• 1.

    Conte JE, Golden JA & Duncan S, et al. Intrapulmonary pharmacokinetics of clarithromycin and of erythromycin. Antimicrob Agents Chemother 1995;39:334338.

  • 2.

    Rodvold KA. Clinical pharmacokinetics of clarithromycin. Clin Pharmacokinet 1999;37:385398.

  • 3.

    Ferrero JL, Bopp BA & Marsh KC, et al. Metabolism and disposition of clarithromycin in man. Drug Metab Dispos 1990;18:441446.

  • 4.

    Fernandes PB, Ramer N & Rode RA, et al. Bioassay for A-56268 (TE-031) and identification of its major metabolite, 14-hydroxy-6-O-methyl erythromycin. Eur J Clin Microbiol Infect Dis 1988;7:7376.

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

    Martin SJ, Garvin CG & McBurney CR, et al. The activity of 14-hydroxy clarithromycin, alone and in combination with clarithromycin, against penicillin- and erythromycin-resistant Streptococcus pneumoniae. J Antimicrob Chemother 2001;47:581587.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Hillidge CJ. Use of erythromycin-rifampin combination in treatment of Rhodococcus equi pneumonia. Vet Microbiol 1987;14:337342.

  • 7.

    Jacks S, Giguère S, Nguyen A. In vitro susceptibilities of Rhodococcus equi and other common equine pathogens to azithromycin, clarithromycin and 20 other antimicrobials. Antimicrob Agents Chemother 2003;47:17421745.

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

    Giguère S, Jacks S & Roberts GD, et al. Retrospective comparison of azithromycin, clarithromycin, and erythromycin for the treatment of foals with Rhodococcus equi pneumonia. J Vet Intern Med 2004;18:568573.

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

    Jacks S, Giguère S & Gronwall RR, et al. Disposition of oral clarithromycin in foals. J Vet Pharmacol Ther 2002;25:359362.

  • 10.

    Drusano GL. Infection site concentrations: their therapeutic importance and the macrolide and macrolide-like class of antibiotics. Pharmacotherapy 2005;25:150S158S.

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

    Baldwin DR, Honeybourne D, Wise R. Pulmonary disposition of antimicrobial agents: methodological considerations. Antimicrob Agents Chemother 1992;36:11711175.

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

    Rennard SI, Basset G & Lecossier D, et al. Estimation of volume of epithelial lining fluid recovered by lavage using urea as marker of dilution. J Appl Physiol 1986;60:532538.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Conte JE, Golden J & Duncan S, et al. Single-dose intrapulmonary pharmacokinetics of azithromycin, clarithromycin, ciprofloxacin, and cefuroxime in volunteer subjects. Antimicrob Agents Chemother 1996;40:16171622.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Jacks S, Giguère S & Gronwall PR, et al. Pharmacokinetics of azithromycin and concentration in body fluids and bronchoalveolar cells in foals. Am J Vet Res 2001;62:18701875.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

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

    • Search Google Scholar
    • Export Citation
  • 16.

    Bedos JP, Azoulay-Dupuis E & Vallee E, et al. Individual efficacy of clarithromycin (A-56268) and its major human metabolite 14-hydroxy clarithromycin (A-62671) in experimental pneumococcal pneumonia in the mouse. J Antimicrob Chemother 1992;29:677685.

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

    Wimsatt JH, Johnson J & Mangone BA, et al. Clarithromycin pharmacokinetics in the desert tortoise (Gopherus agassizii). J Zoo Wildl Med 1999;30:3643.

    • Search Google Scholar
    • Export Citation
  • 18.

    Gan VN, Chu SY & Kusmiesz HT, et al. Pharmacokinetics of a clarithromycin suspension in infants and children. Antimicrob Agents Chemother 1992;36:24782480.

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

    Chu SY, Deaton R, Cavanaugh J. Absolute bioavailability of clarithromycin after oral administration in humans. Antimicrob Agents Chemother 1992;36:11471150.

