Therapeutic Efficacy of Tulathromycin, a Novel Triamilide Antimicrobial, against Bovine Respiratory Disease in Feeder Calves*

Therapeutic Efficacy of Tulathromycin, a Novel Triamilide Antimicrobial, against Bovine Respiratory Disease in Feeder Calves* W. Randal Kilgore, DVM Michael S. Spensley, DVM Fangshi Sun, PhD Robert G. Nutsch, DVM, MS, MBA Kathleen A. Rooney, MS, DVM Terry L. Skogerboe, DVM, MBA Pfizer Animal Health Veterinary Medicine Research and Development 7000 Portage Road Kalamazoo, MI 49001 CLINICAL RELEVANCE Efficacy and field safety of tulathromycin administered as a single-dose treatment to crossbreed beef calves with undifferentiated bovine respiratory disease (BRD) were evaluated in a multicenter field study conducted at four US feedlots. Two hundred castrated male calves were enrolled at each study site. The treatment groups were physiologic saline (n = 160) at 0.02 ml/kg SC, tulathromycin (n = 320) at 2.5 mg/kg SC, and tilmicosin (n = 320) at 10 mg/kg SC. Nasopharyngeal swabs for bacterial culture were obtained before treatment. The cure rate for calves treated with tulathromycin (78%) and tilmicosin (65%) was significantly (P.0001) higher than that of calves treated with saline (23.8%). The cure rate of calves treated with tulathromycin (78.4%) was significantly (P =.0007) higher than that of calves treated with tilmicosin (64.9%). No adverse events related to tulathromycin were reported. Under the conditions of this study, tulathromycin administered as a single-dose treatment was efficacious in the treatment of undifferentiated BRD. INTRODUCTION Bovine respiratory disease (BRD) is considered the most costly disease in the beef cattle industry. A review of economic data by Griffin 1 demonstrated that the cost of BRD *This work was sponsored by Pfizer. Dr. Sun now resides in Waterford, CT. from weaning to harvest was approximately 7% of the total production cost of feeder calves. Global economic losses related to BRD are measured in billions of dollars a year, 2 4 with an estimated $3 billion spent annually on all beef animals for prevention and treatment of BRD. 1 143

Veterinary Therapeutics Vol. 6, No. 2, Summer 2005 Respiratory disease is generally regarded as the most frequent and serious cause of mortality associated with the feedlot industry. 5,6 In one retrospective cohort study of 21.8 million cattle entering 121 US feedlots from 1994 to 1999, respiratory tract disorders were the most common cause of death, accounting for 57.1% of all deaths and representing a mortality ratio of 12.6 deaths/1,000 cattle. 7 Depending on source and management history of cattle with BRD, morbidity rates may range from 5% to 50% with fatality rates (number of animals that died total number of animals treated) typically 5% to 10%. 8 Environmental, viral, and bacterial factors are all involved in BRD, and clinical presentations range from subclinical to severe effective when directed toward calves at or before their arrival in the feedlot. 11 Treatment of calves during the preclinical stage of BRD (metaphylaxis) can reduce morbidity and mortality in the feedlot. 13 The incidence of M. haemolytica colonization is reduced by administration of florfenicol 14 or tilmicosin 15 at time of arrival in a feedlot. The incidence of BRD can be reduced by the use of both preconditioning programs and on-arrival administration of antimicrobials. However, even with these management practices, the manner in which feeder cattle are often assembled and transported over long distances to feedlots makes the necessity of BRD treatment inevitable. Tulathromycin (Draxxin Injectable Solution, Pfizer Animal Health) is the first in a novel se- Respiratory disease is generally regarded as the most frequent and serious cause of mortality associated with the feedlot industry. acute bronchopneumonia or fibrinous pneumonia. 