In vitro pharmacokinetics/pharmacodynamics of FL058 (a novel beta-lactamase inhibitor) combined with meropenem against carbapenemase-producing Enterobacterales
Objective: FL058 is a novel beta-lactamase inhibitor with a broad spectrum of activity and a favorable safety profile. The objective of this study was to evaluate pharmacokinetic/pharmacodynamic (PK/PD) relationships for the combination of FL058 and meropenem in an in vitro infection model.Methods:...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-04-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2024.1282480/full |
| _version_ | 1797214681950060544 |
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| author | Zhiwei Huang Zhiwei Huang Xingchen Bian Xingchen Bian Yi Li Jiali Hu Beining Guo Xinyi Yang Yi Jin Shansong Zheng Xinmei Wang Cong Gao Jing Zhang Xiaojie Wu |
| author_facet | Zhiwei Huang Zhiwei Huang Xingchen Bian Xingchen Bian Yi Li Jiali Hu Beining Guo Xinyi Yang Yi Jin Shansong Zheng Xinmei Wang Cong Gao Jing Zhang Xiaojie Wu |
| author_sort | Zhiwei Huang |
| collection | DOAJ |
| description | Objective: FL058 is a novel beta-lactamase inhibitor with a broad spectrum of activity and a favorable safety profile. The objective of this study was to evaluate pharmacokinetic/pharmacodynamic (PK/PD) relationships for the combination of FL058 and meropenem in an in vitro infection model.Methods: By simulating human concentration-time profiles in the in vitro model, meropenem combined with FL058 when administered 1 g/0.5 g, 1 g/1 g, 2 g/1 g, and 2 g/2 g q8h by 3-h infusion achieved approximately 2- and 4-log10 kill to KPC/OXA-producing Klebsiella pneumoniae and Escherichia coli; the combination therapy could not inhibit NDM-producing K. pneumoniae but could maintain NDM-producing E. coli around a baseline.Results: The PK/PD indexes that best described the bacterial killing from baseline in log10 CFU/mL at 24 h were the percent time of free drug above the minimal inhibitory concentration (MIC) (%fT > MIC, MIC with FL058 at 4 mg/L) for meropenem and the percent time of free drug above 1 mg/L (%fT > 1 mg/L) for FL058. The targets for achieving a static effect and the 1- and 2-log10 kill were 74, 83, and 99 for %fT > MIC of meropenem and 40, 48, and 64 for %fT > 1 mg/L of FL058, respectively. The PK/PD index of %fT > 1 mg/L can provide a basis for evaluating clinical dosing regimens for FL058 combined with meropenem.Conclusion: FL058 combined with meropenem might be a potential treatment for KPC- and/or OXA-48-producing Enterobacterales infection. |
| first_indexed | 2024-04-24T11:18:03Z |
| format | Article |
| id | doaj.art-60441e5558104525a9d7e9a014220d30 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-24T11:18:03Z |
| publishDate | 2024-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-60441e5558104525a9d7e9a014220d302024-04-11T05:11:40ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122024-04-011510.3389/fphar.2024.12824801282480In vitro pharmacokinetics/pharmacodynamics of FL058 (a novel beta-lactamase inhibitor) combined with meropenem against carbapenemase-producing EnterobacteralesZhiwei Huang0Zhiwei Huang1Xingchen Bian2Xingchen Bian3Yi Li4Jiali Hu5Beining Guo6Xinyi Yang7Yi Jin8Shansong Zheng9Xinmei Wang10Cong Gao11Jing Zhang12Xiaojie Wu13Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, ChinaPhase I Clinical Research Center, Huashan Hospital, Fudan University, Shanghai, ChinaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, ChinaPhase I Clinical Research Center, Huashan Hospital, Fudan University, Shanghai, ChinaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, ChinaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, ChinaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, ChinaPhase I Clinical Research Center, Huashan Hospital, Fudan University, Shanghai, ChinaPhase