Value of Single-Dose Therapy June 2006 The value of single-dose extended therapy with Sterile Suspension Timothy Baker, BS; Gloria Basse, MBA; David Galligan, VMD, MBA; Christopher Hollenbeak, PhD; Michael Layfield, BS; Roger Saltman, DVM, MBA; Sonja Sorensen, MPH Key Points Compliance in U.S. dairies is one of the least considered aspects of successful antibiotic therapy. The impact and cost of non-compliance encompasses management, economic, and animal health factors. Economic modeling now enables analysis of the financial impact of antibiotic treatment compliance. Proven effectiveness for bovine respiratory disease (BRD) organisms shows a single dose of (ceftiofur crystalline free acid) Sterile Suspension provides extended therapy in cattle, now available for lactating dairy cattle. administered as a single treatment according to label instructions requires no milk discard. Introduction In well-controlled clinical trials, ideal (100%) compliance with antibiotic regimens is inherent in clinical study protocols. In daily practice, however, compliance is often overlooked as being an essential aspect of successful antibiotic therapy. Strong and consistent evidence links treatment failure with noncompliance in human medicine, 1,2,3, but few studies of compliance exist in the veterinary literature. The impact of non-compliance includes treatment failure, suboptimal therapy, additional expense, and increased risk of side effects. 5 Economic modeling now allows dairy producers to analyze the costs and benefits of improved compliance. What is Compliance? The simplest definition of compliance is administering medication as directed the prescribed dose at the prescribed time(s) for the prescribed duration. 5 Full compliance encompasses numerous factors related to the patient, the product, and the person administering treatment. For example, compliance in dairies includes keeping accurate records and observing milk discard and pre-slaughter withdrawals as well as administering drugs correctly. umerous other management, economic, and animal health factors also influence compliance in dairy operations.
Mapping the flow of treatment events and their consequences (Figure 1) serves as the basis for assessing the economic impact of compliance with treatment. The cost of antibiotic therapy is driven by the cost of initial treatment, subsequent therapy, and losses due to treatment failure, such as mortality or culling, discarded milk, decreased milk production, weight loss, and impaired reproductive health. In the flow of treatment events, the consequences of poor compliance include decreased symptom resolution and increased downstream costs. While full compliance increases the probability of complete symptom resolution, it also increases initial drug costs. Economic modeling offers producers the opportunity to determine if this increase is offset by the cost and consequences of non-compliance (lack of symptom resolution). Figure 1. Treatment Events and Their Consequences 2 Table 1. Key Variables for Economic Modeling Simple Treatment Comparison Model of cattle in herd and infection rate Average weight, dosage and length of treatment Acquisition cost of medication Time to administer medication, and administrator hourly wages Length of milk discard, average daily production, price of milk Current State of Compliance Few studies have examined compliance with antibiotic therapy for cattle. A recent survey of antibiotic use in 113 dairy herds also included a review of individual animal health records in 33 dairies. 6 Half of the 113 farms kept written records of antibiotic treatment. Twenty-one percent of the producers had written plans for treating sick animals, and 32% always sought a veterinarian s advice before administering antibiotics. nly 2% of the dairy producers said they always completed the course of antibiotic treatment. Earlier surveys of dairy producers identified poor record-keeping, 7 inadequate knowledge of drug withdrawal periods, 7 and reliance on personal experience for antibiotic choice and dosage 8 as factors leading to inappropriate antibiotic use and violative drug residues. Compliance Model (Additional Variables) Symptom resolution rates ( Cure rates ) of days of treatment typically completed Lost milk production Culling and death rates, retreatment rate Replacement cost, salvage value, cost per day open In human medicine, improved compliance has been associated with infrequent doses, 9 short-term therapy, convenient administration, and lack of side effects. 10 These factors might also be expected to improve compliance in veterinary medicine. Assuring full compliance aligns with judicious use principles for antimicrobial therapy, 11 and could help avoid suboptimal response, as well as limit the time and expense of treating recurrent infections. 5 Quantifying the Value of Compliance Two economic models, developed by scientists at United BioSource Corp. and the University of Pennsylvania, and available from Pfizer, now enable financial analysis of increased compliance with antibiotic therapy. Economic modeling facilitates analyses of complex interactions based on selected variables and their associated costs. Developed from the perspective of a dairy producer, the new models analyze the year-long financial impact of treatment for BRD by comparing (ceftiofur sodium) Sterile Powder, RTU (ceftiofur hydrochloride) Sterile Suspension, Polyflex (ampicillin trihydrate for injectable suspension, veterinary), Liquamycin LA-200 (oxytetracycline), or penicillin G procaine regimens for lactating cows. The computerized spreadsheet allows users to customize the major variables affecting compliance. The year-long perspective captures one milk-production cycle. The Simple Treatment Comparison Model considers the cost of labeled drug use, assuming equal efficacy and perfect compliance for all of the drugs. The Compliance Model estimates the economic impact of partial/noncompliance with labeled antibiotic treatment. Key variables for the two models are listed in Table 1. The Simple Treatment Comparison Model allows a straightforward comparison of different economic outcomes from different treatment regimens. The time necessary to identify and restrain a cow for treatment, give the injection, and record the treatment is included in this comparison. A default value of 5.63 minutes to give an injection is included in the model. 12 This example assumes a 500 cow herd of 1,350 lbs avg. body weight animals with a 5% infection rate over a milking cycle. ther assumptions include: 1. Herd average of 80 lbs of milk/cow/day 2. Labor cost of $10/hr. 3. 30% of these infected animals require a veterinary visit that costs $75 per visit. Label milk discard times (when used according to the label) Figure 2. Simple Treatment Cost Comparison Using this Simple Treatment Comparison Model, a single-dose regimen of can be compared to the use of penicillin G procaine or RTU at appropriate (based on label) dosage and duration of treatment (Table 2). The magnitude of these relative costs are graphically compared in Figure 2. A more comprehensive approach for comparing the relative costs of these different treatment strategies utilizes the Compliance Model. As indicated in Table 1, this model includes assumptions 0 500 1000 1500 2000 2500 Table 2. Simple Treatment Comparison Model (25 Treated Cows) Cost Component * 1 Procaine 2 RTU 3 about Maximum Symptom Resolution if treatments are given according to label ( full compliance ) or if labels are not followed ( non-compliance in dosage or duration of treatment). Table 3 shows the results of this Compliance Model for comparing the relative costs of the three treatments when full compliance to label recommendations is used. In addition to the assumptions used for the Simple Treatment Comparison Model, further assumptions include: 1. 85% Maximum Symptom Resolution Rates for all 3 treatments when full compliance is used 2. 20% Spontaneous Symptom Resolution Rate 3. Price of milk = $13.00 per cwt.. Cost of feed to produce 1 cwt. of milk = $.00 5. Avg. cost of a replacement heifer = $1600 6. Avg. value of a cull cow = $700 7. f the cows that do not resolve their symptoms, 15% will die and 60% will be culled (25% will remain in the herd with subnormal production) Procaine RTU Drug acquisition $7 $109 $8 -$635 $99 Drug administration $23 $70 $70 $7 $7 Milk discarded $0 $1,0 $0 $1,0 $0 Veterinary services $563 $563 $563 $0 $0 Total Cost $1,330 $2,182 $1,76 $852 $16 * Costs rounded to nearest whole dollar. 1 Assumes 1 dose, 1.5 ml/100 lbs, zero milk discard. 2 Assumes 3 daily doses, dose estimated from common farm practice, 72 hr. milk discard. 3 Assumes 3 daily doses, 1.5 ml/100 lbs, zero milk discard. Table 3. Compliance Model (25 Treated Cows) Cost Component* 1 Procaine 2 RTU 3 Procaine RTU Initial drug acquisition $7 $109 $8 -$635 $99 Initial drug administration $23 $70 $70 $7 $7 Retreatment costs (acq. and admin.) $58 $13 $69 -$ $11 Milk production lost to sickness (beyond what is discarded) $172 $25 $152 -$17 -$20 Milk discard costs $0 $1,57 $0 $1,57 $0 Reproduction costs $37 $37 $37 $0 $0 Replacement of culled cows $1,16 $1,16 $1,16 $0 $0 Replacement of dead cows $518 $518 $518 $0 $0 Veterinary services $563 $563 $563 $0 $0 Total Cost $3,279 $,073 $3,17 $795 $137 * Costs rounded to nearest whole dollar. 1 Assumes 1 dose, 1.5 ml/100 lbs, zero milk discard. 2 Assumes 3 daily doses, dose estimated from common farm practice, 72 hr. milk discard. 3 Assumes 3 daily doses, 1.5 ml/100 lbs, zero milk discard. 3
This analysis shows that the expected total costs were: Excede = $3,279 ($131/cow), penicillin G procaine = $,073 ($163/cow), and Excenel RTU = $3,17 ($137/cow). Initial drug acquisition and administration and milk discard (no milk discard) comprise about 23 to 27% of the total costs while costs due to retreatment, milk production loss from sickness, the impact on reproduction, the cost of veterinary services, and the replacement of culled and dead cows comprise the remainder for both Excede and Excenel RTU. For penicillin G procaine, drug acquisition costs are lower, but milk discard costs and drug administration costs are higher (compared to Excede). Initial drug acquisition and administration and milk discard comprise about 3% of the total costs while costs due to retreatment, milk production loss from infection (beyond what is discarded), the impact on reproduction, the cost of veterinary services, and the replacement of culled and dead cows constitute the remainder for penicillin G procaine. Quantifying the Cost of on-compliance The cost of non-compliance is the extra cost in retreatment (with concurrent administration and milk discard costs), increase in milk production loss from cows not curing, decreased reproductive success, and dead and cull animals that occur when Symptom Resolution Rates ( Cure rates ) decrease. If penicillin G procaine or Excenel RTU are administered for 2 days rather than the recommended full 3-day course of treatment, symptom resolution rates drop from 85% to 63% (Adjusted Resolution Rates). Although drug acquisition and administration and first treatment milk discard costs decrease, the extra costs of retreatment and treatment failures can be significant. In this example, compared to the full compliance course of treatment, non-compliant treatment (2 days of treatment versus 3 days of treatment for the daily dose therapies) created total costs of $7,86 for penicillin G procaine and $6,90 for Excenel RTU (Table ). Even more important economically, comparing these noncompliant treatments with the full compliance course of treatment achieved with a single dose of Excede, the use of Excede decreases the cost of treatment by $,206 compared to penicillin G procaine and $3,210 compared to Excenel RTU. Table. Cost of on-compliance Using Compliance Model (25 Treated Cows) Cost Component* Procaine full compliance 1 day less compliant Extra Cost Compared to Conclusions Proven effectiveness for BRD organisms shows a single dose of provides extended therapy in lactating dairy cattle with no milk discard. Dairy producers can now estimate the economic impact of partial/non-compliance with labeled antibiotic treatment using computerized models. These models allow dairy producers to evaluate the economic implications of improved compliance by selecting variables that reflect their own operations. As with all drugs, the use of Sterile Suspension is contraindicated in animals previously found to be hypersensitive Though safe in cattle when properly given, inadvertent intra-arterial injection in the ear is possible and is fatal. has a pre-slaughter withdrawal time of 13 days. As with all drugs, AXCEL should not be used in animals found to be hypersensitive to the product. AXCEL has a pre-slaughter withdrawal time of days in cattle. As with all drugs, RTU should not be used in animals found to be hypersensitive to the product. RTU has a pre-slaughter withdrawal time of 3 days in cattle. RTU full compliance 1 day less compliant, and AXCEL are registered trademarks of Pharmacia and Upjohn Company LLC, a division of Pfizer Inc. LA-200 is a registered trademark of Pfizer Inc. The Beef Friendly logo is a trademark of Pfizer Inc. Polyflex is a registered trademark of Fort Dodge Animal Health, a division of Wyeth. 2006 Pfizer Inc. All rights reserved. Extra Cost Compared to Initial drug acquisition $7 $109 $73 -$671 $8 $562 -$182 Initial drug administration $23 $70 $7 $23 $70 $7 $23 Retreatment costs $58 $13 $22 -$36 $69 $112 $5 Milk production lost to sickness (beyond what is discarded) $172 $25 $72 -$100 $152 $212 $0 Milk discard costs $0 $1,57 $1,715 $1,715 $0 $0 $0 Reproduction costs $37 $37 $108 $71 $37 $108 $71 Replacement of culled cows $1,16 $1,16 $3,383 $2,218 $1,16 $3,383 $2,218 Replacement of dead cows $518 $518 $1,503 $986 $518 $1,503 $986 Veterinary services $563 $563 $563 $0 $563 $563 $0 Total Cost $3,279 $,073 $7,86 $,206 $3,17 $6,90 $3,210 * Costs rounded to nearest whole dollar. References 1 Anastasio GD, Little JM, Robinson MD, et al. Impact of compliance and side effects on the clinical outcome of patients treated with oral erythromycin. Pharmacotherapy 199;1(2):229-23. 2 Pakistan MASCT pneumonia study group. Clinical efficacy of 3 days versus 5 days of oral amoxicillin for treatment of childhood pneumonia: a multicentre double-blind trial. Lancet 2002;360(9336):835-81. 3 Agarwal G, Awasthi S, Kabra SK, et al. Three day versus five day treatment with amoxicillin for non-severe pneumonia in young children: a multicentre randomised controlled trial. BMJ 200;328(73):791. Jordan WC. Doxycycline vs. tetracycline in the treatment of men with gonorrhea: the compliance factor. Sex Transm Dis 1981;8(suppl):105-109. 5 Aucoin DP. Antimicrobial therapy: the factors and costs of non-compliance. Compend Contin Educ Pract Vet 2000;22(3A, suppl):62-65. 6 Sawant AA, Sordillo LM, Jayarao BM. A survey on antibiotic usage in dairy herds in Pennsylvania. J Dairy Sci 2005;88:2991-2999. 7 Kaneene JB, Ahl AS. Drug residues in dairy cattle industry: epidemiological evaluation of factors influencing their occurrence. J Dairy Sci 1987;70:2176-2180. 8 Zwald AG, Ruegg PL, Kaneene JB, et al. Management practices and reported antimicrobial usage on conventional and organic dairy farms. J Dairy Sci 200;87:191-201. 9 Greenberg R. verview of patient compliance with medication dosing: a literature review. Clin Ther 198;6:592-599. 10 Kardas P. Patient compliance with antibiotic treatment for respiratory tract infections. J Antimicrob Chemother 2002;9:897-903. 11 Judicious Use Principles. Available at: www. fda.gov/cvm/fsi/judprin.htm. Accessed on: ov. 22, 2005. 