Cefpodoxime proxetil and cephalexin are the most frequently administered oral formulations of cephalosporins in dogs. Cefpodoxime is a third-generation oral formulation approved for use in dogs. Cephalexin is a first-generation oral formulation that is used in an extralabel manner in dogs. The human generic formulation of cephalexin is the product most often prescribed for use in dogs. Both antimicrobials are effective for the treatment of bacterial infection in dogs. Studies have revealed the efficacy of cephalexin when administered orally for the treatment of skin infections (eg, pyoderma) in dogs at dosages between 22 and 35 mg/kg administered every 12 hours,1 15 mg/kg administered every 12 hours,2,a–c and 30 mg/kg administered every 24 hours.2,a–c Cephalexin (26 to 39 mg/kg, PO, q 12 h) is effective (90% of dogs had good or excellent response to treatment) when used for the treatment of skin, soft tissue, urinary tract, and respiratory tract infections associated with bacterial infection in dogs.3 Cephalexin and cefadroxil were equally effective for the treatment of pyoderma associated with bacterial infections in dogs at dosages ranging from 22 to 35 mg/kg when administered orally every 12 hours.1 In another study,4 157 dogs with pyoderma associated with bacterial infection were treated with cefpodoxime (5 mg/kg, PO, q 24 h) or cephalexin (26 mg/kg, PO, q 12 h) and treatment success was 96.8% and 93.9% for cefpodoxime-treated and cephalexin-treated dogs, respectively.
Pharmacokinetic studies in dogs have been reported for the oral administration of cefpodoxime5,d and cephalexin,6–11,e,f but these studies were limited to the measurement of total (protein-bound and protein-unbound fractions) plasma concentrations. In addition, investigators in these studies reported only the pharmacokinetics of plasma concentrations and did not indicate the concentration of drug at the biophase (site of infection) or determine the effect of protein binding on drug concentrations.
Antimicrobial experts have concluded that measurement of active drug concentrations in extracellular fluid is the preferred method to correlate pharmacokinetic-pharmacodynamic indices with clinical efficacy12,13 In another study,14 investigators provided evidence that indicated antimicrobial concentrations at the target site (ie, ISF) are responsible for the antimicrobial effect and are more relevant than are plasma concentrations for predicting therapeutic efficacy. This conclusion was reiterated by other veterinary pharmacologists,15 who stated that plasma protein binding should be taken into account when examining pharmacokinetic factors because antimicrobial activity is dependent on the unbound drug concentration, rather than the total drug concentration, and that the protein-unbound drug concentration at the site of action (ie, ISF) is the most important predictor of therapeutic efficacy. Failure to recognize the differences between total plasma antimicrobial concentrations and active ISF antimicrobial concentrations may result in misinterpretation of pharmacokinetic-pharmacodynamic properties of a drug and its therapeutic efficacy.
Studies16–18 in dogs have revealed that drug concentrations in the ISF of tissues are determined more by plasma protein binding than by other chemical features of the drug. Investigators in those studies16–18 used an in vivo ultrafiltration device, which was a reliable and convenient method for collecting ISF samples from tissues in dogs. The use of an ultrafiltration device is the preferred method, rather than collection of tissue biopsy specimens or use of tissue cages, in animals because of ease of insertion and the ability to collect serial samples with the same device, without residual wounds or lesions after removal of the ultrafiltration probes. In addition, an ultrafiltration device provides a convenient method for continuous collection of samples and monitoring of drug distribution in unrestrained animals.
Other methods for measuring tissue drug concentrations in animals have traditionally included the processing of homogenized tissues or samples collected from implanted tissue cages. Pharmacology experts agree that the method of obtaining whole tissues, homogenizing them, and measuring the whole tissue concentration is of little value for understanding the relationship between tissue concentration and drug effect, particularly when evaluating this relationship in antimicrobials.19–25 The flaw in relying on this type of tissue concentration data was indicated in a review report.25 Evaluation of tissue biopsy specimens can overestimate lipophilic and underestimate hydrophilic drug concentrations because of the artificial mixing of intracellular fluid, blood, and tissue components during homogenization.21–23 In addition, because tissue biopsy specimens require that animals be euthanatized or that animals be anesthetized for biopsy procedures, it is difficult to achieve serial collection of samples for measurement of plasma-tissue fluid dynamics.
Tissue cages, which have been used by some investigators to estimate tissue drug concentrations, do not represent natural compartments.21–23 Furthermore, sedation, anesthesia, or both is required for cage implantation, and a 4- to 6-week waiting period is necessary before samples can be collected. Influx of fibrin into cages prevents repeated collection of samples and long-term use of the cages. The artificial compartments that arise from the use of tissue cages have a high volume because of the sample space within the device, and the actual volume of extracellular fluid of the tissues cannot be estimated from these compartments. Tissue cages are used to determine drug concentrations in fluids collected from tissues, but they typically misrepresent the true ISF concentrations because of delayed peaks and overestimated rates of drug elimination from tissues.26–29 In addition, drug concentrations in fluids collected in tissue cages may overrepresent the microbiologically active drug fraction in tissues because fluids include protein-bound and protein-unbound drug fractions, and only the protein-unbound fraction is microbiologically active. The purpose of the study reported here was to determine the effect of protein binding on the pharmacokinetics and distribution of cephalexin and cefpodoxime from tissues to ISF in dogs and to compare observed drug concentrations with the MIC90 of Staphylococcus pseudintermedius30,31 (formerly Staphylococcus intermedius) and Escherichia coli.31
Area under the time-concentration curve
Drug clearance per fraction of the dose absorbed
Fraction of the dose absorbed
High-pressure liquid chromatography
Concentration required to inhibit the growth of 90% of bacterial isolates
Time of maximum concentration
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Simplicef tablets for dogs, Pfizer Animal Health, New York, NY.
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Domitor, Pfizer Animal Health, New York, NY.
In vivo ultrafiltration sampling kit, canine ultrafiltration probe, Bioanalytical Systems Inc, West Lafayette, Ind.
Antisedan, Pfizer Animal Health, New York, NY.
Agilent 1100 Series solvent delivery system, Agilent Technologies, Wilmington, Del.
Agilent 1100 Series autosampler, Agilent Technologies, Wilmington, Del.
Agilent 1100 Series Variable Wavelength Detector, Agilent Technologies, Wilmington, Del.
Agilent 1100 Series Chemstation 2D software, Agilent Technologies, Wilmington, Del.
Zorbax Rx C18 column, Agilent Technologies, Wilmington, Del.
Cephalexin reference standard, Sigma Chemical Co, St Louis, Mo.
Cefpodoxime reference standard (PNU-0076253), Pfizer Corp, Kalamazoo, Mich.
Solid-phase extraction cartridges, Sep-Pak C18, 3 mL, 500-mg cartridges, Waters Corp, Milford, Mass.
CentrifreeMicropartition system, Amicon Millipore, Billerica, Mass.
WinNonlin, version 5.2, Pharsight Corp, Mountain View, Calif.
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