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A label-free electrochemical immunosensor was developed to rapidly detect tilmicosin (TMC) residues in pork and milk. The immunosensor was constructed by immobilizing a high-affinity monoclonal antibody against TMC on an rGO-PEI-Ag nanocomposite-modified electrode. The rGO-PEI-Ag nanocomposites were prepared by mixing polyethyleneimine (PEI) modified reduced graphene oxide (rGO) with AgNO3 solution. The prepared rGO-PEI-Ag nanocomposites showed good redox activity and conductivity, as characterized by ultraviolet-visible spectroscopy (UV-Vis), transmission electron microscopy (TEM), and X-ray diffraction (XRD). During the preparation process, staphylococcal protein A (SPA) was added to targetedly bind the Fc segment of the monoclonal antibody. The immunosensor showed a low detection limit (LOD) of 0.0013 ng/mL, a linear range of 0.01-100 ng/mL, and recoveries ranging from 92.77 to 100.02% in pork and 92.26-101.23% in milk. Furthermore, the immunosensor exhibited good stability, reproducibility, and specificity in detecting TMC in pork and milk real samples.

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Mycoplasma synoviae (MS) infection is a serious threat to poultry industry in China. Tilmicosin is a semisynthetic macrolide antibiotic used only in animals and has shown potential efficacy against MS, but there were no reported articles concerning the pharmacokinetics/pharmacodynamics (PK/PD) interactions of tilmicosin against MS in vitro and vivo. This study aimed to assess the antibacterial activity of tilmicosin against MS in vitro and in vivo using PK/PD model to provide maximal efficacy. The minimum inhibitory concentration (MIC) and killing rates of different drug concentrations were measured using the microdilution method in vitro. Then, tilmicosin was administered orally to the MS-infected chickens at doses of 7.5 and 60 mg/kg, and the PK parameters of tilmicosin in joint dialysates were determined using high-pressure liquid chromatography/tandem mass spectrometry (HPLC-MS/MS) combined with the microdialysis technique. The antibacterial effect (△E) was calculated when the infected chickens were administered a single oral dose of tilmicosin at 4, 7.5, 15, 30, and 60 mg/kg b.w. The PK and PD data were fitted using the Sigmoid Emax model to evaluate the PK/PD interactions of tilmicosin against MS. The bactericidal activity of tilmicosin against MS was concentration dependent. Furthermore, the PK/PD index of AUC0-72h/MIC exhibited the most optimal fitting results (R2 = .98). The MS load decreased by 1, 2, and 3 Log10 CFU/mL, then AUC/MIC was determined as 13.99, 20.53, and 28.23 h, respectively, and the bactericidal effect can be achieved when the dose of MS-infected chickens is at 31.64 mg/kg b.w. The findings of this study hold significant implications for optimizing the treatment regimen for MS infection.

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Intrinsic resistance to macrolides in Gram-negative bacteria is primarily attributed to the low permeability of the outer membrane, though the underlying genetic and molecular mechanisms remain to be fully elucidated. Here, we used transposon directed insertion-site sequencing (TraDIS) to identify chromosomal non-essential genes involved in Escherichia coli intrinsic resistance to a macrolide antibiotic, tilmicosin. We constructed two highly saturated transposon mutant libraries of >290,000 and >390,000 unique Tn5 insertions in a clinical enterotoxigenic strain (ETEC5621) and in a laboratory strain (K-12 MG1655), respectively. TraDIS analysis identified genes required for growth of ETEC5621 and MG1655 under 1/8 MIC (n = 15 and 16, respectively) and 1/4 MIC (n = 38 and 32, respectively) of tilmicosin. For both strains, 23 genes related to lipopolysaccharide biosynthesis, outer membrane assembly, the Tol-Pal system, efflux pump, and peptidoglycan metabolism were enriched in the presence of the antibiotic. Individual deletion of genes (n = 10) in the wild-type strains led to a 64- to 2-fold reduction in MICs of tilmicosin, erythromycin, and azithromycin, validating the results of the TraDIS analysis. Notably, deletion of surA or waaG, which impairs the outer membrane, led to the most significant decreases in MICs of all three macrolides in ETEC5621. Our findings contribute to a genome-wide understanding of intrinsic macrolide resistance in E. coli, shedding new light on the potential role of the peptidoglycan layer. They also provide an in vitro proof of concept that E. coli can be sensitized to macrolides by targeting proteins maintaining the outer membrane such as SurA and WaaG.

