Dose Optimization of Combined Linezolid and Fosfomycin against Enterococcus by Using an In Vitro Pharmacokinetic/Pharmacodynamic Model
ABSTRACT The rapid spread of antibiotic resistance among Enterococcus has prompted considerable interest in determining the dosage regimen of linezolid combined with fosfomycin. A checkerboard assay was employed to evaluate whether linezolid combined with fosfomycin had a synergistic effect on Enter...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2021-12-01
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| Series: | Microbiology Spectrum |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/Spectrum.00871-21 |
| _version_ | 1818973856852869120 |
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| author | Jun Mao Ting Li Na Zhang Shuaishuai Wang Yaowen Li Yu Peng Huiping Liu Guang Yang Yisong Yan Lifang Jiang Yanyan Liu Jiabin Li Xiaohui Huang |
| author_facet | Jun Mao Ting Li Na Zhang Shuaishuai Wang Yaowen Li Yu Peng Huiping Liu Guang Yang Yisong Yan Lifang Jiang Yanyan Liu Jiabin Li Xiaohui Huang |
| author_sort | Jun Mao |
| collection | DOAJ |
| description | ABSTRACT The rapid spread of antibiotic resistance among Enterococcus has prompted considerable interest in determining the dosage regimen of linezolid combined with fosfomycin. A checkerboard assay was employed to evaluate whether linezolid combined with fosfomycin had a synergistic effect on Enterococcus isolates from the hospital, including three drug-resistant strains (MIC of linezolid [MICLZD], ≥8 mg/L; MIC of fosfomycin [MICFOF], ≥256 mg/L). The in vitro static time-kill assay, dynamic pharmacokinetic (PK)/pharmacodynamic (PD) model, and semimechanistic PK/PD model were used to explore and predict effective combined dosage regimens. The checkerboard assay and in vitro static time-kill assay demonstrated that linezolid combined with fosfomycin has a synergistic effect on drug-resistant and sensitive Enterococcus. In the in vitro PK/PD model, the dosage regimen of linezolid (8 mg/L or 12 mg/L, steady-state concentration) combined with fosfomycin (6 g or 8 g) via a 0.5-h infusion every 8 h effectively suppressed bacterial growth at 24 h with a 3 log10 CFU/mL decrease compared with the initial inocula against two resistant and one sensitive Enterococcus isolates. The semimechanistic PK/PD model predicted that linezolid (more than 16 mg/L) combined with fosfomycin (6 g or 10 g) via a 0.5-h infusion every 8 h was required to achieve a 4 log10 CFU/mL decrease at 24 h against Enterococcus isolates (MICLZD ≥ 8 mg/L and MICFOF ≥ 256 mg/L). According to the prediction of the semimechanical PK/PD model, the effect of the combination was driven by linezolid, with fosfomycin enhancing the effect. Our study is the first to explore the synergistic effects of these two drugs from a qualitative and quantitative perspective and provides a simulation tool for future studies. IMPORTANCE In this study, we found that linezolid combined with fosfomycin could kill Enterococcus in vitro and that the administered dose was significantly lower after the combination treatment, which could reduce adverse effects and the development of drug resistance. The potential mechanism of the two-drug combination against Enterococcus was revealed from a quantitative perspective, which is an important step toward dose optimization in simulated humans. We hope that our research will help build a better relationship between clinicians and patients as we work together to address the challenges of antibiotic resistance in the 21st century. |
| first_indexed | 2024-12-20T15:30:49Z |
| format | Article |
| id | doaj.art-5485bfc72d444473909441cd94ebafb8 |
| institution | Directory Open Access Journal |
| issn | 2165-0497 |
| language | English |
| last_indexed | 2024-12-20T15:30:49Z |
| publishDate | 2021-12-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | Microbiology Spectrum |
| spelling | doaj.art-5485bfc72d444473909441cd94ebafb82022-12-21T19:35:37ZengAmerican Society for MicrobiologyMicrobiology Spectrum2165-04972021-12-019310.1128/Spectrum.00871-21Dose Optimization of Combined Linezolid and Fosfomycin against Enterococcus by Using an In Vitro Pharmacokinetic/Pharmacodynamic ModelJun Mao0Ting Li1Na Zhang2Shuaishuai Wang3Yaowen Li4Yu Peng5Huiping Liu6Guang Yang7Yisong Yan8Lifang Jiang9Yanyan Liu10Jiabin Li11Xiaohui Huang12Department of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Hefei, ChinaCenter for Drug Clinical Research, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaDepartment of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Hefei, ChinaDepartment of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Hefei, ChinaDepartment