Pharmacokinetics/pharmacodynamics of polymyxin B in patients with bloodstream infection caused by carbapenem-resistant Klebsiella pneumoniae
Introduction: Polymyxin B is a last-line therapy for carbapenem-resistant microorganisms. However, a lack of clinical pharmacokinetic/pharmacodynamic (PK/PD) data has substantially hindered dose optimization and breakpoint setting.Methods: A prospective, multi-center clinical trial was undertaken wi...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-12-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.975066/full |
| _version_ | 1798005623975051264 |
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| author | Zhenwei Yu Xiaofen Liu Xiaoxing Du Huiying Chen Feng Zhao Zhihui Zhou Yu Wang Yang Zheng Phillip J. Bergen Xi Li Renhua Sun Li Fang Wanzhen Li Yaxin Fan Hailan Wu Beining Guo Jian Li Yunsong Yu Jing Zhang Jing Zhang |
| author_facet | Zhenwei Yu Xiaofen Liu Xiaoxing Du Huiying Chen Feng Zhao Zhihui Zhou Yu Wang Yang Zheng Phillip J. Bergen Xi Li Renhua Sun Li Fang Wanzhen Li Yaxin Fan Hailan Wu Beining Guo Jian Li Yunsong Yu Jing Zhang Jing Zhang |
| author_sort | Zhenwei Yu |
| collection | DOAJ |
| description | Introduction: Polymyxin B is a last-line therapy for carbapenem-resistant microorganisms. However, a lack of clinical pharmacokinetic/pharmacodynamic (PK/PD) data has substantially hindered dose optimization and breakpoint setting.Methods: A prospective, multi-center clinical trial was undertaken with polymyxin B [2.5 mg/kg loading dose (3-h infusion), 1.25 mg/kg/12 h maintenance dose (2-h infusion)] for treatment of carbapenem-resistant K. pneumoniae (CRKP) bloodstream infections (BSI). Safety, clinical and microbiological efficacy were evaluated. A validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was applied to determine the concentrations of polymyxin B in blood samples. Population pharmacokinetic (PK) modeling and Monte Carlo simulations were conducted to examine the susceptibility breakpoint for polymyxin B against BSI caused by CRKP.Results: Nine patients were enrolled and evaluated for safety. Neurotoxicity (5/9), nephrotoxicity (5/9), and hyperpigmentation (1/9) were recorded. Blood cultures were negative within 3 days of commencing therapy in all 8 patients evaluated for microbiological efficacy, and clinical cure or improvement occurred in 6 of 8 patients. Cmax and Cmin following the loading dose were 5.53 ± 1.80 and 1.62 ± 0.41 mg/L, respectively. With maintenance dosing, AUCss,24 h was 79.6 ± 25.0 mg h/L and Css,avg 3.35 ± 1.06 mg/L. Monte Carlo simulations indicated that a 1 mg/kg/12-hourly maintenance dose could achieve >90% probability of target attainment (PTA) for isolates with minimum inhibitory concentration (MIC) ≤1 mg/L. PTA dropped substantially for MICs ≥2 mg/L, even with a maximally recommended daily dose of 1.5 mg/kg/12-hourly.Conclusion: This is the first clinical PK/PD study evaluating polymyxin B for BSI. These results will assist to optimize polymyxin B therapy and establish its breakpoints for CRKP BSI. |
| first_indexed | 2024-04-11T12:42:23Z |
| format | Article |
| id | doaj.art-ba77508fd5414c4ebc67cf26cab4206c |
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| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-11T12:42:23Z |
| publishDate | 2022-12-01 |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-ba77508fd5414c4ebc67cf26cab4206c2022-12-22T04:23:27ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-12-011310.3389/fphar.2022.975066975066Pharmacokinetics/pharmacodynamics of polymyxin B in patients with bloodstream infection caused by carbapenem-resistant Klebsiella pneumoniaeZhenwei Yu0Xiaofen Liu1Xiaoxing Du2Huiying Chen3Feng Zhao4Zhihui Zhou5Yu Wang6Yang Zheng7Phillip J. Bergen8Xi Li9Renhua Sun10Li Fang11Wanzhen Li12Yaxin Fan13Hailan Wu14Beining Guo15Jian Li16Yunsong Yu17Jing Zhang18Jing Zhang19Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, ChinaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, ChinaSir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, ChinaSir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, ChinaSir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, ChinaSir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, ChinaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, ChinaZhejiang Provincial People’s