Pharmacokinetics, optimal dosing, and safety of linezolid in children with multidrug-resistant tuberculosis: Combined data from two prospective observational studies
Linezolid is increasingly important for multidrug-resistant tuberculosis (MDR-TB) treatment. However, among children with MDR-TB, there are no linezolid pharmacokinetic data, and its adverse effects have not yet been prospectively described. We characterised the pharmacokinetics, safety, and optimal...
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| Vydáno v: | PLoS medicine Ročník 16; číslo 4; s. e1002789 |
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| Hlavní autoři: | , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
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United States
Public Library of Science
30.04.2019
Public Library of Science (PLoS) |
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| ISSN: | 1549-1676, 1549-1277, 1549-1676 |
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| Abstract | Linezolid is increasingly important for multidrug-resistant tuberculosis (MDR-TB) treatment. However, among children with MDR-TB, there are no linezolid pharmacokinetic data, and its adverse effects have not yet been prospectively described. We characterised the pharmacokinetics, safety, and optimal dose of linezolid in children treated for MDR-TB.
Children routinely treated for MDR-TB in 2 observational studies (2011-2015, 2016-2018) conducted at a single site in Cape Town, South Africa, underwent intensive pharmacokinetic sampling after either a single dose or multiple doses of linezolid (at steady state). Linezolid pharmacokinetic parameters, and their relationships with covariates of interest, were described using nonlinear mixed-effects modelling. Children receiving long-term linezolid as a component of their routine treatment had regular clinical and laboratory monitoring. Adverse events were assessed for severity and attribution to linezolid. The final population pharmacokinetic model was used to derive optimal weight-banded doses resulting in exposures in children approximating those in adults receiving once-daily linezolid 600 mg. Forty-eight children were included (mean age 5.9 years; range 0.6 to 15.3); 31 received a single dose of linezolid, and 17 received multiple doses. The final pharmacokinetic model consisted of a one-compartment model characterised by clearance (CL) and volume (V) parameters that included allometric scaling to account for weight; no other evaluated covariates contributed to the model. Linezolid exposures in this population were higher compared to exposures in adults who had received a 600 mg once-daily dose. Consequently simulated, weight-banded once-daily optimal doses for children were lower than those currently used for most weight bands. Ten of 17 children who were followed long term had a linezolid-related adverse event, including 5 with a grade 3 or 4 event, all anaemia. Adverse events resulted in linezolid dose reductions in 4, temporary interruptions in 5, and permanent discontinuation in 4 children. Limitations of the study include the lack of very young children (none below 6 months of age), the limited number who were HIV infected, and the modest number of children contributing to long-term safety data.
Linezolid-related adverse effects were frequent and occasionally severe. Careful linezolid safety monitoring is required. Compared to doses currently used in children in many settings for MDR-TB treatment, lower doses may approximate current adult target exposures, might result in fewer adverse events, and should therefore be evaluated. |
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| AbstractList | Linezolid is increasingly important for multidrug-resistant tuberculosis (MDR-TB) treatment. However, among children with MDR-TB, there are no linezolid pharmacokinetic data, and its adverse effects have not yet been prospectively described. We characterised the pharmacokinetics, safety, and optimal dose of linezolid in children treated for MDR-TB. Children routinely treated for MDR-TB in 2 observational studies (2011-2015, 2016-2018) conducted at a single site in Cape Town, South Africa, underwent intensive pharmacokinetic sampling after either a single dose or multiple doses of linezolid (at steady state). Linezolid pharmacokinetic parameters, and their relationships with covariates of interest, were described using nonlinear mixed-effects modelling. Children receiving long-term linezolid as a component of their routine treatment had regular clinical and laboratory monitoring. Adverse events were assessed for severity and attribution to linezolid. The final population pharmacokinetic model was used to derive optimal weight-banded doses resulting in exposures in children approximating those in adults receiving once-daily linezolid 600 mg. Forty-eight children were included (mean age 5.9 years; range 0.6 to 15.3); 31 received a single dose of linezolid, and 17 received multiple doses. The final pharmacokinetic