I Clinical Research Center, Huashan Hospital, Fudan University, Shanghai, ChinaQilu Pharmaceutical Co Ltd, Jinan, ChinaQilu Pharmaceutical Co Ltd, Jinan, ChinaQilu Pharmaceutical Co Ltd, Jinan, ChinaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, ChinaPhase I Clinical Research Center, Huashan Hospital, Fudan University, Shanghai, ChinaObjective: FL058 is a novel beta-lactamase inhibitor with a broad spectrum of activity and a favorable safety profile. The objective of this study was to evaluate pharmacokinetic/pharmacodynamic (PK/PD) relationships for the combination of FL058 and meropenem in an in vitro infection model.Methods: By simulating human concentration-time profiles in the in vitro model, meropenem combined with FL058 when administered 1 g/0.5 g, 1 g/1 g, 2 g/1 g, and 2 g/2 g q8h by 3-h infusion achieved approximately 2- and 4-log10 kill to KPC/OXA-producing Klebsiella pneumoniae and Escherichia coli; the combination therapy could not inhibit NDM-producing K. pneumoniae but could maintain NDM-producing E. coli around a baseline.Results: The PK/PD indexes that best described the bacterial killing from baseline in log10 CFU/mL at 24 h were the percent time of free drug above the minimal inhibitory concentration (MIC) (%fT > MIC, MIC with FL058 at 4 mg/L) for meropenem and the percent time of free drug above 1 mg/L (%fT > 1 mg/L) for FL058. The targets for achieving a static effect and the 1- and 2-log10 kill were 74, 83, and 99 for %fT > MIC of meropenem and 40, 48, and 64 for %fT > 1 mg/L of FL058, respectively. The PK/PD index of %fT > 1 mg/L can provide a basis for evaluating clinical dosing regimens for FL058 combined with meropenem.Conclusion: FL058 combined with meropenem might be a potential treatment for KPC- and/or OXA-48-producing Enterobacterales infection.https://www.frontiersin.org/articles/10.3389/fphar.2024.1282480/fullbeta-lactamase inhibitormeropenemin vitro modelpharmacokinetics/pharmacodynamicscarbapenemase-producing Enterobacterales |
| spellingShingle | Zhiwei Huang Zhiwei Huang Xingchen Bian Xingchen Bian Yi Li Jiali Hu Beining Guo Xinyi Yang Yi Jin Shansong Zheng Xinmei Wang Cong Gao Jing Zhang Xiaojie Wu In vitro pharmacokinetics/pharmacodynamics of FL058 (a novel beta-lactamase inhibitor) combined with meropenem against carbapenemase-producing Enterobacterales Frontiers in Pharmacology beta-lactamase inhibitor meropenem in vitro model pharmacokinetics/pharmacodynamics carbapenemase-producing Enterobacterales |
| title | In vitro pharmacokinetics/pharmacodynamics of FL058 (a novel beta-lactamase inhibitor) combined with meropenem against carbapenemase-producing Enterobacterales |
| title_full | In vitro pharmacokinetics/pharmacodynamics of FL058 (a novel beta-lactamase inhibitor) combined with meropenem against carbapenemase-producing Enterobacterales |
| title_fullStr | In vitro pharmacokinetics/pharmacodynamics of FL058 (a novel beta-lactamase inhibitor) combined with meropenem against carbapenemase-producing Enterobacterales |
| title_full_unstemmed | In vitro pharmacokinetics/pharmacodynamics of FL058 (a novel beta-lactamase inhibitor) combined with meropenem against carbapenemase-producing Enterobacterales |
| title_short | In vitro pharmacokinetics/pharmacodynamics of FL058 (a novel beta-lactamase inhibitor) combined with meropenem against carbapenemase-producing Enterobacterales |
| title_sort | in vitro pharmacokinetics pharmacodynamics of fl058 a novel beta lactamase inhibitor combined with meropenem against carbapenemase producing enterobacterales |
| topic | beta-lactamase inhibitor meropenem in vitro model pharmacokinetics/pharmacodynamics carbapenemase-producing Enterobacterales |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2024.1282480/full |
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