Resistant cutoff values and optimal scheme establishments for florfenicol against Escherichia coli with PK‐PD modeling analysis in pigs

Florfenicol, a structural analog of thiamphenicol, has broad‐spectrum antibacterial activity against gram‐negative and gram‐positive bacteria. This study was conducted to investigate the epidemiological, pharmacokinetic–pharmacodynamic cutoff, and the optimal scheme of florfenicol against Escherichia coli (E. coli) with PK‐PD integrated model in the target infectious tissue. 220 E. coli strains were selected to detect the susceptibility to florfenicol, and a virulent strain P190, whose minimum inhibitory concentration (MIC) was similar to the MIC₅₀ (8 μg/ml), was analyzed for PD study in LB and ileum fluid. The MIC of P190 in the ileum fluid was 0.25 times lower than LB. The ratios of MBC/MIC were four both in the ileum and LB. The characteristics of time‐killing curves also coincided with the MBC determination. The recommended dosages (30 mg/kg·body weight) were orally administrated in healthy pigs, and both plasma and ileum fluid were collected for PK study. The main pharmacokinetics (PK) parameters including AUC_24 hr, AUC_0–∞, T_max, T_1/2, C_max, CL_b, and K_e were 49.83, 52.33 μg*h/ml, 1.32, 10.58 hr, 9.12 μg/ml, 0.50 L/hr*kg, 0.24 hr^?1 and 134.45, 138.71 μg*hr/ml, 2.05, 13.01 hr, 16.57 μg/ml, 0.18 L/hr*kg, 0.14 hr^?1 in the serum and ileum fluid, respectively. The optimum doses for bacteriostatic, bactericidal, and elimination activities were 29.81, 34.88, and 36.52 mg/kg for 50% target and 33.95, 39.79, and 42.55 mg/kg for 90% target, respectively. The final sensitive breakpoint was defined as 16 μg/ml. The current data presented provide the optimal regimens (39.79 mg/kg) and susceptible breakpoint (16 μg/ml) for clinical use, but these predicted data should be validated in the clinical practice.     

Tilmicosin enteric granules and premix to pigs: Antimicrobial susceptibility testing and comparative pharmacokinetics

The purpose of this study was to compare the pharmacokinetics and relative bioavailability of tilmicosin enteric granules and premix after oral administration at a dose of 40 mg/kg in pigs. Three kinds of different respiratory pathogens were selected for determination of minimal inhibitory concentration (MIC) to tilmicosin. Eight healthy pigs were assigned to a two‐period, randomized crossover design. A modified rapid, sensitive HPLC method was used for determining the concentrations of tilmicosin in plasma. Pharmacokinetic parameters were calculated by using WinNonlin 5.2 software. The MIC₉₀ of tilmicosin against Haemophilus parasuis, Actinbacillus pleuropneumoniae, and Pasteurella multocida were all 8 μg/ml. These results indicated that these common pig respiratory bacteria are sensitive to tilmicosin. The main parameters of time to reach maximum plasma concentration (T_max), elimination half‐life (t_1/2β), mean residence time (MRT), and apparent volume of distribution (V_F) were 2.03 ± 0.37 hr, 29.31 ± 5.56 hr, 25.22 ± 2.57 hr, 4.06 ± 1.04 L/kg, and 3.05 ± 0.08 hr, 17.06 ± 1.77 hr, 15.55 ± 1.37 hr, 2.95 ± 0.62 L/kg after the orally administrated tilmicosin enteric granules and premix. The relative bioavailability of tilmicosin enteric granules to premix was 114.97 ± 7.19%, according to the AUC_0‐t values. These results demonstrated that tilmicosin enteric granules produced faster tilmicosin absorption, slower elimination, larger tissue distribution, and higher bioavailability compared to the tilmicosin premix. The present study results manifest that tilmicosin enteric granules can be used as a therapeutic alternative to premix in clinical treatment.     

