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Compatibility of a Combination of Tiamulin plus Chlortetracycline with Salinomycin in Feed During a Long-Term Co-Administration in Broilers

K. M. S. Islam^*,1, S. Afrin^*, M. J. Khan^*, P. M. Das, M. M. Hassan, M. Valks, D. G. S. Burch^# and G. M. Pesti^||

^* Department of Animal Nutrition, and Department of Pathology, Bangladesh Agricultural University, Mymensingh 2202, Bangladesh; Novartis Animal Health (Bangladesh) Ltd., House 50, Road 2A, Dhanmondi R.A., Dhaka 1209, Bangladesh; Novartis Animal Health, CH 4058 Basel, Switzerland; ^# Octagon Services Ltd., Old Windsor, Berkshire, SL4 2NR, United Kingdom; and ^|| Department of Poultry Science, University of Georgia, Athens 30602-2772

¹ Corresponding author: kmsislam1{at}yahoo.com

	ABSTRACT

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The pleuromutilin antibiotic tiamulin (TIA) is known to produce a negative interaction in broilers when administered in combination with several ionophore anticoccidials such as salinomycin (SAL). Chlortetracycline (CTC), when administered simultaneously with TIA, has demonstrated a synergistic antimicrobial effect. A 35-d feeding study was conducted in cages to evaluate the interaction effect of a combination of TIA plus CTC at increasing inclusion levels when administered concurrently with SAL. A total of 200 one-day-old broiler chicks were distributed into 4 groups, and each group consisted of 5 cages containing 10 birds in each. Replicate cages were distributed randomly. Feed for all groups contained 60 ppm SAL, but additionally, 0, 20, 30, and 50 ppm TIA and 0, 60, 90, and 150 ppm CTC were included, respectively. Several enzymes (creatine phosphokinase, lactate dehydrogenase, and aspartate aminotransferase) were determined from blood samples taken at the end of the trial. Blood samples were also collected during d 0, 19, and 35 and were analyzed for antibody titers against Mycoplasma gallisepticum and Mycoplasma synoviae. Necropsy of a few birds (20, 8, 20, 12, and 12 on d 7, 14, 21, 28, and 35, respectively) was conducted at weekly intervals. Results indicated that there was a significant depression of weight gain (P < 0.05) in group 4 (TIA 50 + CTC 150) only. The final weights were 1,809 ± 130, 1,859 ± 52, 1,703 ± 47, and 1,617 ± 98 g for groups 1 (TIA 0 + CTC 0), 2 (TIA 20 + CTC 60), 3 (TIA 30 + CTC 90), and 4 (TIA 50 + CTC 150), respectively. However, feed intake and feed conversion efficiency (g of weight gain/kg of feed intake) were not significantly affected in any of the groups. There was no dose-related adverse effect on mortality or clinical signs exhibited during the trial, and this was supported by necropsy. Maternally derived antibodies against M. gallisepticum were present at the beginning of the trial but disappeared within 19 d. Otherwise, there was no apparent infection by M. gallisepticum or M. synoviae throughout the trial. The results demonstrate that 50 ppm TIA plus 150 ppm CTC along with 60 ppm SAL caused only a depression of growth, but no adverse signs of interaction were detected. Taking into consideration all the aspects of the cost of production, the 20 ppm TIA plus 60 ppm CTC was the most cost-effective level to administer continuously with 60 ppm SAL via the feed, but it would be important to do an additional study using an artificial infection with M. gallisepticum or M. synoviae to know whether this inclusion rate would be sufficient to protect against an infectious challenge.

Key Words: broiler • compatibility • chlortetracycline • health • performance

	INTRODUCTION

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Coccidiosis, a protozoal disease caused by Eimeria spp., in poultry is prevented by the widespread use of coccidiostats as feed additives. They are added to the feed of broilers from 1 d of age until near the end of production, with a withdrawal period for consumer protection of 3 to 5 d before slaughter. Among the ionophore coccidiostats, salinomycin (SAL) has a broad spectrum of anticoccidial activity against Eimeria spp. at a dietary inclusion level of 60 ppm and is commonly used.

