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Draxxin® (tulathromycin) Injectable Solution: Duration of Effectiveness in an Actinobacillus Pleuropneumoniae Challenge Model

by 5m Editor
23 June 2008, at 12:00am

By Alan Scheidt, DVM, MS Pfizer Animal Health, Pfizer Inc. Published in a Pfizer Animal Health Technical Bulletin.

Executive Summary

An Actinobacillus pleuropneumoniae (APP) challenge model was used to evaluate the duration of antibiotic effectiveness of DraxxinR Injectable Solution against clinical disease caused by intranasally administered APP serotype 5. Draxxin Injectable Solution was administered intramuscularly at 2.5 mg/kg of body weight at intervals of 11, 9, 7, 5, and 3 days before challenge. The primary decision variable was mortality, and the secondary variable was percentage of total lung lesions. The APP challenge model produced peracute, severe pleuropneumonia. Pigs given Draxxin Injectable Solution at 9, 7, 5, and 3 days prior to challenge had a significantly (P<0.05) lower mortality rate than the control group (see figure below). Additionally, lung lesion data showed significant (P<0.05) differences between animals treated with Draxxin Injectable Solution and untreated animals at 3 and 5 days following treatment and approached significance at 7 days after treatment. Collectively, the results demonstrated the extended therapeutic activity of a single dose of Draxxin Injectable Solution and provided clinical validation of the existing pharmacokinetic profile of Draxxin Injectable Solution.

Draxxin Injectable Solution contains the active ingredient tulathromycin, the first member of a new macrolide class of antimicrobials known as triamilides (semisynthetic derivatives of erythromycin), which have been developed exclusively for use in veterinary medicine. The product is formulated in an aqueous vehicle for intramuscular (IM) injection as a ready-to-use (RTU) single dose (2.5 mg/kg) that provides a full course of treatment against key bacterial pathogens associated with the swine respiratory disease (SRD) complex. In the U.S., approval has been granted for treatment of SRD associated with Actinobacillus pleuropneumoniae, Pasteurella multocida, Bordetella bronchiseptica and Haemophilus parasuis.

The pharmacokinetic behavior of Draxxin Injectable Solution in swine was demonstrated in two studies following a single 2.5 mg/kg body weight dose (Table 1).1 In the first study, tulathromycin achieved similar IM and intravenous (IV) plasma concentrations; was rapidly released from the IM injection site, reaching maximum plasma concentration in less than one hour; and was extensively distributed with an approximate 88% bioavailability. In the second study, tulathromycin achieved lung concentrations 61 times higher than the plasma concentrations; reached a peak lung concentration of 3.47 ìg/mL within 24 hours of dosing, far surpassing the mean peak plasma concentration of 0.581 ìg/mL; and was slowly released from lung tissue, with a an elimination half-life (t1/2) of approximately 6 days (142 hours). The high concentrations and extended localization of tulathromycin in lung tissue are presumed to account for the high levels of efficacy that have been observed from a single dose of Draxxin Injectable Solution.2-4 The study presented here was conducted to confirm the clinical relevance of Draxxin’s extended pharmacokinetic profile by evaluating the duration of effectiveness of a single IM injection of 2.5 mg/kg body weight given at different times prior to intranasal challenge with a highly virulent strain of Actinobacillus pleuropneumoniae (APP) serotype 5. The study was conducted under close veterinary supervision and was pre-approved by an Institutional Animal Care and Use Committee.



Study Overview: Design, Challenge Model, Assessments, and Analysis

Study Design

A total of 240 clinically healthy female and castrated male crossbred pigs, approximately 6 weeks of age, were purchased for the study. Upon arrival at the study site, the animals were randomly assigned to one of six treatment groups according to a generalized block design (Table 2) and housed in 20 pens of 12 pigs each (2 per treatment group). A 10-day acclimation period preceded initiation of the study. On site processing excluded vaccinations against APP and porcine respiratory and reproductive syndrome (PRRS). Pigs assigned to receive Draxxin Injectable Solution (groups T02 through T06) were administered a single 2 mg/kg body weight dose by deep IM injection in the neck, and pigs in the control group (T01) were left untreated. No additional medication with systemic antimicrobial or anti-inflammatory agents was allowed during the study. In accordance with the study protocol, pigs requiring therapy for conditions other than APP were to be removed from the investigation and analysis.