Pharmacokinetic–pharmacodynamic integration and modelling of oxytetracycline for the calf pathogens Mannheimia haemolytica and Pasteurella multocida

A calf tissue cage model was used to study the pharmacokinetics (PK) and pharmacodynamics (PD) of oxytetracycline in serum, inflamed (exudate) and noninflamed (transudate) tissue cage fluids. After intramuscular administration, the PK was characterized by a long mean residence time of 28.3 hr. Based on minimum inhibitory concentrations (MICs) for six isolates each of Mannheimia haemolytica and Pasteurella multocida, measured in serum, integration of in vivo PK and in vitro PD data established area under serum concentration–time curve (AUC_0–∞)/MIC ratios of 30.0 and 24.3 hr for M. haemolytica and P. multocida, respectively. Corresponding AUC_0–∞/MIC ratios based on MICs in broth were 656 and 745 hr, respectively. PK‐PD modelling of in vitro bacterial time–kill curves for oxytetracycline in serum established mean AUC_0–24 hr/MIC ratios for 3log₁₀ decrease in bacterial count of 27.5 hr (M. haemolytica) and 60.9 hr (P. multocida). Monte Carlo simulations predicted target attainment rate (TAR) dosages. Based on the potency of oxytetracycline in serum, the predicted 50% TAR single doses required to achieve a bacteriostatic action covering 48‐hr periods were 197 mg/kg (M. haemolytica) and 314 mg/kg (P. multocida), respectively, against susceptible populations. Dosages based on the potency of oxytetracycline in broth were 25‐ and 27‐fold lower (7.8 and 11.5 mg/kg) for M. haemolytica and P. multocida, respectively.     

Pharmacokinetics of enrofloxacin and danofloxacin in premature calves

The aim of this study was to determine the pharmacokinetics/pharmacodynamics of enrofloxacin (ENR) and danofloxacin (DNX) following intravenous (IV) and intramuscular (IM) administrations in premature calves. The study was performed on twenty‐four calves that were determined to be premature by anamnesis and general clinical examination. Premature calves were randomly divided into four groups (six premature calves/group) according to a parallel pharmacokinetic (PK) design as follows: ENR‐IV (10 mg/kg, IV), ENR‐IM (10 mg/kg, IM), DNX‐IV (8 mg/kg, IV), and DNX‐IM (8 mg/kg, IM). Plasma samples were collected for the determination of tested drugs by high‐pressure liquid chromatography with UV detector and analyzed by noncompartmental methods. Mean PK parameters of ENR and DNX following IV administration were as follows: elimination half‐life (t_1/2λz) 11.16 and 17.47 hr, area under the plasma concentration–time curve (AUC_0‐48) 139.75 and 38.90 hr*µg/ml, and volume of distribution at steady‐state 1.06 and 4.45 L/kg, respectively. Total body clearance of ENR and DNX was 0.07 and 0.18 L hr^?1 kg^?1, respectively. The PK parameters of ENR and DNX following IM injection were t_1/2λz 21.10 and 28.41 hr, AUC_0‐48 164.34 and 48.32 hr*µg/ml, respectively. The bioavailability (F) of ENR and DNX was determined to be 118% and 124%, respectively. The mean AUC_0‐48CPR/AUC_0‐48ENR ratio was 0.20 and 0.16 after IV and IM administration, respectively, in premature calves. The results showed that ENR (10 mg/kg) and DNX (8 mg/kg) following IV and IM administration produced sufficient plasma concentration for AUC_0‐24/minimum inhibitory concentration (MIC) and maximum concentration (C_max)/MIC ratios for susceptible bacteria, with the MIC₉₀ of 0.5 and 0.03 μg/ml, respectively. These findings may be helpful in planning the dosage regimen for ENR and DNX, but there is a need for further study in naturally infected premature calves.     

