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Optimal Regimens and Cutoff Evaluation of Tildipirosin Against Pasteurella multocida
Pasteurella multocida (PM) can invade the upper respiratory tract of the body and cause death and high morbidity. Tildipirosin, a new 16-membered-ring macrolide antimicrobial, has been recommended for the treatment of respiratory diseases. The objective of this research was to improve the dose regim...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071545/ https://www.ncbi.nlm.nih.gov/pubmed/30093860 http://dx.doi.org/10.3389/fphar.2018.00765 |
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author | Lei, Zhixin Liu, Qianying Qi, Yi Yang, Bing Khaliq, Haseeb Xiong, Jincheng Moku, Gopi Krishna Ahmed, Saeed Li, Kun Zhang, Hui Zhang, Wenqiu Cao, Jiyue He, Qigai |
author_facet | Lei, Zhixin Liu, Qianying Qi, Yi Yang, Bing Khaliq, Haseeb Xiong, Jincheng Moku, Gopi Krishna Ahmed, Saeed Li, Kun Zhang, Hui Zhang, Wenqiu Cao, Jiyue He, Qigai |
author_sort | Lei, Zhixin |
collection | PubMed |
description | Pasteurella multocida (PM) can invade the upper respiratory tract of the body and cause death and high morbidity. Tildipirosin, a new 16-membered-ring macrolide antimicrobial, has been recommended for the treatment of respiratory diseases. The objective of this research was to improve the dose regimes of tildipirosin to PM for reducing the macrolides resistance development with the pharmacokinetic/pharmacodynamic (PK/PD) modeling approach and to establish an alternate cutoff for tildipirosin against PM. A single dose (4 mg/kg body weight) of tildipirosin was administered via intramuscular (i.m.) and intravenous (i.v.) injection to the pigs. The minimum inhibitory concentration (MIC) values of clinical isolates (112) were measured in the range of 0.0625–32 μg/ml, and the MIC(50) and MIC(90) values were 0.5 and 2 μg/ml, respectively. The MIC of the selected PM04 was 2 and 0.5 μg/ml in the tryptic soy broth (TSB) and serum, respectively. The main pharmacokinetic (PK) parameters including the area under the curve at 24 h (AUC(24 h)), AUC, terminal half-life (T(1/2)), the time to peak concentration (T(max)), peak concentration (C(max)), relative total systemic clearance (CL(b)), and the last mean residence time (MRT(last)) were calculated to be 7.10, 7.94 μg(∗)h/ml, 24.02, NA h, NA μg/ml, 0.46 L/h(∗)kg, 8.06 h and 3.94, 6.79 μg(∗)h/ml, 44.04, 0.25 h, 0.98 μg/ml, 0.43 L/h(∗)kg, 22.85 h after i.v. and i.m. induction, respectively. Moreover, the bioavailability of i.m. route was 85.5%, and the unbinding of tildipirosin to serum protein was 78%. The parameters AUC(24 h)/MIC in serum for bacteriostatic, bactericidal, and elimination activities were calculated as 18.91, 29.13, and 34.03 h based on the inhibitory sigmoid E(max) modeling. According to the Monte Carlo simulation, the optimum doses for bacteriostatic, bactericidal, and elimination activities were 6.10, 9.41, and 10.96 mg/kg for 50% target and 7.86, 12.17, and 14.57 mg/kg for 90% target, respectively. The epidemiological cutoff value (ECV) was calculated to be 4 μg/ml which could cover 95% wild-type clinical isolates distribution. The PK-PD cutoff (CO(PD)) was analyzed to be 0.25 μg/ml in vitro for tildipirosin against PM based on the Monte Carlo simulation. Compared with these two cutoff values, the finial susceptible breakpoint was defined as 4 μg/ml. The data presented now provides the optimal regimens (12.17 mg/kg) and susceptible breakpoint (4 μg/ml) for clinical use, but these predicted data should be validated in the clinical practice. |
format | Online Article Text |