12 Galligan D, Ferguson J. Unpublished study. Univ. of Penn, 2006. Excenel RTU brand of ceftiofur hydrochloride sterile suspension For intramuscular and subcutaneous use in cattle and intramuscular use in swine. This product may be used in lactating dairy cattle. CAUTI: Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian. RTU Sterile Suspension is a ready to use formulation that contains the hydrochloride salt of ceftiofur, which is a broad spectrum cephalosporin antibiotic. Each ml of this ready-to-use sterile suspension contains ceftiofur hydrochloride equivalent to 50 mg ceftiofur, 0.50 mg phospholipon, 1.5 mg sorbitan monooleate, 2.25 mg sterile water for injection, and cottonseed oil. Structure: Figure 1. S H 2 C C H CH 3 S CH S C 2 CH HCl Chemical ame of Ceftiofur Hydrochloride: 5-Thia-1-azabicyclo[,2.0]oct-2-ene-2-carboxylic acid, 7-[[(2- amino--thiazolyl)(methoxyimino)-acetyl]amino]-3-[[(2-furanylcarbonyl)thio]methyl]-8-oxo-,hydrochloride salt [6R-[6α,7β(Z)]]- : RTU Sterile Suspension is indicated for treatment/control : RTU Sterile Suspension is indicated for treatment of the following bacterial diseases: Bovine respiratory disease (BRD, shipping fever, pneumonia) associated with Mannheimia haemolytica, Pasteurella multocida and Histophilus somni. Acute bovine interdigital necrobacillosis (foot rot, pododermatitis) associated with Fusobacterium necrophorum and Bacteroides melaninogenicus. Acute metritis (0 to 1 days post-partum) associated with bacterial organisms susceptible to ceftiofur. Shake well before using. : Administer intramuscularly at a dosage of 1.36 to 2.27 mg ceftiofur equivalents/lb (3.0 to 5.0 mg/kg) BW (1 ml of sterile suspension per 22 to 37 lb BW). Treatment should be repeated at 2 h intervals for a total of three consecutive days. : For bovine respiratory disease and acute bovine interdigital necrobacillosis: administer by intramuscular or subcutaneous administration at the dosage of 0.5 to 1.0 mg ceftiofur equivalents/lb (1.1 to 2.2 mg/kg) BW (1 to 2 ml sterile suspension per 100 lb BW). Administer daily at 2 h intervals for a total of three consecutive days. Additional treatments may be administered on Days and 5 for animals which do not show a satisfactory response (not recovered) after the initial three treatments. In addition, for BRD only, administer intramuscularly or subcutaneously 1.0 mg ceftiofur equivalents/lb (2.2 mg/kg) BW every other day on Days 1 and 3 (8 h interval). Do not inject more than 15 ml per injection site. Selection of dosage level (0.5 to 1.0 mg/lb) and regimen/duration (daily or every other day for BRD only) should be based on an assessment of the severity of disease, pathogen susceptibility and clinical response. For acute post-partum metritis: administer by intramuscular or subcutaneous administration at the dosage of 1.0 mg ceftiofur equivalents/lb (2.2 mg/kg) BW (2 ml sterile suspension per 100 lb BW). Administer at 2 h intervals for five consecutive days. Do not inject more than 15 ml per injection site. As with all drugs, the use of RTU Sterile Suspension is contraindicated in animals previously found to be hypersensitive Penicillins and cephalosporins can cause allergic reactions in sensitized individuals. Topical exposures to such antimicrobials, including ceftiofur, may elicit mild to severe allergic reactions in some individuals. Repeated or prolonged exposure may lead to sensitization. Avoid direct contact of the product with the skin, eyes, mouth, and clothing. Persons with a known hypersensitivity to penicillin or cephalosporins should avoid exposure to this product. In case of accidental eye exposure, flush with water for 15 minutes. In case of accidental skin exposure, wash with soap and water. Remove contaminated clothing. If allergic reaction occurs (e.g., skin rash, hives, difficult breathing), seek medical attention. The material safety data sheet contains more detailed occupational safety information. To obtain a material safety data sheet (MSDS) please call 1-800-733-5500. To report any adverse event please call 1-800-366-5288. RESIDUE : : When used according to label indications, dosage, and route of administration, treated swine must not be slaughtered for days following the last treatment. Use of dosages in excess of those indicated or by unapproved routes of administration may result in illegal residues in edible tissues. : When used according to label indications, dosage and route of administration, treated cattle must not be slaughtered for 3 days following indications, dosage and route of administration, a milk discard time is not required. Uses of dosages routes of administration, such as intramammary, may result in illegal residues in edible tissues and/or milk. A withdrawal period has not been established in pre-ruminating calves. Do not use in calves to be processed for veal. The effects of ceftiofur on cattle and swine reproductive performance, pregnancy, and lactation have not been determined. : Areas of discoloration associated with the injection site at time periods of 11 days or less may result in trim-out of edible The safety of ceftiofur has not been demonstrated for pregnant swine or swine intended for breeding. : Following intramuscular or subcutaneous administration in the neck, areas of discoloration at the site may persist beyond 11 days resulting in trim loss of edible Following intramuscular administration in the rear leg, areas of discoloration at the injection site may persist beyond 28 days resulting in trim loss of edible CLIICAL PHARMACLGY : Ceftiofur administered as either ceftiofur sodium or ceftiofur hydrochloride is metabolized rapidly to desfuroylceftiofur, the primary metabolite. Administration of ceftiofur to swine as either the sodium or hydrochloride salt provides effective concentrations of ceftiofur and desfuroylceftiofur metabolites in plasma above the MIC90 for the labeled pathogens: Actinobacillus pleuropneumoniae, Pasteurella multocida, Streptococcus suis and Salmonella choleraesuis for the 2 hour (h) period between the dosing intervals. The MIC90 for Salmonella choleraesuis (1.0 µg/ml) is higher than the other three pathogens and plasma concentrations exceed this value for the entire dosing interval only after the 2.27 mg/lb (5.0 mg/kg) body weight (BW) dose. Comparative Bioavailability Summary Comparable plasma concentrations of ceftiofur administered as ceftiofur hydrochloride sterile suspension ( RTU Sterile Suspension) or ceftiofur sodium sterile solution (AXCEL Sterile Powder) were demonstrated after intramuscular administration of 2.27 mg ceftiofur equivalents/lb (5.0 mg/kg) BW. See Table 1 and Figure 2. Table 1. plasma concentrations and related parameters* of ceftiofur and desfuroylceftiofur metabolites after RTU Sterile Suspension (ceftiofur hydrochloride sterile suspension, 50 mg/ml) or AXCEL Sterile Powder (ceftiofur sodium, 50 mg/ml) administered at 2.27 mg/lb ceftiofur equivalents/lb (5.0 mg/kg) BW IM. Ceftiofur hydrochloride Ceftiofur sodium Cmax µg/ml: 26.1 ± 5.02 29.2 ± 5.01 tmax h: 0.66 2.0 (range) 0.33 2.0 (range) AUC0-LQ µg h/ml: 321 ± 50.2 31 ± 55.1 t1/2 h: 16.2 ± 1.55 1.0 ± 1.23 C2 h µg/ml: 3.5 ± 0.31 3.53 ± 0.791 C72 h µg/ml: 0.518 ± 0.126 0.07 ± 0.0675 t>0.2 h: 93.8 ± 7.98 85.0 ± 7.71 Definitions: Cmax maximum plasma concentration in µg/ml. tmax the time after initial injection to when Cmax occurs, measured in hours. AUC0-LQ the area under the plasma concentration vs. time curve from time of injection to the limit of quantitation of the assay (0.15 µg/ml). t1/2 the plasma half life of the drug in hours. C2 h the concentration of drug at 2 h after administration. C72 h the concentration of drug at 72 h after administration. t>0.2 the time (in hours) plasma concentrations remain above 0.2 µg/ml. * Due to significant period effect and significant sequence effect in this study, data from period 1 only were used to evaluate these parameters. Figure 2. plasma concentrations of ceftiofur and desfuroylceftiofur metabolites after RTU Sterile Suspension (ceftiofur hydrochloride sterile suspension, 50 mg/ml) or AXCEL Sterile Powder (ceftiofur sodium, 50 mg/ml) were administered intramuscularly at 2.27 mg ceftiofur equivalents/lb (5.0 mg/kg) BW. Plasma concentration (mcg/ml) 30 28 26 2 22 20 18 16 1 12 10 8 6 2 0 Treatment Ceftiofur HCl Ceftiofur a 0 10 20 30 0 50 60 70 80 90 100 Time (hours) Concentrations of total ceftiofur in the lungs of pigs administered radiolabeled ceftiofur at 2.27 or 3.1 mg ceftiofur equivalents/lb (5.0 or 7.5 mg/kg) BW 12 h after the last of three daily intramuscular injections at 2 h intervals averaged 3.66 and 5.63 µg/g. : Ceftiofur administered as either ceftiofur sodium or ceftiofur hydrochloride is metabolized rapidly to desfuroylceftiofur, the primary metabolite. Administration of ceftiofur to cattle as either the sodium or hydrochloride salt provides effective concentrations of ceftiofur and desfuroylceftiofur metabolites in plasma above the MIC90 for the bovine respiratory disease (BRD) label pathogens Mannheimia haemolytica, Pasteurella multocida and Histophilus somni for at least 8 h. The relationship between plasma concentrations of ceftiofur and desfuroylceftiofur metabolites above the MIC90 in plasma and efficacy has not been established for the treatment of bovine interdigital necrobacillosis (foot rot) associated with Fusobacterium Comparative Bioavailability Summary The comparability of plasma concentrations of ceftiofur following administration of ceftiofur hydrochloride sterile suspension ( RTU Sterile Suspension) or ceftiofur sodium sterile solution (AXCEL Sterile Powder) was demonstrated after intramuscular or subcutaneous administration of ceftiofur hydrochloride and intramuscular administration of ceftiofur sodium at 1.0 mg ceftiofur equivalents/lb (2.2 mg/kg) BW. See Table 2 and Figure 3. Table 2. plasma concentrations and related parameters of ceftiofur and desfuroylceftiofur metabolites after RTU Sterile Suspension (ceftiofur hydrochloride sterile suspension, 50 mg/ml) administered intramuscularly or subcutaneously at 1.0 mg ceftiofur equivalents/lb (2.2 mg/kg) BW and AXCEL Sterile Powder (ceftiofur sodium, 50 mg/ml) administered intramuscularly at 1.0 mg ceftiofur equivalents/lb (2.2 mg/kg) BW. Ceftiofur hydrochloride Ceftiofur sodium IM SC IM C max µg/ml 11.0 ± 1.69 8.56 ± 1.89 1. 16.5 tmax h 1 (range) 1 5 (range) 0.33 3.0 t>0.2 h 60.5 ± 6.27 51.0 ± 6.53 50.7 50.9 AUC0-LQ µg h/ml 160 ± 30.7 95. ± 17.8 115 12 t1/2 h 12.0 ± 2.63 11.5 ± 2.57 9.50 11.1 C2 h µg/ml 1.7 ± 0.380 0.926 ± 0.257 0.86 1.16 C8 h µg/ml 0.30 ± 0.110 0.271 ± 0.086 0.250 0.268 Definitions: Cmax maximum concentration of drug in plasma in µg/ml tmax the time after initial injection to when C max occurs, measured in hours t>0.2 the time (in hours) plasma drug concentrations remain above 0.2 µg/ml AUC0-LQ the area under the plasma drug concentration vs. time curve from time of injection to the limit of quantitation of the assay (0.15 µg/ml) t1/2 the drug half life in plasma expressed in hours C2 h the plasma drug concentration 2 h after administration C8 h the plasma drug concentration 8 h after administration Values represent the separate means from each study. Figure 3. plasma concentrations of ceftiofur and desfuroylceftiofur metabolites after RTU Sterile Suspension (ceftiofur hydrochloride sterile suspension, 50 mg/ml) was administered either intramuscularly or subcutaneously or AXCEL Sterile Powder (ceftiofur sodium, 50 mg/ml) was administered intramuscularly at 1.0 mg ceftiofur equivalents/lb (2.2 mg/kg) BW. Plasma concentration (mcg/ml) 1 9-1 Total residues of ceftiofur were measured in the lungs of cattle administered radiolabeled ceftiofur at 1.0 mg ceftiofur equivalents/lb (2.2 mg/kg) BW at 2 h intervals for five consecutive days. Twelve h after the fifth injection of ceftiofur hydrochloride, total ceftiofur concentrations in the lung averaged 1.15 µg/g, while total ceftiofur concentrations in the lung 8 h after the fifth ceftiofur sodium injection averaged 1.18 µg/g. 0 10 20 30 0 50 60 70 80 Time (hours) HCl (IM) Mean a (IM) Mean HCl (SC) Mean 5
7 6 RTU Sterile Suspension is a ready to use formulation that contains the hydrochloride salt of ceftiofur, which is a broad spectrum cephalosporin antibiotic active against gram-positive and gram-negative bacteria including β-lactamase-producing strains. Like other cephalosporins, ceftiofur is bacteriocidal, in vitro, resulting in inhibition : Studies with ceftiofur have demonstrated in vitro and in vivo activity against gram-negative pathogens, including Actinobacillus (Haemophilus) pleuropneumoniae, Pasteurella multocida, Salmonella choleraesuis, and the gram-positive pathogen Streptococcus suis, all of which can be associated with swine bacterial respiratory disease SRD (swine bacterial pneumonia). A summary of the minimum inhibitory concentration (MIC) values from SRD pathogens isolated from clinical field effectiveness studies is found in Table 3. Historic diagnostic laboratory MIC values for SRD pathogens from the US and Canada are found in Table. : Studies with ceftiofur have demonstrated in vitro and in vivo activity against Mannheimia haemolytica, Pasteurella multocida and Histophilus somni, the three major pathogenic bacteria associated with bovine respiratory disease (BRD, pneumonia, shipping fever), and against Fusobacterium necrophorum and Bacteroides melaninogenicus, two of the major pathogenic anaerobic bacteria associated with acute bovine interdigital necrobacillosis (foot rot, pododermatitis). A summary of the MIC values for BRD and foot rot pathogens isolated from clinical field effectiveness studies is found in Table 3. Historic diagnostic MIC values for BRD and foot rot pathogens from the US and Canada are found in Table. Antimicrobial Susceptibility Summaries of MIC data are presented in Tables 3 and. Testing followed Clinical and Laboratory Standards Institute (CLSI) Guidelines. swine and cattle after a single intramuscular injection of 1.36 to 2.27 mg ceftiofur equivalents/lb (3.0 to 5.0 mg/kg) BW (swine) or 0.5 to 1.0 mg ceftiofur equivalents/lb (1.1 to 2.2 mg/kg) BW (cattle) and the MIC and disk (30 µg) diffusion data, the following breakpoints are recommended by CLSI. Zone Diameter MIC Interpretation A report of Susceptible indicates that the pathogen is likely to be inhibited by generally achievable blood levels. A report of Intermediate is a technical buffer zone and isolates falling into this category should be retested. Alternatively the organism may be successfully treated if the infection is in a body site where drug is physiologically concentrated. A report of Resistant indicates that the achievable drug concentrations are unlikely to be inhibitory and other therapy should be selected. Standardized procedures 1 require the use of laboratory control organisms for both standardized diffusion techniques and standardized dilution techniques. The 30 µg ceftiofur sodium disk should give the following zone diameters and the ceftiofur sodium standard reference powder (or disk) should provide the following MIC values for the reference strain. Ceftiofur sodium disks or powder reference standard is appropriate for both ceftiofur salts. Table 5. Acceptable quality control ranges for ceftiofur against ational Committee for Clinical Laboratory Standards recommended American type Culture Collection (ATCC) reference strains name (ATCC o.) Staphylococcus aureus (29213) 0.25 1.0 Staphylococcus aureus (25923) 27 31 Pseudomonas aeruginosa (27853) 1 18 16.0 6.0 Actinobacillus pleuropneumoniae (27090) 3 2** 0.00 0.015*** Histophilus somni (700025) 36 6** 0.0005 0.00*** ** Quality control ranges are applicable only to tests performed by disk diffusion test using a chocolate Mueller-Hinton agar, incubated in 5-7% C2 for 20-2 hours. *** MIC quality control ranges are applicable only to tests perform- ed by broth microdilution procedures using veterinary fastidious medium (VFM). CLIICAL EFFICACY : In addition to demonstrating comparable plasma concentrations, the following clinical efficacy data are provided. A clinical study was conducted to evaluate the efficacy of ceftiofur hydrochloride administered subcutaneously for the treatment of the bacterial component of BRD under natural field conditions. When uniform clinical signs of BRD were present, 60 cattle (111 to 207 kg) were randomly assigned to one of the following treatment groups: negative control or ceftiofur hydrochloride at 0.5 or 1.0 ceftiofur equiva- lents/lb (1.1 or 2.2 mg/kg) BW. Treatments were administered daily for three consecutive days. were evaluated daily and animals that died or were euthanatized were necropsied and the lung lesions scored. n Day 15, all surviving animals were euthan- atized and necropsied and the lung lesions scored. Mortality rates were 65%, 10% and 5% for negative controls, 0.5 mg ceftiofur equivalents/lb and 1.0 mg ceftiofur equivalents/lb, (1.1 or 2.2 mg/kg) BW, respectively. Mortality rates for both ceftiofur hydrochloride treatment groups were lower than for negative controls (P < 0.0001). Rectal temperatures 2 h after third treatment were 10.0 F, 103.1 F and 102.8 F for negative controls, 0.5 mg/lb and 1.0 mg/lb (1.1 or 2.2 mg/kg) BW, respectively. The temperatures for both ceftiofur hydrochloride treatment groups were lower than the negative controls (P 0.05). Ceftiofur hydrochloride administered subcutaneously for three consecutive days at 0.5 or 1.0 mg ceftiofur equivalents/lb (1.1 or 2.2 mg/kg) BW is an effective treatment for the bacterial component of BRD. A three-location clinical field study was conducted to evaluate the efficacy of ceftiofur hydrochloride administered intramuscularly daily for three days or every other day (Days 1 and 3) for the treatment of the bacterial component of naturally occurring BRD. When uniform signs of BRD were present, 360 beef crossbred cattle were randomly assigned to one of the following treatment groups: negative control, ceftiofur sodium at 0.5 mg ceftiofur equivalents/lb (1.1 mg/kg) BW daily for three days, ceftiofur hydrochloride at 1.0 mg ceftiofur equivalents/lb (2.2 mg/ kg) BW daily for three days, or ceftiofur hydrochloride at 1.0 mg ceftiofur equivalents/lb BW on Days 1 and 3 (every other day). All treatments were administered intramuscularly. All ceftiofur treatment groups (hydrochloride and sodium) and treatment regimens (every day and every other day) significantly (P < 0.05) reduced Day rectal temperature as compared to the negative control. Clinical success on Days 10 and 28 and mortality to Day 28 were not different for the ceftiofur groups (hydrochloride and sodium) and treatment regimens (every day and every other day). The results of this study demonstrate that daily and every other day (Days 1 and 3) intramuscular administration of ceftiofur hydrochloride are effective treatment regimens for the bacterial component of BRD. An eight location study was conducted under natural field conditions to evaluate the efficacy of ceftiofur hydrochloride for the treatment of acute post-partum metritis (0 to 1 days post-partum). When clinical signs of acute post-partum metritis (rectal temperature 103 F and fetid vaginal discharge) were observed, 361 lactating dairy cows were assigned randomly to treatment or negative control. were dosed either subcutaneously or intramuscularly, daily for five consecutive days. n days 1, 5 and 9 after the last day of dose administration, cows were evaluated for clinical signs of acute post-partum metritis. A cure was defined as rectal temperature <103 F and lack of fetid discharge. Cure rate for the 1.0 mg ceftiofur equivalents/lb (2.2 mg/kg) BW dose group was significantly improved relative to cure rate of the negative control on Day 9. The results of this study demonstrate that ceftiofur hydrochloride administered daily for five consecutive days at a dose of 1.0 mg ceftiofur equivalents/lb (2.2 mg/kg) BW is an effective treatment for acute postpartum metritis. : Results from a five-day tolerance study in normal feeder pigs indicated that ceftiofur sodium was well tolerated when administered at 57 mg ceftiofur equivalents/lb (125 mg/kg) (more than 25 times the highest recommended daily dosage of 2.27 mg/ lb (5.0 mg/kg)) BW for five consecutive days. Ceftiofur administered intramuscularly to pigs produced no overt adverse signs of toxicity. To