Pharmacokinetic-Pharmacodynamic Study of Ampicillin-Cloxacillin Combination in Indian Thoroughbred Horses (Equus caballus) and Safety Evaluation of the Computed Dosage Regimen.

The pharmacokinetics of ampicillin-cloxacillin, given as single intravenously dose of 10 mg.kg-1 (5 mg.kg-1 of ampicillin plus 5 mg.kg-1 of cloxacillin) was examined in clinically presented Indian thoroughbred horses (n = 6) in order to design appropriate dosing strategies. Drug concentrations in plasma were determined by high performance liquid chromatography (HPLC) and pharmacokinetic parameters were derived by non-compartmental analysis using WinNonlin software. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of ampicillin-cloxacillin against quality control strains of Escherichia coli and Staphylococcus aureus, grown in Muller Hinton Broth, were determined by broth microdilution method. For ampicillin, area under plasma drug concentration time curve (AUC) was 15.2 ± 0.54 µg.h.ml-1, mean residence time (MRT) was 1.33 ± 0.06 h and clearance (Cl) was 0.33 ± 0.01 L.h-1.kg-1. For cloxacillin, AUC was 18.0 ± 0.9 µg.h.ml-1, MRT was 1.28 ± 0.02 h and Cl was 0.28 ± 0.01 L.h-1.kg-1. MIC of ampicillin-cloxacillin combination against E. coli and S. aureus was determined to be 0.4 µg.ml-1. PK-PD integration indicated that to maintain %T > MIC value 50% for bacteria with MIC ≤ 0.4 µg.ml-1, an appropriate intravenous dosage regimen of ampicillin-cloxacillin combination in horses would be 15 mg.kg-1 (i.e. 7.5 mg.kg-1 of ampicillin plus 7.5 mg.kg-1 of cloxacillin), to be repeated at 12 h intervals. Safety profile of the recommended regimen did not significantly alter any of the 16 biochemical or haematological parameters studied.

Pharmacokinetics and tissue concentrations of firocoxib in sows following oral administration.

The objectives of this study were to describe the pharmacokinetics of firocoxib following oral (PO) dosing and intravenous (IV) injection in sows. Seven healthy sows were administered 0.5 mg firocoxib/kg IV. Following a 23-d washout period, sows were administered firocoxib at 4.0 mg firocoxib/kg PO. Blood samples were collected at predetermined times for 72 hr after IV and 120 hr after PO administration. Plasma firocoxib concentration was measured using UPLC-MS/MS, and pharmacokinetic analysis was performed using noncompartmental procedures. Tissue firocoxib concentrations were determined at 5, 10 (n = 2/time point), and 21 d (n = 3) after PO administration. The geometric mean half-life following IV and PO administration was 16.6 and 22.5 hr, respectively. A mean peak plasma concentration (Cmax) of 0.06 µg/ml was recorded at 7.41 hr (Tmax ) after oral administration. Mean oral bioavailability was determined to be 70.3%. No signs of NSAID toxicity were observed on macroscopic and microscopic investigation. Firocoxib was detected in the skin with subcutaneous fat (0.02 µg/g) of one of three sows at 21 days postadministration. Additional work to establish appropriate meat withhold intervals in sows is required. Firocoxib was readily absorbed following PO administration. Further work is needed to better understand the analgesic effects for sows and piglets nursing sows administered firocoxib.

Association between antimicrobial drug class selection for treatment and retreatment of bovine respiratory disease and health, performance, and carcass quality outcomes in feedlot cattle.