Pharmacokinetic/pharmacodynamic integration and modelling of oxytetracycline for the porcine pneumonia pathogens Actinobacillus pleuropneumoniae and Pasteurella multocida

Pharmacokinetic–pharmacodynamic (PK/PD) integration and modelling were used to predict dosage schedules of oxytetracycline for two pig pneumonia pathogens, Actinobacillus pleuropneumoniae and Pasteurella multocida. Minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) were determined in broth and porcine serum. PK/PD integration established ratios of average concentration over 48 h (C_av0–48 h)/MIC of 5.87 and 0.27 μg/mL (P. multocida) and 0.70 and 0.85 μg/mL (A. pleuropneumoniae) for broth and serum MICs, respectively. PK/PD modelling of in vitro time–kill curves established broth and serum breakpoint values for area under curve (AUC_0–24 h)/MIC for three levels of inhibition of growth, bacteriostasis and 3 and 4 log₁₀ reductions in bacterial count. Doses were then predicted for each pathogen, based on Monte Carlo simulations, for: (i) bacteriostatic and bactericidal levels of kill; (ii) 50% and 90% target attainment rates (TAR); and (iii) single dosing and daily dosing at steady‐state. For 90% TAR, predicted daily doses at steady‐state for bactericidal actions were 1123 mg/kg (P. multocida) and 43 mg/kg (A. pleuropneumoniae) based on serum MICs. Lower TARs were predicted from broth MIC data; corresponding dose estimates were 95 mg/kg (P. multocida) and 34 mg/kg (A. pleuropneumoniae).     

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 (C_max) 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 (AUC_0–∞D1 = 7.67 ± 0.719 µg × hr/ml) and day 5 (AUC_0‐∞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: C_max/MIC and AUC_0–24hr/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.     

Physicochemical characterization and pharmacokinetics in broiler chickens of a new recrystallized enrofloxacin hydrochloride dihydrate

Enrofloxacin, a key antimicrobial agent in commercial avian medicine, has limited bioavailability (60%). This prompted its chemical manipulation to yield a new solvate‐recrystallized enrofloxacin hydrochloride dihydrate entity (enro_C). Its chemical structure was characterized by means of mass spectroscopy, Fourier transformed infrared spectroscopy, X‐ray powder diffraction, and thermal analysis. Comparative oral pharmacokinetics (PK) of reference enrofloxacin (enro_R) and enro_C in broiler chickens after oral administration revealed noticeable improvements in key parameters and PK/PD ratios. Maximum serum concentration values were 2.61 ± 0.21 and 5.9 ± 0.42 μg/mL for enro_R and enro_C, respectively; mean residence time was increased from 5.50 ± 0.26 h to 6.20 ± 0.71 h and the relative bioavailability of enro_C was 336%. Considering C_max/MIC and AUC/MIC ratios and the MIC values for a wild‐type Escherichia coli O78/H12 (0.25 μg/mL), optimal ratios will only be achieved by enro_C (C_max/MIC = 23.6 and AUC/MIC = 197.7 for enro_C; vs. C_max/MIC = 10.4 and AUC/MIC = 78.1 for enro_R). Furthermore, enro_C may provide in most cases mutant prevention concentrations (C_max/MIC ≥ 16). Ready solubility of powder enro_C in drinking water at concentrations regularly used (0.01%) to provide an additional advantage of enro_C in the field. Further development of enro_C is warranted before it can be recommended for clinical use in veterinary medicine.     

Comparative pharmacokinetics of florfenicol in healthy and Pasteurella multocida‐infected Gaoyou ducks