model consisted of a one-compartment model characterised by clearance (CL) and volume (V) parameters that included allometric scaling to account for weight; no other evaluated covariates contributed to the model. Linezolid exposures in this population were higher compared to exposures in adults who had received a 600 mg once-daily dose. Consequently simulated, weight-banded once-daily optimal doses for children were lower than those currently used for most weight bands. Ten of 17 children who were followed long term had a linezolid-related adverse event, including 5 with a grade 3 or 4 event, all anaemia. Adverse events resulted in linezolid dose reductions in 4, temporary interruptions in 5, and permanent discontinuation in 4 children. Limitations of the study include the lack of very young children (none below 6 months of age), the limited number who were HIV infected, and the modest number of children contributing to long-term safety data. Linezolid-related adverse effects were frequent and occasionally severe. Careful linezolid safety monitoring is required. Compared to doses currently used in children in many settings for MDR-TB treatment, lower doses may approximate current adult target exposures, might result in fewer adverse events, and should therefore be evaluated. Background Linezolid is increasingly important for multidrug-resistant tuberculosis (MDR-TB) treatment. However, among children with MDR-TB, there are no linezolid pharmacokinetic data, and its adverse effects have not yet been prospectively described. We characterised the pharmacokinetics, safety, and optimal dose of linezolid in children treated for MDR-TB. Methods and findings Children routinely treated for MDR-TB in 2 observational studies (2011-2015, 2016-2018) conducted at a single site in Cape Town, South Africa, underwent intensive pharmacokinetic sampling after either a single dose or multiple doses of linezolid (at steady state). Linezolid pharmacokinetic parameters, and their relationships with covariates of interest, were described using nonlinear mixed-effects modelling. Children receiving long-term linezolid as a component of their routine treatment had regular clinical and laboratory monitoring. Adverse events were assessed for severity and attribution to linezolid. The final population pharmacokinetic model was used to derive optimal weight-banded doses resulting in exposures in children approximating those in adults receiving once-daily linezolid 600 mg. Forty-eight children were included (mean age 5.9 years; range 0.6 to 15.3); 31 received a single dose of linezolid, and 17 received multiple doses. The final pharmacokinetic model consisted of a one-compartment model characterised by clearance (CL) and volume (V) parameters that included allometric scaling to account for weight; no other evaluated covariates contributed to the model. Linezolid exposures in this population were higher compared to exposures in adults who had received a 600 mg once-daily dose. Consequently simulated, weight-banded once-daily optimal doses for children were lower than those currently used for most weight bands. Ten of 17 children who were followed long term had a linezolid-related adverse event, including 5 with a grade 3 or 4 event, all anaemia. Adverse events resulted in linezolid dose reductions in 4, temporary interruptions in 5, and permanent discontinuation in 4 children. Limitations of the study include the lack of very young children (none below 6 months of age), the limited number who were HIV infected, and the modest number of children contributing to long-term safety data. Conclusions Linezolid-related adverse effects were frequent and occasionally severe. Careful linezolid safety monitoring is required. Compared to doses currently used in children in many settings for MDR-TB treatment, lower doses may approximate current adult target exposures, might result in fewer adverse events, and should therefore be evaluated. Background Linezolid is increasingly important for multidrug-resistant tuberculosis (MDR-TB) treatment. However, among children with MDR-TB, there are no linezolid pharmacokinetic data, and its adverse effects have not yet been prospectively described. We characterised the pharmacokinetics, safety, and optimal dose of linezolid in children treated for MDR-TB. Methods and findings Children routinely treated for MDR-TB in 2 observational studies (2011–2015, 2016–2018) conducted at a single site in Cape Town, South Africa, underwent intensive pharmacokinetic sampling after either a single dose or multiple doses of linezolid (at steady state). Linezolid pharmacokinetic parameters, and their relationships with covariates of interest, were described using nonlinear mixed-effects modelling. Children receiving long-term linezolid as a component of their routine treatment had regular clinical and laboratory monitoring. Adverse events were assessed for severity and attribution to linezolid. The final population pharmacokinetic model was used to derive optimal