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    Mean ± SD plasma concentrations of CAM after IM administration of 1 dose of CCFA (10 mg/kg) in 14 healthy adult helmeted guineafowl.

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    Lust E. Ceftiofur crystalline-free acid, ceftiofur HCL, ceftiofur sodium. In: Plumb DC, ed. Veterinary drug handbook. 6th ed. Ames, Iowa: Blackwell Publishing Professional, 2008; 159166.

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Pharmacokinetics of long-acting ceftiofur crystalline-free acid in helmeted guineafowl (Numida meleagris) after a single intramuscular injection

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  • 1 Chicago Zoological and Aquatic Animal Residency Program, College of Veterinary Medicine, University of Illinois, Urbana, IL 61802
  • | 2 Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois, Urbana, IL 61802
  • | 3 Chicago Zoological Society, Brookfield Zoo, 3300 Golf Rd, Brookfield, IL 60513
  • | 4 Chicago Zoological Society, Brookfield Zoo, 3300 Golf Rd, Brookfield, IL 60513
  • | 5 Department of Comparative Medicine, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996
  • | 6 Lincoln Park Zoo, 2001 N Clark St, Chicago, IL 60614.

Abstract

Objective—To evaluate the elimination pharmacokinetics of a single IM injection of a long-acting ceftiofur preparation (ceftiofur crystalline-free acid [CCFA]) in healthy adult helmeted guineafowl (Numida meleagris).

Animals—14 healthy adult guineafowl.

Procedures—1 dose of CCFA (10 mg/kg) was administered IM to each of the guineafowl. Blood samples were collected intermittently via jugular venipuncture over a 144-hour period. Concentrations of ceftiofur and all desfuroylceftiofur metabolites were measured in plasma via high-performance liquid chromatography.

Results—No adverse effects of drug administration or blood collection were observed in any bird. The minimal inhibitory concentration (MIC) for many bacterial pathogens of poultry and domestic ducks (1 μg/mL) was achieved by 1 hour after administration in most birds and by 2 hours in all birds. A maximum plasma concentration of 5.26 μg/mL was reached 19.3 hours after administration. Plasma concentrations remained higher than the MIC for at least 56 hours in all birds and for at least 72 hours in all but 2 birds. The harmonic mean ± pseudo-SD terminal half-life of ceftiofur was 29.0 ± 4.93 hours. The mean area under the curve was 306 ± 69.3 μg•h/mL, with a mean residence time of 52.0 ± 8.43 hours.

Conclusions and Clinical Relevance—A dosage of 10 mg of CCFA/kg, IM, every 72 hours in helmeted guineafowl should provide a sufficient plasma drug concentration to inhibit growth of bacteria with an MIC ≤ 1 μg/mL. Clinical use should ideally be based on bacterial culture and antimicrobial susceptibility data and awareness that use of CCFA in avian patients constitutes extralabel use of this product.

Abstract

Objective—To evaluate the elimination pharmacokinetics of a single IM injection of a long-acting ceftiofur preparation (ceftiofur crystalline-free acid [CCFA]) in healthy adult helmeted guineafowl (Numida meleagris).

Animals—14 healthy adult guineafowl.

Procedures—1 dose of CCFA (10 mg/kg) was administered IM to each of the guineafowl. Blood samples were collected intermittently via jugular venipuncture over a 144-hour period. Concentrations of ceftiofur and all desfuroylceftiofur metabolites were measured in plasma via high-performance liquid chromatography.

Results—No adverse effects of drug administration or blood collection were observed in any bird. The minimal inhibitory concentration (MIC) for many bacterial pathogens of poultry and domestic ducks (1 μg/mL) was achieved by 1 hour after administration in most birds and by 2 hours in all birds. A maximum plasma concentration of 5.26 μg/mL was reached 19.3 hours after administration. Plasma concentrations remained higher than the MIC for at least 56 hours in all birds and for at least 72 hours in all but 2 birds. The harmonic mean ± pseudo-SD terminal half-life of ceftiofur was 29.0 ± 4.93 hours. The mean area under the curve was 306 ± 69.3 μg•h/mL, with a mean residence time of 52.0 ± 8.43 hours.

Conclusions and Clinical Relevance—A dosage of 10 mg of CCFA/kg, IM, every 72 hours in helmeted guineafowl should provide a sufficient plasma drug concentration to inhibit growth of bacteria with an MIC ≤ 1 μg/mL. Clinical use should ideally be based on bacterial culture and antimicrobial susceptibility data and awareness that use of CCFA in avian patients constitutes extralabel use of this product.

