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Influence of therapeutic use of feedgrade tetracyclines in combination with tulathromycin metaphylaxis on animal health and performance of Holstein steer calves

Influence of therapeutic use of feedgrade tetracyclines in combination with tulathromycin... Downloaded from https://academic.oup.com/tas/advance-article-abstract/doi/10.1093/tas/txy135/5235607 by Ed 'DeepDyve' Gillespie user on 10 January 2019 Influence of therapeutic use of feedgrade tetracyclines in combination with tulath- romycin metaphylaxis on animal health and performance of Holstein steer calves † † † † † Josh I. Szasz, Casey P. McMurphy, Tony C. Bryant, Job Luque, Cristobal Barcelo, † ‡ ‡ ‡,||,2 Gabriel Sepulveda, K. Shawn Blood, Bryan C. Bernhard, and Heather D. Hughes, † ‡ || Five Rivers Cattle Feeding, Greeley, CO 80634; Zoetis, Parsippany, NJ 07054; and SciWrite Consulting, LLC, Canyon, TX 79015 −1 −1 ABSTRACT: Feedgrade chlortetracycline (CTC) OTC+TUL were administered 4 g OTC·steer ·d as and oxytetracycline (OTC) are approved for use in part of a complete diet for 14 consecutive days begin- beef cattle diets for the control of bovine respira- ning on 10 DOF. Within the first 30 d of the feed- tory disease (BRD). The objectives of this experi- ing period, BRD first pulls were reduced (P  = 0.001) ment were to compare CTC and OTC, administered for CTC+TUL, OTC+TUL, and TUL relative to according to label, for the treatment of BRD in CTC alone. Percentage of BRD first pulls and total Holstein calves and to characterize the influence of morbidity were lowest (P  =  0.001) for CTC+TUL tulathromycin metaphylaxis in combination with tet- across the feeding period, with OTC+TUL and racycline treatment. Summer-placed Holstein steer TUL being intermediate, and CTC alone exhibiting calves (n = 6,800) were randomly assigned to one of the highest percentage. Death loss and railers were four treatments (11 blocks; initial BW = 140 ± 18 kg) not influenced (P ≥ 0.58) by treatment. Dry matter as they passed through the squeeze chute at initial intake was greater (P = 0.001) for CTC+TUL than processing in a commercial feedlot. Treatments con- all other treatments. Final BW and ADG were great- sisted of: (i) CTC and tulathromycin metaphylaxis est for CTC+TUL, lowest for TUL alone, and inter- (CTC+TUL), (ii) OTC and tulathromycin metaphy- mediate for the remaining treatments (P < 0.05) on laxis (OTC+TUL), (iii) tulathromycin metaphylaxis a deads-and-railers-out basis. Deads-and-railers-in only (TUL), or (iv) CTC only (CTC). Cattle were ADG was greatest (P < 0.05) for CTC+TUL com- fed for an average of 118 d. Tetracycline feeding was pared to all other treatments. Feed conversion was instituted based on visual assessment of the attending not influenced (P ≥ 0.22) by treatment. In the current veterinarian in accordance with the veterinary feed study, supplementation of OTC in combination with directive. When applicable, CTC was fed as a top- tulathromycin metaphylaxis did not benefit health −1 −1 dress at a rate of 4 g CTC·steer ·d for 5 consecu- over tulathromycin alone. Results suggest that CTC tive days, beginning on 6 d on feed (DOF). Three 5-d in combination with tulathromycin metaphylaxis pulses were delivered to CTC+TUL and CTC cat- reduces morbidity in Holstein steers calves, which tle, with a 48-h time lapse between pulses. Cattle on may lead to improved performance. Key words: bovine respiratory disease, cattle, feedgrade tetracyclines, health, metaphylaxis © The Author(s) 2019. Published by Oxford University Press on behalf of the American Society of Animal Science. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Transl. Anim. Sci. 2018.XX:XX–XX doi: 10.1093/tas/txy135 1 2 Funding for this study was provided by Zoetis, Inc. No Corresponding author: heather@sciwriteconsulting.com employees of the sponsor were directly involved in the con- Received November 26, 2018. duct of the experiment. Accepted December 6, 2018. 1 Downloaded from https://academic.oup.com/tas/advance-article-abstract/doi/10.1093/tas/txy135/5235607 by Ed 'DeepDyve' Gillespie user on 10 January 2019 2 Szasz et al. INTRODUCTION administered in a top-dress application to eliminate related milling issues. Cattle entering the feedlot, particularly those Data that compare the bioavailability and/or that are lightweight and/or high risk, are more sus- efficacy of CTC vs. OTC in cattle are limited. When ceptible to bovine respiratory disease (BRD) than treating non-intestinal pathogens such as BRD with any other health challenge (Taylor et  al., 2010b). oral antibiotics, it is imperative that the antimicro- In weaned dairy calves specifically, BRD is the bial be effectively absorbed into the bloodstream primary cause of death; a fact that has remained to reach targeted tissues of the respiratory tract unchanged in the last few decades, demonstrating (del Castillo et al., 1998). Luthman and Jacobsson a need for improvement in preventing and con- (1983) observed greater bioavailability of CTC rel- trolling the disease (Gordon and Plummer, 2010). ative to OTC (37% vs. 5%, respectively) following BRD is multi-factorial in nature, as it involves oral administration to non-fasted calves, conclud- infectious disease agents, compromised host immu- ing that CTC is more suitable than OTC for oral nity, and environmental factors that may include therapy. However, limited data exist that evaluate transport and feedlot processing activities that ulti- and compare the therapeutic use of feedgrade tet- mately result in bronchopneumonia (Grissett et al., racyclines in reducing BRD, particularly in light- 2015). Therefore, implementing health and produc- weight Holstein calves. tion strategies in lightweight cattle is necessary for A second and more characterized method for reducing stress, minimizing disease, and optimizing controlling BRD in lightweight, high-risk calves performance (Nickell and White, 2010). Despite the is metaphylaxis, which is the mass medication of improvements in managing feedlot health in recent calves with antibiotics upon arrival to the feedlot years, the complex nature of BRD, in addition to (Abell et al., 2017). While metaphylaxis is effective an ever-changing landscape of government regula- at reducing morbidity and mortality, the prevalence tion, perpetuates morbidity and mortality rates in and challenges associated with BRD remain, sug- the feedlot (Windeyer et al., 2017). gesting a need for additional measures for control One method for controlling BRD in newly of the disease (Ives and Richeson, 2015). Therefore, received cattle is through the therapeutic use of the objectives of this experiment were to compare feedgrade tetracyclines. Chlortetracycline (CTC) feedgrade CTC and OTC for the treatment of BRD and oxytetracycline (OTC) are 2 naturally occur- in Holstein calves and to characterize the influence ring tetracycline compounds approved for use in of tulathromycin metaphylaxis in combination with beef cattle diets. Feeding antimicrobials may be the use of feedgrade tetracyclines. beneficial in decreasing the amount of “pulls” from the feedlot home pen and the associated stress of MATERIALS AND METHODS being removed and doctored (Thomson and White, 2015). Consequently, the judicial use of feedgrade This study was conducted from July 2017 antibiotics, in accordance with the VFD, may and December 2017 in a feedyard in southwest- decrease the necessity for injectable antibiotics ern Arizona and followed an approved protocol from antimicrobial classes which are categorized as whereby routine management practices of the com- “highest priority critically important antimicrobi- mercial feedlot are in accordance with 7 U.S.C. 54 als” by the World Health Organization (third-gen- and FASS (2010). eration cephalosporins, fluoroquinolones, and macrolides) (Agga, Schmidt, and Arthur, 2016). Cattle Arrival and Processing Aside from chemical structure, differences between Summer-placed Holstein steer calves OTC and CTC relate to their physical application (n = 6,800; initial BW = 140 ± 18 kg) acquired from (feed delivery), their antimicrobial properties, and various dairy farms in the western United States, their absorption into the bloodstream (bioavaila- which underwent standard dairy calf management bility) (Agwuh and MacGowan, 2006). Feed appli- including colostrum feeding, standard vaccination cation of the type A version of these tetracyclines procedures, and acclimation to grain-based diets, differs in that OTC contains a higher concentration were used in this trial. Steers were received between than CTC (220 and 440 g/kg for type A CTC and July 27, 2017 and August 26, 2017, allowed an aver- OTC, respectively), which decreases bulk in the age of 3 d rest (range  =  1 to 5 d) with access to ration, labor, and batching times when included feed and water, prior to being randomized to one in a complete diet, relative to CTC; however, CTC of four4 treatments as they passed through the is also available as a type C product which may be Translate basic science to industry innovation Downloaded from https://academic.oup.com/tas/advance-article-abstract/doi/10.1093/tas/txy135/5235607 by Ed 'DeepDyve' Gillespie user on 10 January 2019 Feedgrade tetracylines 3 squeeze chute at initial processing using a chute- using visual signs of anorexia, dull eyes, depression, side personal computer containing a randomiza- weakness, cough, nasal discharge, watery eyes, lack tion application. As cattle exited the squeeze chute, of fill, stiff gait, loose feces, and increased respira- they were sorted into one of four pens according to tory rate. Feedgrade CTC is approved for use in treatment assignment. Sort