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Performance and Health Improvements of Pigs Treated with DRAXXIN® (tulathromycin) Injectable Solution: A Mycoplasma hyopneumoniae Challenge Model

by 5m Editor
24 March 2009, at 12:00am

A field study showed the efficacy of DRAXXIN (tulathromycin) in an injectable solution in a Mycoplasma hyopneumoniae challenge model writes Thayer C. Hoover, DVM, from Pfizer Animal Health.

Key Points
  • Economic losses associated with Mycoplasma hyopneumoniae infection of swine accrue from decreased weight gain, increased feed conversion, increased variability of weights, and increased medication costs.1,2

  • A study was conducted over the course of 60 days to evaluate the long-term performance and health of pigs treated with a single intramuscular dose of DRAXXIN® (tulathromycin) Injectable Solution following induction of swine respiratory disease (SRD) using a recent US M. hyopneumoniae field isolate.3

  • DRAXXINR-treated pigs showed a significantly (P≤0.0121) improved average daily gain (1.63 to 1.99 lb/hd/day) compared with saline-treated control pigs (1.35 to 1.77 lb/hd/day).

  • DRAXXIN®-treated pigs consumed more feed with a markedly improved overall feed:gain ratio (2.78) compared with saline-treated control pigs (3.58; P = 0.1032).

  • DRAXXIN®-treated pigs had lower mortality compared with saline-treated control pigs (4.2 per cent vs 8.7 per cent, respectively).

  • The proportion of pigs scoring “normal” for attitude/depression and respiratory character was 11 per cent and 24 per cent higher, respectively, at the 10-day post-treatment evaluation in DRAXXIN®-treated pigs than in saline-treated control pigs.

Mycoplasma hyopneumoniae —the primary agent of enzootic pneumonia of swine—is distributed worldwide and causes major economic losses to the pork production industry.1,2,4 The pathogen is transmitted from sow to piglets in farrowing facilities and from pig to pig in nurseries, growers, and finisher units. After transmission, a variable incubation period ensues, followed by a nonfatal pneumonia when pigs reach 6 to 10 weeks of age.5 The first sign of enzootic pneumonia is a dry, nonproductive cough. In three-site production systems, the coughing typically occurs 3 to 10 weeks after pigs move to the finishing unit.6 The cough may last from 1 to 3 weeks or persist indefinitely. Pigs with mild infections do not appear to be sick; however, as the pneumonia becomes more severe, appetite and growth rate decrease, feed utilization suffers, hogs become chronic poor-doers, and treatment and control costs escalate.2 In the US, cost for enzootic pneumonia has been estimated at $4.08 per pig, exclusive of the cost of medications used to treat or reduce disease effects.5

M. hyopneumoniae attaches to and damages ciliated cells of the respiratory tract, and induces inflammation. The bacterium also plays a primary role in establishing the mixed infections of the swine respiratory disease (SRD) complex and in potentiating porcine reproductive and respiratory syndrome virus (PRRSV)- induced pneumonia. An Iowa State University study found the majority of severe SRD cases examined were positive for both PRRSV and M. hyopneumoniae.7 Pigs infected with PRRSV and M. hyopneumoniae developed pneumonia of greater severity and duration than pigs infected with PRRSV alone. The study concluded that in cases of mixed infection, M. hyopneumoniae potentiated PRRSV-induced disease and lesions but that PRRSV did not influence severity of M. hyopneumoniae infection, suggesting that control of M. hyopneumoniae in mixed infections may be of primary importance.7 Other investigators have shown that swine experimentally infected with M. hyopneumoniae are predisposed to pneumonia caused by Pasteurella multocida and Actinobacillus pleuropneumoniae. 8,9 The USDA’s 2006 National Animal Health and Monitoring Survey (NAHMS) underscored the economic damage done by SRD to the pork industry in the US. Across sites ranging in size from fewer than 2,000 pigs to more than 5,000, respiratory disease accounted for 44.2 per cent of nursery deaths and 61.1 per cent of deaths in grower/finisher pigs.10

