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      Pharmacokinetics and Pharmacodynamics of Tildipirosin Against Pasteurella multocida in a Murine Lung Infection Model

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          Abstract

          Tildipirosin, a 16-membered-ring macrolide antimicrobial, has recently been approved for the treatment of swine respiratory disease and bovine respiratory disease. This macrolide is extensively distributed to the site of respiratory infection followed by slow elimination. Clinical efficacy has been demonstrated in cattle and swine clinical field trials. However, the pharmacokinetic/pharmacodynamic (PK/PD) index that best correlates with the efficacy of tildipirosin remains undefined. The objective of this study was to develop a PK/PD model following subcutaneous injection of tildipirosin against Pasteurella multocida in a murine lung infection model. The PK studies of unbound ( f) tildipirosin in plasma were determined following subcutaneous injection of single doses of 1, 2, 4, 6, and 8 mg/kg of body weight in neutropenic lung-infected mice. The PD studies were conducted over 24 h based on twenty intermittent dosing regimens, of which total daily dose ranged from 1 to 32 mg/kg and dosage intervals included 6, 8, 12, and 24 h. The minimum inhibitory concentration (MIC) of tildipirosin against P. multocida was determined in serum. The inhibitory effect I max model was employed for PK/PD modeling. The area under the unbound concentration-time profile over 24 h to MIC ( fAUC 0-24 h/MIC) was the PK/PD index that best described the antibacterial activity in the murine infection model. The fAUC 0-24 h/MIC targets required to achieve the bacteriostatic action, a 1-log 10 kill and 2-log 10 kill of bacterial counts were 19.93, 31.89, and 53.27 h, respectively. These results can facilitate efforts to define more rational designs of dosage regimens of tildipirosin using classical PK/PD concepts for the treatment of respiratory diseases in pigs and cattle.

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          Bovine respiratory disease in feedlot cattle: environmental, genetic, and economic factors.

          The objective of this study was to characterize genetic, environmental, and economic factors related to the incidence of bovine respiratory disease (BRD) in feedlot calves. Records from 18,112 calves representing 9 breeds (Angus, Braunvieh, Charolais, Gelbvieh, Hereford, Limousin, Pinzgauer, Red Poll, and Simmental) and 3 composite types (MARC I, MARC II, and MARC III) over a 15-yr period (1987 to 2001) were evaluated. Disease incidence was observed and recorded by station veterinary and technical staff. The incidence of BRD varied across years, with the annual observed incidence ranging from 5 to 44%. From 1987 to 1992, the annual average incidence generally exceeded 20%. However, in later years the annual incidence did not exceed 14%. The epidemiological pattern indicated that BRD infection increased dramatically after 5 d on feed and remained high until approximately 80 d on feed. Previous BRD infection during the preweaning period did not influence subsequent BRD infection in the feedlot. Steers were more likely to become sick with BRD than heifers; castration before entry in the feedlot may be a predisposing cause. Few significant differences among breeds were detected for BRD incidence. Adjusted solutions from mixed model analyses indicated that Herefords were generally more susceptible to BRD infection (P < 0.05) than MARC I and III composite types. Composite breed types had similar susceptibility compared with other purebred breeds. Mortality associated with BRD was greatest in Red Poll calves (9%) compared with the average over all breeds (4%). Estimates of heritability for resistance to BRD ranged from 0.04 to 0.08 +/- 0.01. When the observed heritability was transformed to an underlying continuous scale, the estimate increased to 0.18. Selection for resistance to BRD could be effective if phenotypes for BRD resistance were known. Thus, development of an inexpensive and humane method of challenging animals with BRD to determine resistance would be an important step in reducing the incidence of BRD. This study also demonstrated that producer-collected field data could be used for selection against this disease. The economic loss associated with lower gains and treatment costs for BRD infection in a 1,000-cattle feedlot was estimated as dollar 13.90 per animal, not including labor and associated handling costs.
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            Elucidation of the pharmacokinetic/pharmacodynamic determinant of colistin activity against Pseudomonas aeruginosa in murine thigh and lung infection models.

            Colistin is increasingly used as last-line therapy against Gram-negative pathogens. The pharmacokinetic (PK)/pharmacodynamic (PD) index that best correlates with the efficacy of colistin remains undefined. The activity of colistin against three strains of Pseudomonas aeruginosa was studied in neutropenic mouse thigh and lung infection models. The PKs of unbound colistin were determined from single-dose PK studies together with extensive plasma protein binding analyses. Dose-fractionation studies were conducted over 24 h with a dose range of 5 to 160 mg/kg of body weight/day. The bacterial burden in the thigh or lung was measured at 24 h after the initiation of treatment. Relationships between antibacterial effect and measures of exposure to unbound (f) colistin (area under the concentration-time curve [fAUC/MIC], maximum concentration of drug in plasma [fC(max)]/MIC, and the time that the concentration in plasma is greater than the MIC [fT > MIC]) were examined by using an inhibitory sigmoid maximum-effect model. Nonlinearity in the PKs of colistin, including its plasma protein binding, was observed. The PK/PD index that correlated best with its efficacy was fAUC/MIC in both the thigh infection model (R(2) = 87%) and the lung infection model (R(2) = 89%). The fAUC/MIC targets required to achieve 1-log and 2-log kill against the three strains were 15.6 to 22.8 and 27.6 to 36.1, respectively, in the thigh infection model, while the corresponding values were 12.2 to 16.7 and 36.9 to 45.9 in the lung infection model. The findings of this in vivo study indicate the importance of achieving adequate time-averaged exposure to colistin. The results will facilitate efforts to define the more rational design of dosage regimens for humans.
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              Increased susceptibility of Pseudomonas aeruginosa to macrolides and ketolides in eukaryotic cell culture media and biological fluids due to decreased expression of oprM and increased outer-membrane permeability.

