Evaluation of Three Antimicrobial Regimens Used as Metaphylaxis in Stocker Calves at High Risk of Developing Bovine Respiratory Disease*

Veterinary Therapeutics Vol. 8, No. 2, Summer 2007 Evaluation of Three Antimicrobial Regimens Used as Metaphylaxis in Stocker Calves at High Risk of Developing Bovine Respiratory Disease* D. L. Step, DVM, DACVIM a Terry Engelken, DVM, MS b Cristina Romano, DVM, MS c Ben Holland, MS d Clint Krehbiel, PhD d a Department of Veterinary Clinical Sciences Center for Veterinary Health Sciences Oklahoma State University Stillwater, OK 74078 b Department of Veterinary Diagnostic and Production Animal Medicine College of Veterinary Medicine Iowa State University Ames, IA 50011 John C. Johnson, DVM, MS e W. Lawrence Bryson, PhD e Cassius M. Tucker, DVM e Edward J. Robb, DVM, MS, DACVN e d Department of Animal Science Division of Agricultural Sciences & Natural Resources Oklahoma State University Stillwater, OK 74078 e Pfizer Animal Health 7000 Portage Road Kalamazoo, MI 49001 c Department of Pathobiology and Population Medicine College of Veterinary Medicine Mississippi State University Starkville, MS 39762 C L I NI CA L R E L E VA N C E A total of 894 calves at high risk for bovine respiratory disease was processed at two sites and randomly assigned to receive one of three antimicrobial metaphylactic regimens to determine if a two-drug regimen offered any advantage over the more conventional one-course regimens. On arrival, calves received either a two-course regimen of ceftiofur crystalline free acid (CCFA) followed by tulathromycin 8 days later (Group 1) or a one-course regimen of CCFA (Group 2) or tilmicosin (Group 3). At Site A, morbidity was significantly lower (52%) in Group 1 than in Group 2 (76.3%) and Group 3 (78.4%). At Site B, morbidity was significantly lower in Group 1 (2.6%) than in Group 2 (9.4%) and Group 3 (7.2%). *This study was funded by Pfizer Animal Health, Kalamazoo, Michigan. Correspondence should be sent to Dr. Johnson: phone, 402-441-2958; fax, 402-441-2782; email, John.C.Johnson@Pfizer.com. 1

D. L. Step, T. Engelken, C. Romano, B. Holland, C. Krehbiel, J. C. Johnson, W. L. Bryson, C. M. Tucker, and E. J. Robb INTRODUCTION Administration of antimicrobials for control (metaphylaxis) of bovine respiratory disease (BRD; also called pneumonia or shipping fever) has proven beneficial in feedlot and stocker operations handling young, lightweight, highly stressed, long-haul, high-shrink calves at risk of developing BRD. 1 5 Broadly and in general, metaphylaxis reduces the impact of bacterial colonization and growth in the bovine respiratory tract, thereby ameliorating pulmonary defense, aiding pathogen clearance, and reducing subclinical infection; the most common pathogens implicated in BRD are Mannheimia (Pasteurella) haemolytica, Pasteurella multocida, and Histophilus subclinical BRD, which is well masked as part of their natural defense against predators. Thus, a fair percentage of cattle never exhibiting clinical signs or pulled for BRD have lung lesions at slaughter. 9 In addition, more than 0% of calves in US cow calf operations are not vaccinated against BRD pathogens before weaning, and a high percentage of these calves are not retained for any reasonable time to allow adaptation and stress reduction as they are moved from their dams, a patterned social structure, and a pasture environment to unfamiliar stocker settings or feedlots. 10 Numerous antimicrobials are effective and have received FDA approval for the control of Many calves arrive at stockers or in feedyards incubating or having subclinical BRD. somni (Haemophilus somnus), with Mycoplasma spp identified in some instances. As a tool in BRD management, antimicrobial metaphylaxis is designed to minimize the cumulative effects and interplay of such stressors as weaning, transport, resocialization, environmental changes (e.g., dust, ambient temperatures, rations, water sources), commingling, and large numbers of cattle moving long distances in close quarters and consequently sharing air space and pathogens. 