Another team of investigators experimentally reproduced postweaning multisystemic wasting syndrome (PMWS) in pigs by dual infection with M. hyopneumoniae and porcine circovirus type 2 (PCV2).11

Opriessnig and Thacker associated M. hyopneumoniae infection with increased replication of PCV2, increased severity of PCV2 lesions (specifically lymphoid depletion), and a higher incidence of PMWS. In a subsequent study published in 2008, Rapp- Gabrielson et al found that controlling M. hyopneumoniae was an important tool in reducing respiratory disease and production losses in herds co-infected with PCV2 and M. hyopneumoniae.12

M. hyopneumoniae continues to cause significant economic losses to the swine industry worldwide despite major efforts directed at controlling the pathogen.10,13 Whereas numerous investigators have demonstrated the in vitro susceptibility of M. hyopneumoniae to a range of antimicrobials,14-19 the pathogen persists under field conditions.1,17,20 As a mucosal pathogen, M. hyopneumoniae colonizes cilia of the trachea, bronchi, and bronchioles,1 locations that require antimicrobial agents to reach therapeutic levels in bronchoalveolar fluid if they are to be effective. 21 Additionally, M. hyopneumoniae lacks a cell wall, making the organism resistant to many therapeutic agents.

One-Dose DRAXXIN (tulathromycin) Approved for Treating M. hyopneumoniae Infections

The pharmacokinetic profile of tulathromycin, active ingredient of DRAXXIN, 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 intramuscular injection site, reaching maximum plasma concentration within 15 minutes.22 The volume of distribution (Vd) following intravenous administration was 13.2 L/kg, indicating a strong tendency to distribute to tissues rather than remain in plasma, and systemic bioavailability following intramuscular administration was extensive at approximately 88 per cent.22 After intramuscular injection, tulathromycin achieved lung concentrations 61 times the plasma area under the curve (AUC), the parameter most likely accounting for the overall amount of drug exposure in target tissue;22 reached a peak lung concentration within 12 hours of dosing; and was slowly released from lung tissue (mean half-life of 5.9 days).22

M. hyopneumoniae was shown to be highly susceptible to tulathromycin as the minimum inhibitory concentration inhibiting growth of 90 per cent of the isolates (MIC90) was 0.05 μg/mL. Moreover, swine lung tissue concentrations of tulathromycin well above the MIC90 level persisted for at least 15 days after a single intramuscular dose (Figure 1).22 Studies with radio-labeled tulathromycin showed that over a 4-hour period, the antimicrobial accumulated in porcine neutrophils and alveolar macrophages about 17- and 8-times the concentration in the extracellular media, respectively (Figure 2). The concentrations of tulathromycin in neutrophils and alveolar macrophages were approximately 6- and 4-times higher than the corresponding accumulation of erythromycin, a positive control macrolide.23 Such results suggested that normal inflammatory responses (neutrophils, macrophages) might serve to transport tulathromycin directly to the site of infection.23


Figure 1—Lung drug concentrations in pigs following a single intramuscular injection of tulathromycin at 2.5 mg/kg body weight.

Figure 2—Tulathromycin uptake by immune cells (5 ìg/mL ; 4-hour incubation)

Subsequent studies in commercial swine herds in Europe and North America indicated that a single dose of DRAXXIN had high levels of efficacy against the SRD complex when M. hyopneumoniae was present.24,25 A single dose of DRAXXIN was shown to have cure rates comparable to multiple doses of ceftiofur sodium and other antiinfectives, and there were no significant (P > 0.05) differences between treatments in average daily gain.24 In December 2007, label indications for DRAXXIN were expanded in the US to include the treatment of SRD caused by M. hyopneumoniae. Here we report the results of a 60-day disease challenge and treatment study, which was conducted to evaluate the long-term performance and health of pigs following treatment of SRD induced using a recent US M. hyopneumoniae field isolate challenge. 3 Overall goal of the study was to collect real-world data that practitioners and producers can use in assessing the longterm clinical and economic value of using DRAXXIN for the treatment of SRD associated with M. hyopneumoniae infection. 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 Design3

The study enrolled 200 Isowean high-health status pigs that were sero-negative for M. hyopneumoniae for use in this evaluation. Within three days of arrival, pigs were identified with duplicate ear tags and were administered a porcine circovirus vaccine. Following a four-week acclimation period, pigs were inoculated once per day for three consecutive days with 10 mL of a recent field isolate of M. hyopneumoniae in a lung homogenate inoculum and returned to their pens. The new isolate was selected in compliance with the USDA regulatory requirements. On each of the three days, pigs were administered the inoculum intratracheally (8.0 mL) and intranasally (2.0 mL; 1.0 mL/naris).