Primary and secondary bacterial infections involving a wide range of pathogens are an important cause of disease and death in avian species.1 Despite the wide diversity in metabolic and physiologic processes among avian species and the large spectrum of available antimicrobials, only a few reports of pharmacokinetic studies involving a limited range of avian species are available to guide clinicians in antimicrobial selection for birds with clinical infections. For this reason, antimicrobial dosages are often chosen on the basis of experience or extrapolated from findings in vastly different species.2 Additional studies on the pharmacokinetics of antimicrobials in avian species are essential for encouraging the selection of appropriate drugs and dosages for the treatment of bacterial disease and for minimizing development of resistant bacterial strains.

Ceftiofur is a broad-spectrum, third-generation cephalosporin used for treating infections caused by various gram-positive, gram-negative, and anerobic bacteria in domestic animals.3,4 After entering the bloodstream and passing through the kidneys and liver, ceftiofur is cleaved into furoic acid and desfuroylceftiofur, which is an active metabolite.3,5–7 Ceftiofur, like most cephalosporins, is bactericidal and acts by inhibiting bacterial cell wall synthesis.3 In the United States, the sodium salt of ceftiofur is approved for use in various domestic species, including cattle, swine, sheep, goats, horses, dogs, and poultry.3,8 The hydrochloride salt of ceftiofur is approved for use in cattle and swine.3,8 Ceftiofur crystalline-free acid (100 and 200 mg/mL concentrations) is marketed as a long-acting preparation of ceftiofur for use as a single dose in cattle and swine for treatment of certain bacterial infections.3,8–10 This form of ceftiofur is also approved for treatment of lower respiratory infections in horses as a series of 2 IM injections9 and is used in an extralabel manner in many nondomestic species, including birds kept as companion animals or in zoological collections.

Ceftiofur crystalline-free acid differs from other preparations of ceftiofur by the salt form of the active ingredient and by the addition of a proprietary oil base, which imparts the extended-release characteristics of this product. Cottonseed oil is also used in CCFA as well as in suspensions of ceftiofur hydrochloride.3 The oil base is a patented mixture of medium-chain triglycerides, fractionated coconut oil, and capric triglyceride.11

Literature regarding the use of CCFA in avian species is lacking, and only limited studies4,12,13 have been conducted to evaluate the pharmacokinetics of other ceftiofur preparations in birds. An extended-release antimicrobial preparation would be beneficial for the treatment of birds with bacterial disease, particularly those that are difficult to medicate orally, by decreasing the need for frequent handling and associated complications. The purpose of the study reported here was to evaluate the elimination pharmacokinetics of a single IM dose of CCFA in healthy adult helmeted guineafowl (Numida meleagris) as a model for other avian species.

Materials and Methods

Birds—Fourteen adult helmeted guineafowl, including a preliminary test group (n = 2), weighing 1.37 to 1.96 kg were used for the study. Birds were housed indoors in 2 groups for a 2-week acclimation period and for the duration of the study. They were fed a commercial poultry diet and were determined to be healthy on the basis of results of a physical examination, CBC, and serum biochemical analysis performed within 2 weeks prior to the start of the study. Blood was obtained for DNA, sex determination, and standard curve generation for analysis of plasma ceftiofur concentrations. No medications or feed additives were administered to the birds prior to or during the study. A CBC and plasma biochemical analysis were repeated 2 weeks after the study concluded. The study protocol was approved by the Chicago Zoological Society Institutional Animal Care and Use Committee.

Drug administration and sample collection—In an initial trial, 2 birds were manually restrained for injection of a 10 mg/kg dose of CCFAa in the left pectoral muscle by use of a 1-mL syringe and 22-gauge needle (time 0). Blood samples (0.6 to 1.0 mL) were collected from the right jugular vein into 3-mL syringes at 1, 2, 4, 6, 9, 12, 18, 24, 28, 32, 48, 56, 72, 96, and 144 hours after CCFA administration. Each sample was immediately transferred into a lithium heparin tube. Plasma was separated via centrifugation, transferred to cryogenic storage vials, and frozen at −70°C within 2 hours after collection. A maximum blood volume of 15 mL/bird was obtained over the 144-hour period. These samples were analyzed to confirm the methodology was appropriate prior to identical processing of the remaining 12 birds.