pens were then assigned beef cattle diets for control of bacterial pneumonia to home pens via a randomization function (Excel, associated with the shipping fever complex caused Microsoft Corporation, Redmond, WA). The study by Pasteurella species susceptible to CTC when fed −1 −1 was comprised of 44 pens, divided into 11 blocks continuously at 350 mg·animal ·d . Additionally, of four treatments each. Pens within a statistical CTC is approved for treatment of bacterial pneu- block were provided similar area (32.3 and 39 m monia cause by P. multocida organisms susceptible for blocks 1 to 6 and 7 to 11, respectively) and bunk to CTC when fed at 22 mg/kg BW daily for no more space (27.4 and 30.5 cm per animal for blocks 1 to than 5 consecutive days. OTC is approved for treat- 6 and 7 to 11, respectively) and were oriented in ment of bacterial pneumonia (shipping fever com- the same direction regarding pen slope. Water tank plex) caused by Pasteurella multocida susceptible to space was identical among pens within a statistical OTC fed at 22 mg/kg BW daily for 7 to 14 d. block (2.4 and 4.6 cm per animal for blocks 1 to 6 Chlortetracycline was fed as a top-dress once and 7 to 11, respectively). daily using a commercially available type C pelleted Cattle were administered various products at top-dress containing 8.8  g/kg CTC, when applic- −1 −1 processing, following a standardized feedlot pro- able, at a rate of 4 g CTC·steer ·d (22 mg/kg BW) tocol which included a dangle identification tag in for 5 consecutive days starting at 6 d on feed (DOF) each ear, 2 mL s.c. in the neck of a five-way mod- (Table 1). Six DOF was chosen as the start date for ified-live respiratory vaccine (Titanium 5, Elanco CTC in an effort to maximize the concentration of Animal Health, Greenfield, IN), 1  mL per naris CTC in lung tissue, based on results from previous of an intranasal respiratory vaccine (Nasalgen IP, studies (Wallace et al., 2009; Thomson et al., 2014). Merck Animal Health, Madison, NJ), 2 mL s.c. in CTC and CTC+TUL calves continued to display the neck of a seven-way clostridial vaccine for pro- BRD symptoms 48  h after the initial CTC pulse tection against Clostridium bacteria (Ultrachoice 7, and were administered a second 5-d pulse of the Zoetis, Kalamazoo, MI), a growth implant in the same dose, per veterinary recommendation. Forty- middle third of caudal aspect of the ear (Synovex eight hours following the second CTC pulse, calves C, Zoetis), and 3.5 mL per animal s.c. in the neck continued to display BRD symptoms and were of tulathromycin (Draxxin, Zoetis Animal Health, administered a third CTC pulse, again upon veteri- Kalamazoo, MI) when applicable due to treatment nary assessment and recommendation. assignment. After processing each block of steers, Cattle assigned to the OTC treatment were sort pens within block were weighed across a plat- fed a complete feed formulated to provide 4  g −1 −1 form scale before moving cattle to one of four OTC·steer ·d (22  mg/kg BW) for 14 consecu- adjacent home pens in the feedlot. Platform scale tive days starting at 10 DOF (Table  1). Ten DOF weights served as initial weights for the study. was selected to account for the starter ration fed previously, which contained an ionophore (Laidlomycin, Cattlyst, Zoetis Animal Health) Experimental Design and Treatments not approved for combination with OTC. Actual −1 −1 Experimental treatments were designed to OTC fed averaged 3.9 g·steer ·d (range = 3.3 to −1 −1 compare two different tetracycline molecules, CTC 4.3 g·steer ·d ). (Aureomycin, Zoetis Animal Health) and OTC Complete feed was delivered once daily and (Terramycin, Phibro Animal Health, Teaneck, NJ), consisted of steam-flaked corn, corn silage, alfalfa and to evaluate tulathromycin (Draxxin, Zoetis and sorghum-Sudan hay, tallow, corn-milling Animal Health) metaphylaxis on health and perfor- byproducts, and supplemental ingredients. All mance of Holstein steer calves. Cattle were assigned cattle were managed using the same feed man- to one of four treatments: (i) CTC and tulathromycin agement philosophy and were adapted to a finish metaphylaxis (CTC+TUL), (ii) OTC and tulathro- ration using a single intermediate ration and a mycin metaphylaxis (OTC+TUL), (iii) tulathromy- series of step-up feeding schedules. Laidlomycin cin metaphylaxis only (TUL), or (iv) CTC only type A (Cattlyst) was included in all diets (11.1 g/ (CTC). Tetracycline feeding was instituted based ton; dry matter basis), except during the OTC upon the assessment of the attending veterinarian feeding period because of combination feeding in accordance with the Veterinary Feed Directive, restrictions. Translate basic science to industry innovation Downloaded from https://academic.oup.com/tas/advance-article-abstract/doi/10.1093/tas/txy135/5235607 by Ed 'DeepDyve' Gillespie user on 10 January 2019 4 Szasz et al. Table 1. Treatment-dose regimen of feedgrade tetracyclines 1 2 3 4 Treatments CTC+TUL OTC+TUL TUL CTC Item 5 5 Pulse 1: 6 to 10 Pulse 1: 6 to 10 Tetracycline DOF Pulse 2: 12 to 16 10 to 23 n/a Pulse 2: 12 to 16 Pulse 3: 18 to 22 Pulse 3: 18 to 22 Ionophore Pre-tetracycline phase Laidlomycin Laidlomycin Laidlomycin Laidlomycin Tetracycline phase Laidlomycin None Laidlomycin Laidlomycin Tetracycline rest days Laidlomycin n/a Laidlomycin Laidlomycin Post-tetracycline phase Laidlomycin Laidlomycin Laidlomycin Laidlomycin 1 −1 Chlortetracycline (Aureomycin type C pellet 8.8 g/kg, L.A. Hearn Company, King City, CA) fed at 4 g·steer ·d for three 5-d treatments plus −1 −1 metaphylaxis with tulathromycin (Draxxin 100 mg/mL, Zoetis Animal Health) injection administered on arrival at 3.5 mL·steer ·d . 2 −1 −1 Oxytetracycline (Terramycin 200 type A 440 g/kg, Phibro Animal Health) fed at 4 g·steer ·d for 14 consecutive days plus metaphylaxis with −1 −1 tulathromycin (Draxxin 100 mg/mL, Zoetis Animal Health) injection administered on arrival at 3.5 mL·steer ·d . 3 −1 −1 Metaphylaxis with tulathromycin (Draxxin 100 mg/mL, Zoetis Animal Health) administered on arrival at 3.5 mL·steer ·d ). 4 −1 −1 Chlortetracycline (Aureomycin type C pellet 8.8 g/kg, L.A. Hearn Company) fed at 4 g·steer ·d for three 5-d treatments. Animals were evaluated by a veterinarian 48 h after each treatment to determine if a subsequent second and third treatment were needed. Days on feed. Laidlomycin type A (110 g/kg), Cattlyst, Zoetis Animal Health. Animal Health Management with 14 gauge x 1.9  cm needles, while all other injectable antimicrobials were administered using Study cattle were observed daily by pen rid- syringes fitted with 16 gauge x 1.6  cm needles. ers, between 0600 and 1000 hours, with a single All antibiotics were administered s.c. according pen rider examining all four pens within a sta- to Beef Quality Assurance guidelines. One case tistical block when possible. Cattle were treated of treatment noncompliance was reported in the between 0900 and 1400 hours, with all cattle TUL treatment group; this steer received an anti- operations ceasing by 1100 hours in the month microbial labeled for treatment of BRD that was of August due to heat. All pulls within a block not included in the regimen in Table 2. This ani- were treated at the same hospital facility. Cattle mal was retained in the data set during statistical on CTC+TUL, OTC+TUL, and TUL experi- analysis. mental treatments were not eligible for pull and Standard feedlot protocols were implemented BRD treatment with injectable antibiotics until a for the treatment of diseases unrelated to BRD and 7-d postmetaphylaxis interval had been reached were consistent for cattle across experimental treat- (Table  2). Table  3 provides the BRD injectable ments. Cattle were allowed to convalesce in hospi- treatment regimen for cattle not receiving met- tal pens for a minimum of 24  h before returning aphylaxis. Post-treatment intervals for animals to home pens. Post-treatment interval and clinical that relapsed and received additional injectable appearance were used to determine whether cattle antibiotic therapy for BRD treatment were as should return to the home pen or receive a subse- follows: tulathromycin (Draxxin, Zoetis Animal quent treatment. Mortalities were subject to post- Health), 7 d; florfenicol and flunixin meglumine mortem examination by a licensed veterinarian or (Resflor, Merck Animal Health), 4 d; dano- trained feedlot employee. Upon study completion, o fl xacin (Advocin, Zoetis Animal Health), 3 d; steers were weighed across a platform scale before OTC (Bio-Mycin 200, Boehringer Ingelheim being re-implanted between 116 and 121 DOF. Vetmedica, Duluth, GA), 2 d.  Cattle pulled a These pen weights served as the official final pen fourth time for BRD were eligible for re-treat- weights for the study. ment with danofloxacin rather than being railed if 45 d had elapsed since receiving their last BRD Statistical Analysis treatment. Cattle were railed if requiring a fourth treatment for the same disease or if pulled for a Data were analyzed as a randomized com- disease for which no practical treatment plan was plete block design with pen as experimental unit. available at the feedyard. Florfenicol and flunixin Continuous data (e.g., initial BW) were analyzed meglumine was administered using a syringe fitted using the MIXED procedure (SAS 9.4 Inc., Cary, Translate basic science to industry innovation Downloaded from https://academic.oup.com/tas/advance-article-abstract/doi/10.1093/tas/txy135/5235607 by Ed 'DeepDyve' Gillespie user on 10 January 2019 Feedgrade tetracylines 5 Table 2. BRD injectable treatment regimen for cat- RESULTS tle receiving tulathromycin metaphylaxis First BRD pulls (rectal temperature ≥40  °C) Pull were lower (P  <  0.05) for CTC+TUL and order Rectal temperature ≥40 °C Rectal temperature <40 °C OTC+TUL in the first 30 DOF compared to TUL 1 Florfenicol and flunixin Oxytetracycline 4 and CTC and lower (P < 0.05) for CTC+TUL com- meglumine pared to all other treatments over the entire feed- 2 Danofloxacin Florfenicol and flunixin meglumine ing period (Table  4). Total morbidity was lowest 3 Rail Danofloxacin for CTC+TUL cattle, greatest for CTC cattle, and 4 n/a Rail intermediate for OTC+TUL and TUL treatments (P < 0.05). However, mortality, railers, and wastage Bovine respiratory disease. 