Treatment and control of bovine respiratory disease (BRD) is predicated on the use of two categories of antimicrobials, namely bacteriostatic drugs that inhibit bacterial growth and replication (STATIC), and bactericidal drugs that kill bacteria in in vitro culture systems (CIDAL). Recently, we reported that initial BRD treatment with a STATIC antimicrobial followed by retreatment with a CIDAL antimicrobial was associated with a higher frequency of multidrug-resistant bacteria isolated from field cases of BRD submitted to a veterinary diagnostic laboratory. The present study was conducted to test the hypothesis that calves administered the same class of antimicrobial for first and second BRD treatment (i.e., CIDAL-CIDAL or STATIC-STATIC) would have improved health and performance outcomes at the feedlot compared to calves that received a different antimicrobial class for retreatment (i.e., STATIC-CIDAL or CIDAL-STATIC). The association between antimicrobial treatments and health, performance, and carcass quality outcomes were determined by a retrospective analysis of 4,252 BRD treatment records from a commercial feedlot operation collected from 2001 to 2005. Data were compared using generalized linear mixed statistical models that included gender, season, and arrival weight as covariates. The mean (±SE) probability of BRD cases identified as requiring four or more treatments compared to three treatments was greater in calves that received STATIC-CIDAL (73.58 ± 2.38%) or STATIC-STATIC (71.32 ± 2.52%) first and second antimicrobial treatments compared to calves receiving CIDAL-CIDAL (50.35 ± 3.46%) first and second treatments (P < 0.001). Calves receiving CIDAL-CIDAL first and second treatments also had an increased average daily gain (1.11 ± 0.03 kg/d) compared to calves receiving STATIC-CIDAL (0.95 ± 0.03 kg/d) and STATIC-STATIC (0.84 ± 0.02 kg/d) treatments (P < 0.001). Furthermore, CIDAL-CIDAL-treated calves had a higher probability of a choice quality grade at slaughter (36.44 ± 4.80%) compared to STATIC-CIDAL calves (28.09 ± 3.88%) (P = 0.037). There was no effect of antimicrobial treatment combination on BRD mortality (P = 0.855) or yield grade (P = 0.240) outcomes. These observations suggest that consideration should be given to antimicrobial pharmacodynamics when selecting drugs for retreatment of BRD. These findings have implications for developing BRD treatment protocols that address both post-treatment production and antimicrobial stewardship concerns.

Implications for dosing regimen of enrofloxacin administered concurrently with dexamethasone in febrile buffalo calves.

The objective of the study was to determine the influence of dexamethasone (DXM) on pharmacokinetics (PK) and pharmacodynamics (PD) of enrofloxacin (ENR) for dosage optimization following concurrent administration of ENR and DXM in febrile buffalo calves. A 2 µg/kg intravenous dosage of lipopolysaccharide derived from Escherichia coli was used to induce fever in calves. After inducing fever, ENR was administered at the dose rate of 12 mg/kg, IM followed by IM injection of DXM (0.05 mg/kg) in calves. Minor alterations in PK of ENR were observed following the administration of ENR + DXM. The PK parameters were t1/2K10 = 6.34 h, Cl/F = 0.729 L/kg/h, and MRT0-∞ = 10.5 h. Antibacterial activity (MIC, MBC, ex vivo time-kill kinetics) of ENR for P. multocida was not affected by DXM. But MPC of ENR against P. multocida was lessened in presence of DXM. Using PK-PD-modeled AUC0-24h/MIC values for bactericidal effect against P. multocida, daily dosages of ENR administered in combination with DXM were 4.02 mg/kg and 16.1 mg/kg, respectively, for MIC90s of 0.125 µg/ml and 0.50 µg/ml. A dose of 5.38 mg/kg was determined for ENR for frequently occurring P. multocida infections having ≤ MIC90 of 0.125 µg/ml and PK-PD modeled dose was comparable with the recommended ENR dose of 5 mg/kg for bovines for mild infections. It is suggested that a recommended dosage of 5-12.5 mg/kg of ENR can be used effectively in combination with DXM to treat P. multocida associated infections in buffalo calves without any risk of resistance amplification.

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.

Pharmacokinetics and pharmacodynamics of intravenous and transdermal flunixin meglumine in alpacas.

The aim of this study was to determine the pharmacokinetics and prostaglandin E2 (PGE2 ) synthesis inhibiting effects of intravenous (IV) and transdermal (TD) flunixin meglumine in eight, adult, female, Huacaya alpacas. A dose of 2.2 mg/kg administered IV and 3.3 mg/kg administered TD using a cross-over design. Plasma flunixin concentrations were measured by LC-MS/MS. Prostaglandin E2 concentrations were determined using a commercially available ELISA. Pharmacokinetic (PK) analysis was performed using noncompartmental methods. Plasma PGE2 concentrations decreased after IV flunixin meglumine administration but there was minimal change after TD application. Mean t1/2 λz after IV administration was 4.531 hr (range 3.355 to 5.571 hr) resulting from a mean Vz of 570.6 ml/kg (range, 387.3 to 1,142 ml/kg) and plasma clearance of 87.26 ml kg-1  hr-1 (range, 55.45-179.3 ml kg-1  hr-1 ). The mean Cmax, Tmax and t1/2 λz for flunixin following TD administration were 106.4 ng/ml (range, 56.98 to 168.6 ng/ml), 13.57 hr (range, 6.000-34.00 hr) and 24.06 hr (18.63 to 39.5 hr), respectively. The mean bioavailability for TD flunixin was calculated as 25.05%. The mean 80% inhibitory concentration (IC80 ) of PGE2 by flunixin meglumine was 0.23 µg/ml (range, 0.01 to 1.38 µg/ml). Poor bioavailability and poor suppression of PGE2 identified in this study indicate that TD flunixin meglumine administered at 3.3 mg/kg is not recommended for use in alpacas.

