June 2013 Technical Update Effects of DRAXXIN

Transcription

1 June 2013 Technical Update Effects of DRAXXIN at weaning for control of swine respiratory disease in pigs experiencing a natural outbreak James W. Eubank, DVM Robyn Fleck, DVM Zoetis Inc. 100 Campus Drive Florham Park, NJ Key Points A study was conducted under field use conditions to determine whether weaned pigs administered a single injection of DRAXXIN (tulathromycin) upon entering the nursery for the control of bacterial infections associated with swine respiratory disease (SRD) would show production advantages. Evaluated in the study were: wean-to-finish percent mortality, percent pulls to the hospital pen, percent pigs re-treated, nursery weight gain, and wean-to-finish weight gain. Pigs that had received DRAXXIN in comparison to pigs that received a placebo injection in the control group: - Had a significantly (P 0.0) lower mortality (16.83% versus 21.4%), and, - As a derived benefit of a reduction in SRD, gained 4.2 lb more on average by the first marketing, a significant (P 0.0) difference. Pigs treated with DRAXXIN had significantly (P 0.0) fewer gilts requiring antibiotic re-treatments (40.% versus 6.9%). Pigs treated with DRAXXIN had significantly (P 0.0) fewer overall pulls to a hospital pen (3.04% versus 7.18%). DRAXXIN for control of SRD provided a 1:1 return on investment: - The DRAXXIN treated group of 0 pigs produced 8,137 more pounds of pork than the 0 control pigs. - The DRAXXIN treated group marketed 29 more pigs than the control group. Comparative weight distribution results showed that more DRAXXIN group pigs reached market weights sooner than control group pigs as a derived benefit resulting from the control of SRD, which suggests that even greater return on investment might be realized as more pigs would hit packer premium price targets, depending on when they leave the finisher. DRAXXIN (tulathromycin) Injectable Solution has been formulated for intramuscular (IM) injection as a ready-to-use single dose (2. mg/kg). DRAXXIN is indicated for the control of SRD associated with A. pleuropneumoniae, Pasteurella multocida and Mycoplasma hyopneumoniae (M. hyo). DRAXXIN also provides a full course of treatment against key bacterial pathogens (Actinobacillus pleuro pneumoniae, Pasteurella multocida, Bordetella bronchiseptica, Haemophilus parasuis, and M. hyo 1 ) associated with SRD. 2,3,4, DRAXXIN persists in the lung tissues, providing a nine-day window of coverage. 6 The preslaughter withdrawal time for DRAXXIN Injectable Solution in swine is five days. DRAXXIN should not be used in animals known to be hypersensitive to the product. Please see full prescribing information (attached). 1

2 The pig flow harbored multiple bacterial and viral agents associated with SRD. The study summarized below was conducted using commercially produced weaned pigs over a 12-day period to evaluate the effects of administer - ing a single intramuscular dose (2. mg/kg body weight) of DRAXXIN for the control of SRD at weaning. Percent mortality, percent pulls to a hospital pen, percent pigs requiring antibiotic re-treatments, nursery weight gain, and wean-tofinish weight gain were determined in DRAXXIN treated pigs in comparison with saline placebotreated pigs. Study Overview: Design, Assessments, and Analysis Study Design The study was conducted in a contract research organization in Nebraska using locally sourced commercial weaned pigs from PRRS positive, M. hyo positive sources. At arrival, 17 pigs were euthanized and necropsied, and SRD was confirmed by a licensed veterinarian. - 1,100 head of pigs were sourced from two commercial sow farms and placed into an all-in/all-out (AIAO) nursery room. - On the day of arrival to the nursery, the newly weaned pigs were uniquely identified with ear tags and stocked in pens to ensure the same square foot per pig. - The pigs were maintained on un-medicated nursery starter feed for the first 21 days of the trial. They did not receive any water medications during this time. - After the nursery phase, the pigs were moved to an AIAO finisher barn until market. Day 0 Using a separate randomization schedule for gilts and barrows and for each sow farm source, pigs 2 were individually weighed and enrolled into either DRAXXIN treatment or saline controls using a blocked design. The pigs from each treatment remained commingled in their pens (Table 1). - Saline treated control pigs (n = 0) were administered 1.0 ml sterile saline per 88 lb body weight IM. - DRAXXIN treated test pigs (n = 0) were administered 1.0 ml DRAXXIN per 88 lb body weight IM. Blood samples were collected from 60 uniquely tagged subset pigs. - Serial blood samples were collected from these pigs at