1 Respiratory problems, including BRD, account for more than 0% of the mortalities in cattle and calves in North America. 7 BRD is a well-recognized and -documented disease complex with a multifactorial pathogenesis. Mortalities and lesions associated with BRD ultimately result from bacterial bronchopneumonia. 8 Morbidity ranges from 10% to 80%, with mortality frequently above 5% and potentially approaching 10% to 20% during explosive outbreaks. 7 Many calves arrive at stockers or in feedyards incubating or having bacterial BRD. 1 Metaphylaxis can conserve resources (drugs, labor, animals, time, economics) and enhance animal welfare 11 by reducing disease incidence and by improving response to treatment in animals that become ill and need therapy. All of the aforementioned factors directly affect an animal s and operation s performance and profitability. Previous studies conducted at six feedlots demonstrated that morbidity was significantly lower for cattle receiving ceftiofur crystalline free acid (CCFA; Excede Sterile Suspension, Pfizer Animal Health) on arrival (10.9%) than for those receiving tilmicosin (21.2%) or no medication (48.9%). 12 The same investigation found that morbidity and mortality through 5 days-on-feed were similar for cattle receiving CCFA followed by a 7-day postmetaphylaxis interval (PMI) and those receiving tilmicosin followed by a -day PMI. The PMI is an observed period during which no further antimicrobials are used. The length of the PMI is 17

Veterinary Therapeutics Vol. 8, No. 2, Summer 2007 based on drug pharmacokinetics in target tissues and on demonstrated clinical efficacy in field studies. Using CCFA and a 7-day PMI reduced the incidence of BRD through day 29 by 28 percentage points and through day 57 by 21 percentage points compared with the control group. 12 Investigators noted that the 7-day PMI allows greater flexibility and focus on the part of pen riders and hospital personnel in terms of BRD surveillance in newly arrived cattle. A separate M. haemolytica challenge-model study established that CCFA controlled BRD for up to 9 days after administration and resulted in lower lung lesion scores, respiratory scores, and rectal temperatures compared with tilmicosin. 1 Pharmacokinetic data show that circulating concentrations of ceftiofur and related metabolites remain above the efficacy threshold of BRD target pathogens (>0.2 μg/ml) for more than 7 days. 14 (The efficacy threshold is three to six times This study was designed to determine whether a two-course metaphylactic regimen offered any advantage over the more conventional one-course regimens and to evaluate the efficacy of the various medications in controlling BRD. This study was designed to determine whether a two-course metaphylactic regimen offered any advantage over the more conventional one-course regimens. higher than the minimum inhibitory concentration required to inhibit the growth of 90% of organisms [MIC 90 ] for BRD target pathogens.) Three previous field studies with stocker steers compared the efficacy of tulathromycin (Draxxin Injectable Solution, Pfizer Animal Health) with that of tilmicosin (Micotil 00 Injection, Elanco Animal Health) and enrofloxacin (Baytril 100, Bayer Animal Health) for the treatment of BRD. 15 In all three studies, first-treatment success was significantly higher (P <.05) and BRD chronics and mortalities significantly lower (P.021) with tulathromycin than with tilmicosin or enrofloxacin. MATERIALS AND METHODS Animals Male crossbred beef stocker calves were purchased from auction markets with the goal of obtaining freshly weaned, lightweight, highstress animals vulnerable to BRD exposure. A total of 0 calves (29 cutter bulls and 7 steers) was purchased from 5 auction markets in the southeastern United States and delivered to a backgrounding lot in Mississippi (Site A). All calves at Site A were maintained in grass paddocks for 80 days at stocking rates typical for the area. Calves initially were housed in six 50-head paddocks; approximately 4 weeks after arrival, they were randomly assigned to three 100-head paddocks. An additional 588 calves (41 steers and 157 cutter bulls) were purchased from two auction markets and enrolled in four installments at a second location in Oklahoma (Site B). Calves at this site were backgrounded in drylot pens with 24 to 27 head/pen for 0 days. Initial processing at both sites included ear tag identification, recording of individual body weights, collection of ear notch skin samples for bovine viral diarrhea virus (BVDV) antigencapture ELISA (Site A) or immunochemistry (Site B), surgical castration of intact males, vac- 18