Pharmacokinetics of transdermal flunixin in sows.

The objective of this study was to describe the pharmacokinetics (PK) of flunixin in 12 nonlactating sows following transdermal (TD) flunixin (3.33 mg/kg) and intravenous (IV; 2.20 mg/kg) flunixin meglumine (FM) administration using a crossover design with a 10-day washout period. Blood samples were collected postadministration from sows receiving IV FM (3, 6, 10, 20, 40 min and 1, 3, 6, 12, 16, 24, 36, and 48 hr) and from sows receiving TD flunixin (10, 20, 40 min and 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, and 72 hr). Liquid chromatography and mass spectrometry were used to determine plasma flunixin concentrations, and noncompartmental methods were used for PK analysis. The geometric mean ± SD area under the plasma concentration-time curve (AUC) following IV injection was 26,820.59 ± 9,033.88 and 511.83 ± 213.98 hr ng/ml for TD route. Mean initial plasma concentration (C0 ) was 26,279.70 ± 3,610.00 ng/ml, and peak concentration (Cmax ) was 14.61 ± 7.85 ng/ml for IV and TD administration, respectively. The percent mean bioavailability of TD flunixin was 1.55 ± 1.00. Our results demonstrate that topical administration is not an efficient route for delivering flunixin in mature sows.

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.

Pharmacokinetic-pharmacodynamic relationship of marbofloxacin for Escherichia coli and Pasturella multocida following repeated intramuscular administration in goats.

The pharmacokinetics (PK) and pharmacodynamics (PD) of marbofloxacin (MBF) were determined in six healthy female goats of age 1.00-1.25 years after repeated administration of MBF. The MBF was administered intramuscularly (IM) at 2 mg kg-1  day-1 for 5 days. Plasma concentrations of MBF were determined by high-performance liquid chromatography, and PK parameters were obtained using noncompartmental analysis. The MBF concentrations peaked at 1 hr, and peak concentration (Cmax ) was 1.760 µg/ml on day 1 and 1.817 µg/ml on day 5. Repeated dosing of MBF caused no significant change in PK parameters except area under curve (AUC) between day 1 (AUC0-∞ D1 = 7.67 ± 0.719 µg × hr/ml) and day 5 (AUC0-∞ D5 = 8.70 ± 0.857 µg × hr/ml). A slight difference in mean residence time between 1st and 5th day of administration and accumulation index (AI = 1.13 ± 0.017) suggested lack of drug accumulation following repeated IM administration up to 5 days. Minimum inhibitory concentration (MIC) demonstrated that Escherichia coli (MIC = 0.04 µg/ml) and Pasturella multocida (MIC = 0.05 µg/ml) were highly sensitive to MBF. Time-kill kinetics demonstrated rapid and concentration-dependent activity of MBF against these pathogens. PK/PD integration of data for E. coli and P. multocida, using efficacy indices: Cmax /MIC and AUC0-24hr /MIC, suggested that IM administration of MBF at a dose of 2 mg kg-1  day-1 is appropriate to treat infections caused by E. coli. However, a dose of 5 mg kg-1  day-1 is recommended to treat pneumonia caused by P. multocida in goats. The study indicated that MBF can be used repeatedly at dosage of 2 mg/kg in goats without risk of drug accumulation up to 5 days.

Transmammary delivery of firocoxib to piglets reduces stress and improves average daily gain after castration, tail docking, and teeth clipping1.