              Macrolides show high minimum inhibitory concentrations (MICs) against Pseudomonas aeruginosa when tested in recommended media (cation-adjusted Muller-Hinton broth [CA-MHB]). Nevertheless, azithromycin is successfully used in cystic fibrosis patients, supposedly because of "nonantibiotic effects." CA-MHB and Roswell Park Memorial Institute (RPMI) 1640 medium (used for growing eukaryotic cells) were compared for measuring azithromycin MICs (with or without Phe-Arg-β-naphthylamide [PAβN], an efflux inhibitor), [(14)C]-clarithromycin accumulation, azithromycin-induced protein synthesis inhibition, oprM (encoding the outer-membrane protein coupled with MexAB and MexXY efflux systems) expression, outer-membrane permeability (tested with 1-N-phenylnaphthylamine and nitrocefin), and synergy (determined by checkerboard assay) between azithromycin and outer-membrane disrupting agents. Key experiments were repeated with CA-MHB supplemented with serum, mouse bronchoalveolar lavage fluid, other macrolides, and other gram-negative bacteria. Azithromycin MICs were ≥128 mg/L in CA-MHB, compared with 1-16 mg/L in RPMI 1640 medium, CA-MHB supplemented with serum, or bronchoalveolar lavage fluid (repeated for RPMI 1640 medium with clarithromycin, other macrolides, and other gram-negative bacteria). [(14)C]-clarithromycin accumulation was 2.2-fold higher in RPMI 1640 medium, compared with CA-MHB. Inhibition of >95% of protein synthesis was obtained with azithromycin at 16 mg/L in RPMI 1640 medium, compared with >512 mg/L in CA-MHB. Strains not expressing oprM showed an MIC of 4 mg/L in CA-MHB. PAβN decreased MICs in CA-MHB but not in RPMI 1640 medium. Real-time polymerase chain reaction showed downregulation of oprM by azithromycin in RPMI 1640 medium. Outer-membrane permeability was 3-4.5 times higher in RPMI 1640 medium or bronchoalveolar lavage fluid, compared with CA-MHB. Azithromycin combined with outer-membrane disrupting agents were synergistic in CA-MHB but indifferent in RPMI 1640 medium. Macrolides show antimicrobial activity against P. aeruginosa in eukaryotic media through increased uptake and reduced efflux. These data may help explain the clinical efficacy of macrolides against pseudomonal infections.
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                Author and article information

                Contributors
                Journal
                Front Microbiol
                Front Microbiol
                Front. Microbiol.
                Frontiers in Microbiology
                Frontiers Media S.A.
                1664-302X
                18 May 2018
                2018
                : 9
                : 1038
                Affiliations
                [1] 1National Reference Laboratory of Veterinary Drug Residues, Laboratory of Veterinary Pharmacology, College of Veterinary Medicine, South China Agricultural University , Guangzhou, China
                [2] 2Institute of Computational Comparative Medicine, Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University , Manhattan, KS, United States
                Author notes

                Edited by: Patrick Rik Butaye, Ross University School of Veterinary Medicine, Saint Kitts and Nevis

                Reviewed by: Boudewijn Catry, Centrum voor Onderzoek in Diergeneeskunde en Agrochemie, Belgium; Pierre-Louis Toutain, École Nationale Vétérinaire de Toulouse, France

                *Correspondence: Zhoumeng Lin, zhoumeng@ 123456ksu.edu Zhenling Zeng, zlzeng@ 123456scau.edu.cn

                Present address: Ronette Gehring, Division of Toxicology and Pharmacology, Institute of Risk Assessment Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands

                This article was submitted to Antimicrobials, Resistance and Chemotherapy, a section of the journal Frontiers in Microbiology

                Article
                10.3389/fmicb.2018.01038
                5968193
                29867911
                f2dae56e-76ed-49da-b7ee-026783fac89a
                Copyright © 2018 Zeng, Sun, Lin, Li, Gehring and Zeng.

                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 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.

                History
                : 21 January 2018
                : 02 May 2018
                Page count
                Figures: 2, Tables: 2, Equations: 1, References: 32, Pages: 6, Words: 0
                Categories
                Microbiology
                Original Research

                Microbiology & Virology
                tildipirosin,pharmacokinetic/pharmacodynamic (pk/pd),murine lung infection model,pasteurella multocida,minimum inhibitory concentration (mic)

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