D. L. Step, T. Engelken, C. Romano, B. Holland, C. Krehbiel, J. C. Johnson, W. L. Bryson, C. M. Tucker, and E. J. Robb cinations (Bovi-Shield GOLD 5 and Ultra- Choice 7, Pfizer Animal Health), and treatment for parasite control (Dectomax Pour On or Dectomax Injectable Solution, Pfizer Animal Health). At Site A, calves grazed native mixed forage in grass paddocks and were offered supplemental milled rations without feed-grade antimicrobials that met National Research Council (NRC) standards. 1 At Site B, calves were offered an antimicrobial-free starting ration also designed to meet NRC standards. Water was available at both locations ad libitum. Moribund calves were excluded from the study, as were animals with systemic disease or physical conditions that could interfere with the in Group received tilmicosin at the label dose of 10 mg/kg (1.5 ml/100 lb) administered SC in the neck. At Site A, all calves received.0 ml of either CCFA or tilmicosin, based on a target arrival mean weight of 400 lb (181.4 kg). At Site B, a dose chart with four 25-lb increments within a 100-lb range was used to ensure that no calves received a suboptimal dose of either CCFA or tilmicosin; for example, all calves weighing 401 to 425 lb received the dose volume prescribed for the 425-lb body weight. On day 8 at both sites, all calves were revaccinated and those in Group 1 received tulathromycin at the label dose of 2.5 mg/kg (1.1 ml/100 lb) administered SC in the neck as a second course of metaphylaxis. Dose The two-course regimen of CCFA and tulathromycin had markedly less morbidity than either of the one-course regimens. evaluation of BRD or response to BRD therapy; lameness; a known history of BRD; recent BRD therapy; severe clinical signs of BRD at processing; or any known or suspected vaccination against M. haemolytica or P. multocida within the previous 0 days. At the investigators discretion, calves could be removed from the study for welfare considerations at any time. Study Design The study was designed to evaluate three regimens for the control of BRD in stocker calves at high risk of developing BRD (Figure 1). Calves at the two sites were randomly assigned to one of three groups, in blocks of three, based on progression through a restraint chute during processing. On arrival, calves assigned to Groups 1 and 2 received CCFA at the label dose of. mg/kg (1.5 ml/100 lb) administered SC in the middle one-third of the posterior aspect of the ear. Calves volumes of tulathromycin ranged from.5 to 5.5 ml at Site A and were calculated at Site B using the dose chart as described previously. According to study design, response to metaphylaxis for Group 1 was defined more stringently than for Groups 2 and because of the second metaphylactic course administered 8 days after processing in Group 1. Therefore, response to metaphylaxis in Group 1 was defined as absence of any observable BRD; in Groups 2 and, response to metaphylaxis was defined as absence of observable BRD or successful treatment of the first incidence of BRD with no subsequent retreatment. Clinical Observations and BRD Management Clinical observers were masked from calf-togroup assignment and observed all calves at least once daily for general health and clinical 19

