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    Concentrations of CFAEs in plasma samples obtained from 14 American black ducks (Anas rubripes) that received a single dose of CCFA (10 mg/kg, IM) at 0 hours. Each symbol represents data for a particular duck, and the values of the predicted model are represented by the line.

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Pharmacokinetics of a single intramuscular injection of ceftiofur crystalline-free acid in American black ducks (Anas rubripes)

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  • 1 Department of Animal Health, Smithsonian National Zoological Park, 3001 Connecticut Ave NW, Washington, DC 20008.
  • | 2 Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.
  • | 3 Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.
  • | 4 Department of Animal Health, Smithsonian National Zoological Park, 3001 Connecticut Ave NW, Washington, DC 20008.
  • | 5 Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.
  • | 6 Smithsonian Conservation Biology Institute, Smithsonian National Zoological Park, 1500 Remount Rd, Front Royal, VA 22630.
  • | 7 Smithsonian Conservation Biology Institute, Smithsonian National Zoological Park, 1500 Remount Rd, Front Royal, VA 22630.
  • | 8 Smithsonian Conservation Biology Institute, Smithsonian National Zoological Park, 1500 Remount Rd, Front Royal, VA 22630.
  • | 9 Department of Animal Health, Smithsonian National Zoological Park, 3001 Connecticut Ave NW, Washington, DC 20008.

Abstract

Objective—To determine the pharmacokinetic properties of 1 IM injection of ceftiofur crystalline-free acid (CCFA) in American black ducks (Anas rubripes).

Animals—20 adult American black ducks (6 in a preliminary experiment and 14 in a primary experiment).

Procedures—Dose and route of administration of CCFA for the primary experiment were determined in a preliminary experiment. In the primary experiment, CCFA (10 mg/kg, IM) was administered to ducks. Ducks were allocated into 2 groups, and blood samples were obtained 0.25, 0.5, 1, 2, 4, 8, 12, 48, 96, 144, 192, and 240 hours or 0.25, 0.5, 1, 2, 4, 8, 24, 72, 120, 168, and 216 hours after administration of CCFA. Plasma concentrations of ceftiofur free acid equivalents (CFAEs) were determined by use of high-performance liquid chromatography. Data were evaluated by use of a naive pooled-data approach.

Results—The area under the plasma concentration versus time curve from 0 hours to infinity was 783 h•μg/mL, maximum plasma concentration observed was 13.1 μg/mL, time to maximum plasma concentration observed was 24 hours, terminal phase half-life was 32.0 hours, time that concentrations of CFAEs were higher than the minimum inhibitory concentration (1.0 μg/mL) for many pathogens of birds was 123 hours, and time that concentrations of CFAEs were higher than the target plasma concentration (4.0 μg/mL) was 73.3 hours.

Conclusions and Clinical Relevance—On the basis of the time that CFAE concentrations were higher than the target plasma concentration, a dosing interval of 3 days can be recommended for future multidose CCFA studies.

Abstract

Objective—To determine the pharmacokinetic properties of 1 IM injection of ceftiofur crystalline-free acid (CCFA) in American black ducks (Anas rubripes).

Animals—20 adult American black ducks (6 in a preliminary experiment and 14 in a primary experiment).

Procedures—Dose and route of administration of CCFA for the primary experiment were determined in a preliminary experiment. In the primary experiment, CCFA (10 mg/kg, IM) was administered to ducks. Ducks were allocated into 2 groups, and blood samples were obtained 0.25, 0.5, 1, 2, 4, 8, 12, 48, 96, 144, 192, and 240 hours or 0.25, 0.5, 1, 2, 4, 8, 24, 72, 120, 168, and 216 hours after administration of CCFA. Plasma concentrations of ceftiofur free acid equivalents (CFAEs) were determined by use of high-performance liquid chromatography. Data were evaluated by use of a naive pooled-data approach.

Results—The area under the plasma concentration versus time curve from 0 hours to infinity was 783 h•μg/mL, maximum plasma concentration observed was 13.1 μg/mL, time to maximum plasma concentration observed was 24 hours, terminal phase half-life was 32.0 hours, time that concentrations of CFAEs were higher than the minimum inhibitory concentration (1.0 μg/mL) for many pathogens of birds was 123 hours, and time that concentrations of CFAEs were higher than the target plasma concentration (4.0 μg/mL) was 73.3 hours.

Conclusions and Clinical Relevance—On the basis of the time that CFAE concentrations were higher than the target plasma concentration, a dosing interval of 3 days can be recommended for future multidose CCFA studies.

Many types of bacteria cause primary or secondary infections in birds. In birds, gram-negative bacteria commonly infect the respiratory or alimentary tract and gram-positive bacteria commonly infect the skin and upper respiratory or gastrointestinal tracts.1 Consequently, antimicrobials are commonly administered to birds for treatment of infections. Pharmacokinetic and pharmacodynamic properties of many antimicrobials, including fluoroquinolones, β-lactams, tetracyclines, and macrolides, have been determined for several species of birds.2–7 Many antimicrobials have a short half-life, which necessitates frequent treatment and potentially causes an increase in handling-related stress for patients, veterinary staff, and owners.

