Pharmacokinetic/pharmacodynamic evaluation of marbofloxacin in the treatment of Haemophilus parasuis and Actinobacillus pleuropneumoniae infections in nursery and fattener pigs using Monte Carlo simulations

This study evaluated the theoretical clinical outcome of three marbofloxacin posology regimens in two groups of pigs (weaners and fatteners) for the treatment of Actinobacillus pleuropneumoniae (App) and Haemophilus parasuis (Hp) infection and the appearance of resistant bacteria due to the antibiotic treatment. The probability of target attainment (PTA) for pharmacokinetic/pharmacodynamics (PK/PD) ratios associated with clinical efficacy and with the appearance of antimicrobial resistance for fluoroquinolones at each minimum inhibitory concentration (MIC) or mutant prevention concentration (MPC) were calculated, respectively. The cumulative fraction of response (CFR) was calculated for the three posology regimens against App and they ranged from 91.12% to 96.37% in weaners and from 93% to 97.43% in fatteners, respectively. In the case of Hp, they ranged from 80.52% to 85.14% in weaners and from 82.01% to 88.49% in fatteners, respectively. Regarding the PTA of the PK/PD threshold associated with the appearance of antimicrobial resistance, results showed that marbofloxacin would prevent resistances in most of the animals up to the MPC value of 1 μg/mL.     

Pharmacokinetic and pharmacodynamic testing of marbofloxacin administered as a single injection for the treatment of bovine respiratory disease

Vallé, M., Schneider, M., Galland, D., Giboin, H., Woehrlé, F. Pharmacokinetic and pharmacodynamic testing of marbofloxacin administered as a single injection for the treatment of bovine respiratory disease. J. vet. Pharmacol. Therap. 35, 519–528. New approaches in Pharmacokinetic/Pharmacodynamic (PK/PD) integration suggested that marbofloxacin, a fluoroquinolone already licensed for the treatment of bovine respiratory disease at a daily dosage of 2 mg/kg for 3–5 days, would be equally clinically effective at 10 mg/kg once (Forcyl^®), whilst also reducing the risk of resistance. This marbofloxacin dosage regimen was studied using mutant prevention concentration (MPC), PK simulation, PK/PD integration and an in vitro dynamic system. This system simulated the concentration–time profile of marbofloxacin in bovine plasma established in vivo after a single 10 mg/kg intramuscular dose and killing curves of field isolated Pasteurellaceae strains of high (minimum inhibitory concentration (MIC) MIC ≤0.03 μg/mL), average (MIC of 0.12–0.25 μg/mL) and low (MIC of 1 μg/mL) susceptibility to marbofloxacin. The marbofloxacin MPC values were 2‐ to 4‐fold the MIC values for all Mannheimia haemolytica, Pasteurella multocida tested. Marbofloxacin demonstrated a concentration‐dependant killing profile with bactericidal activity observed within 1 h for most strains. No resistance development (MIC ≥4 μg/mL) was detected in the dynamic tests. Target values for risk of resistance PK/PD surrogates (area under the curve (AUC) AUC_{24 h}/MPC and T_>MPC/T_MSW ratio) were achieved for all clinically susceptible pathogens. The new proposed dosing regimen was validated in vitro and by PK/PD integration confirming the single‐injection short‐acting antibiotic concept.     

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/pharmacodynamic integration of cefquinome against Pasteurella Multocida in a piglet tissue cage model

To explore the in vivo antimicrobial activity of cefquinome against Pasteurella multocida in piglets, a piglet tissue cage infection model was used in this study. After the population of P. multocida reached 10⁷ CFU/mL in a tissue cage, piglets received an intramuscular administration of cefquinome at 0.2, 0.4, 0.8, 1, 2, and 4 mg/kg once daily for 3 days. To assess the tissue cage pharmacokinetics (PKTCF) of cefquinome, tissue cage fluid was collected for cefquinome analysis at 1, 3, 6, 9, 12, and 24 hr after each of the 3 daily drug administrations. Bacteria were counted every 24 hr after drug administration and at 48 and 72 hr after the last administration. Evaluation of the relationship between pharmacokinetic/pharmacodynamic (PK/PD) parameters and the antibacterial effect showed that the surrogate of %T > minimum inhibitory concentration (MIC) (R² = 0.981) was the best PK/PD index that correlated with effectiveness of cefquinome against P. multocida. The respective values of %T > MIC required for continuous 1/3‐log, 1/2‐log, and 1‐log reductions were 14.23, 34.45, and 73.44%, respectively, during each 24‐hr treatment period. In conclusion, cefquinome exhibited a potent antibacterial effect against P. multocida. When %T > MIC reached 73.44%, cefquinome exhibited a bactericidal effect against P. multocida after three successive daily administrations.     

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.     

