• View in gallery
    Figure 1—

    Mean ± SD plasma concentrations of marbofloxacin in samples obtained from 8 rabbits after the first (black circles) and last (white circles) doses (5 mg of marbofloxacin/kg, PO) administered every 24 hours for 10 consecutive days.

  • 1.

    Mahmood I, Martinez M, Hunter RP. Interspecies allometric scaling. Part I: prediction of clearance in large animals. J Vet Pharmacol Ther 2006;29:415423.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    US Pet Ownership & Demographics Sourcebook, 2007. Schaumburg, Ill: AVMA. Available at: www.avma.org/reference/marketstats/ownership.asp. Accessed Feb 5, 2008.

  • 3.

    Inglis S, Stahle D, Schwartz J-L, et al. Compendium of veterinary products. Port Huron, Mich: North American Compendiums Ltd, 2006;21382139.

    • Search Google Scholar
    • Export Citation
  • 4.

    Aliabadi FS, Lees P. Pharmacokinetics and pharmacokinetic/pharmacodynamic integration of marbofloxacin in calf serum, exudate and transudate. J Vet Pharmacol Ther 2002;25:161174.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Waxman S, Rodriguez C, González F, et al. Pharmacokinetic behavior of marbofloxacin after intravenous and intramuscular administrations in adult goats. J Vet Pharmacol Ther 2001;24:375378.

    • Search Google Scholar
    • Export Citation
  • 6.

    Spreng M, Deleforge J, Thomas V, et al. Antibacterial activity of marbofloxacin. A new fluoroquinolone for veterinary use against canine and feline isolates. J Vet Pharmacol Ther 1995;18:284289.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Cotard JP, Gruet P, Pechereau D, et al. Comparative study of marbofloxacin and amoxicillin-clavulanic acid in the treatment of urinary tract infections in dogs. J Small Anim Pract 1995;36:349353.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Gruet P, Richard P, Thomas E, et al. Prevention of surgical infections in dogs with a single intravenous injection of marbofloxacin: an experimental model. Vet Rec 1997;140:199202.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Paradis M, Abbey L, Baker B, et al. Evaluation of the clinical efficacy of marbofloxacin (Zeniquin) tablets for the treatment of canine pyoderma: an open clinical trial. Vet Dermatol 2001;12:163169.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Horspool LJI, van Larr P, van den Bos R, et al. Treatment of canine pyoderma with ibafloxacin and marbofloxacin-fluoroquinolones with different pharmacokinetic profiles. J Vet Pharmacol Ther 2004;27:147153.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Schneider M, Thomas V, Boisrame B, et al. Pharmacokinetics of marbofloxacin in dogs after oral and parenteral administration. J Vet Pharmacol Ther 1996;19:5661.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Gibaldi M, Perrier P. Noncompartmental analysis based on statistical moment theory. In: Pharmacokinetics. 2nd ed. New York: Marcel-Dekker Inc, 1982;409417.

    • Search Google Scholar
    • Export Citation
  • 13.

    Williams PL. Noncompartment models. In: Riviere JE, ed. Comparative pharmacokinetics: principles, techniques, and applications. Ames, Iowa: Iowa State University Press, 1999;148167.

    • Search Google Scholar
    • Export Citation
  • 14.

    Cester CC, Schneider M, Toutain PL. Comparative kinetics of two orally administered fluoroquinolones in dog: enrofloxacin versus marbofloxacin. Rev Méd Vét 1996;147:703716.

    • Search Google Scholar
    • Export Citation
  • 15.

    Frazier DL, Thompson L, Trettien A, et al. Comparison of fluoroquinolone pharmacokinetic parameters after treatment with marbofloxacin, enrofloxacin, and difloxacin in dogs. J Vet Pharmacol Ther 2000;23:293302.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Heinen E. Comparative serum pharmacokinetics of the fluoroquinolones enrofloxacin, difloxacin, marbofloxacin, and orbifloxacin in dogs after single dose administration. J Vet Pharmacol Ther 2002;25:15.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Albarellos GA, Montoya L, Landoni MF. Pharmacokinetics of marbofloxacin after single intravenous and repeat oral administration to cats. Vet J 2005;170:222229.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Petracca K, Riond JL, Graser T, et al. Pharmacokinetics of the gyrase inhibitor marbofloxacin: influence of pregnancy and lactation in sows. Zentralbl Veterinarmed [A] 1993;40:7379.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Shem-Tov M, Ziv G, Glickman A, et al. Pharmacokinetics and penetration of marbofloxacin from blood into the milk of cows and ewes. Zentralbl Veterinarmed [A] 1997;44:511519.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Laraje R, Talmi A, Bounaga R, et al. Comparative pharmacokinetics of marbofloxacin after a single intramuscular administration at two dosages to camels (Camelus dromedarius). J Vet Pharmacol Ther 2006;29:229231.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21.

    Carretero M, Rodríguez C, San Andrés MI, et al. Pharmacokinetics of marbofloxacin in mature horses after single intravenous and intramuscular administration. Equine Vet J 2002;34:360365.

    • Search Google Scholar
    • Export Citation
  • 22.

