Robust Control Based on Adaptive Neural Network for the Process of Steady Formation of Continuous Contact Force in Unmanned Aerial Manipulator.

Contact force control for Unmanned Aerial Manipulators (UAMs) is a challenging issue today. This paper designs a new method to stabilize the UAM system during the formation of contact force with the target. Firstly, the dynamic model of the contact process between the UAM and the target is derived. Then, a non-singular global fast terminal sliding mode controller (NGFTSMC) is proposed to guarantee that the contact process is completed within a finite time. Moreover, to compensate for system uncertainties and external disturbances, the equivalent part of the controller is estimated by an adaptive radial basis function neural network (RBFNN). Finally, the Lyapunov theory is applied to validate the global stability of the closed-loop system and derive the adaptive law for the neural network weight matrix online updating. Simulation and experimental results demonstrate that the proposed method can stably form a continuous contact force and reduce the chattering with good robustness.

Development and Validation for Quantification of Cephapirin and Ceftiofur by Ultraperformance Liquid Chromatography with Triple Quadrupole Mass Spectrometry.

Cross contamination of ß-lactams is one of the highest risks for patients using pharmaceutical products. Penicillin and some non-penicillin ß-lactams may cause potentially life-threatening allergic reactions. The trace detection of ß-lactam antibiotics in cleaning rinse solutions of common reactors and manufacturing aids in pharmaceutical facilities is very crucial. Therefore, the common facilities adopt sophisticated cleaning procedures and develop analytical methods to assess traces of these compounds in rinsed solutions. For this, a highly sensitive and reproducible ultra-performance liquid chromatography with triple quadrupole mass spectrometry (UHPLC-MS/MS) method was developed for the analysis of Cephapirin and Ceftiofur. As per the FDA guidelines described in FDA-2011-D-0104, the contamination of these ß-lactam antibiotics must be regulated. The analysis was performed on an XBridge C18 column with 100 mm length, 4.6 mm diameter, and 3.5 µm particle size at an oven temperature of about 40 °C. The mobile phase was composed of 0.15% formic acid in water and acetonitrile as mobile phases A and B, and a flow rate was set to 0.6 mL/min. The method was validated for Cephapirin and Ceftiofur. The quantification precision and accuracy were determined to be the lowest limit of detection 0.15 parts per billion (ppb) and the lowest limit of quantification 0.4 ppb. This method was linear in the range of 0.4 to 1.5 ppb with the determination of coefficient (R2 > 0.99). This sensitive and fast method was fit-for-purpose for detecting and quantifying trace amounts of ß-lactam contamination, monitoring cross contamination in facility surface cleaning, and determining the acceptable level of limits for regulatory purposes.

Short communication: Efficacy of a second intrauterine cephapirin infusion for the treatment of purulent vaginal discharge and endometritis in postpartum dairy cows.

The objective of this study was to quantify the efficacy of a second intrauterine cephapirin treatment administered 14 d after the initial one on subsequent reproductive performance of postpartum dairy cows affected by purulent vaginal discharge (PVD) or endometritis (ENDO). In total, 4,140 Holstein cows from 30 commercial herds were enrolled in a randomized clinical trial. At 36 (±7) d in milk, cows were examined using the Metricheck device to diagnose PVD. An endometrial cytology sample was also collected from each cow to perform a leukocyte esterase test for diagnosing ENDO. Diagnosis of PVD and ENDO was done cow-side. Cows diagnosed with PVD or ENDO were assigned to receive 1 of 2 treatments: (1) a single intrauterine cephapirin infusion (500 mg of cephapirin benzathin; Metricure, Merck Animal Health, Kirkland, QC, Canada) at the time of initial examination or (2) a single intrauterine infusion at the time of initial examination and a second one 14 d later. Subsequent reproductive and culling events were collected until 200 d in milk. Statistical analyses were performed using univariable and multivariable mixed logistic regression models. In cows affected by PVD, a second intrauterine cephapirin infusion increased the pregnancy risk at first insemination in comparison with cows that only received one treatment (28.0 vs. 38.8%). In cows affected by ENDO, a second treatment also increased the pregnancy risk at first insemination compared with cows that only received one treatment (30.3 vs. 39.2%). Overall, these results demonstrate that administering a second intrauterine cephapirin infusion 14 d after the initial treatment in postpartum cows affected by PVD or ENDO did improve their subsequent reproductive performance.

Short communication: Increasing temperature and pH can facilitate reductions of cephapirin and antibiotic resistance genes in dairy manure slurries.