days 0, 33, and PRRSV PCR assays were run on pools of five at days 0 and Ten of the 60 subset pigs were left unvaccinated for M. hyo and M. hyo titers were tested via ELISA on days 0, 33, and 98. Day 4 Pigs were weighed a second time. Day 12 Pigs were weighed a final time before the first animals were marketed. Days 0-12 Each pig that died was necropsied by a veterinarian and the cause of death determined. - Bacterial cultures were performed on the lungs of the first 73 pigs that died or were euthanized and diagnosed with SRD. Any pig that had a respiratory or depression score of 1 or above (scoring system ranged from 0 3) was re-treated with EXCEDE for the first re-treatment or Baytril for the second and third re-treatments. A seven-day treatment moratorium was observed between treatments to enable the pig to respond. Any pig that was deemed unable to compete in its home pen was pulled to a hospital pen. Table 1 Design of study comparing the performance of pigs administered saline or DRAXXIN within 24 hours of placement No. Day of Article Days of Days of Blood Group Animals Treatment Administered Weighing Sampling T1 0 0 DRAXXIN T2 0 0 Saline 0, 4,12 0, 33, 98

3 For every 19 pigs treated with DRAXXIN at weaning, one pig was preserved from dying. Statistical Analysis The individual animal was the experimental unit for all statistical analyses. Initial body weight, weight gain, and ADG were analyzed by a Linear Mixed Model (LMM) approach. Percent re-treatments, hospital pen moves, and mortalities were defined as binary variables (yes=1, no=0) and analyzed using a Generalized Linear Mixed Model (GLMM). If the interaction of treatment-by-gender was significant at the % level for any parameter, an analysis was performed for that parameter separately for each gender. Results SRD Outbreak Pigs were PRRS positive at arrival in that 8/12 pools of serum were PCR positive to PRRS. The lowest cycle time was for one pool, indicating a heavy infection. By day 33, 1/11 pools was positive and the lowest cycle time was 31.4, indicating persisting PRRS viremia. PRRS outbreaks such as this one in newly weaned pigs can produce significant mortality due to secondary bacterial infections. 7,8,9 Table 2 Cause of death at necropsy for all mortalities Treatment Group Cause of death at necropsy DRAXXIN Saline CNS 2 1 CNS-SRD GIT Torsion 2 Lame 2 Navel Ill 1 Rectal Prolapse 1 SRD Septicemia-SRD 2 1 Septicemia 11 3 Grand Total Necropsies on all animals indicated that there was a large component of SRD, with the saline treated pigs having 89 deaths due to SRD, compared with the DRAXXIN pigs, which had 48 deaths (Table 2). Besides SRD, Streptococcus suis meningitis, which is commonly associated with PRRS outbreaks, 10,11 was found in both groups (Table 2). /11 of the M. hyo unvaccinated sentinel pigs were positive to M. hyo at weaning, indicating presence of maternal antibodies. By study day 21, 0/10 were positive, but by study day 98, /6 pigs were positive, indicating that M. hyo exposure had occurred during the growing period. 12,13 Percent Death Loss Pigs in the study group treated with DRAXXIN at weaning had 29 more live pigs at first marketing than the saline treated group (P < 0.0). The difference in mortality was a result of controlling SRD in the DRAXXIN treated pigs (Table 3). Table 3 DRAXXIN effect on the control of SRD mortality Treatment Group Performance Measure DRAXXIN Placebo Death Loss 91/0 120/0 (% Mortality ) 16.8%b 21.4% a a,bvalues within the same row with different superscripts are significantly (P < 0.0) different. DRAXXIN treated pigs were 24% less likely to die than saline treated pigs. For every 19 pigs treated with DRAXXIN at weaning, one pig was prevented from dying. Nursery and Finisher Weight Gain Pigs in the study group treated with DRAXXIN at weaning gained pounds by day 4 versus 40.6 pounds in the saline treated control pigs, for a difference of 2.21 pounds at the end of the nursery phase (P < 0.0) (Table 4). Pigs in the DRAAXIN treated group gained pounds from weaning to first marketing versus the saline treated control pigs that gained pounds. This difference of 4.2 pounds of weight gain was statistically significant (P < 0.0) (Table 4). CNS = central nervous system; SRD = swine respiratory disease; GIT = gastrointestinal tract 3