Challenge Model

On study day 0, all pigs in all treatment groups (T01 through T06) were challenged with a 4 mL (2 mL/nostril) broth culture containing an APP serotype 5 isolate. Administered by way of rapid intranasal inoculation during inhalation, the challenge inoculum contained 2.0 x 108 colony forming units (CFU)/mL, or a total of 8.0 x 108 CFU per pig. The tulathromycin minimum inhibitory concentration (MIC) of the isolate was 8.0 µg/mL (ambient air) and 32.0µg/mL (5% carbon dioxide).

Assessments

Each pig was observed daily for general health, and respiratory and attitude scores were assigned on days 1, 3, 5, and 7. Respiratory scores were assigned using the following scale:

0 = normal rate and character
1 = slightly increased rate and/or abnormal character
2 = moderately increased rate and/or character
3 = severely increased rate and markedly abnormal character (e.g., openmouth breathing)

Attitude scores were assigned using the following scale:

0 = normal: bright, alert, and responsive, with normal appetite
1 = mild depression: reduced responsiveness and/or decreased appetite
2 = moderate or marked depression: may be reluctant to stand
3 = severely depressed or moribund: unable to stand without assistance

Moribund animals were euthanized for humane reasons and submitted for necropsy examination. All remaining study pigs were euthanized on day 7 and submitted for necropsy examination. With the exception of personnel administering test articles and study monitors, all individuals participating in the study were masked to treatments until the end of the animal phase of the study.

Study Analysis

The primary variable was mortality (1 = died; 0 = survived), which was analyzed using the GLIMMIX procedure in SAS®‚ The procedure used the binomial error with a logit link. The model included the fixed effect of treatment and the random effects of pen and residual. The experimental unit for treatment was the animal.

The secondary variable was percentage of total lung lesions. Lesions were both visually examined and physically palpated to determine the amount of consolidation or other lesions in each of the lobes. Percent gross involvement of each lung lobe was weighted (left cranial 10%, left middle 10%, left caudal 25%, right cranial 10%, right middle 10%, right caudal 25%, and accessory 10%), summed across lobes to yield the percentage of total lung with lesions, and analyzed using a linear mixed model. The model included the fixed effect of treatment and the random effects of pen and residual. The experimental unit for treatment was the animal. Lesion scores from all animals were included in the analysis, regardless if they were recorded as a death or were euthanized on day 7.

Back-transformed least squares (LS) means were used as estimates of treatment means for both mortality and percentage of total lung lesions. Standard errors of LS means were estimated, and 95% confidence intervals were constructed. If the treatment main effects were significant, a priori contrasts were used to assess treatment differences at the 5% level of significance (P<05).

Results

Mortality

The APP challenge was successful, causing peracute, severe pleuropneumonia resulting in the death and removal of 31 animals. The 20.0% (8/40) mortality rate for animals treated with Draxxin on day -11 (group T02) was not significantly (P>.05) different from the mortality rate of 32.5% (13/40) for animals in the untreated control group. Mortality rates for pigs in all remaining Draxxin groups (T03 through T06) were significantly (P<0.0113) different from that of the untreated control group. Pigs treated with Draxxin on each of days -9, -7, or -5 had mortality rates of 7.5% (3/40), whereas pigs treated on day-3 had the lowest mortality rate (2.5%, 1/40) observed in the study. The mortality rate of 2.5% for pigs treated with Draxxin on day -3 was also significantly (P = 0.0398) lower than the mortality rate of 20.0% for pigs treated with Draxxin on day -11. All other treatment comparisons for mortality were not significant (Figure 1).

