Marbofloxacin Concentrations Research Articles

Marbofloxacin pharmacokinetics in goats during the lactation

The purposes of this study were to compare the pharmacokinetic profile of marbofloxacin and antibiotic penetration from blood to milk after intramuscular administration in goats at the beginning, at the peak milk yield and at the end of lactation and to apply the PK/PD modelling approach, so that effective dosage recommendations for this specie could be made. Five healthy lactating goats at 4–9; 25–30 and 150–155 days postpartum were used. At each experience 2 mg/kg intramuscular marbofloxacin was administered. Plasma and milk samples were obtained. Marbofloxacin concentrations were determined by microbiological assay using Klebsiella pneumoniae ATCC 10031 as test microorganism. Plasma pharmacokinetic parameters were calculated from the individual disposition curves, and significant differences between the different moments of lactation were found for AUC (significantly larger for the end of lactation vs the others moments). Milk concentrations were detected for 12 hs postadministration. Our results show that the lactation stage modified the pharmacokinetic profile of marbofloxacin, however these differences are of little consequence from a practical point of view. Volume of milk produced modified milk concentrations of marbofloxacin. A 2 mg/Kg dose level of marbofloxacin would be effective for treating microorganisms with MIC lower than 0.04 μg/mL as E. coli or P. multocida.

The effects of Mannheimia haemolytica and albendazole on marbofloxacin pharmacokinetics in lambs.

The study aimed to define the effects of M. haemolytica and a single oral dose of albendazole on the single-dose pharmacokinetics of marbofloxacin in lambs. The pharmacokinetic-pharmacodynamic integration of marbofloxacin was applied to describe a 3mg/kg intramuscular dose in lambs. The 6 healthy and 12 naturally infected with M. haemolytica lambs (Akkaraman, males weighing 10-15kg and aged 2-3months) were used in this study. In the marbofloxacin group, 6 healthy lambs received marbofloxacin. In the albendazole group after 2weeks washout period, the same animals received marbofloxacin on 1h after albendazole. In the diseased marbofloxacin group, 6 lambs naturally infected with M. haemolytica received marbofloxacin. In the diseased albendazole group, 6 lambs naturally infected with M. haemolytica received marbofloxacin on 1h after albendazole. The marbofloxacin and albendazole were administered each as a single dose of 3mg/kg intramuscular and 7.5mg/kg oral, respectively, in the respective groups. Plasma concentration of marbofloxacin was measured with HPLC-UV and pharmacokinetic parameters were analyzed by non-compartmental model. Albendazole did not change the pharmacokinetic profiles of marbofloxacin in healthy and diseased lambs. However, M. haemolytica affected the pharmacokinetics of marbofloxacin in diseased lambs, AUC0-24/MIC90 ratio was not found to be higher than 125, but Cmax/MIC90 ratios was found to be higher than 10 for an MIC value of 0.25μg/mL in all groups. The marbofloxacin dose described in this study may not be effective for the treatment of infections due to M. haemolytica in lambs, with MIC ≤ 0.25μg/mL.

In vitro antimicrobial activity of topical otological antimicrobials and Tris-EDTA against resistant Staphylococcus pseudintermedius and Pseudomonas aeruginosa isolates from dogs.

The value of susceptibility tests for the selection of topical otological antimicrobial agents is unclear. Laboratories test antibiotic concentrations substantially lower than concentrations supplied in topical formulations. Additionally, microbiological consensus statements are not available for topical antimicrobials. The primary aim of this study was to measure the minimum inhibitory and bactericidal concentrations of enrofloxacin, gentamicin, marbofloxacin, neomycin, orbifloxacin, polymyxin B and silver sulfadiazine from concentrations available in otological formulations (COF) to 1:59,000 dilution. The secondary aim was to evaluate the effect of Tris-EDTA in conjunction with these antimicrobial agents. Twenty resistant clinical isolates [Staphylococcus pseudintermedius (n = 10) and Pseudomonas aeruginosa (n = 10)] were tested by broth microdilution using a concentrated inoculum (3.75 × 107 cfu/mL). Concentrations available in otological formulations were at least 26× greater than the MICs for S. pseudintermedius and P. aeruginosa. COFs of polymyxin B and SSD were 27× greater than the MBCs for P. aeruginosa, whereas all other antimicrobial COFs were equal to or less than the MBCs for both organisms. Tris-EDTA significantly reduced the MICs of all antimicrobials, except with SSD for P. aeruginosa, and it significantly increased the MIC of SSD for S. pseudintermedius. Further studies are warranted to validate the present results in vivo. COFs are inhibitory and less likely bactericidal, with few exceptions, against resistant strains of these organisms. Tris-EDTA may be advantageous for P. aeruginosa whereas no additional benefit is afforded against S. pseudintermedius. Susceptibility tests may not be useful for the selection of topical otological antimicrobial agents.