4 DRAXXIN treated pigs were significantly less likely to be pulled to a hospital pen. Table 4 Derived benefits of improved weight gain Least Squares Mean + Standard Deviation (Minimum to Maximum Range) Performance Measure DRAXXIN Placebo Initial Weight (lb) n = 0 n = ± 2.0 a ± 1.9b ( ) ( ) Weight Gain to n = 471 n = 444 Day 4 (lb) ± a 40.6 ± 10.68b ( ) ( ) Weight Gain to n = 49 n = 430 Day 12 (lb) ± 32. a ± 33.9b ( ) ( ) a,bvalues within the same row with different superscripts are significantly (P < 0.0) different. Initial weight was used as a covariate in the analysis of day 4 and 12 weights. Comparison of the distribution of weights at day 0 (Figure 1) and at day 12 (Figure 2) demonstrates that the population of smaller pigs on the left side of the distribution was reduced in the DRAXXIN treated pigs by the time of first marketing. This made more pigs available to the packer grid in the DRAXXIN treated group than the saline treated group. Re-treatments and Pulls to Hospital Pen Gilts given DRAXXIN at weaning were 31% less likely to require re-treatment with another antibiotic versus those receiving saline (P < 0.0). There were also numerically fewer barrows requiring re-treatments in the DRAXXIN treated animals than those receiving saline (Table ). Pigs receiving DRAXXIN at weaning were 60% less likely to be pulled to a hospital pen than those receiving saline (P < 0.0) (Table ). Economic Analysis Performance measurements for each phase of the study are presented in Table 6. The economic analysis was based upon the difference in the pounds of pork produced up to day 12. The cost of DRAXXIN ($421.9, based on the 100 ml bottle price) represented the sole input variability. The effects associated with taking additional inputs into account are expected to provide even greater benefits. Table Re-treatments and hospital pulls in pigs receiving DRAXXIN or saline at weaning Least Squares Mean Percents Performance Measure DRAXXIN Placebo Wean to Finish Re-treatments (Barrows) 141/ / %.4% Re-treatments (Gilts) 10/264 13/ % b 6.9%a Hospital Pen Pulls 16/0 40/0 3.04% b 7.18% a a,bvalues within the same row with different superscripts are significantly (P < 0.0) different. DRAXXIN SALINE Percent Percent WEIGHT Figure 1 Histogram of pig weight distribution by treatment group at enrollment 4

5 In this study, return on investment in DRAXXIN was 1:1. Table 6 Economic impact of DRAXXIN for control of SRD DRAXXIN Total Pounds Gained 100,213 Control Total Pounds Gained 92,07 Difference 8,137 Value of Additional Pounds (assuming $0.40/lb profit) $3,24.00 DRAXXIN Number of Pigs Marketed 49 Control Number of Pigs Marketed 430 Difference 29 Value of Mortality Savings (assuming $0.00/pig cost) $1,40.00 Total Savings $4, DRAXXIN Investment 0 (includes labor) $313.0 Return on Investment 1:1 SRD = swine respiratory disease Because SRD mortality was controlled in the nursery, pigs treated with DRAXXIN produced 8,137 more pounds of pork at the end of the finisher phase as compared with the same number of pigs treated with saline. Total value of the extra pounds of pork was estimated at $3,24.80 based on a profit (additional revenue minus additional feed cost) for the pork of $0.40/lb. Based on an estimated value of $0.00 for each dead pig (weaned pig purchase price, feed, vaccines, transportation etc), it was determined that the 29 extra head that survived in the DRAXXIN group provided a comparative savings of $1,40.00 versus saline controls. The total value to DRAXXIN was realized through prevention of losses ($1,40.00) plus additional profit from weight gain ($3,24.80), which totaled $4, Assuming an input cost of ($313.00) to treat 0 pigs, investigators determined that the return on investment for controlling SRD in weaned piglets was 1:1. SALINE Percent DRAXXIN Percent WEIGHT Figure 2 Histogram of pig weight distribution by treatment group at the first marketing

6 Finisher weight distribution results suggest more DRAXXIN treated pigs would hit packer premium price targets. Conclusion and Discussion The study showed that administration of DRAXXIN at weaning reduced mortality in pigs in a flow harboring multiple bacterial and viral agents associated with SRD. The resulting improvement in pig performance resulted in increased economic returns. The distribution of weight among DRAXXIN treated pigs suggests that even greater returns on investment might be realized as more treated pigs would hit packer premium price targets upon leaving the finisher. Similar health and performance improvements were reported previously in a trial in which DRAXXIN was administered to weaned pigs contact exposed to multiple bacterial and viral pathogens including PRRSV associated with the SRD. 14 Whereas the potent antibacterial and anti-mycoplasmal activities of DRAXXIN are well documented and likely have a positive effect on production, no studies have been conducted to identify whether ancillary benefits might result from the administration of this novel antimicrobial. The study reported here illustrated that DRAXXIN, as an injectable product that provides an extended therapeutic period for the treatment of respiratory