Pasteurella multocida is the causative agent of fowl cholera, and florfenicol (FF) has potent antibacterial activity against P. multocida and is widely used in the poultry industry. In this study, we established a P. multocida infection model in ducks and studied the pharmacokinetics of FF in serum and lung tissues after oral administration of 30 mg/kg bodyweight. The maximum concentrations reached (C_max) were lower in infected ducks (13.88 ± 2.70 μg/ml) vs. healthy control animals (17.86 ± 1.57 μg/ml). In contrast, the mean residence time (MRT: 2.35 ± 0.13 vs. 2.27 ± 0.18 hr) and elimination half‐life (T_½β: 1.63 ± 0.08 vs. 1.57 ± 0.12 hr) were similar for healthy and diseased animals, respectively. As a result, the area under the concentration curve for 0–12 hr (AUC_0–12 hr) for FF in healthy ducks was significantly greater than that in infected ducks (49.47 ± 5.31 vs. 34.52 ± 8.29 μg hr/ml). The pharmacokinetic differences of FF in lung tissues between the two groups correlated with the serum pharmacokinetic differences. The C_max and AUC_0–12 hr values of lung tissue in healthy ducks were higher than those in diseased ducks. The concentration of FF in lung tissues was approximately 1.2‐fold higher than that in serum both in infected and healthy ducks indicating that FF is effective in treating respiratory tract infections in ducks.     

Pharmacokinetics of levofloxacin after single intravenous,oral and subcutaneous administration to dogs

The pharmacokinetic properties of the fluoroquinolone levofloxacin (LFX) were investigated in six dogs after single intravenous, oral and subcutaneous administration at a dose of 2.5, 5 and 5 mg/kg, respectively. After intravenous administration, distribution was rapid (T_½dist 0.127 ± 0.055 hr) and wide as reflected by the volume of distribution of 1.20 ± 0.13 L/kg. Drug elimination was relatively slow with a total body clearance of 0.11 ± 0.03 L kg^?1 hr^?1 and a T_½ for this process of 7.85 ± 2.30 hr. After oral and subcutaneous administration, absorption half‐life and T_max were 0.35 and 0.80 hr and 1.82 and 2.82 hr, respectively. The bioavailability was significantly higher (p ? 0.05) after subcutaneous than oral administration (79.90 vs. 60.94%). No statistically significant differences were observed between other pharmacokinetic parameters. Considering the AUC_24 hr/MIC and C_max/MIC ratios obtained, it can be concluded that LFX administered intravenously (2.5 mg/kg), subcutaneously (5 mg/kg) or orally (5 mg/kg) is efficacious against Gram‐negative bacteria with MIC values of 0.1 μg/ml. For Gram‐positive bacteria with MIC values of 0.5 μg/kg, only SC and PO administration at a dosage of 5 mg/kg showed to be efficacious. MIC‐based PK/PD analysis by Monte Carlo simulation indicates that the proposed dose regimens of LFX, 5 and 7.5 mg/kg/24 hr by SC route and 10 mg/kg/24 hr by oral route, in dogs may be adequate to recommend as an empirical therapy against S. aureus strains with MIC ≤ 0.5 μg/ml and E. coli strains with MIC values ≤0.125 μg/ml.     

Pharmacokinetics of enrofloxacin HCl‐2H2O (ENRO‐C), PK/PD,and Monte Carlo modeling vs. Leptospira spp. in cows

The pharmacokinetics, PK/PD ratios, and Monte Carlo modeling of enrofloxacin HCl‐2H₂O (Enro‐C) and its reference preparation (Enro‐R) were determined in cows. Fifty‐four Jersey cows were randomly assigned to six groups receiving a single IM dose of 10, 15, or 20 mg/kg of Enro‐C (Enro‐C₁₀, Enro‐C₁₅, Enro‐C₂₀) or Enro‐R. Serial serum samples were collected and enrofloxacin concentrations quantified. A composite set of minimum inhibitory concentrations (MIC) of Leptospira spp. was utilized to calculate PK/PD ratios: maximum serum concentration/MIC (C_max/MIC₉₀) and area under the serum vs. time concentration of enrofloxacin/MIC (AUC_0‐24/MIC₉₀). Monte Carlo simulations targeted C_max/MIC = 10 and AUC_0‐24/MIC = 125. Mean C_max obtained were 6.17 and 2.46 μg/ml; 8.75 and 3.54 μg/ml; and 13.89 and 4.25 μg/ml, respectively for Enro‐C and Enro‐R. C_max/MIC₉₀ ratios were 6.17 and 2.46, 8.75 and 3.54, and 13.89 and 4.25 for Enro‐C and Enro‐R, respectively. Monte Carlo simulations based on C_max/MIC₉₀ = 10 indicate that only Enro‐C₁₅ and Enro‐C₂₀ may be useful to treat leptospirosis in cows, predicting a success rate ≥95% when MIC₅₀ = 0.5 μg/ml, and ≥80% when MIC₉₀ = 1.0 μg/ml. Although Enro‐C₁₅ and Enro‐C₂₀ may be useful to treat leptospirosis in cattle, clinical trials are necessary to confirm this proposal.     