Measurements—Body weight was measured at time 0 and once daily for the duration of the study. Behavioral observations were made when each blood sample was collected and at least 3 times daily throughout the study. Attitude, posture, plumage, location in flock, locomotion, appetite, and waste elimination were observed prior to handling. Monitoring during capture and handling included resistance to capture, strength, mucous membrane color, respiratory rate and effort, and interval to recovery after handling.

Plasma analysis—Analysis of CAM in plasma samples was conducted by use of reversed-phase high-performance liquid chromatography at the University of Tennessee College of Veterinary Medicine Department of Comparative Medicine. The system consisted of a separation module and a UV detector.b Separation was attained on a C18 4.6 × 250-mm (5-μm) column preceded by a 5-μm guard column.c The mobile phase was a mixture of 0.1% trifluoroacetic acid in water and 0.1% trifluoroacetic acid in acetonitrile. This mixture was pumped at a starting gradient of 90% trifluoroacetic acid in water and 10% trifluoroacetic acid in acetonitrile and was adjusted to 75% trifluoroacetic acid in water and 25% trifluoroacetic acid in acetonitrile over 25 minutes and back to initial conditions over 3 minutes. Drug concentration was quantified via UV detection at 265 nm at a flow rate of 1.0 mL/min. The column was at ambient temperature (21° to 22°C).

Ceftiofur was extracted from plasma samples by use of a derivatization method that converts CAM to desfuroylceftiofur acetamide. Briefly, previously frozen plasma samples were thawed and mixed with a vortex machine, 500 μL of plasma was transferred to a clean test tube, and 75 μL of internal standard (100 μg of cefotaxime/mL) was added. Seven milliliters of 0.4% dithioerythritol in borate buffer was added, and then tubes were placed in a 50°C water bath for 15 minutes. The tubes were removed and allowed to cool to room temperature, and then 1.5 mL of iodoacetamide buffer was added. The solution was passed through a prewetted hydrophilic-lipophilic balanced extraction column.d Samples were eluted with a solution of 5% glacial acetic acid in methanol, which was subsequently evaporated to dryness under a steady stream of nitrogen gas. Samples were reconstituted in 200 μL of mobile phase, and 50 μL was injected into the high-performance liquid chromatography system.

Standard curves for plasma analysis were prepared by adding ceftiofur directly to untreated plasma to produce a linear concentration range of 0.1 to 100 μg/mL. These standards were analyzed as experimental plasma samples. Mean ceftiofur recovery was 99%. Intra-assay variability ranged from 0.7% to 4.5%, and interassay variability ranged from 3.6% to 8.8%.

Pharmacokinetic analysis—Plasma concentrations of CAM were analyzed by means of noncompartmental analysis with the aid of a computer program. Means and SDs were calculated for Tmax, Cmax, AUCobs, and mean residence time. Mean residence time and AUCobs were calculated from time 0 to the last measured concentration. The harmonic mean and pseudo-SD were calculated for elimination half-life. The terminal slope was calculated by use of data from at least 3 time points, with most birds (11/14) having data for > 4 time points in the terminal slope.

Statistical analysis—Mean ± SD plasma CAM concentrations at each time point were calculated by use of standard methods. Similar values were calculated for prestudy and poststudy measurements of plasma uric acid concentrations.

Results

Birds—Initial physical examinations and hematologic analyses revealed no apparent health abnormalities other than biochemical changes consistent with reproductive activity in some female birds. Sex determination by use of a DNA probe showed an even sex distribution (7 males and 7 females) in the study group. Results of the CBC and plasma biochemical analysis performed 2 weeks after the study ended were unremarkable other than an increase in uric acid concentration (mean ± SD, 12 ± 2.2 mg/dL), compared with the concentration before the study (4.7 ±1.1 mg/dL).

All birds were tolerant of handling and sample collection, and no birds were removed from the study prematurely because of welfare concerns. Appetite was lower than typical during the first few days of the most frequent blood collection and handling but subsequently returned to usual. A mild transient lameness, suspected secondary to handling or intraspecific aggression, was observed in 2 birds. No adverse drug reactions, including injection site reaction, were observed in any bird.