disease, was associated with the improved post-weaning performance of pigs in a flow with a high level of PRRS virus involvement and a mix of bacterial agents, several of which are well-established contributors to SRD. Important Safety Information: The preslaughter withdrawal time for DRAXXIN Injectable Solution in swine is five days. DRAXXIN should not be used in animals known to be hypersensitive to the product. Please see full prescribing information (attached). References 1. McKelvie J, Morgan JH, Nanjiani IA, Sherington J, Rowan TG, and Sunderland SJ Evaluation of tulathromycin for the treatment of pneumonia following experimental infection of swine with Mycoplasma hyopneumoniae. Vet Ther 200;6(2): Data on file, Study Report No. 1123R , Zoetis Inc. 3. Hoover TC. Health and performance improvements of pigs treated with DRAXXIN (tulathromycin) injectable solution for swine respiratory disease under field conditions. Pfizer Animal Technical Update June 2011:1 4. Publication DXS Nutsch RG, Hart FJ, Rooney KA, et al. Efficacy of tulathromycin injectable solution for the treatment of naturally occurring swine respiratory disease. Vet Ther 200;6: Nanjiani IA, McKelvie J, Benchaoui HA, et al. Evaluation of the therapeutic activity of tulathromycin against swine respiratory disease on farms in Europe. Vet Ther 200;6(2): Benchaoui HA, Nowakowski M, Sherington J, et al. Pharmacokinetics and lung tissue concentrations of tulathromycin in swine. J Vet Pharmacol Therap 2004;27: White M. Porcine respiratory disease complex (PRDC) Part 1: Introduction. Livestock 2011;16(2): Brockmeier SL, Halbur PG, Thacker EL. Porcine respiratory disease complex. In: Brogden KA, Guthmiller JM (eds). Polymicrobial Diseases. Washington DC: ASM Press;2002: Stevenson GW, Van Alstine WG, Kanitz CL. Characterization of infection with endemic porcine reproductive and respiratory syndrome virus in a swine herd. JAVMA 1994;204(12): Feng W-H, Laster SM, Tompkins M, et al. In utero infection by porcine reproductive and respiratory syndrome virus is sufficient to increase susceptibility of piglets to challenge by Streptococcus suis Type II. J Virol 2001;7(10):

7 DRAXXIN provided an extended therapeutic period in a pig flow with a high level of PRRS virus involvement and a mix of SRD bacterial agents. 11. Galina L, Pijoan C, Sitjar M, et al. Interaction between Streptococcus suis serotype 2 and porcine reproductive and respiratory syndrome virus in specific pathogen-free piglets. Vet Rec 1994;134(3): Thacker EL, Halbur PG, Ross RF, et al. Mycoplasma hyopneumoniae potentiation of porcine reproductive and respiratory syndrome virus-induced pneumonia. J Clin Microbiol 1999;37: Halbur PG. PRRS Plus PRRS virus infection in combination with other agents. In: Fact Sheet Pork Information Gateway, PRRS Compendium Producer Edition 2009; King D, Fleck R, Amodie D. Effects of Draxxin at Weaning in pigs on control of swine respiratory disease including low level of PRRS involvement and subsequent performance of pigs. Proceedings of the American Association of Veterinarians, 2013 San Diego, CA, poster 97. A special thanks to Deborah M. Amodie, Biometrician, Outcomes Research for the statistical analysis. All brands are the property of Zoetis Inc., its affiliates and/or its licensors. All other trademarks are the property of their respective owners Zoetis Inc. All rights reserved. Printed in USA. DXS

8 Antibiotic 100 mg of tulathromycin/ml For subcutaneous injection in beef and non-lactating dairy cattle and intramuscular injection in swine only. Not for use in female dairy cattle 20 months of age or older or in calves to be processed for veal. CAUTION Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian. DESCRIPTION DRAXXIN Injectable Solution is a ready-to-use sterile parenteral preparation containing tulathromycin, a semi-synthetic macrolide antibiotic of the subclass triamilide. Each ml of DRAXXIN contains 100 mg of tulathromycin as the free base in a 0% propylene glycol vehicle, monothioglycerol ( mg/ml), with citric and hydrochloric acids added to adjust ph. DRAXXIN consists of an equilibrated mixture of two isomeric forms of tulathromycin in a 9:1 ratio. Structures of the isomers are shown below. Figure 1. The chemical names of the isomers are (2R,3S,4R,R,8R,10R,11R,12S,13S,14R)-13- [[2,6-dideoxy-3-C-methyl-3- -methyl-4-c-[(propylamino)methyl]- -L-ribo-hexopyrano- syl]oxy]-2-ethyl-3,4,10-trihydroxy-3,,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3- (dimethylamino)- -D-xylo-hexopyranosyl]-oxy]-1-oxa-6-azacyclopentadecan-1-one and(2s,3s,6r,8r,9r,10s,11s,12r)-11-[[2,6-dideoxy-3-c-methyl-3- -methyl-4-c- [(propylamino)methyl]- -L-ribohexopyranosyl]oxy]-2-[(1R,2R)-1,2-dihydroxy-1-methylbutyl]- 