Quantifying antibiotics and antibiotic resistance genes (ARG) in manure exposed to various temperature and pH treatments could guide the development of cost-effective manure handling methods to minimize the spread of antibiotic resistance following land application of manure. This study aimed to investigate the effect of various temperatures and initial pH shocks on the persistence of a cephalosporin antibiotic and ARG in dairy manure slurries. Feces and urine were collected from 5 healthy dairy cows administered with cephapirin (cephalosporin antibiotic) at dry-off via intramammary infusion and were mixed with sterile water to generate manure slurries. In a 28-d incubation study, dairy manure slurries either were continuously exposed to 1 of 3 temperatures (10, 35, and 55°C) or received various initial pH (5, 7, 9, and 12) shocks. Cephapirin was detected in the initial samples and on d 1 following all treatments, but it was undetectable thereafter. This indicates that cephapirin can be rapidly degraded irrespective of temperature and pH treatments. However, degradation was greater on d 1 with the mesophilic (35°C) and thermophilic (55°C) environments compared with the psychrophilic environment (10°C). Increasing pH beyond neutral also accelerated degradation as cephapirin concentrations were lower on d 1 after initial alkaline adjustments (pH 9 and 12) than after neutral and acidic adjustments (pH 7 and 5). No significant effect of temperature or initial pH was observed on abundances of a ß-lactam ARG, cfxA, and a tetracycline ARG, tet(W), implying that bacteria that encoded cfxA or tet(W) genes were not sensitive to temperature or pH in dairy manure slurries. However, abundances of a macrolide ARG, mefA, were decreased in the psychrophilic and thermophilic environments and also following exposure to a strong alkaline shock (pH 12). Our results suggest that increasing temperature or pH during storage of dairy manure slurries could be used together with other on-farm practices that are tailored to reduce the transfer of ARG from manure to the environment following land application.

Clinical efficacy of intrauterine cephapirin benzathine administration on clearance of uterine bacteria and subclinical endometritis in postpartum buffaloes.

This study examined the effect of single IU administration of cephapirin on clinical recovery, clearance of uterine bacteria and reproductive performance of postpartum buffaloes with subclinical endometritis (SCE). Buffaloes (n = 86) at 35 days postpartum (DPP) with >10% polymorphonuclear (PMN) cells in endometrial cytosmears were designated as positive (SCEP, n = 29), and buffaloes with ≤10% PMN cell were designated as negative (SCEN, n = 57) for SCE. Out of 29 positive buffaloes, 15 were administered a single intrauterine dose of cephapirin benzathine on 40 DPP (SCEP-CB), while the remaining 14 animals were kept as untreated control (SCEP-C). All animals were observed regularly for oestrous signs and were again subjected to cytobrush sampling on the first postpartum (FPP) oestrus. Buffaloes positive for SCE at 35 DPP were later considered "recovered" if their PMN cells dropped to ≤5% on the FPP oestrus. Presence of Escherichia coli, Arcanobacterium pyogenes and Fusobacterium necrophorum in uterus was detected based upon PCR amplification of genes related to bacteria-specific virulence factors. A total of 66.7% of SCEP-CB group buffaloes recovered as compared to 28.6% in SCEP-C (χ2  = 4.21; p < 0.05). Rate of bacterial clearance did not differ between treated (38.5%) and untreated buffaloes (8.3%) (χ2  = 1.67; p > 0.05). The median days to first service did not differ significantly (p > 0.05) among the three groups, whereas cephapirin administration reduced (p < 0.05) the days open by 14 days in SCEP-CB compared to SCEP-C buffaloes. SCEP-CB buffaloes were as likely to conceive as SCEN, whereas SCEP-C had 0.28 hazard ratio for pregnancy. In conclusion, a single treatment with cephapirin benzathine at 40 DPP improved the reproductive performance of buffaloes with subclinical endometritis.

Randomized noninferiority field trial evaluating cephapirin sodium for treatment of nonsevere clinical mastitis.