Determination of minimum inhibitory concentrations for silver sulfadiazine and other topical antimicrobial agents against strains of Pseudomonas aeruginosa isolated from canine otitis externa.

Otitis externa is a common presenting complaint in practice. Ear infections by Pseudomonas aeruginosa are particularly problematic due to the organism's high level of resistance and ability to damage the tympanum. Treatment should be based on susceptibility testing although minimum inhibitory concentrations (MICs) are not available for all treatment options. Silver sulfadiazine has been used in cases of recurrent P.aeruginosa otitis, although a MIC for silver sulfadiazine as a single agent has not been established. To describe susceptibility patterns of P.aeruginosa isolated from canine otitis externa and determine the MIC for silver sulfadiazine and other topical antimicrobials. Thirty-six P.aeruginosa isolates were collected from client-owned dogs, suffering from otitis externa. Susceptibility patterns were established using disc diffusion susceptibility testing against 17 antimicrobial agents. For determination of the MIC, selected strains were tested against increasing concentrations of marbofloxacin, enrofloxacin, gentamicin, polymyxin B and silver sulfadiazine using broth microdilution. For nine of 17 antimicrobial agents, complete resistance was seen in all isolates tested via disk diffusion susceptibility testing. Approximately 94% and 96% of isolates were susceptible to gentamicin and imipenem, respectively. These findings were consistent with broth dilution, where all strains were susceptible to gentamicin. Resistance was higher against polymyxin B and the fluoroquinolones. Silver sulfadiazine was effective invitro with a MIC ranging from 1 to 64μg/mL. As the MIC of silver sulfadiazine was lower than the concentration in a 1% preparation, such a product potentially represents a treatment option for dogs with P.aeruginosa otitis.

Inhibition of Salmonella Typhimurium adhesion, invasion, and intracellular survival via treatment with methyl gallate alone and in combination with marbofloxacin

Salmonella enterica serovar Typhimurium infects intestinal epithelia and macrophages, which is prevented by inhibiting adhesion and cell invasion. This study aimed to investigate the role of methyl gallate (MG) in adhesion, invasion, and intracellular survival of Salmonella Typhimurium in Caco-2 and RAW 264.7 cells via a gentamicin protection assay, confocal microscopy, and quantitative reverse-transcription polymerase chain reaction. MG (30 µg/mL) inhibited adhesion and invasion of Salmonella Typhimurium by 54.01% and 60.5% in RAW 264.7 cells, respectively. The combination of MG with sub-minimum inhibitory concentration (MIC) of marbofloxacin (MRB) inhibited the adhesion, invasion, and intracellular survival by 70.49%, 67.36%, and 74%, respectively. Confocal microscopy further revealed reductions in bacterial count in Caco-2 cells treated with MG alone or with sub-MIC of MRB. Furthermore, MG alone or in combination with sub-MIC of MRB decreased the motility of Salmonella Typhimurium. Quorum sensing genes including sdiA, srgE, and rck were downregulated by 52.8%, 61.7%, and 22.2%, respectively. Moreover, rac-1 was downregulated by 56.9% and 71.9% for MG alone and combined with sub-MIC of MRB, respectively, in mammalian cells. Furthermore, MG downregulated virulence genes of Salmonella Typhimurium including cheY, ompD, sipB, lexA, and ompF by 59.6%, 60.2%, 20.5%, 31.4%, and 16.2%, respectively. Together, the present results indicate that MG alone or in combination with a sub-MIC of MRB effectively inhibited the adhesion, invasion, and intracellular survival of Salmonella Typhimurium in vitro by downregulating quorum sensing and virulence genes.