8-hydroxy-3,6,8,10,12-pentamethyl-9-[[3,4,6-trideoxy-3-(dimethylamino)- -D-xylohexopyranosyl]oxy]-1-oxa-4-azacyclotridecan-13-one,respectively. INDICATIONS Beef and Non-lactating Dairy BRD DRAXXIN Injectable Solution is indicated for the treatment of bovine respiratory disease (BRD) associated with Mannheimia haemolytica, Pasteurella multocida, Histophilus somni, and Mycoplasma bovis; and for the control of respiratory disease in cattle at high risk of developing BRD associated with Mannheimia haemolytica, Pasteurella multocida, Histophilus somni, and Mycoplasma bovis. IBK DRAXXIN Injectable Solution is indicated for the treatment of infectious bovine keratoconjunctivitis (IBK) associated with Moraxella bovis. Foot Rot DRAXXIN Injectable Solution is indicated for the treatment of bovine foot rot (interdigital necrobacillosis) associated with Fusobacterium necrophorum and Porphyromonas levii. DRAXXIN Injectable Solution is indicated for the treatment of swine respiratory disease (SRD) associated with Actinobacillus pleuropneumoniae, Pasteurella multocida, Bordetella bronchiseptica, Haemophilus parasuis, and Mycoplasma hyopneumoniae; and for the control of SRD associated with Actinobacillus pleuropneumoniae, Pasteurella multocida, and Mycoplasma hyopneumoniae in groups of pigs where SRD has been diagnosed. DOSAGE AND ADMINISTRATION Inject subcutaneously as a single dose in the neck at a dosage of 2. mg/kg (1.1 ml/100 lb) body weight (BW). Do not inject more than 10 ml per injection site. Table 1. DRAXXIN Dosing Guide Animal Weight (Pounds) Dose Volume (ml) Inject intramuscularly as a single dose in the neck at a dosage of 2. mg/kg (0.2 ml/22 lb) BW. Do not inject more than 2. ml per injection site. Table 2. DRAXXIN Dosing Guide Animal Weight (Pounds) Dose Volume (ml) CONTRAINDICATIONS The use of DRAXXIN Injectable Solution is contraindicated in animals previously found to be hypersensitive to the drug. WARNINGS FOR USE IN ANIMALS ONLY. NOT FOR HUMAN USE. KEEP OUT OF REACH OF CHILDREN. NOT FOR USE IN CHICKENS OR TURKEYS. RESIDUE WARNINGS intended for human consumption must not be slaughtered within 18 days from the last treatment. Do not use in female dairy cattle 20 months of age or older. A withdrawal period has not been established for this product in pre-ruminating calves. Do not use in calves to be processed for veal. intended for human consumption must not be slaughtered within days from the last treatment. 8 PRECAUTIONS The effects of DRAXXIN on bovine reproductive performance, pregnancy, and lactation have not been determined. Subcutaneous injection can cause a transient local tissue reaction that may result in trim loss of edible tissue at slaughter. The effects of DRAXXIN on porcine reproductive performance, pregnancy, and lactation have not been determined. Intramuscular injection can cause a transient local tissue reaction that may result in trim loss of edible tissue at slaughter. ADVERSE REACTIONS In one field study, two calves treated with DRAXXIN at 2. mg/kg BW exhibited transient hypersalivation. One of these calves also exhibited transient dyspnea, which may have been related to pneumonia. In one field study, one out of 40 pigs treated with DRAXXIN at 2. mg/kg BW exhibited mild salivation that resolved in less than four hours. CLINICAL PHARMACOLOGY At physiological ph, tulathromycin (a weak base) is approximately 0 times more soluble in hydrophilic than hydrophobic media. This solubility profile is consistent with the extracellular pathogen activity typically associated with the macrolides. 1 Markedly higher tulathromycin concentrations are observed in the lungs as compared to the plasma. The extent to which lung concentrations represent free (active) drug was not examined. Therefore, the clinical relevance of these elevated lung concentrations is undetermined. Although the relationship between tulathromycin and the characteristics of its antimicrobial effects has not been characterized, as a class, macrolides tend to be primarily bacteriostatic, but may be bactericidal against some pathogens. 2 They also tend to exhibit concentration independent killing; the rate of bacterial eradication does not change once serum drug concentrations reach 2 to 3 times the minimum inhibitory concentration (MIC) of the targeted pathogen. Under these conditions, the time that serum concentrations remain above the MIC becomes the major determinant of antimicrobial activity. Macrolides also exhibit a post-antibiotic effect (PAE), the duration of which tends to be both drug and pathogen dependent. In general, by increasing the macrolide concentration and the exposure time, the PAE will increase to some maximal duration. Of the two variables, concentration and exposure time, drug concentration tends to be the most powerful determinant of the duration of PAE. Tulathromycin is eliminated from the body primarily unchanged via biliary excretion. 