Marbofloxacin disposition after intravenous administration of a single dose in wild mallard ducks (Anas platyrhynchos).
Key words: pharmacokinetics, antibiotic, fluoroquinolone, marbofloxacin, avian, anseriform, mallard duck, Anas platyrhynchos
One of the most challenging problems for birds in captivity is the incidence of infection. When possible, an intravenous route for antimicrobial administration has been proposed as a rapid and efficient means of treating birds with fulminant bacterial infections. The broad spectrum and potent activity of fluoroquinolones are among the characteristics that make them valuable antibiotics. Other important properties of this drug class include excellent bioavailability, good tissue penetrability, and a relatively low incidence of adverse and toxic effects. (1)
Marbofloxacin was developed specifically for veterinary use. It has an antibacterial spectrum equal to or broader than other fluoroquinolones, a marked postantibiotic effect, and excellent activity against Enterobacteriaceae and other gram-negative bacteria. (2) Pharmacokinetic studies in dogs have demonstrated that marbofloxacin administered at a dosage of 2 mg/kg q24h was able to maintain effective plasma activities for longer than enrofloxacin administered at a dosage of 5 mg/kg q24h, (3) which indicates the potential suitability of marbofloxacin for once-daily dosing. However, the elimination half-life values found in other mammals (horses, goats, cows, and sows) have been considerably lower than those reported in dogs. (4-8)
The pharmacokinetics of marbofloxacin appear to vary greatly among avian species. The permanence of marbofloxacin is shorter in buzzards (Buteo buteo), (9) chickens, (10-11) and ostriches (Struthio camelus) (12) compared with dogs (3); however, a recent study in vultures (Gyps fulvus) showed a permanence of 12.51 hours, which is similar to the value in dogs (12.40 hours). (13) Because such differences could be responsible for therapeutic failure or toxic effects, the pharmokinetics of marbofloxacin should ideally be evaluated in each species. The purpose of the present study was to assess the disposition of marbofloxacin in wild juvenile mallard ducks after intravenous administration.
Material and Methods
The study protocol was approved by the Animal Use Committee of the Universidad Complutense de Madrid. Six juvenile healthy mallard ducks (Anas platyrhynchos), of unknown sex and weighing 866-943 g, were used in the study. The birds were nonreleasable individuals obtained from a wild population presented to the Buitrago Wildlife Rehabilitation Centre, Buitrago de Lozoya, Madrid, Spain. The birds were housed in captivity and fed a commercial duck food. No antibiotics or anthelmintics were administered to the birds for a minimum of 2 months before the start of the study. The birds were examined 1 week before the study and were assessed as healthy based on physical examination, routine acceptance of daily meals, maintenance of body weight, and normal results of a complete blood cell count, biochemical analysis, and fecal flotation.
Drug administration and sample collection
Marbofloxacin (2 mg/kg; Marbocyl 2% injectable solution, Vetoquinol, Lure, France) was administered by bolus injection into the basilic vein. A blood sample (0.6 mL) was collected from the contralateral basilic vein at 0, 10, 20, and 40 minutes and at 1, 2, 4, 6, 8, 10, 12, 24, and 30 hours after the injection. The accumulated blood volume sampled from each bird was < 10% of the total body blood volume. The samples were centrifuged at 4500g for 10 minutes, and plasma was separated and stored at -80[degrees]C. Plasma analysis was performed within 4 weeks after blood sample collection.
For each blood sample, 200 [micro]L of plasma, 50 [micro]L of the internal standard solution (ofloxacin, 2.5 [micro]g/mL in formic acid 0.1 N), and 3 mL of trichloromethane were placed into screw-capped tubes. The samples were placed in a horizontal agitator for 10 minutes and then were centrifuged at 4500g for another 10 minutes. The trichloromethane organic layer was transferred to another tube from which it was evaporated under a nitrogen stream at 80[degrees]C. The samples were redissolved in 125 [micro]L of the mobile phase, and a 50-[micro]L aliquot of the reconstituted sample was injected into the high-performance liquid chromatography system (Spectra System, Thermo Separation Products, Madrid, Spain). Separation was accomplished by using an ion-pairing reversed-phase column (PR C-18, 5 [micro]m, 150 x 4.6 mm; precolumn: PR C-18, 5 [micro]m, 15 x 4.6 mm) operated at room temperature. (6) The mobile phase was composed of a 0.4% aqueous solution of tetrabutylammonium hydrogen sulphate (wt/vol) and diammonium hydrogen phosphate (wt/vol) buffer (pH 2.7): methanol:acetonitrile:acetic acid : triethylamine (74 : 20 : 4 : 1 : 1, v : v : v : v : v). The ultraviolet detection wavelength was 295 nm, and the flow rate was 1 mL/min. Ofloxacin (2.5 [micro]/mL; Sigma-Aldrich, St Louis, MO, USA) was used as the internal standard. Marbofloxacin (Vetoquinol) at 0.025, 0.05, 0.1, 0.5, 1, 2.5, 5, and 10 [micro]/mL was used for the preparation of calibration standards. The quantification limit of the assay method was 0.025 [micro]/mL, and the standard curve was linear up to 10 [micro]/mL. The intra- and interassay coefficients of variation were each < 10%, and the accuracy oscillated between 80% and 120%.