determine the safety margin in swine, a safety/ toxicity study was conducted. Five barrows and five gilts per group were administered ceftiofur sodium intramuscularly at 0, 2.27, 6.81 and 11.36 mg ceftiofur equivalents/lb (0, 5, 15, 25 mg/kg) BW for 15 days. This is 0, 1, 3 and 5 times the highest recommended dose of 2.27 mg/lb (5.0 mg/kg) BW/day and 5 times the recommended treatment length of 3 days. There were no adverse systemic effects observed, indicating that ceftiofur has a wide margin of safety when injected intramuscularly into feeder pigs at the highest recommended dose of 2.27 mg ceftiofur equivalents/lb (5.0 mg/kg) BW daily for 3 days or at levels up to 5 times the highest recommended dose for 5 times the recommended length of treatment. A separate study evaluated the injection site tissue tolerance of RTU (ceftiofur hydrochloride) in swine when administered intramuscularly in the neck at 1.36 and 2.27 mg ceftiofur equivalents/lb (3.0 to 5.0 mg/kg) BW. Animals were necropsied at intervals to permit evaluations at 12 h, and 3, 5, 7, 9, 11, 15, 20, and 25 days after last injection. Injection sites were evaluated grossly at necropsy. o apparent changes (swelling or inflammation) were observed clinically after 12 h post-injection. Areas of discoloration associated with the injection site were observed at time periods less than 11 days after last injection. : Results from a five-day tolerance study in feeder calves indicated that ceftiofur sodium was well tolerated at 25 times (25 mg ceftiofur equivalents/lb {55 mg/kg} BW) the highest recommended dose of 1.0 mg ceftiofur equivalents/lb (2.2 mg/kg) BW for five consecutive days. Ceftiofur administered intramuscularly had no adverse systemic effects. In a 15-day safety/toxicity study, five steer and five heifer calves per group were administered ceftiofur sodium intramuscularly at 0 (vehicle control), 1, 3, 5 and 10 times the highest recommended dose of 1.0 mg ceftiofur equivalents/lb (2.2 mg/kg) BW to determine indicating that ceftiofur sodium has a wide margin of safety when Table 3. Ceftiofur MIC Values of Bacterial Isolates from Clinical Field Studies in the USA Mannheimia haemolytica 61 1988 1992 0.06 0.03 0.13 Mannheimia haemolytica 2 1993 0.015 0.003 0.03 Pasteurella multocida 8 1993 0.003 0.003 0.015 Fusobacterium necrophorum 17 199 0.06 no range Pasteurella multocida 7 1993 0.03 0.03 0.06 Streptococcus suis 9 1993 0.25 0.03 1.0 beta hemolytic Streptococcus spp. 2 1993 0.03 0.03 0.06 Table. Ceftiofur MIC Values of Bacterial Isolates from Diagnostic Laboratories* in the USA and Canada * 12 199 16.0 0.13 >16.0 anaerobius 12 199 2.0 0.13 2.0 * The following in vitro data are available but their clinical significance is unknown. * 70 80 ) Mean injected intramuscularly into the feeder calves at 10 times (10 mg ceftiofur equivalents/lb {22 mg/kg} BW) the recommended dose for three times (15 days) the recommended length of treatment of three to five days. Local tissue tolerance to intramuscular injection of ceftiofur hydrochloride was evaluated in the following study. Results from a tissue tolerance study indicated that ceftiofur hydrochloride was well tolerated and produced no systemic toxicity in cattle when administered intramuscularly in the neck and rear leg at a dose of 1.0 mg ceftiofur equivalents/lb (2.2 mg/kg) BW at each injection site. This represents a total dose per animal of 2.0 mg ceftiofur equivalents/lb (. mg/kg) BW. Clinically noted changes (local swelling) at injection sites in the neck were very infrequent (2/8 sites) whereas noted changes in rear leg sites were more frequent (21/8 sites). These changes in the rear leg injection sites were generally evident on the day following injection and lasted from 1 to 11 days. At necropsy, injection sites were recognized by discoloration of the subcutaneous tissues and muscle that resolved in approximately 7 to 15 days in the neck and 19 to 28 days in the rear leg. Results from another tissue tolerance study indicated that ceftiofur hydrochloride was well tolerated and produced no systemic toxicity to cattle when administered subcutaneously at 0.5 or 1.0 mg ceftiofur equivalents/lb (1.1 or 2.2 mg/kg) BW at 2 h intervals for 5 days. Mild and usually transient, clinically visible or palpable reactions (local swelling) were localized at the injection site. At necropsy, injection sites were routinely recognized by edema, limited increase in thickness and color changes of the subcutaneous tissue and/or fascial surface of underlying muscle. The fascial surface of the muscle was visibly affected in most cases through 9.5 days after injection. Underlying muscle mass was not involved. There were no apparent differences in tissue response to administration of ceftiofur hydrochloride at 0.5 or 1.0 mg ceftiofur equivalents/lb (1.1 or 2.2 mg/kg) BW. : Radiolabeled residue metabolism studies established tolerances for ceftiofur residues in swine kidney, liver, and muscle. These tolerances of ceftiofur residues are 0.25 ppm in kidney, 3.0 ppm in liver and 2.0 ppm in muscle. swine. In this study, pigs received 2.27 mg of ceftiofur per lb body weight (5 mg of ceftiofur per kg body weight) per day for three consecutive days. Ceftiofur residues in tissues were less than the tolerances for ceftiofur residues in tissues such as kidney, liver and muscle by days after dosing. These data collectively support a -day pre-slaughter withdrawal period in swine when used according to label directions. : A radiolabeled residue metabolism study established tolerances for ceftiofur residues in cattle kidney, liver and mus- cle. These tolerances of ceftiofur residues are 0. ppm in kidney, 2.0 ppm in liver, 1.0 ppm in muscle, and 0.1 ppm in milk. cattle. In this study, cattle received a subcutaneous injection of 1.0 mg of ceftiofur per lb body weight (2.2 mg of ceftiofur per kg body weight) for five consecutive days. Ceftiofur residues in tissues were less than the tolerances for ceftiofur residues in tissues such as kidney, liver and muscle by 3 days after dosing. These data collectively support a 3-day pre-slaughter withdrawal period in cattle when used according to label directions. Store at controlled room temperature 20 to 25 C (68 to 77 F) [see USP]. Shake well before using. Protect from freezing. RTU Sterile Suspension is available in 100 ml vials. 1 Clinical and Laboratory Standards Institute (CLSI). Perform- ance Standards for Antimicrobial Disk and Dilution Suscep- tibility Tests for Bacteria Isolated from Animals; Approved Standard Second Edition. CCLS document M31-A2. CLSI, 90 West Valley Road, Suite 100, Wayne, Pennsylvania 19087-1898, 2002. ADA #10-890, Approved by FDA U.S. Patent os.,902,683; 5,736,151 816 323 311 69231 350-03-000 suspension wine and cattle after a single intrats/lb (3.0 to 5.0 mg/kg) BW (swine) g) BW (cattle) and the MIC and disk mmended by CLSI. Interpretation (S) Susceptible (I) Intermediate (R) Resistant is likely to be inhibited by generally technical buffer zone and isolates y the organism may be successfully ysiologically concentrated. A report trations are unlikely to be inhibitory ry control organisms for both stann techniques. The 30 µg ceftiofur d the ceftiofur sodium standard ref- IC values for the reference strain. ppropriate for both ceftiofur salts. concentrations, the following cliniof ceftiofur hydrochloride adminisl component of BRD under natural e present, 60 cattle (111 to 207 kg) t groups: negative control or ceftio- (1.1 or 2.2 mg/kg) BW. Treatments le were evaluated daily and animals lung lesions scored. n Day 15, all d the lung lesions scored. Mortality.5 mg ceftiofur equivalents/lb and espectively. Mortality rates for both for negative controls (P < 0.0001)..0 F, 103.1 F and 102.8 F for nega- BW, respectively. The temperatures lower than the negative controls neously for three consecutive days g) BW is an effective treatment for o evaluate the efficacy of ceftiofur e days or every other day (Days 1 naturally occurring BRD. When unittle were randomly assigned to one ftiofur sodium at 0.5 mg ceftiofur fur hydrochloride at 1.0 mg ceftiofur ftiofur hydrochloride at 1.0 mg cefy). All treatments were administered ride and sodium) and treatment reg-.05) reduced Day rectal temperass on Days 10 and 28 and mortality drochloride and sodium) and treatsults of this study demonstrate that dministration of ceftiofur hydrochlomponent of BRD. field conditions to evaluate the effipost-partum metritis (0 to 1 days metritis (rectal temperature 103 F ing dairy cows were assigned ransed either subcutaneously or intra- 5 and 9 after the last day of dose acute post-partum metritis. A cure f fetid discharge. Cure rate for the up was significantly improved relasults of this study demonstrate that Excenel RTU brand of ceftiofur hydrochloride sterile suspension : pigs indicated that ceftiofur sodium was well tolerated when administered at 57 mg ceftiofur equivalents/lb (125 mg/kg) (more than 25 times the highest recommended daily dosage of 2.27 mg/lb (5.0 mg/kg) ) BW for five consecutive days. Ceftiofur administered intramuscularly to pigs produced no overt adverse signs of toxicity. To determine the safety margin in swine, a safety/toxicity study was conducted. Five barrows and five gilts per group were administered ceftiofur sodium intramuscularly at 0, 2.27, 6.81 and 11.36 mg ceftiofur equivalents/lb (0, 5, 15, 25 mg/kg) BW for 15 days. This is 0, 1, 3 and 5 times the highest recommended dose of 2.27 mg/lb (5.0 mg/kg) BW/day and 5 times the recommended treatment length of 3 days. There were no adverse systemic effects observed, indicating that ceftiofur has a wide margin of safety when injected intramuscularly into feeder pigs at the highest recommended dose of 2.27 mg ceftiofur equivalents/lb (5.0 mg/kg) BW daily for 3 days or at levels up to 5 times the highest recommended dose for 5 times the recommended length of treatment. A separate study evaluated the injection site tissue tolerance of RTU (ceftiofur hydrochloride) in swine when administered intramuscularly in the neck at 1.36 and 2.27 mg ceftiofur equivalents/lb (3.0 to 5.0 mg/kg) BW. Animals were necropsied at intervals to permit evaluations at 12 h, and 3, 5, 7, 9, 11, 15, 20, and 25 days after last injection. Injection sites were evaluated grossly at necropsy. o apparent changes (swelling or inflammation) were observed clinically after 12 h post-injection. Areas of discoloration associated with the injection site were observed at time periods less than 11 days after last injection. : Results from a five-day tolerance study in feeder calves indicated that ceftiofur sodium was well tolerated at 25 times (25 mg ceftiofur equivalents/lb {55 mg/kg} BW) the highest recommended dose of 1.0 mg ceftiofur equivalents/lb (2.2 mg/kg) BW for five consecutive days. Ceftiofur administered intramuscularly had no adverse systemic effects. In a 15-day safety/toxicity study, five steer and five heifer calves per group were administered ceftiofur sodium intramuscularly at 0 (vehicle control), 1, 3, 5 and 10 times the highest recommended dose of 1.0 mg ceftiofur equivalents/lb (2.2 mg/kg) BW to determine the safety factor. There were no adverse systemic effects indicating that ceftiofur sodium has a wide margin of safety when injected intramuscularly into the feeder calves at 10 times (10 mg ceftiofur equivalents/lb {22 mg/kg} BW) the recommended dose for three times (15 days) the recommended length of treatment of three to five days. Local tissue tolerance to intramuscular injection of ceftiofur hydrochloride was evaluated in the following study. Results from a tissue tolerance study indicated that ceftiofur hydrochloride was well tolerated and produced no systemic toxicity in cattle when administered intramuscularly in the neck and rear leg at a dose of 1.0 mg ceftiofur equivalents/lb (2.2 mg/kg) BW at each injection site. This represents a total dose per animal of 2.0 mg ceftiofur equivalents/lb (. mg/kg) BW. Clinically noted changes (local swelling) at injection sites in the neck were very infrequent (2/8 sites) whereas noted changes in rear leg sites were more frequent (21/8 sites). These changes in the rear leg injection sites were generally evident on the day following injection and lasted from 1 to 11 days. At necropsy, injection sites were recognized by discoloration of the subcutaneous tissues and muscle that resolved in approximately 7 to 15 days in the neck and 19 to 28 days in the rear leg. Results from another tissue tolerance study indicated that ceftiofur hydrochloride was well tolerated and produced no systemic toxicity to cattle when administered subcutaneously at 0.5 or 1.0 mg ceftiofur equivalents/lb (1.1 or 2.2 mg/kg) BW at 2 h intervals for 5 days. Mild and usually transient, clinically visible or palpable reactions (local swelling) were localized at the injection site. At necropsy, injection sites were routinely recognized by edema, limited increase in thickness and color changes of the subcutaneous tissue and/or fascial surface of underlying muscle. The fascial surface of the muscle was visibly affected in most cases through 9.5 days after injection. Underlying muscle mass was not involved. There were no apparent differences in tissue response to administration of ceftiofur hydrochloride at 0.5 or 1.0 mg ceftiofur equivalents/lb (1.1 or 2.2 mg/kg) BW. : Radiolabeled residue metabolism studies established tolerances for ceftiofur residues in swine kidney, liver, and muscle. These tolerances of ceftiofur residues are 0.25 ppm in kidney, 3.0 ppm in liver and 2.0 ppm in muscle. swine. In this study, pigs received 2.27 mg of ceftiofur per lb body weight (5 mg of ceftiofur per kg body weight) per day for three consecutive days. Ceftiofur residues in tissues were less than the tolerances for ceftiofur residues in tissues such as kidney, liver and muscle by days after dosing. These data collectively support a -day pre-slaughter withdrawal period in swine when used according to label directions. : A radiolabeled residue metabolism study established tolerances for ceftiofur residues in cattle kidney, liver and muscle. These tolerances of ceftiofur residues are 0. ppm in kidney, 2.0 ppm in liver, 1.0 ppm in muscle, and 0.1 ppm in milk. cattle. In this study, cattle received a subcutaneous injection of 1.0 mg of ceftiofur per lb body weight (2.2 mg of ceftiofur per kg body weight) for five consecutive days. Ceftiofur residues in tissues were less than the tolerances for ceftiofur residues in tissues such as kidney, liver and muscle by 3 days after dosing. These data collectively support a 3-day pre-slaughter withdrawal period in cattle when used according to label directions. Store at controlled room temperature 20 to 25 C (68 to 77 F) [see USP]. Shake well before using. Protect from freezing. RTU Sterile Suspension is available in 100 ml vials. 1 Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk and Dilution Susceptibility Tests for Bacteria Isolated from Animals; Approved Standard Second Edition. CCLS document M31-A2. CLSI, 90 West Valley Road, Suite 100, Wayne, Pennsylvania 19087-1898, 2002. ADA #10-890, Approved by FDA U.S. Patent os.,902,683; 5,736,151 Revised February 2006 816 323 311 69231 350-03-000 diameter* mm) 6 31 0.25 1.0 0.25 1.0 7 31 18 16.0 6.0 2** 0.00 0.015*** 6** 0.0005 0.00*** fur against Clinical and d American type Culture rformed by disk diffusion test using 2 for 20-2 hours. ts performed by broth microdilution. Division of Pfizer Inc, Y, Y 10017 Excenel RTU brand of ceftiofur hydrochloride sterile suspension For intramuscular and subcutaneous injection in cattle only. For intramuscular injection in swine, sheep, goats, and horses. For subcutaneous injection only in dogs, day-old chickens and day-old turkey poults. This product may be used in lactating dairy cattle, sheep, and goats. CAUTI: Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian. AXCEL Sterile Powder contains the sodium salt of ceftiofur which is a broad spectrum cephalosporin antibiotic active against gram-positive and gram-negative bacteria including β-lactamase-producing strains. Like other cephalosporins, ceftiofur is bactericidal in vitro, resulting from inhibition Each ml of the reconstituted drug contains The ph was adjusted with sodium hydroxide and monobasic potassium phosphate. Chemical Structure of Ceftiofur Sodium 5-Thia-1-azabicyclo[.2.0]oct-2-ene-2-carboxylic acid, 7-[[(2-amino--thiazolyl)(methoxyimino)-acetyl]amino]-3-[[(2-furanylcarbonyl) thio] methyl]-8-oxo-, monosodium salt, [6R- [6α,7β (Z)]]- 1 gram vial Reconstitute with 20 ml Sterile Water for Injection. Each ml of the resulting solution contains gram vial Reconstitute with 80 ml Sterile Water for Injection. Each ml of the resulting solution contains AXCEL Sterile Powder is indicated for treatment of bovine respiratory disease (shipping fever, pneumonia) associated with Mannheimia haemolytica, Pasteurella multocida and Histophilus somni. AXCEL Sterile Powder is also indicated for treatment of acute bovine interdigital necrobacillosis (foot rot, pododermatitis) associated with Fusobacterium AXCEL Sterile Powder is indicated for treatment/control of swine bacterial respiratory disease (swine bacterial pleuropneumoniae, Pasteurella multocida, Salmonella choleraesuis AXCEL Sterile Powder is indicated for treatment of sheep respiratory disease (sheep pneumonia) associated with Mannheimia haemolytica and Pasteurella multocida. AXCEL Sterile Powder is indicated for treatment of caprine respiratory disease (goat pneumonia) associated with Mannheimia haemolytica and Pasteurella multocida. AXCEL Sterile Powder is indicated for treatment of respiratory infections in horses associated with Streptococcus zooepidemicus. AXCEL Sterile Powder is indicated for the treatment of canine urinary tract infections associated with Escherichia coli and Proteus mirabilis. early mortality, associated with E. coli organisms susceptible to ceftiofur, in day-old chicks. early mortality, associated with E. coli organisms susceptible to