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

    Vilmanyi E, Kung K & Riond JL, et al. Clarithromycin pharmacokinetics after oral administration with or without fasting in crossbred beagles. J Small Anim Pract 1996;37:535539.

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

    Davis JL, Gardner SY & Jones SL, et al. Pharmacokinetics of azithromycin in foals after i.v. and oral dose and disposition into phagocytes. J Vet Pharmacol Ther 2002;25:99104.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22.

    Lakritz J, Wilson WD & Marsh AE, et al. Effects of prior feeding on pharmacokinetics and estimated bioavailability after oral administration of a single dose of microencapsulated erythromycin base in healthy foals. Am J Vet Res 2000;61:10111015.

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

    Lakritz J, Wilson WD & Marsh AE, et al. Pharmacokinetics of erythromycin estolate and erythromycin phosphate after intragastric administration to healthy foals. Am J Vet Res 2000;61:914919.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24.

    Prescott JF, Hoover DJ, Dohoo IR. Pharmacokinetics of erythromycin in foals and in adult horses. J Vet Pharmacol Ther 1983;6:6773.

  • 25.

    Lakritz J, Wilson WD, Mihalyi JE. Comparison of microbiologic and high-performance liquid chromatography assays to determine plasma concentrations, pharmacokinetics, and bioavailability of erythromycin base in plasma of foals after intravenous or intragastric administration. Am J Vet Res 1999;60:414419.

    • Search Google Scholar
    • Export Citation
  • 26.

    Craig WA. Postantibiotic effects and the dosing of macrolides, azalides, and streptogramins. In: Zinner SH, Young LS, Acar JF, et al, eds.Expanding indications for the new macrolides, azalides, and streptogramins. 3rd ed. New York: Marcel Dekker Inc, 1997;2738.

    • Search Google Scholar
    • Export Citation
  • 27.

    Tessier PR, Kim MK & Zhou W, et al. Pharmacodynamic assessment of clarithromycin in a murine model of pneumococcal pneumonia. Antimicrob Agents Chemother 2002;46:14251434.

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

    Fietta A, Merlini C, Gialdroni GG. Requirements for intracellular accumulation and release of clarithromycin and azithromycin by human phagocytes. J Chemother 1997;9:2331.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29.

    Mandell GL, Coleman E. Uptake, transport, and delivery of antimicrobial agents by human polymorphonuclear neutrophils. Antimicrob Agents Chemother 2001;45:17941798.

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

    Retsema JA, Bergeron JM & Girard D, et al. Preferential concentration of azithromycin in an infected mouse thigh model. J Antimicrob Chemother 1993;31 (suppl E):516.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31.

    Rodvold KA, Gotfried MH & Danziger LH, et al. Intrapulmonary steady-state concentrations of clarithromycin and azithromycin in healthy adult volunteers. Antimicrob Agents Chemother 1997;41:13991402.

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

    Maglio D, Capitano B & Banevicius MA, et al. Differential efficacy of clarithromycin in lung versus thigh infection models. Chemotherapy 2004;50:6366.

  • 33.

    Patel KB, Xuan D & Tessier PR, et al. Comparison of bronchopulmonary pharmacokinetics of clarithromycin and azithromycin. Antimicrob Agents Chemother 1996;40:23752379.

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

    Alvarez-Elcoro S, Enzler MJ. The macrolides: erythromycin, clarithromycin, and azithromycin. Mayo Clin Proc 1999;74:613634.

  • 35.

    Stratton-Phelps M, Wilson WD, Gardner IA. Risk of adverse effects in pneumonic foals treated with erythromycin versus other antibiotics: 143 cases (1986–1996). J Am Vet Med Assoc 2000;217:6873.

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

    Anderson G, Esmonde TS & Coles S, et al. A comparative safety and efficacy study of clarithromycin and erythromycin stearate in community-acquired pneumonia. J Antimicrob Chemother 1991;27 (suppl A):117124.