8 The major bacterial pathogens include Mannheimia (Pasteurella) haemolytica, Pasteurella multocida, Histophilus somni (Haemophilus somnus), and Mycoplasma spp, with M. haemolytica regarded as the most common primary pathogen recovered from cattle with clinical signs of BRD. 6,8,9 These bacteria are often found in the nasopharynx and upper respiratory tract of clinically healthy cattle, with M. haemolytica proliferating rapidly in the nasopharynx of calves during transport and those with virus-induced illness. 10 Although preconditioning programs (combinations of vaccination and/or weaning management) of feedlot calves may represent the most comprehensive tool for prevention of BRD morbidity after arrival in feedlots, 11 the cattle industry has not accepted preconditioning programs as a standard. 11,12 Preventive efforts may be most ries of semisynthetic, tribasic, macrolide antimicrobials designated as triamilides, 16 developed to improve the potency and spectrum of activity of macrolides currently used as therapies for BRD. 17 Tulathromycin has demonstrated a broad spectrum of activity against the bacterial pathogens of BRD. 18 Structural modifications of this subclass of compounds were designed to improve tissue distribution and to extend the drug elimination half-life in the lungs. 16 Pharmacokinetic studies of tulathromycin administered at 2.5 mg/kg have demonstrated excellent bioavailability and rapid absorption followed by extensive distribution into lung tissue. 19 Tulathromycin has also been shown to accumulate in bovine phagocytes. 20 Because of its single-dose treatment regimen, tilmicosin (Micotil 300 Injection, Elanco Animal Health), a semisynthetic macrolide given at the label dose of 10 mg/kg, is one of 144

TABLE 1. Calves from which Selected BRD Pathogens Were Isolated before Treatment No. (%) of Calves with Positive Pretreatment Nasopharyngeal Culture Treatment Group M. haemolytica P. multocida H. somni Mycoplasma spp Saline (n = 160) 98 (61.3) 30 (18.8) 12 (7.5) 88 (55.0) Tulathromycin (n = 319) 202 (63.3) 69 (21.6) 12 (3.8) 188 (58.9) Tilmicosin phosphate (n = 317) 211 (66.6) 82 (25.9) 12 (3.8) 205 (64.7) All groups combined (n = 796) 511 (64.2) 181 (22.7) 36 (4.5) 481 (60.4) TABLE 2. MICs (µg/ml) of Tulathromycin and Tilmicosin against BRD Pathogens a M. haemolytica P. multocida H. somni Mycoplasma bovis (n = 642) (n = 221) (n = 36) (n = 35) Agent Min Max MIC 90 Min Max MIC 90 Min Max MIC 90 Min Max MIC 90 Tulathromycin 0.5 64 2 0.25 64 1 1 4 4 0.063 2 1 Tilmicosin 2 >64 8 0.5 >64 8 2 16 8 0.063 >64 >64 a Of the total number of isolates, 141 M. haemolytica, 54 P. multocida, 18 H. somnus, and 13 M. bovis were obtained from saline-treated nonresponders in a four-location multicenter metaphylactic study. Max = maximum; MIC 90 = concentration that inhibited at least 90% of the isolates tested; min = minimum. the most common therapeutic agents currently being used in feedlots for BRD. 2 4,21 Historical acceptance of this single-dose, long-acting therapy by the cattle industry demonstrates the advantage of single-dose, extended efficacy antimicrobials that result in higher cure rates with fewer BRD relapses. Improved clinical efficacy minimizes the economic impact of clinical respiratory disease, which at a minimum includes the increased costs of treatment and handling, reduced weight gain, diminished carcass quality, and death loss. The purpose of this four-location multicenter study was to evaluate the efficacy and field safety of a single dose of tulathromycin when administered to newly arrived feedlot calves as a treatment for naturally occurring BRD compared with saline and tilmicosin. All studies followed the same study design. Each study was conducted according to the FDA Center of Veterinary Medicine guideline, Good Target Animal Study Practices. 22 Husbandry and care of cattle in these studies were in accordance with the Guide for the Care and Use of Agricultural Animals in Agricultural Research and Teaching. 23 MATERIALS AND METHODS Animals Feeder steers were selected from calves assembled at order buyers and transported to four US research feedlots: Calves purchased in Mississippi (n = 350; body weight, 414 640 lb) were transported to Agri Research Center, Canyon, TX. Calves purchased in Washington and Idaho (n = 453; body weight, 434 704 lb) were transported to Johnson Research, Parma, ID. 145