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Tilmicosin (TMC), a semi-synthetic macrolide antibiotic, is widely used in veterinary medicine due to its broad-spectrum, bacteriostatic properties. Frequently administered in various birds species, it is likely used off-label in geese as well. The study sought to investigate TMC's pharmacokinetics, tissue residues, in geese through in vivo experiments. The study involved longitudinal open studies on 15 healthy adult males, with three phases separated by one-month washout periods. Geese were administered TMC through intravenous (IV, 5 mg/kg), subcutaneous (SC, 10 mg/kg), and oral (PO, 25 mg/kg for five consecutive days) routes, with blood samples drawn at specific intervals. Tissue samples were also collected for subsequent analysis at pre-assigned times. TMC in goose plasma was quantified by a fully validated HPLC method. Plasma concentrations were quantified up to 4 hr for the PO and IV routes, and up to 10 hr in the SC route. Significant variations in bioavailability were observed between SC (87%) and PO (4%) routes. The body extraction ratio was low at 0.03, suggesting minimal ability of the liver and kidneys to eliminate TMC. Multiple oral doses showed no plasma accumulation, but tissue data revealed extensive distribution and prolonged residence, up to 120 h, suggesting a sustained therapeutic effect despite the brief plasma half-life. Regarding the multiple PO doses, provisional withdrawal times of 6, 7.5, and 8 days were suggested for the liver, muscles, and kidneys, respectively, according to the MRL set for these matrices in chickens by EMA. In conclusion, while the practical oral administration is discouraged at the population level, SC administration of TMC may be appropriate for geese, albeit impractical for flock therapy.

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Tilmicosin (TIL) is a semisynthetic macrolide antibiotic with a broad spectrum of activity derived from tylosin. TIL is effective in the treatment of bovine and ovine respiratory diseases caused by different microbes. In parallel, Rhodiola rosea (RHO) is a popular herbal remedy because of its anti-inflammatory and antioxidant qualities. The experiment lasted for 12 days. Depending on the experimental group, the animals received either distilled water or RHO root extract dissolved in distilled water for 12 days through a stomach tube, and the single subcutaneous injection on day 6 of the experiment of either 500 µL of 0.9% NaCl or TIL dissolved in 500 µL 0.9% NaCl. Samples and blood were collected for serum analysis, gene expression, and immunohistochemistry screening at liver and kidney levels. TIL injection increased serum levels of hepatic and renal markers (ALP, ALT, AST, TC, TG, creatinine, and urea) with decreased total proteins. In parallel, TIL induced hepatic and renal oxidative stress as there was an increase in malondialdehyde levels, with a decrease in catalase and reduced glutathione activities. Of interest, pre-administration of RHO inhibited TIL-induced increase in hepato-renal markers, decreased oxidative stress, and increased liver and kidney antioxidant activities. Quantitative RT-PCR showed that TIL increased the liver's HSP70 (heat shock protein), NFkB, and TNF-α mRNA expression. Moreover, TIL upregulated the expression of desmin, nestin, and vimentin expression in the kidney. The upregulated genes were decreased significantly in the protective group that received RHO. Serum inflammatory cytokines and genes of inflammatory markers were affected in liver tissues (HSP70, NFkB, and TNF-α) and kidney tissues (desmin, nestin, and vimentin)-TIL-induced hepatic vacuolation and congestion together with glomerular atrophy. The immunoreactivity of PCNA and HMGB1 was examined immunohistochemically. At cellular levels, PCNA was decreased while HMGB1 immunoreactivity was increased in TIL-injected rats, which was improved by pre-administration of RHO. RHO administration protected the altered changes in liver and renal histology. Current findings support the possible use of RHO to shield the liver and kidney from the negative effects of tilmicosin.

