PHARMACOKINETIC STUDIES ON TULATHROMYCIN IN CONTROLLING RESPIRATORY DISEASES IN HEALTHY AND FEBRILE FEEDLOT CALVES

Dept of Pharmacology,

Animal Health Research Institute, Tanta provincial lab.

Pharmacokinetic studies on tulathromycin in controlling respiratory diseases in healthy and febrile feedlot calves                             

(With 2 Tables and One Figure)

By

W.M.A. El-Sheikh

(Received at 14/6/2011)

دراسات فارماکوکينيتيکية على التلاثرومايسين في عجول التسمين

السليمة والمحمومة

وجيه مصطفي عبد السلام الشيخ

أجريت هذه الدراسة على المسار الحرکي لعقار التلاثرومايسين في عجول التسمين السليمة والمحمومة ، حيث تم حقن جرعة واحدة من العقار تحت الجلد 5‚2 مليجرام/کجم في عدد 10 من العجول (عدد 5 سليمة وعدد 5 محمومة) تتراوح أعمارها من 4-6 أشهر وتم جمع عينات من مصل الدم لقياس مستوى الدواء بها. أظهرت النتائج أن امتصاص التلاثرومايسين کان سريع ومکثف ووصل لأعلى مستوى في مصل الدم خلال ساعتين بعد الحقن ، حيث کان أعلى ترکيز في السيرم 0.65 و 0.59 ميکروجرام/مل بعد 2 و2ساعة وفترة نصف العمر 25.17 و 24.14ساعة للعقار في العجول المحمومة والسليمة على التوالي. کما أظهرت النتائج أن ترکيز التلاثرومايسين  يظل في مصل الدم مساو أو أعلي من أقل ترکيز مثبط لـ 90% من الميکروبات الرئيسية المسببة للأمراض التنفسية في العجول (المونيميا هيمولتکا- باستريلا مالتوسيدا- هستوفلاس سيموني- ميکوبلازما بوفز) لمدة 7 أيام وفي أنسجة الرئة لمدة 10أيام على الأقل خصوصا في العجول المحمومة.

SUMMARY

The present study was carried for studying the pharmacokinetic of tulathromycin in healthy and febrile feedlot calves. A single dose of tulathromycin (2.5 mg/kg b.w.) was injected subcutaneously to ten Friesian beef calves (5 healthy and 5 febrile) 4 to 6 months of age, weighing 110 to 128 kg. Blood samples were collected after injection from all calves for determination of the concentrationsof the drug by HPLC. Results showed that, the drug was rapidly absorbed reaching the highest plasma concentrations during 2 hours after dosing where C_max, t_1/2el, AUC and MRT was significantly higher in diseased (0.65h; 25.17h, 23.62 µg h ml^_1 and 35.98h) than in healthy calves (0.59h; 24.14h, 20.78µg h ml^_1 and 34.58h) respectively. Tulathromycin concentrations were maintained in the serum of injected calves equal to or higher than the MIC₉₀ of major BRD pathogens (Mannheimia haemolytica, Pasteurella multocida, Histophilus somni, and Mycoplasma bovis) for about 7 days and in lung tissues at least 10 days especially in febrile ones.

Key words: Tulathromycin, respiratory diseases, feedlot calves.

INTRODUCTION

Bovine respiratory disease (BRD) is responsible for over 20% of pre-weaning and 50% of post-weaning calf deaths, for example annually; the U.S. feedlot industry faces enormous losses attributed to bovine respiratory disease (Martin et al., 1989). Approximately 75% of the morbidity and up to 70% of the mortality observed in U.S. feedlot cattle is linked to BRD (USDA-APHIS, 1994; Edwards, 1996). Economic losses attributed to BRD includes death loss, therapeutic treatment cost (Martin et al., 1982; Perino, 1992), performance loss (Bateman et al., 1990; Morck et al., 1993), and reduced carcass value (McNeill et al., 1996; Larson, 2005). Management of this disease complex involves both metaphylactic and therapeutic administration of parenteral antimicrobials. Several studies have demonstrated the therapeutic efficacy of various antimicrobials, including florfenicol, tilmicosin, trimethoprim sulfadoxine, ceftiofur, and oxytetracycline, for the treatment of UF/BRD while few ones carried on tulathromycin (Jim      et al., 1992; Hoar et al., 1998).