    Peyrou M, Bousquet-Melou A, Laroute V, et al. Enrofloxacin and marbofloxacin in horses: comparison of pharmacokinetic parameters, use of urinary and metabolite data to estimate first-pass effect and absorbed fraction. J Vet Pharmacol Ther 2006;29:337344.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Lees P, Aliabadi FS. Marbofloxacin in equine medicine: have we got the doses right? Equine Vet J 2002;34:322325.

  • 24.

    Anadón A, Martínez-Larrañaga MR, Díaz MJ, et al. Pharmacokinetic characteristics and tissue residues for marbofloxacin and its metabolite N-desmethyl-marbofloxacin in broiler chickens. Am J Vet Res 2002;63:927933.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25.

    Haritova AM, Rusenova NV, Parvanov PR, et al. Integration of pharmacokinetics and pharmacodynamic indices of marbofloxacin in turkeys. Antimicrob Agents Chemother 2006;50:37793785.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26.

    Coke RL, Isaza R, Koch DE, et al. Preliminary single-dose pharmacokinetics of marbofloxacin in ball pythons (Python regius). J Zoo Wildl Med 2006;37:610.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27.

    Hunter RP, Koch DE, Coke RL, et al. Identification and comparison of marbofloxacin metabolites from the plasma of ball pythons (Python regius) and blue and gold macaws (Ara ararauna). J Vet Pharmacol Ther 2007;30:257262.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28.

    Carpenter JW, Hunter RP, Olsen JH, et al. Pharmacokinetics of marbofloxacin in blue and gold macaws (Ara ararauna). Am J Vet Res 2006;67:947950.

  • 29.

    de Lucas JJ, Rodriguez C, Waxman S, et al. Pharmacokinetics of marbofloxacin after intravenous and intramuscular administration to ostriches. Vet J 2005;170:364368.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30.

    Chitty JR, Eyett-Burton CA. Preliminary investigation into the use of marbofloxacin in raptors, in Proceedings. 4th Conf Eur Comm Assoc Avian Vet 1997;162170.

    • Search Google Scholar
    • Export Citation
  • 31.

    García-Montijano M, Waxman S, Sánchez C. The disposition of marbofloxacin in Eurasian buzzards (Buteo buteo) after intravenous administration. J Vet Pharmacol Ther 2001;24:155157.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32.

    García-Montijano M, González F, Waxman S, et al. Pharmacokinetics of marbofloxacin after oral administration to Eurasian buzzards (Buteo buteo). J Avian Med Surg 2003;17:185190.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33.

    KuKanich B, Huff D, Riviere JE, et al. Naïve averaged, naïve pooled, and population pharmacokinetics of orally administered marbofloxacin in juvenile harbor seals. J Am Vet Med Assoc 2007;230:390395.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34.

    Bidgood TL, Papich MG. Plasma and interstitial fluid pharmacokinetics of enrofloxacin, its metabolite ciprofloxacin, and marbofloxacin after oral administration and a constant rate intravenous infusion in dogs. J Vet Pharmacol Ther 2005;28:329341.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35.

    Lefebvre HR, Schneider M, Dupouy V, et al. Effect of experimental renal impairment on disposition of marbofloxacin and its metabolites in the dog. J Vet Pharmacol Ther 1998;21:453461.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36.

    Rougier S, Galland D, Boucher S, et al. Epidemiology and susceptibility of pathogenic bacteria responsible for upper respiratory tract infections in pet rabbits. Vet Microbiol 2006;115:192198.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37.

    Toutain PL, Lees P. Integration and modelling of pharmacokinetic and pharmacodynamic data to optimize dosage regimens in veterinary medicine. J Vet Pharmacol Ther 2004;27:467477.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38.

    Aliabadi FS, Ali BH, Landoni MF, et al. Pharmacokinetics and PK-PD modelling of danofloxacin in camel serum and tissue cage fluids. Vet J 2003;165:104118.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 39.

    Barger A, Fuhst C, Wiedemann B. Pharmacological indices in antibiotic therapy. J Antimicrob Chemother 2003;52:893898.

  • 40.

    Mueller M, de la Peña A, Derendorf H. Issues in pharmacokinetics and pharmacodynamics of anti-infective agents: kill curves versus MIC. Antimicrob Agents Chemother 2004;48:369377.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41.

    Clinical and Laboratory Standards Institute. Performance standards for antimicrobial disk and dilution susceptibility tests for bacteria isolated from animals. 2nd ed. CLSI document M31– A2. Wayne, Pa: Clinical and Laboratory Standards Institute, 2002.

    • Search Google Scholar
    • Export Citation
  • 42.

    Ligabue M, Lucchetti D, Catone T, et al. Rapid depletion of marbofloxacin residues in rabbit after therapeutic treatment. J Food Prot 2005;68:24802484.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 43.

    Regnier A, Schneider M, Concordet D, et al. Intraocular pharmacokinetics of intravenously administered marbofloxacin in rabbits with experimentally induced acute endophthalmitis. Am J Vet Res 2008;69:410415.