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Tilmicosin, a macrolide antibiotic, has the potential to treat bacterial infections in donkeys. However, the pharmacokinetics of tilmicosin in donkeys have not been reported. The aim of this study was to investigate the pharmacokinetics of tilmicosin in donkey plasma, urine, and feces after a single intragastric administration to determine the suitability of tilmicosin for donkeys. A total of 5 healthy male donkeys with similar body weights were selected. The donkeys were administered a single dose of 10 mg · kg-1 body weight (BW) tilmicosin by gavage. The concentrations of tilmicosin in plasma, urine, and feces were determined. The results showed that after a single intragastric administration of 10 mg · kg-1 body weight, tilmicosin in donkey plasma reached a maximum concentration of 11.23 ± 5.37 mg · L-1 at 0.80 ± 0.10 h, with a half-life of 14.49 ± 7.13 h, a mean residence time of 28.05 ± 3.05 h, a Cl/F of 0.48 ± 0.18 L · kg-1 · h-1, and a Vd/F of 9.28 ± 2.63 Lkg-1. The percentage of tilmicosin excreted through the urine of donkeys is 2.47%, and the percentage excreted through the feces is 66.43%. Our study provides data to inform the use of tilmicosin in donkeys.

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The degradation of tilmicosin (TLM), a semi-synthetic 16-membered macrolide antibiotic, has been receiving increasing attention. Conventionally, there are three tilmicosin degradation methods, and among them microbial degradation is considered the best due to its high efficiency, eco-friendliness, and low cost. Coincidently, we found a new strain, Glutamicibacter nicotianae sp. AT6, capable of degrading high-concentration TLM at 100 mg/L with a 97% removal efficiency. The role of tryptone was as well investigated, and the results revealed that the loading of tryptone had a significant influence on TLM removals. The toxicity assessment indicated that strain AT6 could efficiently convert TLM into less-toxic substances. Based on the identified intermediates, the degradation of TLM by AT6 processing through two distinct pathways was then proposed.

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This paper introduces a novel, sensitive, and rapid method for the quantification of oxytetracycline, tetracycline, tilmicosin, and tylosin residues in cow's milk. The method involves a two-step process of extraction and detection. The extraction process uses acetonitrile and salting-out assisted liquid-liquid extraction to isolate the antibiotics from the milk. The detection process employs Liquid Chromatography coupled with photo-diode array detector (PDA) to quantify the antibiotics. The method has been successfully applied to milk samples, demonstrating its effectiveness and potential for widespread use in residue analysis.•The calibration curves for the antibiotics were found to be linear within the range of 0.06-3.0 µg/mL to 0.1-3.0 µg/mL.•The limits of detection for oxytetracycline, tetracycline, tilmicosin, and tylosin were 0.03 µg/mL, 0.02 µg/mL, 0.04 µg/mL, and 0.02 µg/mL respectively.•The method demonstrated an average recovery rate of over 90% from milk samples with peak values reaching up to 0.100-0.200 µg/mL.

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This study aimed to examine the depletion of tilmicosin residues in Gushi chickens following the administration at a concentration of 75 mg/L in their drinking water for three consecutive days. Plasma, liver, kidney, lung, muscle, and skin + fat samples were collected from 6 chickens at 6 h, 1, 3, 5, and 7 days after the treatment. Tilmicosin concentrations in the samples were determined using a high-performance liquid chromatography (HPLC) method. The findings revealed that the highest tilmicosin residues were detected in the liver, followed by the kidney, lung, skin + fat, muscle, and plasma. Notably, at 7 days post-treatment, no drug residue was detected in all samples except for the liver and kidney. The non-compartmental model was employed to calculate relevant pharmacokinetic parameters. The elimination half-lives (t1/2λz ) of tilmicosin were as follows, ranked from long to short: skin + fat (45.42 h), liver (44.17 h), kidney (40.06 h), plasma (37.64 h), lung (31.39 h), and muscle (30.05 h). Considering the current residue depletion and the maximum residue limits (MRLs) set by Chinese regulatory authorities, the withdrawal times for tilmicosin were estimated as 18.91, 10.81, and 8.58 days in the kidney, liver, and skin + fat, respectively. A rounded-up value of 19 days was selected as the conclusive withdrawal time. Furthermore, based on the observed tilmicosin concentrations in plasma and lung, combined with previously reported minimum inhibitory concentration (MIC) values against Mycoplasma gallisepticum, the current dosing regimen was deemed adequate for treating Mycoplasma gallisepticum infections in Gushi chickens.