Veterinary Therapeutics Vol. 8, No. 2, Summer 2007 Metaphylaxis Regimen Eligible for Initial BRD Treatment (as needed) BRD Retreatement Group 1 Excede on day 0 + Draxxin on day 8 Beginning on day 1 (Site A) or on day 15 2 (Site B) SFLT Group 2 Excede on day 0 Beginning on day 8 SFLT Group 3 Micotil on day 0 Beginning on day SFLT Calves were purchased from auction markets; the study included 588 calves at Site A (Oklahoma) and 0 calves at Site B (Mississippi). Figure 1. Three metaphylactic regimens for bovine respiratory disease (BRD). Investigators evaluated three antimicrobial regimens: one using ceftiofur crystalline free acid (CCFA; Excede; 6.6 mg/kg SC in middle third of the posterior aspect of the ear) followed by tulathromycin (Draxxin, 2.5 mg/kg SC in the neck) 8 days later (Group 1), one using CCFA (Group 2), and a third using tilmicosin (Micotil, 10 mg/kg SC in the neck; Group 3). Calves meeting BRD criteria were eligible for treatment based on their group assignment (see below for details). (SFLT = standard feedlot therapy) signs of BRD. Calves were scored by exception, with only those showing evidence of BRD given a Clinical Attitude Score (CAS) as follows: 1 = Mild depression; signs of weakness usually not present 2 = Moderate depression; some signs of weakness; may be reluctant to stand 3 = Severe depression; difficulty standing; head lowered or extended 4 = Moribund; unable to rise or stand; unable to take feed or water; near death Calves with a CAS of 1 or 2 were pulled and treated for BRD only if their rectal temperature exceeded 40.0 C (104 F); calves with a CAS of or 4 were pulled and treated regardless of rectal temperature. Calves meeting BRD criteria were eligible for treatment based on their group assignment: Group 1: Eligible for standard feedlot therapy (SFLT), which consisted of florfenicol (Nuflor Injectable Solution, Schering- Plough Animal Health; 40 mg/kg SC in the neck) once beginning on day 1 at Site A (i.e., after a 5-day PMI following tulathromycin administration on day 8) or on day 15 to 2 at Site B (after a 7- to 14-day 140

D. L. Step, T. Engelken, C. Romano, B. Holland, C. Krehbiel, J. C. Johnson, W. L. Bryson, C. M. Tucker, and E. J. Robb PMI) and followed by long-acting oxytetracycline (Liquamycin LA-200 Injection, Pfizer Animal Health; 19.8 mg/kg SC in the neck) and then danofloxacin (A180, Pfizer Animal Health;.0 mg/kg SC in the neck q48h). Group 2: Eligible for BRD treatment with tulathromycin (2.5 mg/kg SC in the neck) once beginning on day 8, followed by SFLT as described for Group 1. Group 3: Eligible for BRD treatment with enrofloxacin (7.5 12.5 mg/kg [.4 5.7 ml/100 lb] SC in the neck) once beginning on day, followed by SFLT as described for Group 1. After treatment, animals were returned to their home paddocks or pens. The posttreatment interval (PTI; i.e., the time during which Statistical Analyses For Group 1, which received a two-course metaphylactic regimen (CCFA and tulathromycin), response to metaphylaxis was defined as no BRD cases occurring during the entire study ; in Groups 2 and, response to metaphylaxis was defined as one or fewer episodes of BRD with no retreatment. At Site A, response to metaphylaxis and BRD mortality were analyzed using a generalized linear mixed model using the logit link; the model included the fixed effect of treatment, and random effects included pasture, block within pasture, and residual. ADG was analyzed using a mixed model; the model included the fixed effect of treatment, and random effects included pasture, block within pasture, and residual. Least squares means (LSM) and 95% CIs were constructed This study lends credence to considering a wider window for metaphylaxis. no further treatment for BRD was permitted unless warranted in the interest of animal welfare) was days following florfenicol administration and 2 days following administration of long-acting oxytetracycline or the second dose of danofloxacin. Study variables included response to metaphylaxis; number of calves never treated for BRD; BRD morbidity, mortality, and chronicity; and weight changes/calf (i.e., mean average daily gain [ADG] and calculated total gain) for 80 days (Site A) or 0 days (Site B). Withdrawal periods were observed for all of the antimicrobials used, and animals moved to or remained on pasture at the study s conclusion, ultimately progressing through routine feeding, management, and harvest practices. for treatments and back-transformed where appropriate. At Site