Another drug named tiamulin (TIA, Denagard, Novartis Animal Health) is a semisynthetic derivative of pleuromutilin and is effectively used in the treatment of airsacculitis, in chickens caused by Mycoplasma spp. Infected animals become more susceptible to different viral infections such as infectious bronchitis and Newcastle disease as well as bacterial pathogens, such as Escherichia coli (coli septicemia). This will lead to reduced growth, impaired feed conversion efficiency, and an increased rate of morbidity and mortality.

Interactions between the ionophore anticoccidials and the antibiotic TIA are well known in chickens and turkeys. The cause was thought to be due to the competitive blocking of the metabolism of the ionophore in the liver by TIA (Meingassner et al., 1979), resulting in an effective overdose of the ionophore. Burch and Stipkovits (1993) showed that TIA co-administered with chlortetracycline (CTC) had synergistic activity against Mycoplasma gallisepticum, and levels of 30 ppm TIA added to feed did not cause any signs of interaction with SAL, monensin, or narasin (Burch and Stipkovits, 1991; Stipkovits et al., 1992, 1999). A few artificial infection trials showed that combinations of TIA and CTC in feed (Burch and Stipkovits, 1994, 1996) reduced air sac lesions and mortality caused by M. gallisepticum infections and improved the performance of the birds without inducing any signs of interaction with SAL. The purpose of this study was to confirm these findings in broiler chicks from a naturally M. gallisepticum-infected flock by the continuous and routine administration of low levels of TIA plus CTC and SAL in feed and also check for any toxic interactions in the chicks.

	MATERIALS AND METHODS

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Two hundred healthy day-old unsexed broiler chicks (Hubbard Classic) were randomly distributed in 20 cages containing 10 birds in each, and 5 cages were allocated to 1 of 4 treatment groups. The birds were handled carefully to avoid any cause of pain and injury to the birds. Group 1 comprised of control birds offered feed containing 60 ppm SAL only. The 3 treatment groups were given SAL at 60 ppm but also TIA plus CTC at increasing levels, group 2, 20 ppm TIA + 60 ppm CTC; group 3, 30 ppm TIA + 90 ppm CTC; and group 4, 50 ppm TIA + 150 ppm CTC. All the drugs were administered continuously via their respective feeds. Mash diets were fed to the birds formulated as conventional broiler feeds using corn-soy-based diet used in commercial practice following nutrient requirements as per recommended by NRC (1994).

The battery unit, in an open-air trial house, comprised 20 cages of steel wire construction and a surface area of 0.91 m² (120 cm x 76 cm) where the 10 birds were reared. Droppings were allowed to drop onto sawdust, which was spread under the cages. Electric light (double neon bulbs) illuminated the trial house over 24 h. The birds had free access to feed and water. Birds were weighed initially and at 7-d intervals. The trial house was cleaned frequently, and the birds were observed for any types of clinical signs. Dead birds were recorded, and necropsies as well as histopathology were conducted at the Department of Pathology, Bangladesh Agricultural University.

An additional 10 birds were killed at the beginning of the trial to collect blood samples to determine the titer value against Mycoplasma. On d 7, 14, 21, 28, and 35, several birds (20, 8, 20, 12, and 12, respectively; similar replicate-treatment in each stage) were selected based on cage average and were killed for necropsy and histopathology. Blood sampling was carried out (5 samples from each group) at the end of the trial (35 d) for serum enzyme tests to determine if there had been any significant muscle or liver damage associated with a TIA-ionophore interaction. Creatine phosphokinase (CPK) for muscle damage, lactate dehydrogenase (LDH), and aspartate aminotransferase (AST) levels for both liver and muscle damage were measured. Blood samples were also collected on d 19 (from the wing vein) and d 35 (from 12 killed chicks and 8 from wing vein) to determine the antibody titer levels against Mycoplasma synoviae and M. gallisepticum using both the rapid plate agglutination test (Aftab Poultry Diagonstic Lab, Bhagalpur, Bajitpur, Bangladesh) and enzyme-linked immunosorbent assay (Synbiotics Corporation, Dhaka, Bangladesh). For histological examinations, samples of liver and pectoral muscle from sacrificed birds were fixed in 10% buffered formaldehyde, embedded in paraffin wax, and sections were stained by hematoxylin and eosin.