Veterinary Therapeutics Vol. 6, No. 2, Summer 2005 TABLE 3. Frequencies of Mortalities, Nonresponders, Day-14 Treatment Failures, and Cures No. (%) of Treatment Failures Day-14 No. (%) Treatment Group No. Mortalities a Nonresponders Nonresponders of Cures b Saline All sites 160 9 (5.6) 107 (66.9) 6 (3.8) 38 (23.8) TX site 40 4 (10.0) 30 (75.0) 0 (0.0) 6 (15.0) ID site 40 0 (0.0) 25 (62.5) 3 (7.5) 12 (30.0) NE site 40 3 (7.5) 25 (62.5) 0 (0.0) 12 (30.0) CA site 40 2 (5.0) 27 (67.5) 3 (7.5) 8 (20.0) Tulathromycin All sites 319 2 (0.6) 57 (17.9) 10 (3.1) 250 (78.4) TX site 80 0 (0.0) 18 (22.5) 1 (1.25) 61 (76.3) ID site 79 0 (0.0) 14 (17.7) 4 (5.1) 61 (77.2) NE site 80 2 (2.5) 6 (7.5) 1 (1.3) 71 (88.8) CA site 80 0 (0.0) 19 (23.8) 4 (5.0) 57 (71.3) Tilmicosin All sites 317 3 (1.0) 88 (27.8) 20 (6.3) 206 (65.0) TX site 80 1 (1.25) 31 (38.8) 6 (7.5) 42 (52.5) ID site 77 0 (0.0) 15 (19.5) 5 (6.5) 57 (74.0) NE site 80 2 (2.5) 12 (15.0) 3 (3.75) 63 (78.8) CA site 80 0 (0.0) 30 (37.5) 6 (7.5) 44 (55.0) a For all studies: saline vs tulathromycin, P =.0011; saline vs tilmicosin, P =.0035; tulathromycin vs tilmicosin, P = 1.0000. b For all studies: saline vs tulathromycin, P.0001; saline vs tilmicosin, P.0001; tulathromycin vs tilmicosin, P =.0007. Calves purchased in South Carolina, Kentucky, and Missouri (n = 561; body weight, 344 584 lb) were transported to Midwest Veterinary Services, Oakland, NE. Calves purchased in Visalia, CA (n = 400; body weight, 330 568 lb) were transported to HMS Veterinary Development, Reedley, CA. Within 24 hours of arrival, calves were processed, held in arrival yards (comparable to commercial feedlots), and observed daily until enrollment. Processing included standard industry practices of vaccination for bovine rhinotracheitis, bovine viral diarrhea, parainfluenza, and bovine respiratory syncytial virus (Bovi-Shield 4, Pfizer Animal Health), administration of clos- tridial bacterins (Ultrabac 7, Ultrabac 8, or Fortress 7, Pfizer Animal Health), and treatment of internal and external parasites (Dectomax, Pfizer Animal Health). Hormonal implants were also injected in the animals at the Texas (Ralgro Magnum, Schering-Plough Animal Health) and Idaho (Synovex S, Fort Dodge Animal Health) sites. No antimicrobials were administered during processing. Ear tags were used to identify individual animals. Calves were enrolled in the study if they demonstrated abnormal respiration (notable increase in rate and/or abnormal character of respiration); mild, moderate, or severe depression; and a rectal temperature of 104 F or greater. Calves were not enrolled in the study if 146

they had concurrent disease, received antimicrobial therapy after arrival, or demonstrated clinical signs of BRD on arrival or between the time of arrival and processing. Intact males were also excluded from the study. Enrollment and Treatments Selection, enrollment, and initiation of treatment occurred on day 0. At each of the four sites, 200 calves were randomly assigned to pens, blocks, and one of three treatments: physiologic saline at 0.02 ml/kg, tulathromycin (Draxxin) at 2.5 mg/kg (1.1 ml/100 lb), or tilmicosin (Micotil, Elanco Animal Health) at 10 mg/kg (1.5 ml/100 lb). Treatments were administered SC once on the lateral side of the neck based on day 0 (day of treatment) body weights. At each injection site, the injection volume of each test material did not exceed 10 ml. Calves were blocked on order of enrollment with five calves in each block: one calf treated with saline, two with tulathromycin, and two with tilmicosin. Each pen contained two blocks of five calves each. Only complete pens