Administration Of Ceftiofur Crystalline Free Acid Research Articles

Pharmacokinetic parameters for single- and multi-dose regimens for subcutaneous administration of a high-dose ceftiofur crystalline-free acid to neonatal foals.

The objective of this study was to determine the pharmacokinetics of single- and multi-dose ceftiofur crystalline-free acid (CCFA) administered subcutaneously at a dose of 13.2mg/kg to 12 neonatal foals 1-3days of age. Six foals received a single subcutaneous dose, while 6 additional foals received 4 doses of CCFA at 48-h intervals. Blood samples were collected at pre-determined times following drug administration, and plasma concentrations of ceftiofur free acid equivalents (CFAE) were measured using high-performance liquid chromatography. Following single-dose administration of CCFA, the mean±standard deviation maximum observed plasma concentration was 3.1±0.6μg/mL and observed time to maximal plasma concentration was 14.0±4.9h. Following multi-dose administration of CCFA, the mean±standard deviation times above CFAE concentrations of ≥0.5μg/mL and ≥2.0μg/mL were 192.95±15.86h and 78.80±15.31h, respectively. The mean±standard deviation area under the concentration vs time curve (AUC0→∝ ) was 246.2±30.7h×μg/mL and 172.7±27.14h×μg/mL following single- and multi-dose CCFA administrations, respectively. Subcutaneous administration of CCFA at 13.2mg/kg in neonatal foals was clinically well- tolerated and resulted in plasma concentrations sufficient for the treatment of most bacterial pathogens associated with neonatal foal septicemia. Multi-dose administration of four doses at dosing interval of 48h between treatments maintains appropriate therapeutic concentrations in neonatal foals.

Endometrial tissue and blood plasma concentration of ceftiofur and metabolites following intramuscular administration of ceftiofur crystalline free acid to mares

Systemic administration of ceftiofur crystalline free acid (CCFA) may be a potential treatment for infectious endometritis caused by Streptococcus equi ssp. zooepidemicus (S. zooepidemicus) and other susceptible bacterial organisms in the mare. To determine if i.m. administration of CCFA at the label dose will exceed the minimum inhibitory concentration (MIC) of S. zooepidemicus in the endometrium following single administration and multiple administration protocols. Experimental pharmacokinetic study. Three mares (Group 1) were administered a single i.m. dose of CCFA (6.6 mg/kg bwt) and blood and endometrial biopsies were collected at selected intervals for 144 h. Six additional mares (Groups 2 and 3) received CCFA at times 0, 4, 11 and 18 days, and were sampled at predetermined times for 25 or 49 days, respectively. Plasma and tissue samples were analysed by high-pressure liquid chromatography with tandem mass spectrometry for desfuroylceftiofur acetamide concentration, which is a direct measure of all ceftofur and ceftiofur metabolites in the sample. A mean plasma desfuroylceftiofur acetamide concentration of 0.367 ± 0.0162 μg/ml (mean ± s.e.) was detected at 96 h following administration. Mean endometrial tissue concentration was 0.510 ± 0.0418 μg/g at 96 h and exceeded the MIC for S. zooepidemicus (0.25 μg/ml) throughout the 144 h monitoring period for Group 1. Mares in Groups 2 and 3, given multiple doses of CCFA, maintained plasma concentrations above the MIC for S. zooepidemicus for 25 days. Endometrial tissue levels remained above the MIC at most data collection points for 25 days. Ceftiofur crystalline free acid reaches appropriate endometrial tissue values to exceed the MIC of S. zooepidemicus, a common cause of bacterial endometritis. Therefore, CCFA should be effective in the treatment of equine bacterial endometritis caused by S. zooepidemicus and other susceptible bacterial pathogens in the mare.

Plasma and pulmonary pharmacokinetics of desfuroylceftiofur acetamide after weekly administration of ceftiofur crystalline free acid to adult horses