The general objective of this study was to evaluate whether cephapirin sodium is noninferior compared with a positive control broad-spectrum product formulated with a combination of antimicrobials for intramammary treatment of nonsevere clinical mastitis. In addition, we compared the efficacy of treatments on the cure risks of pathogen groups (gram-positive, gram-negative, and cultures with no growth) based on culture results. A total of 346 cows distributed in 31 commercial dairy herds were selected to participate in the study, although only 236 met the criteria for evaluation of microbiological cure. Coagulase-negative staphylococci were the most isolated gram-positive pathogens in pretreatment milk samples, whereas the most common gram-negative bacterium was Escherichia coli. Cows attending the postadmission criteria were treated with 4 intramammary infusions (12 h apart) of one of the following antimicrobials: 300 mg of cephapirin sodium + 20 mg of prednisolone (CS), or the positive control treatment formulated with a combination of antimicrobials (200 mg of tetracycline + 250 mg of neomycin + 28 mg of bacitracin + 10 mg of prednisolone; TNB). Noninferiority analysis and mixed regression models (overall and considering the pathogen groups) were performed for the following outcomes: bacteriological cure (absence of the causative pathogens in cultures performed in milk samples collected at 14 and 21 ± 3 d after enrollment), pathogen cure (absence of any pathogen on both follow-up samples), clinical cure (absence of clinical sign in the milk and mammary gland at 48 h after the last antimicrobial infusion), extended clinical cure (normal milk and normal gland on the second posttreatment sample collection (d 21), and linear score of somatic cell count cure [linear score of somatic cell count recovery (≤4.0) on d 21 ± 3 after enrollment]. No significant differences were observed between treatments regarding any of the evaluated outcomes in both regression models (overall and considering the pathogen groups). Noninferiority of CS relative to TNB was inconclusive for bacteriological cure (CS = 0.68; TNB = 0.73) and clinical cure (CS = 0.88; TNB = 0.94), as the confidence intervals crossed the pre-stated margin of noninferiority (Δ = -0.15). Cephapirin sodium was noninferior compared with TNB for pathogen cure (CS = 0.36; TNB = 0.35), extended clinical cure (CS = 0.93; TNB = 0.92), and linear score of somatic cell count cure (CS = 0.29; TNB = 0.28). In conclusion, the use of intramammary CS for treatment of nonsevere clinical mastitis has similar efficacy as a treatment regimen with a combination of antimicrobial agents (tetracycline + neomycin + bacitracin), although noninferiority analysis showed inconclusive results for bacteriological and clinical cures.

In vitro antibiotic susceptibility and biofilm production of Staphylococcus aureus isolates recovered from bovine intramammary infections that persisted or not following extended therapies with cephapirin, pirlimycin or ceftiofur.

Staphylococcus aureus intramammary infections (IMIs) have low cure rates using standard antibiotic treatment and increasing the duration of treatment usually improves therapeutic success. Chronic IMIs are thought to be caused by bacteria presenting a specific virulence phenotype that includes the capacity to produce greater amounts of biofilm. In this study, antibiotic susceptibility and biofilm production by S. aureus isolates recovered from IMIs that were cured or not following an extended therapy with cephapirin, pirlimycin or ceftiofur for 5, 8 and 8 days, respectively, were compared. An isolate was confirmed as from a persistent case (not cured) if the same S. aureus strain was isolated before and after treatment as revealed by the same VNTR profile (variable number of tandem repeats detected by multiplex PCR). The antibiotic minimal inhibitory concentrations (MICs) were determined for these isolates as well as the capacity of the isolates to produce biofilm. Isolates from persistent cases after extended therapy with cephapirin or ceftiofur had higher MICs for these drugs compared to isolates from non-persistent cases (p < 0.05) even though the antibiotic susceptibility breakpoints were not exceeded. Isolates of the ceftiofur study significantly increased their biofilm production in presence of a sub-MIC of ceftiofur (p < 0.05), whereas isolates from the pirlimycin group produced significantly less biofilm in presence of a sub-MIC of pirlimycin (p < 0.001). Relative antibiotic susceptibility of the isolates as well as biofilm production may play a role in the failure of extended therapies. On the other hand, some antibiotics may counteract biofilm formation and improve cure rates.

Interspecies scaling of urinary excretory amounts of nine drugs belonging to different therapeutic areas with diverse chemical structures - accurate prediction of the human urinary excretory amounts.

1. The human urinary excretory amounts of total drug (parent + metabolites) were predicted for nine drugs with diverse chemical structures using simple allometry. The drugs used for scaling were cephapirin, olanzapine, labetolol, carisbamate, voriconazole, tofacitinib, nevirapine, ropinirole, and cyclindole. 2. The traditional allometric scaling was attempted using Y = aWb relationship. The corresponding predicted urinary amounts were converted into % recovery by using appropriate human dose. Appropriate statistical tests comprising of fold-difference (predicted/observed values) and error calculations (MAE and RMSE) were performed. 3. The interspecies scaling of all nine drugs tested showed excellent correlation (r > 0.9672). The predictions for eight out of nine drugs (exception was cephaphirin) were contained within 0.80-1.25 fold-differences. The MAE and RMSE were within ± 18% and 14.64%, respectively. 4. The present work supported the potential application of prospective allometry scaling to predict the urinary excretory amounts of the total drug and gauge any issues for the renal handling of the total drug.

Clinical outcome comparison of immediate blanket treatment versus a delayed pathogen-based treatment protocol for clinical mastitis in a New York dairy herd.