2 (sum of mortality and railers) were not influenced Tulathromycin (100  mg/mL) administered at 3.5  mL/animal; Draxxin, Zoetis Animal Health. (P ≥ 0.58) by treatment. A post-metaphylactic interval of 7 d was imposed prior to cattle Cattle were fed for an average of 118 d.  Dry being eligible for treatment with an injectable antibiotic. matter intake was greater (P < 0.05) for CTC+TUL Florfenicol (300  mg/mL) and flunixin meglumine (16.5mg/mL) compared to all other treatments (Table  5). administered at 6  mL/45.4  kg BW; Resflor, Merck Animal Health; Final BW and ADG were greater (P  <  0.05) for post-treatment interval was 4 d. CTC+TUL compared to OTC+TUL, TUL, and Oxytetracycline (200 mg/mL) administered at 4.5 mL/45.4 kg BW; Bio-Mycin 200, Boehringer Ingelheim Vetmedica; post-treatment CTC and were lower (P  <  0.05) for TUL cattle interval was 2 d. relative to OTC+TUL or CTC treatments on a Danofloxacin (180  mg/mL) administered at 2  mL/45.4  kg BW; deads-and-railers-out basis. On a deads-and-rail- Advocin, Zoetis Animal Health; post-treatment interval was 3 d. ers-in basis, final BW was greater (P  <  0.05) for CTC+TUL compared to TUL or CTC alone, but Table 3. BRD injectable treatment regimen for cat- was similar (P  =  0.16) to OTC+TUL. ADG was tle not receiving metaphylaxis greater (P < 0.05) for CTC+TUL cattle than TUL Pull or CTC treatments with OTC+TUL animals being order Rectal temperature ≥40 °C Rectal temperature <40 °C intermediate (P  <  0.05) on a deads-and-railers-in 2 3 1 Tulathromycin Oxytetracycline basis. Treatment had no effect (P > 0.22) on G:F on 2 Florfenicol and flunixin Tulathromycin 4 a DM basis. meglumine 3 Danofloxacin Danofloxacin 4 Rail Rail DISCUSSION Bovine respiratory disease. In the current study, tulathromycin metaphy- Tulathromycin (100 mg/mL) administered at 1.13 mL/45.4 kg BW; laxis alone improved health over feeding CTC alone Draxxin, Zoetis Animal Health; post-treatment interval of 7 d. and was overall similar to OTC+TUL. Several Oxytetracycline (200 mg/mL) administered at 4.5 mL/45.4 kg BW; studies have demonstrated reductions in morbid- Bio-Mycin 200, Boehringer Ingelheim Vetmedica; post-treatment ity when implementing metaphylaxis with paren- interval of 2 d. teral antibiotics upon arrival of young cattle to Florfenicol (300  mg/mL) and flunixin meglumine (16.5  mg/mL) administered at 6  mL/45.4  kg BW; Resflor, Merck Animal Health; the feedlot (van Donkersgoed, 1992; Frank et  al., post-treatment interval of 4 d. 2002; Macartney et  al., 2003) and more specifi- Danofloxacin (180  mg/mL) administered at 2  mL/45.4  kg BW; cally when administering tulathromycin on arrival Advocin, Zoetis Animal Health; post-treatment interval of 3 d. (Step et  al., 2007; Wellman and O’Connor, 2007). NC), with treatment as a fixed effect and block as Furthermore, Rooney et  al. (2005), in three sepa- a random effect. A generalized linear mixed model rate studies, observed superior efficacy of tulath- (GLIMMIX, SAS 9.4 Inc.) was used to analyze romycin at decreasing morbidity and mortality in categorical data with the model effects described newly received, high-risk calves compared to tilm- previously. Model estimation was performed using icosin and florfenicol. Chlortetracycline alone did a logit scale to link events/trials responses to a bino- not improve health relative to other treatments in mial distribution. Initial estimates of treatment the current study; however, it is important to note means and respective standard errors are reported that there was not a negative control treatment on the data scale using an inverse link method for full evaluation of its effect. Other studies have (ILINK Option, SAS 9.4 Inc.). When overall treat- demonstrated health improvements in response to ment effect was significant (P  <  0.10), treatment oral CTC. First pulls and morbidity were reduced means were partitioned using Tukey’s HSD post in multiple earlier studies in cattle supplemented hoc analysis. with CTC compared to negative control treatments Translate basic science to industry innovation Downloaded from https://academic.oup.com/tas/advance-article-abstract/doi/10.1093/tas/txy135/5235607 by Ed 'DeepDyve' Gillespie user on 10 January 2019 6 Szasz et al. Table 4. Influence of feedgrade tetracycline and arrival metaphylaxis on health of Holstein steer calves Treatments 1 2 3 4 5 Item CTC+TUL OTC+TUL TUL CTC SEM P-value No. of pens 11 11 11 11 — — BRD first pulls ≥40 °C, % of enrolled 7 a a b c First 30 DOF 7.0 6.8 8.9 13.0 1.79 0.001 a b b c Entire feeding period 12.8 16.2 16.9 19.7 1.83 0.001 BRD first pulls, % of enrolled a a a b First 30 DOF 9.7 9.3 11.1 15.9 1.97 0.001 a b b,c c Entire feeding period 19.1 22.8 24.1 25.8 1.92 0.001 BRD relapses , % of all BRD first pulls 45.3 40.7 42.2 46.6 3.06 0.329 Bullers, % 0.18 0.06 0.06 0.12 0.102 0.696 Skeletal morbidity, % of enrolled 0.53 0.18 0.24 0.53 0.184 0.230 Other morbidity, % of enrolled 0.12 0.47 0.35 0.35 0.201 0.393 11 a b b,c c Total morbidity, % of enrolled 20.0 23.6 24.9 26.9 1.97 0.001 Deathloss, % of enrolled BRD 0.93 1.17 1.46 1.17 0.303 0.576 Digestive 0.47 0.29 0.29 0.47 0.166 0.716 Other 0.46 0.58 0.35 0.29 0.196 0.581 Total 1.87 2.04 2.10 1.92 0.366 0.959 Railers, % of enrolled BRD 1.41 1.65 1.35 1.41 0.303 0.576 Total 1.58 1.87 1.46 1.81 0.343 0.765 DOF at time of death 49 59 48 49 6.7 0.550 DOF at time of rail 79 82 86 79 4.9 0.734 Wastage 3.41 3.87 3.53 3.70 0.526 0.894 a–c Treatments with unlike superscripts differ (P ≤ 0.10). 1 −1 −1 Chlortetracycline (Aureomycin type C pellet 8.8 g/kg, L.A. Hearn Company) fed at 4 g·steer ·d for three 5-d treatments beginning on day 6 −1 −1 plus metaphylaxis with tulathromycin (Draxxin 100 mg/mL, Zoetis Animal Health) injection administered on arrival at 3.5 mL·steer ·d ; animals were assessed by a veterinarian 48-h after each treatment dose to determine if a second or third subsequent dose was necessary. 2 −1 −1 Oxytetracycline (Terramycin type A 440 g/kg, Phibro Animal Health) fed at 4 g·steer ·d for 14 consecutive d beginning on day 10 plus meta- −1 −1 phylaxis with tulathromycin (Draxxin 100 mg/mL, Zoetis Animal Health) injection administered on arrival at 3.5 mL·steer ·d . 3 −1 −1 Metaphylaxis with tulathromycin (Draxxin 100 mg/mL, Zoetis Animal Health) administered on arrival at 3.5 mL·steer ·d . 4 −1 −1 Chlortetracycline (Aureomycin type C pellet 8.8 g/kg, L.A. Hearn Company) fed at 4 g·steer ·d for three 5-d treatments. P-value associated with the overall effect of experimental treatment. Bovine respiratory disease. Days on feed. Cattle treated for BRD more than once. Steers repeatedly mounted by pen cohorts. Injuries or diseases related to skeletal structures of the feet, limbs, back, shoulder, and hip. Total first pulls for all diseases includes bullers. Death loss plus railers. (Hale et al., 1967; Drake, Smart, and Smith, 1968). limited. Wallace et al. (2009) did not observe a sim- More recently, Thomson et  al. (2014) reported ilar additive effect of tulathromycin and CTC on improvement morbidity and re-treatment rates health variables when compared to diets containing when feeding CTC and decoquinate to steers when no CTC; however, CTC was top-dressed for only compared to negative control animals. Perhaps most two 5-d treatments, rather than 3, and began earlier notable with regard to health in the current study in the feeding period (one and seven DOF) than the was the improvement in health variables in cattle on current study, which may indicate that the timing of the CTC+TUL treatment relative to all other treat- the treatment doses should have been delayed for a ments, as evidenced by a decrease in morbidity. This more optimal response. may suggest an additive effect of CTC and TUL on Performance overall was improved for the improving health. However, studies examining the CTC+TUL treatment relative to other treatments implementation of tetracyclines fed at therapeutic and may partly be explained by the increase in DMI doses in combination with metaphylaxis are quite observed, as healthy cattle tend to consume more Translate basic science to industry innovation Downloaded from https://academic.oup.com/tas/advance-article-abstract/doi/10.1093/tas/txy135/5235607 by Ed 'DeepDyve' Gillespie user on 10 January 2019 Feedgrade tetracylines 7 Table 5. Influence of feedgrade tetracycline and arrival metaphylaxis on growth performance of Holstein steer calves Treatments 1 2 3 4 5 Item CTC+TUL OTC+TUL TUL CTC SEM P-value No. of pens 11 11 11 11 — — Steers enrolled 1,700 1,700 1,700 1,700 — — Initial BW, kg 142 141 141 141 2.45 0.70 DOF 118 118 118 118 — — a b b b DMI, kg 5.36 5.13 5.08 5.13 0.07 0.001 Deads and railers out a b c b Final BW, kg 301 298 293 296 3.45 0.001 a b c b ADG, kg 1.35 1.33 1.29 1.31 0.023 0.001 G:F 0.253 0.260 0.253 0.255 0.002 0.215 Deads and railers in a a,b c b,c Final BW, kg 295 291 286 288 3.63 0.003 a b c b,c ADG, kg 1.27 1.24 1.21 1.22 0.014 0.001 G:F 0.238 0.242 0.236 0.236 0.001 0.376 a–c Treatments with unlike superscripts differ (P ≤ 0.10). 