Lung Lesion Scores

No significant (P>.05) differences were observed in the weighted percentage of total lung lesions between pigs treated with Draxxin on days -11 (29.6%), -9 (20.2%), and -7 (18.4%) and pigs in the untreated group (27.5%). Pigs treated with Draxxin on either day -5 (16.8%) or day -3 (10.5%) had weighted lung lesions that were significantly (P<0.0282) less than pigs in the untreated control group (27.5%). The weighted percentage of total lung lesions for pigs treated with Draxxin on either day -7 (18.4%), -5 (16.8%), or -3 (10.5%) was also significantly (P<0.0214) less than that of the pigs treated on day -11 (29.6%). Additionally, pigs treated with Draxxin on day -3 (10.5%) had weighted lung lesions that were significantly (P=0.0214) less than those of pigs treated on day -9 (20.2%). All other treatment comparisons for lung lesions were not significant (Figure 2).

Discussion

Lung lesion data from this APP challenge study showed significant differences between untreated controls and Draxxin-treated pigs at 3 and 5 days following treatment and approached significance at 7 days. Mortality data indicate that the duration of antimicrobial effectiveness of Draxxin in swine against clinical disease caused by intranasal inoculation of APP serotype 5 was up to 9 days. Results of this study are consistent with those achieved in a previous study in which Draxxin administered intramuscularly at 2.5 mg/kg provided effective singledose treatment of pneumonia caused by an experimental challenge with A. pleuropneumoniae.5 In that earlier study, treatment with Draxxin compared favorably to a 3-day regimen of Naxcel® (ceftiofur sodium, Pfizer Animal Health), a well-established therapy for respiratory disease in swine caused by APP (Figure 3). Additional clinical assessments comparing cure rates obtained with a single dose of Draxxin Injectable Solution and multiples doses of Naxcel, Baytril® 5% Injection (enrofloxacin, Bayer Animal Health), Nuflor® Swine Injectable (florfenicol, Schering-Plough Animal Health), or Tiamutin® (tiamulin, Novartis Animal Health) also showed high levels of efficacy against clinical cases of bacterial respiratory disease in commercial swine operations in Europe and North America.3,4,6

The prolonged drug levels in lung and other tissue are thought to result from the intrinsically slow rate at which tulathromycin is metabolized. As previously demonstrated in a bioavailability study conducted in pigs, drug concentrations in the lung remained at levels higher than 1.2 ìg/g for 10 days.1 Thus, time of bacterial exposure to tulathromycin is increased, which likely optimizes the drug’s antibacterial activity because with macrolides efficacy results from time of exposure above the MIC, as opposed to peak plasma concentration. The long half-life of tulathromycin allows for achievement of therapeutic effects with only a single dose and has the key practical and economic advantage of reducing the need for repeat handling of sick, debilitated pigs, a factor that could improve client compliance with recommended dosing regimens.

Conclusion

Collectively, study results provide clinical validation of the existing pharmacokinetic data for Draxxin Injectable Solution and underscore several of the important practical benefits of product use, namely, improved convenience, dosing compliance, and animal welfare, plus a potential reduction in labor costs. Intramuscular injection in swine may produce transient local tissue reactions which persist beyond the five-day withdrawal period.

References

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

2. Evans NA, Skogerboe TL, Mann DD, et al. Therapeutic efficacy of tulathromycin against naturally occurring bovine respiratory disease [poster abstract 511]. Poster Abstracts Proc 23rd World Buiatrics Congress 2004;66-67.

3. 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(2):214-224.

4. 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.

5. McKelvie J, et al. Comparative efficacy of tulathromycin injectable solution (Draxxin) for the treatment of experimentally induced respiratory infections in swine. American Association of Swine Veterinarians. Toronto, 2005.

6. McKelvie J, Morgan JH, Nanjiani IA, et al. Evaluation of tulathromycin for the treatment of pneumonia following experimental infection of swine with Mycoplasma hyopneumoniae. Vet Ther 2005;6(2):197-202.

January 2007