The purpose was to compare immediate intramammary antimicrobial treatment of all cases of clinical mastitis with a selective treatment protocol based on 24-h culture results. The study was conducted at a 3,500-cow commercial farm in New York. Using a randomized design, mild to moderate clinical mastitis cases were assigned to either the blanket therapy or pathogen-based therapy group. Cows in the blanket therapy group received immediate on-label intramammary treatment with ceftiofur hydrochloride for 5 d. Upon receipt of 24 h culture results, cows in the pathogen-based group followed a protocol automatically assigned via Dairy Comp 305 (Valley Agricultural Software, Tulare, CA): Staphylococcus spp., Streptococcus spp., or Enterococcus spp. were administered on-label intramammary treatment with cephapirin sodium for 1 d. Others, including cows with no-growth or gram-negative results, received no treatment. A total of 725 cases of clinical mastitis were observed; 114 cows were not enrolled due to severity. An additional 122 cases did not meet inclusion criteria. Distribution of treatments for the 489 qualifying events was equal between groups (pathogen-based, n = 246; blanket, n = 243). The proportions of cases assigned to the blanket and pathogen-based groups that received intramammary therapy were 100 and 32%, respectively. No significant differences existed between blanket therapy and pathogen-based therapy in days to clinical cure; means were 4.8 and 4.5 d, respectively. The difference in post-event milk production between groups was not statistically significant (blanket therapy = 34.7 kg; pathogen-based = 35.4 kg). No differences were observed in test-day linear scores between groups; least squares means of linear scores was 4.3 for pathogen-based cows and 4.2 for blanket therapy cows. Odds of survival 30 d postenrollment was similar between groups (odds ratio of pathogen-based = 1.6; 95% confidence interval: 0.7-3.7) as was odds of survival to 60 d (odds ratio = 1.4; 95% confidence interval: 0.7-2.6). The one significant difference found for the effect of treatment was in hospital days; pathogen-based cows experienced, on average, 3 fewer days than blanket therapy cows. A majority (68.5%) of moderate and mild clinical cases would not have been treated if all cows on this trial were enrolled in a pathogen-based protocol. The use of a strategic treatment protocol based on 24-h postmastitis pathogen results has potential to efficiently reduce antimicrobial use.

Randomized clinical trial of intrauterine cephapirin infusion in dairy cows for the treatment of purulent vaginal discharge and cytological endometritis.

The objectives of this study were to quantify the effect of an intrauterine infusion of cephapirin on reproductive performance at first service of postpartum dairy cows affected by purulent vaginal discharge (PVD) and cytological endometritis (ENDO) using different diagnostic strategies, and to determine if the presence of prolonged anovulation would influence the magnitude of treatment benefit. In total, 2,259 Holstein cows in 28 herds were enrolled in a randomized clinical trial. At 35 (± 7) days in milk (DIM), cows were diagnosed with PVD using the Metricheck device (Simcro, Hamilton, New Zealand), with cytological endometritis using endometrial cytology (ENDO-CYTO), and with cytological endometritis using leukocyte esterase (ENDO-LE). Regardless of reproductive tract disease status, cows were randomly assigned to receive an intrauterine cephapirin infusion or to not be treated. Serum progesterone was measured at 35 and 49 (± 7) DIM (14 d apart); cows were considered to have prolonged anovulation if progesterone was <1 ng/mL at both times. Reproductive events of cows were collected until 200 DIM. Statistical analyses were conducted using multivariable mixed logistic regression models. Intrauterine cephapirin treatment was associated with an increased first-service pregnancy risk in cows diagnosed with PVD (no treatment: 15.4%; treatment: 31.4%), ENDO-CYTO (no treatment: 16.2%, treatment: 24.4%), and ENDO-LE (no treatment: 15.8%; treatment: 25.1%), but not in cows unaffected by any form of reproductive tract disease (no treatment: 34.8%; treatment: 32.6%). Cephapirin treatment was also associated with an increased first-service reproductive performance in cows affected simultaneously by both PVD and ENDO-CYTO (no treatment: 8.7%; treatment: 23.4%). The effect of cephapirin treatment in anovular cows (no treatment: 21.0%; treatment: 26.4%) was numerically lower than in cyclic cows (no treatment: 22.7%; treatment: 34.1%). Overall, an intrauterine infusion of cephapirin improved first-service pregnancy risk in cows with postpartum reproductive tract disease and this effect was influenced by postpartum anovulation status.

Treatments of clinical mastitis occurring in cows on 51 large dairy herds in Wisconsin.