B, success was analyzed using the Cochran Mantel Haenszel method stratified by pen. BRD morbidity was analyzed using a generalized linear mixed model using the logit link; the model included the fixed effect of treatment, and random effects included pen, block within pen, treatment by pen, and residual. ADG was analyzed using a mixed model, including the fixed effect of treatment; random effects included enrollment time, pen within enrollment time, block within pen within enrollment time, and residual. The LSM and 95% CIs were constructed for treatments and back-transformed where appropriate. Differences were assessed at the 5% level of significance (P.05). The null hypothesis was 141

Veterinary Therapeutics Vol. 8, No. 2, Summer 2007 TABLE 1. Numbers of Animals Enrolled and Removed and Average Daily Gain (Sites A and B) Group 1 Group 2 Group 3 Day 0 CCFA Day 0 CCFA Day 0 tilmicosin Day 8 tulathromycin Treat BRD from day 8 Treat BRD from day Treat BRD after PMI on with tulathromycin on with enrofloxacin Site A No. of animals Day 0 102 102 102 Day 80 99 9 99 No. of animals 2 (BRD mortality); 1 (non-brd mortality); (BRD mortality) removed (reason) 1 (lameness) (BVDV-PI); 1 (protocol error); 1 (lameness) ADG (kg [lb]) 1.1 (2.55) 1.10 (2.42) 1.11 (2.45) P value.527 Site B No. of animals Day 0 197 19 a 195 b Day 0 190 191 194 No. of animals 4 (BVDV-PI); 1(BVDV-PI); 2 (lameness); 1 (BVDV-PI); removed (reason) 1 (lameness); 2 (day 1 (bloat); 1 (non-brd 1 (protocol error) 0 weight not recorded) mortality); 1 (protocol error); 1 (day 0 weight recorded twice) ADG (kg [lb]) 1.1 (2.50) 1.10 (2.44) 1.12 (2.47) P value.5974 a Group 2: 198 calves were enrolled on day 0; two were removed retroactive to day 0 (data on file). b Group : 19 calves were enrolled on day 0; one was removed retroactive to day 0 (data on file). ADG = average daily gain; BRD = bovine respiratory disease; BVDV-PI = persistently infected with bovine viral diarrhea virus; CCFA = ceftiofur crystalline free acid; PMI = postmetaphylaxis interval. that the three regimens were equivalent in the control of BRD. RESULTS Site A The numbers of calves enrolled in and completing the study to final weights (i.e., day 80) are shown in Table 1. The response to metaphylaxis in Groups 1, 2, and was 48.0%, 58.2%, and 40.2%, respectively (P =.0791; Table 2), numerically favoring the one-course CCFA metaphylaxis regimen with tulathromycin used for first treatment (Group 2). However, as shown in Table, the number of calves never treated for BRD ranged from a high of 48% (49 of 102) in Group 1 to 2.5% (2 of 98) in Group 2 and a low of 21.5% (22 of 102) in Group. The BRD cas- 142

D. L. Step, T. Engelken, C. Romano, B. Holland, C. Krehbiel, J. C. Johnson, W. L. Bryson, C. M. Tucker, and E. J. Robb TABLE 2. Response to Metaphylaxis (Site A) Group 1 Group 2 Group 3 Antimicrobial No. % Antimicrobial No. % Antimicrobial No. % Day 0 CCFA 102 100.0 CCFA 102 100.0 Tilmicosin 102 100.0 Day 8 Tulathromycin 102 100.0 Response a 49 48.0 57 58.2 b 41 40.2 Overall P Value.0791 a Defined as no BRD through day 80 (Group 1) or the absence of observable BRD or successful treatment of the first incidence of BRD with no subsequent retreatment (Groups 2 and ). b 58.2% = 57 of 98 calves; four calves were removed within 7 days of arrival (one postcastration mortality, three persistently infected with bovine viral diarrhea virus). es in Groups 2 and, while part of the response to metaphylaxis definition, also represented BRD occurrence (morbidity). As such, morbidity in Group 1 (52.0%; 5 of 102) was significantly lower (P <.0057) than in either Group 2 (7.%; 74 of 98) or Group (78.4%; 80 of 102); morbidity was similar between Groups 2 and (P =.725). The percent of calves needing retreatment in Groups 1 and 2 was similar: 5.