ceftiofur, in day-old turkey poults. Administer to cattle by intramuscular or subcutaneous injection at the dosage of 0.5 to 1.0 mg ceftiofur per pound (1.1 to 2.2 mg/kg) of body weight (1-2 ml reconstituted sterile solution per 100 intervals for a total of three consecutive days. Additional treatments may be given on days four and five for animals after the initial three treatments. Selection of dosage (0.5 to of severity of disease (i.e., for respiratory disease, extent of elevated body temperature, rate, coughing and/or loss of appetite; and for foot rot, extent of swelling, lesion and severity of lameness). Administer to swine by intramuscular injection at the dosage of 1.36 to 2.27 mg ceftiofur per pound (3.0 to 5.0 mg/kg) of body weight (1 ml of reconstituted sterile solution per 22 to 37 intervals for a total of three consecutive days. Administer to sheep by intramuscular injection at the dosage of 0.5 to 1.0 mg ceftiofur per pound (1.1 to 2.2 mg/kg) intervals for a total of three consecutive days. Additional which do not show a satisfactory response (not recovered) after the initial three treatments. Selection of dosage (0.5 to of severity of disease (i.e., extent of elevated body temperature, Administer to goats by intramuscular injection at the dosage of 0.5 to 1.0 mg ceftiofur per pound (1.1 to 2.2 mg/kg) lbs body weight). Treatment should be repeated at 2-hour intervals for a total of three consecutive days. Additional which do not show a satisfactory response (not recovered) after the initial three treatments. Selection of dosage (0.5 to of severity of disease (i.e., extent of elevated body temperature, depressed physical appearance, increased respiratory Pharmacokinetic data indicate that elimination of the drug is more rapid in lactating does. For lactating does, the high end of the dose range is recommended. Administer to horses by intramuscular injection at the dosage of 1.0 to 2.0 mg ceftiofur per pound (2.2 to. mg/kg) of body weight (2- ml reconstituted sterile solution per 100 lbs body weight). A maximum of 10 ml may be administered per injection site. Treatment should be repeated at 2-hour intervals, continued for 8 hours after clinical signs have disappeared and should not exceed 10 days. Administer to dogs by subcutaneous injection at the dosage of 1.0 mg ceftiofur per pound (2.2 mg/kg) of body weight (0.1 ml reconstituted sterile solution per 5 lbs body weight). Treatment should be repeated at 2-hour intervals for 5-1 days. Reconstituted AXCEL Sterile Powder is to be administered to dogs by subcutaneous injection. o vial closure should be entered more than 20 times. Therefore, only the 1 gram vial is approved for use in dogs. of day-old chicks at the dosage of 0.08 to 0.20 mg ceftiofur/chick. ne ml of the 50 mg/ml reconstituted solution will treat approximately 250 to 625 day-old chicks. only. A sterile 26 gauge needle and syringe or properly cleaned automatic injection of day-old turkey poults at the dosage of 0.17 to 0.5 mg ceftiofur/poult. ne ml of the 50 mg/ml reconstituted solution will treat approximately 100 to 29 day-old turkey poults. only. As with all drugs, the use of AXCEL Sterile Powder is contraindicated in animals previously found to be hypersensitive Penicillins and cephalosporins can cause allergic reactions in sensitized individuals. Topical exposures to such antimicrobials, including ceftiofur, may elicit mild to severe allergic reactions in some individuals. Repeated or prolonged exposure may lead to sensitization. Avoid direct contact of the product with the skin, eyes, mouth, and clothing. Persons with a known hypersensitivity to penicillin or cephalosporins should avoid exposure to this product. In case of accidental eye exposure, flush with water for 15 minutes. In case of accidental skin exposure, wash with soap and water. Remove contaminated clothing. If allergic reaction occurs (e.g., skin rash, hives, difficult breathing), seek medical attention. The material safety data sheet contains more detailed occupational safety information. To obtain a material safety data sheet (MSDS) please call 1-800-733-5500. To report any adverse event please call 1-800-366-5288. RESIDUE : : When used according to label indications, dosage and routes of administration, treated cattle must not be slaughtered for days following the last treatment. When used according to label indications, dosage and routes of administration, a milk discard time is not required. Use of dosages in excess of those indicated or by in edible tissues and/or in milk. : When used according to label indications, dosage and route of administration, treated pigs must not be slaughtered for days following the last treatment. Use unapproved routes of administration may result in illegal residues in edible tissues. : either a pre-slaughter drug withdrawal interval nor a milk discard time is required when dosage, or by intramammary, may result in illegal residues : either a pre-slaughter drug withdrawal interval nor a milk discard time is required when dosage, or by intramammary, may result in illegal residues : Do not use in horses intended for human consumption. The effects of ceftiofur on the reproductive performance, pregnancy, and lactation of cattle, swine, sheep, and goats have not been determined. Following subcutaneous administration of ceftiofur sodium in the neck, small areas of discoloration at the site may persist beyond five days, potentially resulting in trim loss of edible As with any parenteral injection, localized post-injection bacterial infections may result in abscess formation. Attention to hygienic procedures can minimize their occurrence. The safety of ceftiofur has not been determined for swine intended for breeding. The safety of ceftiofur has not been determined for horses intended for breeding. The administration of antimicrobials to horses under conditions of stress may be associated with acute diarrhea that could be fatal. If acute diarrhea is observed, discontinue use of this antimicrobial and initiate appropriate therapy. The safety of ceftiofur has not been determined for dogs intended for breeding, or pregnant dogs. The use of ceftiofur may result in some signs of immediate and transient local pain to the animal. Summaries of MIC data are presented in Tables 1 and 2. Testing followed Clinical and Laboratory Standards Institute (CLSI) Guidelines. Animal MIC 90 * Bovine Mannheimia haemolytica 61 1988-1992 0.06 0.03-0.13 Mannheimia haemolytica 2 1993 0.015 0.003-0.03 Pasteurella multocida 318 1988-1992 0.06 0.03-0.25 Pasteurella multocida 8 1993 0.003 0.003-0.015 Histophilus somni 109 1988-1992 0.06 0.03-0.13 Histophilus somni 59 1993 0.0019 no range Fusobacterium necrophorum 17 199 0.06 no range Actinobacillus pleuropn. 83 1993 0.03 0.03-0.06 Pasteurella multocida 7 1993 0.03 0.03-0.06 Streptococcus suis 9 1993 0.25 0.03-1.0 Salmonella choleraesuis 50 1993 1.0 1.0-2.0 beta-hemolytic Streptococcus spp. 2 1993 0.03 0.03-0.06 Actinobacillus suis 77 1998 0.0078 0.0019-0.0078 Haemophilus parasuis 76 1998 0.06 0.0039-0.25 Mannheimia haemolytica 39 1992 0.13 0.03-0.13 Pasteurella multocida 23 1992 0.03 no range Canine Escherichia coli 1992.0 0.06-6.0 Escherichia coli 18 1990 0.25 0.13-0.5 Proteus mirabilis 17 1990 0.06 0.06-0.5 Proteus mirabilis 23 1992 1.0 0.06-.0 Turkey Escherichia coli 120 1995 1.0 0.13->32.0 Animal MIC 90 ** Bovine Mannheimia haemolytica 110 1997-1998 0.06 0.03-0.25 Mannheimia haemolytica 139 1998-1999 0.03 0.03-0.5 Mannheimia haemolytica 209 1999-2000 0.03 0.03-0.12 Mannheimia haemolytica 189 2000-2001 0.03 0.03-0.12 Pasteurella multocida 107 1997-1998 0.03 0.03-0.25 Pasteurella multocida 181 1998-1999 0.03 0.03-0.5 Pasteurella multocida 208 1999-2000 0.03 0.03-0.12 Pasteurella multocida 259 2000-2001 0.03 0.03-0.12 Histophilus somni 8 1997-1998 0.03 0.03-0.25 Histophilus somni 87 1998-1999 0.03 0.03-0.125 Histophilus somni 77 1999-2000 0.03 0.03-0.06 Histophilus somni 129 2000-2001 0.03 0.03-0.12 Bacteroides fragilis group 29 199 16.0 0.06->16.0 12 199 16.0 0.13->16.0 anaerobius 12 199 2.0 0.13-2.0 Actinobacillus pleuropn. 97 1997-1998 0.03 no range Actinobacillus pleuropn. 111 1998-1999 0.03 0.03-0.25 Actinobacillus pleuropn. 126 1999-2000 0.03 0.03-0.06 Actinobacillus pleuropn. 89 2000-2001 0.03 0.03-0.06 Pasteurella multocida 11 1997-1998 0.03 0.03-1.0 Pasteurella multocida 17 1998-1999 0.03 0.03-0.5 Pasteurella multocida 173 1999-2000 0.03 0.03-0.06 Pasteurella multocida 186 2000-2001 0.03 0.03-0.12 Streptococcus suis 106 1997-1998 0.5 0.03-.0 Streptococcus suis 12 1998-1999 0.25 0.03-1.0 Streptococcus suis 16 1999-2000 0.06 0.03-.0 Streptococcus suis 167 2000-2001 0.06 0.03-.0 Salmonella choleraesuis 96 1999-2000 1.0 0.03->.0 Salmonella choleraesuis 101 2000-2001 1.0 0.5-2.0 Equine subsp. equi 12 199 0.0019 no range subsp. equi 29 2002 0.03 0.03-0.05 Streptococcus zooepidemicus 8 199 0.0019 no range Table 2. Ceftiofur MIC Values of Bacterial Isolates from Diagnostic Laboratories in the USA and Canada* (continued) For intramuscular and subcutaneous injection in cattle only. For intramuscular injection in swine, sheep, goats, and horses. For subcutaneous injection only in dogs, day-old chickens and day-old turkey poults. This product may be used in lactating dairy cattle, sheep, and goats. CAUTI: Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian. AXCEL Sterile Powder contains the sodium salt of ceftiofur which is a broad spectrum cephalosporin antibiotic active against gram-positive and gram-negative bacteria including β-lactamase-producing strains. Like other cephalosporins, ceftiofur is bactericidal in vitro, resulting from inhibition Each ml of the reconstituted drug contains ceftiofur sodium equivalent to 50 mg ceftiofur. The ph was adjusted with sodium hydroxide and monobasic potassium phosphate. Chemical Structure of Ceftiofur Sodium 5-Thia-1-azabicyclo[.2.0]oct-2-ene-2-carboxylic acid, 7-[[(2-amino--thiazolyl)(methoxyimino)-acetyl]amino]- 3-[[(2-furanyl-carbonyl)thio]methyl]-8-oxo-, monosodium salt, [6R-[6α,7β (Z)]]- 1 gram vial Reconstitute with 20 ml Sterile Water gram vial Reconstitute with 80 ml Sterile Water AXCEL Sterile Powder is indicated for treatment of bovine respiratory disease (shipping fever, pneumonia) associated with Mannheimia haemolytica, Pasteurella multocida and Histophilus somni. AXCEL Sterile Powder is also indicated for treatment of acute bovine interdigital necrobacillosis (foot rot, pododermatitis) associated with Fusobacterium AXCEL Sterile Powder is indicated for treatment/control AXCEL Sterile Powder is indicated for treatment of sheep respiratory disease (sheep pneumonia) associated with Mannheimia haemolytica and Pasteurella multocida. AXCEL Sterile Powder is indicated for treatment of caprine respiratory disease (goat pneumonia) associated with Mannheimia haemolytica and Pasteurella multocida. AXCEL Sterile Powder is indicated for treatment of respiratory infections in horses associated with Streptococcus zooepidemicus. AXCEL Sterile Powder is indicated for the treatment of canine urinary tract infections associated with Escherichia coli and Proteus mirabilis. to ceftiofur, in day-old chicks. to ceftiofur, in day-old turkey poults. Administer to cattle by intramuscular or subcutaneous injection at the dosage of 0.5 to 1.0 mg ceftiofur per pound (1.1 to 2.2 mg/kg) of body weight (1-2 ml reconstituted sterile solution per 100 lbs body weight). Treatment should be repeated at 2-hour intervals for a total of three consecutive days. Additional treatments may be given on days four and five for animals which do not show a satisfactory response (not recovered) after the initial three treatments. Selection of dosage (0.5 to 1.0 mg/lb) should be based on the practitioner s judgement of severity of disease (i.e., for respiratory disease, extent of elevated body temperature, depressed physical appearance, increased respiratory rate, coughing and/or loss of appetite; and for foot rot, extent of swelling, lesion and severity of lameness). Administer to swine by intramuscular injection at the dosage of 1.36 to 2.27 mg ceftiofur per pound (3.0 to 5.0 mg/kg) of body weight (1 ml of reconstituted sterile solution per 22 to 37 lbs body weight). Treatment should be repeated at 2- hour intervals for a total of three consecutive days. Administer to sheep by intramuscular injection at the dosage Administer to goats by intramuscular injection at the dosage Pharmacokinetic data indicate that elimination of the drug is more rapid in lactating does. For lactating does, the high end of the dose range is recommended. Administer to horses by intramuscular injection at the dosage of 1.0 to 2.0 mg ceftiofur per pound (2.2 to. mg/ kg) of body weight (2- ml reconstituted sterile solution per 100 lbs body weight). A maximum of 10 ml may be administered per injection site. Treatment should be repeated at 2-hour intervals, continued for 8 hours after clinical signs have disappeared and should not exceed 10 days. Administer to dogs by subcutaneous injection at the dosage of 1.0 mg ceftiofur per pound (2.2 mg/kg) of body weight (0.1 ml reconstituted sterile solution per 5 lbs body weight). Treatment should be repeated at 2-hour intervals for 5-1 days. tered to dogs by subcutaneous injection. o vial closure should be entered more than 20 times. Therefore, only the 1 gram vial is approved for use in dogs. of day-old chicks at the dosage of 0.08 to 0.20 mg ceftiofur/ chick. ne ml of the 50 mg/ml reconstituted solution will treat approximately 250 to 625 day-old chicks. tered by subcutaneous injection only. A sterile 26 gauge needle and syringe or properly cleaned automatic injection of day-old turkey poults at the dosage of 0.17 to 0.5 mg ceftiofur/poult. ne ml of the 50 mg/ml reconstituted solution will treat approximately 100 to 29 day-old turkey poults. Reconstituted AXCEL Sterile Powder is to be administered by subcutaneous injection only. As with all drugs, the use of AXCEL Sterile Powder is contraindicated in animals previously found to be hypersensitive Penicillins and cephalosporins can cause allergic reactions in sensitized individuals. Topical exposures to such antimicrobials, including ceftiofur, may elicit mild to severe allergic reactions in some individuals. Repeated or prolonged exposure may lead to sensitization. Avoid direct contact of the product with the skin, eyes, mouth, and clothing. Persons with a known hypersensitivity to penicillin or cephalosporins should avoid exposure to this product. In case of accidental eye exposure, flush with water for 15 minutes. In case of accidental skin exposure, wash with soap and water. Remove contaminated clothing. If allergic reaction occurs (e.g., skin rash, hives, difficult breathing), seek medical attention. The material safety data sheet contains more detailed occupational safety information. To obtain a material safety data sheet (MSDS) please call 1-800-733-5500. To report any adverse event please call 1-800-366-5288. RESIDUE : : When used according to label indications, dosage and routes of administration, treated cat- tle must not be slaughtered for days following indications, dosage and routes of administration, a milk discard time is not required. Use of dosages routes of administration, such as : When used according to label indica- tions, dosage and route of administration, treated pigs must not be slaughtered for days following the last treatment. Use of dosages in excess of those indicated or by unapproved routes of administration may result in illegal residues in edible tissues. : either a pre-slaughter drug withdrawal : either a pre-slaughter drug withdrawal : Do not use in horses intended for human consumption. The effects of ceftiofur on the reproductive performance, pregnancy, and lactation of cattle, swine, sheep, and goats have not been determined. Following subcutaneous administration of ceftiofur sodium in the neck, small areas of discoloration at the site may persist beyond five days, potentially resulting in trim loss of edible As with any parenteral injection, localized post-injection bacterial infections may result in abscess formation. Attention to hygienic procedures can minimize their occurrence. The safety of ceftiofur has not been determined for swine intended for breeding. The safety of ceftiofur has not been determined for horses intended for breeding. The administration of antimicrobials to horses under conditions of stress may be associated with acute diarrhea that could be fatal. If acute diarrhea is observed, discontinue use of this antimicrobial and initiate appropriate therapy. The safety of ceftiofur has not been determined for dogs intended for breeding, or pregnant dogs. The use of ceftiofur may result in some signs of immediate and transient local pain to the animal. Summaries of MIC data are presented in Tables 1 and 2. Testing followed Clinical and Laboratory Standards Institute (CLSI) Guidelines. swine and cattle after a single intramuscular injection of 1.36 to 2.27 mg ceftiofur equivalents/lb (3.0 to 5.0 mg/kg) BW (swine) or 0.5 to 1.0 mg ceftiofur equivalents/lb (1.1 to 2.2 mg/kg) BW (cattle) and the MIC and disk (30 µg) diffusion data, the following breakpoints are recommended by CLSI. Zone Diameter MIC Interpretation A report of Susceptible indicates that the pathogen is likely to be inhibited by generally achievable blood levels. A report of Intermediate is a technical buffer zone and isolates falling into this category should be retested. Alternatively the organism may be successfully treated if the infection is in a body site where drug is physiologically concentrated. A are unlikely to be inhibitory and other therapy should be selected. horses after a single intramuscular injection of 1 mg ceftiofur equivalents/lb (2.2 mg/kg) BW, clinical effectiveness data and MIC data, the following breakpoint is recommended by CLSI. Zone Diameter MIC Interpretation 22 0.25 (S) Susceptible The susceptible only category is used for populations of organisms (usually one species) for which regression analysis (disk vs. MIC) cannot be performed. These breakpoints will permit detection of strains with decreased susceptibility as compared to the original population. Standardized procedures 1 require the use of laboratory control organisms for both standardized diffusion techniques and standardized dilution techniques. The 30 µg ceftiofur sodium disk should give the following zone diameters and the ceftiofur sodium standard reference powder (or disk) should provide the following MIC values for the reference strain. Ceftiofur sodium disks or powder reference standard is appropriate for both ceftiofur salts. Mannheimia haemolytica 61 1988 1992 0.06 0.03 0.13 Mannheimia haemolytica 2 1993 0.015 0.003 0.03 Pasteurella multocida 8 1993 0.003 0.003 0.015 Fusobacterium necrophorum 17 199 0.06 no range Pasteurella multocida 7 1993 0.03 0.03 0.06 Streptococcus suis 9 1993 0.25 0.03 1.0 beta hemolytic Streptococcus spp. 2 1993 0.03 0.03 0.06 SHEEP Mannheimia haemolytica 39 1992 0.13 0.03 0.13 Pasteurella multocida 23 1992 0.03 no range Escherichia coli 1992.0 0.06 6.0 Escherichia coli 18 1990 0.25 0.13 0.5 Proteus mirabilis 17 1990 0.06 0.06 0.5 Proteus mirabilis 23 1992 1.0 0.06.0 Escherichia coli 120 1995 1.0 0.13 >32.0 Table 2. Ceftiofur MIC Values of Bacterial Isolates from Diagnostic Laboratories in the USA and Canada* * 12 199 16.0 0.13 >16.0 anaerobius 12 199 2.0 0.13 2.0 EQUIE subsp. equi 12 199 0.0019 no range subsp. equi 29 2002 0.03 0.03 0.05 Streptococcus zooepidemicus 8 199 0.0019 no range Streptococcus zooepidemicus 59 2002 0.03 0.03 0.25 Rhodococcus equi 66 1998.0 0.03 16.0 Rhodococcus equi 2 2002 8.0 0.03 >32.0 Bacteroides fragilis group 32 1995 >16.0 0.13 >16.0 12 1995.0 0.25.0 Fusobacterium necrophorum 16 1995 0.06 no range Escherichia coli 26 2000 32 0.25 >32.0 Proteus mirabilis 1 2000 0.25 0.06 0.25 Escherichia coli 17 1998-1999 1.0 0.25 1.0 Escherichia coli 25 1999-2000 0.50 0.12 0.5 Escherichia coli 20 2000-2001 2.0 0.12 16.0 Citrobacter spp. 37 1995 32.0 0.5 >32.0 Enterobacter spp. 51 1995 >32.0 0.13 >32.0 Klebsiella spp. 100 1995 1.0 0.13 2.0 Proteus spp. 19 1995 1.0 0.06 32.0 Pseudomonas spp.