    • Crossref
    • Search Google Scholar
    • Export Citation

Advertisement

Single- and multiple-dose pharmacokinetics of marbofloxacin after oral administration to rabbits

James W. CarpenterDepartment of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.

Search for other papers by James W. Carpenter in
Current site
Google Scholar
PubMed
Close
 MS, DVM
,
Christal G. PollockDepartment of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.

Search for other papers by Christal G. Pollock in
Current site
Google Scholar
PubMed
Close
 DVM
,
David E. KochDepartment of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.

Search for other papers by David E. Koch in
Current site
Google Scholar
PubMed
Close
 MS
, and
Robert P. HunterDepartment of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.

Search for other papers by Robert P. Hunter in
Current site
Google Scholar
PubMed
Close
 PhD

Abstract

Objective—To determine the pharmacokinetics of marbofloxacin after oral administration every 24 hours to rabbits during a 10-day period.

Animals—8 healthy 9-month-old female New Zealand White rabbits.

Procedures—Marbofloxacin (5 mg/kg) was administered orally every 24 hours to 8 rabbits for 10 days. The first day of administration was designated as day 1. Blood samples were obtained at 0, 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours on days 1 and 10 of marbofloxacin administration. Plasma marbofloxacin concentrations were quantitated by use of a validated liquid chromatography–mass spectrometry assay. Pharmacokinetic analysis of marbofloxacin was analyzed via noncompartmental methods.

Results—After oral administration, mean ± SD area under the curve was 10.50 ± 2.00 μg·h/mL and 10.90 ± 2.45 μg·h/mL, maximum plasma concentration was 1.73 ± 0.35 μg/mL and 2.56 ± 0.71 μg/mL, and harmonic mean terminal half-life was 8.0 hours and 3.9 hours for days 0 and 10, respectively.

Conclusions and Clinical Relevance—Marbofloxacin administered orally every 24 hours for 10 days appeared to be absorbed well and tolerated by rabbits. Administration of marbofloxacin at a dosage of 5 mg/kg, PO, every 24 hours is recommended for rabbits to control infections attributable to susceptible bacteria.

Abstract

Objective—To determine the pharmacokinetics of marbofloxacin after oral administration every 24 hours to rabbits during a 10-day period.

Animals—8 healthy 9-month-old female New Zealand White rabbits.

Procedures—Marbofloxacin (5 mg/kg) was administered orally every 24 hours to 8 rabbits for 10 days. The first day of administration was designated as day 1. Blood samples were obtained at 0, 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours on days 1 and 10 of marbofloxacin administration. Plasma marbofloxacin concentrations were quantitated by use of a validated liquid chromatography–mass spectrometry assay. Pharmacokinetic analysis of marbofloxacin was analyzed via noncompartmental methods.

Results—After oral administration, mean ± SD area under the curve was 10.50 ± 2.00 μg·h/mL and 10.90 ± 2.45 μg·h/mL, maximum plasma concentration was 1.73 ± 0.35 μg/mL and 2.56 ± 0.71 μg/mL, and harmonic mean terminal half-life was 8.0 hours and 3.9 hours for days 0 and 10, respectively.

Conclusions and Clinical Relevance—Marbofloxacin administered orally every 24 hours for 10 days appeared to be absorbed well and tolerated by rabbits. Administration of marbofloxacin at a dosage of 5 mg/kg, PO, every 24 hours is recommended for rabbits to control infections attributable to susceptible bacteria.

Ownership of exotic pets in North America, especially small exotic mammals, has increased dramatically. Because there is limited therapeutic information available on exotic pets, drug use in these species often requires extrapolation from other animals. In many cases, extrapolation of dosages is no more than an educated guess and may even result in detriments to the health of the animal being treated.1

Domestic rabbits (Oryctolagus cuniculus) are popular exotic animals; there are 6.17 million rabbits owned by 1.87 million households in the United States.2 This number is far larger when considering the number of domestic rabbits throughout the world that are also used as laboratory animals and in food production. Although marbofloxacin is used clinically in rabbits, there have been no systemic pharmacokinetic studies published on this antimicrobial in this species.

Marbofloxacin is a synthetic fluoroquinolone antimicrobial that was developed exclusively for veterinary use and is approved in the United States for the treatment of dogs and cats with infections of the skin and soft tissues and for dogs with urinary tract infections (ie, cystitis).3 Outside of the United States, marbofloxacin is used in treating cattle with respiratory system infections and neonatal calves with diarrhea.4,5 Similar to other fluoroquinolones, marbofloxacin acts by inhibiting bacterial DNA gyrase, an enzyme responsible for packaging DNA within cells. Marbofloxacin is safe and efficacious in other species and has rapid bactericidal activity at relatively low concentrations against many gram-negative and some gram-positive aerobic organisms.5 In vivo and in vitro efficacy against Staphylococcus intermedius, Escherichia coli, Proteus mirabilis, Pseudomonas spp, Pasteurella multocida, and Mannheima haemolytica have been reported.3,4,6–10

Management of bacterial infections with antimicrobials is a challenging aspect of treatment in rabbits. Therefore, the study reported here was designed to determine the pharmacokinetics of marbofloxacin in domestic rabbits, which are commonly kept as companion animals, food animals, and research animals. Data derived from this study will be helpful in designing treatment regimens for rabbits with diseases caused by marbofloxacin-susceptible bacteria.