Third-generation cephalosporins, such as ceftiofur, are bactericidal, have a broad spectrum of activity against bacteria, and have low toxicity. Cephalosporins inhibit bacterial cell wall synthesis and are typically more resistant to deactivation by β-lactamases than are penicillins.8 Third-generation cephalosporins have fair to good activity against gram-positive bacteria, excellent activity against gram-negative bacteria, and activity against some anaerobic bacteria.9 Studies10,11 have revealed that the MIC of ceftiofur for many bacteria (eg, Escherichia coli, Salmonella spp, Proteus spp, Klebsiella spp, and Staphylococcus intermedius) isolated from poultry is ≤ 1.0 μg/mL. Toxicoses and adverse reactions attributable to ceftiofur are rare but include gastrointestinal tract and hypersensitivity reactions.8,9 Anemia and thrombocytopenia have been detected in dogs that received an overdose or had a prolonged duration of administration of cephalosporins.8

The interval during which the concentration of a cephalosporin is higher than the MIC of that drug for a pathogen is considered the most accurate predictor of its efficacy against that pathogen.12 A β-lactam antimicrobial is typically efficacious against a pathogen when the serum or plasma concentration of that drug is higher than the MIC for 50% to 60% of the dosage interval, provided the β-lactam has a postantibiotic effect for that pathogen.13 Maintenance of an effective circulating concentration of a cephalosporin in birds often requires more frequent administration and a higher dose than those required for mammals. Cephalosporin dosage regimens that are effective against bacteria may differ among species of bird. In birds, cephalosporins typically have elimination half-lives < 2 hours,1 and higher doses of ceftiofur are required for birds than for mammals to achieve the same Cmax.6 Additionally, the size and species of bird affect the pharmacokinetics of cephalosporins.6,14 Therefore, it may be necessary to include several species of bird in studies of cephalosporins to properly characterize the efficacy of those antimicrobials. An effective, long-acting, third-generation cephalosporin could be a useful addition to the antimicrobials that are currently available for use in birds. Such an antimicrobial would provide broad-spectrum activity against bacteria and allow a substantially longer dosing interval than that required for other types of antimicrobial.

Ceftiofur crystalline-free acida is a suspension of ceftiofur in sterile oil, which substantially increases the terminal half-life of the drug versus other formulations of ceftiofur. It is approved by the US FDA for treatment of gram-negative, gram-positive, and anaerobic bacterial infections in cattle and swine and for treatment of Streptococcus equi subsp zooepidemicus infections in horses.15–17 Because it is a bactericidal, broad-spectrum, and long-acting antimicrobial, CCFA could be a useful antimicrobial for treatment of bacterial diseases in birds. The objective of the study reported here was to determine the pharmacokinetic properties of CCFA following a single IM injection in American black ducks (Anas rubripes).

Materials and Methods

Animals—Three male and 3 female adult American black ducks (mean ± SD weight, 1.14 ± 0.09 kg [range, 1.02 to 1.26 kg]; age range, 3 to 8 years) were included in a preliminary experiment to determine the dose and route of administration of CCFA that would be used in the primary experiment. Seven male and 7 female adult American black ducks (mean ± SD weight, 1.60 ± 0.21 kg [range, 1.15 to 2.0 kg]; age range, 3 to 8 years) were included in the primary experiment. Ducks were housed in outdoor pens at the Smithsonian Conservation Biology Institute in Front Royal, Va. Each duck was determined to be healthy on the basis of results of a physical examination. All experiments were approved by the Smithsonian National Zoological Park Animal Care and Use Committee.

Preliminary experiment—Six ducks were injected SC with 10, 15, or 20 mg of CCFA/kg (2 ducks [1 male and 1 female]/dose). Blood samples (0.75 to 1.4 mL) were collected ≤ 1 week prior to dosing (0 hours) and 0.25, 0.5, 1, 4, 8, 24, 72, 120, and 168 hours after SC administration of CCFA to the ducks. After a washout period of 3 months, 4 of those same ducks were injected IM with 10 or 20 mg of CCFA/kg (2 ducks [1 male and 1 female]/dose). Blood samples (0.8 to 1.3 mL) were collected ≤ 1 week prior to dosing (0 hours) and 0.25, 0.5, 1, 2, 4, 8, 12, 24, 72, and 120 hours after IM administration of CCFA to the ducks. Blood samples were collected from a jugular or cutaneous ulnar vein. Blood samples were centrifuged (2,500 × g for 20 minutes), and plasma supernatant was placed in 500-μL vials; plasma samples were stored at −70°C until they were shipped frozen on dry ice for sample analysis at the University of California-Davis School of Veterinary Medicine Veterinary Drug Residue Laboratory. To monitor for adverse effects of administration of CCFA or repeated handling of ducks, a physical examination (including inspection of the injection site) was performed for each duck each time it was handled. For each duck, a plasma biochemical analysis was performed ≤ 1 week before and 3 to 5 weeks after SC and IM administrations of CCFA and a CBC was performed ≤ 1 week before and 3 to 5 weeks after IM administration of CCFA to detect adverse effects of administration of that drug. Results of plasma biochemical analyses and CBCs were interpreted by comparison of results with those for blood samples that had been collected from healthy ducks and evaluated at the National Zoological Park Clinical Pathology Laboratory. Plasma samples were analyzed to determine noncompartmental pharmacokinetic variables (t1/2 λz, Cmax, Tmax, time that concentrations of CFAEs were higher than MIC, AUC0–∞, and AUC0–∞/dose of CCFA) of CCFA for each duck in the preliminary experiment. Time that concentrations of CFAEs were higher than MIC was defined as the time during which the concentration (1.0 μg/mL) of CFAEs was higher than that required to exceed the MIC for many pathogens of birds.