of calves were enrolled on any enrollment day. Personnel not responsible for any other clinical assessments administered treatments to maintain masking. Data Collection Nasopharyngeal swabs for culture, isolation, and identification of BRD pathogens were obtained from all calves before treatment. Minimum inhibitory concentrations (MICs) of bacterial pathogens were determined by Colorado Animal Research Enterprise at Fort Collins, CO. Mycoplasmal identification and MIC determination were performed at the Animal Disease and Diagnostic Laboratory at Purdue University following methods previously described. 24 26 Microdilution plates with broth containing doubling dilutions of both tulathromycin and tilmicosin ranging from 0.063 to 64 µg/ml were used to determine MIC values according to applicable National Committee for Clinical Laboratory Standards (NCCLS; now called Clinical and Laboratory Standards Institute [CLSI]). 27 Respiratory scores were defined as: 0 = Normal; rate and character of respiration within normal limits for recently transported cattle 1 = Abnormal; notable increase in rate and/or abnormal character of respiration Attitude scores were defined as: 0 = Normal; bright, alert, responsive 1 = Mild depression 2 = Moderate to marked depression; may be reluctant to stand 3 = Severe depression; may be moribund or unable to stand without assistance At each study site, a veterinarian who was masked to treatment group assignment assessed respiration and attitude and measured rectal temperature. Calves were allowed 3 days after treatment with saline, tulathromycin, or tilmicosin to respond before a determination of nonresponse was allowed, unless death or euthanasia occurred. On days 1 and 2, at approximately the same time each morning, respiratory and attitude scores were assessed and recorded before rectal temperatures were measured and recorded. Morning assessments continued on days 3 through 14, except rectal temperatures were measured only if the respiratory and attitude scores were abnormal. Calves with rectal temperatures of less than 104 F were returned to study pens for continued daily observation, while those meeting nonresponse criteria of respiratory and attitude scores of 1 or higher and with rectal temperatures of 104 F or greater were removed from the study and sub- 147

Veterinary Therapeutics Vol. 6, No. 2, Summer 2005 TABLE 4. Number of Animals Classified as Treatment Failures (Nonresponders and Mortalities) Day of Study Treatment Group 1 a 2 a 3 4 5 6 7 8 9 10 11 12 13 14 Total Saline 3 5 63 13 8 9 7 1 0 4 0 3 0 6 122 (n = 160) Tulathromycin 0 2 28 9 6 5 1 2 2 1 0 2 1 10 69 (n = 319) Tilmicosin 0 3 26 15 13 7 9 6 2 3 1 3 2 21 111 (n = 317) a Treatment failures on days 1 and 2 were BRD mortalities. sequently managed according to the standard feedlot BRD antimicrobial therapy procedures at each study site. On day 14, the final day of the study, rectal temperature was measured in all remaining calves regardless of respiratory or attitude score. Any calf with a rectal temperature of 104 F or greater on day 14 was considered a nonresponder. A calf was therefore considered a treatment cure only if it remained in the study through day 14 without being classified as a nonresponder or a day-14 nonresponder and it did not die of causes related to BRD. Necropsies were performed on calves that died during the study, and tissue samples and swabs of pneumonic lung for bacterial isolation and identification were obtained from calves treated with saline. Housing, Feed, and Water Calves were housed in outdoor group pens with two blocks of study animals per pen. The approximate square footage of pen space and linear feet of bunk space, respectively, were 93.6 and 1.8 at the Texas site, 166.8 and 2.3 at the Idaho site, 60.0 and 1.25 at the Nebraska site, and 129.0 and 1.6 at the California site. Calves at all four sites were fed ad libitum with a ration typical of regional feedlots formulated to meet