Antimicrobials are frequently used for treatment of bovine mastitis and few studies have examined modern treatment strategies on large US dairy farms. The objective of this study was to describe treatment practices for clinical mastitis occurring in cows on large dairy herds in Wisconsin. Treatments performed on 747 cows experiencing cases of mild, moderate, or severe symptoms of clinical mastitis were recorded on 51 Wisconsin dairy farms. Duplicate milk samples were collected from the affected quarter for microbiological analysis at the onset of clinical mastitis and 14 to 21 d after treatment ended. Cows were treated according to individual farm protocol. Drugs and doses used for treatments were recorded for each case. Among all herds, 5 intramammary (IMM) antimicrobials (amoxicillin, hetacillin, pirlimycin, ceftiofur, and cephapirin) were used to treat cows for clinical mastitis. Of 712 cows with complete treatment data, 71.6% were treated with IMM ceftiofur either solely or combined with other antimicrobials (administered either IMM or systemically). Of cows experiencing severe symptoms of clinical mastitis, 43.8% received IMM treatment concurrent with systemic antimicrobials. Of all cows treated, 23.1% received an additional secondary treatment (either IMM, systemic, or both) because of perceived lack of response to the initial treatment. The majority of IMM treatments were administered to cows with a microbiological diagnosis of no growth (34.9%) or Escherichia coli (27.2%). Half of the cows experiencing cases caused by E. coli were treated using systemic antimicrobials in contrast to only 6.8% of cows experiencing cases caused by coagulase-negative staphylococci. In conflict with FDA regulations, which do not allow extra-label treatments using sulfonamides, a total of 22 cows from 8 farms were treated with systemic sulfadimethoxine either solely or in combination with oxytetracycline. Antimicrobial drugs were used on all herds and many cows received extra-label treatments. Great opportunity exists to improve mastitis therapy on large dairy herds, but use of more diagnostic methodologies is necessary to guide treatments. Farmers and veterinarians should work together to create protocols based on the herd needs considering reduced inappropriate and excessive use of antimicrobials.

Estimation of epidemiological cut-off values for eight antibiotics used for treatment of bovine mastitis caused by Streptococcus uberis and Streptococcus dysgalactiae subsp. dysgalactiae.

Interpretive criteria for antimicrobial susceptibility testing are lacking for most antimicrobials used for bovine streptococcal mastitis. The objectives of this study were to determine (tentative) epidemiological cut-off ((T)ECOFF) values for clinically relevant antibiotics used for treatment of bovine mastitis, and to estimate the proportion of acquired resistance (non-wild-types) in Streptococcus dysgalactiae subsp. dysgalactiae and Streptococcus uberis. A total of 255 S. uberis and 231 S. dysgalactiae subsp. dysgalactiae isolates were obtained in Denmark and Norway from bovine mastitis. The isolates were tested for susceptibility to 10 antibiotics using broth microdilution. In accordance with the European Committee on Antimicrobial Susceptibility Testing (EUCAST) standard operating procedure, additional published MIC distributions were included for the estimation of ECOFFs for cloxacillin, cephapirin, lincomycin and tylosin, and TECOFFs for amoxicillin, benzylpenicillin, cephapirin and oxytetracycline. The proportion of non-wild-type (NWT) isolates for the beta-lactams was significantly higher in the Danish S. uberis (45-55%) compared to the Norwegian isolates (10-13%). For oxytetracycline, the proportion of NWT was significantly higher in the Danish isolates, both for S. uberis (28% vs. 3%) and S. dysgalactiae (22% vs. 0%). A bridging study testing in parallel MICs in a subset of isolates (n = 83) with the CLSI-specified and the EUCAST-specified broths showed excellent correlation between the MICs obtained with the two methods. The new ECOFFs and TECOFFs proposed in this study can be used for surveillance of antimicrobial resistance, and - for antimicrobials licensed for streptococcal bovine mastitis - as surrogate clinical breakpoints for predicting their clinical efficacy for this indication.

Comparison between intrauterine application of an antibiotic and an herbal product to treat clinical endometritis in dairy cattle - A randomized multicentre field study.