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An experimental study has been conducted to investigate the efficacy of geraniol (GNL) isolated from lemomgrass in protecting against cardiac toxicity induced by tilmicosin (TIL) in albino mice. Compared to TIL-treated mice, those supplemented with GNL had a thicker left ventricular wall and a smaller ventricular cavity. Studies of TIL animals treated with GNL showed that their cardiomyocytes had markedly changed in diameter and volume, along with a reduction in numerical density. After TIL induction, animals showed a significant increase in the protein expression of TGF-ß1, TNF-α, nuclear factor kappa B (NF-kB), by 81.81, 73.75 and 66.67%, respectively, and hypertrophy marker proteins ANP, BNP, and calcineurin with respective percentages of 40, 33.34 and 42.34%. Interestingly, GNL significantly decreased the TGF-ß1, TNF-α, NF-kB, ANP, BNP, and calcineurin levels by 60.94, 65.13, 52.37, 49.73, 44.18 and 36.84%, respectively. As observed from histopathology and Masson's trichrome staining, supplementation with GNL could rescue TIL-induced cardiac hypertrophy. According to these results, GNL may protect the heart by reducing hypertrophy in mice and modulating biomarkers of fibrosis and apoptosis.

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To avoid false negative results due to the low cross-reactivity rate (CR) in rapid immunoassay, a group-specific antibody with homogeneous CR toward target compounds is needed for accuracy. In this study, tylosin (TYL) and tilmicosin (TM) were selected as model molecules. Firstly, two-dimensional similarity, electrostatic potential energy, spatial conformation and charge distribution of the haptens TYL-CMO, TYL-6-ACA, TYL-4-APA, TYL-CHO and DES-CMO and target compounds of TYL and TM were obtained using Gaussian 09W and Discovery Studio. The optimal hapten was DES-CMO because it is the most similar to TYL and TM. Subsequently, the mAb 14D5 cell line was obtained with IC50 values of 1.59 and 1.72 ng/mL for TYL and TM, respectively, and a CR of 92.44%. Finally, amorphous carbon nanoparticles (ACNPs) were conjugated with mAb 14D5 to develop an accurate lateral flow immunoassay (LFA) for detection of TYL and TM by the reflectance value under natural light. The recoveries of TYL and TM ranged from 77.18 to 112.04% with coefficient of variation < 13.43%. The cut-off value in milk samples was 8 ng/mL, and the limits of detection were 11.44, 15.96, 22.29 and 25.53 µg/kg for chicken muscle, bovine muscle, porcine muscle and porcine liver samples, respectively, and the results being consistent with HPLC-UV. The results suggest that the developed LFA is accurate and potentially useful for on-site screening of TYL and TM in milk and animal tissue samples.

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Tilmicosin (TIL) is a common macrolide antibiotic in veterinary medicine. High doses of TIL can have adverse cardiovascular effects. This study examined the effects of Rhodiola rosea (RHO) that have anti-inflammatory, antioxidant, and anti-fibrotic effects on tilmicosin (TIL)-induced cardiac injury targeting anti-inflammatory, antioxidant, apoptotic, and anti-apoptotic signaling pathways with anti-fibrotic outcomes. Thirty-six male Wistar albino rats were randomly divided into groups of six rats each. Rats received saline as a negative control, CARV 1 mL orally (10 mg/kg BW), and RHO 1 mL orally at 400 mg/kg BW daily for 12 consecutive days. The TIL group once received a single subcutaneous injection (SC) dose of TIL (75 mg/kg BW) on the sixth day of the experiment to induce cardiac damage. The standard group (CARV + TIL) received CARV daily for 12 consecutive days with a single TIL SC injection 1 h after CARV administration only on the sixth day of study and continued for another six successive days on CARV. The protective group (RHO + TIL) received RHO daily for the same period as in CARV + TIL-treated rats and with the dosage mentioned before. Serum was extracted at the time of the rat's scarification at 13 days of study and examined for biochemical assessments in serum lactate dehydrogenase (LDH), cardiac troponin I (cTI), and creatine phosphokinase (CK-MB). Protein carbonyl (PC) contents, malondialdehyde (MDA), and total antioxidant capacity (TAC) in cardiac homogenate were used to measure these oxidative stress markers. Quantitative RT-PCR was used to express interferon-gamma (INF-γ), cyclooxygenase-2 (COX-2), OGG1, BAX, caspase-3, B-cell lymphoma-2 (Bcl-2), and superoxide dismutase (SOD) genes in cardiac tissues, which are correlated with inflammation, antioxidants, and apoptosis. Alpha-smooth muscle actin (α-SMA), calmodulin (CaMKII), and other genes associated with Ca2+ hemostasis and fibrosis were examined using IHC analysis in cardiac cells (myocardium). TIL administration significantly increased the examined cardiac markers, LDH, cTI, and CK-MB. TIL administration also increased ROS, PC, and MDA while decreasing antioxidant activities (TAC and SOD mRNA) in cardiac tissues. Serum inflammatory cytokines and genes of inflammatory markers, DNA damage (INF-γ, COX-2), and apoptotic genes (caspase-3 and BAX) were upregulated with downregulation of the anti-apoptotic gene Bcl-2 as well as the DNA repair OGG1 in cardiac tissues. Furthermore, CaMKII and α-SMA genes were upregulated at cellular levels using cardiac tissue IHC analysis. On the contrary, pretreatment with RHO and CARV alone significantly decreased the cardiac injury markers induced by TIL, inflammatory and anti-inflammatory cytokines, and tissue oxidative-antioxidant parameters. INF-γ, COX-2, OGG1, BAX, and caspase-3 mRNA were downregulated, as observed by real-time PCR, while SOD and Bcl-2 mRNA were upregulated. Furthermore, the CaMKII and α-SMA genes' immune reactivities were significantly decreased in the RHO-pretreated rats.