Between 11 and 23 days after challenge, 96 pigs meeting SRD criteria for attitude (depression) AND respiratory character (scores ≥ 2; scale: 0 to 3; 0 = normal) were enrolled in the study and assigned to one of 24 pens (3 to 5 pigs/pen) according to a randomized design (Table 1). Each pen, as the experimental unit, contained only salinetreated or DRAXXIN-treated pigs. The 96 enrolled pigs were assigned equally to saline (T1) and DRAXXIN (T2) treatment groups. Day 0 was defined as the day of treatment administration. T1 pigs received an intramuscular dose of saline (0.025 mL/kg body weight) and T2 pigs an intra-muscular dose of DRAXXIN (2.5 mg/kg body weight). All pigs were weighed on Days 0, 10, 20, 30, 45, and 60 (± 2 days), evaluated for clinical signs of SRD on Days 0 and 10, and were observed daily from Days 11 through 60 for reoccurrence of SRD. On Day 10, pigs again meeting the enrollment criteria for SRD were re-treated, and remained in the pen and study. Antimicrobials for SRD therapy after Day 10 excluded DRAXXIN (to assess long-term cure rates with a single dose), and were the same across both T1 and T2 treatment groups. Throughout the study, all feed placed in pen feeders was recorded.

Table 1—Treatment groups in study assessing performance and health of pigs treated with DRAXXIN following experimental induction of M. hyopneumoniae swine respiratory disease
Treatment Group No. pigs (No. pens) Dosage Dosing Day/Route Evaluations, Timing
T1 Saline 48 (12) 0.025 mL/kga Day 0/IM (neck) General health — daily
T2 DRAXXIN 48 (12) 2.5 mg/kgb Day 0/IM (neck) SRD clinical signs — Days 0 and 10
Weight— Days 0, 10, 20, 30, 45, 60
Feed placement, weigh back—Days 0, 10, 20, 30, 45, 60
SRD reoccurrence — Days 11 –60
IM = intramuscular
aVolume equivalent to DRAXXIN Injectable Solution administered at 2.5 mg/kg
bDose justification: This dose has been approved by the Center for Veterinary Medicine (CVM) for treatment of M. hyopneumoniae swine respiratory disease.

Assessments

Pig weights and feed consumption were measured at Days 10, 20, 30, 45, and 60. At each of the interim weigh days and end of the study, feeders were emptied and the remaining feed weighed back. Average daily gain (ADG), average daily feed intake (ADFI), and feed to gain (F:G) were determined at the weighing intervals and for the entire study period (Day 0–Day 60).

Secondary variables included animal health (treatment response, number of additional treatments, and mortality) and other health events. Pigs were monitored and scored on Days 0 and 10 for signs of respiratory disease. Attitude signs were scored on a scale ranging from 0 (normal) to 3 (severely depressed); respiratory character signs on a scale ranging from 0 (normal) to 3 (dyspneic; gasping or open-mouthed breathing, thumping). From Day 11 through Day 60 all pigs were observed for reoccurrence of SRD (additional treatments) and mortality. Pigs that died or were euthanized for causes unrelated to SRD, as confirmed by clinical and laboratory diagnosis, were not included in the study summaries.

Study Analysis

In this study, the pen was the experimental unit for statistical analysis. The primary assessment for efficacy was based on performance differences (weight change, feed consumption) between saline-treated control pigs and DRAXXIN-treated pigs at Days 10, 20, 30, 45, and 60. Weight and feed consumption were analyzed using a mixed model. Treatment differences were assessed at the 10 per cent level of significance (P ≤ 0.10). Secondary variables included clinical scores for Days 0 and 10, reoccurrence of SRD (additional treatments), and mortality.