Materials and Methods

Animals—Eight 9-month-old New Zealand White female rabbits weighing 3.8 to 4.1 kg (mean, 4.0 kg) were used in this study. Rabbits were obtained from a commercially available source and were specific-pathogen (Pasteurella spp) free. Rabbits were housed in indoor runs (1.8 × 0.9 × 1.8 m) in our research facility. Each run contained 2 medium-sized pet carriers that the rabbits frequently used for sleeping or if disturbed. Water was available ad libitum via sipper bottles. Photoperiod was 16 hours of light and 8 hours of dark. Rabbits were fed a diet consisting of alfalfa-based pelletsa and timothy hay.b Immediately prior to the study, each rabbit underwent a physical examination. Examination findings, values for Hct and total plasma protein concentration, results of urinalysis, and behavioral characteristics were determined to be within acceptable limits. This nonterminal study was approved by the Institutional Animal Care and Use Committee of Kansas State University.

Experimental design—A marbofloxacin suspension was used in this study. Marbofloxacin tabletsc (25 mg/tablet; 90 tablets) were ground to a fine powder and combined with 14 mL of distilled water, 2 mL of an artificial flavor,d 100 mL of a suspending vehicle,e and 100 mL of a sugar-free sweetener.f The final suspension contained 10 mg of marbofloxacin/mL, was refrigerated when not in use, and had a shelf life of at least 14 days, which was in accordance with United States Pharmacopeia recommendations.g Marbofloxacin (5 mg/kg, q24h for 10 days) was administered orally to each rabbit by inserting a 3-mL syringe into the mouth between the incisors and premolars. Time of drug administration on each day was designated as time 0, and the first day of administration was designated as day 1. Blood samples (1 mL) were collected from lateral saphenous and cephalic veins or from a central ear artery by use of heparinized syringes and a 25-gauge needle immediately prior to time 0 and at 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours after drug administration on days 1 and 10. Thus, 30 blood samples were obtained from each rabbit during the study. Plasma was separated via centrifugation (10 minutes at approx 2,000 × g) and stored at −70°C until analyzed.

Marbofloxacin analysis—Concentrations of marbofloxacin in plasma were determined by use of a high-performance liquid chromatographyh system with a mass spectrometeri for detection. The mobile phase consisted of 20:80 (vol:vol) acetonitrile:water and 10mM formic acid, with a flow rate of 0.2 mL/min. The acetonitrile was high-performance liquid chromatography grade, water was deionized, and the formic acid was certified as American Chemical Society grade. The mass spectrometer used electrospray with positive ionization as the ionization source. Source voltage was set at 4.5 kV, sheath gas flow rate was set at 65 arbitrary units, and auxiliary gas was set at 10 units. The capillary was heated to a temperature of 135°C and had a voltage of 28 V. Tube lens offset was 45 V, intermultipole lens voltage was −16 V, octapole 1 offset was −3 V, and octapole 2 offset was −5.5 V. The ions with a mass-to-charge ratio of 363.2 and 360.2 were used for quantitation of marbofloxacin and enrofloxacin, respectively.

Standard and quality-control samples were prepared in bulk by adding marbofloxacin-naïve rabbit plasma to aliquots of water containing at least 10 times the intended final concentration of marbofloxacin. The resulting solutions were used for quality-control purposes and had concentrations of 0.01, 0.1, and 1.0 μg/mL. Five quality-control samples at each concentration were extracted and assayed on the day of validation; for each subsequent assay, 2 quality-control samples at each concentration were thawed and extracted. Standards were prepared in duplicate for each day on which samples were assayed. The standard curve was linear and weighted 1/x; concentrations ranged from 0.001 to 5.0 μg/mL. The intraday and interday validation results were within 10% of intended values for precision and accuracy. Recovery was > 70% over the range of the assay.

A 200-μL aliquot of each unknown plasma sample was pipetted into a test tube, and a 50-μL aliquot of internal standard (water containing 4 μg of enrofloxacin/mL) was added. The solution was mixed, and a 3-mL aliquot of acetonitrile was added. The sample was vortexed for 10 minutes and then centrifuged for 10 minutes at 2,000 × g. After centrifugation, the supernatant was transferred to a clean test tube and dried under nitrogen gas in a 40°C water bath. The sample was reconstituted with 200 μL of mobile phase, and the mixture was vortexed for 1 minute before the liquid was transferred to a vial for injection onto the liquid chromatography–mass spectroscopy system. Injection volume was 50 μL.11

Pharmacokinetic analysis—Values of pharmacokinetic variables were determined for each rabbit by use of noncompartmental analysis12,13 performed with commercially available software.j Variables calculated for plasma included AUC0–d (first dose), AUC216–240 (last dose), AUMC, and MRT (first dose). Values for AUC and AUMC were calculated by use of the trapezoidal rule. The percentage extrapolated was < 5%. The Cmax of marbofloxacin in plasma and the Tmax were determined directly from the data. The value for λ was determined from the slope of the terminal phase of the plasma concentration curve that included a minimum of 3 points. The apparent t1/2 was calculated as 0.693/L after the first and last doses and was reported as a harmonic mean.