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Tilmicosin is a semi-synthetic macrolide for veterinary use with strong antibacterial effect on respiratory bacteria. In this study, the pharmacokinetic/pharmacodynamic (PK/PD) integration of tilmicosin against Pasteurella multocida (P. multocida) was evaluated by establishing a piglet tissue cage infection model. Concentration of tilmicosin and bacterial numbers of P. multocida in the tissue-cage fluid were monitered. After the population of P. multocida was equal to or greater than 107 CFU/mL in a tissue cage, piglets received an oral administration of tilmicosin at a dose of 30, 40, 50, and 60 mg/kg b.w., once daily for 3 days, respectively. Bacteria were counted every 24 h after drug administration and at 48 and 72 h after the last administration. A sigmoidal Emax model was used to fit the relationship between PK/PD parameters and the antibacterial effect. AUC24h/MIC was the best PK/PD index that correlated with effectiveness of tilmicosin against P. multocida. The magnitude of AUC24h/MIC required for continuous 1/3-log, 1/2-log, and 3/4-log reductions were 19.65 h, 23.86 h, and 35.77 h, respectively, during each 24 h treatment period. In this study, when the dosage was >50 mg/kg, the AUC24h/MIC was still >35.77 h in the period of 24-48 h after the last administration due to the slow elimination, that is, tilmicosin exhibited a potent antibacterial effect against P. multocida after three successive daily administrations. The data provide meaningful guidance to optimize regimens of tilmicosin to treat respiratory tract infections caused by P. multocida.

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A straightforward, rapid, and selective fluorescent probe for determination of tilmicosin has been developed based on novel nitrogen and sulfur co-doped CDs (NS-CD). The NS-CDs were synthesized, for the first time, through green, simple one step microwave pyrolysis in only 90 s using glucose as carbon source and l-cysteine as nitrogen and sulfur source. This proposed synthesis method was energy-efficient and resulted in NS-CDs with high production yield (54.27 wt%) and narrow particle size distribution. Greenness of NS-CDs synthesis method was assessed using EcoScale and was proven to be excellent green synthesis. The produced NS-CDs were applied as a nano-probe for determination of tilmicosin in its marketed formulation and milk based on dynamic quenching mechanism. The developed probe showed a good performance for tilmicosin detection in marketed oral solution and pasteurized milk and linearity range of 9-180 µM and 9-120 µM, respectively.