or exceed National Research Council nutritional requirements for maintenance and expected growth. All calves had ad libitum access to water tanks shared with adjacent pens except for the calves at the Idaho research site, where a pen line water delivery system was used. Statistical Analysis Each animal was considered an experimental unit. The primary assessment of efficacy was cure rate. For a calf to be considered a cure, it must not have died or been classified as a nonresponder. According to the criteria described in the study methods, a nonresponder was defined on days 3 through 14 as a calf with respiratory and attitude scores of 1 or above and a rectal temperature of 104 F or higher. Additionally, calves with a rectal temperature of 104 F or higher on day 14 were considered nonresponders. Cure rate was defined as the number of calves classified as cures in a treatment group divided by calves enrolled in a treatment group minus calves removed for reasons other than BRD. Cure and mortality rates were analyzed using a Cochran-Mantel-Haenszel test stratified on study followed by Fisher s exact test for specific treatment contrasts. Rectal temperature data 148

were analyzed using the repeated measures (mixed linear) model with the addition of terms for study and for treatment by block within interactions. A priori contrasts for rectal temperature were constructed to test treatment effect within days. The 5% level of significance (P.05) was used to assess statistical differences for all tests. RESULTS Of the 800 feeder calves (160 treated with vs tilmicosin, P =.3840. saline, 320 treated with tulathromycin, and 320 treated with tilmicosin) enrolled in this study, only four calves (one treated with tulathromycin and three with tilmicosin; all at the Idaho site) were removed from the study for reasons other than BRD. Clinical signs observed using the criteria defined within the attitude and respiratory scores and pyrexia were typical of acute BRD associated with bacterial respiratory disease. Frequencies of isolation of M. haemolytica, P. multocida, H. somni, and Mycoplasma spp from pretreatment nasopharyngeal swabs supported bacterial and mycoplasmal etiologies of the clinical respiratory disease observed across all treatment groups (Table 1). MICs of tulathromycin and tilmicosin for all four major BRD pathogens are provided in Table 2. The frequencies of treatment failures (mortalities, nonresponders, and day-14 nonresponders) and cures for each study location and for the multistudy analyses are listed in Table 3. The overall cure rate of the calves treated with tulathromycin (78.4%) was significantly (P TABLE 5. Rectal Temperatures on Study Days 0 (before treatment), 1, and 2 Least Squares Means Rectal Temperature ( F ± standard error) Treatment Group Day 0 a Day 1 b Day 2 c Saline 105.3 (0.25) 104.6 (0.26) 104.1 (0.26) (n = 160) Tulathromycin 105.3 (0.25) 102.9 (0.25) 102.6 (0.25) (n = 319) Tilmicosin 105.3 (0.24) 103.0 (0.24) 102.5 (0.24) (n = 317) a Saline vs tulathromycin, P =.9594; saline vs tilmicosin, P =.9267; tulathromycin vs tilmicosin, P =.9638. b Saline vs tulathromycin, P.0001; saline vs tilmicosin, P.0001; tulathromycin vs tilmicosin, P =.1916. c Saline vs tulathromycin, P.0001; saline vs tilmicosin, P.0001; tulathromycin.0001) higher than that of the calves treated with saline (23.8%) (Table 3). Calves treated with tilmicosin also had a higher cure rate than those treated with saline (64.9% vs 23.8%; P 0.0001). The cure rate of calves treated with tulathromycin (78.4%) was also significantly (P =.0007) higher than that of calves treated with tilmicosin (64.9%). Subcategories of treatment failures (mortalities, nonresponders, and day-14 nonresponders) are also provided in Table 3. Mortalities were summarized only for cattle over the 14- day study duration. When a calf became a treatment failure (nonresponder) and was removed from the study, data from additional antimicrobial treatment regimens and outcome (i.e., BRD-associated mortality) were not collected. The frequency of treatment failures (mortalities and nonresponders) by day of study showed that the majority of saline treatment group failures occurred within 7 days of treatment (Table 4). The number of tulathromycin and tilmicosin treatment failures was similar on days 2 149