*** 31 1995 >32.0 0.06 >32.0 Salmonella spp. 2 1995 1.0 0.5 1.0 (coagulase positive) 17 1995 2.0 1.0 2.0 (coagulase negative) 26 1995 8.0 0.13 >32.0 CHICKE Escherichia coli 62 1997-1998 0.50 0.25 2.0 Escherichia coli 53 1998-1999.0 0.25 >.0 Escherichia coli 67 1999-2000 0.50 0.12 16.0 Escherichia coli 90 2000-2001 1.0 0.03 8.0 * The following in vitro data are available but their clinical significance is unknown. * ***MIC50 is 32 µg/ml. Table 3. Acceptable quality control ranges for ceftiofur against ational Committee for Clinical Laboratory Standards recommended American type Culture Collection (ATCC) reference strains name (ATCC o.) Staphylococcus aureus (29213) 0.25 1.0 Staphylococcus aureus (25923) 27 31 Pseudomonas aeruginosa (27853) 1 18 16.0 6.0 Actinobacillus pleuropneumoniae (27090) 3 2** 0.00 0.015*** Histophilus somni (700025) 36 6** 0.0005 0.00*** ** Quality control ranges are applicable only to tests performed by disk diffusion test using a chocolate Mueller-Hinton agar, incubated in 5-7% C2 for 20-2 hours. *** MIC quality control ranges are applicable only to tests performed by broth microdilution procedures using veterinary fastidious medium (VFM). calves indicated that formulated ceftiofur was well tolerated at 25 times (25 mg/lb/day) the highest recommended dose of 1.0 mg/lb/day for five consecutive days. Ceftiofur administered intramuscularly had no adverse systemic effects. In a 15-day safety/toxicity study, five steer and five heifer calves per group were intramuscularly administered formulated ceftiofur at 0 (vehicle control), 1, 3, 5 and 10 times the highest recommended dose of 1.0 mg/lb/day to determine indicating that the formulated ceftiofur has a wide margin of safety when injected intramuscularly into the feeder calves at 10 times (10 mg/lb/day) the recommended dose for three times (15 days) the recommended three to five days of therapy. The formulation was shown to be a slight muscle irritant based on results of histopathological evaluation of the injection sites at 1 and 3 times the highest recommended dose of 1.0 mg/lb/day. The histopathological evaluations were conducted at posttreatment days 1, 3, 7 and 1. The injection of AXCEL Sterile Powder at the recommended dose administered SC in the neck of cattle was well tolerated. However, a several square centimeter area of yellowred discoloration resulting from a single SC injection persisted in many of the cattle beyond.5 days post-injection. Also, one of the animals developed an abscess at the injection site. pigs indicated that formulated ceftiofur was well tolerated when administered at 57 mg/lb (more than 25 times the high- est recommended daily dosage of 2.27 mg/lb of body weight) for five consecutive days. Ceftiofur administered intramuscu- larly to pigs produced no overt adverse signs of toxicity. To determine the safety factor and to measure the muscle irritancy potential in swine, a safety/toxicity study was conducted. Five barrows and five gilts per group were intramuscularly administered formulated ceftiofur at 0, 2.27, 6.81 and 11.36 mg/lb of body weight for 15 days which is 0, 1, 3 and 5 times the highest recommended dose of 2.27 mg/lb of body weight/day and 5 times the recommended treatment length of 3 days. There were no adverse systemic effects indicating that formulated ceftiofur has a wide margin of safety when injected intramuscularly into feeder pigs at the highest recommended dose of 2.27 mg/lb/day for 3 days or at levels up to 5 times the highest recommended dose for 5 times the recommended length of treatment. The formulation was shown to be a slight muscle irritant based on results of histopathological evaluation of the injection sites at posttreatment days 1, 2, 3 and. By day 10 post injection the muscle reaction was subsiding and at day 15 post injection there was little evidence of muscle damage in any of the pigs in any of the treatment groups. In a 15-day safety/toxicity study in sheep, three wether and three ewe lambs per group were given formulated ceftiofur sodium by the intramuscular route 0 (sterile water vehicle), 1, 3 or 5 times the recommended dose of 1.0 mg/lb/day for 3 times the recommended maximum duration of 5 days of treatment. There were no adverse systemic effects indicating that formulated ceftiofur is well tolerated and has a wide margin of safety in sheep. Based on examination of injection sites from study days 9, 11, 13 and 15, a low incidence of visual changes and histopathologic findings of mild, reversible inflammation from all groups including the controls indicated that the formulation is a slight muscle irritant. In a 15-day safety/toxicity study 5 lactating does, 5 dry does, and 5 wethers were given formulated ceftiofur by the intramuscular route with 11 mg/kg/day for 15 days. This constitutes 5 times the recommended dose for 3 times the recommended maximum duration of 5 days of treatment. There were no adverse systemic effects indicating that formulated ceftiofur is well tolerated and has a wide margin of safety in goats. In a safety study, horses received a daily intramuscular injection of either 0 mg/lb/day (saline control), 1.0 mg/lb/day (50 mg/ml), 3.0 mg/lb/day (100 mg/ml), or 5.0 mg/lb/day (200 mg/ml) of an aqueous solution of ceftiofur sodium for 30 or 31 days. Ceftiofur sodium was well tolerated when administered intramuscularly to male and female horses at doses up to 5.0 mg/lb/day for 30 or 31 days. o clinical evidence of irritation was noted at any dose. The drug-related changes detected in this study were limited to a transient decrease in food consumption in horses receiving 3.0 or 5.0 mg/lb/day ceftiofur, and general mild skeletal muscle irritation at the injection sites which resolved by regeneration of muscle fibers. In a tolerance study, horses received a single daily intravenous infusion of either 0 (saline), 10.0 or 25.0 mg/lb/day of an aqueous solution (50 mg/ml) of ceftiofur for 10 days. The results indicated that ceftiofur administered intravenously at a dose of 10.0 or 25.0 mg/lb/day apparently can change the bacterial flora of the large intestine thereby leading to inflammation of the large intestine with subsequent diarrhea and other clinical signs (loose feces, eating bedding straw, dehydration, rolling or colic and a dull, inactive demeanor). Decreased food consumption, a loss of body weight, hematologic changes related to acute inflammation and stress, and serum chemistry changes related to decreased food consumption and diarrhea were also associated with treatment at these doses. The adverse effects were most severe a few days after dosing was initiated and tended to become less severe toward the end of the 10-day dosing period. Ceftiofur sodium was well tolerated at the therapeutic dose and is safe for the treatment of urinary tract infections in dogs. In the acute safety study, ceftiofur was well tolerated by dogs at the recommended level (1.0 mg/lb) for 5-1 days. When administered subcutaneously for 2 consecutive days, one of four females developed thrombocytopenia (15 days) and anemia (36 days). Thrombocytopenia and anemia also occurred at the 3X and 5X dose levels. In the reversibility phase of the study (5X dose), the thrombocytopenia reversed within 8 days, and of the two anemic animals the male recovered within 6 weeks and the female was sacrificed due to the severity of the anemia. In the 15-day tolerance study in dogs, high subcutaneous doses (25 and 125 times the recommended therapeutic dose) produced a progressive and dose-related thrombocytopenia, with some dogs also exhibiting anemia and bone marrow changes. The hematopoietic changes noted in dogs treated with ceftiofur were similar to those associated with long-term cephalosporin administration in dogs and also man. The hematopoietic effects are not expected to occur as a result of recommended therapy. In an acute toxicity study of ceftiofur in day-old chicks, a total of 60 male and 60 female chicks were each given single subcutaneous injections of 10, 100 or 1,000 mg/kg of body weight. Treatment on day 1 was followed by 6 days of observation; body weight was determined on days 1, and 7; and selected hematology parameters were evaluated on day. o meaningful differences were noted among the treated and control groups of chicks for the parameters eval- uated. Histopathologic evaluation of all deaths and chicks surviving to termination did not reveal a target organ or tissue of potential toxicity of ceftiofur when administered at up to 20 times (100 mg/kg) the intended highest use dosage. In an acute toxicity study of ceftiofur in day-old turkey poults, a total of 30 male and 30 female poults were each administered single subcutaneous injections of 100, 00 or 800 mg/kg body weight. Injection on day 1 was followed by 6 days of observation; body weight on days 1,, and 7; and selected hematology parameters on day. o meaningful differences were noted between the treated groups at 100 or 00 mg ceftiofur/kg and a negative control group for the parameters evaluated. Histopathologic evaluation of all deaths and poults surviving to termination did not reveal a For intramuscular and subcutaneous injection in cattle only. For intramuscular injection in swine, sheep, goats, and horses. For subcutaneous injection only in dogs, day-old chickens and day-old turkey poults. This product may be used in lactating dairy cattle, sheep, and goats. CAUTI: Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian. AXCEL Sterile Powder contains the sodium salt of ceftiofur which is a broad spectrum cephalosporin antibiotic active against gram-positive and gram-negative bacteria including β-lactamase-producing strains. Like other cephalosporins, ceftiofur is bactericidal in vitro, resulting from inhibition Each ml of the reconstituted drug contains The ph was adjusted with sodium hydroxide and monobasic potassium phosphate. Chemical Structure of Ceftiofur Sodium 5-Thia-1-azabicyclo[.2.0]oct-2-ene-2-carboxylic acid, 7-[[(2-amino--thiazolyl)(methoxyimino)-acetyl]amino]-3-[[(2-furanylcarbonyl) thio] methyl]-8-oxo-, monosodium salt, [6R- [6α,7β (Z)]]- 1 gram vial Reconstitute with 20 ml Sterile Water for Injection. Each ml of the resulting solution contains gram vial Reconstitute with 80 ml Sterile Water for Injection. Each ml of the resulting solution contains AXCEL Sterile Powder is indicated for treatment of bovine respiratory disease (shipping fever, pneumonia) associated with Mannheimia haemolytica, Pasteurella multocida and Histophilus somni. AXCEL Sterile Powder is also indicated for treatment of acute bovine interdigital necrobacillosis (foot rot, pododermatitis) associated with Fusobacterium AXCEL Sterile Powder is indicated for treatment/control of swine bacterial respiratory disease (swine bacterial pleuropneumoniae, Pasteurella multocida, Salmonella choleraesuis AXCEL Sterile Powder is indicated for treatment of sheep respiratory disease (sheep pneumonia) associated with Mannheimia haemolytica and Pasteurella multocida. AXCEL Sterile Powder is indicated for treatment of caprine respiratory disease (goat pneumonia) associated with Mannheimia haemolytica and Pasteurella multocida. AXCEL Sterile Powder is indicated for treatment of respiratory infections in horses associated with Streptococcus zooepidemicus. AXCEL Sterile Powder is indicated for the treatment of canine urinary tract infections associated with Escherichia coli and Proteus mirabilis. early mortality, associated with E. coli organisms susceptible to ceftiofur, in day-old chicks. early mortality, associated with E. coli organisms susceptible to ceftiofur, in day-old turkey poults. Administer to cattle by intramuscular or subcutaneous injection at the dosage of 0.5 to 1.0 mg ceftiofur per pound (1.1 to 2.2 mg/kg) of body weight (1-2 ml reconstituted sterile solution per 100 intervals for a total of three consecutive days. Additional treatments may be given on days four and five for animals after the initial three treatments. Selection of dosage (0.5 to of severity of disease (i.e., for respiratory disease, extent of elevated body temperature, rate, coughing and/or loss of appetite; and for foot rot, extent of swelling, lesion and severity of lameness). Administer to swine by intramuscular injection at the dosage of 1.36 to 2.27 mg ceftiofur per pound (3.0 to 5.0 mg/kg) of body weight (1 ml of reconstituted sterile solution per 22 to 37 intervals for a total of three consecutive days. Administer to sheep by intramuscular injection at the dosage of 0.5 to 1.0 mg ceftiofur per pound (1.1 to 2.2 mg/kg) intervals for a total of three consecutive days. Additional which do not show a satisfactory response (not recovered) after the initial three treatments. Selection of dosage (0.5 to of severity of disease (i.e., extent of elevated body temperature, Administer to goats by intramuscular injection at the dosage of 0.5 to 1.0 mg ceftiofur per pound (1.1 to 2.2 mg/kg) lbs body weight). Treatment should be repeated at 2-hour intervals for a total of three consecutive days. Additional which do not show a satisfactory response (not recovered) after the initial three treatments. Selection of dosage (0.5 to of severity of disease (i.e., extent of elevated body temperature, depressed physical appearance, increased respiratory Pharmacokinetic data indicate that elimination of the drug is more rapid in lactating does. For lactating does, the high end of the dose range is recommended. Administer to horses by intramuscular injection at the dosage of 1.0 to 2.0 mg ceftiofur per pound (2.2 to. mg/kg) of body weight (2- ml reconstituted sterile solution per 100 lbs body weight). A maximum of 10 ml may be administered per injection site. Treatment should be repeated at 2-hour intervals, continued for 8 hours after clinical signs have disappeared and should not exceed 10 days. Administer to dogs by subcutaneous injection at the dosage of 1.0 mg ceftiofur per pound (2.2 mg/kg) of body weight (0.1 ml reconstituted sterile solution per 5 lbs body weight). Treatment should be repeated at 2-hour intervals for 5-1 days. Reconstituted AXCEL Sterile Powder is to be administered to dogs by subcutaneous injection. o vial closure should be entered more than 20 times. Therefore, only the 1 gram vial is approved for use in dogs. of day-old chicks at the dosage of 0.08 to 0.20 mg ceftiofur/chick. ne ml of the 50 mg/ml reconstituted solution will treat approximately 250 to 625 day-old chicks. only. A sterile 26 gauge needle and syringe or properly cleaned automatic injection of day-old turkey poults at the dosage of 0.17 to 0.5 mg ceftiofur/poult. ne ml of the 50 mg/ml reconstituted solution will treat approximately 100 to 29 day-old turkey poults. only. As with all drugs, the use of AXCEL Sterile Powder is contraindicated in animals previously found to be hypersensitive Penicillins and cephalosporins can cause allergic reactions in sensitized individuals. Topical exposures to such antimicrobials, including ceftiofur, may elicit mild to severe allergic reactions in some individuals. Repeated or prolonged exposure may lead to sensitization. Avoid direct contact of the product with the skin, eyes, mouth, and clothing. Persons with a known hypersensitivity to penicillin or cephalosporins should avoid exposure to this product. In case of accidental eye exposure, flush with water for 15 minutes. In case of accidental skin exposure, wash with soap and water. Remove contaminated clothing. If allergic reaction occurs (e.g., skin rash, hives, difficult breathing), seek medical attention. The material safety data sheet contains more detailed occupational safety information. To obtain a material safety data sheet (MSDS) please call 1-800-733-5500. To report any adverse event please call 1-800-366-5288. RESIDUE : : When used according to label indications, dosage and routes of administration, treated cattle must not be slaughtered for days following the last treatment. When used according to label indications, dosage and routes of administration, a milk discard time is not required. Use of dosages in excess of those indicated or by in edible tissues and/or in milk. : When used according to label indications, dosage and route of administration, treated pigs must not be slaughtered for days following the last treatment. Use unapproved routes of administration may result in illegal residues in edible tissues. : either a pre-slaughter drug withdrawal interval nor a milk discard time is required when dosage, or by intramammary, may result in illegal residues : either a pre-slaughter drug withdrawal interval nor a milk discard time is required when dosage, or by intramammary, may result in illegal residues : Do not use in horses intended for human consumption. The effects of ceftiofur on the reproductive performance, pregnancy, and lactation of cattle, swine, sheep, and goats have not been determined. Following subcutaneous administration of ceftiofur sodium in the neck, small areas of discoloration at the site may persist beyond five days, potentially resulting in trim loss of edible As with any parenteral injection, localized post-injection bacterial infections may result in abscess formation. Attention to hygienic procedures can minimize their occurrence. The safety of ceftiofur has not been determined for swine intended for breeding. The safety of ceftiofur has not been determined for horses intended for breeding. The administration of antimicrobials to horses under conditions of stress may be associated with acute diarrhea that could be fatal. If acute diarrhea is observed, discontinue use of this antimicrobial and initiate appropriate therapy. The safety of ceftiofur has not been determined for dogs intended for breeding, or pregnant dogs. The use of ceftiofur may result in some signs of immediate and transient local pain to the animal. Summaries of MIC data are presented in Tables 1 and 2. Testing followed Clinical and Laboratory Standards Institute (CLSI) Guidelines. Animal Da Tes Bovine Mannheimia haemolytica 61 1988- Mannheimia haemolytica 2 19 Pasteurella multocida 318 1988- Pasteurella multocida 8 19 Histophilus somni 109 1988- Histophilus somni 59 19 Fusobacterium necrophorum 17 19 Actinobacillus pleuropn. 