Pharmacokinetics and bioavailability of marbofloxacin in lambs following administration of intravenous, intramuscular and subcutaneous

In this study, the pharmacokinetic disposition and bioavailability of marbofloxacin (MB) were determined in lambs after single intravenous (IV), intramuscular (IM), and subcutaneous (SC) administrations at a dose of 3 mg/kg. The plasma concentration of MB was measured using high-performance liquid chromatography-UV, and the pharmacokinetic parameters were analyzed using a non-compartmental analysis. Following IV, IM, and SC administrations, the mean terminal half-life (t1/2ʎz) was 11.48, 12.64, and 24.86 h, respectively, and the mean residence time (MRT) was 7.27, 7.81, and 10.11 h, respectively. The bioavailability (F) was 96.01 and 126.39%, after IM and SC administration, respectively. This study showed that SC administration of MB at a dose of 3 mg/kg exhibited flip-flop pharmacokinetics in lambs. These results suggested that MB could be useful in the treatment of severe systemic infections, such as those with M. haemolytica (MIC = 0.035 μg/mL), in lambs since high AUC0-24/MIC and Cmax/MIC ratios were achieved after IV and IM administration at 3 mg/kg. However, MB administration (3 mg/kg) via the IV, IM, and SC routes might not be effective in the treatment of respiratory infections caused by organisms with MIC90 value in lambs.

Pharmacokinetic Behavior of Marbofloxacin in Plasma from Chickens at Different Seasons

Abstract The purpose of this study was to evaluate the differences in the disposition and plasma pharmacokinetic behavior of marbofloxacin (MAR) in broiler chickens at different seasons. Chicken broilers (n = 345) were used, in lots of 5 individuals, divided into 6 groups depending on the way of administration, intravenous or oral (dose 2 mg/kg) and the test period. Post-administration plasma samples were obtained at different times, intravenously (0.08 to 24 hours) and orally (0.25 to 120 hours). A liquid-liquid extraction of MAR was performed by high-performance liquid chromatography (HPLC) with a fluorescent detector. The plasma concentrations obtained at the different sampling times of each season, were analyzed with ANOVA and pharmacokinetic analysis was conducted with the PK Solution 2.0 software. The concentration of marbofloxacin in plasma was significantly lower in winter and summer than in spring, with MAR being detected in winter up to 72 hours post-application, coinciding with the differences in MAR pharmacokinetics parameters with increase in the average residence time (MRT) is 9.4 hours in winter. Increased clearance MAR in summer (7.5 ml/min/kg) coincides with MRT 6.3 hours. Finally, the oral bioavailability of MAR is lower in summer and winter (86 ± 1.7% and 78 ± 3.1%) than in spring (94 ± 5.2 %). There are differences in the disposition and plasma pharmacokinetic behavior of MAR applied orally in broiler chickens, coinciding with the physiological changes in the thermoregulation of birds, considering its correct therapeutic management and contributing to provide safe food for human consumption.

Pharmacokinetics of marbofloxacin administered via intravenous regional limb perfusion in dairy cows: evaluation of two different tourniquets

ObjectivesThis study evaluated synovial and systemic plasma pharmacokinetic variables of marbofloxacin after a single intravenous regional limb perfusion (IVRLP) performed using two different tourniquets in clinically healthy, standing, non-sedated dairy...

The phenotypic and molecular resistance induced by a single-exposure to sub-mutant prevention concentration of marbofloxacin in Salmonella Typhimurium isolates from swine