Pharmacokinetic properties—Mean concentrations of CAM in the plasma were determined for each sampling point after IM administration of CCFA. Results from the first 2 birds tested were combined with those of other birds because drug administration, sample collection, and plasma analysis were identical. Plasma concentrations of ceftiofur at time 0 were assumed to be 0 on the basis of previous analysis of pooled plasma used for the preparation of standard curves and assay validation. One bird had an extreme value for CAM concentration at 9 hours, and this value was not included in the calculation of mean plasma concentration; however, the value was included in the calculation of other pharmacokinetic values because the 9-hour time point was prior to the terminal elimination phase and inclusion of the data point did not considerably change the results.

Mean plasma concentration versus time was graphed (Figure 1). Harmonic mean ± pseudo-SD for the elimination half-life in plasma was 29.0 ± 4.93 hours. The Tmax and Cmax were 19.3 ± 9.71 hours and 5.26 ± 1.54 μg/mL, respectively. The mean AUC was 306 ± 69.3 μg•h/mL, with a mean residence time of 52.0 ± 8.43 hours. Apparent volume of distribution and systemic clearance were 1,660 ± 509 mL/kg and 38.9 ± 12.4 mL/kg/min, respectively; however, bioavailability could not be determined in this study because a comparative IV administration study was not performed.

Figure 1—
Figure 1—

Mean ± SD plasma concentrations of CAM after IM administration of 1 dose of CCFA (10 mg/kg) in 14 healthy adult helmeted guineafowl.

Citation: American Journal of Veterinary Research 72, 11; 10.2460/ajvr.72.11.1514

Plasma ceftiofur concentrations reached 1 μg/mL (the reported ceftiofur MIC for many poultry and duck pathogens7,14–17) by 1 hour after CCFA administration in 12 of 14 birds and by 2 hours in all birds. Plasma concentrations remained > 1 μg/mL for at least 56 hours in all birds and for 72 hours in 12 of 14 birds.

Discussion

Helmeted guineafowl are in the order Galliformes, which includes turkeys, chickens, pheasants, grouse, and quail. They are commonly kept by zoological institutions and private owners. Guineafowl were chosen for our study because of their abundance, ease of handling and sample collection, and large body size, allowing adequate blood volumes for analysis and extrapolation of findings to other avian species, particularly other galliforms. Of the 72 species of galliforms that are considered critically endangered or vulnerable,18 many are evaluated for veterinary care in a zoological setting. An antimicrobial with a long dosing interval would be advantageous for these endangered species as well as other birds that may be difficult to medicate.

Until the present study, no pharmacokinetic analysis of CCFA had been published in an avian species, although analysis of ceftiofur sodium has been performed in a limited number of species, including domestic ducks, cockatiels (Nymphicus hollandicus), orange-winged Amazon parrots (Amazona amazonica), turkey poults, and domestic chicks.4,13

A previous study4 of ceftiofur sodium in various bird species demonstrated that birds required substantially higher ceftiofur doses than did mammals to reach similar peak plasma concentrations. The avian dose for ceftiofur sodium recommended by those investigators was 10 mg/kg, with the dosing interval differing between species, which provided the basis for the dose of CCFA chosen for the present study. This dose exceeds the published mammalian CCFA doses (6.6 mg/kg in cattle and horses; 5 mg/kg in swine).3,9 Maximal plasma concentrations for cockatiels in the aforementioned study4 involving ceftiofur sodium (5.25 μg/mL) were comparable with those found in guineafowl that received CCFA (5.26 ± 1.54 μg/mL), although the Cmax for ceftiofur sodium in Amazon parrots (10.99 μg/mL) and turkey poults (8.96 ± 2.08 μg/mL) was higher than the Cmax for CCFA in guineafowl. The mean residence time and half-life were substantially higher in guinea-fowl that received CCFA than in cockatiels and Amazon parrots that received ceftiofur sodium, which was expected on the basis of the in vivo release characteristics of the CCFA drug preparation.