Results

Average Daily Gain

ADG was significantly (P ≤ 0.0121) greater for DRAXXIN-treated pigs than for salinetreated control pigs at each of the weighing intervals and for the entire evaluation period (Table 2). Over the course of the study, DRAXXIN-treated pigs gained 1.63 to 1.99 lb/head/day, whereas saline-treated control pigs gained 1.35 to 1.77 lb/head/day, a weight gain advantage for DRAXXIN-treated pigs that ranged from 0.23 to 0.31 lb/head/day (Figure 3).

Table 2—Average daily gain by weighing day
Treatment Group Average daily gain (lb/hd/day) by weighing day (No. pigs)
Day 0–10 Day 0–20 Day 0–30 Day 0–45 Day 0–60
T1 Saline 1.35 (46) 1.48 (45) 1.55 (44) 1.63 (42) 1.77 (42)
T2 DRAXXIN 1.63 (47) 1.79 (46) 1.85 (46) 1.90 (46) 1.99 (46)
Difference (T2-T1) 0.28 0.31 0.30 0.27 0.23
P-value 0.0121 0.0013 0.0005 0.0011 0.0015



Figure 3—Average daily gain by treatment group (Day 0 to Da y X).

Feed Consumption

Feed (offered, remaining) was weighed for each pen to determine an ADFI in pounds (Table 3). For the overall ADFI (Day 0–60), DRAXXIN-treated pigs consumed significantly (P ≥ 0.0861) more feed than saline-treated control pigs.

Table 3—Average daily feed intake by weighing interval
Treatment Group Average daily feed intake (lb/day)
Day 0–10 Day 10–20 Day 20–30 Day 30–45 Day 45–60 Day 0–60
T1 Saline 5.59 4.20 4.68 5.34 4.45 4.85
T2 DRAXXIN 5.96 4.51 5.14 5.60 4.63 5.17
Difference (T2-T1) 0.37 0.31 0.46 0.25 0.18
P-value 0.2808 0.2140 0.1052 0.2514 0.3317 0.0861

Feed to Gain

Feed to gain (F:G) ratios, pounds of feed per one pound of weight gain, were determined and analyzed by weighing interval and for the entire study period (Table 4). The overall F:G ratio for DRAXXIN-treated pigs (2.78) compared with saline-treated control pigs (3.58) approached significance (P = 0.1032), showing improved feed utilization following treatment.

Table 4—Feed (lb) to gain (lb) ratios by weighing interval
Treatment Group Average daily feed intake (lb/day)
Day 0–10 Day 10–20 Day 20–30 Day 30–45 Day 45–60 Day 0–60
T1 Saline 5.59 4.20 4.68 5.34 4.45 4.85
T2 DRAXXIN 5.96 4.51 5.14 5.60 4.63 5.17
Difference (T2-T1) 0.37 0.31 0.46 0.25 0.18
P-value 0.2808 0.2140 0.1052 0.2514 0.3317 0.0861

Mortality

Overall, 6 mortalities (4 in the saline-treated control pigs and 2 in the DRAXXIN-treated pigs) occurred during the study, with 3 deaths (2 in the salinetreated control pigs and 1 in the DRAXXIN-treated pigs) occurring during the initial 10-day post-treatment period (Table 5). Necropsy examination showed that all of the pigs that died had gross lesions of SRD. The difference between treatment groups was not significant (P = 0.3357).

Table 5—Pig deaths by treatment group
Treatment Group Live: Number (%) Dead: Number (%) P-value
T1 Saline 42 (91.3) 4 (8.7) 0.3357
T2 DRAXXIN 46 (95.8) 2 (4.2)

Clinical Scores (Attitude, Respiratory Character)

On Study Day 0, all pigs had an attitude score of 2 (moderate depression) and 98 per cent to 100 per cent had a respiratory character score of at least 2 (moderately severe signs and change in respiratory character). At the Day 10 health evaluation, the proportion of pigs returning to or scoring normal for attitude/ depression and respiratory character was 11 per cent and 24 per cent higher, respectively, for DRAXXIN-treated pigs than for salinetreated control pigs (Table 6).