In the present study, the molecular mechanisms of antibiotic resistance in Salmonella Typhimurium clinical isolates from pigs were investigated using a single-step mutation model of exposure to sub-mutant prevention concentrations (MPCs) of marbofloxacin. The minimum inhibitory concentrations (MICs) of seven antibacterial drugs were evaluated against 30 S. Typhimurium clinical isolates from different pigs. MPCs of marbofloxacin were also determined. The mechanism of marbofloxacin-resistance was investigated by sequencing analysis of target gene mutations and quantifying the overexpression of efflux pumps and their regulators by quantitative RT-PCR. Marbofloxacin showed the highest potency against all isolates (23.3%), including multi-drug resistant isolates. The MPC50 (0.5μg/mL) and MPC90 (2μg/mL) of marbofloxacin were determined, as were MPC/MIC ratios of 2.5 to 8. A gyrA mutation (Ser83Phe or Asp87His) was detected in isolates with an MIC>0.06μg/mL and all single-step mutants. Moreover, expression of acrAB-tolC and marA/soxS/ramA increased following a single-step mutation, but only ramA expression showed a positive correlation with the resistance phenotype of clinical isolates and single-step mutants (p<0.05). Furthermore, the acrR mutation was detected in two clinical isolates and 50% of single-step mutants, regardless of whether the gyrA mutation was present. This is the first report of acrR mutations in S. Typhimurium isolates from pigs in Korea. Our findings suggest that a single-exposure to sub-MPCs of marbofloxacin was sufficient to reduce the susceptibility of Salmonella isolates. Therefore, optimized dosing based on application with the MPC concept is required to reduce the chances of marbofloxacin resistance.

Determination of renal handling of marbofloxacin in Lohi sheep (Ovis aries) following a single intravenous administration.

The objective of present study was to investigate renal clearance, urinary excretion and underlying excretory mechanism of marbofloxacin in Lohi sheep. For this purpose, marbofloxacin was administered intravenously (IV) as single bolus dose (2.5 mg/kg body weight) to eight healthy sheep of Lohi breed. After start of experiment, blood and urine samples were drawn at predetermined time intervals and marbofloxacin concentrations in the samples were measured by reverse phase high performance liquid chromatography (RP-HPLC) using UV/Vis detector. The mean ± SD values of creatinine in plasma and urine were 15.37 ± 0.65 µg/ml and 246.7 ± 48.05 µg/ml, respectively. Glomerular filtration rate was 1.29 ± 0.22 ml/min/kg whereas urinary flow rate was observed to be 0.084 ± 0.016 ml/min/kg. The renal clearance of marbofloxacin in Lohi sheep was 9.45 ± 2.12 ml/min/kg. Cumulative percentage dose excreted was seen to be maximum at 24 h post drug administration. It was concluded that renal handling of marbofloxacin in Lohi sheep involved both glomerular filtration and active tubular secretion.

Evaluation of the Pharmacokinetic Properties of a Combination of Marbofloxacin and Imipenem Administered by Regional Limb Perfusion to Standing Horses

To evaluate the compatibility and the pharmacokinetic (PK) properties of a combination of marbofloxacin and imipenem administered by regional limb perfusion (RLP) to standing horses and to determine if the concentrations of imipenem in the synovial fluid would be as high as when imipenem was administered alone. Experimental study—Six healthy, adult horses participated in the study; that was approved by the University Animal Care and Use Committee. Under sedation, a tourniquet was applied on one, randomly selected forelimb. One gram of marbofloxacin and 500 mg of imipenem diluted to 100 mL were injected, into the cephalic vein, using a 22g butterfly catheter. Synovial samples were collected from the metacarpophalangeal (MCP) joint and blood samples were collected from the jugular vein on times: 0, 0.5 (tourniquet release time), 2, 6, 12, 24, and 36 hours after injection. All samples were analyzed for marbofloxacin and imipenem concentration using liquid chromatography tandem mass spectrometry. Maximum concentration (Cmax) of imipenem and marbofloxacin in the MCP joint was 71 and 73 μg/mL, respectively. No significant differences in PK values were detected when this study results were compared with the results of a previous study evaluating the PK of imipenem administered alone by intravenous (IV) RLP. This study results indicate that combining imipenem with marbofloxacin during IV-RLP in normal horses delivered high therapeutic concentrations of both drugs and that the combination does not negatively affect the concentration of imipenem attained in the synovial fluid.

Tissue distribution of marbofloxacin in pigs after a single intramuscular injection.