The Tmax of CCFA in guineafowl in the present study was similar to that observed in mammalian species in which CCFA use has been approved (cattle and swine).9 However, the half-life, Cmax, and AUC of CCFA were lower than those in some mammalian species after dose normalization of Cmax and AUC.9 For example, the Tmax in beef cattle, dairy cattle, and swine is 19.8 ± 5.81 hours, 19.0 ± 8.02 hours, and 22.0 ± 12.2 hours, respectively,9 which is similar to the 19.3 ± 9.71 hours for guineafowl reported here. The Cmax for ceftiofur and its metabolites has been reported for beef cattle, dairy cattle, and swine.9 When normalized for a common dose, these Cmax values become 0.968 ± 0.154 μg/mL, 0.672 ± 0.250 μg/mL, and 0.834 ± 0.184 μg/mL, respectively, compared with the 0.526 ± 0.154 μg/mL observed for guineafowl in our study. The area under the curve for guineafowl was also lower after dose normalization (30.6 ± 6.92 μg•h/mL) than values for beef cattle, dairy cattle, and swine (62.4 ± 10.2 μg•h/mL, 47.4 ± 12.9 μg•h/mL, and 74.6 ± 11.2 μg•h/mL respectively). On the other hand, the half-life in guineafowl is much shorter than the half-life in those other species, which has important implications for administration frequency in guineafowl and other birds. The half-life in beef cattle, dairy cattle, and swine was 40.7 ± 11.2 hours, 43.9 ± 9.84 hours, and 49.6 ± 11.8 hours, compared with a half-life of 29.0 ± 4.93 hours in guineafowl. When the same dose of CCFA used in the guineafowl was evaluated in American black ducks (Anas rubripes),f the result was a similar Tmax, slightly longer but comparable half-life, and a Cmax double the concentration in guineafowl. Differences in the pharmacokinetic parameters between these 2 avian species may be attributable to differences in methods used in data collection and sample analysis or differences in drug absorption, metabolism, distribution, protein binding, or elimination.

Interspecies differences in pharmacokinetic parameters have been reported for cephalosporins, with smaller birds having a shorter half-life and higher clearance than larger birds.4,19 Ceftiofur sodium in cockatiels has a shorter half-life and requires administration every 4 hours, compared with the recommended dosing of every 8 to 12 hours in Amazon parrots.4 Similar findings have been reported for other cephalosporins evaluated in avian species, with administration in birds of lower body weight yielding a shorter half-life than in heavier birds.19 This phenomenon can be explained by the theory of metabolic scaling, which proposes that animals of smaller body mass have proportionally higher metabolic rates than do larger animals. However, the theory does not explain pharmacokinetic differences in all drugs or species evaluated and, furthermore, becomes tenuous when some mammalian data are used for extrapolation of dosages to avian species.20,21 For example, even in species that are closely related taxonomically, variation in pharmacokinetic responses may exist.22,23 Animals of the same species can also have vastly different pharmacokinetic responses to the same dosage because of individual differences in health status or metabolism.24 Additional research is needed to determine whether similar pharmacokinetic differences exist for CCFA among avian species.

Various MICs have been reported for bacteria isolated from domestic ducks, turkeys, and chickens. The MIC90 is ≤ 1 μg/mL for many potential pathogens, including Escherichia coli, Klebsiella spp, Proteus spp, and Salmonella spp from turkey poults and E coli, Pasteurella multocida, and Salmonella spp from poultry.7,14–16 The same is true for E coli, Salmonella spp, Proteus mirabilis, Staphylococcus aureus, and Staphylococcus intermedius isolated from Pekin ducks with septicemia and air-sacculitis.16 On the other hand, the MIC90 values reported for Riemerella anatipestifer isolates from domestic ducks and Citrobacter spp, Enterobacter spp, and Pseudomonas spp from turkey poults are 32 μg/mL.11,15 Staphylococci, streptococci, and enterococci also have an MIC90 > 1 μg/mL (2.0 to > 32.0 μg/mL),16 which underscores the importance of bacterial culture and antimicrobial sensitivity testing when making therapeutic decisions.

In guineafowl in the present study, plasma concentrations of 1 μg of CAM/mL were reached by 1 hour after drug administration in most birds and by 2 hours in all birds. Plasma concentrations remained > 1 μg/mL for at least 56 hours in all birds and for at least 72 hours in 12 of 14 birds. Because ceftiofur is a time-dependent antimicrobial, meaning that the drug is most effective against bacteria when the plasma concentrations remain above MIC,25 inhibition of susceptible organisms is likely to occur for the entire period that plasma concentrations of CAM exceed the MIC.

The derivatization method used in the present study converts all desfuroylceftiofur metabolites (desfuroylceftiofur, desfuroylceftiofur cysteine disulfide, desfuroylceftiofur glutathione disulfide, and desfuroylceftiofur covalently bound to amino acids and proteins) of ceftiofur that have an intact β-lactam ring structure to a derivative that can be analyzed. Therefore, the assay does not distinguish between parent compound and the various conjugates of desfuroylceftiofur that are formed after metabolism. All metabolites that are converted to desfuroylceftiofur acetamide have the intact β-lactam ring that is required for antimicrobial activity.