83 19 Pasteurella multocida 7 19 Streptococcus suis 9 19 Salmonella choleraesuis 50 19 beta-hemolytic Streptococcus spp. 2 19 Actinobacillus suis 77 19 Haemophilus parasuis 76 19 Mannheimia haemolytica 39 19 Pasteurella multocida 23 19 Canine Escherichia coli 19 Escherichia coli 18 19 Proteus mirabilis 17 19 Proteus mirabilis 23 19 Turkey Escherichia coli 120 19 Table 1. Ceftiofur MIC Values of Bacterial Isolates from *Minimum inhibitory concentration (MIC) for 90% of the iso Animal Da Tes Bovine Mannheimia haemolytica 110 1997- Mannheimia haemolytica 139 1998- Mannheimia haemolytica 209 1999- Mannheimia haemolytica 189 2000- Pasteurella multocida 107 1997- Pasteurella multocida 181 1998- Pasteurella multocida 208 1999- Pasteurella multocida 259 2000- Histophilus somni 8 1997- Histophilus somni 87 1998- Histophilus somni 77 1999- Histophilus somni 129 2000- Bacteroides fragilis group 29 199 12 199 anaerobius 12 199 Actinobacillus pleuropn. 97 1997- Actinobacillus pleuropn. 111 1998- Actinobacillus pleuropn. 126 1999- Actinobacillus pleuropn. 89 2000- Pasteurella multocida 11 1997- Pasteurella multocida 17 1998- Pasteurella multocida 173 1999- Pasteurella multocida 186 2000- Streptococcus suis 106 1997- Streptococcus suis 12 1998- Streptococcus suis 16 1999- Streptococcus suis 167 2000- Salmonella choleraesuis 96 1999- Salmonella choleraesuis 101 2000- Equine subsp. equi 12 199 subsp. equi 29 200 Streptococcus zooepidemicus 8 199 Table 2. Ceftiofur MIC Values of Bacterial Isolates from and Canada* For intramuscular and subcutaneous injection in cattle only. For intramuscular injection in swine, sheep, goats, and horses. For subcutaneous injection only in dogs, day-old chickens and day-old turkey poults. This product may be used in lactating dairy cattle, sheep, and goats. CAUTI: Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian. AXCEL Sterile Powder contains the sodium salt of ceftiofur which is a broad spectrum cephalosporin antibiotic active against gram-positive and gram-negative bacteria including β-lactamase-producing strains. Like other cephalosporins, ceftiofur is bactericidal in vitro, resulting from inhibition Each ml of the reconstituted drug contains ceftiofur sodium equivalent to 50 mg ceftiofur. The ph was adjusted with sodium hydroxide and monobasic potassium phosphate. Chemical Structure of Ceftiofur Sodium 5-Thia-1-azabicyclo[.2.0]oct-2-ene-2-carboxylic acid, 7-[[(2-amino--thiazolyl)(methoxyimino)-acetyl]amino]- 3-[[(2-furanyl-carbonyl)thio]methyl]-8-oxo-, monosodium salt, [6R-[6α,7β (Z)]]- 1 gram vial Reconstitute with 20 ml Sterile Water gram vial Reconstitute with 80 ml Sterile Water AXCEL Sterile Powder is indicated for treatment of bovine respiratory disease (shipping fever, pneumonia) associated with Mannheimia haemolytica, Pasteurella multocida and Histophilus somni. AXCEL Sterile Powder is also indicated for treatment of acute bovine interdigital necrobacillosis (foot rot, pododermatitis) associated with Fusobacterium AXCEL Sterile Powder is indicated for treatment/control AXCEL Sterile Powder is indicated for treatment of sheep respiratory disease (sheep pneumonia) associated with Mannheimia haemolytica and Pasteurella multocida. AXCEL Sterile Powder is indicated for treatment of caprine respiratory disease (goat pneumonia) associated with Mannheimia haemolytica and Pasteurella multocida. AXCEL Sterile Powder is indicated for treatment of respiratory infections in horses associated with Streptococcus zooepidemicus. AXCEL Sterile Powder is indicated for the treatment of canine urinary tract infections associated with Escherichia coli and Proteus mirabilis. to ceftiofur, in day-old chicks. to ceftiofur, in day-old turkey poults. Administer to cattle by intramuscular or subcutaneous injection at the dosage of 0.5 to 1.0 mg ceftiofur per pound (1.1 to 2.2 mg/kg) of body weight (1-2 ml reconstituted sterile solution per 100 lbs body weight). Treatment should be repeated at 2-hour intervals for a total of three consecutive days. Additional treatments may be given on days four and five for animals which do not show a satisfactory response (not recovered) after the initial three treatments. Selection of dosage (0.5 to 1.0 mg/lb) should be based on the practitioner s judgement of severity of disease (i.e., for respiratory disease, extent of elevated body temperature, depressed physical appearance, increased respiratory rate, coughing and/or loss of appetite; and for foot rot, extent of swelling, lesion and severity of lameness). Administer to swine by intramuscular injection at the dosage of 1.36 to 2.27 mg ceftiofur per pound (3.0 to 5.0 mg/kg) of body weight (1 ml of reconstituted sterile solution per 22 to 37 lbs body weight). Treatment should be repeated at 2- hour intervals for a total of three consecutive days. Administer to sheep by intramuscular injection at the dosage Administer to goats by intramuscular injection at the dosage Pharmacokinetic data indicate that elimination of the drug is more rapid in lactating does. For lactating does, the high end of the dose range is recommended. Administer to horses by intramuscular injection at the dosage of 1.0 to 2.0 mg ceftiofur per pound (2.2 to. mg/ kg) of body weight (2- ml reconstituted sterile solution per 100 lbs body weight). A maximum of 10 ml may be administered per injection site. Treatment should be repeated at 2-hour intervals, continued for 8 hours after clinical signs have disappeared and should not exceed 10 days. Administer to dogs by subcutaneous injection at the dosage of 1.0 mg ceftiofur per pound (2.2 mg/kg) of body weight (0.1 ml reconstituted sterile solution per 5 lbs body weight). Treatment should be repeated at 2-hour intervals for 5-1 days. tered to dogs by subcutaneous injection. o vial closure should be entered more than 20 times. Therefore, only the 1 gram vial is approved for use in dogs. of day-old chicks at the dosage of 0.08 to 0.20 mg ceftiofur/ chick. ne ml of the 50 mg/ml reconstituted solution will treat approximately 250 to 625 day-old chicks. tered by subcutaneous injection only. A sterile 26 gauge needle and syringe or properly cleaned automatic injection of day-old turkey poults at the dosage of 0.17 to 0.5 mg ceftiofur/poult. ne ml of the 50 mg/ml reconstituted solution will treat approximately 100 to 29 day-old turkey poults. Reconstituted AXCEL Sterile Powder is to be administered by subcutaneous injection only. As with all drugs, the use of AXCEL Sterile Powder is contraindicated in animals previously found to be hypersensitive Penicillins and cephalosporins can cause allergic reactions in sensitized individuals. Topical exposures to such antimicrobials, including ceftiofur, may elicit mild to severe allergic reactions in some individuals. Repeated or prolonged exposure may lead to sensitization. Avoid direct contact of the product with the skin, eyes, mouth, and clothing. Persons with a known hypersensitivity to penicillin or cephalosporins should avoid exposure to this product. In case of accidental eye exposure, flush with water for 15 minutes. In case of accidental skin exposure, wash with soap and water. Remove contaminated clothing. If allergic reaction occurs (e.g., skin rash, hives, difficult breathing), seek medical attention. The material safety data sheet contains more detailed occupational safety information. To obtain a material safety data sheet (MSDS) please call 1-800-733-5500. To report any adverse event please call 1-800-366-5288. RESIDUE : : When used according to label indications, dosage and routes of administration, treated cat- tle must not be slaughtered for days following indications, dosage and routes of administration, a milk discard time is not required. Use of dosages routes of administration, such as : When used according to label indica- tions, dosage and route of administration, treated pigs must not be slaughtered for days following the last treatment. Use of dosages in excess of those indicated or by unapproved routes of administration may result in illegal residues in edible tissues. : either a pre-slaughter drug withdrawal : either a pre-slaughter drug withdrawal : Do not use in horses intended for human consumption. The effects of ceftiofur on the reproductive performance, pregnancy, and lactation of cattle, swine, sheep, and goats have not been determined. Following subcutaneous administration of ceftiofur sodium in the neck, small areas of discoloration at the site may persist beyond five days, potentially resulting in trim loss of edible As with any parenteral injection, localized post-injection bacterial infections may result in abscess formation. Attention to hygienic procedures can minimize their occurrence. The safety of ceftiofur has not been determined for swine intended for breeding. The safety of ceftiofur has not been determined for horses intended for breeding. The administration of antimicrobials to horses under conditions of stress may be associated with acute diarrhea that could be fatal. If acute diarrhea is observed, discontinue use of this antimicrobial and initiate appropriate therapy. The safety of ceftiofur has not been determined for dogs intended for breeding, or pregnant dogs. The use of ceftiofur may result in some signs of immediate and transient local pain to the animal. Summaries of MIC data are presented in Tables 1 and 2. Testing followed Clinical and Laboratory Standards Institute (CLSI) Guidelines. swine and cattle after a single intramuscular injection of 1.36 to 2.27 mg ceftiofur equivalents/lb (3.0 to 5.0 mg/kg) BW (swine) or 0.5 to 1.0 mg ceftiofur equivalents/lb (1.1 to 2.2 mg/kg) BW (cattle) and the MIC and disk (30 µg) diffusion data, the following breakpoints are recommended by CLSI. Zone Diameter MIC Interpretation A report of Susceptible indicates that the pathogen is likely to be inhibited by generally achievable blood levels. A report of Intermediate is a technical buffer zone and isolates falling into this category should be retested. Alternatively the organism may be successfully treated if the infection is in a body site where drug is physiologically concentrated. A are unlikely to be inhibitory and other therapy should be selected. horses after a single intramuscular injection of 1 mg ceftiofur equivalents/lb (2.2 mg/kg) BW, clinical effectiveness data and MIC data, the following breakpoint is recommended by CLSI. Zone Diameter MIC Interpretation 22 0.25 (S) Susceptible The susceptible only category is used for populations of organisms (usually one species) for which regression analysis (disk vs. MIC) cannot be performed. These breakpoints will permit detection of strains with decreased susceptibility as compared to the original population. Standardized procedures 1 require the use of laboratory control organisms for both standardized diffusion techniques and standardized dilution techniques. The 30 µg ceftiofur sodium disk should give the following zone diameters and the ceftiofur sodium standard reference powder (or disk) should provide the following MIC values for the reference strain. Ceftiofur sodium disks or powder reference standard is appropriate for both ceftiofur salts. Mannheimia haemolytica 61 1988 1992 0.06 0.03 0.13 Mannheimia haemolytica 2 1993 0.015 0.003 0.03 Pasteurella multocida 8 1993 0.003 0.003 0.015 Fusobacterium necrophorum 17 199 0.06 no range Pasteurella multocida 7 1993 0.03 0.03 0.06 Streptococcus suis 9 1993 0.25 0.03 1.0 beta hemolytic Streptococcus spp. 2 1993 0.03 0.03 0.06 SHEEP Mannheimia haemolytica 39 1992 0.13 0.03 0.13 Pasteurella multocida 23 1992 0.03 no range Escherichia coli 1992.0 0.06 6.0 Escherichia coli 18 1990 0.25 0.13 0.5 Proteus mirabilis 17 1990 0.06 0.06 0.5 Proteus mirabilis 23 1992 1.0 0.06.0 Escherichia coli 120 1995 1.0 0.13 >32.0 Table 2. Ceftiofur MIC Values of Bacterial Isolates from Diagnostic Laboratories in the USA and Canada* * 12 199 16.0 0.13 >16.0 anaerobius 12 199 2.0 0.13 2.0 EQUIE subsp. equi 12 199 0.0019 no range subsp. equi 29 2002 0.03 0.03 0.05 Streptococcus zooepidemicus 8 199 0.0019 no range Streptococcus zooepidemicus 59 2002 0.03 0.03 0.25 Rhodococcus equi 66 1998.0 0.03 16.0 Rhodococcus equi 2 2002 8.0 0.03 >32.0 Bacteroides fragilis group 32 1995 >16.0 0.13 >16.0 12 1995.0 0.25.0 Fusobacterium necrophorum 16 1995 0.06 no range Escherichia coli 26 2000 32 0.25 >32.0 Proteus mirabilis 1 2000 0.25 0.06 0.25 Escherichia coli 17 1998-1999 1.0 0.25 1.0 Escherichia coli 25 1999-2000 0.50 0.12 0.5 Escherichia coli 20 2000-2001 2.0 0.12 16.0 Citrobacter spp. 37 1995 32.0 0.5 >32.0 Enterobacter spp. 51 1995 >32.0 0.13 >32.0 Klebsiella spp. 100 1995 1.0 0.13 2.0 Proteus spp. 19 1995 1.0 0.06 32.0 Pseudomonas spp.*** 31 1995 >32.0 0.06 >32.0 Salmonella spp. 2 1995 1.0 0.5 1.0 (coagulase positive) 17 1995 2.0 1.0 2.0 (coagulase negative) 26 1995 8.0 0.13 >32.0 CHICKE Escherichia coli 62 1997-1998 0.50 0.25 2.0 Escherichia coli 53 1998-1999.0 0.25 >.0 Escherichia coli 67 1999-2000 0.50 0.12 16.0 Escherichia coli 90 2000-2001 1.0 0.03 8.0 * The following in vitro data are available but their clinical significance is unknown. * ***MIC50 is 32 µg/ml. Table 3. Acceptable quality control ranges for ceftiofur against ational Committee for Clinical Laboratory Standards recommended American type Culture Collection (ATCC) reference strains name (ATCC o.) Staphylococcus aureus (29213) 0.25 1.0 Staphylococcus aureus (25923) 27 31 Pseudomonas aeruginosa (27853) 1 18 16.0 6.0 Actinobacillus pleuropneumoniae (27090) 3 2** 0.00 0.015*** Histophilus somni (700025) 36 6** 0.0005 0.00*** ** Quality control ranges are applicable only to tests performed by disk diffusion test using a chocolate Mueller-Hinton agar, incubated in 5-7% C2 for 20-2 hours. *** MIC quality control ranges are applicable only to tests performed by broth microdilution procedures using veterinary fastidious medium (VFM). calves indicated that formulated ceftiofur was well tolerated at 25 times (25 mg/lb/day) the highest recommended dose of 1.0 mg/lb/day for five consecutive days. Ceftiofur administered intramuscularly had no adverse systemic effects. In a 15-day safety/toxicity study, five steer and five heifer calves per group were intramuscularly administered formulated ceftiofur at 0 (vehicle control), 1, 3, 5 and 10 times the highest recommended dose of 1.0 mg/lb/day to determine indicating that the formulated ceftiofur has a wide margin of safety when injected intramuscularly into the feeder calves at 10 times (10 mg/lb/day) the recommended dose for three times (15 days) the recommended three to five days of therapy. The formulation was shown to be a slight muscle irritant based on results of histopathological evaluation of the injection sites at 1 and 3 times the highest recommended dose of 1.0 mg/lb/day. The histopathological evaluations were conducted at posttreatment days 1, 3, 7 and 1. The injection of AXCEL Sterile Powder at the recommended dose administered SC in the neck of cattle was well tolerated. However, a several square centimeter area of yellowred discoloration resulting from a single SC injection persisted in many of the cattle beyond.5 days post-injection. Also, one of the animals developed an abscess at the injection site. pigs indicated that formulated ceftiofur was well tolerated when administered at 57 mg/lb (more than 25 times the high- est recommended daily dosage of 2.27 mg/lb of body weight) for five consecutive days. Ceftiofur administered intramuscu- larly to pigs produced no overt adverse signs of toxicity. To determine the safety factor and to measure the muscle irritancy potential in swine, a safety/toxicity study was conducted. Five barrows and five gilts per group were intramuscularly administered