Tissue distribution of marbofloxacin was studied in pigs after a single intramuscular injection at 2.5 mg/kg body weight. Samples of plasma, muscle, liver, kidney, heart, lung, and muscle at the injection site were randomly collected from five pigs at 2, 6, 10, 24, 48, 72, and 96 h after administration. Marbofloxacin concentrations were determined by using high-performance liquid chromatography with ultraviolet detection and were subjected to non-compartmental analysis to obtain kinetic parameters. The elimination half-life (t1/2λz) of marbofloxacin at the injection site was 22.12 h, while those in kidney, plasma, liver, lung, heart, and muscle were 16.75, 21.48, 21.84, 24.00, 24.45, and 28.91 h, respectively. Areas under the concentration-time curve from 0 h to ∞ (AUC0–∞s) were calculated to be 31.17 h·µg·mL−1 for plasma and 32.97, 33.92, 34.78, 37.58, 42.02, and 98.80 h·µg·g−1 for heart, muscle, lung, liver, kidney, and injection site, respectively. The peak concentration (Cmax) of marbofloxacin was 1.62 µg/mL in plasma and 1.71, 1.74, 1.86, 1.93, 2.45, and 7.64 µg/g in heart, lung, muscle, kidney, liver, and injection site, respectively. The results show that marbofloxacin was fast absorbed, extensively distributed, and slowly eliminated from pigs after a single intramuscular administration.

Factors influencing the potency of marbofloxacin for pig pneumonia pathogens Actinobacillus pleuropneumoniae and Pasteurella multocida

For the pig respiratory tract pathogens, Actinobacillus pleuropneumoniae and Pasteurella multocida, Minimum Inhibitory Concentration (MIC) of marbofloxacin was determined in recommended broths and pig serum at three inoculum strengths. MICs in both growth matrices increased progressively from low, through medium to high starting inoculum counts, 104, 106 and 108CFU/mL, respectively. P. multocida MIC ratios for high:low inocula were 14:4:1 for broth and 28.2:1 for serum. Corresponding MIC ratios for A. pleuropneumoniae were lower, 4.1:1 (broth) and 9.2:1 (serum). MIC high:low ratios were therefore both growth matrix and bacterial species dependent. The effect of alterations to the chemical composition of broths and serum on MIC were also investigated. Neither adjusting broth or serum pH in six increments over the range 7.0 to 8.0 nor increasing calcium and magnesium concentrations of broth in seven incremental steps significantly affected MICs for either organism. In time-kill studies, the killing action of marbofloxacin had the characteristics of concentration dependency against both organisms in both growth matrices. It is concluded that MIC and time-kill data for marbofloxacin, generated in serum, might be preferable to broth data, for predicting dosages of marbofloxacin for clinical use.

Bioavailability pharmacokinetics and residues of marbofloxacin in normal and E.coli infected broiler chicken

The pharmacokinetics of marbofloxacin was studied following a single intravenous, oral administration in normal broiler chickens and repeated oral administrations in normal and experimentally E.coli infected broiler chickens. The pharmacokinetic parameters following a single intravenous injection of 2 mg/kg b.wt., revealed that marbofloxacin obeyed a two compartments open model, distribution half-life (t0.5(α)) was 0.25±0.02 h, volume of distribution (Vdss) was 0.76±0.08 L/kg, elimination half-life (t0.5(β)) was 5.43±0.87 h and total body clearance (CLtot) was 0.09±0.002 l/kg/h. Following a single oral administration, marbofloxacin was rapidly and efficiently absorbed through gastrointestinal tract of chickens as the absorption half-life (t0.5 (ab): 0.62±0.02 h). Maximum serum concentration (Cmax) was 1.15±0.01 μg/ml, reached its maximum time (tmax) at 2.53±0.04 h, elimination half-life (t0.5 (el)) was 7.36±0.20 h indicating the tendency of chickens to eliminate marbofloxacin in slow rate. Oral bioavailability was 73.57± 1.90 % indicating good absorption of marbofloxacin after oral administration. Serum concentrations of marbofloxacin following repeated oral administration of 2 mg/kg b.wt. once daily for five consecutive days, peaked 2 hours after each oral dose with lower significant values recorded in experimentally infected broiler chickens than in normal ones. Tissues residues of marbofloxacin in slaughtered normal chickens was highly in those tissues lung, liver, and kidneys in chickens and the chicken must not be slaughtered before 3 days of stopping of drug administration. It was concluded that the in- vitro protein binding was 12.33±0.82%.