% (0 of 5) in Group 1 and 54.0% (40 of 74) in Group 2. In contrast, a much larger number of retreatments were necessary in Group (7.2%, 1 of 80). A total of 98, 151, and 207 treatments for BRD (initial and retreatments) was administered in Groups 1, 2, and, respectively. Eight calves were classified as chronically ill (one in Group 1, four in Group 2, and three in Group ). Five mortalities were attributable to BRD. ADG was 1.1 kg/day (2.55 lb/day; mean total: 20 lb) in Group 1, 1.10 kg/day (2.42 lb/day; mean total: 19 lb) in Group 2, and 1.11 kg (2.45 lb/day; mean total: 19 lb) in Group (Table 1). There were no differences among groups affecting ADG (P =.527), and there were no adverse or unexpected drug-related events. Site B The numbers of calves enrolled and completing the study to final weights (i.e., day 0) are shown in Table 1. The response to metaphylaxis in Groups 1, 2, and was 97.4%, 100.0%, and 98.4%, respectively (P =.0811; Table 4), numerically favoring the one-course CCFA metaphylaxis regimen with tulathromycin used for first treatment (Group 2). In addition, with 588 calves enrolled, there was sufficient statistical power to detect a significant difference between Groups 1 and 2 despite the overall low morbidity (P =.02; Table 4). As shown in Table 5, 97.4% (187 of 192) of the calves in Group 1 were never treated for BRD compared with 90.% (174 of 192) in Group 2 and 92.8% (180 of 194) in Group. Further, morbidity in Group 1 (2.%; 5 of 192) was significantly lower (P <.0208) than in either Group 2 (9.4%; 18 of 192) or Group (7.2%; 14 of 194); morbidity was similar between Groups 2 and (P =.19; Table 5). Of the initial BRD cases, % in Group 2 and 57% in Group were noted in the first 7 days after the PMI, whereas the first BRD case in Group 1 occurred 29 days after processing. ADG in Group 1 was 1.1 kg/day (2.50 14

Veterinary Therapeutics Vol. 8, No. 2, Summer 2007 TABLE 3. Bovine Respiratory Disease (BRD) Occurrence, Treatment, and Retreatments (Site A) BRD Group 1 Group 2 Group 3 Occurrence Therapy No. % Therapy No. % Therapy No. % None 49 48.0 2 2.5 22 21.5 BRD 1 Florfenicol 5 52.0 Tulathromycin 74 7. Enrofloxacin 80 78.4 (first occurrence) BRD 2 Oxytetracycline 0 5. Florfenicol 40 54.0 Florfenicol 1 7.2 (first retreatment) BRD Danofloxacin 15 5.7 Oxytetracycline 24 1.5 Oxytetracycline 9.9 (second retreatment) BRD 4 0 0.0 Danofloxacin 1 54.2 Danofloxacin 27 7.0 (third retreatment) Dead a 2.8 0 0.0.8 Chronic b 1 1.0 4 4.2 2.9 P Values (first occurrence, BRD 1) Overall.0045 Group 1 vs. 2.0057 Group 1 vs..001 Group 2 vs..725 a Case fatality percentage (per initial BRD cases). b Percentage of 98 (Group 1), 92 (Group 2), or 99 (Group ). lb/day; mean total: 150 lb) versus 1.10 kg/day (2.44 lb/day; mean total: 14.4 lb) in Group 2 and 1.12 kg/day (2.47 lb/day; mean total: 148.2 lb) in Group (Table 1). There were no treatment differences affecting performance as measured by ADG (P =.5974). In terms of unexpected events, two calves were depressed after processing: one in Group, observed on day 0, and the other in Group 1, observed after revaccination and tulathromycin administration on day 8. Both calves improved without intervention and were normal at the next observation. DISCUSSION A negative control or nonmedicated group of contemporary calves (with no antimicrobial metaphylaxis administered on arrival) was not included in the study design; therefore, it was not possible to determine a morbidity baseline. The difference in morbidity between Site A and Site B was paradoxical but, in retrospect, 144

D. L. Step, T. Engelken, C. Romano, B. Holland, C. Krehbiel, J. C. Johnson, W. L. Bryson, C. M. Tucker, and E. J. Robb TABLE 4. Response to Metaphylaxis (Site B) Group 1 Group 2 Group 3 Antimicrobial No. % Antimicrobial No. % Antimicrobial No. % Day 0 CCFA 197 100.0 CCFA 19 100.0 Tilmicosin 195 100.0 Day 8 Tulathromycin 192 100.0 Response a 187 97.4 192 100.0 191 98.4 P Values Overall.0811 Group 1 vs. 2.02 Group 1 vs..5278 Group 2 vs..5278 a Defined as no BRD through day 0 (Group 1) or the absence of observable BRD or successful treatment of the first incidence of BRD with no subsequent retreatment (Groups 2 and ). provided valuable insight about the similarity of outcomes. The timed, two-course metaphylactic regimen was included to observe what effect, if any, the sequential administration of two antimicrobials might have on BRD morbidity and mortality and calf performance. The two-course