Swine respiratory disease (SRD), a complex syndrome caused by multiple bacterial and viral agents in combination with various environmental factors and management practices,^1-4 is the most important disease problem affecting the swine industry worldwide. Virtually every herd is affected to some degree.^1,9 Despite good control measures, SRD outbreaks and subclinical forms occur even in high-health status herds, causing substantial health problems and escalating overall production costs.^9,10 At herd level, the total cost of SRD is the sum of output losses—increased mortality, decreased weight gain, increased feed consumption, increased variability of weights, decreased meat quality or payment—and of control expenditures— vaccination programs, treatments, hygiene procedures, and extra labor.¹¹ For mortality alone, respiratory disease accounts for 44.2 per cent of nursery deaths and 61.1 per cent of deaths in grower/finisher pigs, according to a 2006 survey taken in the US.¹²

A notable characteristic of SRD is the frequency with which the causative bacterial agents appear in the swine population, including herds with subclinical infection. For example, it has been estimated that most herds are infected with one or more serotypes of Actinobacillus pleuropneumoniae, although not all serotypes have the same economic importance.⁵ One national survey noted that 6.4 per cent of sites with nursery-age pigs reported disease caused by A. pleuropneumoniae, with a higher prevalence of 13.4 per cent in sites with 10,000 or more pigs. Among sites with grower/finisher pigs, the overall prevalence of disease caused by A. pleuropneumoniae was said to be 8.1 per cent, whereas prevalence among medium- (2,000 to 10,000 pigs) and large- (10,000+ pigs) size units was 14.9 per cent and 21.0 per cent, respectively.⁶ The same national survey noted that disease caused by Mycoplasma hyopneumoniae was reported in 19.6 per cent of sites with nursery-age pigs and in 29.0 per cent of sites with grower/ finisher pigs. Prevalence again was said to be highest in medium- and largesize units (41.5 per cent and 52.7 per cent, respectively, for nursery units; 55.7 per cent and 68.0 per cent, respectively, for grower/ finisher units).⁶ Other investigators noted that Haemophilus parasuis also is gaining notoriety as an important contributor to SRD, as it has been associated with high morbidity and mortality in high-health status herds.⁷

Single-Dose DRAXXIN for Swine

DRAXXIN Injectable Solution has been formulated for intramuscular (IM) injection as a ready-to-use single dose (2.5 mg/kg) that provides a full course of treatment against the key bacterial pathogens (A. pleuropneumoniae, Pasteurella multocida, Bordetella bronchiseptica, H. parasuis, and M. hyopneumoniae) associated with the SRD complex.

The pharmacokinetic profile of tulathromycin is characterized by rapid and extensive absorption followed by high distribution and slow elimination. Following administration of a single 2.5 mg/kg body weight intramuscular dose, tulathromycin was shown to be rapidly released from the IM injection site, reaching maximum plasma concentration in less than one hour, and was extensively distributed with an approximate 88 per cent bioavailability.¹³ Tulathromycin achieved lung concentrations 61 times the plasma area under the curve (AUC), the parameter that most likely accounts for the overall amount of drug exposure in target tissue;¹³ reached a peak lung concentration within 12 hours of dosing; and was slowly released from lung tissue (mean half-life of 5.9 days).¹³

Primarily because tulathromycin is slowly eliminated from target cells in lung and other tissue, DRAXXIN has an extended therapeutic period for the treatment of respiratory disease as compared with other injectable veterinary antimicrobials. In previous clinical assessments conducted in European and US commercial swine operations, a single dose of DRAXXIN was demonstrated to have high levels of efficacy against several of the most frequently diagnosed bacterial and mycoplasmal agents associated with the SRD complex.^14-16 Moreover, a single dose of DRAXXIN was shown to have cure rates comparable to multiple doses of ceftiofur sodium and other antimicrobials. ^14-16 In a recently published duration of effect study, a single intramuscular dose of tulathromycin provided up to 9 days of protection against death and severe morbidity in an A. pleuropneumoniae respiratory disease challenge model in swine.¹⁷

