mg/mL MEL for 3, 6, and 24 h. Meloxicam prevented the increase of mRNA abundance of key inflammatory mediators in response to LPS and lipoteichoic acid, such as tumor necrosis factor, serum amyloid A, inducible nitric oxide synthase, and the chemokines IL-8 and CXC chemokine ligands 3 and 5. The prostaglandin E

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biomarkers; Cattle; Cyclooxygenase 2 Inhibitors; Epithelial Cells; Escherichia coli; Female; Inflammation; Lipopolysaccharides; Mammary Glands, Animal; Mastitis, Bovine; Meloxicam; Staphylococcus aureus; Teichoic Acids

Recently, it has been shown that the addition of meloxicam to standard antimicrobial therapy for clinical mastitis (CM) improves the conception rate of dairy cows contracting CM in the first 120 d in milk. The objective of our study was to assess whether this improved reproduction through additional treatment with meloxicam would result in a positive net economic benefit for the farmer. We developed a stochastic bio-economic simulation model, in which a dairy cow with CM in the first 120 d in milk was simulated. Two scenarios were simulated in which CM cases were treated with meloxicam in conjunction with antimicrobial therapy or with antimicrobial therapy alone. The scenarios differed for conception rates (31% with meloxicam or 21% without meloxicam) and for the cost of CM treatment. Sensitivity analyses were undertaken for the biological and economic components of the model to assess the effects of a wide range of inputs on inferences about the cost effectiveness of meloxicam treatment. Model results showed an average net economic benefit of €42 per CM case per year in favor of the meloxicam scenario. Cows in the no-meloxicam treatment scenario had higher returns on milk production, lower costs upon calving, and reduced costs of treatment. However, these did not outweigh the savings associated with lower feed intake, reduced number of inseminations, and the reduced culling rate. The net economic benefit favoring meloxicam therapy was a consequence of the better reproductive performance in the meloxicam scenario in which cows had a shorter calving to conception interval (132 vs. 143 d), a shorter intercalving interval (405 vs. 416 d), and fewer inseminations per conception (2.9 vs. 3.7) compared with cows in the no-meloxicam treatment scenario. This resulted in a shorter lactation, hence a lower lactational milk production (8,441 vs. 8,517 kg per lactation) with lower feeding costs in the meloxicam group. A lower culling rate (12 vs. 25%) resulted in lower replacement costs in the meloxicam treatment scenario. All of the scenarios evaluated in the sensitivity analyses favored meloxicam treatment over no meloxicam. This study demonstrated that improvements in conception rate achieved by the use of meloxicam, as additional therapy for mild to moderate CM in the first 120 d in milk, have positive economic benefits. This inference remained true over a wide range of technical and economic inputs, demonstrating that use of meloxicam is likely to be cost effect

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Cattle; Dairying; Female; Lactation; Mastitis, Bovine; Meloxicam; Milk; Models, Economic; Reproduction; Stochastic Processes; Thiazines; Thiazoles