of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Hefei, ChinaDepartment of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Hefei, ChinaDepartment of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Hefei, ChinaDepartment of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Hefei, ChinaDepartment of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Hefei, ChinaDepartment of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Hefei, ChinaDepartment of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, ChinaDepartment of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, ChinaDepartment of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Hefei, ChinaABSTRACT The rapid spread of antibiotic resistance among Enterococcus has prompted considerable interest in determining the dosage regimen of linezolid combined with fosfomycin. A checkerboard assay was employed to evaluate whether linezolid combined with fosfomycin had a synergistic effect on Enterococcus isolates from the hospital, including three drug-resistant strains (MIC of linezolid [MICLZD], ≥8 mg/L; MIC of fosfomycin [MICFOF], ≥256 mg/L). The in vitro static time-kill assay, dynamic pharmacokinetic (PK)/pharmacodynamic (PD) model, and semimechanistic PK/PD model were used to explore and predict effective combined dosage regimens. The checkerboard assay and in vitro static time-kill assay demonstrated that linezolid combined with fosfomycin has a synergistic effect on drug-resistant and sensitive Enterococcus. In the in vitro PK/PD model, the dosage regimen of linezolid (8 mg/L or 12 mg/L, steady-state concentration) combined with fosfomycin (6 g or 8 g) via a 0.5-h infusion every 8 h effectively suppressed bacterial growth at 24 h with a 3 log10 CFU/mL decrease compared with the initial inocula against two resistant and one sensitive Enterococcus isolates. The semimechanistic PK/PD model predicted that linezolid (more than 16 mg/L) combined with fosfomycin (6 g or 10 g) via a 0.5-h infusion every 8 h was required to achieve a 4 log10 CFU/mL decrease at 24 h against Enterococcus isolates (MICLZD ≥ 8 mg/L and MICFOF ≥ 256 mg/L). According to the prediction of the semimechanical PK/PD model, the effect of the combination was driven by linezolid, with fosfomycin enhancing the effect. Our study is the first to explore the synergistic effects of these two drugs from a qualitative and quantitative perspective and provides a simulation tool for future studies. IMPORTANCE In this study, we found that linezolid combined with fosfomycin could kill Enterococcus in vitro and that the administered dose was significantly lower after the combination treatment, which could reduce adverse effects and the development of drug resistance. The potential mechanism of the two-drug combination against Enterococcus was revealed from a quantitative perspective, which is an important step toward dose optimization in simulated humans. We hope that our research will help build a better relationship between clinicians and patients as we work together to address the challenges of antibiotic resistance in the 21st century.https://journals.asm.org/doi/10.1128/Spectrum.00871-21linezolidfosfomycinPK/PD modelEnterococcuscombination therapy |
| spellingShingle | Jun Mao Ting Li Na Zhang Shuaishuai Wang Yaowen Li Yu Peng Huiping Liu Guang Yang Yisong Yan Lifang Jiang Yanyan Liu Jiabin Li Xiaohui Huang Dose Optimization of Combined Linezolid and Fosfomycin against Enterococcus by Using an In Vitro Pharmacokinetic/Pharmacodynamic Model Microbiology Spectrum linezolid fosfomycin PK/PD model Enterococcus combination therapy |
| title | Dose Optimization of Combined Linezolid and Fosfomycin against Enterococcus by Using an In Vitro Pharmacokinetic/Pharmacodynamic Model |
| title_full | Dose Optimization of Combined Linezolid and Fosfomycin against Enterococcus by Using an In Vitro Pharmacokinetic/Pharmacodynamic Model |
| title_fullStr | Dose Optimization of Combined Linezolid and Fosfomycin against Enterococcus by Using an In Vitro Pharmacokinetic/Pharmacodynamic Model |
| title_full_unstemmed | Dose Optimization of Combined Linezolid and Fosfomycin against Enterococcus by Using an In Vitro Pharmacokinetic/Pharmacodynamic Model |
| title_short | Dose Optimization of Combined Linezolid and Fosfomycin against Enterococcus by Using an In Vitro Pharmacokinetic/Pharmacodynamic Model |
| title_sort | dose optimization of combined linezolid and fosfomycin against enterococcus by using an in vitro pharmacokinetic pharmacodynamic model |
| topic | linezolid fosfomycin PK/PD model Enterococcus combination therapy |
| url | https://journals.asm.org/doi/10.1128/Spectrum.00871-21 |
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