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Field study of the comparative efficacy of gamithromycin and tulathromycin for the control of undifferentiated bovine respiratory disease complex in beef feedlot calves at high risk of developing respiratory tract disease

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  • 1 Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.
  • | 2 Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.
  • | 3 Department of Statistics, College of Arts and Sciences, Kansas State University, Manhattan, KS 66506.
  • | 4 Large Animal Veterinary Services, Merial Ltd, 3239 Satellite Blvd, Duluth, GA 30096.
  • | 5 Department of Animal Sciences and Industry, College of Agriculture, Kansas State University, Manhattan, KS 66506.

Abstract

Objective—To compare the efficacy of gamithromycin with that of tulathromycin for control of undifferentiated bovine respiratory disease complex (BRDC) in feedlot calves.

Animals—2,529 weaned crossbred beef calves.

Procedures—At each of 2 feedlots, calves at risk of developing BRDC were administered a single dose of gamithromycin (6.0 mg/kg, SC; n = 1,263) or tulathromycin (2.5 mg/kg, SC; 1,266) metaphylactically. Health (BRDC morbidity, mortality, case-fatality, and retreatment rates) and performance (average daily gain, dry matter intake, and feed-to-gain ratio) outcomes were compared between treatments via classical hypothesis testing. Bioequivalence limits for gamithromycin and tulathromycin were established for outcomes for which no significant difference between treatments was detected.

Results—Mean BRDC morbidity rate (31.0%) for calves administered gamithromycin was greater than that (22.9%) for calves administered tulathromycin; otherwise, health and performance did not differ between treatments. Limits for mean differences within which gamithromycin was considered bioequivalent to tulathromycin were ± 10% for BRDC retreatment rate, ± 3.5% for BRDC mortality rate, ± 16% for case-fatality rate, ± 37 kg for final body weight, ± 0.1 kg/d for average daily gain, ± 0.3 kg/d for dry matter intake, and ± 0.7 for feed-to-gain ratio.

Conclusions and Clinical Relevance—The efficacy of gamithromycin did not differ from that of tulathromycin for all outcomes except morbidity rate; calves administered gamithromycin had a higher BRDC morbidity rate than did calves administered tulathromycin. On the basis of the bioequivalence limits established for this dataset, gamithromycin was considered equivalent to tulathromycin for the control of BRDC.

Abstract

Objective—To compare the efficacy of gamithromycin with that of tulathromycin for control of undifferentiated bovine respiratory disease complex (BRDC) in feedlot calves.

Animals—2,529 weaned crossbred beef calves.

Procedures—At each of 2 feedlots, calves at risk of developing BRDC were administered a single dose of gamithromycin (6.0 mg/kg, SC; n = 1,263) or tulathromycin (2.5 mg/kg, SC; 1,266) metaphylactically. Health (BRDC morbidity, mortality, case-fatality, and retreatment rates) and performance (average daily gain, dry matter intake, and feed-to-gain ratio) outcomes were compared between treatments via classical hypothesis testing. Bioequivalence limits for gamithromycin and tulathromycin were established for outcomes for which no significant difference between treatments was detected.

Results—Mean BRDC morbidity rate (31.0%) for calves administered gamithromycin was greater than that (22.9%) for calves administered tulathromycin; otherwise, health and performance did not differ between treatments. Limits for mean differences within which gamithromycin was considered bioequivalent to tulathromycin were ± 10% for BRDC retreatment rate, ± 3.5% for BRDC mortality rate, ± 16% for case-fatality rate, ± 37 kg for final body weight, ± 0.1 kg/d for average daily gain, ± 0.3 kg/d for dry matter intake, and ± 0.7 for feed-to-gain ratio.

Conclusions and Clinical Relevance—The efficacy of gamithromycin did not differ from that of tulathromycin for all outcomes except morbidity rate; calves administered gamithromycin had a higher BRDC morbidity rate than did calves administered tulathromycin. On the basis of the bioequivalence limits established for this dataset, gamithromycin was considered equivalent to tulathromycin for the control of BRDC.

