Pharmacokinetic and pharmacodynamic modelling of marbofloxacin administered alone and in combination with tolfenamic acid in calves

In a four-period, cross-over study, the fluoroquinolone antibacterial drug marbofloxacin (MB) was administered to calves, alone and in combination with the nonsteroidal anti-inflammatory drug tolfenamic acid (TA). Both drugs were administered intramuscularly (IM) at doses of 2 mg/kg. A tissue cage model of inflammation, based on the actions of the mild irritant carrageenan, was used to evaluate the pharmacokinetics (PK) of MB and MB in combination with TA. MB mean values of area under concentration-time curve (AUC) were 15.1 μg·h/mL for serum, 12.1 μg·h/mL for inflamed tissue cage fluid (exudate) and 9.6 μg·h/mL for noninflamed tissue cage fluid (transudate). Values of C(max) were 1.84, 0.35 and 0.31 μg/mL, respectively, for serum, exudate and transudate. Mean residence time (MRT) of 23.6 h (exudate) and 22.6 h (transudate) also differed significantly from serum MRT (8.6 h). Co-administration of TA did not affect the PK profile of MB. The pharmacodynamics of MB was investigated using a bovine strain of Mannheimia haemolytica. Time-kill curves were established ex vivo on serum, exudate and transudate samples. Modelling the ex vivo serum time-kill data to the sigmoid E(max) equation provided AUC(24 h) /MIC values required for bacteriostatic (18.3 h) and bactericidal actions (92 h) of MB and for virtual eradication of the organism was 139 h. Corresponding values for MB + TA were 20.1, 69 and 106 h. These data were used to predict once daily dosage schedules for a bactericidal action, assuming a MIC(90) value of 0.24 μg/mL, a dose of 2.6 mg/kg for MB and 2.19 mg/kg for MB + TA were determined, which are similar to the currently recommended dose of 2.0 mg/kg.Facultad de Ciencias Veterinaria

Pharmacokinetics of oral and subcutaneous meloxicam: Effect on indicators of pain and inflammation after knife castration in weaned beef calves

Oral meloxicam is labelled for reducing pain and inflammation associated with castration in cattle in Canada, however, subcutaneous meloxicam is only labelled for pain associated with dis-budding and abdominal surgery. The aim of this project was to determine the pharmacokinetic profile of oral (PO; 1.0 mg/kg BW) and subcutaneous meloxicam (SC; 0.5 mg/kg BW), and to assess the effect of meloxicam on physiological and behavioural indicators of pain associated with knife castration in 7–8 month old calves. Twenty-three Angus crossbred beef calves (328 ± 4.4 kg BW) were randomly assigned to two treatments: PO n = 12 or SC n = 11 administration of meloxicam immediately before knife castration. Physiological parameters included salivary and hair cortisol, substance P, haptoglobin, serum amyloid-A, weight, complete blood count, scrotal and rectal temperature. Behavioural parameters included standing and lying behaviour, pen behaviour and feeding behaviour. Data were analyzed using PROC GLIMMIX (SAS), with repeated measures using mixed procedures including treatment as a fixed effect and animal and pen as a random effect. The pharmacokinetic profile of the drug including area under the curve, volume of distribution and clearance was greater (P < 0.05) in PO than SC calves. After surgery, substance P concentrations, white blood cell counts (WBC), weight and lying duration were greater (P < 0.05) in PO than SC calves, while scrotal circumference was lower (P < 0.05) in PO calves than SC calves. Although statistical differences were observed for pharmacokinetic, physiological and behavioural parameters differences were small and may lack biological relevance.info:eu-repo/semantics/publishedVersio

Effect of meloxicam and lidocaine administered alone or in combination on indicators of pain and distress during and after knife castration in weaned beef calves.

