Pharmacokinetic/Pharmacodynamic Relationships of Tulathromycin Against Actinobacillus pleuropneumoniae in a Porcine Tissue Cage Infection Model

Yao, Lihua; Yang, Lan; Ling, Yuzhou; Wei, Yongxiang; Shen, Xiu; Ding, Huanzhong

doi:10.3389/fvets.2022.822432

Cited by 5 publications

(5 citation statements)

References 33 publications

(37 reference statements)

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“…The C max values of reference drug (Draxxin) and four generic drugs (Tulaject, Tulazen, Tulshot and T-raxxin) were 1100.08 ± 102.97, 1027.97 ± 77.06, 1110.04 ± 56.78, 1031.15 ± 80.09 and 1028.99 ± 18.95 ng/mL, respectively. The MICs of tulathromycin were 0.25 µg/mL and 0.03 µg/mL against A. pleuropneumoniae and P. multocida in the infection model [20,21]. The C max values of tulathromycin from the reference and generic products were at least four times the MIC (≤0.25 µg/mL) against common microorganisms such as A. pleuropneumoniae and P. multocida.…”

Section: Discussionmentioning

confidence: 96%

Evaluation of Biological Equivalence for Generic Tulathromycin Injections in Cattle

Kang,

Chae,

Jeong

et al. 2023

IJMS

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The recent expiration of patents for the antibiotic tulathromycin has led to a significant increase in the number of generic tulathromycin products (GTPs) available. This study aims to evaluate the bioequivalence of four GTPs, which experienced a rapid increase in market share. The bioequivalence was evaluated by performing pharmacokinetic assessments. The four selected GTPs (Tulaject, Tulagen, Toulashot, and T-raxxin) were compared with the reference product, Draxxin. A dose of 2.5 mg/kg.bw/day was administered via subcutaneous injection, and blood samples were collected 460 times from 20 Holstein cattle. Plasma concentrations of tulathromycin were measured over time using LC-MS/MS analysis. Bioequivalence was evaluated using a statistical program for pharmacokinetic parameters, including the area under the concentration time curve (AUC) and the maximum plasma concentration (Cmax). The bioequivalence was considered proven if the difference between the test and reference products was within 20% for both AUC and Cmax. The results showed that the confidence interval (CI, 90%) for both AUC and Cmax values was within the 80~120% range, demonstrating the bioequivalence of the four GTPs compared to Draxxin. This study provides evidence for the bioequivalence of the selected GTPs, contributing to their validation for use as effective antibiotics.

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Section: Discussionmentioning

confidence: 96%

Evaluation of Biological Equivalence for Generic Tulathromycin Injections in Cattle

Kang,

Chae,

Jeong

et al. 2023

IJMS

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“…They showed that the AUC 168 h /MIC required to achieve a reduction of 1, 2, 3, and 4 Log 10 CFU/mL of H. parasuis was 366.06, 552.51, 728.47, and 916.90 h in serum, and 507.20, 1,227.11, 2,126.44, and 3,462.62 h in lung tissue, respectively. Yao et al ( 17 ) studied the PK/PD of tulathromycin against APP in a tissue-cage infection model. They discovered that %T > MIC was the best PK/PD parameter for predicting the antibacterial effect ( R 2 = 0.9421) and the values required to achieve a reduction of 1 Log 10 CFU/mL and 3 Log 10 CFU/mL were 50.8 and 96.38%, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…For measurement of the drug concentration, equal volumes of sample and acetonitrile were mixed and centrifuged (12,000 × g , 10 min, 4°C). Then, the supernatant (200 μL) was added to the mobile phase (800 μL), vortex-mixed, and passed through a 0.22-μm filter membrane for analysis by HPLC-MS/MS according to a protocol described previously ( 17 ). The limit of detection and limit of quantification were 5 and 10 ng/mL, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…Tulathromycin is a macrolide drug approved for the treatment of respiratory diseases in pigs. The PK/PD of tulathromycin against APP has been analyzed in tissue-cage fluid from piglets ( 17 ). However, the PK characteristics of tulathromycin in tissue-cage fluid from pigs are obviously different from those in lung tissue (target tissue of APP infection).…”

Section: Introductionmentioning

confidence: 99%

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Susceptibility evaluation and PK/PD integration of tulathromycin against Actinobacillus pleuropneumoniae during the mutant selection window

Wang,

Zhang

2024

Front. Vet. Sci.