Pharmacokinetic and pharmacodynamic integration and modeling of acetylkitasamycin in swine for Clostridium perfringens

The aim of this study was to establish an integrated pharmacokinetic/pharmacodynamic (PK/PD) modeling approach of acetylkitasamycin for designing dosage regimens and decreasing the emergence of drug‐resistant bacteria. After oral administration of acetylkitasamycin to healthy and infected pigs at the dose of 50 mg/kg body weights (bw), a rapid and sensitive LC–MS/MS method was developed and validated for determining the concentration change of the major components of acetylkitasamycin and its possible metabolite kitasamycin in the intestinal samples taken from the T‐shape ileal cannula. The PK parameters, including the integrated peak concentration (C_max), the time when the maximum concentration reached (T_max) and the area under the concentration–time curve (AUC), were calculated by WinNonlin software. The minimum inhibitory concentration (MIC) of 60 C. perfringens strains was determined following CLSI guideline. The in vitro and ex vivo activities of acetylkitasamycin in intestinal tract against a pathogenic strain of C. perfringens type A (CPFK122995) were established by the killing curve. Our PK data showed that the integrated C_max, T_max, and AUC were 14.57–15.81 μg/ml, 0.78–2.52 hR, and 123.84–152.32 μg hr/ml, respectively. The PD data show that MIC₅₀ and MIC₉₀ of the 60 C. perfringens isolates were 3.85 and 26.45 μg/ml, respectively. The ex vivo growth inhibition data were fitted to the inhibitory sigmoid E_max equation to provide the values of AUC/MIC to produce bacteriostasis (4.84 hr), bactericidal activity (15.46 hr), and bacterial eradication (24.99 hr). A dosage regimen of 18.63 mg/kg bw every 12 hr could be sufficient in the prevention of C. perfringens infection. The therapeutic dosage regimen for C. perfringens infection was at the dose of 51.36 mg/kg bw every 12 hr for 3 days. In summary, the dosage regimen for the treatment of C. perfringens in pigs administered with acetylkitasamycin was designed using PK/PD integrate model. The designed dose regimen could to some extent decrease the risk for emergence of macrolide resistance.     

Pharmacokinetic and pharmacodynamic characterization of ceftiofur crystalline‐free acid following subcutaneous administration in domestic goats

Pharmacokinetic (PK)–pharmacodynamic (PD) integration of crystalline ceftiofur‐free acid (CCFA) was established in six healthy female goats administered subcutaneously (s.c.) on the left side of the neck at a dosage of 6.6 mg/kg body weight. Serum concentrations of ceftiofur and desfuroylceftiofur (DFC) were determined using high‐performance liquid chromatography. Mutant prevention concentration (MPC), minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of ceftiofur were determined for Pasteurella (P.) multocida. Mean terminal half‐life and mean residence time of ceftiofur + DFC were 48.6 h and 104 h, respectively. In vitro plasma protein binding of ceftiofur was 46.6% in goats. The MIC and MBC values of ceftiofur were similar in serum and MHB and a very small difference between these values confirmed bactericidal activity of drug against P. multocida. In vitro and ex vivo time–kill curves for P. multocida demonstrated a time‐dependent killing action of drug. Considering target serum concentration of 0.20 μg/mL, PK‐PD values for AUC_24 h/MIC₉₀ and T > MIC₉₀, respectively, were 302 h and 192 h against P. multocida. A MPC/MIC ratio of 10–14 indicated that selective pressure for proliferation of resistant mutants of P. multocida is minimal after CCFA single‐dose administration. Based on MPC = 1.40 μg/mL for P. multocida, the PK‐PD indices, viz. T > MPC and AUC₂₄/MPC, were 48 h and 43 h, respectively. The data suggested the use of single dose (6.6 mg/kg, s.c.) of CCFA in goats to obtain clinical and bacteriological cure of pneumonia due to P. multocida.     

