Efficacy of DRAXXIN or Baytril for treatment of naturally occurring bovine respiratory disease in calves at 3 feedlots

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1 August 7 Efficacy of or for treatment of naturally occurring bovine respiratory disease in calves at 3 feedlots Key Points Clinical success was significantly higher (P=.9, P=.31, P=.31) for calves treated with (tulathromycin) Injectable Solution (87.9%, 8.%, 87.8%) than for those treated with (enrofloxacin) Injectable Solution (7.2%, 62.5%, 74.7%). Fewer animals treated with required second (n=44) and third (n=13) treatments than animals treated with (n=97 and n=, respectively). Consequently, fewer total treatments were administered to cattle in the groups than to cattle in the groups. administered as a single subcutaneous (SC) injection was safe and effective for the initial treatment of bovine respiratory disease (BRD) in calves at 3 feedlots. Introduction is a highly effective, singledose antimicrobial medication indicated for control of BRD in cattle at high risk of developing BRD caused by Mannheimia haemolytica, Pasteurella multocida and Histophilus somni, and for treatment of BRD caused by these three organisms and Mycoplasma bovis. When administered according to the label dose of 2.5 mg tulathromycin/kg body weight (BW), tulathromycin is rapidly absorbed, distributes widely and provides concentrations in bovine lung for an extended period. 1 Clinical efficacy of for treatment of BRD, as well as for control of respiratory disease in cattle at high risk of developing BRD, has been well documented in multiple studies. 2,3,4 This technical bulletin presents the results of a multilocation study designed to compare the efficacy of or for treatment of naturally occurring BRD in feedlot calves. The same study protocol was used at all three sites. Results were analyzed separately by site, and results from two sites have been published in the peer-reviewed literature. 5

2 Materials and Methods In ctober and November 5, calves were purchased at livestock markets in Mississippi and Texas and transported to the commercial feedlots in Colorado (n=86 mixed-breed steers), Texas site I (n=742 mixed-breed heifers) and Texas site II (n=82 mixed-breed heifers). Animals were processed on arrival using standard methods for commercial stocker/ feeder operations, but were not vaccinated against Mannheimia or Pasteurella species. Calves with clinical signs of BRD were evaluated and enrolled if they had a clinical attitude score (CAS) of 1, 2 or 3 and pyrexia (rectal temperature 14ºF). According to the CAS system, =normal, bright, alert, responsive; 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; or 4=moribund. Calves that met the inclusion criteria were randomly assigned to treatment with either (5.7 mg enrofloxacin/lb; 12.5 mg/kg BW) or (1.1 mg tulathromycin/lb; 2.5 mg tulathromycin/kg BW; Figure 1). Animals were blocked (2 animals per block, 1 from each group) by order of enrollment to avoid bias. ne-hundred-twenty-five animals per treatment group were enrolled at each site and commingled in treatment pens to maintain masking of the treatment groups. Enrollment occurred during a 3-day period in Colorado, an 18-day period in Texas I and a 13-day period in Texas II. Figure 1. Experimental Design 3 feedlots: C, TX I, TX II n=125 n=125 Abnormal CAS & T >_ 14ºF 1st treatment, day 3 2 Eligible for 2nd treatment LA- 2 CAS on 1 to 28 bserved on 1 to 6 (+_ 3) SFLT=standard feedlot treatment Eligible for 3rd treatment Nuflor Chronics SFLT Success Response/ No response Response/ No response Removed Animals were assessed daily and CAS scores recorded for 28 following enrollment; animals were observed for treatment response/nonresponse for 63 in Colorado, 59 in Texas I and 58 in Texas II. Clinical assessors were masked to treatments. Animals were eligible for secondary treatments on day 3 after enrollment (day ). n 3 to the end of the study, animals with CAS scores of 1 or 2 and pyrexia (rectal temperature 14ºF) were considered nonresponders and received a second treatment with LIQUAMYCIN LA- (9. mg oxytetracycline/lb;. mg oxytetracycline/kg). Animals that were a minimum of 2 following treatment with LA- and met nonresponder criteria received a third treatment with Nuflor (florfenicol) Injectable Solution (18. mg florfenicol/lb;. mg florfenicol/ kg). Animals that met nonresponder criteria and were a minimum of 2 post-treatment with Nuflor were classified as chronics and received the standard feedlot treatment (SFLT). According to the study protocol, animals were to be removed from the study before analysis for non-brd reasons (concurrent disease or other physical conditions that might interfere with the progression of BRD or evaluation of response to therapy) or protocol deviations (allotment entry errors, errors in administration of medication, animals not evaluated/treated in a timely manner). Clinical success was defined as requiring no subsequent treatment. Mortality, CAS scores, body weights and weight gains were summarized for each treatment. Treatment differences were assessed at the 5% level of significance (P<.5). Results Colorado The clinical success for study to 59 was significantly higher (P=.9) for animals treated with (87.9%) than for those treated with (7.2%; Table 1). Figure 2a displays the cumulative treatment success by day. Animals with an in-pen CAS equal to (normal) after the initial treatment are displayed in Figure 3a. Second treatments were administered to 37 animals in the group and 15 in the group. Third treatments were administered to 9 animals in the group and 4 in the group. Weight gains were numerically greater (P=.51) for animals treated with (18.9 lb) than for those treated with (173. lb). ne animal in the group was declared a chronic; no deaths due to BRD occurred in either group. was significantly more efficacious than for treatment of naturally occurring BRD at this site. Texas I The clinical success for study to 63 was significantly higher (P=.31) for animals treated with (8.%) than for those treated with (62.5%; Table 1). This is also displayed in Figure 2b as cumulative treatment success by day. Animals displaying an in-pen CAS equal to after the initial treatment are displayed in Figure 3b. Second treatments were administered to 44 animals in the group and 23 in the group. Third treatments were administered to 17 animals in the group and 9 in the group. Seventeen animals were classified as chronics, 7 in the group and 8 in the group. ne animal in each group died before SFLT. Weight gains were numerically greater (P=.89) for animals treated with (78.1 lb) than for those treated with (71.6 lb). Mortality was similar for both groups: 6 animals in the group and 5 in the group. was significantly more efficacious than for treatment of naturally occurring BRD at this site. Texas II Two-hundred-fifty animals were enrolled in the study. Seventyseven animals were excluded from the study analyses for non- 2