Veterinary Therapeutics Vol. 6, No. 2, Summer 2005 and 3. From day 4 through day 8, there were fewer treatment failures in the tulathromycin group than in the tilmicosin group. The number of treatment failures was again similar on days 9 through 13. On the final day of the studies (day 14), when all calves had rectal temperatures measured regardless of visual observations, the number of tilmicosin treatment failures was twice that of the tulathromycin group. Mean rectal temperature of calves in the three treatment groups at the time of treatment on day 0 was 105.3 F (Table 5). Mean rectal temperature confirmation that the respiratory disease was responsive to antimicrobial therapy, and the use of the active control group treated with tilmicosin provided a well-known baseline to evaluate the efficacy of tulathromycin against BRD. The finding that the cure rate of the tulathromycin-treated cattle was significantly higher than that of a widely accepted antimicrobial agent such as tilmicosin is noteworthy. These results are similar to those previously reported in a study that used fewer cattle, wherein the cure rate of cattle similarly treated The cure rate of calves treated with tulathromycin was higher than that of calves treated with tilmicosin. of calves treated with tulathromycin or tilmicosin was significantly (P.0001) lower than that of the calves treated with saline on day 1 (102.9 F, 103.0 F, and 104.6 F, respectively) and day 2 (102.6 F 102.5 F, and 104.1 F, respectively). On days 1 and 2, there were no significant differences in mean rectal temperatures of calves treated with tulathromycin compared with calves treated with tilmicosin. Average daily weight gains (lb ± SD) were calculated only for animals remaining in the study through day 14. Results for the saline, tulathromycin, and tilmicosin groups were 0.1 (±4.5), 3.4 (±2.7), and 2.5 (±3.0) lb, respectively. No adverse drug experiences were reported in the 319 tulathromycin-treated calves. DISCUSSION In this large, multicenter, 14-day study, a single injection of tulathromycin was effective in the treatment of BRD associated with M. haemolytica, P. multocida, H. somni, and Mycoplasma spp, pathogens commonly found in the respiratory tract of cattle. The contrasts with the saline-treated control group provided with tulathromycin was significantly higher than the cure rate of cattle treated with tilmicosin. 28 Tilmicosin has been extensively used as a first-line antimicrobial for the treatment of BRD, in part because of its single-dose regimen and duration of activity. 2 4,29 The duration of tilmicosin has been illustrated by drug lung concentrations higher than the reported MIC 90 (concentration inhibiting 90% of the isolates) of 4.0 µg/ml for M. haemolytica for approximately 3 days after treatment. 29 Additionally, the accumulation of tilmicosin in phagocytic cells is another factor that may explain its efficacy in BRD. 29 The greater magnitude of antimicrobial response of tulathromycin compared with tilmicosin may be related to its pharmacokinetic and pharmacodynamic profile. Pharmacokinetic studies in cattle administered tulathromycin at 2.5 mg/kg SC demonstrated excellent bioavailability, with rapid absorption followed by extensive distribution into lung tissue. 19 In fact, mean time of maximum plasma concentration (T max ) following SC injection was only 15 minutes, with a mean plasma maximum concentration 150