Bovine respiratory disease complex is the most common and expensive disease of feedlot cattle in the United States,1–3 accounting for approximately 50% of the morbidity rate and > 75% of deaths.4 It has been estimated that BRDC results in annual economic losses of $1 billion because of treatment costs, reduced performance, and death.2,5 Bovine respiratory disease complex is a multifactorial syndrome caused by a combination of environmental factors, management practices, animal susceptibility, and viral and bacterial pathogens.5,6 Preventive and control measures for BRDC include management practices that enhance immune response, optimize nutrition, reduce animal stress, and minimize pathogen challenge.5,6 An effective strategy to reduce the negative effects of BRDC on health and performance of feedlot cattle is metaphylaxis, which typically consists of mass administration of an approved antimicrobial to cattle at high risk of developing BRDC.6 Risk factors for the development of BRDC include transportation stress, commingling of various cattle populations, calves with a low body weight at entry into the feedlot, and extreme weather conditions.1 Tulathromycin is a triamilide, a recently recognized subclass of the macrolide antimicrobial group, that is labeled for metaphylactic use in cattle to control BRDC.3,7,8 Calves at high risk of developing BRDC that were administered tulathromycin at entry into a feedlot had a reduced morbidity rate and increased ADG, compared with those of control calves that were administered saline (0.9% NaCl) solution.6 Gamithromycin is an azalide, another subclass of the macrolide antimicrobial group, that is labeled for the treatment and control of BRDC in cattle.3,9,10 Calves at high risk of developing BRDC that were metaphylactically administered gamithromycin had a reduced morbidity rate, compared with that of control calves that were metaphylactically administered saline solution.10,11 Both triamilide and azalide antimicrobials inhibit bacterial protein synthesis by binding the 50S prokaryotic ribosomal subunit.3,9 Macrolides are generally considered bacteriostatic; however, results of 1 study3 indicate that gamithromycin has bactericidal activity against Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni, 3 pathogens frequently associated with BRDC. In field studies,7,12 the clinical efficacy of tulathromycin was superior for the treatment of cattle with BRDC, compared with that of tilmicosin, another macrolide. To our knowledge, no field studies have been conducted to evaluate health and performance outcomes for feedlot calves metaphylactically administered gamithromycin, compared with those for feedlot calves metaphylactically administered tulathromycin. The objectives of the study reported here were to compare the clinical efficacy of gamithromycin with that of tulathromycin for the control of BRDC in beef calves at high risk of developing BRDC in a commercial feedlot setting and establish some preliminary bioequivalence limits, which could be used as templates for future comparisons between the 2 drugs and assist veterinarians and feedlot producers in developing BRDC management plans. Because gamithromycin and tulathromycin both belong to the macrolide antimicrobial group, we hypothesized that that the clinical efficacy of gamithromycin would not differ significantly from that of tulathromycin.

Materials and Methods

Animals—All study procedures were approved by the Kansas State University Institutional Animal Care and Use Committee. The study was conducted at 2 commercial beef feedlots located in Kansas and Nebraska, the managers of which consented to participate in the study prior to its initiation. Weaned crossbred beef calves purchased from auction markets located in Mississippi and northeast Oklahoma between October 2 and December 30, 2010, were considered for study enrollment. At processing within 24 hours after arrival at the feedlot, calves that weighed ≤ 409 kg and did not have clinical signs of disease or injury as determined by a study investigator were enrolled into the study, whereas calves that weighed > 409 kg or had clinical signs of systemic disease, injury, or other debilitation or a history of being treated with an antimicrobial prior to feedlot arrival were excluded from the study.

Calves were housed in open-air group pens for the duration of the study observation period (approx 180 days). The mean number of calves per pen was 50 at the Kansas feedlot and 110 at the Nebraska feedlot. All calves had ad libitum access to water and were fed a ration that was formulated to meet or exceed the National Research Council's requirements for maintenance and expected growth of beef cattle.13

Processing of calves—Calves were placed in pens by date of arrival at the feedlot. Within 24 hours after feedlot arrival, all calves were processed (day 0), which included the application of an ear tag for individual calf identification, recording of body weight and rectal temperature, surgical castration of sexually intact bull calves, treatment of internal and external parasites with fenbendazolea and ivermectin,b and vaccination against clostridial pathogens.c At the Nebraska feedlot, calves were administered a multivalent modified-live virus vaccine that contained bovine herpesvirus type 1, parainfluenza virus type 3, and bovine respiratory syncytial virus,d intranasally. At the Kansas feedlot, calves were administered a multivalent modified-live virus vaccine that contained bovine herpesvirus type 1, parainfluenza virus type 3, bovine respiratory syncytial virus, and bovine viral diarrhea virus types 1 and 2,e parenterally, and an anabolic implant containing zeranol,f SC.