Tulathromycin is a triamilide antibiotic that maintains therapeutic concentrations for an extended period of time and approved for treatment of respiratory diseases in cattle and swine and is occasionally used in goats (Young et al., 2011). Few studies shows that a single dose of tulathromycin is effective in treating cattle and swine with respiratory disease and in preventing high-risk cattle from developing respiratory disease (Evans et al., 2005). It is a new promising bactericidal semi-synthetic macrolide antibiotic specifically developed for the treatment and prevention of UF/BRD (Kilgore et al., 2005; Nutsch et al., 2005). And added it is highly effective, as a single antimicrobial dose indicated at high risk for control of BRD in cattle caused by Mannheimia haemolytica, Pasteurella multocida, Histophilus somni, and Mycoplasma bovis.

So this investigation was carried for studying the pharmacokinetic profiles of a single dose from tulathromycin; a novel antibacterial, when injected in healthy and febrile feedlot calves in maintaining serum level above MIC₉₀ recorded for main BRD pathogens isolated from such infected calves for adequate time.

MATERIALS AND METHODS

A-Drug:-

Tulathromycin:- (Draxxin; Pfizer Ltd) a semi-synthetic macrolide antibiotic of the subclass; triamilide. Each mL of DRAXXIN contains 100 mg of tulathromycin, injectable solution indicated for the treatment of BRD. Itsin vitro activity has been previously demonstrated against the main pathogens associated with BRD(Carbon, 1998).

B- Animals:-

Ten Friesian (5 healthy, 5 febrile, temp ≥ 40°C) beef calves 4 to 6 months of age, weighing 110 to 128kg, fed antibiotic free ration, not received any drug for at least three weeks were underwent to this study. All animals were injected once subcutaneously, by DRAXXIN (2.5 mg tulathromycin/kg BW).

C- Sampling:-

            Blood samples were collected from all calves just prior to the drug injection, 1/2, 1, 2, 3, 6, 12, 18h, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11 days post injection. Blood plasma was stored at –20°C until estimation of drug concentrations. Tulathromycin concentrations were measured by HPLC with UV detector with quantitation limits of 0.01 mg/ml according methods described by )Nowakowski et al., 2004).

D- Statistical analysis:-

Statistical analysis was carried out using "t" test according to SAS (1999), and the kinetic parameters (C_max, t_max, t_1/2el, and AUC) were calculated according to Baggot (1977).

RESULTES

Tulathromycin concentrations in serum shown that the drug was rapidly absorbed reaching the highest plasma concentrations during two hours after dosing (Table1). Pharmacokinetic parameters for the drug used in this study were shown in Table (2).

Table 1: Mean tulathromycin plasma concentrations (mg/ml) following a single subcutaneous dose of Draxxin at 2.5mg/kg in healthy (n=5) and febrile (n=5)feedlot calves.

Table 2: Pharmacokinetic parameters from noncompartmental analysis of tulathromycinfollowing a single subcutaneous dose of Draxxin at 2.5mg/kg in healthy and febrile feedlot calves.

    * P< 0.05;         ** P≤ 0.001 when compared to healthy animals

     N.B. The C_max (maximum plasma concentration) and T_max (time of maximum plasma concentration) were taken directly  

     from the curve.  T_½: is the half-lives of drug. T_max: time to peak concentration. C_max: maximum plasma concentration.; AUC_0-∞: the area under the plasma concentration-time curve from zero to infinity. AUMC: area under the moment curve. Cl_B: total body  clearance. B: zero time intercept of the regression line of the elimination phase. β: IS the first-order rate constants related to the elimination phases. MRT: mean residential time. V_c : volume of central compartment. V_d(area): volume of distribution based on the total area under the plasma drug concentration time curve. **p≤ 0.05, ***p≤ 0.001.

Fig. 1: Mean tulathromycin plasma concentrations (mg/ml) following a single subcutaneous dose of Draxxin at 2.5mg/kg in healthy (n=5) and febrile (n=5) feedlot calves.

DISCUSSION

Bovine veterinarians and beef cattle producers know there is no time to wait when a calf has BRD, especially valuable dairy replacement heifers,  so they all time search for fast-acting, broad-spectrum BRD therapy killing major BRD-causing bacteria (Mannheimia haemolytica, Pasteurella multocida and Histophilus somniand Mycoplasma bovis) to be the first-line for treatment. And if a single dose is sufficient to save time, labor, costs, reduces animal stress as well as the risk of workers and animals in such cases it considered a drug of choice. So Draxxin as a single dose, fast-acting and broad-spectrum BRD therapy may consider an ideal option in such cases.    