Uterine diseases are main indications for antibiotic use in dairy cows. To test a non-antibiotic treatment option, we compared the effect of an intrauterine cephapirin (Metricure®; cefapirin benzathin 500 mg per dosis; CEPH) with an intrauterine applied herbal product (25 ml of EucaComp® PlantaVet containing alcoholic extracts of Calendula officinalis L., Mellissa officinalis L., Origanum majorana L. and Eucalyptus globulus Labill. (EUC)) on the clinical cure of endometritis. Examinations of 816 cows between 21 and 35 days after calving were performed and cases of clinical endometritis (n = 169) were included. Diagnosis based on a scoring system for vaginal discharge. Study animals were randomly assigned to one of two treatment groups and treated immediately. After excluding animals with incomplete datasets, 136 cows (EUC: n = 61; CEPH: n = 75) remained for the final analysis. In total, 64% (EUC: 61%, CEPH: 67%) of analysed endometritis cases were considered as clinically cured 14 ± 2 days after the first treatment, 15% stayed uncured after the application of a maximum of two consecutive treatments, leading to an overall clinical cure rate of 85% (EUC: 82%, CEPH: 88%). No statistically difference in clinical cure rates could be observed between both treatment groups nor 14 ± 2 days after the first treatment (p = 0.956) neither regarding the overall cure rate (p = 0.923). In conclusion, the clinical cure of dairy cows' endometritis after the intrauterine application of the herbal product was non-inferior to the intrauterine application of the antibiotic cephapirin. These results could contribute to reduce the antimicrobial use in the daily veterinary routine treatment of endometritis.

Elimination kinetics of cephapirin sodium in milk after an 8-day extended therapy program of daily intramammary infusion in healthy lactating Holstein-Friesian cows.

The objective of this study was to determine the elimination kinetics of extended therapy with intramammary (IMM) cephapirin in lactating dairy cattle. Eight healthy Holstein-Friesian cows were administered cephapirin (200mg) into all 4 mammary glands every 24 h after milking. Cows were milked 3 times per day and concentrations of cephapirin and desacetyl cephapirin were determined in bucket milk using liquid chromatography-mass spectrometry. Milk concentration-time data after the last of the 8 IMM infusions were fitted using compartment and noncompartmental models. The maximum cephapirin concentration was 128±57 µg/mL (mean ± SD), the elimination rate constant from the central compartment was 0.278±0.046 (h(-1)), clearance was 0.053±0.023 L/h, the half time for elimination was 2.55±0.40 h, and the mean residence time was 2.65±0.79 h. The cephapirin concentration was below the approved tolerance in all cows by 96 h after the last infusion, which is the labeled withholding time for the preparation used. Extended therapy for 8 d provided milk cephapirin concentrations above the minimum inhibitory concentration for common gram-positive mastitis pathogens (0.1 to 1.0 µg/mL) for the duration of therapy and for an additional 16 to 32 h after the end of treatment. Our findings suggest that this IMM cephapirin sodium formulation, which is labeled for 2 doses 12 h apart, could be administered at a 24-h interval for up to 8 d in cows milked 3 times per day, with no significant effect on residue levels by 96 h after the last treatment. Longer withdrawal times would be prudent for cows with low milk production.

Noninferiority trial comparing a first-generation cephalosporin with a third-generation cephalosporin in the treatment of nonsevere clinical mastitis in dairy cows.

The objective of this study was to evaluate the noninferiority of 2 intramammary treatments for nonsevere clinical mastitis. The 2 treatments were a first-generation cephalosporin (cephapirin sodium, 2 treatments 12h apart) and a third-generation cephalosporin (ceftiofur hydrochloride, treatments once a day for 5d). A total of 296 cases on 7 farms met the enrollment criteria for the study. Streptococcus dysgalactiae was the most common bacterial species identified in milk samples from cows with mild to moderate clinical mastitis, followed by Escherichia coli, other esculin-positive cocci, Streptococcus uberis, and Klebsiella spp. Treatment was randomly allocated as either cephapirin sodium or ceftiofur hydrochloride via intramammary infusion according to label standards. Bacteriological cure was defined based on 2 posttreatment milk samples taken at 10 and 17d after enrollment. Noninferiority of cephapirin relative to ceftiofur was shown for bacteriological cure of gram-positive cases and for clinical cure of all cases. Ceftiofur showed a significantly higher bacteriological cure in gram-negative cases. Treatments showed no significant difference in bacteriological cure of all cases and in time to exit from the study, where the absence of a difference does not imply noninferiority. Based on the findings from this study, farm-specific treatment protocols that differ for gram-positive and gram-negative cased may be developed.

Hot topic: investigating the risk of violative meat residues in bob veal calves fed colostrum from cows treated at dry-off with cephapirin benzathine.