Study design—To ensure that the number of calves in the treatment groups at each feedlot was approximately equal, calves enrolled in the study were grouped in pairs on the basis of the order of processing through the handling facility. Within each pair, one calf was administered a single dose of gamithromycing (6.0 mg/kg [2 mL/50 kg], SC) and the other was administered a single dose of tulathromycinh (2.5 mg/kg [1.25 mL/50 kg], SC) on the basis of a treatment randomization schedule that was created for each feedlot prior to study initiation. When an odd number of calves within a processing group were eligible for study enrollment, the calf that was not paired with another calf was administered the treatment designated for animal 1 in the next pairing on the treatment randomization schedule; the randomization schedule was adjusted accordingly by 1 animal for the subsequent processing group. The assigned treatment was administered by a study investigator during processing. All treatments were injected (maximum volume of antimicrobial/injection site, 10 mL) in the neck region cranial to the shoulder joint, and for all study calves within a feedlot, all antimicrobial injections were administered on the same side of the body.

Following processing, calves were allocated to pens by treatment, such that each pen contained calves from a single treatment group (ie, gamithromycin or tulathromycin) and that had arrived at the feedlot on the same date. At completion of study enrollment and processing, the Kansas feedlot had 10 pens/treatment group, and the Nebraska feedlot had 7 pens/treatment group.

The general health of all study calves was monitored daily from day 0 (processing) to 120 by feedlot personnel trained in cattle healthcare and who were unaware of the assigned treatments. At each feedlot, morbid calves were moved to a centralized treatment area, examined by trained feedlot personnel, and classified as having BRDC or some other (eg, gastrointestinal or musculoskeletal) abnormality. Morbid calves were treated in accordance with standardized treatment protocols developed for each feedlot and returned to their assigned pen. The standard BRDC treatment protocol was similar for both feedlots; the initial BRDC treatment consisted of a single dose of florfenicoli (40 mg/kg [6 mL/45 kg], SC), and the second (retreatment) BRDC treatment consisted of a single dose of enrofloxacinj (7.5 to 12.5 mg/kg [3.75 to 6.25 mL/50 kg], SC). Calves that required a third treatment for BRDC were administered ceftiofurk (6.6 mg/kg [1.5 mL/45 kg], SC in the base of an ear) at the Kansas feedlot and oxytetracyclinel (20 mg/kg [1 mL/10 kg], IM) at the Nebraska feedlot. Moribund calves were euthanized in accordance with the guidelines of the Animal Welfare Committee of the American Association of Bovine Practitioners.14 Qualified personnel (ie, trained feedlot employees who were responsible for routine veterinary care of cattle) performed necropsies on all calves that died or were euthanized during days 0 to 120; gross evidence of bronchopneumonia was required for a diagnosis of BRDC.

Statistical analysis—Calf health and performance data were obtained throughout the feeding period (ie, processing [day 0] until removal from the feedlot for slaughter [approx day 180]). Calves that died or were euthanized for reasons other than BRDC were not included in the calculations for BRDC mortality and case-fatality rates. The BRDC retreatment rate for each treatment group was calculated as the number of calves in that treatment group that were treated for BRDC a second time divided by the number of calves in that treatment group that were treated for BRDC once. The BRDC mortality rate for each treatment group was calculated as the number of calves in that treatment group that died with gross evidence of BRDC divided by the number of calves in that treatment group. The case-fatality rate for each treatment group was calculated as the number of calves in that treatment group that died with gross evidence of BRDC and were treated for BRDC at least once divided by the number of calves in that treatment group that were treated for BRDC at least once.

For performance calculations, the initial body weight for each calf was defined as the mean calf weight for the pen in which that calf was housed following processing on day 0 (ie, each pen of calves was weighed as a group), and the final body weight for each calf was defined as the mean calf weight for the pen in which that calf was housed just prior to transportation to the slaughter facility. Data were analyzed with (deads-in) and without (deads-out) the inclusion of data from study calves that died or were euthanized because of BRDC during the first 120 days of the feeding period. For each pen, ADG on a deads-in basis was calculated by use of the following equation:

article image

The feed-to-gain ratio on a deads-in basis was calculated as the daily DMI divided by the ADG on a deads-in basis. For each pen, ADG on a deads-out basis was calculated by use of the following equation:

article image

where calf days was the sum of the number of days each calf within the pen (including those that died) was fed. The feed-to-gain ratio on a deads-out basis was calculated as the daily DMI divided by the ADG on a deads-out basis.