The present study showed that tulathromycin was rapidly absorbed and during two hours after dosing reaching the highest plasma concentrations which significant higher in febrile than in healthy calves where C_max was 0.65 ± 0.03 and 0.59 ± 0.04 µg mL^-1, while T_max  were 2.00 ± 0.20 and 2.00 ± 0.45h in febrile and healthy calves respectively. Nearly similar results in healthy calves were recorded by Young et al. (2011) where they recorded C_max 0.633±0.3 µg /ml and Cox et al. (2010) where T_max was 3h. But the present results were not completely similar to that reported by Evans et al. (2005) where they foundC_max 0.489µg/ml but T_max was shorter (0.5h) after injection of tulathromycin to feeder calves 2.5 mg /kg b.w. And added linear pharmacokinetics for tulathromycin is observed, rapid release and absorption from the injection site, extensive distribution and slow elimination. Furthermore, in this study t_1/2el was 25.17 ± 1.33 and 24.14 ±1.24 in febrile and healthy calves respectively that shorter than results of Cox et al. (2010) for t_1/2el that was 64 h; Evans et al. (2005) where t_1/2el 2.75 days and EMEA (2004) recorded t_1/2el more than 70 hours for tulathromycin in plasma of healthy calves.   

Thediseaseconditions are known to markedly alter the disposition of antimicrobials (Burrows, 1985). Fever is one of the most common manifestations of infectious diseases and is reported to induce biochemical and physiological alterations in the cells (Van-Miert, 1987; Lohuis et al., 1988). It may affect the absorption, distribution, and elimination of drugs and these changes in pharmacokinetics vary with the animal species, antibiotic and agent that cause a febrile reaction (Bojana, 1999).This study illustrated, t_1/2el, AUC and MRT was significantly higher in diseased (25.17h, 23.62 µg h ml^_1 and 35.98h) than in healthy calves (24.14h, 20.78µg h ml^_1 and 34.58h). These significant variations between t_1/2el, AUC and MRT in febrile and healthy calves in the present study were in agreement with the results ofIsmail and El-Kattan (2007) following i.m. administration of marbofloxacin in healthy and Mannheimia haemolytica infected calves. They found t_1/2el, AUC and MRT were significantly longer in diseased calves (8h, 22.24µg h ml^_1 and 12h) than in healthy ones (4.7h; 12µg h ml^_1 and 7.4h), respectively. They added the C_max/MIC and AUC₂₄/MIC ratios were significantly higher in diseased (13.0–64.4 and 125–618 h) than in healthy calves (8–38.33 and 66.34–328 h). And concluded (C_max/MIC, AUC/MIC and T ≥ MIC) indicate the excellent pharmacodynamic characteristics of the drug in diseased calves, which can be expected to optimize the clinical efficacy and minimize the development of resistance. Moreover, the present findings are consistent with those reported for other fluoroquinolones in febrile goats (Jha et al., 1996; Rao et al., 2000), but it was inconsistent with that reported in M. haemolytica infected calves treated with erythromycin (Burrows, 1985). In this respect Baggot (1980) mentioned that the elimination half-life (t_1/2b) and mean residence time (MRT) of marbofloxacin were longer in pneumonic calves than in healthy ones. This delay in the elimination of the drug may be the result of renal and/or hepatic abnormalities caused by fever and endotoxin production accompanied with M. haemolytica infection (Hodgson et al., 2003). Endotoxin produces direct tubular cell injury as well as some functional changes in the kidney, including a decrease in the renal blood flow and glomerular filtration rate, and changes the intrarenal hemodynamics (Jernigan et al., 1988). In addition, endotoxin causes metabolic acidosis and reduces urinary pH in febrile animals (Baggot, 1980; Salam Abdullah and Baggot, 1984; Spurlock     et al., 1985; Van-Miert, 1990). It is probable that the decrease in glomerular filtration rate and metabolic acidosis induced by endotoxin plays an important role in the reduction of body clearance of marbofloxacin and consequently increases its elimination half-life (Waxman et al., 2003). This decrease in body clearance has been previously observed for danofloxacin and marbofloxacin in pneumonic calves (Apley and Upson, 1993; Thomas et al., 1994b).

