tiamulin and salinomycin

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 stud

Topics: Animals; Anti-Bacterial Agents; Aspartate Aminotransferases; Body Weight; Chickens; Chlortetracycline; Coccidiostats; Creatine Kinase; Diterpenes; Drug Synergism; Female; L-Lactate Dehydrogenase; Male; Poultry Diseases; Pyrans

In an earlier study, the continuous medication of broiler feed with a combination of tiamulin (TIA; 20 mg/kg), chlortetracycline (CTC; 60 mg/kg), and the ionophore anticoccidial salinomycin (SAL; 60 mg/kg) caused an initial increase in BW and feed efficiency (FE; g of weight gain/kg of feed intake). However, as doses increased to combinations of 30 mg/kg of TIA and 90 mg/kg of CTC or 50 mg/kg of TIA and 150 mg/kg of CTC, there was a dose-related reduction in growth rate and FE. This was thought to be due to the interaction between TIA and SAL. In this study, using a protocol similar to the previous trial, broiler chicks were administered SAL at 60 mg/kg via the feed and the same inclusion rates of TIA + CTC. However, instead of feeding the birds continuously, considering the cost of TIA and possibly to compensate for the depressed growth attributable to the interaction with SAL, they were pulse-dosed for 1 to 10 d and again at 21 to 27 d, and the whole trial lasted 35 d to see if the intermittent pulses might reduce production losses. A total of 200 straight-run 1-d-old broiler chicks (Hubbard classic) were randomly distributed into 4 groups, with each group consisting of 5 cages containing 10 birds. The 20 cages were allocated to the 4 treatment groups on a random basis. The control diet, containing only SAL at 60 mg/kg, was fed to all birds throughout the 35-d trial, including the period during the gaps between dosing (i.e., d 11 to 20 and d 28 to 35). Feed and water were available for the whole trial period. Several serum enzymes (creatine kinase, lactate dehydrogenase, and aspartate aminotransferase) were determined from blood samples taken on d 35. Blood samples were also collected at 1, 19, and 35 d of age and were examined for antibody titers to Mycoplasma gallisepticum and Mycoplasma synoviae. Necropsy and histopathology of the birds (n = >or=4) were conducted during weekly intervals. There was no significant difference in weight gain, feed intake, and FE when the groups treated with TIA + CTC were compared with the control group (P > 0.05). There was no relationship between mortality and inclusion rates of the medication. No clinical signs of an interaction were exhibited during the trial, which was supported by necropsy and serum enzyme results. Maternally derived antibodies against M. gallisepticum were identified at the start of the trial but disappeared within 19 d, and infection with M. gallisepticum or M. synoviae was found neither serologi

Topics: Animal Feed; Animals; Anti-Bacterial Agents; Chickens; Chlortetracycline; Diterpenes; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Female; Male; Pyrans; Weight Gain

Salinomycin is a polyether antibiotic showing anticancer activity. There are many reports of its toxicity to animals but little is known about the potential adverse effects in humans. The action of the drug may be connected to its metabolism. That is why we investigated the cytotoxicity of salinomycin and pathways of its biotransformation using human primary hepatocytes, human hepatoma cells (HepG2), and the mouse fibroblast cell line (Balb/c 3T3). The cytotoxicity of salinomycin was time-dependent, concentration-dependent, and cell-dependent with primary hepatocytes being the most resistant. Among the studied models, primary hepatocytes were the only ones to efficiently metabolize salinomycin but even they were saturated at higher concentrations. The main route of biotransformation was monooxygenation leading to the formation of monohydroxysalinomycin, dihydroxysalinomycin, and trihydroxysalinomycin. Tiamulin, which is a known inhibitor of CYP450 izoenzymes, synergistically induced cytotoxicity of salinomycin in all cell types, including non-metabolising fibroblasts. Therefore, the pharmacokinetic interaction cannot fully explain tiamulin impact on salinomycin toxicity.

Topics: Animals; Anti-Bacterial Agents; BALB 3T3 Cells; Cell Line; Diterpenes; Drug Resistance; Hep G2 Cells; Hepatocytes; Humans; Mice; Prednisolone; Pyrans

Salinomycin (SAL) is a polyether antibiotic, which is commonly used as a coccidiostat and has recently shown to exhibit anticancer activity. The toxic action of the drug may be connected with the extent and routes of its biotransformation. The cytotoxic potential of SAL and its combination with tiamulin and prednisolone was investigated using three cell models from rat: primary hepatocytes, hepatoma cells (FaO) and myoblasts (L6). The four biochemical endpoints were assessed: mitochondrial and lysosomal activity, total cell protein content and membrane integrity. The metabolites of SAL in the medium from cell cultures were determined using LC-MS/MS. The cytotoxicity of SAL was time-, concentration- and cells dependent. The most sensitive endpoint was the inhibition of lysosomal activity. Tiamulin increased SAL cytotoxicity, whereas the opposite results were observed for prednisolone. Primary hepatocytes were the most efficient in SAL biotransformation both in terms of its intensity and number of produced metabolites. The range of the cytotoxicity and mode of salinomycin interaction with tiamulin and prednisolone cannot be explained by the biotransformation alone.