3 BRD reasons or protocol deviations defined before the study began. Additionally, for the 37 animals excluded for protocol deviations, 29 block mates were also excluded to avoid potential bias. (The numbers differ because in some instances both animals in a block were excluded for protocol deviations.) Data collected from 83 animals in the group and animals in the group were analyzed and are reported here. Because of the number of animals affected by protocol deviations, preliminary analysis of all cattle at this site was conducted and demonstrated no effect on statistical results. Table 1 summarizes the response to treatment at this site. As depicted in Figure 2c, clinical success was significantly greater (P=.31) for animals treated with (87.8%) than for those treated with (74.7%). Second treatments were administered to 16 animals in the group and 6 in the group. Third treatments were administered to 1 animal in the group and in the group. Animals displaying an in-pen CAS equal to after the initial treatment are displayed in Figure 3c. A significant advantage (P=.) in mean weight gains was observed for animals treated with (2.7 lb) compared to those treated with (172.9 lb). Nine animals in the group and 5 in the group died. Discussion At all three sites, clinical success was significantly higher for calves treated with (87.9%, 8% and 87.8%) than for those treated with (7.2%, 62.5%, 74.7%). The results of the primary study variable first-treatment success were similar at all sites. The treatment success for cattle treated with was better at each individual site and collectively for all three sites. The numbers of cattle treated with that required further treatment ranged from 6 to 15 per site compared to 16 to 44 per site for the cattle treated with. The first-treatment success and total number of treatments administered were more favorable at every site for the cattle treated with. At all three sites, a total of 57 calves in the groups and 124 calves in the groups required second and third treatments. Consequently, fewer antimicrobial treatments were administered to animals in the groups than in the groups. Taken together, evidence from the three sites demonstrates that provides effective and consistent results in treating BRD in feedlot calves compared with. Enrollment times (3, 18 and 13 ) reflect realistic variances in groups of cattle and typical commercial-receiving conditions. The initial variable for enrollment was the CAS, which relies on clinical signs as evidence of BRD. Numerous factors could result in different CAS values among sites, including cattle source, disease exposure, transport conditions and local weather. The individuals responsible for evaluation and treatment of the cattle were blinded to the treatments administered and to the allocation and blocking of cattle in the treatment groups, so the cattle were treated similarly within each site regardless of the time required for treatment allocation. In addition, the results were similar across sites in that there was a similar magnitude of difference in first-treatment successes between the treatment groups and no difference in mortality or chronics. It is important to note that in this three-site study, comparing to, cattle were eligible for retreatment three following initial treatment. This interval was chosen in part to preserve masking of the treatments. However, the trend of successful treatment of BRD with is supported by other studies with longer post-treatment intervals (PTIs). 2,3,4 The PTI is a period of time after treatment with an antimicrobial when no further treatment is administered. significantly reduced mortality and lung lesions in cattle if given as long as 9 before experimental intratracheal inoculation of M. haemolytica. 6 In a companion study, cattle with naturally occurring BRD were treated with and no additional treatments were allowed for intervals of 7, 1 or There was no difference in firsttreatment success, mortality or weight gain in the three groups. These two additional studies provide experimental and clinical evidence that exerts a clinical effect against BRD in cattle for longer than the three-day PTI reported here for the three feedlot sites. Clinical effect in response to bacterial pneumonias is, in part, a function of spectrum of activity, as most cases of bacterial pneumonias are the result of a mixed bacterial infection. Multiple factors, many of which are not clearly defined, make up the biological equation termed response to treatment or in this study CAS. From an anti-infective standpoint, spectrum of activity against the important target pathogens and length of effective treatment are important components. is labeled for treatment of all four major bacterial pathogens causing BRD in cattle, including Mycoplasma bovis. Recent studies indicate that the two most common microbial agents associated with nonresponsive BRD are M. bovis and BVDV. 7,8 The improved first-treatment success seen with vs. in this three-site study parallels the results of studies comparing with Micotil (tilmicosin injection) and Nuflor. 3,4 The antimicrobial spectrum and pharmacokinetics of in cattle provide measurable clinical advantages over these other antimicrobials used to treat BRD. Conclusions Using for initial treatment of BRD in calves resulted in significantly greater first-treatment success and fewer second and third treatments than achieved with at three feedlots. Do not use in female dairy cattle months of age or older. Do not use in calves to be processed for veal. has a pre-slaughter time of 18. Prepared from study reports 1133R , 1133R and 1133R and LIQUAMYCIN LA- are registered trademarks of Pfizer Inc. is a registered trademark of Bayer Aktiengesellschaft. Micotil is a registered trademark of Eli Lilly and Company. Nuflor is a registered trademark of Schering-Plough Veterinary Corp. 7 Pfizer Inc. All rights reserved. 3