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The application of manures leads to the contamination of agricultural soils with veterinary antibiotics (VAs). These might exert toxicity on the soil microbiota and threaten environmental quality, and public health. We obtained mechanistic insights about the impact of three VAs, namely, sulfamethoxazole (SMX), tiamulin (TIA) and tilmicosin (TLM), on the abundance of key soil microbial groups, antibiotic resistance genes (ARGs) and class I integron integrases (intl1). In a microcosm study, we repeatedly treated two soils (differing in pH and VA dissipation capacity) with the studied VAs, either directly or via fortified manure. This application scheme resulted in accelerated dissipation of TIA, but not of SMX, and accumulation of TLM. Potential nitrification rates (PNR), and the abundance of ammonia-oxidizing microorganism (AOM) were reduced by SMX and TIA, but not by TLM. VAs strongly impacted the total prokaryotic and AOM communities, whereas manure addition was the main determinant of the fungal and protist communities. SMX stimulated sulfonamide resistance, while manure stimulated ARGs and horizontal gene transfer. Correlations identified opportunistic pathogens like Clostridia, Burkholderia-Caballeronia-Paraburkholderia, and Nocardioides as potential ARG reservoirs in soil. Our results provide unprecedented evidence about the effects of understudied VAs on soil microbiota and highlight risks posed by VA-contaminated manures. ENVIRONMENTAL IMPLICATION: The dispersal of veterinary antibiotics (VAs) through soil manuring enhances antimicrobial resistance (AMR) development and poses a threat to the environment and the public health. We provide insights about the impact of selected VAs on their: (i) microbially-mediated dissipation in soil; (ii) ecotoxicity on the soil microbial communities; (iii) capacity to stimulate AMR. Our results (i) demonstrate the effects of VAs and their application-mode on the bacterial, fungal, and protistan communities, and on the soil ammonia oxidizers; (ii) describe natural attenuation processes against VA dispersal, (iii) depict potential soil microbial AMR reservoirs, essential for the development of risk assessment strategies.

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In order to overcome the treatment difficulty of Lawsonia intracellularis (L.intracellularis) using antibiotics, the tilmicosin (TIL)-loaded sodium alginate (SA)/gelatin composite nanogels modified with bioadhesive substances were designed. The optimized nanogels were prepared by electrostatic interaction between SA and gelatin at a mass ratio of 1:1 and CaCl2 as an ionic crosslinker and further modified with guar gum (GG). The optimized TIL-nanogels modified with GG had a uniform spherical shape with a diameter of 18.2 ± 0.3 nm, LC of 29.4 ± 0.2 %, EE of 70.4 ± 1.6 %, PDI of 0.30 ± 0.04, and ZP of -32.2 ± 0.5 mv. The FTIR, DSC, and PXRD showed that GG was covered on the surface of TIL-nanogels in a pattern of staggered arrangements. The TIL-nanogels modified with GG had the strongest adhesive strength amongst those with I-carrageenan and locust bean gum and the plain nanogels, and thus significantly enhanced the cellular uptake and accumulation of TIL via clathrin-mediated endocytosis. It exhibited an increased therapeutic effect against L.intracellularis in vitro and in vivo. This study will provide guidance for developing nanogels for intracellular bacterial infection treatment.

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There is often abuse of drugs in livestock and poultry production, and the improper use of drugs leads to the existence of a low level of residues in eggs, which is a potential threat to human safety. Enrofloxacin (EF) and tilmicosin (TIM) are regularly combined for the prevention and treatment of poultry diseases. The current studies on EF or TIM mainly focus on a single drug, and the effects of the combined application of these two antibiotics on EF metabolism in laying hens are rarely reported. In this study, liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to determine the residual EF and TIM in laying hens and to investigate the effect of TIM on the EF metabolism in laying hens. In this paper, we first establish a method that can detect EF and TIM simultaneously. Secondly, the results showed that the highest concentration of EF in the egg samples was 974.92 ± 441.71 µg/kg on the 5th day of treatment. The highest concentration of EF in the egg samples of the combined administration group was 1256.41 ± 226.10 µg/kg on the 5th day of administration. The results showed that when EF and TIM were used in combination, the residue of EF in the eggs was increased, the elimination rate of EF was decreased, and the half-life of EF was increased. Therefore, the use of EF and TIM in combination should be treated with greater care and supervision should be strengthened to avoid risks to human health.