Blood concentrations of marbofloxacin and its in vivo effect in yellow-bellied slider turtles (Trachemys scripta scripta) after a single intracoelomic injection at 3 dose rates

Marbofloxacin is a common antibiotic drug used to treat bacterial infections in pet animals. Similar to other fluoroquinolones, marbofloxacin is subject to the emerging problem of antimicrobial resistance. Thus, it is necessary to use pharmacokinetic/pharmacodynamic (PK/PD) integration and modeling to minimize the selection of resistant mutants of bacteria and extend the useful life of antimicrobial agents, including marbofloxacin. This study evaluated the PKs and the in vivo efficacy of marbofloxacin in Trachemys scripta scripta after a single intracoelomic injection. Three groups of healthy adult turtles (n = 8 per group) were each treated with 0.4, 2, and 10mg/kg of marbofloxacin. Blood samples and rectal swabs were collected to measure marbofloxacin concentrations in blood (using high-performance liquid chromatography with fluorescence detection validated method) and to evaluate in vitro antimicrobial susceptibility (using Kirby-Bauer Method), respectively. The PK profiles of marbofloxacin fit a bicompartmental model and were dose dependent. The Tmax and half-life ranged between 2.82 to 4.64 hours and 16.14 to 30.68 hours, respectively. Bacterial isolation showed the presence of both Escherichia coli and Salmonella spp. Salmonella spp. were isolated only 48 hours after the administration of marbofloxacin, and all strains were considered resistant. Results seem to suggest that even if marbofloxacin is able to reach considerable plasma concentrations, it can still be ineffective against bacteria that are potential animal and human pathogens.

Pharmacokinetics of marbofloxacin in freshwater crocodiles (Crocodylus siamensis) after intravenous and intramuscular administration.

To evaluate the fate and disposition of marbofloxacin (MBF) in freshwater crocodiles (Crocodylus siamensis), MBF was administered either intravenously (i.v.) or intramuscularly (i.m.) at a dosage of 2.0mg/kg body weight. The concentrations of MBF in plasma were measured using high-performance liquid chromatography equipped with a fluorescence detector. The concentrations of MBF in the plasma were measurable up to 144h after i.v. and i.m. administration. After the first 45min, the mean pharmacokinetic profiles produced by the two administration routes were almost identical. No statistically significant differences in the pharmacokinetic parameters between the groups were observed. The half-life was long (about 2.5days), the volume of distribution was large (about 1.44L/kg), λz was small (0.01 h-1 ), and the clearance was slow (22.6mL/h/kg). The absolute i.m. bioavailability (F%) was 105.36%. The dose of MBF administered in this study seems to produce appropriate PK-PD parameters that predict antibacterial success for disease caused by susceptible bacteria. More studies are warranted to evaluate the likely residues after administration of multiple doses.

Danofloxacin and Marbofloxacin Activity on Some Bacterial Isolates from Camels (Camelus dromedarius)

Bacterial diseases in camel cause morbidity, mortality, suffering and significant economic losses. This study assessed the types of bacteria involved in different types of lesions encountered in camel's lung and liver slaughtered at municipal slaughter houses of Rabat, Morocco. Bacterial species isolated and identified included Staphylococcus aureus (19.2%), Staphylococcus sp (46.1%), Streptococcus sp (7.6%), Corynebacterium sp (15.3%) and Acinetobacter sp (11.5%). The percentage of resistance of isolates to the antibiotics varied from 0 to 84.6%. The most frequent resistance was to Ampicillin and Penicillin G (84.6%) followed by Gentamycin and Tetracycline (11.5. %), while all the isolates were susceptible to Cephalothin and Ciprofloxacin. Minimum inhibitory concentrations (MIC) of danofloxacin and marbofloxacin were determined against these bacteria. Time-kill curves against staphylococcus aureus (MIC=0.25μg/ml), Streptococcus sp (MIC=0.5μg/ml), Corynebacterium sp (MIC=0.5μg/ml) for both danofloxacin and marbofloxacin, and Acinetobacter sp (MIC=0.125μg/ml for marbofloxacin and 0.25 μg/ml for danofloxacin) were then determined according to a broth microdilution test. The pharmacodynamic parameters as lowest effective concentration (LEC) and optimal bactericidal concentration (OBC) were determined. Optimal values of surrogate markers predicting the antimicrobial effect and preventing the development of resistance were widely reached.

Comparison of pharmacokinetics of marbofloxacin after subcutaneous administration of various multiple-dose regimens to water buffalo calves (Bubalus bubalis).