id | pubmed-6071545 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-60715452018-08-09 Optimal Regimens and Cutoff Evaluation of Tildipirosin Against Pasteurella multocida Lei, Zhixin Liu, Qianying Qi, Yi Yang, Bing Khaliq, Haseeb Xiong, Jincheng Moku, Gopi Krishna Ahmed, Saeed Li, Kun Zhang, Hui Zhang, Wenqiu Cao, Jiyue He, Qigai Front Pharmacol Pharmacology Pasteurella multocida (PM) can invade the upper respiratory tract of the body and cause death and high morbidity. Tildipirosin, a new 16-membered-ring macrolide antimicrobial, has been recommended for the treatment of respiratory diseases. The objective of this research was to improve the dose regimes of tildipirosin to PM for reducing the macrolides resistance development with the pharmacokinetic/pharmacodynamic (PK/PD) modeling approach and to establish an alternate cutoff for tildipirosin against PM. A single dose (4 mg/kg body weight) of tildipirosin was administered via intramuscular (i.m.) and intravenous (i.v.) injection to the pigs. The minimum inhibitory concentration (MIC) values of clinical isolates (112) were measured in the range of 0.0625–32 μg/ml, and the MIC(50) and MIC(90) values were 0.5 and 2 μg/ml, respectively. The MIC of the selected PM04 was 2 and 0.5 μg/ml in the tryptic soy broth (TSB) and serum, respectively. The main pharmacokinetic (PK) parameters including the area under the curve at 24 h (AUC(24 h)), AUC, terminal half-life (T(1/2)), the time to peak concentration (T(max)), peak concentration (C(max)), relative total systemic clearance (CL(b)), and the last mean residence time (MRT(last)) were calculated to be 7.10, 7.94 μg(∗)h/ml, 24.02, NA h, NA μg/ml, 0.46 L/h(∗)kg, 8.06 h and 3.94, 6.79 μg(∗)h/ml, 44.04, 0.25 h, 0.98 μg/ml, 0.43 L/h(∗)kg, 22.85 h after i.v. and i.m. induction, respectively. Moreover, the bioavailability of i.m. route was 85.5%, and the unbinding of tildipirosin to serum protein was 78%. The parameters AUC(24 h)/MIC in serum for bacteriostatic, bactericidal, and elimination activities were calculated as 18.91, 29.13, and 34.03 h based on the inhibitory sigmoid E(max) modeling. According to the Monte Carlo simulation, the optimum doses for bacteriostatic, bactericidal, and elimination activities were 6.10, 9.41, and 10.96 mg/kg for 50% target and 7.86, 12.17, and 14.57 mg/kg for 90% target, respectively. The epidemiological cutoff value (ECV) was calculated to be 4 μg/ml which could cover 95% wild-type clinical isolates distribution. The PK-PD cutoff (CO(PD)) was analyzed to be 0.25 μg/ml in vitro for tildipirosin against PM based on the Monte Carlo simulation. Compared with these two cutoff values, the finial susceptible breakpoint was defined as 4 μg/ml. The data presented now provides the optimal regimens (12.17 mg/kg) and susceptible breakpoint (4 μg/ml) for clinical use, but these predicted data should be validated in the clinical practice. Frontiers Media S.A. 2018-07-26 /pmc/articles/PMC6071545/ /pubmed/30093860 http://dx.doi.org/10.3389/fphar.2018.00765 Text en Copyright © 2018 Lei, Liu, Qi, Yang, Khaliq, Xiong, Moku, Ahmed, Li, Zhang, Zhang, Cao and He. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Lei, Zhixin Liu, Qianying Qi, Yi Yang, Bing Khaliq, Haseeb Xiong, Jincheng Moku, Gopi Krishna Ahmed, Saeed Li, Kun Zhang, Hui Zhang, Wenqiu Cao, Jiyue He, Qigai Optimal Regimens and Cutoff Evaluation of Tildipirosin Against Pasteurella multocida |
title | Optimal Regimens and Cutoff Evaluation of Tildipirosin Against Pasteurella multocida |
title_full | Optimal Regimens and Cutoff Evaluation of Tildipirosin Against Pasteurella multocida |
title_fullStr | Optimal Regimens and Cutoff Evaluation of Tildipirosin Against Pasteurella multocida |
title_full_unstemmed | Optimal Regimens and Cutoff Evaluation of Tildipirosin Against Pasteurella multocida |
title_short | Optimal Regimens and Cutoff Evaluation of Tildipirosin Against Pasteurella multocida |
title_sort | optimal regimens and cutoff evaluation of tildipirosin against pasteurella multocida |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071545/ https://www.ncbi.nlm.nih.gov/pubmed/30093860 http://dx.doi.org/10.3389/fphar.2018.00765 |
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