Integration of pharmacokinetic–pharmacodynamic for dose optimization of doxycycline against Haemophilus parasuis in pigs

The aims of this study were to establish optimal doses of doxycycline (dox) against Haemophilus parasuis on the basis of pharmacokinetic–pharmacodynamic (PK‐PD) integration modeling. The infected model was established by intranasal inoculation of organism in pigs and confirmed by clinical signs, blood biochemistry, and microscopic examinations. The recommended dose (20 mg/kg b.w.) was administered in pigs through intramuscular routes for PK studies. The area under the concentration 0‐ to 24‐hr curve (AUC_0–24), elimination half‐life (T_½ke), and mean residence time (MRT) of dox in healthy and H. parasuis‐infected pigs were 55.51 ± 5.72 versus 57.10 ± 4.89 μg·hr/ml, 8.28 ± 0.91 versus 9.80 ± 2.38 hr, and 8.43 ± 0.27 versus 8.79 ± 0.18 hr, respectively. The minimal inhibitory concentration (MIC) of dox against 40 H. parasuis isolates was conducted through broth microdilution method, the corresponding MIC₅₀ and MIC₉₀ were 0.25 and 1 μg/ml, respectively. The Ex vivo growth inhibition data suggested that dox exhibited a concentration‐dependent killing mechanism. Based on the observed AUC_24 hr/MIC values by modeling PK‐PD data in H. parasuis‐infected pigs, the doses predicted to obtain bacteriostatic, bactericidal, and elimination effects for H. parasuis over 24 hr were 5.25, 8.55, and 10.37 mg/kg for the 50% target attainment rate (TAR), and 7.26, 13.82, and 18.17 mg/kg for 90% TAR, respectively. This study provided a more optimized alternative for clinical use and demonstrated that the dosage 20 mg/kg of dox by intramuscular administration could have an effective bactericidal activity against H. parasuis.     

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.     

Validating an empiric sulfadiazine–trimethoprim dosage regimen for treatment of Escherichia coli and Staphylococcus delphini infections in mink (Neovison vison)

Antimicrobial agents are used extensively off‐label in mink, as almost no agents are registered for this animal species. Pharmacokinetic (PK) and pharmacodynamic (PD) data are required to determine antimicrobial dosages specifically targeting mink bacterial pathogens. The aims of this study were to assess, in a PKPD framework, the empirical dosage regimen for a combination of trimethoprim (TMP) and sulfadiazine (SDZ) in mink, and secondarily to produce data for future setting of clinical breakpoints. TMP and SDZ PK parameters were obtained experimentally in 22 minks following IV or oral administration of TMP/SDZ (30 mg/kg, i.e. 5 mg/kg TMP and 25 mg/kg SDZ). fAUC/MIC with a target value of 24 hr was selected as the PKPD index predictive of TMP/SDZ efficacy. Using a modeling approach, PKPD cutoffs for TMP and SDZ were determined as 0.062 and 16 mg/L, respectively. By incorporating an anticipated potentiation effect of SDZ on TMP against Escherichia coli and Staphylococcus delphini, the PKPD cutoff of TMP was revised to 0.312 mg/L, which is above the tentative epidemiological cutoffs (TECOFF) for these species. The current empirical TMP/SDZ dosage regimen (30 mg/kg, PO, once daily) therefore appears adequate for treatment of wild‐type E. coli and S. delphini infections in mink.     

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.     

Pharmacokinetics,milk penetration and PK/PD analysis by Monte Carlo simulation of marbofloxacin,after intravenous and intramuscular administration to lactating goats

The main objectives of this study were (i) to evaluate the serum pharmacokinetic behaviour and milk penetration of marbofloxacin (MFX; 5 mg/kg), after intravenous (IV) and intramuscular (IM) administration in lactating goats and simulate a multidose regimen on steady‐state conditions, (ii) to determine the minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) of coagulase negative staphylococci (CNS) isolated from caprine mastitis in Córdoba, Argentina and (iii) to make a PK/PD analysis by Monte Carlo simulation from steady‐state pharmacokinetic parameters of MFX by IV and IM routes to evaluate the efficacy and risk of the emergence of resistance. The study was carried out with six healthy, female, adult Anglo Nubian lactating goats. Marbofloxacin was administered at 5 mg/kg bw by IV and IM route. Serum and milk concentrations of MFX were determined with HPLC/uv. From 106 regional strains of CNS isolated from caprine mastitis in herds from Córdoba, Argentina, MICs and MPCs were determined. MIC₉₀ and MPC₉₀ were 0.4 and 6.4 μg/ml, respectively. MIC and MPC‐based PK/PD analysis by Monte Carlo simulation indicates that IV and IM administration of MFX in lactating goats may not be adequate to recommend it as an empirical therapy against CNS, because the most exigent endpoints were not reached. Moreover, this dose regimen could increase the probability of selecting mutants and resulting in emergence of resistance. Based on the results of Monte Carlo simulation, the optimal dose of MFX to achieve an adequate antimicrobial efficacy should be 10 mg/kg, but it is important take into account that fluoroquinolones are substrates of efflux pumps, and this fact may determine that assumption of linear pharmacokinetics at high doses of MFX may be incorrect.     