The objective was to conduct a study to investigate if violative meat residues are detected in very young bob veal calves that are fed first-milking colostrum harvested from cows that were dry treated, on-label, with cephapirin benzathine. First-milking colostrum was collected from cows that were given intramammary treatment at dry off, on-label, with cephapirin benzathine (ToMORROW, Boehringer Ingelheim Vetmedica Inc., St. Joseph, MO). Newborn bull calves meeting study inclusion criteria were removed from their dams shortly after birth and before suckling, and assigned to 1 of 2 trials. For the first trial, 6 treated calves were fed 3.8L of fresh maternal colostrum and 1 control calf was fed 1.5 doses of a plasma-derived colostrum replacer (Secure Calf Colostrum Replacer, VitaPlus Inc., Madison, WI) within 1h after birth. For the second trial, 5 treated calves were fed 3.8L of fresh maternal colostrum and 1 control calf was fed 1.5 doses of Secure Calf Colostrum Replacer within 1h after birth. All calves were humanely euthanized at 24h (trial 1) or 48h (trial 2) of age, and tissues were harvested for antimicrobial residue testing. Samples of maternal colostrum and colostrum replacer were also submitted for antimicrobial residue testing. Kidneys collected from all study calves tested negative for cephapirin benzathine residues when using both the KIS assay (Charm Sciences, Lawrence, MA) and liquid chromatography-tandem mass spectrometry analysis. The potential transfer of cephapirin from cows treated on-label at dry off to calves via colostrum may not be a significant source of cephapirin residues in veal tissues.

Randomized noninferiority clinical trial evaluating 3 commercial dry cow mastitis preparations: II. Cow health and performance in early lactation.

The objective of this randomized noninferiority clinical trial was to compare the effect of treatment with 3 different dry cow therapy formulations at dry-off on cow-level health and production parameters in the first 100 d in milk (DIM) in the subsequent lactation, including 305-d mature-equivalent (305 ME) milk production, linear score (LS), risk for the cow experiencing a clinical mastitis event, risk for culling or death, and risk for pregnancy by 100 DIM. A total of 1,091 cows from 6 commercial dairy herds in 4 states (California, Iowa, Minnesota, and Wisconsin) were randomly assigned at dry-off to receive treatment with 1 of 3 commercial products: Quartermaster (QT; Zoetis Animal Health, Madison, NJ), Spectramast DC (SP; Zoetis Animal Health) or ToMorrow Dry Cow (TM; Boehringer Ingelheim Vetmedica Inc., St Joseph, MO). All clinical mastitis, pregnancy, culling, and death events occurring in the first 100 DIM were recorded by farm staff using an on-farm electronic record-keeping system. Dairy Herd Improvement Association test-day records of milk production and milk component testing were retrieved electronically. Mixed linear regression analysis was used to describe the effect of treatment on 305ME milk production and LS recorded on the last Dairy Herd Improvement Association test day before 100 DIM. Cox proportional hazards regression analysis was used to describe the effect of treatment on risk for experiencing a case of clinical mastitis, risk for leaving the herd, and risk for pregnancy between calving and 100 DIM. Results showed no effect of treatment on adjusted mean 305 ME milk production (QT=11,759 kg, SP=11,574 kg, and TM=11,761 kg) or adjusted mean LS (QT=1.8, SP=1.9, and TM=1.6) on the last test day before 100 DIM. Similarly, no effect of treatment was observed on risk for a clinical mastitis event (QT=14.8%, SP=12.7%, and TM=15.0%), risk for leaving the herd (QT=7.5%, SP=9.2%, and TM=10.3%), or risk for pregnancy (QT=31.5%, SP=26.1%, and TM=26.9%) between calving and 100 DIM.

Randomized noninferiority clinical trial evaluating 3 commercial dry cow mastitis preparations: I. Quarter-level outcomes.

The study objective was to compare the efficacy of 3 commercial dry cow mastitis formulations regarding quarter-level prevalence of intramammary infections (IMI) postcalving, cure of preexisting infections over the dry period, prevention of new infections during the dry period, and risk for a clinical mastitis case between calving and 100d in milk (DIM). A total of 1,091 cows (4,364 quarters) from 6 commercial dairy herds in 4 different states (California, Iowa, Minnesota, and Wisconsin) were enrolled and randomized to 1 of the 3 treatments at dry-off: Quartermaster (QT; 1,000,000 IU of procaine penicillin G and 1 g of dihydrostreptomycin; Pfizer Animal Health, New York, NY), Spectramast DC (SP; 500 mg of ceftiofur hydrochloride; Pfizer Animal Health), or ToMorrow Dry Cow (TM; 300mg of cephapirin benzathine; Boehringer Ingelheim Vetmedica Inc., St. Joseph, MO). Quarter milk samples were collected for routine bacteriological culture before dry cow therapy treatment at dry-off, 0 to 6 DIM, and 7 to 13 DIM and an on-farm record-keeping system was used to retrieve data on clinical mastitis cases. Noninferiority analysis was used to evaluate the effect of treatment on the primary outcome, risk for a bacteriological cure during the dry period. Multivariable logistic regression techniques were used to describe the effect of treatment on risk for presence of IMI postcalving and risk of a new IMI during the dry period. Cox proportional hazards regression was used to describe the effect of treatment on the risk and time for quarters to experience an episode of clinical mastitis between calving and 100 DIM. The overall crude quarter-level prevalence of infection at dry-off was 19.2%. The most common pathogen isolated from milk samples at dry-off was coagulase-negative Staphylococcus, followed by Aerococcus spp. and other Streptococcus spp. Noninferiority analysis showed no effect of treatment on risk for a cure between dry-off and calving [least squares means (LSM): QT=93.3%, SP=92.6%, and TM=94.0%] and secondary analysis showed no effect of treatment on risk for presence of an IMI at 0 to 6 DIM (LSM: QT=16.5%, SP=14.1%, and TM=16.0%), risk for development of a new IMI between dry-off and 0 to 6 DIM (LSM: QT=14.8%, SP=12.3%, and TM=14.2%), or risk of experiencing a clinical mastitis event between calving and 100 DIM (LSM: QT=5.3%, SP=3.8%, and TM=4.1%). In conclusion, no difference was observed in efficacy among the 3 products evaluated when assessing the aforementioned quarter-level outcomes.