Current labelling for the use of ceftiofur crystalline free acid (CCFA) in horses states that 2 i.m. doses must be administered 4 days apart to provide 10 days of therapeutic coverage. A 10 day treatment regimen is not sufficient for the long-term treatment of horses with severe lung consolidation or pleuropneumonia. There are currently no data to guide an appropriate dosing interval when a longer treatment regimen is warranted. To determine steady-state plasma and pulmonary epithelial lining fluid (PELF) concentrations of desfuroylceftiofur acetamide (DCA) after weekly i.m. administration of CCFA to adult horses. Experimental study. Seven adult horses received i.m. CCFA at a dose of 6.6 mg/kg bwt on Day 0, Day 4 and every 7 days thereafter for 3 additional doses. Concentrations of DCA in plasma and PELF were measured at various time intervals. After weekly i.m. administration, the mean (± s.d.) steady-state peak DCA concentration in plasma (2.87 ± 1.50 μg/ml) was significantly higher than that in PELF (0.84 ± 0.53 μg/ml). Mean terminal half-lives in plasma (77.5 ± 17.5 h) and PELF (92.8 ± 59.0 h) were not significantly different. Concentrations of DCA in plasma and PELF remained in the therapeutic range for the entire dosing interval. After the initial 2-dose regimen 4 days apart, weekly i.m. administration of CCFA was well tolerated and resulted in plasma and PELF DCA concentrations above the minimal inhibitory concentration that inhibits growth of at least 90% of common lower respiratory tract pathogens of horses. Weekly administration of CCFA would appear appropriate when a treatment regimen longer than 10 days is warranted based on clinical signs and disease severity.

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

To determine the pharmacokinetic properties of 1 IM injection of ceftiofur crystalline-free acid (CCFA) in American black ducks (Anas rubripes). 20 adult American black ducks (6 in a preliminary experiment and 14 in a primary experiment). 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. 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. 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.

Pharmacokinetics of ceftiofur crystalline free acid after single and multiple subcutaneous administrations in healthy alpacas (Vicugna pacos)

Six adult male alpacas received one subcutaneous administration of ceftiofur crystalline free acid (CCFA) at a dosage of 6.6 mg/kg. After a washout period, the same alpacas received three subcutaneous doses of 6.6 mg/kg CCFA at 5-day intervals. Blood samples collected from the jugular vein before and at multiple time points after each CCFA administration were assayed for ceftiofur- and desfuroylceftiofur-related metabolite concentrations using high-performance liquid chromatography. Pharmacokinetic disposition of CCFA was analyzed by a noncompartmental approach. Mean pharmacokinetic parameters (± SD) following single-dose administration of CCFA were Cmax (2.7 ± 0.9 μg/mL); Tmax (36 ± 0 h); area under the curve AUC0→∞ (199.2 ± 42.1 μg·h/mL); terminal phase rate constant λz (0.02 ± 0.003/h); and terminal phase rate constant half-life t1/2λz (44.7 h; harmonic). Mean terminal pharmacokinetic parameters (±SD) following three administrations of CCFA were Cmax (2.0 ± 0.4 μg/mL); Tmax (17.3 ± 16.3 h); AUC0→∞ (216.8 ± 84.5 μg·h/mL); λz (0.01 ± 0.003/h); and t1/2λz (65.9 h; harmonic). The terminal phase rate constant and the Tmax were significantly different between single and multiple administrations. Local reactions were noted in two alpacas following multiple CCFA administrations.

Effect of intrauterine dextrose or antibiotic therapy on reproductive performance of lactating dairy cows diagnosed with clinical endometritis

The objectives of this study were to assess the responses to treatments (clinical cure and cow survival 14d posttherapy) of cows with clinical endometritis (CE) that received intrauterine infusion of a hypertonic solution of 50% dextrose (DEX) or subcutaneous ceftiofur crystalline free acid (CCFA) and subsequent pregnancy per artificial insemination (P/AI) in cows with CE compared with cows without CE. Cows (n=760) from 2 dairy herds were screened for CE using vaginoscopy and measurement of cervix diameters [exam 1; 26±3d in milk (DIM)]. Cows with vaginal discharge scores of 2 or 3 (scale 0–3) were stratified by parity and randomly allocated into 1 of 3 treatment groups: (1) intrauterine infusion (∼200mL) of 50% DEX solution (n=79); (2) 6.6mg/kg single-dose of subcutaneous administration of CCFA (n=75); or (3) untreated control animals (CON, n=83). Fourteen days posttherapy (at 40±3 DIM), cows with CE were re-examined (exam 2; 40±3 DIM) to assess the response to treatments. All cows were presynchronized with 2 injections of PGF2α given 14d apart (starting at 26±3 DIM) followed by Ovsynch (OV; GnRH–7 d–PGF–56 h–GnRH 16 h–timed-AI) 12 to 14d later. Cows displaying signs of standing estrus any time during the protocol were inseminated, whereas the remaining cows were subjected to timed AI 16h after the second GnRH of OV. Pregnancy diagnosis was performed via transrectal ultrasonography at 39±3d post-AI followed by pregnancy reconfirmation 30d after the first pregnancy diagnosis. Uterine swabs revealed that Arcanobacterium pyogenes and Escherichia coli were the most predominant bacteria isolated at the time of treatments. Mortality within 14d posttherapy was not different among treatment groups. Cows with CE had greater cervical diameter at exam 1 and decreased P/AI compared with cows without CE. Treatment with CCFA or DEX increased the proportion of cows with clear vaginal discharge (score 0; clinical cure) 14d posttherapy compared with CON cows. Pregnancy per AI from DEX (29.8±4%) cows tended to differ from that of CON (21.1±4%) or CCFA cows (19.7±4%), but it resulted in similar P/AI as those cows without CE (39.1±2%). The use of intrauterine DEX alone or as an adjunct of antibiotic therapy for the treatment of CE needs further investigation.