Pharmacokinetic and statistical analysis
Plasma levels of marbofloxacin were subjected to compartmental analysis by using a nonlinear least-squares regression analysis (PCnonlin V4.0 software package, Statistical Consultants Inc, Lexington, KY, USA). Akaike's Information Criterion, residual sum of squares, and analysis of residuals plots were used to discriminate among models. The area under the curve (AUC), area under the first moment curve, and mean residence time were calculated by using the trapezoidal rule and by extrapolating to infinity. Extrapolated areas did not exceed 7%. A descriptive statistical analysis was performed (SPSS 17.0 software, SPSS Inc, Chicago, IL, USA.)
[FIGURE 1 OMITTED]
The mean plasma marbofloxacin concentration versus time and mean values of pharmacokinetic parameters after intravenous administration of marbofloxacin are presented in Figure 1 and Table 1, respectively. The plasma marbofloxacin concentration decreased in a biexponential manner over time, with data best fitting a 2-compartment open model. The volume of distribution at steady state (Vss) was 1.78 [+ or -] 0.37 L/kg, the distribution half-life ([T.sub.1/2[alpha]]) was 1.58 [+ or -] 0.43 hours, and the total plasma clearance (Cl) was 0.59 [+ or -] 0.08 (L/kg per hour). Results of the elimination half-life ([T.sub.1/2[beta]], 2.81 [+ or -] 1.20 hours), terminal half-life ([T.sub.1/2[lambda]], 2.43 [+ or -] 0.61 hours), and mean residence time (2.99 [+ or -] 0.52 hours) demonstrated a relatively short permanence.
Data on the pharmacokinetics of fluoroquinolones in anseriform species are limited, and specific pharmacokinetic information for ducks, particularly wild birds, are scarce. The biexponential fit of marbofloxacin observed in the ducks in this study is similar to the results of pharmacokinetic parameters previously reported in broiler chickens (10) and birds of prey. (9) The distribution of marbofloxacin in mallard ducks was relatively prolonged, as reflected by the [T.sub.1/2[alpha]] of 1.58 hours compared with a [T.sub.1/2[beta]] of 2.81 hours. The [T.sub.1/2[beta]] is similar to that reported in broiler chickens. (11) The Vss of 1.78 L/kg was similar to the values observed in vultures, turkeys, and buzzards. (9,13,14) This is in contrast to relatively high (3.22 L/kg) (12) and low (0.77 and 1.05 L/kg) (10,11) values reported in ostriches and broiler chickens, respectively.