1 −1 −1 Chlortetracycline (Aureomycin type C pellet 8.8 g/kg, L.A. Hearn Company) fed at 4 g·steer ·d for three 5-d treatments plus metaphylaxis −1 −1 with tulathromycin (Draxxin 100 mg/mL, Zoetis Animal Health) injection administered on arrival at 3.5 mL·steer ·d ; animals were assessed by a veterinarian 48 h after each treatment dose to determine if a second or third subsequent dose was necessary. 2 −1 −1 Oxytetracycline (Terramycin type A 440 g/kg, Phibro Animal Health) fed at 4 g·steer ·d for 14 consecutive days plus metaphylaxis with tulath- −11 −1 romycin (Draxxin 100 mg/mL, Zoetis Animal Health) injection administered on arrival at 3.5 mL·steer ·d . 3 −1 −1 Metaphylaxis with tulathromycin (Draxxin 100 mg/mL, Zoetis Animal Health) administered on arrival at 3.5 mL·steer ·d . 4 −1 −1 Chlortetracycline (Aureomycin type C pellet 8.8 g/kg, L.A. Hearn Company) fed at 4 g·steer ·d for three 5-d treatments. P-value associated with the overall effect of experimental treatment. Pen weights from cattle weighed in one or more drafts on a platform scale. Days on feed. Four percent pencil shrink applied. feed than animals experiencing greater immuno- current study. Thomson et al. (2014) did observe an suppression and subsequent decreased appetite. increase in DMI when feeding CTC (22 mg/kg BW) Repartitioning of nutrients away from growth for a 5-d treatment (one to five DOF), in combi- and toward the immune system during an immune nation with decoquinate at 0.5 mg/kg BW. Clearly, challenge further necessitates nutrient intake in these studies differ in dosage, feed-duration of order to minimize muscle protein degradation in CTC, and their respective treatment comparisons; immunosuppressed animals (Carroll and Forsberg, therefore, it would be presumptuous to generalize 2007). GrowSafe Technologies (GrowSafe Systems, across these trials. Furthermore, many factors con- Airdrie, Alberta, Canada) have indicated that a tribute to DMI, such as ration composition, man- 30% decrease in time at the bunk occurs in newly agement conditions, disease incidence, which are received sick cattle and that feed intake differences likely variable across studies. Tulathromycin, when are most pronounced during the first 4 d in the compared to other antibiotics administered to feed- feedlot (Sowell et al., 1998, 1999). Effects of feed- lot cattle, has elicited significantly lower undifferen- ing CTC on DMI are variable across studies. Dry tiated fever, treatment and relapse rates, morbidity matter intake was increased in cattle fed CTC vs. and mortality in addition to a greater DMI and control animals when cross-bred steers and heifers ADG response, all of which are consistent with the were finished on a grain-based diet that included current experiment (Booker et al., 2007). Given the a sub-therapeutic dosage of CTC (35  mg/kg DM; results of the current study, it seems plausible that ad libitum feeding) for the duration of the trial the tulathromycin in combination with CTC pro- (Beacom et al., 1988.) In contrast, no effect of CTC duced an additive feed intake response that did not was observed on DMI compared to CTC in com- occur when tulathromycin was fed in combination bination with sulfamethazine when fed to newly with OTC or when CTC or tulathromycin were weaned calves in the feedlot for a 5-d treatment (five administered alone. This may be a result of the −1 −1 to nine DOF) at a rate of 6 g·animal ·d (Gibb health improvements observed in the CTC+TUL et  al., 2006); a therapeutic dosage similar to the animals relative to other treatments. Translate basic science to industry innovation Downloaded from https://academic.oup.com/tas/advance-article-abstract/doi/10.1093/tas/txy135/5235607 by Ed 'DeepDyve' Gillespie user on 10 January 2019 8 Szasz et al. Consistent with increased DMI was the an effort to maximize the concentration in the lung improved final BW and ADG in CTC+TUL steers tissue in conjunction with tulathromycin. relative to other treatments, on a deads-and-rail- An additional factor to consider is that the ers-out basis. However, it is important to note body of literature related to feeding CTC, OTC, that this improvement in ADG (1.2% and 2.4% or administering metaphylaxis to newly received, on a deads-and-railers-in/out basis, respectively) high-risk cattle upon arrival primarily consists was not reflected in improved feed efficiency, an of experiments conducted on beef breeds, rather important indicator of health status. Few studies than Holstein steers. Not only do dairy cattle pos- have observed the effects of feeding CTC at a ther- sess different performance characteristics than apeutic 5-d treatment dose of 22  mg/kg of BW, typical beef breeds, such as a slightly lower ADG while multiple studies have demonstrated improve- and greater DMI across the feeding period due to ments in ADG in cattle fed CTC at sub-thera- larger maintenance requirements, Holsteins are peutic doses. Brown et  al. (1975) conducted four also more susceptible to environmental stressors feedlot trials in which ADG was improved over because of their thinner hide and hair coat and controls when CTC was fed at a rate of 70 mg·an- less subcutaneous fat (Hulbert and Moisa, 2016). −1 −1 imal ·d for the duration of the feeding period. However, multiple studies have examined ex vivo Similarly, Beacom et  al. (1988) fed CTC to fin- immune factors and observed that after weaning, −1 −1 ishing cattle in the feedlot at 35 mg·kg ·DM Holstein calves did not differ immunologically on an ad libitum basis for the duration of the from their conventionally fed beef animal coun- feeding period and observed increased ADG over terparts (Nonnecke et al., 2003; Foote et al., 2005, controls. In a study where 4,325 high-risk feeder 2007; Ballou, 2012; Obeidat et  al., 2013; Ballou calves were fed a conventional ration plus a feed et al., 2015). Nonetheless, we are not aware of any −1 −1 additive containing 350 mg·animal ·d each of studies to date that have compared the effects of CTC and sulfamethazine from the time of arrival feedgrade CTC or OTC, or in combination with until 56 DOF, ADG was significantly improved, tulathromycin metaphylaxis, on Holstein steers as were morbidity and mortality attributed to entering the feedlot. It is also important to note BRD (Gallo and Berg, 1995). Feeding CTC in a that treatment effects are potentially more reliably similar fashion to the current study, Kreikemeier interpreted in the current study due to the homo- et  al. (1996) observed improved ADG over con- geneity of genetics among Holstein steers derived trol cattle when feeding a therapeutic dose of from calf ranches. CTC to newly received, high-stressed calves In conclusion, BRD continues to be the pri- beginning on one DOF, for a 5-d treatment of mary threat to newly received, high-risk feedlot 22 mg/kg of BW. Similarly, Thomson et al. (2014) cattle despite the use of metaphylaxis; therefore, it fed a therapeutic dose of CTC (22  mg/kg BW) may be beneficial to administer feedgrade antibi- for a 5-d treatment beginning on either one or six otics in conjunction with metaphylaxis to improve DOF, depending on treatment, to newly received health and performance of Holstein steers. Based steer calves and observed improvements in ADG on this study and prior research, it appears nec- in all cattle receiving CTC vs. control animals. It essary to consider the timing of treatment dosing should be noted here that CTC treatments in the feedgrade tetracyclines relative to metaphylaxis. Thomson et  al. experiment received 0.5  mg/kg Feeding OTC in combination with tulathromycin BW of a coccidiostat (decoquinate) in the diet for metaphylaxis did not improve health over tulath- 28 d, whereas control steers did not. romycin alone; whereas health parameters were Interestingly, in the current study, the TUL improved when feeding CTC in combination treatment exhibited decreased ADG compared to with tulathromycin. To our knowledge, no other all other treatments when deads and railers were experiments to date have observed the effects of excluded, which further substantiates the possibil- the therapeutic use of feedgrade tetracyclines in ity of an additive effect of CTC and tulathromycin combination with tulathromycin metaphylaxis on metaphylaxis on performance. In contrast, as pre- Holstein steer calves. The homogeneity of genet- viously mentioned, Wallace et  al. (2009) observed ics among Holsteins may suggest more repeatable no differences in performance when administering results in the future and warrants further research tulathromycin metaphylaxis concurrent with feed- of the combination of these health technologies to ing CTC; however, this is again most likely due to reduce BRD. timing differences, in which the first CTC treatment Conflict of interest statement. None declared. was delayed until six DOF in the current study in Translate basic science to industry innovation Downloaded from https://academic.oup.com/tas/advance-article-abstract/doi/10.1093/tas/txy135/5235607 by Ed 'DeepDyve' Gillespie user on 10 January 2019 Feedgrade tetracylines 9 protein and energy on composition and functional capac- LITERATURE CITED ities of blood mononuclear cells from vaccinated, Abell, K. M., M. E.  Theurer, R. L.  Larson, B. J.  White, neonatal calves. Int. J.  Vitam. Nutr. Res. 75:357–368. and M.  Apley. 2017. A mixed treatment comparison doi:10.1024/0300-9831.75.5.357. meta-analysis of metaphylaxis treatments for bovine res- Frank, G. H., R.  E. Briggs, G. C. Duff, R. W. Loan, and C. piratory disease in beef cattle. J. Anim. Sci. 95(2):626–63. W. Purdy. 2002. Effects of vaccination prior to transit and doi: 10.2527/jas.2016.1062 administration of florfenicol at time of arrival in a feed- Agga, G. E., J.  W. Schmidt, and T. M.  Arthur. 2016. 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Can. calves during the preweaning and immediate postweaned J. Anim. Sci. 86:457–460. doi:10.4141/A06-024 periods when fed varying planes of milk replacer. J. Dairy Gordon, P.J. and P.  Plummer. 2010. Control, management, Sci. 95:7319–7330. doi:10.3168/jds.2012-5970 and prevention of bovine respiratory disease in dairy Ballou, M. A., D. L. Hanson, C. J. Cobb, B. S. Obeidat, M. D. calves and cows. Vet. Clin. North Am. Food Anim. Pract. Sellers, A. R. Pepper-Yowell, J. A. Carroll, T. J. Earleywine, 26(2):243–259. doi: 10.1016/j.cvfa.2010.03.004 and S. D. Lawhon. 2015. Plane of nutrition influences the Grissett, G. P., B. J. White, and R. L. Larson. 2015. Structured performance, innate leukocyte responses, and resistance literature review of responses of cattle to viral and bacte- to an oral Salmonella enterica serotype typhimurium rial pathogens causing bovine respiratory disease complex. challenge in jersey calves. J. Dairy Sci. 98:1972–1982. J. Vet. Intern. 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Influence of therapeutic use of feedgrade tetracyclines in combination with tulathromycin metaphylaxis on animal health and performance of Holstein steer calves