Prednisolone and cefapirin act synergistically in resolving experimental Escherichia coli mastitis.

Mastitis in dairy cows is typically treated with intramammary antibiotics. The combination of antibiotics with corticosteroids tends to have a large market share where these products are registered. Our objective was to investigate the effect of prednisolone in combination with cefapirin on the inflammatory response of experimentally induced Escherichia coli mastitis. Six midlactating Holstein-Friesian cows were challenged in 3 quarters with E. coli and treated at 4, 12, 24, and 36 h postinfection with 300 mg of cefapirin in 1 quarter and a combination of 300 mg of cefapirin and 20mg of prednisolone in another quarter. At 24h (n=3) or 48 h (n=3) postinfection cows were euthanized for tissue sampling. Clinical scores, somatic cell count, and California mastitis test scores, as well as IL-1ß, IFN-γ, IL-4, and IL-10 levels and bacterial growth in milk, were measured every 6h. Experimental inoculation caused a moderate clinical mastitis in all cows in challenged, untreated quarters. The E. coli challenge strain was recovered from all infected quarters and confirmed by PCR-based fingerprinting. Challenged, untreated control quarters showed increased concentrations of all measured cytokines together with recruitment of polymorphonuclear neutrophilic leukocytes at 24 and 48 h postchallenge. Both treatments reduced udder swelling and sensitivity with no statistically significant difference between treatment groups. Administration of cefapirin alone or in combination with prednisolone resulted in significantly lower concentrations of IFN-γ, IL-1ß, and IL-10 compared with challenged, untreated quarters. Treated quarters did show IL-4 production, but concentrations were significantly decreased compared with untreated, challenged quarters. Quarters treated with the combination of cefapirin and prednisolone showed a significantly lower concentration of IL-4 compared with cefapirin-only treatment. At both 24 and 48 h postinoculation, the level of polymorphonuclear neutrophilic leukocyte recruitment was lowest in challenged quarters treated with a combination of cefapirin and prednisolone, followed by cefapirin alone. Taken together, treatment with cefapirin alone inhibited bacterial growth in milk and reduced the host inflammatory responses. Addition of prednisolone to cefapirin had a synergistic effect, resulting in a lower density of leukocytes in tissue and milk and a quicker restoration of milk quality.

Evaluating the solubility of compounds intended for intramammary infusion based upon tests conducted across a range of milk matrices.

The ability to evaluate drug solubility in milk and milk-related products has relevance both to human and veterinary medicine. Model compounds explored in a previous investigation focused on drug solubility assessments when delivered in milk-associated vehicles for administration to human patients. In the current investigation, we focus on the solubility of drugs intended for delivery via intramammary infusion to cattle. Because there are logistic challenges typically associated with obtaining raw milk samples for these tests, there is a need to determine potential alternative media as a substitute for raw bovine milk. Given the complexity of the milk matrix, aqueous media do not reflect the range of factors that could impact these solubility assessments. This led to the current effort to explore the magnitude of differences that might occur when substituting raw bovine milk with off-the-shelf milk products such as whole milk, skim milk, or reconstituted whole milk powder. We considered conclusions based upon the solubility assessments derived from the use of the model compounds studied in our previous report and compared them to conclusions obtained when testing two drugs with differing physicochemical characteristics that are approved for administration via bovine intramammary infusion: cephapirin benzathine and cephapirin sodium. Based upon these results, we recommend that whole milk or reconstituted whole milk can substitute for bovine raw milk for the solubility assessment of compounds intended for administration via intramammary infusion. However, unlike the human drug situation, these tests should be conducted at 38°C.