To assess the effect of meloxicam and lidocaine on indicators of pain associated with castration, forty-eight Angus crossbred beef calves (304 ± 40.5 kg of BW, 7-8 months of age) were used in a 28 day experiment. The experiment consisted of a 2 × 2 factorial design where main factors included provision of analgesia and local anaesthesia. Analgesia consisted of: no-meloxicam (N; n = 24) single s.c. administration of lactated ringer's solution and meloxicam (M; n = 24) single dose of 0.5 mg/kg of s.c. meloxicam. Local anesthesia consisted of: no-lidocaine (R; n = 24) ring block administration of lactated ringer's solution or lidociane (L; n = 24) ring block administration of lidocaine. To yield the following treatments: no meloxicam + no lidocaine (N-R; n = 12), no meloxicam + lidocaine (N-L; n = 12), meloxicam + no lidocaine (M-R; n = 12) and meloxicam + lidocaine (M-L; n = 12). Salivary cortisol concentrations were lower (lidocaine × time effect; P 0.05) were observed for average daily gain (ADG), weights or feeding behaviour. Overall, both lidocaine and meloxicam reduced physiological and behavioural indicators of pain. Although there was only one meloxicam × lidocaine interaction, lidocaine and meloxicam reduced physiological and behavioural parameters at different time points, which could be more effective at mitigating pain than either drug on its own

Pharmacokinetics of oral and subcutaneous meloxicam: Effect on indicators of pain and inflammation after knife castration in weaned beef calves.

Oral meloxicam is labelled for reducing pain and inflammation associated with castration in cattle in Canada, however, subcutaneous meloxicam is only labelled for pain associated with dis-budding and abdominal surgery. The aim of this project was to determine the pharmacokinetic profile of oral (PO; 1.0 mg/kg BW) and subcutaneous meloxicam (SC; 0.5 mg/kg BW), and to assess the effect of meloxicam on physiological and behavioural indicators of pain associated with knife castration in 7-8 month old calves. Twenty-three Angus crossbred beef calves (328 ± 4.4 kg BW) were randomly assigned to two treatments: PO n = 12 or SC n = 11 administration of meloxicam immediately before knife castration. Physiological parameters included salivary and hair cortisol, substance P, haptoglobin, serum amyloid-A, weight, complete blood count, scrotal and rectal temperature. Behavioural parameters included standing and lying behaviour, pen behaviour and feeding behaviour. Data were analyzed using PROC GLIMMIX (SAS), with repeated measures using mixed procedures including treatment as a fixed effect and animal and pen as a random effect. The pharmacokinetic profile of the drug including area under the curve, volume of distribution and clearance was greater (P < 0.05) in PO than SC calves. After surgery, substance P concentrations, white blood cell counts (WBC), weight and lying duration were greater (P < 0.05) in PO than SC calves, while scrotal circumference was lower (P < 0.05) in PO calves than SC calves. Although statistical differences were observed for pharmacokinetic, physiological and behavioural parameters differences were small and may lack biological relevance

Association between antimicrobial drug class for treatment and retreatment of bovine respiratory disease (BRD) and frequency of resistant BRD pathogen isolation from veterinary diagnostic laboratory samples.

Although 90% of BRD relapses are reported to receive retreatment with a different class of antimicrobial, studies examining the impact of antimicrobial selection (i.e. bactericidal or bacteriostatic) on retreatment outcomes and the emergence of antimicrobial resistance (AMR) are deficient in the published literature. This survey was conducted to determine the association between antimicrobial class selection for treatment and retreatment of BRD relapses on antimicrobial susceptibility of Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni. Pathogens were isolated from samples submitted to the Iowa State University Veterinary Diagnostic Laboratory from January 2013 to December 2015. A total of 781 isolates with corresponding animal case histories, including treatment protocols, were included in the analysis. Original susceptibility testing of these isolates for ceftiofur, danofloxacin, enrofloxacin, florfenicol, oxytetracycline, spectinomycin, tilmicosin, and tulathromycin was performed using Clinical and Laboratory Standards Institute guidelines. Data were analyzed using a Bayesian approach to evaluate whether retreatment with antimicrobials of different mechanistic classes (bactericidal or bacteriostatic) increased the probability of resistant BRD pathogen isolation in calves. The posterior distribution we calculated suggests that an increased number of treatments is associated with a greater probability of isolates resistant to at least one antimicrobial. Furthermore, the frequency of resistant BRD bacterial isolates was greater with retreatment using antimicrobials of different mechanistic classes than retreatment with the same class. Specifically, treatment protocols using a bacteriostatic drug first followed by retreatment with a bactericidal drug were associated with a higher frequency of resistant BRD pathogen isolation. In particular, first treatment with tulathromycin (bacteriostatic) followed by ceftiofur (bactericidal) was associated with the highest probability of resistant M. haemolytica among all antimicrobial combinations. These observations suggest that consideration should be given to antimicrobial pharmacodynamics when selecting drugs for retreatment of BRD. However, prospective studies are needed to determine the clinical relevance to antimicrobial stewardship programs in livestock production systems