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Mycoplasma synoviae (MS) infection is a serious threat to poultry industry in China, thus it is essential to study the pharmacokinetics (PK) in the target site of MS-infected chickens, but there are no relevant reports at present. The aim of this study was to compare the PK of tilmicosin in plasma and joint dialysate in MS-infected chickens. The MS infection model was established by evaluating the influence factors of the susceptibility of chicken species, day age of chicken, infection routes, infection cycle, infection dose, and stress response. The clinical symptoms, pathogen isolation, PCR identification, and ELISA antibody were detected to determine whether the MS infection model has been successfully established. Eight-week-old Mahuang chickens were challenged with MS by joint combined with footpad, 2 mL each time, twice a day for 5 d, then the MS infection model was successfully established. The infection group was orally administrated a single dose of 15 mg/kgbody weight (b. w.) tilmicosin. The joint dialysate was collected by the microdialysis technique, then the concentration of tilmicosin in plasma samples and joint dialysate were determined by triple quadrupole high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). There was no significant difference in elimination half-life (t1/2) and the mean residence time (MRT) of dialysate and plasma. In contrast, the time of the area under the concentration-time curve (AUC) and the (maximum concentration of tilmicosin in plasma) Cmax of tilmicosin in plasma was 2.1 and 1.4 times higher than in dialysate. The distribution coefficient of tilmicosin in joint and plasma (AUCdialysate/AUCplasma) was 0.51. In conclusion, tilmicosin concentration in joints of MS-infected chicken was much lower than that of plasma, which may result in the poor clinical effect and drug resistance. The study could provide a reference for the clinical use of tilmicosin against MS.

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The aim of this study was to investigate the cardiotoxic effect of the combination of tilmicosin and diclofenac sodium in sheep. Thirty-two sheep were used and were randomly divided into four equal groups as tilmicosin (T), diclofenac sodium (D), tilmicosin+diclofenac sodium (TD) and control (C) group. Group T received a single dose of tilmicosin, Group D was administered diclofenac sodium once a day for 3 days, and group TD was administered diclofenac and tilmicosin at the same doses as group T and D. Group C received NaCl in a similar way. The blood samples were taken before dosing and at 4th, 8th, 24th and 72nd hour post-dosing for measurement of cardiac markers such as H-FABP, cTn-I, CK-MB. H-FABP level of group TD was found to be significantly (p⟨0.05) higher than of group C at the 8th, 24th and 72nd hour and group D and T at the 72nd hour. cTn-I and CK-MB levels of group TD were found significantly (p⟨0.05) higher compared with other groups. In conclusion, the combined use of tilmicosin and diclofenac in sheep causes an increase in cardiac biomarkers and it can be stated that this combination of drugs may cause cardiac damage.

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In this study, the presence and level of macrolide group antibiotics (tylosin and tilmicosin) were analyzed by the High-Performance Liquid Chromatography (HPLC) method in a total of 126 raw meat samples, including 42 chicken breast and 84 beef neck, available for consumption in the Burdur province (Turkey). The method demonstrated good linearity (R2 > 0.999) over the assayed concentration range (0.10-10 µg/mL). Intra-day and inter-day recoveries were used to express the accuracy of the method at three different levels of 0.5, 1, 2.5 µg/mL. Intraday recoveries and relative standard deviation values ranged from 97.270 (0.054)% to 98.643 (0.061)%, and inter-day recoveries and relative standard deviation values ranged from 97.057 (0.070)% to 98.197(0.042)% for tylosin. Intraday recoveries and relative standard deviation values ranged from 96.360 (0.065)% to 98.153 (0.046)%, and inter-day recoveries and relative standard deviation values ranged from 96.050 (0.058)% to 97.053 (0.096)% for tilmicosin. The limit of detection (LOD) value was calculated as 0.473 µg/kg for tylosin, and 0.481 µg/kg for tilmicosin; the limit of quantification (LOQ) value was calculated as 1.561 µg/kg for tylosin, and 1.587 µg/kg for tilmicosin. In general, tylosin and tilmicosin were determined in the range of 8-256 µg/kg and 30-447 µg/kg, respectively, in chicken breast meat samples; also, they were detected in the range of 36-1209 µg/kg and 30-1102 µg/kg, respectively, in beef neck meat samples. It was also found that the residues of tylosin and tilmicosin in chicken and beef meats from the market were at a much higher level than the acceptable limits specified in the regulations. This creates serious problems in terms of the ecosystem, food technology, and public health, and causes significant economic losses.

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