The study summarized below was conducted over the course of 56 days to evaluate and define the long-term health and performance effects of DRAXXIN administered as a single intramuscular dose (2.5 mg/kg body weight) for the treatment of SRD under exposure and outbreak conditions. Clinical responses to treatment with tulathromycin and weight gain were evaluated in Isowean pigs in comparison with a conventional “on-farm therapy” (OFT). Study results may prove helpful to practitioners and producers making data-based decisions about choice of the most effective antimicrobial therapy for treating the mixed bacterial and mycoplasmal infections associated with the SRD complex. The study was conducted under close veterinary supervision and was pre-approved by an Institutional Animal Care and Use Committee.

Study Overview: Design, Assessments, and Analysis

Study Design⁸

The study site acquired 370 pigs, 17 to 21 days of age, for use in this investigation. Of the total, 200 were high-health, crossbred Isowean pigs from a single herd and the remaining 170 were low-health, crossbred pigs from two herds positive for various SRD pathogens (M. hyopneumoniae, PRRS virus, A. pleuropneumoniae, and swine influenza virus). Upon arrival at the study site, pigs from all three herds were commingled and penned in a slatted-floor, conventional swine finisher unit equipped with an Auto-Sort Food Court (ASFC) system that provided feed and electronically captured individual pig weights by way of radio-frequency identification ear tags.

After commingling, pigs demonstrating clinical signs of SRD had to fulfill the following criteria for attitude (depression) and respiratory character to be eligible for enrollment and treatment:

• Attitude score ≥ 2. A score of 2 or greater indicated the pig had at least moderate depression. If recumbent, the pig might rise when stimulated but remained depressed or lethargic. A gaunt appearance and/or rough hair coat indicated anorexia.
• Respiratory character score ≥ 2. Pigs with a score equal to or greater than 2 had at least a moderate increase, or change, in respiratory rate and effort, and/or an obvious cough (several coughing episodes within a few minutes time). Pigs showing more severe signs (dyspnea, open-mouth breathing, thumping, extensive coughing episodes, and/or cyanotic appearance) received scores of 3.

Altogether, 135 pigs met the enrollment criteria and were randomly assigned in a 1:2:2 ratio to treatments as follows (Table 1):

Assessments

Pigs were monitored daily from Day 0 (day of treatment) through Day 56. Attitude (depression) signs were scored on a scale ranging from 0 (normal) to 3 (severely depressed or moribund), and respiratory signs on a scale ranging from 0 (normal rate and character) to 3 (severely increased rate and markedly abnormal character; may exhibit open-mouth breathing). Mortalities to Day 7 and to Day 56 were recorded. On Day 7, pigs in all treatment groups were clinically re-evaluated and weighed, and on Day 56, all pigs remaining in the study were again weighed.

Study Analysis

The primary efficacy variable was the percentage of pigs per group with BOTH attitude and respiratory scores ≥ 1. Success was denoted as a binary variable (1=success; 0=failure) and was analyzed using a generalized linear mixed model (GLMM). The model included the fixed effect of treatment and the random effects of block and residual. Mortality to Day 7 and Day 56 was analyzed using a similar binary variable approach as was used for success rate. Weight gain to Days 7 and 56 was analyzed using the MIXED procedure of SAS using analysis of covariance. The mixed model included the fixed effect of treatment and the random effects of block and residual. The model included initial weight as a covariate.

Results

Clinical Success

At seven days after treatment, DRAXXIN-treated pigs had a 71.5 per cent success rate (attitude AND respiratory scores ≥ 1) compared with a 55 per cent rate for OFT-treated pigs and a 46.6 per cent rate for saline-treated control pigs (Figure 1). The difference in clinical success between DRAXXIN-treated and OFT OFT-treated pigs was significant (P=0.0389), whereas there was no difference (P = 0.2294) in clinical success between saline-treated control pigs and OFT-treated pigs (Table 2).