Primary experiment—On the basis of results of the preliminary experiment, a dose (10 mg/kg) and route of administration (IM) of CCFA were selected for use in the primary experiment. Ducks were weighed ≤ 24 hours before the start of the primary experiment. The CCFA was mixed thoroughly and aspirated into a syringe ≤ 1 minute before administration to each duck to prevent precipitate from blocking the needle bore during injection. Each duck was injected with 10 mg of CCFA/kg in a pectoral muscle (0 hours). Injections were performed with 1-mL syringes and 22-gauge needles.

To ensure that a sufficient number of blood samples were obtained at each time point for analysis and to minimize the total volume of blood obtained from each duck within a 7-day period after injection of CCFA, ducks were randomly allocated into 2 groups. Blood samples (0.9 to 1.3 mL) were collected into tubes containing lithium heparin from 4 male and 4 female ducks (weight range, 1.15 to 2.0 kg) at ≤ 2 weeks prior to dosing (0 hours) and 0.25, 0.5, 1, 2, 4, 8, 12, 48, 96, 144, 192, and 240 hours after administration of CCFA and from 3 male and 3 female ducks (weight range, 1.3 to 1.7 kg) at ≤ 2 weeks prior to dosing (0 hours) and 0.25, 0.5, 1, 2, 4, 8, 24, 72, 120, 168, and 216 hours after administration of CCFA. Blood samples were collected from a jugular or cutaneous ulnar vein. The total volume of blood collected from each duck within a 7-day period after administration of CCFA was < 10% of its estimated total volume of blood. Blood samples were centrifuged (2,500 × g for 20 minutes), and plasma supernatant was transferred to 500-μL vials; plasma samples were stored at −70°C until they were shipped frozen on dry ice for analysis at the University of California-Davis School of Veterinary Medicine Veterinary Drug Residue Laboratory. Ducks were examined to detect injection site reactions by visual inspection every day and by palpation every time they were handled for blood sample collection for 10 days after administration of CCFA. Activity, appetite, and fecal output of the ducks were monitored daily by keeper staff.

Plasma sample analysis—Preliminary and primary experiment plasma samples were analyzed to determine concentrations of CFAEs (including ceftiofur and desfuroylceftiofur-related metabolites) by use of high-performance liquid chromatography.18 Dithioerythritol (100 mg/0.5 mL of plasma) was added to plasma samples to cleave macromolecule-bound desfuroylceftiofur metabolites. Plasma samples were passed through a C18 solid-phase extraction columnb and derivatized with iodoacetamide to yield desfuroylceftiofur acetamide. Highperformance liquid chromatography analysis was performed isocratically (mobile phase solvent, 7% acetonitrile and 1% acetic acid with 90 mg of heptanesulfonic acid sodium salt/L; pH, 4.0) by use of a C18 columnc (particle size, 4-μm; column dimensions, 3.9 × 150-mm) and UV (240 nm) detection. The limit of detection of the assay for CFAEs was 0.05 μg/mL, and the limit of quantification of the assay for CFAEs was 0.1 μg/mL. Calibration standards for the assay were prepared by dilution of ceftiofurd in duck plasma (collected from ducks prior to ceftiofur administration) at concentrations of 0.2, 0.5, 1, 2, 5, and 10 μg/mL (for analysis of preliminary experiment plasma samples) and at concentrations of 0.1, 0.2, 0.5, 1, 5, and 10 μg/mL (for analysis of primary experiment plasma samples). The matrix blank sample and standard curve samples were prepared with unmedicated duck plasma (ie, duck plasma that did not contain drugs). Intraday and interday coefficients of variation and recovery for the assay were determined by use of standards that were prepared by dilution of ceftiofurd in ammonium acetate buffer (0.2, 1.0, and 5.0 μg/mL). The intra-assay coefficient of variation was 6.0%, with intraday accuracies of 92%, 95%, and 99% for the 0.2, 1.0, and 5.0 μg/mL standards, respectively. The interassay coefficient of variation was 8.9%, with interday accuracies of 93%, 95%, and 98% for the 0.2, 1.0, and 5.0 μg/mL standards, respectively. The mean recovery was 95.1%.