Pharmacokinetic–pharmacodynamic integration and modelling of florfenicol in calves

Florfenicol was administered subcutaneously to 10 calves at a dose of 40 mg/kg. Pharmacokinetic–pharmacodynamic (PK‐PD) integration and modelling of the data were undertaken using a tissue cage model, which allowed comparison of microbial growth inhibition profiles in three fluids, serum, exudate and transudate. Terminal half‐lives were relatively long, so that florfenicol concentrations were well maintained in all three fluids. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration were determined in vitro for six strains each of the calf pneumonia pathogens, Mannhemia haemolytica and Pasteurella multocida. An PK‐PD integration for three serum indices provided mean values for P. multocida and M. haemolytica, respectively, of 12.6 and 10.4 for C_max/MIC, 183 and 152 h for AUC_0–24 h/MIC and 78 and 76 h for T>MIC. Average florfenicol concentrations in serum exceeded 4 × MIC and 1.5 × MIC for the periods 0–24 and 48–72 h, respectively. Ex vivo growth inhibition curves for M. haemolytica and P. multocida demonstrated a rapid (with 8 h of exposure) and marked (6 log₁₀ reduction in bacterial count or greater) killing response, suggesting a concentration‐dependent killing action. During 24‐h incubation periods, inhibition of growth to a bacteriostatic level or greater was maintained in serum samples collected up to 96 h and in transudate and exudate samples harvested up to 120 h. Based on the sigmoidal E_max relationship, PK‐PD modelling of the ex vivo time–kill data provided AUC_0–24 h/MIC serum values for three levels of growth inhibition, bacteriostatic, bactericidal and 4 log₁₀ decrease in bacterial count; mean values were, respectively, 8.2, 26.6 and 39.0 h for M. haemolytica and 7.6, 18.1 and 25.0 h for P. multocida. Similar values were obtained for transudate and exudate. Based on pharmacokinetic and PK‐PD modelled data obtained in this study and scientific literature values for MIC distributions, Monte Carlo simulations over 100 000 trials were undertaken to predict once daily dosages of florfenicol required to provide 50% and 90% target attainment rates for three levels of growth inhibition, namely, bacteriostasis, bactericidal action and 4 log₁₀ reduction in bacterial count.     

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.     

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 and pharmacodynamics of gamithromycin in pulmonary epithelial lining fluid in naturally occurring bovine respiratory disease in multisource commingled feedlot cattle

The objectives of this study were to determine (i) whether an association exists between individual pharmacokinetic parameters and treatment outcome when feeder cattle were diagnosed with bovine respiratory disease (BRD) and treated with gamithromycin (Zactran^®) at the label dose and (ii) whether there was a stronger association between treatment outcome and gamithromycin concentration in plasma or in the pulmonary epithelial lining fluid (PELF) effect compartment. The study design was a prospective, blinded, randomized clinical trial utilizing three groups of 60 (362–592 lb) steers/bulls randomly allocated within origin to sham injection or gamithromycin mass medication. Cattle were evaluated daily for signs of BRD by a veterinarian blinded to treatment. Animals meeting the BRD case definition were enrolled and allocated to a sample collection scheme consisting of samples for bacterial isolation (bronchoalveolar lavage fluid and nasopharyngeal swabs) and gamithromycin concentration determination (PELF and plasma). Gamithromycin susceptibility of M. haemolytica (n = 287) and P. multocida (n = 257) were determined using broth microdilution with frozen panels containing gamithromycin at concentrations from 0.03 to 16 μg/mL. A two‐compartment plasma pharmacokinetic model with an additional compartment for gamithromycin in PELF was developed using rich data sets from published and unpublished studies. The sparse data from our study were then fit to this model using nonlinear mixed effects modeling to estimate individual parameter values. The resulting parameter estimates were used to simulate full time–concentration profiles for each animal in this study. These profiles were analyzed using noncompartmental methods so that PK/PD indices (AUC₂₄/MIC, AUC_∞/MIC, C_MAX/MIC) could be calculated for plasma and PELF (also T>MIC) for each individual. The calculated PK/PD indices were indicative that for both M. haemolytica and P. multocida a higher drug exposure in terms of concentration, and duration of exposure relative to the MIC of the target pathogen, was favorable to a successful case outcome. A significant association was found between treatment success and PELF AUC_0–24/MIC for P. multocida. The calves in this study demonstrated an increased clearance and volume of distribution in plasma as compared to the healthy calves in two previously published reports. Ultimately, the findings from this study indicate that higher PK/PD indices were predictive of positive treatment outcomes.     