The Cl of marbofloxacin (0.59 L/kg per hour) observed in mallard ducks was higher than that observed in many avian species (0.10, 0.15, 0.20, 0.29, 0.17-0.19 L/kg per hour, for vultures, turkeys, broiler chickens, buzzards, and macaws (Ara ararauna), respectively), (9-11,13-15) but lower than that described in ostriches (2.19 L/kg per hour). (12) The [T.sub.1/2[beta]] in the study mallards (2.81 hours) was shorter than in buzzards (4.11 hours), (9) broiler chickens (5.26 and 6.52 hours), (10,11) turkeys (7.37 hours), (14) and vultures (12.51 hours) (13) but longer than in ostriches (1.51 hours). (12) The relatively high Cl observed in the present study could help explain the short permanence and low AUC (3.75 [micro]g x h/mL) relative to the AUC that corresponds to various marbofloxacin doses in buzzards (2 mg/kg; 9.98 [micro]g x h/ mL), (9) vultures (2 mg/kg; 19.46 [micro]g x h]mL), (13) turkeys (2 mg/kg; 12.94 [micro]g x h/mL), (14) and chickens (2.5 mg/ kg; 11.81 [micro]g x h/mL (10) and 13.95 [micro]g x h/mL (11)). However, the AUC in the study mallards was relatively higher than that of 2.32 [micro]g x h/mL found in ostriches given marbofloxacin at a dose of 5 mg/ kg IV. (12)
Goudah and Mouneir (16) found a T[T.sub.1/2[beta]] of 3.91 hours for danofloxacin administered intravenously once at a dose of 5 mg/kg in Muscovy ducks (Cairina moschata) compared with values of 6.73 hours and 8.64 hours in broiler chickens (17) and turkeys, (14) respectively. The researchers hypothesized that the difference could be attributed to variations in assay methods, age, or species. In contrast, after a single intravenous dose of moxifloxacin (5 mg/kg), other researchers observed similar pharmacokinetic behavior between Muscovy ducks (Cl, 0.32 L/kg per hour; Vss, 1.02 L/kg; and [T.sub.1/2[beta]], 2.49 hours) (18) and chickens (Cl, 0.36 L/kg per hour; Vss, 1.04 L/kg; and [T.sub.1/2[beta]], 2.27 hours). (19)
Species variation may explain the different Cl values for meloxicam (0.013, 0.061, and 0.72 L/kg per hour) and flunixin (0.009, 0.140, and 0.500 L/kg per hour) found by Baert and De Backeres (20) among chickens, mallard ducks, and ostriches, respectively. In that study, the data were analyzed to determine the correlation of pharmacokinetics to body mass. However, contrary to the usual principles that involved weight in allometric scaling, the largest birds (ostriches) had a faster elimination half-life than the smaller birds. In contrast, the pharmacokinetic behavior observed in mallards appears to follow the principles of allometric scaling.
The Vss for marbofloxacin in mallard ducks (1.78 L/kg) was lower than the value previously reported for danofloxacin after a single dose of 5 mg/kg IV in Muscovy ducks (5.41 L/kg). (16) The researchers of the previous study hypothesized that the large volume of danofloxacin distribution could be related to its high lipid solubility, low protein binding, adenosine-5'-triphosphate-dependent efflux transporters, and high intracellular penetration. When the octanol/water partition coefficient of each fluoroquinolone was determined by Tejedor et al, (21) marbofloxacin had the least lipophilicity and the smallest Vss value in contrast to the greatest lipophilicity and highest Vss value demonstrated by danofloxacin. These findings could justify some of the pharmacokinetic differences found between these quinolones.
Fluoroquinolones are concentration-dependent drugs. Based on previously published reports on the value of efficacy parameters to predict clinical success, a maximum concentration ([C.sub.max]):minimum inhibitory concentration (MIC) ratio of 10 and an AUC:MIC ratio of 125:250, have been associated with optimal bactericidal effects. (22) High [C.sub.max] : MIC ratios have also been associated with a lower incidence of antimicrobial resistance. (22) However, some researchers suggest that, in immunocompetent patients, values of AUC: MIC < 125 are also likely to be effective. (22) There are no published data concerning the antibacterial activity of marbofloxacin against bacterial isolates from ducks. In previous studies, the MIC value of marbofloxacin is generally [less than or equal to] 0.20 [micro]g/mL for gram-negative bacteria other than Pseudomonas aeruginosa. (10) An MIC value of 0.125 [micro]g/mL for an Escherichia coli strain isolated from turkeys was determined by Haritova et al. (14) Extrapolating from these results in the current study, we used reference MIC values of 0.20 and 0.125 [micro]g/mL. An MIC breakpoint of 0.125 [micro]g/mL yielded values of 9.37 [+ or -] 0.99 and 29.99 [+ or -] 4.51 for [C.sub.max] : MIC and AUC : MIC, respectively, whereas an MIC breakpoint of 0.2 [micro]g/mL resulted in corresponding values of 5.85 [+ or -] 0.62 and 18.74 [+ or -] 2.82, for [C.sub.max] : MIC and AUC: MIC, respectively. These values calculated from our study in mallard ducks do not meet the requirements for efficacy parameters discussed above, particularly with regard to the AUC/MIC index. In contrast, when marbofloxacin was administered to vultures at 2 mg/kg IV, by using an MIC of 0.125 [micro]/mL yielded a [C.sub.max] : MIC and AUC : MIC of 17.97 [+ or -] 1.98 and 155.67 [+ or -] 26.12, respectively; and an MIC of 0.2 [micro]/mL resulted in a [C.sub.max] : MIC and AUC : MIC of 11.23 [+ or -] 1.24 and 97.30 [+ or -] 16.33, respectively. (13)