regimen (Group 1, CCFA and tulathromycin) had markedly less morbidity than either of the onecourse regimens, regardless of location, supporting field observations that the risk period for BRD can extend well beyond the first 5 to 7 days after arrival. The timing of a one-course, on-arrival metaphylaxis program may not correlate with highest disease risk, especially when dealing with large numbers of highly commingled calves, presumably in various stages of disease incubation with multiple pathogens. Thus, this study lends credence to considering a wider window for metaphylaxis, particularly in instances in which 0% to 40% of cattle develop BRD following a one-course metaphylactic regimen. 11 The two-course regimen (Group 1) capitalized on the unique properties of CCFA 17 and tulathromycin, 18 demonstrated by previous work showing a prolonged clinical effect or benefit using either compound for the treatment of naturally occurring BRD. Despite the difference in morbidity at the two sites, calves receiving CCFA on arrival (Groups 1 and 2) at both sites responded better to first BRD treatment compared with Group. Reflecting the low morbidity at Site B, there were six BRD treatments in Group 1 versus 18 each in Groups 2 and. Similarly, but with a notably higher BRD morbidity at Site A, there were 98 BRD treatments in Group 1, 151 in Group 2, and 207 in Group. The lower numbers of treatments administered in Groups 1 and 2 at Site A represented an 80% to 90% improvement in treatment response over Group calves, which had a higher number of second and third retreatments. Lower morbidity and an improvement in treatment response following the two-course regimen of metaphylaxis suggest that the spectrum of activity, timing of administration, PMI, and PTI are all important factors influencing the antimicrobial chosen to provide optimal control of BRD in cattle at high risk of disease. 145

Veterinary Therapeutics Vol. 8, No. 2, Summer 2007 TABLE 5. Bovine Respiratory Disease (BRD) Occurrence, Treatment, and Retreatments (Site B) BRD Group 1 Group 2 Group 3 Occurrence Therapy No. % Therapy No. % Therapy No. % None 187 97.4 174 90. 180 92.8 BRD 1 Florfenicol 5 2. Tulathromycin 18 9.4 Enrofloxacin 14 7.2 (first occurrence) BRD 2 Oxytetracycline 1 20.0 0 0.0 Florfenicol 21.4 (first retreatment) BRD 0 0.0 0 0.0 Oxytetracycline 1. (second retreatment) Dead 0 0.0 0 0.0 0 0.0 Chronic 0 0.0 0 0.0 0 0.0 P Values (first occurrence, BRD 1) Overall.0180 Group 1 vs. 2.00 Group 1 vs..0208 Group 2 vs..19 CONCLUSIONS In this study conducted at two sites, the metaphylactic regimen consisting of CCFA administered on arrival (Group 2) proved to be better for handling new, freshly weaned stocker calves based on the definition of response to metaphylaxis in the study design (Sites A and B, Group 2 P =.0791 and.0811, respectively). However, the twocourse regimen (CCFA followed by tulathromycin on day 8) used in Group 1 numerically reduced BRD morbidity compared with either one-course regimen using CCFA or tilmicosin (Sites A and B, Group 1 vs. Group 2 P =.0057 and.00, respectively, and Group 1 vs. Group P =.001 and.0208, respectively). Calves receiving CCFA on arrival, followed by tulathromycin either as the second course of the metaphylactic regimen or as treatment for clinical BRD, demonstrated a consistent and improved response (absence of clinical signs) with fewer retreatments compared with tilmicosin administered on arrival followed by enrofloxacin for BRD treatment. Differences among the metaphylactic regimens were shown at both sites numerically favoring Group 2 both at Site A and Site B. This body of evidence suggests that successful and reasonable application of metaphylaxis in high-risk cattle reduces morbidity and improves BRD treatment response in stocker calves. Previous studies have demonstrated prolonged clinical effect in treating naturally occurring BRD 14