Pharmacokinetic/pharmacodynamic relationship of cefquinome against Pasteurella multocida in a tissue‐cage model in yellow cattle

The cephalosporin antimicrobial drug cefquinome was administered to yellow cattle intravenously (i.v.) and intramuscularly (i.m.) at a dose of 1 mg/kg of body weight in a two‐period crossover study. The pharmacokinetic (PK) properties of cefquinome in serum, inflamed tissue‐cage fluid (exudate), and noninflamed tissue‐cage fluid (transudate) were studied using a tissue‐cage model. The in vitro and ex vivo activities of cefquinome in serum, exudate, and transudate against a pathogenic strain of Pasteurella multocida (P. multocida) were determined. A concentration‐independent antimicrobial activity of cefquinome was confirmed for levels lower than 4 × MIC. Integration of in vivo pharmacokinetic data with the in vitro MIC provided mean values for the time that drug levels remain above the MIC (T > MIC) in serum was 14.10 h after intravenous and 14.46 h after intramuscular dosing, indicating a likely high level of effectiveness in clinical infections caused by P. multocida of MIC 0.04 μg/mL or less. These data may be used as a rational basis for setting dosing schedules, which optimize clinical efficacy and minimize the opportunities for emergence of resistant organisms.     

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.     

Pharmacokinetic/pharmacodynamic integration and modelling of amoxicillin for the calf pathogens Mannheimia haemolytica and Pasteurella multocida

The antimicrobial properties of amoxicillin were determined for the bovine respiratory tract pathogens, Mannheima haemolytica and Pasteurella multocida. Minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC) and time‐kill curves were established. Pharmacokinetic (PK)/pharmacodynamic (PD) modelling of the time‐kill data, based on the sigmoidal E_max equation, generated parameters for three levels of efficacy, namely bacteriostatic, bactericidal (3log₁₀ reduction) and 4log₁₀ reduction in bacterial counts. For these levels, mean AUC_(0–24 h)/MIC serum values for M. haemolytica were 29.1, 57.3 and 71.5 h, respectively, and corresponding values for P. multocida were 28.1, 44.9 and 59.5 h. Amoxicillin PK was determined in calf serum, inflamed (exudate) and noninflamed (transudate) tissue cage fluids, after intramuscular administration of a depot formulation at a dosage of 15 mg/kg. Mean residence times were 16.5 (serum), 29.6 (exudate) and 29.0 h (transudate). Based on serum MICs, integration of in vivo PK and in vitro PD data established maximum concentration (C_max)/MIC ratios of 13.9:1 and 25.2:1, area under concentration–time curve (AUC_0–∞)/MIC ratios of 179 and 325 h and T>MIC of 40.3 and 57.6 h for P. multocida and M. haemolytica, respectively. Monte Carlo simulations for a 90% target attainment rate predicted single dose to achieve bacteriostatic and bactericidal actions over 48 h of 17.7 and 28.3 mg/kg (M. haemolytica) and 17.7 and 34.9 mg/kg (P. multocida).     

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.     

In vivo activity of cefquinome against Riemerella anatipestifer using the pericarditis model in the duck

Cefquinome is a fourth‐generation cephalosporin with broad‐spectrum antibacterial activity, including activity against enteric gram‐negative bacilli such as Riemerella anatipestifer. The pericarditis model was used to examine the pharmacodynamic characteristics of cefquinome against R. anatipestifer. Serum levels of cefquinome following the administration of different doses were determined by LC‐MS/MS. Ducks with ca. 10⁶ CFU/mL at the initiation of therapy were treated with cefquinome at doses that ranged from 0.0156 to 2 mg/kg of body weight/day (in 3, 6, 12, or 24 divided doses) for 24 h. The percentage of a 24‐h dosing interval that the unbound serum cefquinome concentrations exceeded the MIC (fT > MIC) were the pharmacokinetic (PK)–pharmacodynamic (PD) parameter that best correlated with efficacy (R² 86.3% for R. anatipestifer, compared with 58.9% for the area under the concentration–time curve/MIC and 10.6% for peak/MIC). A sigmoid E_max model was used to estimate the magnitudes of the %fT > MIC associated with net bacterial stasis, a 1‐log₁₀ CFU reduction from baseline, and a 2‐log₁₀ CFU reduction from baseline; the corresponding values were (22.5 ± 1.3) %, (35.2 ± 4.5) %, and (42.4 ± 2.7) %. These data showed that treatment with cefquinome results in marked antibacterial effects in qvivo against R. anatipestifer and that the host's immunity may also play a key role in the anti‐infective therapy process.     

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.