4 References 1 Nowakowski MA, Inskeep P, Risk J, Skogerboe TL, Benchaoui HA, Meinert TR. Sherington J, Sunderland SJ. Pharmacokinetics and lung tissue concentrations of tulathromycin, a new triamilide antibiotic, in cattle. Vet Ther 4;5: Nutsch RG, Skogerboe TL, Rooney KA, Weigel DJ, Gajewski K, Lechtenberg KF. Comparative efficacy of tulathromycin, tilmicosin and florfenicol in the treatment of bovine respiratory disease in stocker cattle. Vet Ther 5;6(2): Skogerboe TL, Rooney KA, Nutsch RG, Weigel DJ, Gajewski K, Kilgore WR. Comparative efficacy of tulathromycin versus florfenicol and tilmicosin against undifferentiated bovine respiratory disease in feedlot cattle. Vet Ther 5;6(2): Rooney KA, Nutsch RG, Skogerboe TL, Weigel DJ, Kimberly K, Kilgore WR. 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 5:6(2): Robb EJ, Tucker CM, Corley L, et al. Efficacy of tulathromycin versus enrofloxacin for initial treatment of naturally occurring bovine respiratory disease in feeder calves. Vet Ther 7;8(2): Rooney KA, Meeuwse DM, Nutsch RG, et al. The efficacy and timing of tulathromycin ( Injectable solution) administration in calves challenged with Mannheimia haemolytica or managed in a feedlot. 7; in press. 7 Shahriar FM, Clark EG, Janzen E, West K, Wobeser G. Coinfection with bovine viral diarrhea virus and Mycoplasma bovis in feedlot cattle with chronic pneumonia. Can Vet J 2;43(11): Haines DM, Martin KM, Clark EG, Jim GK, Janzen ED. The immunohistochemical detection of Mycoplasma bovis and bovine viral diarrhea virus in tissues of feedlot cattle Figure with 2a. chronic, Cumulative unresponsive Treatment respiratory Success disease (Colorado) and/or arthritis. Can Vet J 1;42(11): Figure 2b. Cumulative Treatment Success (Te P= DR Clinical success was significantly higher (P=.9) for animals treated with (87.9%) than for those treated with (7.2%). 4 Clinical success was significantly higher (P=.31) for an (8.%) than for those treated with (62.5