(C max ) of 0.4 µg/ml and a mean area under the time-concentration curve (AUC 0 360h ) of 16,000 (ng hr/ml). 19 Conversely, lung homogenate had much higher concentrations at the first sampling time of 12 hours (3.2 µg/g), and the highest mean concentration of 4.1 µg/g was seen at 24 hours after dosing. 19 With a long elimination half-life in the lungs (7.7 days), mean lung concentrations were still 1.9 µg/g 10 days after injection, with a mean AUC 0 360h of 903,600 (ng hr/ml). 19 This extended period of tulathromycin lung concentrations results in a prolonged period of antimicrobial exposure to bacterial pathogens, which is favorable for antimicrobials that are characterized by time- Tulathromycin has excellent bioavailability, rapid absorption, and extensive distribution into lung tissue. dependent activity. Pharmacodynamic studies with most macrolides have suggested that the length of time that the plasma concentration of a drug is above MIC (time dependence) is considered the pharmacodynamic parameter most highly correlated with clinical efficacy of this antimicrobial group. 30,31 The pharmacodynamic model that captures both time above MIC and magnitude of drug concentration, plasma AUC/MIC, has been suggested for azithromycin, a similar human antimicrobial agent, based on animal models. 32 Given the pharmacokinetic profile of tulathromycin with plasma concentrations remaining below the MIC 90 of the BRD pathogens and the efficacy reported in this study, lung concentrations of tulathromycin may be more informative, and it may well be that the best pharmacodynamic model correlating with clinical success is the lung AUC/MIC ratio rather than plasma time above MIC. 26 Further efficacy studies will be useful in confirming this theory. In light of tulathromycin pharmacokinetics, lung homogenate concentrations may provide the best means to explain clinical success seen in this study, but they do not clarify the concentrations of drug available at the extracellular site of the common bacterial respiratory pathogens. Like some other macrolides, the in vitro accumulation of tulathromycin by bovine phagocytes 20 provides a potential mechanism of increasing drug concentration at sites of infection by localized recruitment of phagocytes. Concentrations of tulathromycin in phagocytic cells lavaged from the lungs of cattle treated 24 hours previously were found to have intracellular tulathromycin concentrations of approximately 18 µg/ml. 33 Therefore, drug efflux from phagocytes could allow for tulathromycin concentrations to remain higher at the site of infection than in lung homogenate. The pharmacokinetic and pharmacodynamic characteristics of antimicrobials can provide a basis for predicting a successful clinical outcome; however, the best evaluation of antimicrobial efficacy is provided by well-controlled clinical studies. In this multicenter study, tulathromycin proved to have superior clinical efficacy compared with tilmicosin. Even though calves showing early acute signs of BRD and treated with one injection of tulathromycin had increased cure rates compared with that of saline- and tilmicosin-treated cattle, this treatment regimen and the 14-day study duration do not address the BRD status over a longer duration (i.e., the number of times cattle were treated for respiratory disease, chronics, and mortality, or the effects of BRD treatment on cattle performance). 151

Veterinary Therapeutics Vol. 6, No. 2, Summer 2005 CONCLUSION Under conditions of this four-location multicenter study, efficacy and field safety of tulathromycin were demonstrated when it was administered as a single-dose treatment for BRD associated with M. haemolytica, P. multocida, H. somni, and Mycoplasma spp. Moreover, tulathromycin showed superior therapeutic efficacy compared with tilmicosin, a macrolide antimicrobial widely used for the treatment of BRD. ACKNOWLEDGMENTS The authors thank the following investigators and their staffs for assistance in conducting these studies: Kelly F. Lechtenberg, DVM, PhD, Midwest Veterinary Services, Oakland, NE; Terry N. Terhune, DVM, PhD, HMS Veterinary Development, Tulare, CA; David T. Bechtol, Agri Research Center, Canyon, TX; and E. G. Johnson, DVM, Johnson Research, Parma, ID. They also thank Donald J. Bade, BS, Colorado Animal Research Enterprises, Fort Collins, CO, and Ching Ching Wu, DVM, PhD, Purdue University, West Lafayette, IN, for the microdilution susceptibility testing and Susan Aiello for assistance in preparing portions of the manuscript. REFERENCES 1. Griffin D: Economic impact associated with respiratory disease in beef cattle. Vet Clin North Am Food Anim Pract 13(3):367 377, 1997. 