Determination of MICs—Minimum inhibitory concentrations of ceftiofur were determined for bacteria that had been isolated from various samples obtained from 175 birds. These samples had been submitted to the William R. Pritchard Veterinary Medical Teaching Hospital Microbiology Laboratory at the University of California-Davis from January 2000 through September 2010. Bacteria had been isolated with 5% sheep blood agar or MacConkey agar and incubation at 35°C in 5% CO2. Identification of bacterial isolates had been performed by use of conventional microbiological methods19 with tubed media and bacterial identification strips.e

Broth microdilution was used to perform antimicrobial susceptibility tests.20 Briefly, 2 mL of brain-heart infusion broth was inoculated with 2 or 3 isolated colonies of bacteria and incubated at 35°C without CO2 for 4 to 5 hours. The broth culture was then added drop-wise to saline (0.9% NaCl) solution to achieve a McFarland standard of 0.5 as determined by a nephelometer. Ten microliters of this suspension was diluted in 11 mL of cation-adjusted Mueller-Hinton broth that contained N-Tris(hydroxymethyl) methyl-2-aminoethane sulfonic acidf; platesg for the determination of antimicrobial resistance were inoculated with 50 μL of this broth/well. The plates were incubated at 35°C without CO2 overnight (16 hours). The MIC of ceftiofur for each bacterial isolate was determined.

Pharmacokinetic analysis—Pharmacokinetic analysis of time versus plasma concentration data was performed with commercial software.h Data were analyzed by use of a naïve pooled-data approach.21 The model that best fit the data was determined by visual examination of line fits and by residual plots of Akaike information criteria.22 Uniform weighting of data was used for the analysis. Because the analytic method that was used to measure plasma ceftiofur concentrations also measures concentrations of other active ceftiofur metabolites, the time that concentrations of CFAEs were higher than the MIC (1.0 μg/mL) and the time that concentrations of CFAEs were higher than the target plasma concentration (4.0 μg/mL) were determined.

Pharmacokinetic variables determined for compartmental analysis included the initial-phase rate constant and the terminal-phase rate constant. For noncompartmental analysis, the following pharmacokinetic variables were determined: terminal-phase rate constant, t1/2 λz, AUC0–∞, time that concentrations of CFAEs were higher than MIC, and time that concentrations of CFAEs were higher than the target plasma concentration. The Cmax and Tmax were determined from plasma samples obtained at predetermined sample collection time points.

Results

Preliminary experiment—During the preliminary experiment, ducks were healthy and no injection site reactions were observed. Results of CBCs and plasma biochemical analyses did not indicate any clinically important findings in ducks after administration of CCFA. Results of plasma biochemical analyses and CBCs were interpreted by comparison of results with those for blood samples that had been collected from healthy ducks and evaluated at the National Zoological Park Clinical Pathology Laboratory.

Plasma concentrations of CFAEs and the pharmacokinetic parameters determined during the preliminary experiment (Table 1) suggested that CCFA seemed to have a longer terminal half-life and the concentration of CFAEs seemed to be higher than the MIC for a longer period after IM administration versus after SC administration in the ducks, although these data were not examined via statistical analysis. A CCFA dose of 10 mg/kg and an IM route of administration were selected for use in the primary experiment because this dose and route of administration resulted in plasma concentrations of CFAEs in ducks of the preliminary experiment that were higher than the plasma concentration of ceftiofur (1.0 μg/mL) required to exceed the MIC for many pathogens of birds.

Table 1—

Noncompartmental pharmacokinetic parameters for American black ducks (Anas rubripes) that received CCFA (10, 15, or 20 mg/kg, SC; and 10 or 20 mg/kg, IM) at 0 hours during a preliminary experiment.

Dose (mg/kg)Route of administrationt1/2 λz (h)Cmax (μg/mL)Tmax (h)Time concentrations of CFAEs ≥ MIC (h)AUC0−∞ (h•μg/mL)AUC0−∞/CCFA dose
10SC12.216.9467.8485.048.5
  10.622.6866.7543.354.3
15SC10.721.6465.7476.831.8
  10.120.4867.7579.138.6
20SC17.818.2871.6830.341.5
  13.426.3871.8867.543.4
10IM29.115.524120.01,114.4111.4
  25.817.124144.41,109.3110.9
20IM17.419.212116.11,550.477.5
  26.832.512119.91,119.456.0

The MIC was defined as 1.0 μg/mL. Results represent data for 2 ducks for each combination of dose and route of administration.

Primary experiment—During the primary experiment, ducks were healthy and adverse effects of CCFA administration were not detected. No injection site reactions were observed, and no adverse effects to the gastrointestinal tract were detected in the ducks.