The objectives of this study were to (1) evaluate the use of a pressure algometer and an automated rumination monitoring system to assess changes in pain sensitivity and rumination time in response to endotoxin-induced clinical mastitis and (2) evaluate the effect of the nonsteroidal antiinflammatory drug meloxicam on pain sensitivity and rumination time, as well as other clinical signs, in dairy cattle with endotoxin-induced clinical mastitis. Clinical mastitis was induced in 12 primiparous and 12 multiparous lactating dairy cows by intramammary infusion of 25 µg of Escherichia coli lipopolysaccharide (LPS) into 1 uninfected quarter. Immediately after, half the cows were injected subcutaneously with meloxicam (treated group) and half with the same volume of a placebo solution (control group). Pain sensitivity was assessed by measuring the difference in pressure required to elicit a response on the control and challenged quarter using an algometer 3 d before, immediately before, and at 3, 6, 12, and 24h after LPS infusion and either meloxicam or placebo injection. Rumination was continuously monitored from 2 d before to 3 d after LPS infusion using rumination loggers. Udder edema, body temperature, somatic cell score, and dry matter intake were also monitored to evaluate the occurrence and the duration of the inflammation after LPS infusion. In control animals, the difference in the pressure applied to the control and challenged quarters (control - challenged quarter) increased by 1.1 ± 0.4 kg of force 6h after LPS infusion compared with the baseline, suggesting an increase in pain sensitivity in the challenged quarter. Neither the LPS infusion nor the meloxicam treatment had an effect on daily rumination time. However, the rumination diurnal pattern on the day of LPS infusion showed an overall deviation from the baseline pattern. Cows spent less time ruminating in the hours following LPS infusion and more time ruminating later in the day. Meloxicam did not alter somatic cell score or dry matter intake. However, meloxicam-treated animals had less udder edema and a lower body temperature in the hours following LPS infusion compared with control animals. In conclusion, pressure algometers and rumination loggers show promise as tools to detect mastitis and monitor recovery on farm. Further, meloxicam has a beneficial effect in relieving pain and decreasing udder edema and body temperature in LPS-induced clinical mastitis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cattle; Digestion; Female; Lipopolysaccharides; Mastitis, Bovine; Meloxicam; Pain; Pain Management; Pain Measurement; Thiazines; Thiazoles

It was hypothesized that treatment of clinical mastitis with a combination of a nonsteroidal antiinflammatory treatment (meloxicam) and a parenteral antibiotic (penethamate hydriodide) would result in lower somatic cell counts (SCC), reduced milk yield losses, improved clinical outcomes, and reduced culling rates compared with antibiotic therapy alone. Cows in 15 herds with clinical mastitis during the first 200 d of lactation (median = 13 d) were treated with 5 g of penethamate hydriodide daily for 3 d, and one-half these cows were treated with 250 mg of the nonsteroidal antiinflammatory drug meloxicam (n = 361 cows), whereas the other half (n = 366 cows) were treated with the vehicle (control group). Milk samples for bacteriology were collected from clinically affected glands before treatment, and samples were collected at 7 (+/-3), 14 (+/-3), and 21 (+/-3) d after commencement of treatment for SCC determination. Additionally, the rectal temperature, udder edema score, California Mastitis Test score, and milk clot score were determined before treatment and daily milk yield data were collected across the lactation. There were no differences between the treatment groups in calving date, days in milk, age, breed, rectal temperature, California Mastitis Test score, clot score, udder edema score, or bacterial pathogens isolated before treatment. There was no difference between treatment groups in the number of cows that were defined as treatment failures (i.e., re-treated within 24 d of initial treatment, died, or the treated gland stopped producing milk); 79 (21.9%) vs. 92 (25.1%) cows in the meloxicam and control groups failed, respectively. The SCC was lower in the meloxicam-treated group compared with the control group after treatment [550 +/- 48 vs. 711 +/- 62 geometric mean (x1,000/mL) +/- standard error of the mean SCC for quarters after treatment with meloxicam vs. control, respectively]. There was no difference in milk yield for the cows treated with meloxicam compared with the control cows within 28 or 200 d after treatment. Fewer meloxicam-treated than control cows were removed (culled) from the herds [39/237 (16.4%) vs. 67/237 (28.2%) for meloxicam vs. control cows, respectively; odds ratio = 0.42, 95% confidence interval = 0.26 to 0.68]. It was concluded that treatment of cows with clinical mastitis with a combination of meloxicam and penethamate resulted in a lower SCC and a reduced risk of removal from the herd (culling) compared with treatmen

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Bacteria; Bacterial Infections; Cattle; Dairying; Female; Kaplan-Meier Estimate; Lactation; Mastitis, Bovine; Meloxicam; Milk; Odds Ratio; Penicillin G; Random Allocation; Thiazines; Thiazoles; Treatment Failure