formulated ceftiofur at 0, 2.27, 6.81 and 11.36 mg/lb of body weight for 15 days which is 0, 1, 3 and 5 times the highest recommended dose of 2.27 mg/lb of body weight/day and 5 times the recommended treatment length of 3 days. There were no adverse systemic effects indicating that formulated ceftiofur has a wide margin of safety when injected intramuscularly into feeder pigs at the highest recommended dose of 2.27 mg/lb/day for 3 days or at levels up to 5 times the highest recommended dose for 5 times the recommended length of treatment. The formulation was shown to be a slight muscle irritant based on results of histopathological evaluation of the injection sites at posttreatment days 1, 2, 3 and. By day 10 post injection the muscle reaction was subsiding and at day 15 post injection there was little evidence of muscle damage in any of the pigs in any of the treatment groups. In a 15-day safety/toxicity study in sheep, three wether and three ewe lambs per group were given formulated ceftiofur sodium by the intramuscular route 0 (sterile water vehicle), 1, 3 or 5 times the recommended dose of 1.0 mg/lb/day for 3 times the recommended maximum duration of 5 days of treatment. There were no adverse systemic effects indicating that formulated ceftiofur is well tolerated and has a wide margin of safety in sheep. Based on examination of injection sites from study days 9, 11, 13 and 15, a low incidence of visual changes and histopathologic findings of mild, reversible inflammation from all groups including the controls indicated that the formulation is a slight muscle irritant. In a 15-day safety/toxicity study 5 lactating does, 5 dry does, and 5 wethers were given formulated ceftiofur by the intramuscular route with 11 mg/kg/day for 15 days. This constitutes 5 times the recommended dose for 3 times the recommended maximum duration of 5 days of treatment. There were no adverse systemic effects indicating that formulated ceftiofur is well tolerated and has a wide margin of safety in goats. In a safety study, horses received a daily intramuscular injection of either 0 mg/lb/day (saline control), 1.0 mg/lb/day (50 mg/ml), 3.0 mg/lb/day (100 mg/ml), or 5.0 mg/lb/day (200 mg/ml) of an aqueous solution of ceftiofur sodium for 30 or 31 days. Ceftiofur sodium was well tolerated when administered intramuscularly to male and female horses at doses up to 5.0 mg/lb/day for 30 or 31 days. o clinical evidence of irritation was noted at any dose. The drug-related changes detected in this study were limited to a transient decrease in food consumption in horses receiving 3.0 or 5.0 mg/lb/day ceftiofur, and general mild skeletal muscle irritation at the injection sites which resolved by regeneration of muscle fibers. In a tolerance study, horses received a single daily intravenous infusion of either 0 (saline), 10.0 or 25.0 mg/lb/day of an aqueous solution (50 mg/ml) of ceftiofur for 10 days. The results indicated that ceftiofur administered intravenously at a dose of 10.0 or 25.0 mg/lb/day apparently can change the bacterial flora of the large intestine thereby leading to inflammation of the large intestine with subsequent diarrhea and other clinical signs (loose feces, eating bedding straw, dehydration, rolling or colic and a dull, inactive demeanor). Decreased food consumption, a loss of body weight, hematologic changes related to acute inflammation and stress, and serum chemistry changes related to decreased food consumption and diarrhea were also associated with treatment at these doses. The adverse effects were most severe a few days after dosing was initiated and tended to become less severe toward the end of the 10-day dosing period. Ceftiofur sodium was well tolerated at the therapeutic dose and is safe for the treatment of urinary tract infections in dogs. In the acute safety study, ceftiofur was well tolerated by dogs at the recommended level (1.0 mg/lb) for 5-1 days. When administered subcutaneously for 2 consecutive days, one of four females developed thrombocytopenia (15 days) and anemia (36 days). Thrombocytopenia and anemia also occurred at the 3X and 5X dose levels. In the reversibility phase of the study (5X dose), the thrombocytopenia reversed within 8 days, and of the two anemic animals the male recovered within 6 weeks and the female was sacrificed due to the severity of the anemia. In the 15-day tolerance study in dogs, high subcutaneous doses (25 and 125 times the recommended therapeutic dose) produced a progressive and dose-related thrombocytopenia, with some dogs also exhibiting anemia and bone marrow changes. The hematopoietic changes noted in dogs treated with ceftiofur were similar to those associated with long-term cephalosporin administration in dogs and also man. The hematopoietic effects are not expected to occur as a result of recommended therapy. In an acute toxicity study of ceftiofur in day-old chicks, a total of 60 male and 60 female chicks were each given single subcutaneous injections of 10, 100 or 1,000 mg/kg of body weight. Treatment on day 1 was followed by 6 days of observation; body weight was determined on days 1, and 7; and selected hematology parameters were evaluated on day. o meaningful differences were noted among the treated and control groups of chicks for the parameters eval- uated. Histopathologic evaluation of all deaths and chicks surviving to termination did not reveal a target organ or tissue of potential toxicity of ceftiofur when administered at up to 20 times (100 mg/kg) the intended highest use dosage. In an acute toxicity study of ceftiofur in day-old turkey poults, a total of 30 male and 30 female poults were each administered single subcutaneous injections of 100, 00 or 800 mg/kg body weight. Injection on day 1 was followed by 6 days of observation; body weight on days 1,, and 7; and selected hematology parameters on day. o meaningful differences were noted between the treated groups at 100 or 00 mg ceftiofur/kg and a negative control group for the parameters evaluated. Histopathologic evaluation of all deaths and poults surviving to termination did not reveal a Division of Pfizer Inc, Y, Y 10017 target organ or tissue of potential toxicity of ceftiofur when administered at up to 50 times (00 mg/kg) the highest use dosage. A dose of 800 mg/kg (100 times the intended highest use dosage) was toxic, resulting in clinical signs and deaths accompanied by gross and microscopic morphologic tissue alterations. A radiolabeled residue metabolism study established tolerances for ceftiofur residues in cattle kidney, liver and muscle. These tolerances of ceftiofur residues are 0. ppm in kidney, 2.0 ppm in liver, 1.0 ppm in muscle, and 0.1 ppm in milk. cattle. In this study, cattle received an intramuscular injec- tion of 1.0 mg of ceftiofur per lb body weight (2.2 mg of ceftiofur per kg body weight) for five consecutive days. Ceftiofur residues in tissues were less than the tolerances for ceftiofur residues in tissues such as kidney, liver and muscle by days after dosing. These data collectively support a -day pre-slaughter withdrawal period in cattle when used according to label directions. Radiolabeled residue metabolism studies established tolerances for ceftiofur residues in swine kidney, liver, and muscle. These tolerances of ceftiofur residues are 0.25 ppm in kidney, 3.0 ppm in liver and 2.0 ppm in muscle. swine. In this study, pigs received 2.27 mg of ceftiofur per lb body weight (5 mg of ceftiofur per kg body weight) per day for three consecutive days. Ceftiofur residues in tissues were less than the tolerances for ceftiofur residues in tissues such as kidney, liver and muscle by days after dosing. These data collectively support a -day pre-slaughter withdrawal period in swine when used according to label directions. Store unreconstituted product at controlled room temperature 20 to 25 C (68 to 77 F) [see USP]. Store reconstituted product either in a refrigerator 2 to 8 C (36 to 6 F) for up to 7 days or at controlled room temperature 20 to 25 C (68 to 77 F) [see USP] for up to 12 hours. Protect from light. Color of the cake may vary from offwhite to a tan color. Color does not affect potency. E-TIME SALVAGE PRCEDURE FR RECSTITU- TED PRDUCT At the end of the 7-day refrigeration or 12-hour room temperature storage period following reconstitution, any remaining reconstituted product may be frozen for up to 8 weeks without loss in potency or other chemical properties. This is a one-time only salvage procedure for the remaining product. To use this salvaged product at any time during the 8-week storage period, hold the vial under warm running water, gently swirling the container to accelerate thawing, or allow the frozen material to thaw at room temperature. Rapid freezing or thawing may result in vial breakage. Any product not used immediately upon thawing should be discarded. AXCEL Sterile Powder is available in the following package sizes: 1 gram vial gram vial 1 Clinical and Laboratory Standards Institute (CLSI). Perform- ance Standards for Antimicrobial Disk and Dilution Suscep- tibility Tests for Bacteria Isolated from Animals; Approved Standard Second Edition. CCLS document M31-A2. CLSI, 90 West Valley Road, Suite 100, Wayne, Pennsyl- vania 19087-1898, 2002. ADA # 10-338, Approved by FDA 81 055 27 3362-03-000 RTU Continued AXCEL Continued
For subcutaneous injection in the posterior aspect of the ear where it attaches to the head (base of the ear) in lactating dairy cattle. For subcutaneous injection in the middle third of the posterior aspect of the ear or in the posterior aspect of the ear where it attaches to the head (base of the ear) in beef and non-lactating dairy cattle. CAUTI Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian. Sterile Suspension is a ready-to-use formulation that contains the crystalline free acid of ceftiofur, which is a broad spectrum cephalosporin antibiotic active against Gram-positive and Gramnegative bacteria including ß-lactamase-producing strains. Like other cephalosporins, ceftiofur is bactericidal, in vitro, resulting from inhibition Each ml of this ready-to-use sterile suspension contains ceftiofur crystalline free acid equivalent to 200 mg ceftiofur, in a Miglyol and cottonseed oil based suspension. Figure 1. Structure of ceftiofur crystalline free acid: Chemical name of ceftiofur crystalline free acid: 7-[[2-(2-Amino--thiazolyl)-2-(methoxyimino)acetyl]amino]-3-[[(2- furanylcarbonyl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[.2.0]oct-2-ene 2-carboxylic acid Sterile Suspension is indicated for treatment of bovine respiratory disease (BRD, shipping fever, pneumonia) associated with Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni in beef, non-lactating dairy, and lactating dairy cattle. Sterile Suspension is also indicated for the control of respiratory disease in beef and non-lactating dairy cattle which are at high risk of developing BRD associated with M. haemolytica, P. multocida, and H. somni. DSAGE Treatment Administer as a single subcutaneous injection in the posterior aspect of the ear where it attaches to the head (base of the ear) to cattle at a dosage of 3.0 mg CE/lb (6.6 mg CE/kg) body weight (1.5 ml sterile suspension per 100 lb body weight). In beef and non-lactating dairy cattle, Sterile Suspension may also be administered as a single subcutaneous injection in the middle third of the posterior aspect of the ear at a dosage of 3.0 mg CE/lb (6.6 mg CE/kg) body weight (1.5 ml sterile suspension per 100 lb body weight). Most animals will respond to treatment within three to five days. If no improvement is observed, the diagnosis should be reevaluated. Control Administer as a subcutaneous injection either in the middle third of the posterior aspect of the ear or in the posterior aspect of the ear where it attaches to the head (base of the ear) to beef and nonlactating dairy cattle at a dosage of 3.0 mg CE/lb (6.6 mg CE/kg) body weight (1.5 ml sterile suspension per 100 lb body weight). Clinical studies indicate that administration of Sterile Suspension is effective for the control of respiratory disease in beef and non-lactating dairy cattle at high risk of developing BRD. ne or more of the following factors typically characterizes calves on arrival at high risk of developing BRD. are from multiple farm origins, cattle have had extended transport times (that may have included few if any rest stops), ambient temperature change from origin to arrival of 30 F or more, cattle have had continued exposure to extremely wet or cold weather conditions, cattle have experienced excessive shrink or excessive arrival processing procedures (such as castration, dehorning). Table 1. Dosing Schedule for Sterile Suspension Treatment at Weight (lb) 3 mg CE/lb (ml) Weight (lb) Treatment at 3 mg CE/lb (ml) 100 1.5 1100 16.5 200 3.0 1200 18.0 300.5 1300 19.5 00 6.0 100 21.0 500 7.5 1500 22.5 600 9.0 1600 2.0 700 10.5 1700 25.5 800 12.0 1800 27.0 900 13.5 1900 28.5 1000 15.0 2000 30.0 ADMIISTRATI ADMIISTRATI FR THE MIDDLE THIRD F THE EAR Shake well before using. Please read the complete package insert before administering Sterile Suspension subcutaneously in the posterior ear of cattle. Deposit as a single subcutaneous injection in the middle third of the posterior aspect of the ear, avoiding all blood vessels. See Figures 2 and 3. Adjust the needle insertion point to avoid any blood vessels, previous implants, ear tags or ear tag holes. Do not administer intra-arterially. Deliver the entire contents of the syringe. When administered correctly, a subcutaneous bleb of Sterile Suspension will appear. When withdrawing the needle, apply pressure to the needle insertion point, and massage toward the base of the ear. ADMIISTRATI FR THE BASE F THE EAR Shake well before using. Please read the complete package insert before administering Sterile Suspension subcutaneously at the posterior aspect of the ear where it attaches to the head (base of the ear). Hold the syringe and needle behind the ear to be dosed so the needle and syringe point in the direction of an imaginary line that would pass through the head toward the animal s opposite eye. See Figures and 5. Insert the needle through the loose skin in the posterior aspect of the ear where it attaches to the head (base of the ear) while maintaining this angle. See Figure. Deliver the entire contents of the syringe. Do not administer Sterile Suspension in the neck. Figure 2. Subcutaneous administration of Sterile Suspension in the middle third of the posterior aspect of the ear. As with all drugs, the use of Sterile Suspension is contraindicated in animals previously found to be hypersensitive FR USE I AIMALS LY. T FR HUMA USE. KEEP UT F REACH F CHILDRE. Penicillins and cephalosporins can cause allergic reactions in sensitized individuals. Topical exposures to such antimicrobials, including ceftiofur, may elicit mild to severe allergic reactions in some individuals. Repeated or prolonged exposure may lead to sensitization. Avoid direct contact of the product with the skin, eyes, mouth and clothing. Sensitization of the skin may be avoided by wearing latex gloves. Persons with a known hypersensitivity to penicillin or cephalosporins should avoid exposure to this product. In case of accidental eye exposure, flush with water for 15 minutes. In case of accidental skin exposure, wash with soap and water. Remove contaminated clothing. If allergic reaction occurs (e.g., skin rash, hives, difficult breathing), seek medical attention. The material safety data sheet contains more detailed occupational safety information. To obtain a material safety data sheet (MSDS) please call 1-800-733-5500. To report any adverse event please call 1-800- 366-5288. Injection of Sterile Suspension into the arteries of the ear is likely to result in sudden death to the animal. RESIDUE Following label use as a single treatment, a 13-day preslaughter withdrawal period is required. Following label use as a single treatment, no milk discard period is required for this product. Use of dosages in excess of 6.6 mg CE/kg or administration by unapproved routes (subcutaneous injection in the neck or intramuscular injection) may cause violative residues. A withdrawal period has not been established for this product in pre-ruminating calves. Do not use in calves to be processed for veal. Following subcutaneous injection in the middle third of the posterior aspect of the ear, thickening and swelling (characterized by aseptic cellular infiltrate) of the ear may occur. As with other parenteral injections, localized post-injection bacterial infections may result in abscess formation. Attention to hygienic procedures can minimize their occurrence. Following injections at the posterior aspect of the ear where it attaches to the head (base of the ear), areas of discoloration and signs of inflammation may persist at least 13 days post administration resulting in trim loss of edible tissue at slaughter. Injection of volumes greater than 20 ml, in the middle third of the ear, may result in open draining lesions in a small percentage of cattle. The effects of ceftiofur on bovine reproductive performance, pregnancy, and lactation have not been determined. ADVERSE EFFECTS Administration of Sterile Suspension into the ear arteries is likely to result in sudden death in cattle. During the conduct of clinical studies, there was a low incidence of acute death (nine out of approximately 6000 animals). Three of these deaths were confirmed to be the result of inadvertent intra-arterial injection. o other adverse systemic effects were noted for either the antibiotic or formulation during any of the clinical and target animal safety studies. CLIICAL PHARMACLGY : Ceftiofur administered as either ceftiofur sodium (AXCEL Sterile Powder), ceftiofur hydrochloride ( RTU Sterile Suspension), or ceftiofur crystalline free acid ( Sterile Suspension) is metabolized rapidly to desfuroylceftiofur, the primary metabolite. Subcutaneous administration of ceftiofur crystalline free acid, either in