The pharmacokinetic parameters were calculated via a naïve pooled-data approach (Table 2). Terminal-phase rate constants were similar (terminal-phase rate constant for compartmental analysis, 0.020 hours−1; terminal-phase rate constant for noncompartmental analysis, 0.022 hours−1), initial rate constant was 0.22 hours−1, t1/2 λz was 32.0 hours, Cmax was 13 μg/mL, mean ± SD AUC0–∞ was 783 ± 156.4 h•μg/mL, mean time that concentrations of CFAEs were higher than the target plasma concentration (4 μg/mL) was 73.3 hours, and time that concentrations of CFAEs were higher than the MIC (1 μg/mL) was 123 hours. It was determined that a 1-compartment model best fit the plasma concentration versus time data (Figure 1).

Figure 1—
Figure 1—

Concentrations of CFAEs in plasma samples obtained from 14 American black ducks (Anas rubripes) that received a single dose of CCFA (10 mg/kg, IM) at 0 hours. Each symbol represents data for a particular duck, and the values of the predicted model are represented by the line.

Citation: American Journal of Veterinary Research 73, 5; 10.2460/ajvr.73.5.620

Table 2—

Compartmental and noncompartmental pharmacokinetic parameters of CCFA (10 mg/kg, IM) in 14 American black ducks.

Pharmacokinetic parameterValue
Kabs (h−1)0.22
Kel (h−1)0.020
λz (h−1)0.022
t1/2 λz (h)32.0
Tmax (h)24
Cmax (μg/mL)13.07
AUC0−∞(h•μg/mL)782.9
Time concentrations of CFAEs ≥ MIC (h)123.3
Time concentrations of CFAEs ≥ target plasma concentration (h)*73.3

Target plasma concentration was defined as 4.0 μg/mL.

Kabs = Initial-phase rate constant (compartmental analysis).

Kel = Terminal-phase rate constant (compartmental analysis).

λz = Terminal-phase rate constant (noncompartmental analysis).

See Table 1 for remainder of key.

MICs—The MICs of ceftiofur for bacteria isolated from various samples obtained from birds were determined (Table 3). Bacterial isolates for which the ceftiofur MIC90 was ≤ 1.0 μg/mL included Enterobacter spp, Klebsiella spp, Pasteurella spp, Proteus spp, Serratia spp, Staphylococcus aureus, and nonfermentative group 3 bacteria. Additional bacterial isolates for which the ceftiofur MIC50 was ≤ 1.0 μg/mL included E coli, S intermedius, coagulase-negative Staphylococcus spp, and Streptococcus spp. Bacterial isolates for which the ceftiofur MIC50 and MIC90 were ≥ 4.0 μg/mL included Acinetobacter spp, Enterococcus spp, and Pseudomonas spp, which indicated that these bacteria were not susceptible to ceftiofur. The MIC data were compared with values of MICs of ceftiofur that have been reported in other studies10,11,23 for bacteria isolated from various samples obtained from birds (Appendix). Among bacteria isolated from Anseriformes or Galliformes in those studies, MIC90 values of ceftiofur for E coli, Klebsiella spp, Proteus spp, Salmonella spp, and S intermedius were 0.5 to 1.0 μg/mL, and MIC90 values of ceftiofur for Citrobacter spp, Enterobacter spp, Enterococcus spp, Pseudomonas spp, coagulase-negative Staphylococcus spp, and Streptococcus spp were > 4.0 μg/mL.

Table 3—

Minimum inhibitory concentrations of ceftiofur for bacteria isolated from various samples that had been obtained from 175 birds and submitted to the William R. Pritchard Veterinary Medical Teaching Hospital Microbiology Laboratory at the University of California-Davis from January 2000 through September 2010.

Bacterial isolateSourceNo. of isolatesMIC50 (μg/mL)MIC90(μg/mL)MIC range (μg/mL)
Acinetobacter sppAnseriforme, Psittaciforme, and NR54.08.04.0 to > 8.0
Escherichia coliAnseriforme, Falconiforme, Galliforme, Psittaciforme, and NR51< 0.5> 4.0< 0.25 to > 4.0
Enterobacter sppAnseriforme, Columbiforme, Coraciforme, Psittaciforme, and NR21< 0.51.0< 0.5 to > 4.0
Enterococcus sppAnseriforme, Falconiforme, Galliforme, Passeriforme, Psittaciforme, and NR32> 4.0> 8.0< 0.5 to > 8.0
Klebsiella sppAnseriforme, Galliforme, Psittaciforme, and NR31< 0.51.0< 0.5 to > 4.0
Nonfermentative group 3Anseriforme, Falconiforme, and Galliforme4< 0.25< 0.5< 0.06 to < 0.5
Pasturella sppAnseriforme, Falconiforme, Galliforme, Psittaciforme, and NR21< 0.5< 0.5< 0.06 to 1.0
Proteus sppAnseriforme, Psittaciforme, and NR10< 0.5< 0.5< 0.5 to 1.0
Pseudomonas sppAnseriforme, Galliforme, Psittaciforme, and NR26> 4.0> 8.02.0 to > 8.0
Serratia sppPsittaciforme and NR4< 0.51.0< 0.5 to 1.0
Staphylococcus aureusFalconiforme, Galliforme, Psittaciforme, and NR161.01.0< 0.5 to 4.0
Staphylococcus intermediusFalconiforme, Psittaciforme, and NR6< 0.58.0< 0.5 to 8.0
Staphylococcus spp (coagulase negative)Falconiforme, Galliforme, Psittaciforme, and NR411.0> 4.0< 0.06 to > 8.0
Streptococcus sppPsittaciforme and NR70.52.0< 0.5 to > 4.0

Source is the order of the birds from which samples for bacterial culture and determination of MICs were obtained.