At the age of d 4 and 14, the birds were vaccinated against infectious bursal disease via eye drop and on d 8 against Newcastle disease, following a similar method.

Initially, the raw data was organized using the computer program Excel (Microsoft Corporation, Renton, WA) and then analyzed using the SPSS 11.5 (SPSS Inc., Chicago, IL) computer program. All data were analyzed by 1-way ANOVA, and Duncan’s multiple range test was conducted to know the differences among the treatment means (Steel and Torrie, 1980).

	RESULTS

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Performance

Live weight gain was numerically greater in group 2 (20 ppm TIA + 60 ppm CTC) but not significantly different from the control group (group 1) during the fourth and fifth weeks and finally on d 35 (Table 1). Only the greatest doses of TIA at 50 ppm (group 4, 50 ppm TIA + 150 ppm CTC) showed significantly lower (P < 0.05) weight gain than control (1,569 g vs. 1,760 g; –11%). The adverse effect of TIA became evident in the fourth week of the trial. Feed intake during the whole trial was not significantly affected in any of the groups (data not shown). The feed conversion efficiency (g of weight gain/kg of feed intake) was also not significantly different among different groups (data not shown). No treatment-related pathology was found in these studies. Only 2 birds died during the 35-d trial (1.0% mortality), and both were in group 2 (20 ppm TIA + 60 ppm CTC), which did not appear to be related to the dietary treatments.

Large increases of the enzymes measured are the main indicators of drug-related toxicity. The results demonstrated that by d 35, there was a nonsignificant increase of LDH (Table 2). There were minor increases of AST values in groups 3 and 4, but CPK values in treatment groups 2 and 3 were significantly lower than the control group (group 1), demonstrating that there was no associated muscle damage from a TIA-SAL interaction.

During placement on the trial, the serum collected from the birds was positive with maternally derived M. gallisepticum antibodies. However, the maternal immunity had disappeared by d 19, because the titer values of M. gallisepticum and M. synoviae were negative. There was no apparent infection with either M. gallisepticum or M. synoviae up to the end of trial, because the M. gallisepticum and M. synoviae titers in serum were still negative on d 35. No gross or microscopic lesions were found consistent with drug treatments.

Cost of Production

Tiamulin is an expensive antibiotic, so its inclusion increases the cost per kilogram of a ration (Table 3). However, from an economic viewpoint, 20 ppm TIA along with 60 ppm CTC given in the feed continuously produced the lowest cost per kilogram of weight gain.

	DISCUSSION

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Some researchers (Frigg et al., 1983; Laczay et al., 1990; Sakar et al., 1991) found depressed feed intake due to TIA interactions with ionophores, and this just begins to appear at 50 ppm TIA and 60 ppm SAL. An additional positive effect obtained in this study is probably the combined growth effects of CTC with TIA (Burch and Stipkovits, 1991, 1993; Stipkovits et al., 1992, 1999).

The results obtained in this study do not agree with some previous findings (Stipkovits et al., 1992; Youxiang et al., 2003) in which improved feed conversion efficiency was observed with co-administration of 20 to 30 ppm TIA and 60 ppm SAL as well as 30 ppm TIA + 100 ppm CTC, but those studies were in naturally M. gallisepticum-infected birds, which were clinically affected.

Similar biochemical results were found (Stipkovits et al., 1999) in 7-d co-administration of 50 ppm TIA along with 60 ppm SAL caused slightly greater (2,659 IU) LDH values than only the SAL group (2,246 IU), but the group receiving no medication had a similar LDH value (2,613 IU). The authors found a significant increase of the LDH activity along with clinical signs only at 150 ppm TIA, (3,493 IU). The CPK and AST values were more useful indicators, and these rose in line with clinical signs and dose from 100 to 150 ppm TIA, whereas at 50 ppm TIA, they were comparatively normal, as in this study.