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Abstract

Downloaded from https://academic.oup.com/tas/advance-article-abstract/doi/10.1093/tas/txy135/5235607 by Ed 'DeepDyve' Gillespie user on 10 January 2019 Influence of therapeutic use of feedgrade tetracyclines in combination with tulath- romycin metaphylaxis on animal health and performance of Holstein steer calves † † † † † Josh I. Szasz, Casey P. McMurphy, Tony C. Bryant, Job Luque, Cristobal Barcelo, † ‡ ‡ ‡,||,2 Gabriel Sepulveda, K. Shawn Blood, Bryan C. Bernhard, and Heather D. Hughes, † ‡ || Five Rivers Cattle Feeding, Greeley, CO 80634; Zoetis, Parsippany, NJ 07054; and SciWrite Consulting, LLC, Canyon, TX 79015 −1 −1 ABSTRACT: Feedgrade chlortetracycline (CTC) OTC+TUL were administered 4 g OTC·steer ·d as and oxytetracycline (OTC) are approved for use in part of a complete diet for 14 consecutive days begin- beef cattle diets for the control of bovine respira- ning on 10 DOF. Within the first 30 d of the feed- tory disease (BRD). The objectives of this experi- ing period, BRD first pulls were reduced (P  = 0.001) ment were to compare CTC and OTC, administered for CTC+TUL, OTC+TUL, and TUL relative to according to label, for the treatment of BRD in CTC alone. Percentage of BRD first pulls and total Holstein calves and to characterize the influence of morbidity were lowest (P  =  0.001) for CTC+TUL tulathromycin metaphylaxis in combination with tet- across the feeding period, with OTC+TUL and racycline treatment. Summer-placed Holstein steer TUL being intermediate, and CTC alone exhibiting calves (n = 6,800) were randomly assigned to one of the highest percentage. Death loss and railers were four treatments (11 blocks; initial BW = 140 ± 18 kg) not influenced (P ≥ 0.58) by treatment. Dry matter as they passed through the squeeze chute at initial intake was greater (P = 0.001) for CTC+TUL than processing in a commercial feedlot. Treatments con- all other treatments. Final BW and ADG were great- sisted of: (i) CTC and tulathromycin metaphylaxis est for CTC+TUL, lowest for TUL alone, and inter- (CTC+TUL), (ii) OTC and tulathromycin metaphy- mediate for the remaining treatments (P < 0.05) on laxis (OTC+TUL), (iii) tulathromycin metaphylaxis a deads-and-railers-out basis. Deads-and-railers-in only (TUL), or (iv) CTC only (CTC). Cattle were ADG was greatest (P < 0.05) for CTC+TUL com- fed for an average of 118 d. Tetracycline feeding was pared to all other treatments. Feed conversion was instituted based on visual assessment of the attending not influenced (P ≥ 0.22) by treatment. In the current veterinarian in accordance with the veterinary feed study, supplementation of OTC in combination with directive. When applicable, CTC was fed as a top- tulathromycin metaphylaxis did not benefit health −1 −1 dress at a rate of 4 g CTC·steer ·d for 5 consecu- over tulathromycin alone. Results suggest that CTC tive days, beginning on 6 d on feed (DOF). Three 5-d in combination with tulathromycin metaphylaxis pulses were delivered to CTC+TUL and CTC cat- reduces morbidity in Holstein steers calves, which tle, with a 48-h time lapse between pulses. Cattle on may lead to improved performance. Key words: bovine respiratory disease, cattle, feedgrade tetracyclines, health, metaphylaxis © The Author(s) 2019. Published by Oxford University Press on behalf of the American Society of Animal Science. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Transl. Anim. Sci. 2018.XX:XX–XX doi: 10.1093/tas/txy135 1 2 Funding for this study was provided by Zoetis, Inc. No Corresponding author: heather@sciwriteconsulting.com employees of the sponsor were directly involved in the con- Received November 26, 2018. duct of the experiment. Accepted December 6, 2018. 1 Downloaded from https://academic.oup.com/tas/advance-article-abstract/doi/10.1093/tas/txy135/5235607 by Ed 'DeepDyve' Gillespie user on 10 January 2019 2 Szasz et al. INTRODUCTION administered in a top-dress application to eliminate related milling issues. Cattle entering the feedlot, particularly those Data that compare the bioavailability and/or that are lightweight and/or high risk, are more sus- efficacy of CTC vs. OTC in cattle are limited. When ceptible to bovine respiratory disease (BRD) than treating non-intestinal pathogens such as BRD with any other health challenge (Taylor et  al., 2010b). oral antibiotics, it is imperative that the antimicro- In weaned dairy calves specifically, BRD is the bial be effectively absorbed into the bloodstream primary cause of death; a fact that has remained to reach targeted tissues of the respiratory tract unchanged in the last few decades, demonstrating (del Castillo et al., 1998). Luthman and Jacobsson a need for improvement in preventing and con- (1983) observed greater bioavailability of CTC rel- trolling the disease (Gordon and Plummer, 2010). ative to OTC (37% vs. 5%, respectively) following BRD is multi-factorial in nature, as it involves oral administration to non-fasted calves, conclud- infectious disease agents, compromised host immu- ing that CTC is more suitable than OTC for oral nity, and environmental factors that may include therapy. However, limited data exist that evaluate transport and feedlot processing activities that ulti- and compare the therapeutic use of feedgrade tet- mately result in bronchopneumonia (Grissett et al., racyclines in reducing BRD, particularly in light- 2015). Therefore, implementing health and produc- weight Holstein calves. tion strategies in lightweight cattle is necessary for A second and more characterized method for reducing stress, minimizing disease, and optimizing controlling BRD in lightweight, high-risk calves performance (Nickell and White, 2010). Despite the is metaphylaxis, which is the mass medication of improvements in managing feedlot health in recent calves with antibiotics upon arrival to the feedlot years, the complex nature of BRD, in addition to (Abell et al., 2017). While metaphylaxis is effective an ever-changing landscape of government regula- at reducing morbidity and mortality, the prevalence tion, perpetuates morbidity and mortality rates in and challenges associated with BRD remain, sug- the feedlot (Windeyer et al., 2017). gesting a need for additional measures for control One method for controlling BRD in newly of the disease (Ives and Richeson, 2015). Therefore, received cattle is through the therapeutic use of the objectives of this experiment were to compare feedgrade tetracyclines. Chlortetracycline (CTC) feedgrade CTC and OTC for the treatment of BRD and oxytetracycline (OTC) are 2 naturally occur- in Holstein calves and to characterize the influence ring tetracycline compounds approved for use in of tulathromycin metaphylaxis in combination with beef cattle diets. Feeding antimicrobials may be the use of feedgrade tetracyclines. beneficial in decreasing the amount of “pulls” from the feedlot home pen and the associated stress of MATERIALS AND METHODS being removed and doctored (Thomson and White, 2015). Consequently, the judicial use of feedgrade This study was conducted from July 2017 antibiotics, in accordance with the VFD, may and December 2017 in a feedyard in southwest- decrease the necessity for injectable antibiotics ern Arizona and followed an approved protocol from antimicrobial classes which are categorized as whereby routine management practices of the com- “highest priority critically important antimicrobi- mercial feedlot are in accordance with 7 U.S.C. 54 als” by the World Health Organization (third-gen- and FASS (2010). eration cephalosporins, fluoroquinolones, and macrolides) (Agga, Schmidt, and Arthur, 2016). Cattle Arrival and Processing Aside from chemical structure, differences between Summer-placed Holstein steer calves OTC and CTC relate to their physical application (n = 6,800; initial BW = 140 ± 18 kg) acquired from (feed delivery), their antimicrobial properties, and various dairy farms in the western United States, their absorption into the bloodstream (bioavaila- which underwent standard dairy calf management bility) (Agwuh and MacGowan, 2006). Feed appli- including colostrum feeding, standard vaccination cation of the type A version of these tetracyclines procedures, and acclimation to grain-based diets, differs in that OTC contains a higher concentration were used in this trial. Steers were received between than CTC (220 and 440 g/kg for type A CTC and July 27, 2017 and August 26, 2017, allowed an aver- OTC, respectively), which decreases bulk in the