5 Figure 2a. Cumulative Treatment Success (Colorado) P= Clinical success was significantly higher (P=.9) for animals treated with (87.9%) than for those treated with (7.2%). Figure 2b. Cumulative Treatment Success (Texas I) P= Clinical success was significantly higher (P=.31) for animals treated with (8.%) than for those treated with (62.5%). xas I) Figure 2c. Cumulative Treatment Success (Texas II) AXXIN P= P= imals treated with %). Clinical success was significantly higher (P=.31) for calves treated with (87.8%) than for those treated with (74.7%). 5

6 rado) Figure 2b. Cumulative Treatment Success (Texas I) Figure 2c. Cumu XXIN P=.9 Figure 3a. Clinical Appearance After Treatment (Colorado): % of treatment % cattle remaining groups free of BRD Animals with CAS of through 28 P= als treated with ) Clinical success was significantly higher (P=.31) for animals treated with (8.%) than for those treated with (62.5%). Clinical success w (87.8%) as I) Figure 2c. Cumulative Treatment Success (Texas II) t (Colorado): XXIN ril P=.31 Figure 3b. Clinical Appearance After Treatment (Texas I): % of treatment % cattle remaining groups free of BRD Animals with CAS of through 28 P= Figure 3c. Clinic Anima % of treatment groups als treated with ) Clinical success was significantly higher (P=.31) for calves treated with (87.8%) than for those treated with (74.7%) t (Texas I): Figure 3c. Clinical Appearance After Treatment (Texas II): Animals with CAS of through 28 il 12 % of treatment groups

7 Table 1. Summary of Response to Treatment D a y 6 D a y 9 D a y D a y 1 8 D a y 2 1 D a y 2 4 D a y 2 7 Colorado Texas I Texas II Animals Treatments, No. Animals Treatments, No. Animals Treatments, No. Enrolled, no Removed from All Analyses Number that Recieved 1st Treatment al Appearance After Treatment (Texas II): ls with CAS of through 28 as significantly higher (P=.31) for calves treated with than for those treated with (74.7%) P=.31 B a yt ri l lative Treatment Success (Texas II) 7 1st Treatment Success, no st Treatment Failure, no st Treatment Success, % 7.2 a 87.9 b 62.5 c 8. d 74.7 e 87.8 f Died before 2nd Treatment, no Removed Non-BRD-Related or Protocol Deviations after 2nd Treatment, no. 1 1 Number that Recieved 2nd Treatment nd Treatment Success, no nd Treatment Failure, no nd Treatment Success, % Died before 3rd Treatment, no Removed Non-BRD Related or Protocol Deviations, no Number that Recieved 3rd Treatment rd Treatment Success, no N/A 3rd Treatment Failure, no rd Treatment Success, % Died before SFLT 1 1 Removed Non-BRD Related or Protocol Deviations, no. 1 SFLT/Chronics, no Total Treatments Administered, no These animals were removed from the study before analyses for non-brd reasons or protocol deviations defined before the study began. The reasons for exclusion at Texas II included: 1 = allotment entry error, 3 = errors in administration of medications, 7 = CAS of 2 and not evaluated further for responder/nonresponder classification, 37 = CAS of 2 and were not evaluated/treated in a timely manner. For the 37 animals excluded for protocol deviations, 29 block mates were also excluded to avoid potential bias. The numbers differ because in some instances both animals in a block were excluded for protocol deviations. Back-transformed least squares mean (LSM). a,b Different superscripts indicate significantly different values (P=.9). c,d Different superscripts indicate significantly different values (P=.31). e,f Different superscripts indicate significantly different values (P=.31). Deads excluded.

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