The results demonstrated that simultaneous routine administration of 50 ppm TIA plus 150 ppm CTC along with 60 ppm SAL caused a small depression of growth in healthy birds, but clinical signs of any negative interaction were not detected in any of the treatment groups. Considering economic and animal production aspects, simultaneous administration of 20 ppm TIA plus 60 ppm CTC as well as 60 ppm SAL performed better than 60 ppm SAL on its own, but a further study is recommended to confirm whether or not this inclusion rate will be enough to protect the birds against a Mycoplasma challenge.

	ACKNOWLEDGMENTS

 
We thank Novartis Animal Health, Basel, Switzerland, for financial support to conduct the study and publication.

Received for publication February 15, 2008. Accepted for publication April 3, 2008.

	REFERENCES

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Burch, D. G. S., and L. Stipkovits. 1991. Dose-related effects of tiamulin and the incompatible ionophores in Mycoplasma infected chicks. Acta Vet. Scand. Suppl. 87:278–280.

Burch, D. G. S., and L. Stipkovits. 1993. Enhancement effect of tiamulin and chlortetracycline or tiamulin and doxycycline combinations against mycoplasmas. Page 167 in Proceedings of the 10th International Congress of the World Veterinary Poultry Association, Sydney, Australia.

Burch, D. G. S., and L. Stipkovits. 1994. Efficacy of tetramutin premix in the prevention of an artificial infection with Mycoplasma gallisepticum in broilers in the presence of SAL. Pages 163–164 in Proceedings of the 9th European Poultry Conference, Glasgow, UK.

Burch, D. G. S., and L. Stipkovits. 1996. The use of tetramutin premix for performance enhancement in birds artificially infected with Mycoplasma gallisepticum. Page 369 in Proceedings of the 20th World’s Poultry Congress, New Delhi, India.

Frigg, M., J. Broz, and G. Weber. 1983. Compatability studies of ionophore anticoccidials with various antibiotics and chemotherapeutics. Arch. Geflugelkd. 47:213–220.

Laczay, P., F. Simon, and J. Lehel. 1990. Untersuchungen ber den Finfluss von Monensin, Tiamulin bzw. der gleichzeitigen Applikation der beiden Substanzen auf die mikrosomalen mischfunktionellen Oxygenasen und auf die Peroxidbildung bei Broilern. Dtsch. Tierärztl. Wschr. 97:354–357.

Meingassner, J. G., F. P. Schmook, R. Czok, and H. And Meth. 1979. Enhancement of the anticoccidial activity of polyether antibiotics in chickens by tiamulin. Poult. Sci. 58:308–313.[Web of Science][Medline]

NRC. 1994. Nutritional Requirements of Poultry. 9th rev. ed. National Academy Press, Washington, DC.

Sakar, D., J. Pompe-Gotal, Z. Belèiæ, S. Blagovic, and V. Kaniaj. 1991. Effect of therapeutic level of tiamulin on higher toxicity of monensin in weaned pigs. Vet. Arch. 61:67–82.

Schuhmacher, A., K. W. Bafundo, K. M. S. Islam, H. Aupperle, R. Glaser, H. A. Schoon, and J. M. Gropp. 2006. Tiamulin and semduramicin: Effects of simultaneous administration on performance and health of growing broiler chickens. Poult. Sci. 85:441–446.[Abstract/Free Full Text]

Steel, G. D., and J. H. Torrie. 1980. Principles and Procedure of Statistics. McGraw-Hill Book Company Inc., New York, NY.

Stipkovits, L., E. Csiba, G. Laber, and D. G. S. Burch. 1992. Simultaneous treatment of chickens with salinomycin and tiamulin in feed. Avian Dis. 36:11–16.[CrossRef][Web of Science][Medline]

Stipkovits, L., G. Salyi, R. Glavits, and D. G. S. Burch. 1999. Testing the compatibility of a combination of tiamulin/chlortetracycline 1:3 premix given in feed at different levels with salinomycin in chickens. Avian Pathol. 28:579–586.[CrossRef][Web of Science]

Youxiang, D., D. Yu, M. Valks, and D. G. S. Burch. 2003. Evaluation of tiamulin and chlortetracycline in feed in the control of CRD in broiler. Page 189 in Proc. XIII Congress of the World Veterinary Association, Denver, CO.

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