Pharmacokinetics of ceftriaxone in Green sea turtles (Chelonia mydas) following intravenous and intramuscular administration at two dosages

Green sea turtles are widely distributed in tropical and subtropical waters. Adult green sea turtles face many threats, primarily from humans, including injuries from boat propellers, being caught in fishing nets, pollution, poaching, and infectious diseases. To the best of our knowledge, limited pharmacokinetic information to establish suitable therapeutic plans is available for green sea turtles. Therefore, the present study aimed to describe the pharmacokinetic characteristics of ceftriaxone (CEF) in green sea turtles, Chelonia mydas, following single intravenous and intramuscular administrations at two dosages of 10 and 25 mg/kg body weight (b.w.). Blood samples were collected at assigned times up to 96 hr. The plasma concentrations of CEF were measured by liquid chromatography tandem mass spectrometry. The concentrations of CEF in the plasma were quantified up to 24 and 48 hr after i.v. and i.m. administrations at dosages of 10 and 25 mg/kg b.w., respectively. The C_max values of CEF were 15.43 ± 3.71 μg/ml and 43.48 ± 4.29 μg/ml at dosages of 10 and 25 mg/kg, respectively. The AUC_last values increased in a dose‐dependent fashion. The half‐life values were 2.89 ± 0.41 hr and 5.96 ± 0.26 hr at dosages of 10 and 25 mg/kg b.w, respectively. The absolute i.m. bioavailability was 67% and 108%, and the binding percentage of CEF to plasma protein was ranged from 20% to 29% with an average of 24.6%. Based on the pharmacokinetic data, susceptibility break‐point and PK‐PD index (T > MIC, 0.2 μg/ml), i.m. administration of CEF at a dosage of 10 mg/kg b.w. might be appropriate for initiating treatment of susceptible bacterial infections in green sea turtles.     

Plasma pharmacokinetics and muscle residue dynamics of mebendazole in Carassius auratus

Mebendazole is approved for use in aquatic animals and is widely used in Chinese aquaculture. We developed a pharmacokinetic and residue analysis for mebendazole levels in the goldfish (Carassius auratus). Plasma and muscle samples of C. auratus were taken after oral administration of 10 mg/kg mebendazole. The maximal drug plasma concentration of 0.55 mg/L was achieved at 48 hr and then declined with the elimination half‐life (T_1/2β) of 7.99 hr. Administration of 10 mg/kg by oral gavage for 5 successive days resulted in a peak mebendazole concentration of 0.70 mg/kg in muscle at 96 hr after the last dose. The drug was then eliminated at a relatively slow rate from muscle with T_1/2β of 68.41 hr. There was no detectable mebendazole in any muscle samples at 24 days postadministration. The AUC_last in plasma and muscle was 19.42 and 105.33 mg hr/L, respectively. These data provide information for dosage recommendations and withdrawal time determinations for mebendazole use in aquariums.     