Results

Mean ± SD plasma concentrations (Figure 1) and pharmacokinetic variables (Table 1) associated with administration of multiple doses of the drug were determined. After oral administration of marbofloxacin on day 1, AUC0–d was 10.50 ± 2.00 μg·h/mL, Cmax was 1.73 ± 0.35 μg/mL, harmonic mean t1/2 was 8.0 hours, MRT was 9.2 ± 2.5 hours, and Tmax was 1.60 ± 0.94 hours. After oral administration on day 10, AUC216–240 was 10.90 ± 2.45 μg·h/mL, Cmax was 2.56 ± 0.71 μg/mL, t1/2 was 3.9 hours, and Tmax was 1.40 ± 0.44 hours.

Figure 1—
Figure 1—

Mean ± SD plasma concentrations of marbofloxacin in samples obtained from 8 rabbits after the first (black circles) and last (white circles) doses (5 mg of marbofloxacin/kg, PO) administered every 24 hours for 10 consecutive days.

Citation: American Journal of Veterinary Research 70, 4; 10.2460/ajvr.70.4.522

Table 1—

Mean ± SD, median, and range of pharmacokinetic variables for marbofoxacin after the first and last doses in 8 rabbits administered the drug (5 mg/kg, PO) every 24 hours for 10 days.

Pharmacokinetic variableDay 1Day 10
Mean ± SDMedianRangeMean ± SDMedianRange
AUC0–∞(μg ▪ h/mL)10.50 ± 2.0010.606.98–13.50
AUC216–240(μg ▪ h/mL)10.90 ± 2.4510.906.98–14.70
AUMC(μg ▪ h2/mL)99.1 ± 37.9108.038.7–138.0
λ(1/h)0.0865 ± 0.00840.08710.0728–0.10300.1790 ± 0.03180.18300.1320–0.2230
t½ (h)8.0*8.06.8–9.53.9*3.83.1–5.2
Cmax(μg/mL)1.73 ± 0.351.681.25–2.442.56 ± 0.712.471.72–3.54
Tmax (h)1.60 ± 0.941.600.45–3.401.40 ±0.441.500.88–2.10
MRT(h)9.2 ± 2.59.05.5–12.0

Harmonic mean.

— = Not applicable.

All rabbits were observed twice daily (once in the morning before any manipulation and once in the late afternoon or early evening) before and throughout the study. Based on our subjective assessments, none of the rabbits had any changes in mentation, attitude, amount of activity, food consumption, or fecal production during the 10-day period, compared with these activities prior to the study. Also, there were no changes in physical examination findings of the rabbits at the conclusion of the study when compared with findings obtained prior to the study.

Discussion

The pharmacokinetic properties of marbofloxacin have been evaluated in other species, including dogs,11,14–16 cats,17 pigs,18 cattle,4,19 sheep,19 goats,5 camels,20 horses,21–23 chickens,24,k turkeys,25 ball pythons (Python regius),26,27 blue and gold macaws (Ara ararauna),27,28 ostriches,29 raptors,30 Eurasian buzzards (Buteo buteo),31,32 and harbor seals.33 Marbofloxacin is rapidly and almost completely absorbed from the gastrointestinal tract after oral administration in dogs from which food has been withheld, with a reported bioavailability of 94%.3 In dogs, approximately 80% of marbofloxacin circulates unbound in the plasma.34 The drug is only minimally (10% to 15% of the drug dose) metabolized by the liver into 2 main metabolites, N-desmethyl-marbofloxacin and N-oxide marbofloxacin.35 Forty percent of an orally administered dose of marbofloxacin in dogs is excreted unchanged in the urine, with the remainder excreted unchanged via the bile in the feces.3 Cats excrete approximately 70% of an orally administered dose in the urine; 85% of the excreted material is marbofloxacin, and the remaining material is excreted as metabolites.3

A Cmax of 1.73 ± 0.35 μg/mL and 2.56 ± 0.71 μg/mL in the rabbits was achieved approximately 1.5 hours after oral administration on days 1 and 10, respectively. In comparison, Cmax in dogs after an orally administered dose of 2 mg/kg was 1.4 μg/mL at 2.5 hours.11 The mean AUC0–d in the rabbits of the study reported here was 10.5 μg·h/mL and is similar to the value obtained in dogs following a single orally administered dose (1 mg/kg).11 Based on the terminal elimination half-life and the dosing interval, steady-state concentrations were reached after the third daily dose in rabbits.