Continuous outcome variables (initial body weight, rectal temperature at processing, final body weight, ADG, DMI, and feed-to-gain ratio) were assessed by means of general linear mixed models. In all models, treatment group (ie, gamithromycin or tulathromycin) was included as a fixed effect. For each outcome variable, random effects were specified to accommodate the experimental design structure and only those with nonzero variance estimates were included in the models. For all outcome variables, a random effect for the interaction between feedlot and treatment group was assessed and dropped from the models because the variance component of that random effect converged to zero. For the outcome variables initial body weight, final body weight, ADG, DMI, and feed-to-gain ratio, a random effect for arrival date was included as a blocking factor in the respective models. For rectal temperature, random effects for arrival date and the interaction between arrival date and treatment group were included in the model. Initial body weight and total days on feed were included as independent variables in the statistical models for the outcome variables rectal temperature, final body weight, ADG, DMI, and feed-to-gain ratio.

Categorical outcome variables (BRDC mortality, case-fatality, morbidity, and retreatment rates) were assessed via generalized linear mixed models with a logit link function and the assumption of a Bernoulli distribution. The respective models for BRDC mortality, morbidity, and retreatment rates included fixed effects for treatment group, rectal temperature at processing (normal [< 40°C] or fever [≥ 40°C]), and initial body weight and a random effect for the interaction between arrival date and treatment group as a proxy for the experimental unit (ie, calves clustered within treatment group by arrival date). The fixed effect of initial body weight was removed from the model for BRDC retreatment rate because of a lack of significance (P > 0.05). The model for case-fatality rate included a fixed effect for treatment group and a random effect for the interaction between arrival date and treatment group.

Estimates for the mean difference between the 2 treatment groups obtained from the statistical models were used to conduct both classical and bioequivalence hypothesis testing. For classical hypothesis testing, ANOVA type III F test statistics with values of P < 0.05 were considered significant. Bioequivalence testing was performed to calculate the mean difference limits within which the 2 drugs would be considered bioequivalent (ie, bioequivalence limits). For each outcome evaluated, a type I error rate of 5% was assumed, and a two 1-sided tests procedure was used as described15 such that the bioequivalence limits were symmetric around 0 and defined by the 90% CI for the mean difference between the 2 treatment groups.

All analyses were performed with statistical software.m A Kenward-Roger approximation was used to estimate degrees of freedom and to make corresponding adjustments in the estimation of SEMs. Pair-wise comparisons were performed with either Tukey-Kramer or Bonferroni methods to adjust for multiple comparisons and prevent type I error inflation.

Results

Animals—A total of 2,529 calves at high risk of developing undifferentiated BRDC because of low body weight (mean ± SD, 230 ± 34 kg) and stress caused by length of transportation (range, 10 to 16 hours) and commingling with other cattle (ie, at the auction market, during transportation, and at arrival to the feedlot) were enrolled in the study. One thousand two calves (mean ± SD body weight, 227 ± 18 kg) were enrolled in the study at the Kansas feedlot, and 1,527 calves (mean ± SD body weight, 235 ± 41 kg) were enrolled in the study at the Nebraska feedlot. One thousand two hundred sixty-three calves were administered gamithromycin and 1,266 calves were administered tulathromycin. No adverse reactions were observed in any of the calves after treatment administration, and none of the calves were removed from the study for reasons other than death before day 120. Initial body weight (P = 0.97), rectal temperature (P = 0.72), the proportion of calves with a fever (≥ 40°C) during processing (P = 0.87), and the proportion of bull calves that were castrated during processing (P = 0.33) did not differ significantly between the treatment groups, which suggested that the randomization procedure was successful.

BRDC morbidity rate—During the first 120 days on feed, 378 calves in the gamithromycin treatment group and 298 calves in the tulathromycin treatment group were treated for BRDC once (Table 1), of which 157 calves in the gamithromycin treatment group and 118 calves in the tulathromycin treatment group were treated for BRDC a second time. The majority (639/676 [95%]) of calves that were treated for BRDC were administered the first treatment within the first 70 days on feed. The mean ± SEM BRDC morbidity rate for all study calves was 31.0 ± 4.0%; however, calves administered gamithromycin had a significantly (P = 0.03) higher BRDC morbidity rate (31.0 ± 3.8%) than did the calves administered tulathromycin (22.9 ± 3.9%). When the initial body weight was fixed at 230 kg, a calf that had a fever during processing was 1.78 times (95% CI, 1.30 to 2.45) as likely to be treated for BRDC during the first 120 days on feed, compared with a calf that did not have a fever during processing, regardless of the metaphylactic treatment administered. Also, compared with a calf that had an initial body weight of 230 kg, the odds that a calf would be treated for BRDC during the first 120 days on feed was 1.41 (95% CI, 1.22 to 1.63) for every 50 kg decrease in initial body weight. Thus, the risk of a calf developing and being treated for BRDC during the first 120 days on feed was negatively associated with its initial body weight; the less a calf weighed at feedlot entry, the greater its risk of developing BRDC and vice versa.