Quantification of theBlaCMY-2in Feces from Beef Feedlot Cattle Administered Three Different Doses of Ceftiofur in a Longitudinal Controlled Field Trial

The objective of this longitudinal controlled trial was to quantitatively compare carriage of a gene encoding for ceftiofur-resistance (bla(CMY-2)), standardized to a reference gene (16SrRNA), among total community DNA extracted from fecal samples collected from cattle treated with three different dose regimens of ceftiofur crystalline-free acid (CCFA) versus those untreated (controls). Sixty-one steers were assigned to three treatment regimens and housed in six pens. In each pen, five steers were treated and five were controls (one of the pens had six controls). CCFA administration was as follows: two-thirds dose treatment (4.4 mg/kg, on day 0), single-dose treatment (6.6 mg/kg, on day 0), and three-dose treatment (6.6 mg/kg, on days 0, 6, and 13). Fecal samples were collected on days 0, 3, 7, 10, 14, 18, 21, and 28. The gene copy numbers/gram of feces for bla(CMY-2) and 16SrRNA were determined in total community DNA samples using quantitative real-time PCR. The relationships between the quantities of standardized bla(CMY-2), nonstandardized bla(CMY-2), and nonstandardized 16SrRNA, and the explanatory variables (treatment, time, and treatment x time) were assessed using repeated measures mixed models. There were significant differences in each of the three models with respect to each explanatory variable. Overall, while steers administered three doses and two-thirds dose of CCFA had significantly higher quantities of nonstandardized bla(CMY-2) than controls, the standardized values were lower. The administration of CCFA in feedlot cattle may provide selection pressure favoring higher levels of bla(CMY-2) carriage, but this may also lead to concurrent reductions in the total bacterial population (as reflected by lowered 16SrRNA) during the treatment period.

Changes in antimicrobial susceptibility in a population of Escherichia coli isolated from feedlot cattle administered ceftiofur crystalline-free acid

To determine effects of administration of ceftiofur crystalline-free acid (CCFA) on antimicrobial susceptibility of Escherichia coli in feedlot cattle. 61 feedlot steers. A cohort study was conducted. Steers were housed in pens (5 pens with 10 steers and 1 pen with 11 steers). Five steers in each pen were administered CCFA, and 5 served as control steers (1 pen had 6 control steers). The CCFA administration included a single-dose regimen (6.6 mg/kg, SC, on day 0), two-thirds-dose regimen (4.4 mg/kg, SC, on day 0), and 3-dose regimen (6.6 mg/kg, SC, on days 0, 6, and 13). Fecal samples were collected on days 0, 2, 6, 9, 13, 16, 20, and 28. Fecal samples were collected immediately before CCFA administration. Minimum inhibitory concentrations of 15 antimicrobials were determined for 3 E coli isolates/fecal sample. Escherichia coli were enumerated by use of direct-plating techniques. Resistance to 1 or more antimicrobials was detected in 986 of 1,441 (68.4%) isolates recovered. Administration of CCFA was associated with a transient increase in the population of ceftiofur-resistant isolates. Susceptibility returned to day 0 values (ie, samples collected immediately before CCFA administration) approximately 2 weeks after completion of CCFA administration. Agreement between ceftiofur resistance and co-resistance to ampicillin, chloramphenicol, streptomycin, sulfisoxazole, and tetracycline was almost perfect (kappa 0.97). We did not detect variation in susceptibility of E coli recovered from commingled control steers. Administration of CCFA provided selection pressure that favored transient expansion of multiple-resistant variants.