To determine pharmacokinetics of marbofloxacin in water buffalo calves (Bubalus bubalis) after multiple SC administrations and to assess differences in regimen efficacy. 18 healthy buffalo calves. Calves (n = 6 calves/group) were assigned to receive marbofloxacin SC in the neck at 1 of 3 dosages (2 mg/kg, q 24 h for 6 days [regimen 1]; 4 mg/kg, q 48 h for 6 days [regimen 2]; and 4 mg/kg, q 24 h for 3 days [regimen 3]). Serum marbofloxacin concentrations were analyzed. Efficacy predictors were estimated on the basis of minimum inhibitory concentration and mutant prevention concentration reported for Pasteurella multocida and Mannheimia haemolytica. Mean ± SD area under the concentration-time curve was 5.92 ± 0.40 μg•h/mL for regimen 1, which differed significantly from that for regimens 2 (14.26 ± 0.92 μg•h/mL) and 3 (14.17 ± 0.51 μg•h/mL). Mean residence time and mean elimination half-life for regimen 2 (9.93 ± 0.20 hours and 8.77 ± 0.71 hours) both differed significantly from those for regimens 1 (721 ± 0.11 hours and 5.71 ± 0.38 hours) and 3 (759 ± 0.13 hours and 737 ± 1.19 hours). Values obtained from indices for P multocida and M haemolytica had an excessively wide range because of the various degrees of antimicrobial susceptibility (low, medium, and high) of the strains. Regimen 3 had the most favorable indices, and it would be conducive for owner compliance and require less handling of animals.

Estimating marbofloxacin withdrawal time in broiler chickens using a population physiologically based pharmacokinetics model.

Residue depletion of marbofloxacin in broiler chicken after oral administration at 5mg/kg/day for three consecutive days was studied in this study. The areas under the concentration-time curve from 0h to ∞ (AUC0-∞ s) of marbofloxacin in tissues and plasma were used to calculate tissue/plasma partition coefficients (PX s). Based on PX s and the other parameters derived from published studies, a flow-limited physiologically based pharmacokinetics (PBPK) model was developed to predict marbofloxacin concentrations, which were then compared with those derived from the residue depletion study so as to validate this model. Considering individual difference in drug disposition, a Monte Carlo simulation included 1000 iterations was further incorporated into the validated model to generate a population PBPK model and to estimate the marbofloxacin residue withdrawal times in edible tissues. The withdrawal periods were compared to those derived from linear regression analysis. The PBPK model presented here successfully predicted the measured concentrations in all tissues. The withdrawal times in all edible tissues derived from the population PBPK model were longer than those from linear regression analysis, and based on the residues in kidney, a withdrawal time of 4days was estimated for marbofloxacin after oral administration at 5mg/kg/day for three consecutive days. It was shown that population PBPK model could be used to accurately predict marbofloxacin residue withdrawal time in edible tissues in broiler chickens.

Pharmacokinetics of marbofloxacin in pigs after intravenous and intramuscular administration of a single dose of 8 mg/kg: dose proportionality, influence of the age of the animals and urinary elimination

The pharmacokinetics of marbofloxacin in pigs were evaluated as a function of dose and animal age following intravenous and intramuscular administration of a 16% solution (Forcyl®). The absolute bioavailability of marbofloxacin as well as the dose proportionality was evaluated in 27-week-old fattening pigs. Blood PK and urinary excretion of marbofloxacin were evaluated after a single intramuscular dose of 8 mg/kg in 16-week-old male pigs. An additional group of 12-week-old weaned piglets was used for the evaluation of age-related kinetics. The plasma and urine concentration of marbofloxacin was determined using a HPLC method. Pharmacokinetic parameters were calculated using noncompartmental methods. After intravenous administration in 27-week-old fattening pigs, the total body clearance was 0.065 L/h·kg. After intramuscular administration to the same animals, the mean observed Cmax was 6.30 μg/mL, and the AUCINF was 115 μg·h/mL. The absolute bioavailability was 91.5%, and dose proportionality was shown within the dose range of 4–16 mg/kg. The renal clearance was about half of the value of the total clearance. The total systemic clearance values significantly decreased as a function of age, being 0.092 L/h·kg and 0.079 L/h·kg in pigs aged 12 and 16 weeks, respectively.