Painful processing procedures in piglets such as tail docking, castration, and teeth clipping are an emerging animal welfare concern. We hypothesized that transmammary delivery of a nonsteroidal anti-inflammatory drug, firocoxib, would reduce pain associated with processing in piglets. This study compared the pharmacokinetics, efficacy, safety, and tissue residue concentrations of 4 doses of firocoxib (0.5, 1.0, 1.5, or 2.0 mg/kg) administered to sows and delivered to nursing piglets prior to processing. Sixteen sows, 5 ± 2 d postpartum, were randomly assigned to 1 of 4 treatment groups. On day 0, sows received a single intramuscular dose of firocoxib at 7 ± 1 h before piglet surgical castration, tail docking, and teeth clipping (males) or sham handling (females). Firocoxib and cortisol concentrations were determined from selected samples collected from sows and 3 piglets per litter (2 barrows and 1 gilt) at 0, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 h after drug administration. On day 21, piglets were weighed and all animals were euthanized and necropsied. Tissues were collected from 3 piglets per litter for histological examination and drug residue analysis. Mean (±SEM) peak plasma firocoxib concentrations (Cmax) were 107.90 ± 15.18, 157.50 ± 24.91, 343.68 ± 78.89, and 452.83 ± 90.27 ng/mL in sows receiving 0.5, 1.0, 1.5, and 2.0 mg/kg firocoxib, respectively, and 9.53 ± 1.21, 31.04 ± 6.79, 53.30 ± 11.1, and 44.03 ± 7.47 ng/mL in their respective piglets. Mean plasma terminal half-life values ranged from 26 to 31 h in sows and 30 to 48 h in piglets. Barrows nursing sows that received 2.0 mg/kg firocoxib had a lower mean plasma cortisol concentration at 1 ± 1 h after processing compared with barrows nursing sows that received 1.0 mg/kg (P = 0.0416) and 0.5 mg/kg of firocoxib (P = 0.0397). From processing to weaning, litters of sows receiving 2.0 mg/kg firocoxib gained more weight than litters of sows that received 0.5 mg/kg (P = 0.008) or 1.0 mg/kg (P = 0.005). No signs of nonsteroidal anti-inflammatory drug toxicity were observed on examination of the kidney, liver, stomach, and small intestine, and concentrations of firocoxib and the descyclopropylmethyl metabolite were below the limit of detection (0.01 µg/g) in all tissues examined from sows and piglets. These findings indicate that maternal delivery of firocoxib to suckling piglets before tail docking and castration may safely reduce processing-induced stress and enhance production by increasing weaning weights.

Pharmacokinetics and pharmacodynamics of intravenous and transdermal flunixin meglumine in meat goats.

The aim of this study was to determine the pharmacokinetics and prostaglandin E2 (PGE2 ) synthesis inhibiting effects of intravenous (IV) and transdermal (TD) flunixin meglumine in eight adult female Boer goats. A dose of 2.2 mg/kg was administered intravenously (IV) and 3.3 mg/kg administered TD using a cross-over design. Plasma flunixin concentrations were measured by LC-MS/MS. Prostaglandin E2 concentrations were determined using a commercially available ELISA. Pharmacokinetic (PK) analysis was performed using noncompartmental methods. Plasma PGE2 concentrations decreased after flunixin meglumine for both routes of administration. Mean λz -HL after IV administration was 6.032 hr (range 4.735-9.244 hr) resulting from a mean Vz of 584.1 ml/kg (range, 357.1-1,092 ml/kg) and plasma clearance of 67.11 ml kg-1  hr-1 (range, 45.57-82.35 ml kg-1  hr-1 ). The mean Cmax , Tmax, and λz -HL for flunixin following TD administration was 0.134 µg/ml (range, 0.050-0.188 µg/ml), 11.41 hr (range, 6.00-36.00 hr), and 43.12 hr (15.98-62.49 hr), respectively. The mean bioavailability for TD flunixin was calculated as 24.76%. The mean 80% inhibitory concentration (IC80 ) of PGE2 by flunixin meglumine was 0.28 µg/ml (range, 0.08-0.69 µg/ml) and was only achieved with IV formulation of flunixin in this study. The PK results support clinical studies to examine the efficacy of TD flunixin in goats. Determining the systemic effects of flunixin-mediated PGE2 suppression in goats is also warranted.

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 < 0.01) in L calves than R calves 0.5 and 1 hours after castration, while concentrations were lower (meloxicam × time effect; P = 0.02) in M calves than N calves at 2, 4 and 48 hours. The serum amyloid-A concentrations were greater (lidocaine × time effect; P < 0.01) in R calves than L calves on days 1, 3, 21 and 28 after castration. Haptoglobin concentrations were greater (meloxicam × time effect; P = 0.01) in N calves than M calves 24 and 48 hours after castration. Lower (lidocaine effect; P < 0.01) visual analog scale (VAS) scores, leg movement frequencies and head movement distance were observed in L calves than R calves at the time of castration. Escape behaviour during castration was lower (lidocaine effect; P < 0.05) in L calves than R calves based on data captured with accelerometer and head gate devices. Scrotal circumference had a triple interaction (lidocaine × meloxicam × time; P = 0.03), where M-R calves had greater scrotal circumference than M-L calves 28 d after castration, but no differences were observed between both groups and N-R and N-L calves. No differences (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.

Pharmacokinetic-pharmacodynamic integration of marbofloxacin after single and repeated intravenous administration in goats.