NR = Not reported.

Discussion

American black ducks did not develop any adverse clinical signs attributable to CCFA administration (10 mg/kg, IM) during the study reported here. Additionally, none of the previously reported adverse effects (eg, gastrointestinal tract disturbances, anaphylactic reactions, or anemia) of ceftiofur administration were detected in the ducks during 2 years after completion of the present study.

Results of the preliminary experiment in the present study indicated that administration of 10 or 20 mg of CCFA/kg resulted in plasma concentrations of CFAEs > 1 μg/mL. Intramuscular administration of CCFA resulted in plasma concentrations of CFAEs > 1.0 μg/mL for a longer period than did SC administration of CCFA. Additionally, CCFA seemed to have greater apparent bioavailability after IM administration than after SC administration, as indicated by the higher AUC0–∞, although these data were not tested via statistical analysis, nor was the IV route of administration included in the study. The doses of CCFA administered IM in the preliminary experiment were chosen on the basis of the dose of CCFA recommended for cattle (6.6 mg/kg). The cattle dose was rounded up (10 mg/kg) for ease of CCFA dose calculation in the present study, and a higher dose of CCFA (20 mg/kg) was also administered to the ducks because ducks likely have a higher metabolic rate than that of cattle. Results of the preliminary experiment indicated that 10 mg of CCFA/kg administered IM was sufficient to achieve plasma concentrations of CFAEs that were expected to be active against bacteria. Because IM administration of 10 mg of CCFA/kg was investigated in the primary experiment in the present study, another study would be required to determine whether IM administration of CCFA doses < 10 mg/kg would achieve plasma concentrations of CFAEs in ducks that are effective against bacteria.

Ceftiofur crystalline-free acid administered IM at a dose of 10 mg/kg had a longer duration of action in American black ducks in the present study than has been reported for other third-generation cephalosporins administered to other species of birds. Results of another study6 indicated that the mean t1/2 λz of ceftiofur sodium in psittacines and domestic birds ranges from 2.5 to 8.7 hours. In comparison, the t1/2 λz of CCFA in ducks in the present study was 32 hours. Ceftriaxone administered IM at a dose of 100 mg/kg has an elimination half-life of 5.1 hours in chickens.24 Cefovecin, a recently developed antimicrobial that has a long terminal half-life in dogs and cats allowing a dosing interval of 14 days, has a mean ± SD plasma half-life of 0.9 ± 0.3 hours in domestic hens after SC administration of a dose of 10 mg/kg.25 Therefore, CCFA appears to have a longer terminal half-life than other third-generation cephalosporins in birds, which suggests that effective circulating antimicrobial concentrations may be maintained for a longer time after CCFA administration than after administration of other ceftiofur formulations.

Ceftiofur crystalline-free acid seemed to have different pharmacokinetic properties in American black ducks in the present study, compared with findings for other cephalosporin formulations evaluated in other species of birds. For example, Tmax of ceftiofur sodium (1 to 11.6 mg/kg, SC) in domestic birds ranges from 0.4 to 2.7 hours,6 and mean ± SD Tmax of cefovecin (10 mg/kg, SC) in hens is 17 ± 3 minutes.25 In contrast, Tmax of CCFA in ducks in the present study was 24 hours. The Cmax of ceftiofur sodium in psittacines and domestic birds ranges from 0.86 to 10.99 μg/mL,6 and mean ± SD Cmax of cefovecin in hens is 6 ± 2 μg/mL,24 whereas Cmax of CCFA in ducks in the present study was 13.1 μg/mL. The AUC0–∞ of ceftiofur sodium in psittacines and domestic birds ranges from 3.4 to 43.8 h•μg/mL,6 and mean ± SD AUC0–∞ of cefovecin in hens is 8 ± 1 h•μg/mL,24 whereas AUC0–∞ of CCFA in ducks in the present study was 783 h•μg/mL.