    • Crossref
    • Search Google Scholar
    • Export Citation

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Pharmacokinetics of clarithromycin and concentrations in body fluids and bronchoalveolar cells of foals

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  • 1 Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32610-0136.
  • | 2 Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32610-0136.
  • | 3 Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32610-0136.
  • | 4 Departments of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32610-0136.

Abstract

Objective—To determine pharmacokinetics of clarithromycin and concentrations in body fluids and bronchoalveolar (BAL) cells of foals.

Animals—6 healthy 2-to 3-week-old foals.

Procedures—In a crossover design, clarithromycin (7.5 mg/kg) was administered to each foal via IV and intragastric (IG) routes. After the initial IG administration, 5 additional doses were administered IG at 12-hour intervals. Concentrations of clarithromycin and its 14-hydroxy metabolite were measured in serum by use of high-performance liquid chromatography. A microbiologic assay was used to measure clarithromycin activity in serum, urine, peritoneal fluid, synovial fluid, CSF, pulmonary epithelial lining fluid (PELF), and BAL cells.

Results—After IV administration, elimination half-life (5.4 hours) and mean ± SD body clearance (1.27 ± 0.25 L/h/kg) and apparent volume of distribution at steady state (10.4 ± 2.1 L/kg) were determined for clarithromycin. The metabolite was detected in all 6 foals by 1 hour after clarithromycin administration. Oral bioavailability of clarithromycin was 57.3 ± 12.0%. Maximum serum concentration of clarithromycin after multiple IG administrations was 0.88 ± 0.19 μg/mL. After IG administration of multiple doses, clarithromycin concentrations in peritoneal fluid, CSF, and synovial fluid were similar to or lower than concentrations in serum, whereas concentrations in urine, PELF, and BAL cells were significantly higher than concentrations in serum.

Conclusions and Clinical Relevance—Oral administration of clarithromycin at 7.5 mg/kg every 12 hours maintains concentrations in serum, PELF, and BAL cells that are higher than the minimum inhibitory concentration (0.12 μg/mL) for Rhodococcus equiisolates for the entire 12-hour dosing interval.

Abstract

Objective—To determine pharmacokinetics of clarithromycin and concentrations in body fluids and bronchoalveolar (BAL) cells of foals.

Animals—6 healthy 2-to 3-week-old foals.

Procedures—In a crossover design, clarithromycin (7.5 mg/kg) was administered to each foal via IV and intragastric (IG) routes. After the initial IG administration, 5 additional doses were administered IG at 12-hour intervals. Concentrations of clarithromycin and its 14-hydroxy metabolite were measured in serum by use of high-performance liquid chromatography. A microbiologic assay was used to measure clarithromycin activity in serum, urine, peritoneal fluid, synovial fluid, CSF, pulmonary epithelial lining fluid (PELF), and BAL cells.

Results—After IV administration, elimination half-life (5.4 hours) and mean ± SD body clearance (1.27 ± 0.25 L/h/kg) and apparent volume of distribution at steady state (10.4 ± 2.1 L/kg) were determined for clarithromycin. The metabolite was detected in all 6 foals by 1 hour after clarithromycin administration. Oral bioavailability of clarithromycin was 57.3 ± 12.0%. Maximum serum concentration of clarithromycin after multiple IG administrations was 0.88 ± 0.19 μg/mL. After IG administration of multiple doses, clarithromycin concentrations in peritoneal fluid, CSF, and synovial fluid were similar to or lower than concentrations in serum, whereas concentrations in urine, PELF, and BAL cells were significantly higher than concentrations in serum.

Conclusions and Clinical Relevance—Oral administration of clarithromycin at 7.5 mg/kg every 12 hours maintains concentrations in serum, PELF, and BAL cells that are higher than the minimum inhibitory concentration (0.12 μg/mL) for Rhodococcus equiisolates for the entire 12-hour dosing interval.

Contributor Notes

Supported by the Florida Thoroughbred Breeders' and Owners' Association.

Address correspondence to Dr. Giguère.