In an epidemiologic study36 aimed at determining the nature, prevalence, and bacteriologic susceptibility of pathogenic bacteria responsible for respiratory tract disease (ie, snuffles), 121 pet rabbits with this condition were evaluated. Isolation of bacterial species from nasal samples; susceptibility testing by use of disk diffusion for marbofloxacin, enrofloxacin, danofloxacin, gentamicin, oxytetracycline, doxycycline, cephalexin, and trimethoprim-sulfamethoxazole; and marbofloxacin MIC determination for each pathogenic bacterium were performed. The main bacterial species isolated were P multocida (54.8%), Bordetella bronchiseptica (52.2%), Pseudomonas spp (27.9%), and Staphylococcus spp (17.4%). Snuffles was mainly attributable to a polybacterial infection, and the most frequently detected combination was P multocida and B bronchiseptica (35 [28.9%] rabbits). Marbofloxacin was the most effective agent against all bacterial strains (depending on the strain, between 87.8% and 100% of isolates were susceptible) except those of B bronchiseptica, for which gentamicin was slightly more effective (96% vs 88.9%). In that study,36 marbofloxacin was a potentially good treatment option for pet rabbits with snuffles.

In human medicine, an AUC:MIC ratio ≥ 100 for fluoroquinolones can eradicate a particular bacterial disease; however, this ratio is not directly related among species, indications, or pathogens.37,38 The human literature also has differing opinions, in that some report a ratio > 25 is best, whereas others state that the ratio must be > 350.39 This is complicated by the fact that for the fluoroquinolone ciprofloxacin, successfully treated patients had AUC:MIC ratios that ranged from 3.6 to 5,675.39 It should be remembered that the in vivo antimicrobial effect is the result of dynamic exposure of the pathogen to the antimicrobial and the host immune system.40 Also, it should be mentioned that the break points for marbofloxacin as reported by the Clinical and Laboratory Standards Institute41 are for dermal infections in dogs and cats. Interpretation of these break points with regard to pathogens in rabbits should be done with caution.

Dosage recommendations vary according to species. The recommended dosage for dogs is 2.75 mg/kg, PO, every 24 hours, but the dose may be increased to 5.5 mg/kg. A minimum dosage of 2 mg/kg, PO, every 24 hours may be appropriate for control of most infections caused by marbofloxacin-susceptible bacteria in chickens.24 Results of studies31,32 in buzzards suggest that marbofloxacin should be administered at 2 mg/kg, IV, every 12 hours or 10 mg/kg, PO, every 24 hours. In macaws, administration of marbofloxacin at 2.5 mg/kg, PO, every 24 hours is recommended.28

On the basis of the study reported here and other studies,11,36,42,43 plasma concentrations of marbofloxacin attained with a dosage of 5 mg/kg, PO, every 24 hours may be effective for treatment of rabbits with infections caused by susceptible bacteria, depending on the MIC value of the target pathogen.36 This dosage, based on the human pharmacokinetic-pharmacodynamic relationship of fluoroquinolones and the susceptibility break points in rabbits determined in another study,36 may provide efficacy. However, clinicians should make changes to the regimen as necessary. The dosing frequency was derived on the basis of suspected rabbit pathogens with an MIC of 1.0 and the break point concentration of 1.0 μg/mL for susceptible pathogens, as determined in dogs and cats by the Clinical and Laboratory Standards Institute.36,41 Because marbofloxacin has bactericidal activity against a wide range of gram-negative and gram-positive organisms, this antimicrobial agent should be efficacious for treatment of rabbits with various bacterial infections of the skin, soft tissues, and urinary tract.

Abbreviations

AUC

Area under the plasma concentration-versus-time curve

AUC0–∞

Area under the plasma concentration-versus-time curve from time 0 through infinity

AUC216–240

Area under the plasma concentration-versus-time curve from time 216 hours through 240 hours

AUMC

Area under the first moment curve

Cmax

Maximum plasma concentration

λ

Plasma elimination rate constant

MIC

Minimum inhibitory concentration

MRT

Mean residence time

t1/2

Terminal half-life

Tmax

Time to reach maximum plasma concentration

a.

Bunny Basics 15/23, Oxbow Pet Products, Murdock, Neb.

b.

Western Timothy Hay, Oxbow Pet Products, Murdock, Neb.

c.

Zeniquin, Pfizer Animal Health, Exton, Pa.

d.

Strawberry Concentrate Artificial Flavor, Gallipot, Saint Paul, Minn.

e.

Ora-Plus, Paddock Laboratories, Minneapolis, Minn.

f.

Ora-Sweet SF, Paddock Laboratories, Minneapolis, Minn.

g.

USP31-NF26, US Pharmacopeia, Rockville, Md.

h.

Synergi Hydro RP (150 × 2.0 mm, 4 μm, 80 Å), Phenomenex, Torrance, Calif.

i.

LCQduo, ThermoFinnigan, San Jose, Calif.

j.

WinNonlin, version 3.1, Pharsight, Mountain View, Calif.

k.

Martínez-Larrañaga MR, Diaz MJ, Fernández-Cruz ML, et al. Pharmacokinetics of marbofloxacin in broiler chickens after intravenous administration (abstr). J Vet Pharmacol Ther 1997;20(suppl 1):197.

References

  • 1.

    Mahmood I, Martinez M, Hunter RP. Interspecies allometric scaling. Part I: prediction of clearance in large animals. J Vet Pharmacol Ther 2006;29:415423.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    US Pet Ownership & Demographics Sourcebook, 2007. Schaumburg, Ill: AVMA. Available at: www.avma.org/reference/marketstats/ownership.asp. Accessed Feb 5, 2008.