Mortality

By Day 7, four mortalities were observed (Table 3): three (10 per cent) among the saline-treated control pigs and one (1.9 per cent) among the DRAXXIN-treated pigs. The mortality rate among OFT-treated pigs (0.0 per cent) was significantly (P=0.0198) lower than among the saline-treated pigs. There was no significant (P=0.3127) difference between the DRAXXIN-treated and OFT-treated pigs or between the DRAXXIN-treated and saline-treated pigs (P=0.1041). At the end of the study (Day 56), the mortality rates for the saline, OFT, and DRAXXIN groups were 34.6 per cent, 12.2 per cent, and 18.5 per cent, respectively. Overall mortality was significantly (P=0.0360) higher in the saline-treated control pigs than in either the OFT- or DRAXXIN-treated pigs.

Figure 1—Clinical success at seven days after treatment for SRD

Table 3—Mortality at Day 7 and Day 56 (back-transformed LSM %)
Treatment Group	T1 Saline	T2 OFT (Pen G proc)			T3 DRAXXIN
Mortality—Day 7	10%	0.0%			1.9%
P-values
OFT < Saline		0.0198			0.0038
DRAXXIN < OFT				0.3127
DRAXXIN < Saline	0.1041
Mortality—Day 56	34.6%	12.2%			18.5%
P-values
OFT < Saline		0.0038
DRAXXIN < OFT				0.3562
DRAXXIN < Saline	0.0360
LSM = least squares mean; Pen G proc = penicillin G procaine

Performance

DAY 7

At seven days after treatment, OFT-treated and DRAXXIN-treated pigs had mean weight gains of 8.1 and 8.3 pounds, respectively (Table 4). While the gains were not different (P = 0.4116) from one another, both gains were significantly (P=0.0587) greater than the 6.2 pound mean weight gain in the saline-treated control pigs.

DAY 56

For the analysis of gain at Day 56, an analysis of covariance showed a significant (P=0.0428) interaction of treatment with Day 0 body weight as the covariate. Therefore, in accordance with standard statistical methodology, the comparison of gain between treatments at Day 56 was evaluated at predetermined intervals, or percentiles (25^th, 50^th, and 75^th) of the Day 0 weight. At the 25^th and 50^th percentiles of the Day 0 body weight, there were no significant (P>0.20) differences among treatment groups for weight gain at Day 56 (Table 5). However, at the 75^th percentile, mean weight gain at Day 56 in DRAXXIN-treated pigs was 10 pounds greater than in OFT-treated pigs (P=0.0597) and 16 pounds greater than in saline-treated control pigs (P=0.0268). Additionally, at the 75^th percentile, the mean gain at day 56 was 6 pounds greater in OFT-treated pigs than in saline-treated control pigs (P=0.2406).

The significant (P = 0.0428) effect of the treatment by covariate (Day 0 weight) interaction indicated that gain increased as initial body weight increased. Further, as the initial body weight increased (for example, at the 75th percentile), DRAXXIN-treated pigs gained more than both saline-treated control and OFT-treated pigs. This is further supported by comparing gains between DRAXXIN- and OFT-treated pigs at lower initial body weights (for example, at the 25th and 50th percentiles) where there were no significant (P > 0.5238) differences (Figure 2).

Figure 2—Weight gain differences at Day 56 by percentile of Day 0 body weight

Discussion

This long-term comparative study was conducted under conditions designed to simulate a natural outbreak of SRD. Susceptible high-health status Isowean pigs were stressed by commingling with pigs from two separate farms and contact exposed to multiple bacterial and viral pathogens associated with the SRD complex. An adequate outbreak occurred, as 135 of the 370 study pigs (36 per cent morbidity) developed moderate to severe signs of SRD. Clinical results observed under these conditions reinforce and expand upon previously published assessments of the effectiveness of DRAXXIN for the treatment of SRD.^14-16 Pigs treated with a single intramuscular dose of DRAXXIN administered at 2.5 mg per kg body weight had a significantly higher treatment success rate at 7-days post-treatment compared with both saline-treated control (P=0.0132) and OFT-treated pigs (P=0.0389). Compared with saline-treated control pigs, DRAXXIN-treated pigs had a reduced mortality at seven days post treatment and a significantly (P=0.0360) lower rate at 56 days after treatment. Further, the study documented the positive effect that the improved health response with DRAXXIN had upon performance. As early as 7 days after treatment, DRAXXIN-treated pigs had a significantly (P=0.0409) higher mean weight gain (8.3 lb) compared to saline-treated control pigs. Over the 56- day course of the study, the mean weight gain in DRAXXIN-treated pigs was 10 lb greater than in OFT-treated pigs (P=0.0597) and 16 lb greater than in saline-treated control pigs (P = 0.0268), when adjusted to the 75^th percentile of mean weight at enrollment.