Table 6—Attitude and respiratory character scores at 10 days post-treatment: Percentage of pigs by group
Treatment Group Attitude Scores
0 1 2 3
T1 Saline 76 13 11 0
T2 DRAXXIN 87 6 6 0
0: Normal—Not used to enroll on Day 0 (pig not eligible)
1: Mild depression. Pig is mildly depressed or lethargic prior to stimulation. Upon stimulation pig appears normal. Not used on Study Day 0 (pig not eligible).
2: Moderate depression. Recumbent pig will rise upon stimulation, but remains depressed or lethargic; evidence of inappetance through gauntness and/or rough haircoat.
3: Severely depressed to moribund. Unable to rise, or very resistant to stimulation but will rise, and immediately returns to or seeks recumbency.
Treatment Group Respiratory Character Scores
0 1 2 3
T1 Saline 65 24 7 4
T2 DRAXXIN 89 4 6 0
0: Normal—Not used to enroll on Day 0 (pig not eligible)
1: Mild increase in respiratory effort and/or occasional cough. Not used on Study Day 0 (pig not eligible).
2: Moderate increase in respiratory effort and/or coughing is repetitive or episodic (several coughing episodes within a few minutes of rising).
3: Dyspnea (e.g., gasping or open-mouthed breathing, thumping); extensive non-productive, repetitive, or episodic periods of coughing.

Additional Treatments

Following the Day 10 health evaluation, 5 saline-treated control pigs and 3 DRAXXIN-treated pigs were treated a second time for SRD. Therapy for each pig was penicillin G procaine administered for two consecutive days.

Discussion

In this study, pigs treated for M. hyopneumoniae-induced SRD with a single intramuscular dose of DRAXXIN showed not only improved therapeutic responses but also positive effects on weight gain and feed consumption efficiency. Compared with saline-treated control pigs, DRAXXIN-treated pigs had lower mortality (8.7 per cent versus 4.2 per cent, respectively) and had a higher proportion of pigs returning to normal respiratory health. At 10 days after treatment, 11% and 24 per cent more DRAXXIN-treated pigs scored “normal” for attitude/depression and respiratory character, respectively, compared with saline-treated control pigs. The observation showing significant (P = 0.0121) improvements in ADG during the study is consistent with weight gain improvements recorded in previously published assessments of the effectiveness of DRAXXIN for the treatment of SRD associated with M. hyopneumoniae infection.26-28 In the study reported here, DRAXXIN-treated pigs also had a notably improved F:G ratio (2.78) compared with saline-treated control pigs (3.58), an indication that DRAXXIN-treated pigs were more efficient in converting feed into muscle mass than saline-treated control pigs.

Under conditions of this study, a single intramuscular dose of DRAXXIN administered at 2.5 mg/kg was effective for the treatment of experimentally-induced SRD associated with a contemporary US isolate of M. hyopneumoniae.

DRAXXIN Injectable Solution was approved in the US for the treatment of SRD associated with M. hyopneumoniae in December 2007. The new label indication further distinguishes the antimicrobial as a significant advance for treating respiratory disease in swine. Previously licensed for the treatment of Actinobacillus pleuropneumoniae, Pasteurella multocida, Bordetella bronchiseptica, and Haemophilus parasuis, DRAXXIN provides an effective one-dose alternative to repeat-treatment regimens for controlling five key bacterial pathogens associated with the SRD complex. DRAXXIN is rapidly dispersed from the injection site and plasma, and rapidly arrives in the lungs where organisms associated with SRD congregate, and then is slowly eliminated from the lungs. DRAXXIN extends the period of antimicrobial treatment during times of stress and/or continued pathogen exposure. 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. 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 efficacy of DRAXXIN in a reproducible SRD challenge model using a recent US M. hyopneumoniae field isolate. This information combined with the results of previous reports demonstrating clinical efficacy in SRD associated with M. hyopneumoniae24-28 provides practitioners with additional evidence for evaluating the suitability of using injectable single-dose DRAXXIN therapy to treat primary or secondary swine pneumonias due to M. hyopneumoniae.