the middle third of the posterior aspect of the ear (middle third of the ear, ME) of beef and non-lactating dairy cattle, or in the posterior aspect of the ear where it attaches to the head (base of the ear, BE) of beef, non-lactating dairy, and lactating dairy cattle, provides therapeutic concentrations of ceftiofur and desfuroylceftiofur-related metabolites in plasma above the MIC90 for the bovine respiratory disease (BRD) label pathogens, Pasteurella multocida, Mannheimia haemolytica and Histophilus somni, for generally not less than 150 hours after a single administration (See Figure 6). The pharmacokinetic parameters for the two subcutaneous locations of injection (ME and BE) are found in Table 2. Statistical analyses of the data from these two subcutaneous injection sites (ME and BE) demonstrate that they are therapeutically equivalent. Figure 6. Average plasma concentrations of ceftiofur and desfuroylceftiofur-related metabolites after administration of Sterile Suspension at 6.6 mg ceftiofur equivalents (CE)/kg via subcutaneous injection into one of two different locations of the ear, middle third of the ear (ME ) and base of the ear (BE ) in beef cattle as well into the base of the ear (BE Lactating) in lactating dairy cattle. Table 2. Pharmacokinetic parameters measured after a single SC administration of 3 mg CE/lb body weight (BW) of Sterile Suspension in either the middle third of the ear or the base of the ear. Pharmacokinetic Parameter Beef - Middle Third of the Ear Mean Value Beef - Base of the Ear Mean Value Dairy Cow - Base of the Ear Mean Value C max 6.90 ± 2.68 6.39 ± 1.79. ± 1.65 t max (h) 12.0 ± 6.2 19.8 ± 5.81 19.00 ± 8.02 AUC0-LQ (µg h/ml) 376 ± 66.1 12 ± 67.3 313 ± 85.5 t >0.2, model (h) 183 ± 0.8 E E t >0.2, nca (h) 26 ± 8.5 218 ± 5.5 205 ± 35.7 t1/2 (h) 62.3 ± 13.5 0.7 ± 11.2 3.92 ± 9.8 C max = maximum plasma concentration (in µg CE/mL). tmax (h) = the time after injection when Cmax occurs (in hours). AUC0-LQ (µg h/ml) = the area under the plasma concentration vs. time curve from time of injection to the limit of quantitation of the assay (0.15 µg CE/mL). Figure 3. Diagram of the approximate locations of the major arteries of the posterior ear and the recommended needle insertion locations. Administration of Sterile Suspension into ear arteries is likely to be fatal. Figure. Subcutaneous administration of Sterile Suspension at the posterior aspect of the ear where it attaches to the head (base of the ear). t>0.2, model (h) = the time plasma concentrations remain above 0.2 µg CE/mL (in hours), estimated using compartmental pharmacokinetic techniques. t>0.2, nca (h) = the time plasma concentrations remain above 0.2 µg CE/mL (in hours), estimated using noncompartmental pharmacokinetic techniques. t1/2 (h) = terminal phase biological half life (in hours) E = ot estimated Ceftiofur has demonstrated in vitro activity against Mannheimia haemolytica, P. multocida and H. somni, the major pathogenic bacteria associated with BRD (Pneumonia, shipping fever). A summary of minimum inhibitory concentrations (MIC) for various cattle pathogens is presented in Table 3. Isolates were obtained in the United States and Canada. Testing followed the Clinical and Laboratory Standards Institute (CLSI) Guidelines. 1 Quality control strains were included in each run and results were within acceptable ranges. Table 3. Ceftiofur MIC values from field studies evaluating BRD in the US (1997-1998) s* MIC90** tested Mannheimia haemolytica 110 0.03 0.25 0.06 1997 1998 Pasteurella multocida 107 0.03 0.25 0.03 1997 1998 Histophilus somni 8 0.03 0.25 0.03 1997 1998 * Clinical isolates supported by clinical data and indications for use. **The minimum inhibitory concentration for 90% of the isolates. Based on pharmacokinetic and clinical effectiveness studies of ceftiofur in cattle after a single administration of 6.6 mg CE/kg (3 mg CE/lb) BW and the MIC and disk (30 µg) diffusion data, the following breakpoints are recommended by the Clinical and Laboratory Standards Institute. Zone Diameter MIC Interpretation 21 2.0 (S) Susceptible 17 8.0 (R) Resistant A report of Susceptible indicates that the pathogen is likely to be inhibited by generally achievable blood levels. A report of Intermediate is a technical buffer zone and isolates falling into this category should be retested. Alternatively the organism may be successfully treated if the infection is in a body site where drug is physiologically concentrated. A are unlikely to be inhibitory and other therapy should be selected. Standardized procedures require the use of laboratory control organisms for both standardized diffusion techniques and standardized dilution techniques. The 30 µg ceftiofur sodium disk and the ceftiofur sodium standard reference powder (or disk) should provide MIC values and zone diameters for the reference strains as presented in Table. Ceftiofur sodium disks or powder reference standard are appropriate for all forms of ceftiofur (sodium, hydrochloride and free acid). Table. Acceptable quality control ranges for ceftiofur against Clinical and Laboratory Standards Institute recommended American Type Culture Collection (ATCC) reference strains (ATCC o.) MIC Zone Diameter Escherichia coli (ATCC 25922) 0.25-1.0 26-31 Staphylococcus aureus (ATCC 29213) 0.25-1.0 S. aureus (ATCC 25923) 27-31 Pseudomonas aeroginosa (ATCC 27853) 16.0-6.0 1-18 CLIICAL EFFECTIVEESS A field dose confirmation study for the treatment of BRD evaluated the effectiveness of single doses of 2 and 3 mg CE/lb BW (. to 6.6 mg CE/kg) for the treatment of the bacterial component of BRD under field conditions. All treatments were administered SC in the middle third of the posterior aspect of the ear. were clinically evaluated on days 2-, 1 and 28 and were observed on all other study days. The 6.6 mg CE/kg (3 mg CE/lb) Sterile Suspension dose significantly (P 0.05) increased day 1 treatment success rate, defined as animals that did not require any ancillary treatment and had a rectal temperature of <10 F, normal respiration index, and had no or mild depression on that day. The effectiveness of a single dose of Sterile Suspension for the control of BRD in feedlot cattle was evaluated in a nine-location field effectiveness study. In addition to standard processing on arrival at feedlots, cattle (n=3911) considered to be at high risk for BRD were assigned to one of four arrival treatments, including Sterile Suspension at 2 or 3 mg CE/lb BW (. or 6.6 mg CE/kg) or negative control. Effectiveness evaluation was based on the incidence of clinical BRD within 28 days following arrival processing. Administration of a single dose of Sterile Suspension administered SC in the middle third of the posterior aspect of the ear at arrival processing significantly reduced the incidence of BRD in high risk feedlot cattle in the 28-day period after arrival processing compared to negative controls. Base of the ear administration (beef and non-lactating dairy cattle) and middle third of the ear administration (lactating dairy cattle) were compared to the middle third of the ear pharmacokinetic data for beef and non-lactating dairy cattle and were found to be therapeutically equivalent. After parenteral administration, Sterile Suspension, ceftiofur sodium and ceftiofur hydrochloride accede to the same principal metabolite, desfuroylceftiofur. Therefore, studies conducted with ceftiofur sodium are adequate to evaluate the systemic safety of Sterile Suspension. Results from a five-day tolerance study conducted with ceftiofur sodium in normal feeder calves indicated that ceftiofur was well tolerated at 25 mg CE/lb/day for five consecutive days, approximately 8 times the highest approved dose of Sterile Suspension (3 mg CE/lb). Ceftiofur administered parenterally had no adverse systemic effects. In a 15-day safety/toxicity study, five steer and five heifer calves per group were administered ceftiofur sodium intramuscularly at 0 (vehicle control), 1, 3, 5 or 10 mg CE/lb/day thus, evaluating up to 3.3 times the highest recommended dose of Sterile Suspension of 3.0 mg CE/lb/day. There were no adverse systemic effects, indicating that ceftiofur has a wide margin of safety when injected intramuscularly into feeder calves. Local tissue tolerance to subcutaneous injection of Sterile Suspension in the posterior ear of cattle was evaluated in a separate study. In approximately 6,000 tested animals, nine animals have died following injection of Sterile Suspension. All deaths were within 30 minutes of the time of injection. The exact cause was confirmed in three animals. These deaths resulted from inadvertent intra-arterial injection of this oil-based suspension into one of the two major auricular (ear) arteries. Intra-arterial injection at this location resulted in direct administration of the oil-based formulation into the arterial blood supply of the brain resulting in embolism and death. Since intra-arterial injection was confirmed in three animals that died following injection of Sterile Suspension, the consequences of purposeful intra-arterial injection of Sterile Suspension were investigated in feeder cattle. Two heifers (body weight approximately Figure 5. Injection location for the subcutaneous administration of Sterile Suspension at the posterior aspect of the ear where it attaches to the head (base of the ear). 225 kg) were given a single 6.6 mg CE/kg bolus dose of Sterile Suspension in the middle auricular artery. Both heifers collapsed immediately and died within approximately eight minutes of injection. Intra-arterial injection of Sterile Suspension in the ear will result in death and must be avoided. Since subcutaneous injection in the ear may potentially result in inadvertent intravenous administration of an injectable product, the consequences of purposeful intravenous injection of Sterile Suspension were investigated in feeder cattle. Three heifers and 3 steers (body weight range 197-223 kg) were given a single 6.6 mg CE/kg bolus dose of Sterile Suspension in the jugular vein and were monitored for adverse effects following injection. ne steer and one heifer had transient (2-5 minutes) increases in heart rate without any other untoward signs in these or the other cattle. Intravenous injection of Sterile Suspension is an unacceptable route of administration. Subcutaneous administration in the middle third of the posterior aspect of the ear A study was designed and conducted to specifically address tissue tolerance in cattle when Sterile Suspension was administered as a single subcutaneous injection into the posterior aspect of the ear of cattle at the recommended dose of 3 mg CE/lb body weight (6.6 mg CE/kg). Results from this study indicate that the subcutaneous injection of Sterile Suspension into the middle third of the posterior aspect of the ear of cattle is well tolerated and characterized by a biphasic thickening of the ear. The initial increase in thickness is attributed to the space required for the volume of injected material. Additional increases in thickness were observed through day 1 after injection. After day 1, post injection ear thickness decreased in all animals. ne animal carried an injected ear in a drooping position for 7 days post injection. At necropsy, subcutaneous areas of discoloration and some foci of hemorrhage were observed in ears of injected cattle. The discoloration was markedly reduced in size by the end of the study. Ears are inedible tissues in the US (9 CFR 301.2). o signs of irritation were observed on the edible portions of the carcass around the base of the ear. The local tolerance of the ear of cattle to a single SC injection of Sterile Suspension was also evaluated in a large multilocation field efficacy study. one of the 1927 animals treated with Sterile Suspension were removed from this trial due to ear irritation although swelling was noted at some injection sites. Leak back and/or bleeding from the injection site was observed in a small fraction of the treated animals immediately after administration. It was concluded that administration of Sterile Suspension in the posterior aspect of the ear was well tolerated and was acceptable under feedlot conditions. A study evaluated the 56-day feedlot performance of beef steers administered Sterile Suspension alone, Sterile Suspension with a growth promoting implant, growth promoting implant alone, or neither product, in a total of 207 Angus and Angus crossbred steers. The administration of Sterile Suspension in the posterior aspect of the ear with or without growth promoting implants was well tolerated by cattle and did not adversely affect feedlot cattle performance. Based upon the results of this study, the location of implants administered after Sterile Suspension may need to be adjusted slightly within the boundaries of the middle third of the ear in some animals. Subcutaneous administration in the posterior aspect of the ear where it attaches to the head (base of the ear) Base of the ear injection in beef cattle: The systemic safety of ceftiofur concentrations resulting from product administration at the base of the ear was established via a pharmacokinetic comparison of the two routes of administration (base of the ear versus middle third of the ear). Based upon the results of this relative bioavailability study, it was determined that the two routes of administration are therapeutically equivalent. The local tolerance of the ear to a single SC injection at the posterior aspect of the ear where it attaches to the head (base of the ear) of Sterile Suspension was evaluated in a multi-location field study in 2926 beef cattle. ormal restraint was adequate for administration of Sterile Suspension for 99.8% of cattle. o post injection problems (excessive bleeding or leak back) were observed in 99.8% of cattle. n Days 28 and 56 post-injection, 97.8% and 98.9% of the cattle had normal (no observed swelling) ears. In a residue study, 72 beef cattle were injected in the posterior aspect of the ear where it attaches to the head (base of the ear) with Sterile Suspension at a dose rate of 6.6 mg CE/kg BW. Injection sites were observed daily from treatment to necropsy (, 7, 10, or 13 days post-injection) for swelling and drooping, and evaluated grossly at necropsy, using skinning and trimming procedures similar to slaughterhouse practices. All animals had injection site swelling during the study; swelling resolved prior to euthanasia in 23 of 72 animals. one of the animals showed ear drooping. At necropsy, signs of inflammation (hemorrhage, congestion, and firmness of tissue) and presence of drug material were seen in the area around the injection site and on the carcass. At 13 days post-injection, gross lesions were found in the inedible portions of the base of the ear in all 18 animals, and in the exposed carcass tissue in 11 of 18 animals. Base of the ear injection in dairy cattle: The local tolerance of the ear to a single SC injection at the posterior aspect of the ear where it attaches to the head (base of the ear) of Sterile Suspension was evaluated in a multi-location field study in 11 adult dairy cattle. Successful injection in the base of the ear was achieved in 97.% of cattle using normal facilities and restraint equipment. o leak back or excessive bleeding was observed following injection for 99.1% of cattle, with injection volumes ranging from 15 to 30 ml. n Days 28 and 56 following injection of Sterile Suspension in the base of the ear, 95.6% and 100% of ears, respectively, were observed as normal with no injection site swelling. In a residue study, 6 dairy cows were injected in the posterior aspect of the ear where it attaches to the head (base of the ear) at a dose rate of 6.6 mg CE/kg of Sterile Suspension. o animals exhibited drooping ears at any time after treatment but all animals had signs of swelling at the injection site at all observations times after treatment. Cows were slaughtered 10 days after injection. At necropsy, all 6 cows showed evidence of injection site inflammation (discoloration of fat tissue/fascia) and of 6 cows had discoloration of tissue dorsal and posterior to the ear canal on the carcass. In addition to discoloration, tan nodules and a milky white fluid exudate were also present at the sectioned surface. A radiolabeled residue metabolism study established tolerances for ceftiofur residues in cattle kidney, liver and muscle. These tolerances of ceftiofur residues are 0. ppm in kidney, 2.0 ppm in liver, 1.0 ppm in muscle, and 0.1 ppm in milk. dairy cattle. In this study, cows received a single injection of 6.6 mg of ceftiofur per kg body weight (3.0 mg per pound). Ceftiofur residues in tissues were less than the tolerances for ceftiofur residues in tissues such as the kidney, liver and muscle by 13 days after dosing. These data collectively support a 13-day pre-slaughter withdrawal period. A pivotal milk residue decline study was conducted in lactating dairy cattle. In this study, cows received a single injection of 6.6 mg of ceftiofur per kg body weight (3.0 mg/pound). Ceftiofur residues in milk were less than tolerances at all time points after treatment. These data collectively support that no milk discard period is required for this product. Store at controlled room temperature 20 to 25 C (68 to 77 F) [see USP]. Shake well before using. Contents should be used within 12 weeks after the first dose is removed. Sterile Suspension is available in the following package size: 100 ml vial 1 ational Committee for Clinical Laboratories Standards (now Clinical and Laboratories Standards Institute). Performance Standards for Antimicrobial Disk and Dilution Susceptibility Tests for Bacteria Isolated from Animals; Approved Standard. CCLS Document M31-A (ISB 1-56238-377-9) CLSI, 90 West Valley Road, Suite 100, Wayne, Pennsylvania 19087-1832, 1999. U.S. Patent o. 5,721,359 and other patents pending. ADA #11-209, Approved by FDA Division of Pfizer Inc, Y, Y 10017 8 www..com or call 1-866-387-2287 EXD06060 818 188 00 69232 725-23-000