Although dosage recommendations for marbofloxacin in ducks have not been published, the following dosages have been suggested for other avian species: 2 mg/kg PO q24h for broiler chickens, 2.5-5 mg/kg PO q24h for macaws, and 10-15 mg/kg PO or IM q12h for raptors. (22,23) Because the routes of administration cited are extravascular, higher dosages may be required to achieve similar plasma concentrations. In other avian species, such as vultures, a dose of 2 mg/kg reaches adequate plasma levels and meets current safety requirements by following the recommended values of pharmacokinetic/pharmacodynamic indices; however, a dose of 2 mg/kg is insufficient in ducks. By using the equation proposed by McKellar et al (24) for calculation of an optimal drug dose per day [((AUC/MIC) x Cl x MIC)/F x fu x 24 h]; where AUC/MIC = 125 (ratio for optimal efficacy), Cl = clearance per day, fu = free fraction of drug in plasma (it was ignored due to a minimal binding), and F = bioavailability (F = 1 for intravenous administration); and by using an MIC = 0.125 or 0.2 [micro]/mL, suggested marbofloxacin dosages for mallard ducks are 9.24 and 14.78 mg/kg per day, respectively. These results, which reflect the relatively high Cl observed in the study, suggest that the marbofloxacin dose used for the treatment of infectious diseases in mallard ducks should be increased after intravenous administration. Intravenous doses of 10-15 mg/kg should be assessed by studying their potential toxicity and relative efficacy in sick birds.
Acknowledgments. This study is part of the UBA-CyT project V603, which is supported by Secretaria de Ciencia y Tecnica, Universidad de Buenos Aires. We thank Vetoquinol for providing marbofloxacin for the high-performance liquid chromatography standard. In addition, we thank Mrs Tatiana Diez, Mr Cristian Viladegut, Mrs Mercedes Blanco, and Mr Mariano Diaz Flores for their technical assistance as well as the staff of the Biblioteca de la Facultad de Veterinaria for their invaluable help.
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Marino Garcia-Montijano, DVM, J. Julio de Lucas, DVM, PhD, Casilda Rodriguez, DVM, PhD, Fernando Gonzalez, DVM, PhD, Manuel Ignacio San Andres, DVM, PhD, and Samanta Waxman, DVM, PhD
From the Hospital de Rapaces Altai, C/ Ontanilla, 2. 28180, Torrelaguna, Madrid, Spain (Garcia-Montijano); the Catedra de Farmacologia, Facultad de Veterinaria, Universidad Complutense de Madrid, Ciudad Universitaria, 28040, Madrid, Spain (de Lucas, Rodriguez, Gonzalez, San Andres); and the Catedra de Farmacologia, Facultad de Ciencias Veterinarias, Universidad de Buenos Aires, C/ Chorroarin 280, 1427, Buenos Aires, Argentina (Waxman).
Table 1. Pharmacokinetic parameters (mean [+ or -] SD) of marbofloxacin after a single intravenous dose of 2 mg/kg in mallard ducks. Pharmacokinetic parameters Mean value SD [alpha] ([h.sup.-1]) 0.47 0.13 [beta] ([h.sup.-1]) 0.28 0.09 [T.sub.1/2[alpha]] (h) 1.58 0.43 [T.sub.1/2[beta]] (h) 2.81 1.20 Vc (L/kg) 1.54 0.15 Vss (L/kg) 1.78 0.37 Cl (L/kg per h) 0.59 0.08 [C.sub.max]([micro]g/mL) 1.34 0.27 [T.sub.1/2[lambda]] (h) 2.43 0.61 [AUC.sub.[infinity]]([micro]g x h/mL) 3.75 0.56 [MRT.sub.[infinity]](h) 2.99 0.52 Abbreviations: [alpha] indicates distribution rate constant; [beta], elimination rate constant; [T.sub.1/2[alpha]], distribution half-life; [T.sub.1/2[beta]], elimination half-life; Vc, volume of distribution of the central compartment; Vss, volume of distribution at steady state; Cl, total plasma clearance; [C.sub.max], maximum concentration reached in the first sampling time after intravenous administration; [T.sub.1-2[lambda]], terminal half-life; [AUC.sub.[infinity]], area under the plasma concentration-time curve from zero to infinity; [MRT.sub.[infinity]], mean residence time to infinity.
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|Author:||Garcia-Montijano, Marino; de Lucas, J. Julio; Rodriguez, Casilda; Gonzalez, Fernando; San Andres, Ma|
|Publication:||Journal of Avian Medicine and Surgery|
|Date:||Mar 1, 2012|
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