Although the transformation of CAM to desfuroylceftiofur acetamide is commonly used in pharmacokinetic analysis when quantifying active drug concentrations in recipients, this derivatization methodology has some limitations, particularly when used for samples from birds. We are unaware of any published information regarding the degree of protein binding to ceftiofur and metabolites and the effects on active drug concentrations in any avian species. In addition, no published information exists regarding the metabolism of ceftiofur to desfuroylceftiofur moieties in birds. In all mammalian species in which ceftiofur has been studied, the predominant plasma metabolite is desfuroylceftiofur, which has the same activity and MICs against common mammalian pathogens as ceftiofur, with the exception of Staphylococcus spp, which had a significantly higher MIC.6,7 To our knowledge, no comparison of the MICs of ceftiofur and desfuroylceftiofur has been published for any avian species, and this should be considered when interpreting the data reported here.

Cephalosporins are considered a safe class of antimicrobials, with few adverse or toxic effects, although allergic reactions may occur in some individuals.3 Adverse effects associated with CCFA in cattle include sudden death from inadvertent intra-arterial administration in the ear, local tissue reactions, and abscessation.3,9 Increased drug residues in production animals and gastrointestinal distress are possible consequences of excess doses, but more clinically important adverse effects are unlikely.3 The increases in uric acid detected at the present study's conclusion were higher than the upper reference limit for guineafowl (9.7 mg/dL)26 but were not considered clinically relevant. Possible causes include subclinical dehydration or tissue damage related to frequent blood sample collection and bird handling or initial IM injection of CCFA. Renal effects secondary to ceftiofur administration were considered but were deemed unlikely given the lack of reported nephrotoxic effects in other species at clinically used doses as well as the lack of clinical signs of renal disease in the study guineafowl. One bird died of an unrelated illness 3 months after the study ended, and no gross or histologic evidence of renal disease was present.

Absorption of CCFA following IM injection in guineafowl was rapid, with therapeutic concentrations reached by 1 to 2 hours following administration. Therapeutic concentrations were maintained for 72 hours in most birds. Given the findings reported here, a CCFA dosage of 10 mg/kg, IM, every 72 hours should provide effective plasma concentrations to inhibit bacteria with an MIC ≤ 1 μg/mL in helmeted guineafowl. Clinical use should ideally be based on bacterial culture and antimicrobial sensitivity data, and clinicians should be aware that the use of CCFA in avian patients constitutes extralabel use of this product.

ABBREVIATIONS

AUC

Area under the plasma concentration versus time curve

CAM

Ceftiofur and all desfuroylceftiofur metabolites

CCFA

Ceftiofur crystalline-free acid

Cmax

Maximum plasma concentration

MIC

Minimal inhibitory concentration

MIC90

Minimal inhibitory concentration required to inhibit the growth of 90% of organisms

Tmax

Time to maximal plasma concentration

a.

Excede, Pfizer, New York, NY.

b.

2487 Ultraviolet detector and 2695 Separation module, Waters, Milford, Mass.

c.

Symmetry separation column and guard, Waters, Milford, Mass.

d.

Oasis HLB column, Waters, Milford, Mass.

e.

WinNonlin, version 5.0.1, Pharsight, Mountain View, Calif.

f.

Katharine Hope, National Zoo, Washington, DC: Personal communication, 2010.

References

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    Dorrestein GM. Bacteriology. In: Altman RB, Clubb SL, eds. Avian medicine and surgery. Philadelphia: WB Saunders Co, 1997;255280.

  • 2.

    Flammer K. Antibiotic drug selection in companion birds. J Exotic Pet Med 2006; 15:166176.

  • 3.

    Lust E. Ceftiofur crystalline-free acid, ceftiofur HCL, ceftiofur sodium. In: Plumb DC, ed. Veterinary drug handbook. 6th ed. Ames, Iowa: Blackwell Publishing Professional, 2008; 159166.

    • Search Google Scholar
    • Export Citation
  • 4.

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Contributor Notes

Supported by the Chicago Board of Trade Endangered Species Fund and the Brookfield Zoo.

The authors thank Dr. Natalie Mylniczenko for technical assistance.

Address correspondence to Dr. Wojick (kwojick@illinois.edu).