age of 3 d rest (range  =  1 to 5 d) with access to ration, labor, and batching times when included feed and water, prior to being randomized to one in a complete diet, relative to CTC; however, CTC of four4 treatments as they passed through the is also available as a type C product which may be Translate basic science to industry innovation Downloaded from https://academic.oup.com/tas/advance-article-abstract/doi/10.1093/tas/txy135/5235607 by Ed 'DeepDyve' Gillespie user on 10 January 2019 Feedgrade tetracylines 3 squeeze chute at initial processing using a chute- using visual signs of anorexia, dull eyes, depression, side personal computer containing a randomiza- weakness, cough, nasal discharge, watery eyes, lack tion application. As cattle exited the squeeze chute, of fill, stiff gait, loose feces, and increased respira- they were sorted into one of four pens according to tory rate. Feedgrade CTC is approved for use in treatment assignment. Sort pens were then assigned beef cattle diets for control of bacterial pneumonia to home pens via a randomization function (Excel, associated with the shipping fever complex caused Microsoft Corporation, Redmond, WA). The study by Pasteurella species susceptible to CTC when fed −1 −1 was comprised of 44 pens, divided into 11 blocks continuously at 350 mg·animal ·d . Additionally, of four treatments each. Pens within a statistical CTC is approved for treatment of bacterial pneu- block were provided similar area (32.3 and 39 m monia cause by P. multocida organisms susceptible for blocks 1 to 6 and 7 to 11, respectively) and bunk to CTC when fed at 22 mg/kg BW daily for no more space (27.4 and 30.5 cm per animal for blocks 1 to than 5 consecutive days. OTC is approved for treat- 6 and 7 to 11, respectively) and were oriented in ment of bacterial pneumonia (shipping fever com- the same direction regarding pen slope. Water tank plex) caused by Pasteurella multocida susceptible to space was identical among pens within a statistical OTC fed at 22 mg/kg BW daily for 7 to 14 d. block (2.4 and 4.6 cm per animal for blocks 1 to 6 Chlortetracycline was fed as a top-dress once and 7 to 11, respectively). daily using a commercially available type C pelleted Cattle were administered various products at top-dress containing 8.8  g/kg CTC, when applic- −1 −1 processing, following a standardized feedlot pro- able, at a rate of 4 g CTC·steer ·d (22 mg/kg BW) tocol which included a dangle identification tag in for 5 consecutive days starting at 6 d on feed (DOF) each ear, 2 mL s.c. in the neck of a five-way mod- (Table 1). Six DOF was chosen as the start date for ified-live respiratory vaccine (Titanium 5, Elanco CTC in an effort to maximize the concentration of Animal Health, Greenfield, IN), 1  mL per naris CTC in lung tissue, based on results from previous of an intranasal respiratory vaccine (Nasalgen IP, studies (Wallace et al., 2009; Thomson et al., 2014). Merck Animal Health, Madison, NJ), 2 mL s.c. in CTC and CTC+TUL calves continued to display the neck of a seven-way clostridial vaccine for pro- BRD symptoms 48  h after the initial CTC pulse tection against Clostridium bacteria (Ultrachoice 7, and were administered a second 5-d pulse of the Zoetis, Kalamazoo, MI), a growth implant in the same dose, per veterinary recommendation. Forty- middle third of caudal aspect of the ear (Synovex eight hours following the second CTC pulse, calves C, Zoetis), and 3.5 mL per animal s.c. in the neck continued to display BRD symptoms and were of tulathromycin (Draxxin, Zoetis Animal Health, administered a third CTC pulse, again upon veteri- Kalamazoo, MI) when applicable due to treatment nary assessment and recommendation. assignment. After processing each block of steers, Cattle assigned to the OTC treatment were sort pens within block were weighed across a plat- fed a complete feed formulated to provide 4  g −1 −1 form scale before moving cattle to one of four OTC·steer ·d (22  mg/kg BW) for 14 consecu- adjacent home pens in the feedlot. Platform scale tive days starting at 10 DOF (Table  1). Ten DOF weights served as initial weights for the study. was selected to account for the starter ration fed previously, which contained an ionophore (Laidlomycin, Cattlyst, Zoetis Animal Health) Experimental Design and Treatments not approved for combination with OTC. Actual −1 −1 Experimental treatments were designed to OTC fed averaged 3.9 g·steer ·d (range = 3.3 to −1 −1 compare two different tetracycline molecules, CTC 4.3 g·steer ·d ). (Aureomycin, Zoetis Animal Health) and OTC Complete feed was delivered once daily and (Terramycin, Phibro Animal Health, Teaneck, NJ), consisted of steam-flaked corn, corn silage, alfalfa and to evaluate tulathromycin (Draxxin, Zoetis and sorghum-Sudan hay, tallow, corn-milling Animal Health) metaphylaxis on health and perfor- byproducts, and supplemental ingredients. All mance of Holstein steer calves. Cattle were assigned cattle were managed using the same feed man- to one of four treatments: (i) CTC and tulathromycin agement philosophy and were adapted to a finish metaphylaxis (CTC+TUL), (ii) OTC and tulathro- ration using a single intermediate ration and a mycin metaphylaxis (OTC+TUL), (iii) tulathromy- series of step-up feeding schedules. Laidlomycin cin metaphylaxis only (TUL), or (iv) CTC only type A (Cattlyst) was included in all diets (11.1 g/ (CTC). Tetracycline feeding was instituted based ton; dry matter basis), except during the OTC upon the assessment of the attending veterinarian feeding period because of combination feeding in accordance with the Veterinary Feed Directive, restrictions. Translate basic science to industry innovation Downloaded from https://academic.oup.com/tas/advance-article-abstract/doi/10.1093/tas/txy135/5235607 by Ed 'DeepDyve' Gillespie user on 10 January 2019 4 Szasz et al. Table 1. Treatment-dose regimen of feedgrade tetracyclines 1 2 3 4 Treatments CTC+TUL OTC+TUL TUL CTC Item 5 5 Pulse 1: 6 to 10 Pulse 1: 6 to 10 Tetracycline DOF Pulse 2: 12 to 16 10 to 23 n/a Pulse 2: 12 to 16 Pulse 3: 18 to 22 Pulse 3: 18 to 22 Ionophore Pre-tetracycline phase Laidlomycin Laidlomycin Laidlomycin Laidlomycin Tetracycline phase Laidlomycin None Laidlomycin Laidlomycin Tetracycline rest days Laidlomycin n/a Laidlomycin Laidlomycin Post-tetracycline phase Laidlomycin Laidlomycin Laidlomycin Laidlomycin 1 −1 Chlortetracycline (Aureomycin type C pellet 8.8 g/kg, L.A. Hearn Company, King City, CA) fed at 4 g·steer ·d for three 5-d treatments plus −1 −1 metaphylaxis with tulathromycin (Draxxin 100 mg/mL, Zoetis Animal Health) injection administered on arrival at 3.5 mL·steer ·d . 2 −1 −1 Oxytetracycline (Terramycin 200 type A 440 g/kg, Phibro Animal Health) fed at 4 g·steer ·d for 14 consecutive days plus metaphylaxis with −1 −1 tulathromycin (Draxxin 100 mg/mL, Zoetis Animal Health) injection administered on arrival at 3.5 mL·steer ·d . 3 −1 −1 Metaphylaxis with tulathromycin (Draxxin 100 mg/mL, Zoetis Animal Health) administered on arrival at 3.5 mL·steer ·d ). 4 −1 −1 Chlortetracycline (Aureomycin type C pellet 8.8 g/kg, L.A. Hearn Company) fed at 4 g·steer ·d for three 5-d treatments. Animals were evaluated by a veterinarian 48 h after each treatment to determine if a subsequent second and third treatment were needed. Days on feed. Laidlomycin type A (110 g/kg), Cattlyst, Zoetis Animal Health. Animal Health Management with 14 gauge x 1.9  cm needles, while all other injectable antimicrobials were administered using Study cattle were observed daily by pen rid- syringes fitted with 16 gauge x 1.6  cm needles. ers, between 0600 and 1000 hours, with a single All antibiotics were administered s.c. according pen rider examining all four pens within a sta- to Beef Quality Assurance guidelines. One case tistical block when possible. Cattle were treated of treatment noncompliance was reported in the between 0900 and 1400 hours, with all cattle TUL treatment group; this steer received an anti- operations ceasing by 1100 hours in the month microbial labeled for treatment of BRD that was of August due to heat. All pulls within a block not included in the regimen in Table 2. This ani- were treated at the same hospital facility. Cattle mal was retained in the data set during statistical on CTC+TUL, OTC+TUL, and TUL experi- analysis. mental treatments were not eligible for pull and Standard feedlot protocols were implemented BRD treatment with injectable antibiotics until a for the treatment of diseases unrelated to BRD and 7-d postmetaphylaxis interval had been reached were consistent for cattle across experimental treat- (Table  2). Table  3 provides the BRD injectable ments. Cattle were allowed to convalesce in hospi- treatment regimen for cattle not receiving met- tal pens for a minimum of 24  h before returning aphylaxis. Post-treatment intervals for animals to home pens. Post-treatment interval and clinical that relapsed and received additional injectable appearance were used to determine whether cattle antibiotic therapy for BRD treatment were as should return to the home pen or receive a subse- follows: tulathromycin (Draxxin, Zoetis Animal quent treatment. Mortalities were subject to post- Health), 7 d; florfenicol and flunixin meglumine mortem examination by a licensed veterinarian or (Resflor, Merck Animal Health), 4 d; dano- trained feedlot employee. Upon study completion, o fl xacin (Advocin, Zoetis Animal Health), 3 d; steers were weighed across a platform scale before OTC (Bio-Mycin 200, Boehringer Ingelheim being re-implanted between 116 and 121 DOF. Vetmedica, Duluth, GA), 2 d.  