2. USDA. 2000. Part I: Baseline Reference of Feedlot Management Practices, 1999. USDA:APHIS:VS, CEAH, National Animal Health Monitoring System. Fort Collins, CO. #N327.0500 3. USDA. 2000. Part II: Baseline Reference of Feedlot Health and Health Management, 1999. USDA: APHIS:VS, CEAH, National Animal Health Monitoring System. Fort Collins, CO. #N335.1000. 4. USDA. 2000. Part III: Health Management and Biosecurity in U.S. Feedlots, 1999. USDA:APHIS: VS, CEAH, National Animal Health Monitoring System. Fort Collins, CO. #N336.1200. 5. Kelly AP, Janzen ED: A review of morbidity and mortality rates and disease occurrence in North American feedlot cattle. Can Vet J 27:496 500, 1986. 6. Mosier DA: Bacterial pneumonia, bovine respiratory disease update. Vet Clin North Am 13(3):483 493, 1997. 7. Loneragan GH, Dargatz DA, Morley PS, Smith MA: Trends in mortality ratios among cattle in US feedlots. JAVMA 219(8):1122 1127, 2001. 8. Perino LJ, Apley M: Bovine respiratory disease, in Howard JL, Smith RA (eds): Current Veterinary Therapy: Food Animal Practice. Philadelphia, WB Saunders, 1999, pp 446 455. 9. Vogel GJ, Laudert SB, Zimmerman A, et al: Effects of tilmicosin on acute undifferentiated respiratory tract disease in newly arrived feedlot cattle. JAVMA 212(12):1919 1924, 1998. 10. Frank GH, Briggs RE, Loan RW, et al: Respiratory tract disease and mucosal colonization by Pasteurella haemolytica in transported cattle. Am J Vet Res 57(9): 1317 1320, 1996. 11. Speer NC, Young C, Roeber D: The importance of preventing bovine respiratory disease: A beef industry review. Bov Pract 35(2):189 195, 2001. 12. Thornsbury RM: Preconditioning for cow-calf producers: A marketing advantage or disadvantage? Compend Contin Educ Pract Vet 13:495 501, 1991. 13. Guthrie CA, Laudert SB, Zimmerman AG: Metaphylaxis for undifferentiated bovine respiratory disease. Compend Contin Educ Pract Vet 22(3):S62 S67, 2000. 14. Frank GH, Briggs RE, Duff GC, et al: Effects of vaccination prior to transit and administration of florfenicol at time of arrival in a feedlot on the health of transported calves and detection of Mannheimia haemolytica in nasal secretions. Am J Vet Res 63(2): 251 256, 2002. 15. Frank GH, Duff GC: Effects of tilmicosin phosphate, administered prior to transport or at time of arrival, and feeding of chlortetracycline, after arrival in a feedlot, on Mannheimia haemolytica in nasal secretions of transported steers. Am J Vet Res 61(12):1479 1483, 2000. 16. Letavic MA, Bronk BS, Bertsche CD, et al: Synthesis and activity of a novel class of tribasic macrocyclic antibiotics: The triamilides. Bioorgan Medic Chem Lett 12: 2771 2774, 2002. 17. Bronk BS, Letavic MA, Bertsche CD, et al: Synthesis, stereochemical assignment and biological activity of a novel series of C-4" modified aza-macrolides. Bioorgan Medic Chem Lett 13:1955 1958, 2003. 18. Norcia LJL, Silvia AM, Santoro SL, et al: In vitro microbiological characterization of a novel azalide, two triamilides and an azalide ketal against bovine and porcine respiratory pathogens. J Antibiot 57(4):280 288, 2004. 19. Nowakowski MA, Inskeep PB, Risk JE, et al: Pharmacokinetics and lung tissue concentrations of tulathromycin, a new triamilide antibiotic, in cattle. Vet Ther 5(1):60 74, 2004. 20. Siegel TW, Earley DL, Smothers CD, et al: Cellular uptake of the triamilide tulathromycin by bovine and 152

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