Sulfadiazine pharmacokinetics in grass carp (Ctenopharyngodon idellus) receiving oral and intravenous administrations

This study aimed to examine the bioavailability (BA) and pharmacokinetic (PK) characteristics of sulfadiazine (SDZ) in grass carp (Ctenopharyngodon idellus) after oral and intravenous administrations. Blood samples were collected at predetermined time points of 0.083, 0.17, 0.5, 1, 2, 4, 8, 16, 24, 48, 72, and 96 hr (n = 6). The samples were extracted and purified by organic reagents and determined by the ultra‐performance liquid chromatography. The software named 3P97 was used to calculate relevant PK parameters. The results demonstrated that the concentration–time profile of SDZ was best described by a one‐compartmental open model with first‐order absorption after a single oral dose. The main PK parameters of the absorption rate constant (K_α), the absorption half‐life (t_{1/2 Kα}), the elimination rate constant (K_e), the elimination half‐life (t_1/2Ke), and the area under concentration–time profile (AUC_0‐∞) were 0.3 1/h, 2.29 hr, 0.039 1/h, 17.64 hr, and 855.78 mg.h/L, respectively. Following intravenous administration, the concentration–time curve fitted to a two‐compartmental open model without absorption. The primary PK parameters of the distribution rate constant (α), the elimination rate constant (β), the distribution half‐life (t_1/2α), the elimination half‐life (t_1/2β), the apparent distribution volume (V_SS), the total clearance (CL), and AUC_0‐∞ were 9.62 1/hr, 0.039 1/hr, 0.072 hr, 17.71 hr, 0.33 L/kg, 0.013 L h^?1 kg^?1, and 386.23 mg.h/L, respectively. Finally, the BA was calculated to be 22.16%. Overall, this study will provide some fundamental information on PK properties in the development of a new formulation SDZ in the future and is partially beneficial for the appropriate usage of SDZ in aquaculture.     

Mutant prevention concentration,pharmacokinetic–pharmacodynamic integration,and modeling of enrofloxacin data established in diseased buffalo calves

The pharmacokinetic–pharmacodynamic (PK/PD) modeling of enrofloxacin data using mutant prevention concentration (MPC) of enrofloxacin was conducted in febrile buffalo calves to optimize dosage regimen and to prevent the emergence of antimicrobial resistance. The serum peak concentration (C_max), terminal half‐life (t_1/2K₁₀₎, apparent volume of distribution (Vd_(area)/F), and mean residence time (MRT) of enrofloxacin were 1.40 ± 0.27 μg/mL, 7.96 ± 0.86 h, 7.74 ± 1.26 L/kg, and 11.57 ± 1.01 h, respectively, following drug administration at dosage 12 mg/kg by intramuscular route. The minimum inhibitory concentration (MIC), minimum bactericidal concentration, and MPC of enrofloxacin against Pasteurella multocida were 0.055, 0.060, and 1.45 μg/mL, respectively. Modeling of ex vivo growth inhibition data to the sigmoid E_max equation provided AUC_24 h/MIC values to produce effects of bacteriostatic (33 h), bactericidal (39 h), and bacterial eradication (41 h). The estimated daily dosage of enrofloxacin in febrile buffalo calves was 3.5 and 8.4 mg/kg against P. multocida/pathogens having MIC₉₀ ≤0.125 and 0.30 μg/mL, respectively, based on the determined AUC_24 h / MIC values by modeling PK/PD data. The lipopolysaccharide‐induced fever had no direct effect on the antibacterial activity of the enrofloxacin and alterations in PK of the drug, and its metabolite will be beneficial for its use to treat infectious diseases caused by sensitive pathogens in buffalo species. In addition, in vitro MPC data in conjunction with in vivo PK data indicated that clinically it would be easier to eradicate less susceptible strains of P. multocida in diseased calves.     