  • 3.

    Inglis S, Stahle D, Schwartz J-L, et al. Compendium of veterinary products. Port Huron, Mich: North American Compendiums Ltd, 2006;21382139.

    • Search Google Scholar
    • Export Citation
  • 4.

    Aliabadi FS, Lees P. Pharmacokinetics and pharmacokinetic/pharmacodynamic integration of marbofloxacin in calf serum, exudate and transudate. J Vet Pharmacol Ther 2002;25:161174.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Waxman S, Rodriguez C, González F, et al. Pharmacokinetic behavior of marbofloxacin after intravenous and intramuscular administrations in adult goats. J Vet Pharmacol Ther 2001;24:375378.

    • Search Google Scholar
    • Export Citation
  • 6.

    Spreng M, Deleforge J, Thomas V, et al. Antibacterial activity of marbofloxacin. A new fluoroquinolone for veterinary use against canine and feline isolates. J Vet Pharmacol Ther 1995;18:284289.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Cotard JP, Gruet P, Pechereau D, et al. Comparative study of marbofloxacin and amoxicillin-clavulanic acid in the treatment of urinary tract infections in dogs. J Small Anim Pract 1995;36:349353.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Gruet P, Richard P, Thomas E, et al. Prevention of surgical infections in dogs with a single intravenous injection of marbofloxacin: an experimental model. Vet Rec 1997;140:199202.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Paradis M, Abbey L, Baker B, et al. Evaluation of the clinical efficacy of marbofloxacin (Zeniquin) tablets for the treatment of canine pyoderma: an open clinical trial. Vet Dermatol 2001;12:163169.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Horspool LJI, van Larr P, van den Bos R, et al. Treatment of canine pyoderma with ibafloxacin and marbofloxacin-fluoroquinolones with different pharmacokinetic profiles. J Vet Pharmacol Ther 2004;27:147153.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Schneider M, Thomas V, Boisrame B, et al. Pharmacokinetics of marbofloxacin in dogs after oral and parenteral administration. J Vet Pharmacol Ther 1996;19:5661.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Gibaldi M, Perrier P. Noncompartmental analysis based on statistical moment theory. In: Pharmacokinetics. 2nd ed. New York: Marcel-Dekker Inc, 1982;409417.

    • Search Google Scholar
    • Export Citation
  • 13.

    Williams PL. Noncompartment models. In: Riviere JE, ed. Comparative pharmacokinetics: principles, techniques, and applications. Ames, Iowa: Iowa State University Press, 1999;148167.

    • Search Google Scholar
    • Export Citation
  • 14.

    Cester CC, Schneider M, Toutain PL. Comparative kinetics of two orally administered fluoroquinolones in dog: enrofloxacin versus marbofloxacin. Rev Méd Vét 1996;147:703716.

    • Search Google Scholar
    • Export Citation
  • 15.

    Frazier DL, Thompson L, Trettien A, et al. Comparison of fluoroquinolone pharmacokinetic parameters after treatment with marbofloxacin, enrofloxacin, and difloxacin in dogs. J Vet Pharmacol Ther 2000;23:293302.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Heinen E. Comparative serum pharmacokinetics of the fluoroquinolones enrofloxacin, difloxacin, marbofloxacin, and orbifloxacin in dogs after single dose administration. J Vet Pharmacol Ther 2002;25:15.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Albarellos GA, Montoya L, Landoni MF. Pharmacokinetics of marbofloxacin after single intravenous and repeat oral administration to cats. Vet J 2005;170:222229.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Petracca K, Riond JL, Graser T, et al. Pharmacokinetics of the gyrase inhibitor marbofloxacin: influence of pregnancy and lactation in sows. Zentralbl Veterinarmed [A] 1993;40:7379.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Shem-Tov M, Ziv G, Glickman A, et al. Pharmacokinetics and penetration of marbofloxacin from blood into the milk of cows and ewes. Zentralbl Veterinarmed [A] 1997;44:511519.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Laraje R, Talmi A, Bounaga R, et al. Comparative pharmacokinetics of marbofloxacin after a single intramuscular administration at two dosages to camels (Camelus dromedarius). J Vet Pharmacol Ther 2006;29:229231.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21.

    Carretero M, Rodríguez C, San Andrés MI, et al. Pharmacokinetics of marbofloxacin in mature horses after single intravenous and intramuscular administration. Equine Vet J 2002;34:360365.

    • Search Google Scholar
    • Export Citation
  • 22.

    Peyrou M, Bousquet-Melou A, Laroute V, et al. Enrofloxacin and marbofloxacin in horses: comparison of pharmacokinetic parameters, use of urinary and metabolite data to estimate first-pass effect and absorbed fraction. J Vet Pharmacol Ther 2006;29:337344.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Lees P, Aliabadi FS. Marbofloxacin in equine medicine: have we got the doses right? Equine Vet J 2002;34:322325.

  • 24.