Of the two active ingredients evaluated in this study, only DRAXXIN is approved for use in swine to treat SRD. The positive control treatment was penicillin G procaine, which was administered intramuscularly for two consecutive days at the rate of 5 mL per 100 lb body weight. Such off-label use of penicillin G procaine is reportedly widespread in the US, as a national survey conducted in 2006 noted that 43.9 per cent of randomly selected sites administer the antibiotic to nursery pigs and 46.6 per cent of randomly selected sites to grower/finisher pigs. The primary reason provided for giving penicillin G procaine was to treat respiratory disease.18 Thus, the positive control therapy used in this study reflected a commonly implemented strategy for treating naturally occurring cases of SRD. The comparison of DRAXXIN to penicillin G procaine was regarded as being useful in evaluating the efficacy of tulathromycin under typical field conditions from the time of treatment for SRD through harvest. Based on analysis of clinical success (attitude and respiration scores ≥ 1) and weight gain performance, results of this study indicated that pigs with moderate to severe clinical signs of SRD given a single dose of DRAXXIN had a significantly improved therapeutic response compared with pigs receiving a conventional OFT using penicillin G procaine. Of key practical importance is the observation that at seven days posttreatment there was no significant difference in success rate (primary efficacy variable) between pigs treated with a saline control article (46.6 per cent) and pigs treated twice with penicillin G procaine (55 per cent), whereas pigs treated once with DRAXXIN had a 71.5 per cent success rate. The improved health response resulted in positive performance effects, as DRAXXIN-treated pigs gained significantly more weight over the course of the 56-day study than saline-treated control pigs or the OFT-treated pigs, when adjusted to the 75^th percentile of mean weight at enrollment.⁸

The complete course of therapy provided by a single dose of DRAXXIN differentiates the product as the choice treatment for SRD, one that potentially could change the way veterinarians and producers manage their herds, minimizing both labor and handling stress. DRAXXIN should not be used in animals known to be hypersensitive to the product. The pre-slaughter withdrawal time for DRAXXIN in swine is five days.

Clinical Implications

The study reported here demonstrates the long-term health and performance benefits that were derived from using DRAXXIN in a natural exposure and SRD outbreak situation. This information combined with the results of previous reports demonstrating clinical efficacy in SRD associated with multiple bacterial pathogens provides additional evidence for evaluating the suitability of using injectable single-dose DRAXXIN therapy to treat primary or secondary disease.

Results of this study indicate that in intensively managed nursery and grower/finisher operations, the administration of DRAXXIN may be:

• An effective herd-health management tool for reducing sickness and death loss due to SRD
  • Following administration of a single dose, tulathromycin reaches maximum plasma concentration in less than an hour, with an approximate 88 per cent bioavailability
    
    
  • Tulathromycin achieves lung concentrations 61 times the plasma area under the curve
    
    
  • Tulathromycin reaches a peak lung concentration within 12 hours of dosing and is slowly released from lung tissue, providing persistent exposure of pathogens to drug
• A cost-effective alternative to existing OFTs for managing output losses linked to SRD
  • A complete course of therapy with a single dose is achieved against major respiratory pathogens
• An effective approach for improving the profitability of pigs affected with SRD.
  • DRAXXIN-treated pigs suffered fewer mortalities and showed improved long-term weight gain
    
  • Single-dose administration minimises both labour costs and handling stress

References

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