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IntroductionActinobacillus pleuropneumoniae (APP) is a serious pathogen that affects the development of livestock breeding. Due to excessive use of antimicrobial drugs, many multidrug-resistant bacteria have emerged and spread, which have threatened the livestock industry. Therefore, we established a peristaltic pump infection model (PPIM) to evaluate the susceptibility change and pharmacokinetic/pharmacodynamic (PK/PD) integration of tulathromycin against APP during the mutant selection window (MSW) for preventing the emergence of mutant-resistant bacteria.MethodsThe 99% minimum inhibitory concentration (MIC99) and mutant prevention concentration (MPC) of tulathromycin against APP were measured using the agar-plate method. After the model of dynamic infection had been established based on tulathromycin data in lungs, different dosages were administered to make the drug concentrations located in different parts of the MSW. The population and sensitivity of APP were monitored. Tulathromycin concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry. Finally, a sigmoid Emax model was used to analyze the relationships between PK/PD parameters and antibacterial effects.Results and discussionThe values of MIC, MIC99, and MPC of tulathromycin against APP were 2, 1.4, and 44.8 μg/mL, respectively. The PPIM was stable. An elimination effect without regrowth was observed at 5.6 to 44.8 μg/mL (−4.48 to −7.05 Log10 CFU/mL, respectively). The MIC of APP increased 32-fold at 8 MIC99. AUC168 h/MIC99 had the best fit with the antibacterial effect (R2 = 0.9867). The AUC168 h/MIC99 required to achieve bacteriostatic, bactericidal, and clearance effects were 1.80, 87.42, and 198 h, respectively. Our results could provide guidance for the clinical application of tulathromycin to treat APP infection and avoid the generation of drug-resistant bacteria.

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“…However, there are more than 19 serovars of A. pleuropneumoniae; therefore, the protective effect of the currently available vaccine is not satisfactory [8]. Consequently, antimicrobials still play an important role in the prevention and treatment of this disease, including cephalosporins, fluoroquinolones, and macrolides [9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Evaluation the kill rate and mutant selection window of danofloxacin against Actinobacillus pleuropneumoniae in a peristaltic pump model

Wang,

Liao,

Ding

et al. 2024

BMC Vet Res

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Background Actinobacillus pleuropneumoniae is a serious pathogen in pigs. The abundant application of antibiotics has resulted in the gradual emergence of drugresistant bacteria, which has seriously affected treatment of disease. To aid measures to prevent the emergence and spread of drug-resistant bacteria, herein, the kill rate and mutant selection window (MSW) of danofloxacin (DAN) against A. pleuropneumoniae were evaluated. Methods For the kill rate study, the minimum inhibitory concentration (MIC) was tested using the micro dilution broth method and time-killing curves of DAN against A. pleuropneumoniae grown in tryptic soy broth (TSB) at a series drug concentrations (from 0 to 64 MIC) were constructed. The relationships between the kill rate and drug concentrations were analyzed using a Sigmoid Emax model during different time periods. For the MSW study, the MIC99 (the lowest concentration that inhibited the growth of the bacteria by ≥ 99%) and mutant prevention concentration (MPC) of DAN against A. pleuropneumoniae were measured using the agar plate method. Then, a peristaltic pump infection model was established to simulate the dynamic changes of DAN concentrations in pig lungs. The changes in number and sensitivity of A. pleuropneumoniae were measured. The relationships between pharmacokinetic/pharmacodynamic parameters and the antibacterial effect were analyzed using the Sigmoid Emax model. Results In kill rate study, the MIC of DAN against A. pleuropneumoniae was 0.016 µg/mL. According to the kill rate, DAN exhibited concentration-dependent antibacterial activity against A. pleuropneumoniae. A bactericidal effect was observed when the DAN concentration reached 4–8 MIC. The kill rate increased constantly with the increase in DAN concentration, with a maximum value of 3.23 Log10 colony forming units (CFU)/mL/h during the 0–1 h period. When the drug concentration was in the middle part of the MSW, drugresistant bacteria might be induced. Therefore, the dosage should be avoided to produce a mean value of AUC24h/MIC99 (between 31.29 and 62.59 h. The values of AUC24h/MIC99 to achieve bacteriostatic, bactericidal, and eradication effects were 9.46, 25.14, and > 62.59 h, respectively. Conclusion These kill rate and MSW results will provide valuable guidance for the use of DAN to treat A. pleuropneumoniae infections.

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Pharmacokinetic/Pharmacodynamic Relationships of Tulathromycin Against Actinobacillus pleuropneumoniae in a Porcine Tissue Cage Infection Model

Cited by 5 publications

References 33 publications

Evaluation of Biological Equivalence for Generic Tulathromycin Injections in Cattle

Evaluation of Biological Equivalence for Generic Tulathromycin Injections in Cattle

Susceptibility evaluation and PK/PD integration of tulathromycin against Actinobacillus pleuropneumoniae during the mutant selection window

Evaluation the kill rate and mutant selection window of danofloxacin against Actinobacillus pleuropneumoniae in a peristaltic pump model

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