Table 1—

Number of calves treated for BRDC and the BRDC cumulative incidence rate by days on feed for weaned crossbred beef calves that were at high risk of developing BRDC and metaphylactically treated with a single dose of gamithromycin (6.0 mg/kg [2 mL/50 kg], SC; n = 1,263) or tulathromycin (2.5 mg/kg [1.25 mL/50 kg], SC; 1,266) during processing (day 0) within 24 hours after feedlot entry.

 Treatment group  
Days on feedGamithromycinTulathromycinTotalCumulative BRDC incidence rate (%)
7683910716
141399923851
21624310567
2839377678
3524254985
4215153089
49851391
5645993
6326894
7031495
7712395
8443796
9104497
9823597
10522498
11243799
120167100
Total378298676NA

The study was conducted at 2 commercial beef feedlots located in Kansas and Nebraska and included calves purchased from auction markets located in Mississippi and northeast Oklahoma between October 2 and December 30, 2010. Calves were considered at high risk of developing BRDC and enrolled in the study if, during processing, they weighed ≤ 409 kg and did not have clinical signs of disease or injury or a history of being treated with an antimicrobial prior to feedlot arrival.

NA = Not applicable.

The mean ± SEM BRDC retreatment rate for all study calves was 40.1 ± 2.6%. The retreatment rate for calves in the gamithromycin treatment group did not differ significantly from that for calves in the tulathromycin treatment group, and the bioequivalence limits for BRDC retreatment rate were ± 10% (Table 2).

Table 2—

Mean ± SEM and bioequivalence limits for BRDC retreatment, mortality, and case-fatality rates during the first 120 days on feed for the calves described in Table 1.

 Treatment group 
VariableGamithromycinTulathromycinBioequivalence limits
BRDC retreatment rate (%)41.5 ± 4.239.5 ± 3.4± 10.0
BRDC mortality rate (%)4.2 ± 1.73.5 ± 1.3± 3.5
Case-fatality rate (%)14.8 ± 3.819.5 ± 3.9± 16.0

The BRDC retreatment rate for each treatment group was calculated as the number of calves in that treatment group that were treated for BRDC a second time divided by the number of calves in that treatment group that were treated for BRDC once. The BRDC mortality rate for each treatment group was calculated as the number of calves in that treatment group that died with gross evidence of BRDC divided by the number of calves in that treatment group. The case-fatality rate for each treatment group was calculated as the number of calves in that treatment group that died with gross evidence of BRDC and were treated for BRDC at least once divided by the number of calves in that treatment group that were treated for BRDC at least once. For each respective outcome, the difference between the 2 treatment groups was evaluated via generalized linear mixed models with a logit link function and the assumption of a Bernoulli distribution and did not differ significantly (P > 0.05). The bioequivalence limits were determined by the assumption of a 5% type I error rate, defined by the 90% CI for the mean difference between the 2 treatment groups, and expressed in the same units as the treatment mean.

See Table 1 for remainder of key.

BRDC mortality and case-fatality rates—During the first 120 days on feed, 95 calves in the gamithromycin treatment group and 79 calves in the tulathromycin treatment group died because of BRDC (Table 3), of which 14 calves in the gamithromycin treatment group and 15 calves in the tulathromycin treatment group had been treated for BRDC at least once. The majority (166/174 [95%]) of calves that died did so within the first 42 days on feed. The mean ± SEM BRDC mortality and case-fatality rates for all study calves were 3.84 ± 1.0% and 15.9 ± 3.1%, respectively, and did not differ significantly between the treatment groups. The mean ± SEM BRDC mortality and case-fatality rates for each treatment group and the corresponding bioequivalence limits were summarized (Table 2).

Table 3—

Number of calves described in Table 1 that died because of BRDC and the cumulative BRDC mortality rate by days on feed.

 Treatment group  
Days on feedGamithromycin TulathromycinTotalCumulative BRDC mortality rate (%) 
71531810
1428295743
211282055
2820143474
3515142991
4226895
4911297
5601197
6311298
7711299
98011100
120000100
Total9579174NA

See Table 1 for key.