The pharmacokinetic properties of CCFA in American black ducks in the present study were comparable to pharmacokinetic properties of CCFA in mammals and other species of birds. Other pharmacokinetic studies have indicated the mean ± SD Tmax of CCFA (5 mg/kg, IM) in swine is 22.0 ± 12.2 hours,26 and the mean ± SD Tmax of CCFA (6.6 mg/kg, administered SC in the middle third of the ear) in beef cattle is 12.0 ± 6.2 hours.27 These results were similar to those for ducks in the present study (Tmax, 24 hours). Results of those other studies reveal that values of t1/2 λz for CCFA in swine26 (49.6 ± 11.8 hours) and beef cattle27 (62.3 ± 13.5 hours) were longer than the t1/2 λz (32.0 hours) detected after administration of CCFA (10 mg/kg, IM) to ducks in the present study. However, in swine26 and beef cattle,27 mean ± SD values of Cmax (4.17 ± 0.92 μg/mL and 6.90 ± 2.68 μg/mL, respectively) and AUC0–∞ (373.0 ± 56.1 h•μg/mL and 376 ± 66.1 h•μg/mL, respectively) differ from the values of Cmax (13.1 μg/mL) and AUC0–∞ (783 h•μg/mL) in ducks in the primary experiment of the present study. This difference in the values of pharmacokinetic variables of CCFA may be attributable to the higher dose of CCFA that was administered to ducks in the present study, compared with the doses administered to swine26 and beef cattle27 in the other studies, or to physiologic differences among these species. Interestingly, a study28 in which CCFA (6.6 mg/kg, SC) was administered to nonlactating goats revealed higher mean ± SD Tmax (26.7 ± 16.5 hours), lower mean ± SD Cmax (2.25 ± 1.13 μg/mL), and lower mean ± SD AUC0–∞ (159.35 ± 19.4 h•μg/mL) of CCFA than the corresponding values for swine,26 beef cattle,27 and ducks (present study).

Authors of a recent study29 in which CCFA (10 mg/kg, IM) was administered to helmeted guineafowl (Numida meleagris) reported a mean ± SD terminal half-life of 29.0 ± 4.9 hours, mean ± SD Cmax of 5.26 ± 1.54 μg/mL, mean ± SD Tmax of 19.3 ± 9.71 hours, and mean ± SD area under the plasma concentration versus time curve of 306 ± 69.3 h•μg/mL. Compared with results for American black ducks in the present study (to which CCFA was administered at that same dose and by that same route of administration), Cmax and AUC0–∞ were lower for those guineafowl and Tmax and terminal half-life were similar for those guineafowl. Plasma concentrations of ceftiofur were higher than the MIC (1 μg/mL) for many bacterial pathogens of poultry and domestic ducks for 72 hours in 12 of 14 guineafowl in that other study.29 In American black ducks in the present study, plasma concentrations of CFAEs were > 1 μg/mL for 123 hours. These results suggested that after IM administration of 10 mg of CCFA/kg, Cmax and AUC0–∞ were higher and the time during which the plasma concentration was > 1 μg/mL was longer for ducks in the present study than for guineafowl in the other study.29 Given that guineafowl in the other study29 and American black ducks in the present study were of similar size, this variation may be attributable to physiologic differences among Galliformes and Anseriformes.

In general, MICs of ceftiofur for bacteria isolated from birds are higher than those for bacteria isolated from cattle, swine, or horses.10,11,23 For many bacteria isolated from cattle, swine, and horses, MIC90 of ceftiofur is < 0.03 μg/mL.23 Bacteria isolated from Anseriformes or Galliformes for which the MIC90 value of ceftiofur is 0.5 to 1.0 μg/mL include E coli, Klebsiella spp, Proteus spp, Salmonella spp, and S intermedius (Appendix).10,11,23 Those same studies10,11,23 revealed that MIC90 values of ceftiofur for Citrobacter spp, Enterobacter spp, Enterococcus spp, Pseudomonas spp, coagulase-negative Staphylococcus spp, and Streptococcus spp are > 4.0 μg/mL. On the basis of the results of the present study, it appears that Enterobacter spp, S aureus, coagulase-negative Staphylococcus spp, and Streptococcus spp isolated from birds may have higher susceptibility to ceftiofur, and S intermedius and E coli isolated from birds may have lower susceptibility to ceftiofur, compared with findings for bacteria isolated from cattle, swine, or horses.10,11,23 Results of the present study support results of the other studies,10,11,23 which indicate that Enterococcus spp and Pseudomonas spp are typically resistant to ceftiofur. Considering these pharmacokinetic and MIC data, bacteria that would be most susceptible to CCFA may include Enterobacter spp, Klebsiella spp, Pasteurella spp, Proteus spp, Serratia spp, S aureus, and nonfermentative group 3 bacteria; E coli, S intermedius, coagulase-negative Staphylococcus spp, and Streptococcus spp may have intermediate susceptibilities to CCFA. However, despite the broad spectrum of action of ceftiofur, antimicrobials should be chosen on the basis of results of culture and susceptibility testing whenever possible.