As previously known, the main four pathogens associated with BRD feedlot calves are Mannheimia haemolytica, Pasteurella multocida, Histophilus somni and Mycoplasma bovis (Mosier, 1997; Carbon 1998; Donachie, 2000; Loneragan et al., 2001; Ames et al., 2002; Nicholas and Ayling, 2003). And its recorded MIC₉₀ with tulathromycin are 2.0, 1.0 and 0.5-2µg/ml (Nightingale, 1997; Godinho et al., 2005a; Kilgore et al., 2005) and 1µg/ml (Godinho et al., 2005b;  Kilgore et al., 2005) respectively.

In vitro the activity of tulathromycin was demonstrated by Carbon (1998) against Mannheimia haemolytica, Pasteurella multocida, Histophilus somni and Mycoplasma bovis. In vivo the clinical efficacy of tulathromycinwasdocumented by Nutsch et al. (2005); Rooney et al. (2005); Skogerboe et al. (2005) in their studies for control and treatment of BRD in cattle caused by Mannheimia haemolytica, Pasteurella multocida, Histophilus somni and Mycoplasma bovis and concluded accumulation of tulathromycin in lung tissues. Previously, Nightingale (1997) noted extensive distribution for tulathromycin into body tissues; especially in lung tissues, EMEA (2004) recorded t_1/2el in plasma more than 70 hours versus 8 days for lung tissue and concluded this was evident from lung/plasma concentration ratios and indicated accumulation of the drug in lung tissues. Likewise Evans et al. (2005) recorded C_max 0.489 and 4.1µg/ml, t_1/2el 2.75 and 8.75 days and AUC_0-48h was 16.7 and 1230 µg-h/ml in serum and lung tissues (the therapeutic target organ) of cattle respectively and lung_AUC/plasma_AUC was 73.7 ratio. They attributed this long elimination half-life to extensive volume of distribution (more than 10 l/kg) for this drug which has linear pharmacokinetics characters. Likewise Galer et al. (2004); Nowakowski et al. (2004) detected the therapeutic concentrations of tulathromycin in lung tissue for 10 to 15 days after a single dose.

Based on the present study and all these mentioned results, the expected levels in lung tissues for tulathromycin were maintained equal to or higher than MIC₉₀ of major BRD pathogens (specially in fibril calves) at least 10 days or more that considered enough for treating BRD caused by that bacteria sensitive in vitro to the drug. This expectation supported by Nowakowski et al. (2004) when said the apparent elimination half- life of tulathromycin in bovine lung tissue is 8 days, and mean concentrations of approximately 3.0, 1.9, and 1.2 µg/g were attained at 7, 10, and 15 days, respectively.

Although the relationship between tulathromycin and the characteristics of its antimicrobial effects has not been characterized, as a class, macrolides tend to be primarily bacteriostatic, but may be bactericidal against some pathogens Nightingale (1997). They also tend to exhibit concentration independent killing; the rate of bacterial eradication does not change once serum drug concentrations reach 2 to 3 times the MIC of the targeted pathogen. And added under these conditions, the time that serum concentrations remain above the MIC becomes the major determinant of antimicrobial activity. Furthermore, macrolides also exhibit a post-antibiotic effect (PAE), the duration of which tends to be both drug and pathogen dependent. So by increasing the macrolide concentration and the exposure time, the PAE will increase to some maximal duration and these two variables, concentration and exposure time, drug concentration tend to be the most powerful determinant of the duration of PAE(Nightingale, 1997).  

Finally can concluded, the drug has a big advantage of the lack of daily handling of the animal with good serum and lung tissues concentrations (about 10 days or more in lung tissues especially in fibril ones) when injected once as a single dose. In keeping with this line,Schnepper, (2006) concluded a single subcutaneous dose of Draxxin will produce an antibiotic level in lung tissues for up to 15 days. This makes it very appealing to the producer, to be able to give one injection upon arrival at a facility and the antibiotic last for 15 days. And added Draxxin goes through a needle very easily and the product is stable at room temperatures for 36 months. Evans et al. (2005); Godinho et al. (2005b); Technical Bulletin (2006) concluded a single dose of DRAXXIN^® (tulathromycin) injectable solution the only antibiotic approved and highly effective for treatment of BRD associated with Mycoplasma bovis.Technical Bulletin (2006) concluded the DRAXXIN^® (tulathromycin) injectable solution administered as a single subcutaneous injection was safe and effective for the treatment of experimentally induced Mycoplasma bovis respiratory infection in calves.  

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