Pharmacokinetic/pharmacodynamic evaluation of marbofloxacin as a single injection for Pasteurellaceae respiratory infections in cattle using population pharmacokinetics and Monte Carlo simulations

Population pharmacokinetic of marbofloxacin was investigated with 52 plasma concentration–time profiles obtained after intramuscular administration of Forcyl® in cattle. Animal's status, pre‐ruminant, ruminant, or dairy cow, was retained as a relevant covariate for clearance. Monte Carlo simulations were performed using a stratification by status, and 1000 virtual disposition curves were generated in each bovine subpopulation for the recommended dosage regimen of 10 mg/kg as a single injection. The probability of target attainment (PTA) of pharmacokinetic/pharmacodynamic (PK/PD) ratios associated with clinical efficacy and prevention of resistance was determined in each simulated subpopulation. The cumulative fraction of response (CFR) of animals achieving a PK/PD ratio predictive of positive clinical outcome was then calculated for the simulated dosage regimen, taking into account the minimum inhibitory concentration (MIC) distribution of Pasteurella multocida, Mannheimia haemolytica, and Histophilus somni. When considering a ratio of AUC_0‐24 hr/MIC (area under the curve/minimum inhibitory concentration) greater than 125 hr, CFRs ranging from 85% to 100% against the three Pasteurellaceae in each bovine subpopulation were achieved. The PTA of the PK/PD threshold reflecting the prevention of resistances was greater than 90% up to MPC (mutant prevention concentration) values of 1 μg/ml in pre‐ruminants and ruminants and 0.5 μg/ml in dairy cows.     

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 (C_max) 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.     

Standard PK/PD concepts can be applied to determine a dosage regimen for a macrolide: the case of tulathromycin in the calf

The pharmacokinetic (PK) profile of tulathromycin, administered to calves subcutaneously at the dosage of 2.5 mg/kg, was established in serum, inflamed (exudate), and noninflamed (transudate) fluids in a tissue cage model. The PK profile of tulathromycin was also established in pneumonic calves. For Mannheimia haemolytica and Pasteurella multocida, tulathromycin minimum inhibitory concentrations (MIC) were approximately 50 times lower in calf serum than in Mueller–Hinton broth. The breakpoint value of the PK/pharmacodynamic (PD) index (AUC_(0–24 h)/MIC) to achieve a bactericidal effect was estimated from in vitro time‐kill studies to be approximately 24 h for M. haemolytica and P. multocida. A population model was developed from healthy and pneumonic calves and, using Monte Carlo simulations, PK/PD cutoffs required for the development of antimicrobial susceptibility testing (AST) were determined. The population distributions of tulathromycin doses were established by Monte Carlo computation (MCC). The computation predicted a target attainment rate (TAR) for a tulathromycin dosage of 2.5 mg/kg of 66% for M. haemolytica and 87% for P. multocida. The findings indicate that free tulathromycin concentrations in serum suffice to explain the efficacy of single‐dose tulathromycin in clinical use, and that a dosage regimen can be computed for tulathromycin using classical PK/PD concepts.     

Pharmacokinetics of a single intramuscular injection of cefquinome in buffalo calves

The objective of this study was to investigate the pharmacokinetics of cefquinome following single intramuscular (IM) administration in six healthy male buffalo calves. Cefquinome was administered intramuscularly (2 mg/kg bodyweight) and blood samples were collected prior to drug administration and up to 24 hr after injection. No adverse effects or changes were observed after the IM injection of cefquinome. Plasma concentrations of cefquinome were determined by high‐performance liquid chromatography. The disposition of plasma cefquinome is characterized by a mono‐compartmental open model. The pharmacokinetic parameters after IM administration (mean ± SE) were C_max 6.93 ± 0.58 μg/ml, T_max 0.5 hr, t_½kα 0.16 ± 0.05 hr, t_½β 3.73 ± 0.10 hr, and AUC 28.40 ± 1.30 μg hr/ml after IM administration. A dosage regimen of 2 mg/kg bodyweight at 24‐hr interval following IM injection of cefquinome would maintain the plasma levels required to be effective against the bacterial pathogens with MIC values ≤0.39 μg/ml. The suggested dosage regimen of cefquinome has to be validated in the disease models before recommending for clinical use in buffalo calves.