Topics: Animals; Anti-Bacterial Agents; Antineoplastic Agents; Cell Survival; Cells, Cultured; Diterpenes; Drug Interactions; Hepatocytes; Lysosomes; Male; Mitochondria; Prednisolone; Pyrans; Rats, Wistar

There are few studies on antimicrobial susceptibility of Brachyspira pilosicoli, therefore this study was performed to investigate the situation among isolates from pigs. The tiamulin and tylosin susceptibility was determined by broth dilution for 93 and 86 porcine B. pilosicoli isolates, respectively. The isolates came from clinical samples taken in Swedish pig herds during the years 2002 and 2003. The tylosin minimal inhibitory concentration (MIC) was >16 microg/ml for 50% (n=43) of the isolates tested. A tiamulin MIC >2 microg/ml was obtained for 14% (n=13) of the isolates and these were also tested against doxycycline, salinomycin, valnemulin, lincomycin and aivlosin. For these isolates the susceptibility to salinomycin and doxycycline was high but the MICs for aivlosin varied. The relationship between the 13 tiamulin resistant isolates was analyzed by pulsed-field gel electrophoresis (PFGE). Among the 13 isolates 10 different PFGE patterns were identified.

Topics: Animals; Anti-Bacterial Agents; Diterpenes; Doxycycline; Drug Resistance, Bacterial; Feces; Microbial Sensitivity Tests; Pyrans; Spirochaetales; Swine; Time Factors; Tylosin

The extensive use of veterinary drugs in agriculture leads to contamination of manure. If this manure is used as fertiliser, soil may be exposed to the respective drugs. Additionally soil exposure may stem from contaminated sewage sludge that is used on some agricultural land as fertiliser. This study focuses on the fate of antibiotics in soil. We present a 120-day degradation experiment of six commonly used antibiotics: erythromycin, roxithromycin oleandomycin, tylosin, salinomycin and tiamulin in soil as well as calculating the resulting half-lives. The half-lives were 20 days for erythromycin, 27 days for oleandomycin, 8 days for tylosin, 16 days for tiamulin and 5 days for salinomycin; all according to 1st order kinetics. The concentration of roxithromycin remained nearly unchanged during the whole experiment.

Topics: Agriculture; Animals; Anti-Bacterial Agents; Diterpenes; Drug Residues; Environmental Monitoring; Humans; Macrolides; Manure; Pyrans; Soil Pollutants; Veterinary Drugs; Water Pollution

The extensive use of veterinary drugs in livestock farming increases the risk that these compounds end up in the environment when manure is used as fertilizer. This study focuses on the fate of antibiotics in liquid manure tanks before the liquid manure is spread on fields. A 180-day degradation experiment of four commonly used antibiotics erythromycin, roxithromycin, salinomycin, and tiamulin in liquid manure was performed. The resulting half-lives during manure storage were calculated as follows: 41 days for erythromycin, 130 days for roxithromycin, and 6 days for salinomycin. A first-order degradation rate was calculated for these three antibiotics. The concentration of tiamulin remained unchanged during the entire experiment. No degradation of tiamulin was detected even after 180 days.

Topics: Animals; Anti-Bacterial Agents; Diterpenes; Erythromycin; Fertilizers; Half-Life; Manure; Pyrans; Roxithromycin; Swine

A method for the analysis of several macrolide and ionophore antibiotics, as well as tiamulin, from soil was developed using pressurized liquid extraction (PLE), reversed-phase liquid chromatography and atmospheric pressure chemical ionisation (APCI) tandem mass spectrometry (LC-APCI+-MS-MS). The analytes were extracted from soil by PLE in 30 min and the extracts were cleaned up by solid-phase extraction (SPE) on a diol SPE cartridge. Liquid chromatographic (LC) separation of the antibiotics was achieved in 35 min. Recovery experiments were performed using spiked soil and concentrations varying from 1 to 2000 microg/kg. By using a macrolide internal standard the recovery rates for the macrolides erythromycin and roxithromycin ranged from 43 to 94% (RSD 20-23%), for the ionophore salinomycin the recovery rate was 76% (RSD 29%), while the pleuromutilin tiamulin was completely recovered. The limits of detection ranged from 0.2 to 1.6 microg/kg. In soil samples a maximum concentration of 0.7 microg/kg tiamulin was found.