The single dose pharmacokinetics (PK) of marbofloxacin was compared with repeated intravenous (IV) administrations in six healthy goats at the dose rate of 2 mg/kg body weight at 24 h interval for 5 days. Blood samples were collected at times: 5, 15, 30 min and 1, 2, 4, 6, 9, 12, 24, 36, 48 and 72 h post drug administration. Plasma drug concentrations were determined by High Performance Liquid Chromatography and concentration-time data were subjected to non-compartment analysis. The MIC and MBC of marbofloxacin against Escherichia (E.) coli and Pasteurella (P.) multocida in Mueller Hinton Broth were determined by broth microdilution method. The t1/2elm = 4.37 ±â€¯0.18 h and ClB = 0.29 ±â€¯0.01 following single administration were not significantly different from t1/2elm = 5.11 ±â€¯0.22 h and ClB = 0.26 ±â€¯0.01 mL/kg/h after repeated administrations of marbofloxacin. Accumulation index (AI = 1.1) indicated no accumulation of marbofloxacin following repeated IV administrations up to 5 days. The respective MICs of marbofloxacin against E. coli and P. multocida were 0.03 µg/mL and 0.4 µg/mL. The AUC0-24h/MIC ratios were 226.64 ±â€¯7.21 h for E. coli and 16.99 ±â€¯0.541 h for P. multocida. PK/PD integration indicated that marbofloxacin daily dose of 2 mg/kg is appropriate for treating E. coli (MIC ≤ 0.03 µg/mL) infections. However, a higher dose of 6 mg/kg/day is suggested to obtain clinical cure against diseases caused by P. multocida having MIC90 = 0.12 µg/mL in goat species.

Comparative plasma and interstitial fluid pharmacokinetics and tissue residues of ceftiofur crystalline-free acid in cattle with induced coliform mastitis.

Ceftiofur (CEF) is a third-generation cephalosporin that is the most widely used antimicrobial in the dairy industry. Currently, violative meat residues in cull dairy cattle are commonly associated with CEF. One potential cause for violative residues is altered pharmacokinetics of the drug due to disease, which could increase the time needed for the residue to deplete. The objectives of this study were (a) to determine the absolute bioavailability of CEF crystalline-free acid (CFA) in healthy versus diseased cows; (b) to compare the plasma and interstitial fluid pharmacokinetics and plasma protein binding of CEF between healthy dairy cows and those with disease; and (c) to determine the CEF residue profile in tissues of diseased cows. For this trial, disease was induced through intramammary Escherichia coli infusion. Following disease induction and CEF CFA administration, for plasma concentrations, there was not a significant effect of treatment (p = 0.068), but the treatment-by-time interaction (p = 0.005) was significant. There was a significantly greater concentration of CEF in the plasma of the DIS cows at T2 hr (p = 0.002), T8 hr (p < 0.001), T12 hr (p = 0.001), and T16 hr (p = 0.002). For PK parameters in plasma, the slope of the terminal phase of the concentration versus time curve was significantly lower (p = 0.007), terminal half-life was significantly longer (p = 0.014), and apparent volume of distribution during the elimination phase was significantly higher (p = 0.028) diseased group. There was no difference in plasma protein binding of CEF and interstitial fluid pharmacokinetics. None of the cows had kidney CEF residues above the US tolerance level following observation of the drug's withdrawal period, but one cow with a larger apparent volume of distribution and longer terminal half-life had tissue residues slightly below the tolerance. Whereas these findings do not support the hypothesis that severely ill cows need longer withdrawal times, alterations in the terminal half-life suggest that it is theoretically possible.

Comparative mutant prevention concentration and antibacterial activity of fluoroquinolones against Escherichia coli in diarrheic buffalo calves.

Owing to emerging threat of antimicrobial resistance, mutant prevention concentration (MPC) is considered as an important parameter to evaluate the antimicrobials for their capacity to restrict/allow the emergence of resistant mutants. Therefore, MPCs of ciprofloxacin, enrofloxacin, levofloxacin, moxifloxacin, and norfloxacin were determined against Escherichia coli isolates of diarrheic buffalo calves. The minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) were also established. The MICs of ciprofloxacin, enrofloxacin, levofloxacin, moxifloxacin and norfloxacin were 0·009, 0·022, 0·024, 0·028, and 0·036 µg/ml, respectively. The MBCs obtained were very close to the MICs of respective drugs that suggested a bactericidal mode of action of antimicrobials. The MPCs (µg/ml) of ciprofloxacin (4·2×MIC), moxifloxacin (4·8×MIC), and norfloxacin (5·1×MIC) were approximately equal but slightly lower than enrofloxacin (7·6×MIC) and levofloxacin (8·5×MIC) against clinical isolates of E. coli. The MPC data suggested that enrofloxacin has the potential for restricting the selection of E. coli mutants during treatment at appropriate dosing.