D. L. Step, T. Engelken, C. Romano, B. Holland, C. Krehbiel, J. C. Johnson, W. L. Bryson, C. M. Tucker, and E. J. Robb with CCFA or tulathromycin. 17,18 The reduction in morbidity and improved treatment response to CCFA and tulathromycin support that their spectra of antimicrobial activity, coupled with their extended clinical effect, are important factors to consider when designing a metaphylactic regimen for high-risk cattle. ACKNOWLEDGMENTS The authors thank Luis Burciaga-Robles and Roy Ball, Oklahoma State University, for their assistance with the animal facilities and staff, animal care, processing, and data collection; and Jimmy Bryan and staff at Prairie Livestock, Inc., West Point, Mississippi. REFERENCES 1. Rooney KA, Nutsch RG, Skogerboe TL, et al: Efficacy of tulathromycin compared with tilmicosin and florfenicol for the control of respiratory disease in cattle at high risk of developing bovine respiratory disease. Vet Ther (2):154 1, 2005. 2. Kilgore WR, Spensley MS, Sun F, et al: Clinical effectiveness of tulathromycin, a novel triamilide antimicrobial, for the control of respiratory disease in cattle at high risk for developing bovine respiratory disease. Vet Ther (2):1 142, 2005.. Booker CW, Schunicht OC, Guichon PT, et al: An evaluation of the metaphylactic effect of ceftiofur crystalline free acid in feedlot calves. Vet Ther 7():257 274, 200. 4. Cusack PM: Effect of mass medication with antibiotics at feedlot entry on the health and growth rate of cattle destined for the Australian domestic market. Aust Vet J 82():154 15, 2004. 5. Schumann FJ, Janzen ED, McKinnon JJ: Prophylactic medication of feedlot calves with tilmicosin. Vet Rec 128(12):278 280, 1991.. Jim GK, Booker CW, Guichon PT, et al: A comparison of florfenicol and tilmicosin for the treatment of undifferentiated fever in feedlot calves in western Canada. Can Vet J 40():179 184, 1999. 7. Clarke CR, Burrows GE, Ames TA: Therapy of bovine bacterial pneumonia. Vet Clin North Am Food Anim Pract 7():9 94, 1991. 8. Young CA: Antimicrobial metaphylaxis for undifferentiated bovine respiratory disease. Compend Contin Educ Pract Vet 17(1):1 142, 1995. 9. Thompson PN, Stone A, Schultheiss WA: Use of treatment records and lung lesion scoring to estimate the effect of respiratory disease on growth during early and late finishing periods in South African feedlot cattle. AABP Proc:29 240, 200. 10. National Animal Health Monitoring Survey, Beef 1997; Part III: Reference of 1997 Beef Cow-Calf Production Management and Disease Control. January 1998, pp 1 48. Accessed March 2007 at www.usda.gov. 11. Thomson DU, White BJ: Thinking outside the shots: Management approach to feedyard morbidity and mortality. AABP Proc:119 122, 200. 12. Hibbard B, Meeuwse DM, Bryson WL, et al: Pfizer Animal Health Technical Bulletin EXD04020: EXCEDE vs. Micotil for Control of Bovine Respiratory Disease Using a Post-Metaphylaxis Interval. New York, Pfizer Animal Health, 2004. 1. Hibbard B, Bryson WL, Follis SL, et al: Pfizer Animal Health Technical Bulletin EXD04019: Duration of Therapy with EXCEDE or Micotil in a Bovine Respiratory Disease Challenge Model. New York, NY, Pfizer Animal Health, 2004. 14. Robinson JA, Kausche FM, Brown SA, et al: Pharmacokinetic Equivalence Study of Ceftiofur in Cattle Treated with Ceftiofur Crystalline Free Acid Sterile Suspension (200 mg ceftiofur equivalents (CE)/mL) by Subcutaneous Injection in the Posterior Ear at a Dose of 6.6 mg CE/kg Body Weight. Kalamazoo, MI, Pharmacia & Upjohn, 2000, SRa0058859. 15. Nutsch R, Skogerboe TL, Rooney KA, et al: Comparative efficacy of tulathromycin, tilmicosin, and florfenicol in the treatment of bovine respiratory disease in stocker cattle. Vet Ther (2):17 179, 2005. 1. Subcommittee on Beef Cattle Nutrition, Committee on Animal Nutrition, Board of Agriculture, National Research Council: Nutrient Requirements of Beef Cattle (Appendices 15 17), 7 th rev ed. Washington DC, National Academic Press, 199. 17. Robb EJ, Hibbard B, Follis SL, et al: Duration of efficacy of ceftiofur crystalline free acid compared to tilmicosin when administered at various times before intratracheal Mannheimia haemolytica challenge in calves. AABP Proc:177, 2004. 18. Evans NA: Tulathromycin: An overview of a new triamilide antimicrobial for livestock respiratory disease. Vet Ther (2):8 95, 2005. 147