When mean initial body weight was fixed at 230 kg, calves that had a fever during processing were 1.49 times (95% CI, 1.045 to 2.130) as likely to die because of BRDC during the first 120 days on feed than were calves that did not have a fever during processing, regardless of metaphylactic treatment. When mean initial body weight was fixed at 230 kg and rectal temperature during processing was controlled, the odds that a calf would die because of BRDC during the first 120 days on feed was 1.29 (95% CI, 1.06 to 1.43) for every 50-kg decrease in initial body weight. Thus, the less a calf weighed at feedlot entry, the greater its risk of dying because of BRDC during the first 120 days on feed.

Animal performance—Final body weight, ADG, DMI, and the feed-to-gain ratio did not differ significantly between the treatment groups on a deads-in or deads-out basis. The mean ± SEM for each treatment group for each respective outcome and the corresponding bioequivalence limits on a deads-in (Table 4) and deads-out (Table 5) basis were summarized.

Table 4—

Mean ± SEM and bioequivalence limits for animal performance variables during the entire feeding period (approx 180 days) for the calves described in Table 1 on a deads-in basis.

 Treatment group 
VariableGamithromycin TulathromycinlimitsBioequivalence
Final body weight (kg)486.0 ± 11.5495.0 ± 11.7± 37.0
ADG (kg/d)1.0 ± 0.031.1 ± 0.03± 0.1
DMI (kg/d)7.3 ± 0.087.4 ± 0.08± 0.3
Feed-to-gain ratio6.8 ± 0.186.6 ± 0.18± 0.7

Analyses included data from study calves that died or were euthanized because of BRDC during the first 120 days of the feeding period. Final body weight for each calf was defined as the mean calf weight for the pen in which that calf was housed just prior to transportation to the slaughter facility. For each pen, ADG was calculated by the use of the following equation: (total weight of calves immediately before slaughter – total weight of calves at processing)/number of days on feed; and the feed-to-gain ratio was calculated as the daily DMI divided by the ADG. For each respective variable, the difference between the 2 treatment groups was evaluated with general linear mixed models and did not differ significantly (P > 0.05).

See Tables 1 and 2 for remainder of key.

Table 5—

Mean ± SEM and bioequivalence limits for animal performance variables during the entire feeding period (approx 180 days) for the calves described in Table 1 on a deads-out basis.

 Treatment group 
VariableGamithromycinTulathromycinBioequivalence limits
Final body weight (kg)529.5 ± 6.3530.1 ± 6.3± 9.5
ADG (kg/d)1.2 ± 0.011.2 ± 0.01± 0.1
Feed-to-gain ratio6.6 ± 0.276.5 ± 0.14± 0.6

Analyses excluded data from study calves that died or were euthanized because of BRDC during the first 120 days of the feeding period. For each pen, ADG was calculated by the use of the following equation: (total weight of calves immediately prior to slaughter – [total weight of all calves at processing – {number of dead calves × mean weight for all calves at processing}])/number of calf days; where calf days was the sum of the number of days each calf within the pen (including those that died) was fed.

See Tables 1, 2, and 4 for remainder of key.

Discussion

Results of the present study suggested that for beef feedlot calves at high risk of developing BRDC, the metaphylactic efficacy of the labeled dose of gamithromycin did not differ from that of the labeled dose of tulathromycin for all health and performance outcomes evaluated except BRDC morbidity rate. Calves administered gamithromycin had a higher BRDC morbidity rate than did calves administered tulathromycin. Although this was a very large and well-replicated study conducted under typical conditions for commercial US feedlots, the wide bioequivalence limits calculated for subjective outcomes such as morbidity and case-fatality rate suggested that moderate to large differences between the gamithromycin and tulathromycin treatment groups would need to exist before the efficacy of the 2 drugs could be considered significantly different. The width of the bioequivalence limits was a function of the large amount of variability within the data, particularly for the subjective outcomes, which was most likely the result of factors that cannot be controlled in a field study, such as pathogen exposure, environmental conditions (ie, extremes in temperature or precipitation), and the immunocompetence of individual calves. Because of the subjective nature and imprecision by which BRDC morbidity is measured, a large sample size is required to assess the efficacy of antimicrobials under field conditions. The calves of the present study were purchased from auction markets, where they were commingled with other cattle and likely exposed to multiple pathogens, and the preconditioning status of the calves was generally unknown. Data variation might have been minimized and the bioequivalence limits narrowed in this study had the study calves been purchased from a single source or appropriately preconditioned before feedlot entry; however, such practices are not commonly implemented by most commercial feedlots in the United States and the study population would not have been representative of the general population of feedlot cattle.