1 Carbon C. Pharmacodynamics of macrolides, azalides, and streptogramins: effect on extracellular pathogens. Clin Infect Dis 1998;27: Nightingale CJ. Pharmacokinetics and pharmacodynamics of newer macrolides. Pediatr Infect Dis J 1997;16: Following subcutaneous administration into the neck of feeder calves at a dosage of 2. mg/kg BW, tulathromycin is rapidly and nearly completely absorbed. Peak plasma concentrations generally occur within 1 minutes after dosing and product relative bioavailability exceeds 90%. Total systemic clearance is approximately 170 ml/hr/ kg. Tulathromycin distributes extensively into body tissues, as evidenced by volume of distribution values of approximately 11 L/kg in healthy ruminating calves. 3 This extensive volume of distribution is largely responsible for the long elimination half-life of this compound [approximately 2.7 days in the plasma (based on quantifiable terminal plasma drug concentrations) versus 8.7 days for total lung concentrations (based on data from healthy animals)]. Linear pharmacokinetics are observed with subcutaneous doses ranging from 1.27 mg/kg BW to.0 mg/kg BW. No pharmacokinetic differences are observed in castrated male versus female calves. 3 Clearance and volume estimates are based on intersubject comparisons of 2. mg/kg BW administered by either subcutaneous or intravenous injection. Following intramuscular administration to feeder pigs at a dosage of 2. mg/kg BW, tulathromycin is completely and rapidly absorbed (Tmax ~0.2 hour). Subsequently, the drug rapidly distributes into body tissues, achieving a volume of distribution exceeding 1 L/kg. The free drug is rapidly cleared from the systemic circulation (CL systemic =187 ml/ hr/kg). However, it has a long terminal elimination half-life (60 to 90 hours) owing to its extensive volume of distribution. Although pulmonary tulathromycin concentrations are substantially higher than concentrations observed in the plasma, the clinical significance of these findings is undetermined. There are no gender differences in swine tulathromycin pharmacokinetics. MICROBIOLOGY Tulathromycin has demonstrated in vitro activity against Mannheimia haemolytica, Pasteurella multocida, Histophilus somni, and Mycoplasma bovis, four pathogens associated with BRD; for Moraxella bovis associated with IBK; and against Fusobacterium necrophorum and Porphyromonas levii associated with bovine foot rot. The MICs of tulathromycin against indicated BRD and IBK pathogens were determined using methods recommended by the Clinical and Laboratory Standards Institute (CLSI, M31-A2). The MICs against foot rot pathogens were also determined using methods recommended by the CLSI (M11-A6). All MIC values were determined using the 9:1 isomer ratio of this compound. BRD The MICs of tulathromycin were determined for BRD isolates obtained from calves enrolled in therapeutic and at-risk field studies in the U.S. in In the therapeutic studies, isolates were obtained from pre-treatment nasopharyngeal swabs from all study calves and from lung swabs or lung tissue of saline-treated calves that died. In the atrisk studies, isolates were obtained from nasopharyngeal swabs of saline-treated nonresponders and from lung swabs or lung tissue of saline-treated calves that died. The results are shown in Table 3. IBK The MICs of tulathromycin were determined for Moraxella bovis isolates obtained from calves enrolled in IBK field studies in the U.S. in Isolates were obtained from pre-treatment conjunctival swabs of calves with clinical signs of IBK enrolled in the DRAXXIN and saline-treated groups. The results are shown in Table 3. Foot Rot The MICs of tulathromycin were determined for Fusobacterium necrophorum and Porphyromonas levii obtained from cattle enrolled in foot rot field studies in the U.S. and Canada in Isolates were obtained from pretreatment interdigital biopsies and swabs of cattle with clinical signs of foot rot enrolled in the DRAXXIN and saline-treated groups. The results are shown in Table 3. Table 3. Tulathromycin minimum inhibitory concentration (MIC) values* for indicated pathogens isolated from field studies evaluating BRD and IBK in the U.S and from foot rot field studies in the U.S. and Canada. Indicated pathogen Date No. of MIC 0 ** MIC 90 ** MIC range isolated isolates (μg/ml) (μg/ml) (μg/ml) Mannheimia haemolytica to 64 Pasteurella multocida to 64 Histophilus somni to 4 Mycoplasma bovis <_ to > 64 Moraxella bovis to 1 Fusobacterium necrophorum <_ 0.2 to >128 Porphyromonas levii <_ 0.2 to >128 * The correlation between in