Cattle pulled a These pen weights served as the official final pen fourth time for BRD were eligible for re-treat- weights for the study. ment with danofloxacin rather than being railed if 45 d had elapsed since receiving their last BRD Statistical Analysis treatment. Cattle were railed if requiring a fourth treatment for the same disease or if pulled for a Data were analyzed as a randomized com- disease for which no practical treatment plan was plete block design with pen as experimental unit. available at the feedyard. Florfenicol and flunixin Continuous data (e.g., initial BW) were analyzed meglumine was administered using a syringe fitted using the MIXED procedure (SAS 9.4 Inc., Cary, Translate basic science to industry innovation Downloaded from https://academic.oup.com/tas/advance-article-abstract/doi/10.1093/tas/txy135/5235607 by Ed 'DeepDyve' Gillespie user on 10 January 2019 Feedgrade tetracylines 5 Table 2. BRD injectable treatment regimen for cat- RESULTS tle receiving tulathromycin metaphylaxis First BRD pulls (rectal temperature ≥40  °C) Pull were lower (P  <  0.05) for CTC+TUL and order Rectal temperature ≥40 °C Rectal temperature <40 °C OTC+TUL in the first 30 DOF compared to TUL 1 Florfenicol and flunixin Oxytetracycline 4 and CTC and lower (P < 0.05) for CTC+TUL com- meglumine pared to all other treatments over the entire feed- 2 Danofloxacin Florfenicol and flunixin meglumine ing period (Table  4). Total morbidity was lowest 3 Rail Danofloxacin for CTC+TUL cattle, greatest for CTC cattle, and 4 n/a Rail intermediate for OTC+TUL and TUL treatments (P < 0.05). However, mortality, railers, and wastage Bovine respiratory disease. 2 (sum of mortality and railers) were not influenced Tulathromycin (100  mg/mL) administered at 3.5  mL/animal; Draxxin, Zoetis Animal Health. (P ≥ 0.58) by treatment. A post-metaphylactic interval of 7 d was imposed prior to cattle Cattle were fed for an average of 118 d.  Dry being eligible for treatment with an injectable antibiotic. matter intake was greater (P < 0.05) for CTC+TUL Florfenicol (300  mg/mL) and flunixin meglumine (16.5mg/mL) compared to all other treatments (Table  5). administered at 6  mL/45.4  kg BW; Resflor, Merck Animal Health; Final BW and ADG were greater (P  <  0.05) for post-treatment interval was 4 d. CTC+TUL compared to OTC+TUL, TUL, and Oxytetracycline (200 mg/mL) administered at 4.5 mL/45.4 kg BW; Bio-Mycin 200, Boehringer Ingelheim Vetmedica; post-treatment CTC and were lower (P  <  0.05) for TUL cattle interval was 2 d. relative to OTC+TUL or CTC treatments on a Danofloxacin (180  mg/mL) administered at 2  mL/45.4  kg BW; deads-and-railers-out basis. On a deads-and-rail- Advocin, Zoetis Animal Health; post-treatment interval was 3 d. ers-in basis, final BW was greater (P  <  0.05) for CTC+TUL compared to TUL or CTC alone, but Table 3. BRD injectable treatment regimen for cat- was similar (P  =  0.16) to OTC+TUL. ADG was tle not receiving metaphylaxis greater (P < 0.05) for CTC+TUL cattle than TUL Pull or CTC treatments with OTC+TUL animals being order Rectal temperature ≥40 °C Rectal temperature <40 °C intermediate (P  <  0.05) on a deads-and-railers-in 2 3 1 Tulathromycin Oxytetracycline basis. Treatment had no effect (P > 0.22) on G:F on 2 Florfenicol and flunixin Tulathromycin 4 a DM basis. meglumine 3 Danofloxacin Danofloxacin 4 Rail Rail DISCUSSION Bovine respiratory disease. In the current study, tulathromycin metaphy- Tulathromycin (100 mg/mL) administered at 1.13 mL/45.4 kg BW; laxis alone improved health over feeding CTC alone Draxxin, Zoetis Animal Health; post-treatment interval of 7 d. and was overall similar to OTC+TUL. Several Oxytetracycline (200 mg/mL) administered at 4.5 mL/45.4 kg BW; studies have demonstrated reductions in morbid- Bio-Mycin 200, Boehringer Ingelheim Vetmedica; post-treatment ity when implementing metaphylaxis with paren- interval of 2 d. teral antibiotics upon arrival of young cattle to Florfenicol (300  mg/mL) and flunixin meglumine (16.5  mg/mL) administered at 6  mL/45.4  kg BW; Resflor, Merck Animal Health; the feedlot (van Donkersgoed, 1992; Frank et  al., post-treatment interval of 4 d. 2002; Macartney et  al., 2003) and more specifi- Danofloxacin (180  mg/mL) administered at 2  mL/45.4  kg BW; cally when administering tulathromycin on arrival Advocin, Zoetis Animal Health; post-treatment interval of 3 d. (Step et  al., 2007; Wellman and O’Connor, 2007). NC), with treatment as a fixed effect and block as Furthermore, Rooney et  al. (2005), in three sepa- a random effect. A generalized linear mixed model rate studies, observed superior efficacy of tulath- (GLIMMIX, SAS 9.4 Inc.) was used to analyze romycin at decreasing morbidity and mortality in categorical data with the model effects described newly received, high-risk calves compared to tilm- previously. Model estimation was performed using icosin and florfenicol. Chlortetracycline alone did a logit scale to link events/trials responses to a bino- not improve health relative to other treatments in mial distribution. Initial estimates of treatment the current study; however, it is important to note means and respective standard errors are reported that there was not a negative control treatment on the data scale using an inverse link method for full evaluation of its effect. Other studies have (ILINK Option, SAS 9.4 Inc.). When overall treat- demonstrated health improvements in response to ment effect was significant (P  <  0.10), treatment oral CTC. First pulls and morbidity were reduced means were partitioned using Tukey’s HSD post in multiple earlier studies in cattle supplemented hoc analysis. with CTC compared to negative control treatments Translate basic science to industry innovation Downloaded from https://academic.oup.com/tas/advance-article-abstract/doi/10.1093/tas/txy135/5235607 by Ed 'DeepDyve' Gillespie user on 10 January 2019 6 Szasz et al. Table 4. Influence of feedgrade tetracycline and arrival metaphylaxis on health of Holstein steer calves Treatments 1 2 3 4 5 Item CTC+TUL OTC+TUL TUL CTC SEM P-value No. of pens 11 11 11 11 — — BRD first pulls ≥40 °C, % of enrolled 7 a a b c First 30 DOF 7.0 6.8 8.9 13.0 1.79 0.001 a b b c Entire feeding period 12.8 16.2 16.9 19.7 1.83 0.001 BRD first pulls, % of enrolled a a a b First 30 DOF 9.7 9.3 11.1 15.9 1.97 0.001 a b b,c c Entire feeding period 19.1 22.8 24.1 25.8 1.92 0.001 BRD relapses , % of all BRD first pulls 45.3 40.7 42.2 46.6 3.06 0.329 Bullers, % 0.18 0.06 0.06 0.12 0.102 0.696 Skeletal morbidity, % of enrolled 0.53 0.18 0.24 0.53 0.184 0.230 Other morbidity, % of enrolled 0.12 0.47 0.35 0.35 0.201 0.393 11 a b b,c c Total morbidity, % of enrolled 20.0 23.6 24.9 26.9 1.97 0.001 Deathloss, % of enrolled BRD 0.93 1.17 1.46 1.17 0.303 0.576 Digestive 0.47 0.29 0.29 0.47 0.166 0.716 Other 0.46 0.58 0.35 0.29 0.196 0.581 Total 1.87 2.04 2.10 1.92 0.366 0.959 Railers, % of enrolled BRD 1.41 1.65 1.35 1.41 0.303 0.576 Total 1.58 1.87 1.46 1.81 0.343 0.765 DOF at time of death 49 59 48 49 6.7 0.550 DOF at time of rail 79 82 86 79 4.9 0.734 Wastage 3.41 3.87 3.53 3.70 0.526 0.894 a–c Treatments with unlike superscripts differ (P ≤ 0.10). 1 −1 −1 Chlortetracycline (Aureomycin type C pellet 8.8 g/kg, L.A. Hearn Company) fed at 4 g·steer ·d for three 5-d treatments beginning on day 6 −1 −1 plus metaphylaxis with tulathromycin (Draxxin 100 mg/mL, Zoetis Animal Health) injection administered on arrival at 3.5 mL·steer ·d ; animals were assessed by a veterinarian 48-h after each treatment dose to determine if a second or third subsequent dose was necessary. 2 −1 −1 Oxytetracycline (Terramycin type A 440 g/kg, Phibro Animal Health) fed at 4 g·steer ·d for 14 consecutive d beginning on day 10 plus meta- −1 −1 phylaxis with tulathromycin (Draxxin 100 mg/mL, Zoetis Animal Health) injection administered on arrival at 3.5 mL·steer ·d . 3 −1 −1 Metaphylaxis with tulathromycin (Draxxin 100 mg/mL, Zoetis Animal Health) administered on arrival at 3.5 mL·steer ·d . 4 −1 −1 Chlortetracycline (Aureomycin type C pellet 8.8 g/kg, L.A. Hearn Company) fed at 4 g·steer ·d for three 5-d treatments. P-value associated with the overall effect of experimental treatment. Bovine respiratory disease. Days on feed. Cattle treated for BRD more than once. Steers repeatedly mounted by pen cohorts. Injuries or diseases related to skeletal structures of the feet, limbs, back, shoulder, and hip. Total first pulls for all diseases includes bullers. Death loss plus railers. (Hale et al., 1967; Drake, Smart, and Smith, 1968). limited. Wallace et al. (2009) did not observe a sim- More recently, Thomson et  al. (2014) reported ilar additive effect of tulathromycin and CTC on improvement morbidity and re-treatment rates health variables when compared to diets containing when feeding CTC and decoquinate to steers when no CTC; however, CTC was top-dressed for only compared to negative control animals. Perhaps most two 5-d treatments, rather than 3, and began earlier notable with regard to health in the current study in the feeding period (one and seven DOF) than the was the improvement in health variables in cattle on current study, which may indicate that the timing of the CTC+TUL treatment relative to all other treat- the treatment doses should have been delayed for a ments, as evidenced by a decrease in morbidity. This more optimal response. may suggest an additive effect of CTC and TUL on Performance overall was improved for the improving health. However, studies examining the CTC+TUL treatment relative to other treatments implementation of tetracyclines fed at therapeutic and may partly be explained by the increase in DMI doses in combination with metaphylaxis are quite observed, as healthy cattle tend to consume more Translate basic science to industry innovation Downloaded from https://academic.oup.com/tas/advance-article-abstract/doi/10.1093/tas/txy135/5235607 by Ed 'DeepDyve' Gillespie user on 10 January 2019 Feedgrade tetracylines 7 Table 5. Influence of feedgrade tetracycline and arrival metaphylaxis on growth performance of Holstein steer calves Treatments 1 2 3 4 5 Item CTC+TUL OTC+TUL TUL CTC SEM P-value No. of pens 11 11 11 11 — — Steers enrolled 1,700 1,700 1,700 1,700 — — Initial BW, kg 142 141 141 141 2.45 0.70 DOF 118 118 118 118 — — a b b b DMI, kg 5.36 5.13 5.08 5.13 0.07 0.001 Deads and railers out a b c b Final BW, kg 301 298 293 296 3.45 0.001 a b c b ADG, kg 1.35 1.33 1.29 1.31 0.023 0.001 G:F 0.253 0.260 0.253 0.255 0.002 0.215 Deads and railers in a a,b c b,c Final BW, kg 295 291 286 288 3.63 0.003 a b c b,c ADG, kg 1.27 1.24 1.21 1.22 0.014 0.001 G:F 0.238 0.242 0.236 0.236 0.001 0.376 a–c Treatments with unlike superscripts differ (P ≤ 0.10). 