In the present study, we chose to monitor health outcomes for 120 days after feedlot entry to assess the long-term efficacy of gamithromycin and tulathromycin for the control of BRDC. Other studies7,10,11,16 that were conducted to evaluate the efficacy of gamithromycin or tulathromycin for the control of BRDC only monitored health outcomes in calves for 10 to 28 days after treatment administration. The longer observation period used in the present study allowed us to identify the period of greatest risk for morbidity and death because of BRDC. Findings of the present study indicated that 95% (639/676) of the cumulative morbidity and 98% (171/174) of the cumulative deaths were observed during the first 70 days on feed. Therefore, in future studies, observation of health outcomes in calves for 70 days after metaphylactic administration of an antimicrobial should be sufficient to evaluate the efficacy of that drug for the control of BRDC and help minimize the expenditure of study resources.

For calves of the present study, initial body weight and rectal temperature during processing were significantly associated with subsequent BRDC morbidity and death, regardless of the metaphylactic treatment administered. Results of this study indicated that the less a calf weighed at feedlot entry, the greater was its risk of being treated for or dying from BRDC, and this finding was similar to that of another study.17 Investigators of 1 study18 suggest that monitoring rectal temperature of feedlot calves during processing has limited value because rectal temperature is affected by ambient temperature, humidity, and animal handling procedures.19 However, in the present study, calves with a rectal temperature ≥ 40°C during processing were 1.8 times as likely to be treated for BRDC and 1.5 times as likely to die because of BRDC during the first 120 days on feed. Thus, we suggest that monitoring rectal temperature of calves at feedlot entry is useful for the early identification of calves at high risk of developing BRDC so that those animals can be closely monitored and managed accordingly.

Gamithromycin and tulathromycin are both macrolides and have the same mechanism of action against microbes; therefore, we did not expect the clinical efficacy of the 2 drugs to differ. Consequently, the reason that the morbidity rate for calves metaphylactically treated with gamithromycin was significantly greater than that for calves metaphylactically treated with tulathromycin is unknown. A possible explanation for the observed difference in morbidity rate between the 2 treatment groups was that there was an inadvertent systematic error in the clinical diagnosis of BRDC, although that seems unlikely because the pens that contained the study calves were monitored by trained and experienced feedlot personnel who were unaware of the metaphylactic treatment administered to the calves in each pen. Moreover, for cattle, diagnosis of BRDC is generally made on the basis of a combination of subjective and objective observations, and the sensitivity (61.8%) and specificity (62.8%) of that method are low, resulting in the misclassification of a substantial proportion of cattle.20 The development of a more sensitive and specific method for the diagnosis of BRDC in cattle is warranted and will allow for more accurate evaluation of BRDC morbidity rates in studies involving feedlot cattle.

The BRDC mortality rate (3.8%) for calves of the present study was higher than the BRDC mortality rate (0%) for calves in other studies10,11 that were conducted to evaluate the metaphylactic efficacy of gamithromycin. This finding suggested that the calves of the present study were at a higher risk for the development of BRDC than were the calves enrolled in the other studies.10,11 For the present study, the primary inclusion criterion was calves with a low (≤ 409 kg) body weight at arrival to the feedlot. The mean initial body weight for all study calves was 230 kg, substantially less than the inclusion criterion cutoff. Additionally, the calves enrolled in the present study were stressed because of transportation and commingling with cattle from multiple sources at the auction market, during transportation, and at arrival to the feedlot, factors that are all associated with the development of BRDC.1,21 Furthermore, calves were enrolled into the present study during the fall and early winter, the period of the year when the BRDC incidence is particularly high because of the factors already cited in addition to sudden and extreme changes in weather conditions.21

Measures of animal performance (ie, final body weight, ADG, DMI, and the feed-to-gain ratio) did not vary significantly between calves that were administered gamithromycin and calves that were administered tulathromycin on a deads-in or deads-out basis in the present study. The lack of a significant difference in ADG between the 2 treatment groups of this study was consistent with findings of a study,16 in which the efficacy of tulathromycin was compared with that of another macrolide, tilmicosin, for the control of respiratory disease in cattle at high risk of developing BRDC.