    Anadón A, Martínez-Larrañaga MR, Díaz MJ, et al. Pharmacokinetic characteristics and tissue residues for marbofloxacin and its metabolite N-desmethyl-marbofloxacin in broiler chickens. Am J Vet Res 2002;63:927933.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25.

    Haritova AM, Rusenova NV, Parvanov PR, et al. Integration of pharmacokinetics and pharmacodynamic indices of marbofloxacin in turkeys. Antimicrob Agents Chemother 2006;50:37793785.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26.

    Coke RL, Isaza R, Koch DE, et al. Preliminary single-dose pharmacokinetics of marbofloxacin in ball pythons (Python regius). J Zoo Wildl Med 2006;37:610.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27.

    Hunter RP, Koch DE, Coke RL, et al. Identification and comparison of marbofloxacin metabolites from the plasma of ball pythons (Python regius) and blue and gold macaws (Ara ararauna). J Vet Pharmacol Ther 2007;30:257262.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28.

    Carpenter JW, Hunter RP, Olsen JH, et al. Pharmacokinetics of marbofloxacin in blue and gold macaws (Ara ararauna). Am J Vet Res 2006;67:947950.

  • 29.

    de Lucas JJ, Rodriguez C, Waxman S, et al. Pharmacokinetics of marbofloxacin after intravenous and intramuscular administration to ostriches. Vet J 2005;170:364368.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30.

    Chitty JR, Eyett-Burton CA. Preliminary investigation into the use of marbofloxacin in raptors, in Proceedings. 4th Conf Eur Comm Assoc Avian Vet 1997;162170.

    • Search Google Scholar
    • Export Citation
  • 31.

    García-Montijano M, Waxman S, Sánchez C. The disposition of marbofloxacin in Eurasian buzzards (Buteo buteo) after intravenous administration. J Vet Pharmacol Ther 2001;24:155157.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32.

    García-Montijano M, González F, Waxman S, et al. Pharmacokinetics of marbofloxacin after oral administration to Eurasian buzzards (Buteo buteo). J Avian Med Surg 2003;17:185190.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33.

    KuKanich B, Huff D, Riviere JE, et al. Naïve averaged, naïve pooled, and population pharmacokinetics of orally administered marbofloxacin in juvenile harbor seals. J Am Vet Med Assoc 2007;230:390395.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34.

    Bidgood TL, Papich MG. Plasma and interstitial fluid pharmacokinetics of enrofloxacin, its metabolite ciprofloxacin, and marbofloxacin after oral administration and a constant rate intravenous infusion in dogs. J Vet Pharmacol Ther 2005;28:329341.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35.

    Lefebvre HR, Schneider M, Dupouy V, et al. Effect of experimental renal impairment on disposition of marbofloxacin and its metabolites in the dog. J Vet Pharmacol Ther 1998;21:453461.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36.

    Rougier S, Galland D, Boucher S, et al. Epidemiology and susceptibility of pathogenic bacteria responsible for upper respiratory tract infections in pet rabbits. Vet Microbiol 2006;115:192198.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37.

    Toutain PL, Lees P. Integration and modelling of pharmacokinetic and pharmacodynamic data to optimize dosage regimens in veterinary medicine. J Vet Pharmacol Ther 2004;27:467477.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38.

    Aliabadi FS, Ali BH, Landoni MF, et al. Pharmacokinetics and PK-PD modelling of danofloxacin in camel serum and tissue cage fluids. Vet J 2003;165:104118.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 39.

    Barger A, Fuhst C, Wiedemann B. Pharmacological indices in antibiotic therapy. J Antimicrob Chemother 2003;52:893898.

  • 40.

    Mueller M, de la Peña A, Derendorf H. Issues in pharmacokinetics and pharmacodynamics of anti-infective agents: kill curves versus MIC. Antimicrob Agents Chemother 2004;48:369377.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41.

    Clinical and Laboratory Standards Institute. Performance standards for antimicrobial disk and dilution susceptibility tests for bacteria isolated from animals. 2nd ed. CLSI document M31– A2. Wayne, Pa: Clinical and Laboratory Standards Institute, 2002.

    • Search Google Scholar
    • Export Citation
  • 42.

    Ligabue M, Lucchetti D, Catone T, et al. Rapid depletion of marbofloxacin residues in rabbit after therapeutic treatment. J Food Prot 2005;68:24802484.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 43.

    Regnier A, Schneider M, Concordet D, et al. Intraocular pharmacokinetics of intravenously administered marbofloxacin in rabbits with experimentally induced acute endophthalmitis. Am J Vet Res 2008;69:410415.

    • Crossref
    • Search Google Scholar
    • Export Citation

Contributor Notes

Dr. Pollock's present address is 2199 Westminster Rd, Cleveland Heights, OH 44118.

Dr. Koch's present address is Department of Geography, College of Arts and Sciences, Kansas State University, Manhattan, KS 66506.

Dr. Hunter's present address is Elanco Animal Health, Food Animal Therapeutics, 2001 W Main St, Greenfield, IN 46140.

Supported by a research grant from Oxbow Animal Health.

Address correspondence to Dr. Carpenter.