The following key attributes of DRAXXIN suggest that the novel antimicrobial meets the needs of producers and veterinarians alike:

  • Injectable dosing with single-administration antimicrobials like DRAXXIN ensures delivery of a full therapeutic dose as opposed to oral medications where the amount of drug delivered is highly variable and often subtherapeutic.
  • Under field conditions, the benefits of treatment with DRAXXIN extend beyond the immediate clinical response.
    • Following administration of a single dose, tulathromycin reaches maximum plasma concentration within 15 minutes
    • Within 12 hours of dosing, tulathromycin reaches peak lung concentrations and is slowly released from lung tissue, providing persistent exposure of pathogens to drug
    • Re-infections are less likely than with other shorter acting anti-infectives
  • The single-dose treatment regimen provides labor savings and improves dosing compliance compared with orally administered and multi-dose injectable programs.
  • One-dose administration also contributes to improved animal welfare and reduced stress as sick pigs need be handled and injected only once.
  • The antimicrobial’s unique activity spectrum covers five of the most important bacterial pathogens causing swine respiratory disease.
  • The M. hyopneumoniae label indication provides a new option to treat complex SRD associated with five major bacterial pathogens of swine (A. pleuropneumoniae, P. multocida, B. bronchiseptica, H. parasuis, and M. hyopneumoniae).7,10,11

References

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  15. Hannan PCT, O’Hanlon PJ, Rogers NH. In vitro evaluation of various quinolone antibacterial agents against veterinary mycoplasmas and porcine respiratory bacterial pathogens. Res Vet Sci. 1989;46:202-211.

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  17. Kobisch M, Friis NF. Swine mycoplasmoses. Rev Sci Tech. 1996;15:1569-1605.

  18. Ross RF. Evaluation of tiamulin for treatment of mycoplasmal pneumonia in swine. J Am Vet Med Assoc. 1988;193:441-446.

  19. Vicca J, Maes D, Jonker L, de Kruif A, Haesebrouck F. Efficacy of in-feed medication with tylosin for the treatment and control of Mycoplasma hyopneumoniae infections. Vet Rec. 2005;156:606-610.

  20. Hannan PCT, Windsor GD, de Jong A, Schmeer N, Stegemann M. Comparative susceptibilities of various animal-pathogenic mycoplasmas to fluoroquinolones. Antimicrob Agents Chemother. 1997;41:2037-2040.

  21. Meyns T. Highly and Low Virulent Mycoplasma hyopneumoniae Isolates: Transmission and Interaction with the Respiratory Tract [Ph D thesis]. Ghent, Belgium: Faculty of Veterinary Medicine, Ghent University; 2007.

  22. Benchaoui HA, Nowakowski M, Sherington J, et al. Pharmacokinetics and lung tissue concentrations of tulathromycin in swine. J Vet Pharmacol Therap. 2004;27:203-210.

  23. Evans NA. DRAXXIN®: a novel triamilide antibiotic for swine respiratory disease. Proc American Association of Swine Veterinarians 2005:217–220.

  24. Nanjiani IA, McKelvie J, Benchaoui HA, et al. Evaluation of the therapeutic activity of tulathromycin against swine respiratory disease on farms in Europe. Vet Ther 2005;6(2):203- 213.

  25. Nutsch RG, Hart FJ, Rooney KA, et al. Efficacy of tulathromycin injectable solution for the treatment of naturally occurring swine respiratory disease. Vet Ther. 2005;6:214-224.

  26. McKelvie J, Hart FJ, Morgan JH, et al. Comparative efficacy of tulathromycin injectable solution (DRAXXIN®) for the treatment of experimentally induced respiratory infections in swine. Proc American Association of Swine Practitioners 2005:221-222.

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  28. Data on file, Pfizer Inc, Study 1121C-60-04- 230.

March 2009