In the present study, bioequivalence testing was performed for each outcome variable for which no difference was detected between the 2 treatment groups via classical hypothesis testing. This allowed us to identify limits for the mean treatment difference within which gamithromycin would be considered to yield an equivalent outcome, compared with that of tulathromycin, and provided information that could not be obtained via classical hypothesis testing. For classical hypothesis testing in a study in which 2 treatments are compared, the null hypothesis is generally that there is no difference between the 2 treatments. Failure to reject that null hypothesis only indicates that the difference between the 2 treatments was insufficient to conclude that a difference actually existed at a given confidence level (typically a type I error rate of 5%); it does not imply that the 2 treatments are equivalent.22 The determination of bioequivalence limits by calculation of the 90% CI for the mean difference between gamithromycin and tulathromycin allowed us to use actual biological data and avoid the complete arbitrariness of bioequivalence limits established a priori on the basis of expert opinion.22 Bioequivalence testing is a standard practice required by the FDA in pharmaceutical testing where conditions are carefully controlled,22,23 but its use to evaluate data obtained from field studies where conditions cannot be as carefully controlled is rather novel. The advantage of the bioequivalence approach is that it provides a clearly communicated standard of difference, as opposed to classical hypothesis testing, which allows each reader to provide their own individual standard of determining difference. The information provided by bioequivalence limits is important for veterinarians and livestock producers who are routinely faced with having to choose between 2 competing products for the treatment or management of a large number of animals on the basis of efficacy as well as cost. The bioequivalence limits calculated for gamithromycin and tulathromycin in the present study should be considered preliminary; however, they may provide guidance for future field studies.

To our knowledge, the present study was the first to compare the efficacy of gamithromycin with that of tulathromycin for the control of BRDC in calves in a commercial feedlot setting. Results indicated that calves metaphylactically administered gamithromycin had a higher morbidity rate than did calves metaphylactically administered tulathromycin; however, no significant differences were detected between the 2 treatments for BRDC retreatment, mortality, and case-fatality rates; ADG; DMI; and feed-to-gain ratio. The wide bioequivalence limits calculated for many of the outcomes suggested that moderate to large differences between the gamithromycin and tulathromycin treatment groups would need to be detected before the 2 drugs would not be considered equivalent and were most likely caused by variability within factors that could not be controlled in a field study such as pathogen exposure, environmental conditions, and the immunocompetence of individual calves. Nevertheless, the bioequivalence limits provided additional information about the efficacy of gamithromycin and tulathromycin that could not be obtained via classical hypothesis testing, and that information could be beneficial for veterinarians and feedlot producers when making decisions regarding management of BRDC.

ABBREVIATIONS

ADG

Average daily gain

BRDC

Bovine respiratory disease complex

CI

Confidence interval

DMI

Dry matter intake

a.

SafeGuard, Intervet/Schering-Plough Animal Health, Millsboro, Del.

b.

Ivomec Plus, Merial Ltd, Duluth, Ga.

c.

Vision 7/Somnus, Intervet/Schering-Plough Animal Health, Millsboro, Del.

d.

Inforce 3, Pfizer Animal Health, New York, NY.

e.

Bovishield Gold 5, Pfizer Animal Health, New York, NY.

f.

Ralgro, Intervet/Schering-Plough Animal Health, Millsboro, Del.

g.

Zactran, Merial Ltd, Duluth, Ga.

h.

Draxxin, Pfizer Animal Health, New York, NY.

i.

Nuflor, Intervet/Schering-Plough Animal Health, Millsboro, Del.

j.

Baytril, Bayer Animal Health, Shawnee Mission, Kan.

k.

Excede, Pfizer Animal Health, New York, NY.

l.

Bio-Mycin, Boehringer Ingelheim Vetmedica, St Joseph, Mo.

m.

SAS, version 9.3, SAS Institute Inc, Cary, NC.

n.

Micotil, Eli Lilly and Co, Indianapolis, Ind.

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Contributor Notes

Dr. Torres' present address is Merck Animal Health, 556 Morris Ave, Summit, NJ 07902.

Supported by Merial Ltd and the Beef Cattle Institute, Kansas State University.

This manuscript represents a portion of a dissertation submitted by Dr. Torres to the Department of Animal Sciences and Industry, College of Agriculture, Kansas State University as a partial fulfillment of the requirements for a Doctor of Philosophy degree.

Presented as an oral presentation at the Phi Zeta Research Day, College of Veterinary Medicine, Kansas State University, Manhattan, Kan, March 2012.

The authors thank Dr. Ron Tessman for technical assistance.

Address correspondence to Dr. Thomson (dthomson@vet.k-state.edu).