To compensate for inactive ceftiofur metabolites that are detected by use of high-performance liquid chromatography, some studies30 conducted to investigate pharmacokinetics of ceftiofur in cattle and swine have used a target MIC value of 0.2 μg/mL, despite the reported MIC of ceftiofur of 0.03 μg/mL for many species of bacteria commonly isolated from these animals.23 Results of a study31 in which the antimicrobial activities of ceftiofur and desfuroylceftiofur were investigated indicate that both of these metabolites have similar activities against gram-negative bacteria but that ceftiofur is 2 to 8 times more active than is desfuroylceftiofur against certain gram-positive bacteria. Because the ratio of circulating ceftiofur to its less active metabolites after administration in birds is unknown, and because the in vivo activities of these metabolites in birds are unknown, a target plasma concentration (4 μg/mL) that was 4 times higher than the MIC (1 μg/mL) was used in the present study. For many bacterial pathogens of birds, the MIC90 of ceftiofur is ≤ 1 μg/mL. Therefore, a target plasma concentration of 4 μg of ceftiofur/mL was used in the present study because that concentration was expected to be active against most of the bacterial isolates that were susceptible to this antimicrobial. On the basis of the finding in the present study that the time that concentrations of CFAEs were higher than the target plasma concentration was 73.3 hours, we suggest a dosing interval of 3 days should be used in future studies conducted to investigate administration of multiple doses of CCFA to ducks.

Although CCFA seems to be a promising long-acting broad-spectrum antimicrobial for use in birds, a study in which multiple doses are administered would be needed to confirm our recommended dosing interval of 3 days. Further studies could be conducted to determine whether administration of CCFA to birds at doses that are the same as those recommended for use in mammals results in half-life, AUC0–∞, and Cmax values that are comparable to those in ducks of the present study. Also, the pharmacokinetics of CCFA may differ among species of birds, and further studies are warranted to characterize these differences.

ABBREVIATIONS

AUC0–∞

Area under the plasma concentration versus time curve from 0 hours to infinity

CCFA

Ceftiofur crystalline-free acid

CFAE

Ceftiofur free acid equivalent

Cmax

Maximum plasma concentration observed

MIC

Minimum inhibitory concentration

MIC50

Minimum inhibitory concentration required to inhibit growth of 50% of bacterial isolates

MIC90

Minimum inhibitory concentration required to inhibit growth of 90% of bacterial isolates

t1/2 λz

Terminal-phase half-life

Tmax

Time to maximum plasma concentration observed

a.

Excede, Pharmacia and Upjohn Co, New York, NY.

b.

Varian Inc, Walnut Creek, Calif.

c.

Nova-pak C18, Waters Corp, Milford, Mass.

d.

Ceftiofur Vetranal analytical standard, Sigma-Aldrich Corp, St Louis, Mo.

e.

API, bioMérieux, Durham, NC.

f.

Trek Diagnostic Systems Inc, Westlake, Ohio.

g.

Trek Sensititre, Trek Diagnostic Systems Inc, Westlake, Ohio.

h.

WinNONLIN, version 5.2, Pharsight Corp, Mountain View, Calif.

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Appendix

Summary of values of MICs of ceftiofur that have been reported in other studies10,11,23 for bacteria isolated from various samples obtained from birds.

Bacterial isolateSourceMIC50 (μg/mL)MIC90(μg/mL)MIC range (μg/mL)
Acinetobacter IwoffiDuckNDND8.0 to 16.0
Aeromonas sppDuckNDND0.13
Escherichia coliTurkeyND0.5–2.00.12 to 16.0
E coliChickenND0.5–4.0< 0.03 to 16.0
E coliDuck0.51.0≤ 0.03 to 32.0
Citrobacter sppTurkey1.032.00.5 to > 32.0
Enterobacter sppTurkey0.5> 32.00.13 to > 32.0
Enterococcus faecalisDuck8.0ND4.0 to > 32.0
Klebsiella sppTurkey0.51.00.13 to 2.0
Pasturella sppDuckNDND≤ 0.03
Proteus sppTurkey0.131.00.06 to 32.0
Proteus mirabilisDuck0.060.50.06 to > 32.0
Pseudomonas sppDuckNDND32.0
Pseudomonas sppTurkey32.0> 32.00.06 to > 32.0
Salmonella sppTurkey1.01.00.5 to 1.0
Salmonella sppDuck1.01.00.5 to 1.0
Staphylococcus spp (coagulase positive)Turkey1.02.01.0 to 2.0
Staphylococcus spp (coagulase negative)Turkey2.08.00.13– > 32.0
Staphylococcus aureusDuck1.02.00.5 to 2.0
Staphylococcus intermediusDuck0.251.00.13 to 2.0
Staphylococcus xylosusDuckNDND2.0 to 4.0
Streptococcus spp and Enterococcus sppTurkey> 32.0> 32.0≤ 0.03 to > 32.0
Vibrio choleraDuckNDND≤ 0.03

Source is the type of bird from which samples for bacterial culture and determination of MICs were obtained.

ND = Not determined.

Contributor Notes

Dr. Padilla's present address is St. Louis Zoo, 1 Government Dr, St Louis, MO 63110.

Supported by the Smithsonian National Zoological Park Departments of Animal Health and Animal Programs and by the Smithsonian Conservation and Biology Institute.

Address correspondence to Dr. Hope (hopek@si.edu).