Topics: Anti-Bacterial Agents; Chromatography, High Pressure Liquid; Diterpenes; Drug Stability; Erythromycin; Mass Spectrometry; Oleandomycin; Pyrans; Quality Control; Roxithromycin; Soil; Solvents; Temperature

The toxicity of the combination of salinomycin (sal.) and tiamulin (tia.) was investigated in dependence upon dosage and feeding method. In addition the efficacy of a safe dose for prophylactic treatment of dysentery was controlled. Following feed medications were tested for toxic effects in pigs: a) 3 mg sal. + 5 mg tia./kg BW, b) 3 mg sal. + 3 mg tia./kg BW, c) 3 mg sal. + 1 mg tia./kg BW, d) 3 mg sal./kg BW, e) 10 mg tia./kg BW, f) 30 mg tia./kg BW. The daily dose was given for 2 weeks by restricted feeding (twice a day) either as bolus or mixed in the whole ration or by feeding ad libitum. Animals were controlled for clinical symptoms and activities of creatine phosphokinase (CK) and aspartate aminotransferase (ASAT) were evaluated daily. Main clinical signs of poisoning were loss of appetite and locomotor disturbances and could be noticed for dosages of 8, 6 and 4 mg sal. + tia./kg BW. Activities of CK and ASAT were increased dose-related, the feeding method also had an influence on the degree of intoxication. Some animals showed locomotor disturbances without any corresponding changes of CK and ASAT levels. Single pigs remaining without any symptoms even at high dosage pointed to differences in individual susceptibility. Toxicity was not found to be age dependent. Feed medication with 60 ppm sal. + 20 ppm tia. (feeding ad libitum) did not result in any signs of toxicity, however, the transmission of Serpulina hyodysenteriae from infected pigs to healthy, treated control animals could not be inhibited efficiently. Therefore the simultaneous application of salinomycin and tiamulin should be avoided generally, because the risk of intoxication is high and subtherapeutical dosage has an insufficient effectiveness against Serpulina hyodysenteriae.

Topics: Animals; Anorexia; Anti-Bacterial Agents; Aspartate Aminotransferases; Brachyspira hyodysenteriae; Creatine Kinase; Diterpenes; Drug Interactions; Motor Activity; Pyrans; Spirochaetales Infections; Swine; Swine Diseases

The combined effect, if any, of salinomycin poisoning and salinomycin-tiamulin interaction on lipid-peroxidative processes and the antioxidative defence system of the liver was studied in domestic fowl. Male broilers (28-day-old), reared on a diet containing 60 mg/kg salinomycin, were treated intraoesophageally with salinomycin (140 mg/kg body mass) or tiamulin (50 mg/kg body mass). Malondialdehyde, reduced glutathione and cytochrome P-450 concentrations as well as glutathione peroxidase and catalase activities of the liver were determined. Liver malondialdehyde concentration rose in the salinomycin-treated group while the amount of cytochrome P-450 increased in both groups treated. Glutathione concentration and glutathione peroxidase activity of the liver decreased rapidly but hepatic catalase activity increased in both groups after the treatment. Manifestation of the effect exerted by salinomycin and salinomycin-tiamulin on lipid-peroxidative processes nearly coincided with the onset of clinical signs and preceded the increase of hepatic cytochrome P-450 concentration. According to the results, the background of the previously reported incompatibility between salinomycin and tiamulin is the synergistic effect exerted on the antioxidant (glutathione) system.

Topics: Animals; Anti-Bacterial Agents; Chickens; Cytochrome P-450 Enzyme System; Diterpenes; Ionophores; Lipid Peroxidation; Liver; Male; Oxidation-Reduction; Pyrans

Topics: Animal Feed; Animals; Diagnosis, Differential; Diterpenes; Poisoning; Pyrans; Swine; Swine Diseases

Topics: Animals; Anti-Bacterial Agents; Diterpenes; Drug Combinations; Poisoning; Pyrans; Swine; Swine Diseases

Topics: Animals; Diterpenes; Drug Interactions; Pyrans; Swine

Topics: Animal Feed; Animals; Anti-Bacterial Agents; Diterpenes; Dose-Response Relationship, Drug; Drug Synergism; Female; Male; Pyrans; Swine

Topics: Animals; Anti-Bacterial Agents; Diterpenes; Drug Interactions; Food Additives; Foodborne Diseases; Pyrans; Swine; Swine Diseases; Switzerland