1 −1 −1 Chlortetracycline (Aureomycin type C pellet 8.8 g/kg, L.A. Hearn Company) fed at 4 g·steer ·d for three 5-d treatments plus metaphylaxis −1 −1 with tulathromycin (Draxxin 100 mg/mL, Zoetis Animal Health) injection administered on arrival at 3.5 mL·steer ·d ; animals were assessed by a veterinarian 48 h after each treatment dose to determine if a second or third subsequent dose was necessary. 2 −1 −1 Oxytetracycline (Terramycin type A 440 g/kg, Phibro Animal Health) fed at 4 g·steer ·d for 14 consecutive days plus metaphylaxis with tulath- −11 −1 romycin (Draxxin 100 mg/mL, Zoetis Animal Health) injection administered on arrival at 3.5 mL·steer ·d . 3 −1 −1 Metaphylaxis with tulathromycin (Draxxin 100 mg/mL, Zoetis Animal Health) administered on arrival at 3.5 mL·steer ·d . 4 −1 −1 Chlortetracycline (Aureomycin type C pellet 8.8 g/kg, L.A. Hearn Company) fed at 4 g·steer ·d for three 5-d treatments. P-value associated with the overall effect of experimental treatment. Pen weights from cattle weighed in one or more drafts on a platform scale. Days on feed. Four percent pencil shrink applied. feed than animals experiencing greater immuno- current study. Thomson et al. (2014) did observe an suppression and subsequent decreased appetite. increase in DMI when feeding CTC (22 mg/kg BW) Repartitioning of nutrients away from growth for a 5-d treatment (one to five DOF), in combi- and toward the immune system during an immune nation with decoquinate at 0.5 mg/kg BW. Clearly, challenge further necessitates nutrient intake in these studies differ in dosage, feed-duration of order to minimize muscle protein degradation in CTC, and their respective treatment comparisons; immunosuppressed animals (Carroll and Forsberg, therefore, it would be presumptuous to generalize 2007). GrowSafe Technologies (GrowSafe Systems, across these trials. Furthermore, many factors con- Airdrie, Alberta, Canada) have indicated that a tribute to DMI, such as ration composition, man- 30% decrease in time at the bunk occurs in newly agement conditions, disease incidence, which are received sick cattle and that feed intake differences likely variable across studies. Tulathromycin, when are most pronounced during the first 4 d in the compared to other antibiotics administered to feed- feedlot (Sowell et al., 1998, 1999). Effects of feed- lot cattle, has elicited significantly lower undifferen- ing CTC on DMI are variable across studies. Dry tiated fever, treatment and relapse rates, morbidity matter intake was increased in cattle fed CTC vs. and mortality in addition to a greater DMI and control animals when cross-bred steers and heifers ADG response, all of which are consistent with the were finished on a grain-based diet that included current experiment (Booker et al., 2007). Given the a sub-therapeutic dosage of CTC (35  mg/kg DM; results of the current study, it seems plausible that ad libitum feeding) for the duration of the trial the tulathromycin in combination with CTC pro- (Beacom et al., 1988.) In contrast, no effect of CTC duced an additive feed intake response that did not was observed on DMI compared to CTC in com- occur when tulathromycin was fed in combination bination with sulfamethazine when fed to newly with OTC or when CTC or tulathromycin were weaned calves in the feedlot for a 5-d treatment (five administered alone. This may be a result of the −1 −1 to nine DOF) at a rate of 6 g·animal ·d (Gibb health improvements observed in the CTC+TUL et  al., 2006); a therapeutic dosage similar to the animals relative to other treatments. Translate basic science to industry innovation Downloaded from https://academic.oup.com/tas/advance-article-abstract/doi/10.1093/tas/txy135/5235607 by Ed 'DeepDyve' Gillespie user on 10 January 2019 8 Szasz et al. Consistent with increased DMI was the an effort to maximize the concentration in the lung improved final BW and ADG in CTC+TUL steers tissue in conjunction with tulathromycin. relative to other treatments, on a deads-and-rail- An additional factor to consider is that the ers-out basis. However, it is important to note body of literature related to feeding CTC, OTC, that this improvement in ADG (1.2% and 2.4% or administering metaphylaxis to newly received, on a deads-and-railers-in/out basis, respectively) high-risk cattle upon arrival primarily consists was not reflected in improved feed efficiency, an of experiments conducted on beef breeds, rather important indicator of health status. Few studies than Holstein steers. Not only do dairy cattle pos- have observed the effects of feeding CTC at a ther- sess different performance characteristics than apeutic 5-d treatment dose of 22  mg/kg of BW, typical beef breeds, such as a slightly lower ADG while multiple studies have demonstrated improve- and greater DMI across the feeding period due to ments in ADG in cattle fed CTC at sub-thera- larger maintenance requirements, Holsteins are peutic doses. Brown et  al. (1975) conducted four also more susceptible to environmental stressors feedlot trials in which ADG was improved over because of their thinner hide and hair coat and controls when CTC was fed at a rate of 70 mg·an- less subcutaneous fat (Hulbert and Moisa, 2016). −1 −1 imal ·d for the duration of the feeding period. However, multiple studies have examined ex vivo Similarly, Beacom et  al. (1988) fed CTC to fin- immune factors and observed that after weaning, −1 −1 ishing cattle in the feedlot at 35 mg·kg ·DM Holstein calves did not differ immunologically on an ad libitum basis for the duration of the from their conventionally fed beef animal coun- feeding period and observed increased ADG over terparts (Nonnecke et al., 2003; Foote et al., 2005, controls. In a study where 4,325 high-risk feeder 2007; Ballou, 2012; Obeidat et  al., 2013; Ballou calves were fed a conventional ration plus a feed et al., 2015). Nonetheless, we are not aware of any −1 −1 additive containing 350 mg·animal ·d each of studies to date that have compared the effects of CTC and sulfamethazine from the time of arrival feedgrade CTC or OTC, or in combination with until 56 DOF, ADG was significantly improved, tulathromycin metaphylaxis, on Holstein steers as were morbidity and mortality attributed to entering the feedlot. It is also important to note BRD (Gallo and Berg, 1995). Feeding CTC in a that treatment effects are potentially more reliably similar fashion to the current study, Kreikemeier interpreted in the current study due to the homo- et  al. (1996) observed improved ADG over con- geneity of genetics among Holstein steers derived trol cattle when feeding a therapeutic dose of from calf ranches. CTC to newly received, high-stressed calves In conclusion, BRD continues to be the pri- beginning on one DOF, for a 5-d treatment of mary threat to newly received, high-risk feedlot 22 mg/kg of BW. Similarly, Thomson et al. (2014) cattle despite the use of metaphylaxis; therefore, it fed a therapeutic dose of CTC (22  mg/kg BW) may be beneficial to administer feedgrade antibi- for a 5-d treatment beginning on either one or six otics in conjunction with metaphylaxis to improve DOF, depending on treatment, to newly received health and performance of Holstein steers. Based steer calves and observed improvements in ADG on this study and prior research, it appears nec- in all cattle receiving CTC vs. control animals. It essary to consider the timing of treatment dosing should be noted here that CTC treatments in the feedgrade tetracyclines relative to metaphylaxis. Thomson et  al. experiment received 0.5  mg/kg Feeding OTC in combination with tulathromycin BW of a coccidiostat (decoquinate) in the diet for metaphylaxis did not improve health over tulath- 28 d, whereas control steers did not. romycin alone; whereas health parameters were Interestingly, in the current study, the TUL improved when feeding CTC in combination treatment exhibited decreased ADG compared to with tulathromycin. To our knowledge, no other all other treatments when deads and railers were experiments to date have observed the effects of excluded, which further substantiates the possibil- the therapeutic use of feedgrade tetracyclines in ity of an additive effect of CTC and tulathromycin combination with tulathromycin metaphylaxis on metaphylaxis on performance. In contrast, as pre- Holstein steer calves. The homogeneity of genet- viously mentioned, Wallace et  al. (2009) observed ics among Holsteins may suggest more repeatable no differences in performance when administering results in the future and warrants further research tulathromycin metaphylaxis concurrent with feed- of the combination of these health technologies to ing CTC; however, this is again most likely due to reduce BRD. timing differences, in which the first CTC treatment Conflict of interest statement. 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