Hospital, Hangzhou, ChinaBiomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne, VIC, AustraliaZhejiang Provincial People’s Hospital, Hangzhou, ChinaZhejiang Provincial People’s Hospital, Hangzhou, ChinaSir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, ChinaInstitute of Antibiotics, 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, ChinaBiomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne, VIC, AustraliaSir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, ChinaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, ChinaPhase I Clinical Trial Center, Huashan Hospital, Fudan University, Shanghai, ChinaIntroduction: Polymyxin B is a last-line therapy for carbapenem-resistant microorganisms. However, a lack of clinical pharmacokinetic/pharmacodynamic (PK/PD) data has substantially hindered dose optimization and breakpoint setting.Methods: A prospective, multi-center clinical trial was undertaken with polymyxin B [2.5 mg/kg loading dose (3-h infusion), 1.25 mg/kg/12 h maintenance dose (2-h infusion)] for treatment of carbapenem-resistant K. pneumoniae (CRKP) bloodstream infections (BSI). Safety, clinical and microbiological efficacy were evaluated. A validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was applied to determine the concentrations of polymyxin B in blood samples. Population pharmacokinetic (PK) modeling and Monte Carlo simulations were conducted to examine the susceptibility breakpoint for polymyxin B against BSI caused by CRKP.Results: Nine patients were enrolled and evaluated for safety. Neurotoxicity (5/9), nephrotoxicity (5/9), and hyperpigmentation (1/9) were recorded. Blood cultures were negative within 3 days of commencing therapy in all 8 patients evaluated for microbiological efficacy, and clinical cure or improvement occurred in 6 of 8 patients. Cmax and Cmin following the loading dose were 5.53 ± 1.80 and 1.62 ± 0.41 mg/L, respectively. With maintenance dosing, AUCss,24 h was 79.6 ± 25.0 mg h/L and Css,avg 3.35 ± 1.06 mg/L. Monte Carlo simulations indicated that a 1 mg/kg/12-hourly maintenance dose could achieve >90% probability of target attainment (PTA) for isolates with minimum inhibitory concentration (MIC) ≤1 mg/L. PTA dropped substantially for MICs ≥2 mg/L, even with a maximally recommended daily dose of 1.5 mg/kg/12-hourly.Conclusion: This is the first clinical PK/PD study evaluating polymyxin B for BSI. These results will assist to optimize polymyxin B therapy and establish its breakpoints for CRKP BSI.https://www.frontiersin.org/articles/10.3389/fphar.2022.975066/fullpolymyxinspharmacokinetics/pharmacodynamicsCRKPbloodstream infectionneurotoxicitynephrotoxicity |
| spellingShingle | Zhenwei Yu Xiaofen Liu Xiaoxing Du Huiying Chen Feng Zhao Zhihui Zhou Yu Wang Yang Zheng Phillip J. Bergen Xi Li Renhua Sun Li Fang Wanzhen Li Yaxin Fan Hailan Wu Beining Guo Jian Li Yunsong Yu Jing Zhang Jing Zhang Pharmacokinetics/pharmacodynamics of polymyxin B in patients with bloodstream infection caused by carbapenem-resistant Klebsiella pneumoniae Frontiers in Pharmacology polymyxins pharmacokinetics/pharmacodynamics CRKP bloodstream infection neurotoxicity nephrotoxicity |
| title | Pharmacokinetics/pharmacodynamics of polymyxin B in patients with bloodstream infection caused by carbapenem-resistant Klebsiella pneumoniae |
| title_full | Pharmacokinetics/pharmacodynamics of polymyxin B in patients with bloodstream infection caused by carbapenem-resistant Klebsiella pneumoniae |
| title_fullStr | Pharmacokinetics/pharmacodynamics of polymyxin B in patients with bloodstream infection caused by carbapenem-resistant Klebsiella pneumoniae |
| title_full_unstemmed | Pharmacokinetics/pharmacodynamics of polymyxin B in patients with bloodstream infection caused by carbapenem-resistant Klebsiella pneumoniae |
| title_short | Pharmacokinetics/pharmacodynamics of polymyxin B in patients with bloodstream infection caused by carbapenem-resistant Klebsiella pneumoniae |
| title_sort | pharmacokinetics pharmacodynamics of polymyxin b in patients with bloodstream infection caused by carbapenem resistant klebsiella pneumoniae |
| topic | polymyxins pharmacokinetics/pharmacodynamics CRKP bloodstream infection neurotoxicity nephrotoxicity |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.975066/full |
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