vitro susceptibility data and clinical effectiveness is unknown. ** The lowest MIC to encompass 0% and 90% of the isolates, respectively. In vitro activity of tulathromycin has been demonstrated against Actinobacillus pleuropneumoniae, Pasteurella multocida, Bordetella bronchiseptica, Haemophilus parasuis, and Mycoplasma hyopneumoniae. The MICs of tulathromycin against indicated SRD pathogens were determined using methods recommended by the Clinical and Laboratory Standards Institute (CLSI, M31-A and M31-A3). MICs for Haemophilus parasuis were determined using Veterinary Fastidious Medium and were incubated up to 48 hours at 3 to 37 C in a CO2-enriched atmosphere. All MIC values were determined using the 9:1 isomer ratio of this compound. Isolates obtained in 2000 and 2002 were from lung samples from saline-treated pigs and non-treated sentinel pigs enrolled in Treatment of SRD field studies in the U.S. and Canada. Isolates obtained in 2007 and 2008 were from lung samples from saline-treated and DRAXXIN-treated pigs enrolled in the Control of SRD field study in the U.S. and Canada. The results are shown in Table Zoetis Inc. All rights reserved. Printed in USA. DXS12006 Table 4. Tulathromycin minimum inhibitory concentration (MIC) values* for indicated pathogens isolated from field studies evaluating SRD in the U.S. and Canada. Indicated pathogen Date No. of MIC 0 ** MIC 90 ** MIC range isolated isolates (μg/ml) (μg/ml) (μg/ml) Actinobacillus pleuropneumoniae to 32 4 to 32 Haemophilus parasuis to > 64 Pasteurella multocida to > <0.03 to 2 Bordetella bronchiseptica to 8 * The correlation between in vitro susceptibility data and clinical effectiveness is unknown. ** The lowest MIC to encompass 0% and 90% of the most susceptible isolates, respectively. EFFECTIVENESS BRD In a multi-location field study, 314 calves with naturally occurring BRD were treated with DRAXXIN. Responses to treatment were compared to saline-treated controls. A cure was defined as a calf with normal attitude/activity, normal respiration, and a rectal temperature of 104 F on Day 14. The cure rate was significantly higher (P 0.0) in DRAXXIN-treated calves (78%) compared to saline-treated calves (24%). There were two BRD-related deaths in the DRAXXIN-treated calves compared to nine BRD-related deaths in the saline-treated calves. Fifty-two DRAXXIN-treated calves and 27 saline-treated calves from the multilocation field BRD treatment study had Mycoplasma bovis identified in cultures from pre-treatment nasopharyngeal swabs. Of the 2 DRAXXIN-treated calves, 37 (71.2%) calves were categorized as cures and 1 (28.8%) calves were categorized as treatment failures. Of the 27 saline-treated calves, 4 (14.8%) calves were categorized as cures and 23 (8.2%) calves were treatment failures. In another multi-location field study with 399 calves at high risk of developing BRD, administration of DRAXXIN resulted in a significantly reduced incidence of BRD (11%) compared to saline-treated calves (9%). Effectiveness evaluation was based on scored clinical signs of normal attitude/activity, normal respiration, and a rectal temperature of 104 F on Day 14. There were no BRD-related deaths in the DRAXXIN-treated calves compared to two BRD-related deaths in the saline-treated calves. Fifty saline-treated calves classified as non-responders in this study had Mycoplasma bovis identified in cultures of post-treatment nasopharyngeal swabs or lung tissue. Two induced infection model studies were conducted to confirm the effectiveness of DRAXXIN against Mycoplasma bovis. A total of 166 calves were inoculated intratracheally with field strains of Mycoplasma bovis. When calves became pyrexic and had abnormal respiration scores, they were treated with either DRAXXIN (2. mg/kg BW) subcutaneously or an equivalent volume of saline. Calves were observed for signs of BRD for 14 days post-treatment, then were euthanized and necropsied. In both studies, mean lung lesion percentages were statistically significantly lower in the DRAXXIN-treated calves compared with saline-treated calves (11.3% vs. 28.9%, P= and 1.0% vs. 30.7%, P<0.0001). IBK Two field studies were conducted evaluating DRAXXIN for the treatment of IBK associated with Moraxella bovis in 200 naturally-infected calves. The primary clinical endpoint of these studies was cure rate, defined as a calf with no clinical signs of IBK and no corneal ulcer, assessed on Days, 9, 13, 17, and 21. Time to improvement, defined as the first day on which a calf had no clinical signs of IBK for both eyes, provided that those scores were maintained at the next day of observation, was assessed as a secondary variable. At all time points, in both studies, the cure rate was significantly higher (P<0.0) for DRAXXIN-treated calves compared to saline-treated calves. Additionally, time to improvement was significantly less (P<0.0001) in both studies for DRAXXIN-treated calves compared to saline-treated calves. Foot Rot The effectiveness of DRAXXIN for the treatment of bovine foot rot was evaluated in 170 cattle in two field studies. diagnosed with bovine foot rot were enrolled and treated with a single subcutaneous dose of DRAXXIN (2. mg/kg BW) or an equivalent volume of saline. were clinically evaluated 7 days after treatment for treatment success, which was based on defined decreases in lesion, swelling, and lameness scores. In both studies, the treatment success percentage was statistically significantly higher in DRAXXIN-treated calves compared with saline-treated calves (60% vs. 8%, P< and 83.3% vs. 0%, P=0.0088). In a multi-location field study to evaluate the treatment of naturally occurring SRD, 266 pigs were treated with DRAXXIN. Responses to treatment were compared to saline-treated controls. Success was defined as a pig with a normal attitude, normal respiration, and a rectal temperature of <104 F on Day 7. The treatment success rate was significantly greater (P 0.0) in DRAXXIN-treated pigs (70.%) compared to saline-treated pigs (46.1%). M. hyopneumoniae was isolated from 106 saline-treated and non-treated sentinel pigs in this study. Two induced infection model studies were conducted to confirm the effectiveness of DRAXXIN against M. hyopneumoniae. Ten days after inoculation intranasally and intratracheally with a field strain of M. hyopneumoniae, 144 pigs were treated with either DRAXXIN (2. mg/kg BW) intramuscularly or an equivalent volume of saline. Pigs were euthanized and necropsied 10 days posttreatment. The mean percentage of gross pneumonic lung lesions was statistically significantly lower (P<0.0001) for DRAXXIN-treated pigs than for saline-treated pigs in both studies (8.2% vs % and 11.31% vs %). The effectiveness of DRAXXIN for the control of SRD was evaluated in a multi-location natural infection field study. When at least 1% of the study candidates showed clinical signs of SRD, all pigs were enrolled and treated with DRAXXIN (226 pigs) or saline (227 pigs). Responses to treatment were evaluated on Day 7. Success was defined as a pig with normal attitude, normal respiration, and rectal temperature of < 104 F. The treatment success rate was significantly greater (P < 0.0) in DRAXXIN-treated pigs compared to saline-treated pigs (9.2% vs. 41.2%). ANIMAL SAFETY Safety studies were conducted in feeder calves receiving a single subcutaneous dose of 2 mg/kg BW, or 3 weekly subcutaneous doses of 2., 7., or 12. mg/kg BW. In all groups, transient indications of pain after injection were seen, including head shaking and pawing at the ground. Injection site swelling, discoloration of the subcutaneous tissues at the injection site and corresponding histopathologic changes were seen in animals in all dosage groups. These lesions showed signs of resolving over time. No other drug-related lesions were observed macroscopically or microscopically. An exploratory study was conducted in feeder calves receiving a single subcutaneous dose of 10, 12., or 1 mg/kg BW. Macroscopically, no lesions were observed. Microscopically, minimal to mild myocardial degeneration was seen in one of six calves administered 12. mg/kg BW and two of six calves administered 1 mg/kg BW. A safety study was conducted in calves 13 to 27 days of age receiving 2. mg/kg BW or 7. mg/kg BW once subcutaneously. With the exception of minimal to mild injection site reactions, no drug-related clinical signs or other lesions were observed macroscopically or microscopically. Safety studies were conducted in pigs receiving a single intramuscular dose of 2 mg/ kg BW, or 3 weekly intramuscular doses of 2., 7., or 12. mg/kg BW. In all groups, transient indications of pain after injection were seen, including restlessness and excessive vocalization. Tremors occurred briefly in one animal receiving 7. mg/kg BW. Discoloration and edema of injection site tissues and corresponding histopathologic changes were seen in animals at all dosages and resolved over time. No other drugrelated lesions were observed macroscopically or microscopically. STORAGE CONDITIONS Store at or below 2 C (77 F). HOW SUPPLIED DRAXXIN Injectable Solution is available in the following package sizes: 0 ml vial, 100 ml vial, 20 ml vial, 00 ml vial U.S. Patents: See US 6,329,34; US 6,420,36; US 6,14,94; US 6,83,274; US 6,777,393 NADA , Approved by FDA To report a suspected adverse reaction call To request a material safety data sheet call For additional DRAXXIN product information call DRAXXIN or go to Made in France. December