weight-banded doses resulting in exposures in children approximating those in adults receiving once-daily linezolid 600 mg. Forty-eight children were included (mean age 5.9 years; range 0.6 to 15.3); 31 received a single dose of linezolid, and 17 received multiple doses. The final pharmacokinetic model consisted of a one-compartment model characterised by clearance (CL) and volume (V) parameters that included allometric scaling to account for weight; no other evaluated covariates contributed to the model. Linezolid exposures in this population were higher compared to exposures in adults who had received a 600 mg once-daily dose. Consequently simulated, weight-banded once-daily optimal doses for children were lower than those currently used for most weight bands. Ten of 17 children who were followed long term had a linezolid-related adverse event, including 5 with a grade 3 or 4 event, all anaemia. Adverse events resulted in linezolid dose reductions in 4, temporary interruptions in 5, and permanent discontinuation in 4 children. Limitations of the study include the lack of very young children (none below 6 months of age), the limited number who were HIV infected, and the modest number of children contributing to long-term safety data. Conclusions Linezolid-related adverse effects were frequent and occasionally severe. Careful linezolid safety monitoring is required. Compared to doses currently used in children in many settings for MDR-TB treatment, lower doses may approximate current adult target exposures, might result in fewer adverse events, and should therefore be evaluated. Linezolid is increasingly important for multidrug-resistant tuberculosis (MDR-TB) treatment. However, among children with MDR-TB, there are no linezolid pharmacokinetic data, and its adverse effects have not yet been prospectively described. We characterised the pharmacokinetics, safety, and optimal dose of linezolid in children treated for MDR-TB.BACKGROUNDLinezolid is increasingly important for multidrug-resistant tuberculosis (MDR-TB) treatment. However, among children with MDR-TB, there are no linezolid pharmacokinetic data, and its adverse effects have not yet been prospectively described. We characterised the pharmacokinetics, safety, and optimal dose of linezolid in children treated for MDR-TB.Children routinely treated for MDR-TB in 2 observational studies (2011-2015, 2016-2018) conducted at a single site in Cape Town, South Africa, underwent intensive pharmacokinetic sampling after either a single dose or multiple doses of linezolid (at steady state). Linezolid pharmacokinetic parameters, and their relationships with covariates of interest, were described using nonlinear mixed-effects modelling. Children receiving long-term linezolid as a component of their routine treatment had regular clinical and laboratory monitoring. Adverse events were assessed for severity and attribution to linezolid. The final population pharmacokinetic model was used to derive optimal weight-banded doses resulting in exposures in children approximating those in adults receiving once-daily linezolid 600 mg. Forty-eight children were included (mean age 5.9 years; range 0.6 to 15.3); 31 received a single dose of linezolid, and 17 received multiple doses. The final pharmacokinetic model consisted of a one-compartment model characterised by clearance (CL) and volume (V) parameters that included allometric scaling to account for weight; no other evaluated covariates contributed to the model. Linezolid exposures in this population were higher compared to exposures in adults who had received a 600 mg once-daily dose. Consequently simulated, weight-banded once-daily optimal doses for children were lower than those currently used for most weight bands. Ten of 17 children who were followed long term had a linezolid-related adverse event, including 5 with a grade 3 or 4 event, all anaemia. Adverse events resulted in linezolid dose reductions in 4, temporary interruptions in 5, and permanent discontinuation in 4 children. Limitations of the study include the lack of very young children (none below 6 months of age), the limited number who were HIV infected, and the modest number of children contributing to long-term safety data.METHODS AND FINDINGSChildren routinely treated for MDR-TB in 2 observational studies (2011-2015, 2016-2018) conducted at a single site in Cape Town, South Africa, underwent intensive pharmacokinetic sampling after either a single dose or multiple doses of linezolid (at steady state). Linezolid pharmacokinetic parameters, and their relationships with covariates of interest, were described using nonlinear mixed-effects modelling. Children receiving long-term linezolid as a component of their routine treatment had regular clinical and laboratory monitoring. Adverse events were assessed for severity and attribution to linezolid. The final population pharmacokinetic model was used to derive optimal weight-banded doses resulting in exposures in children approximating those in adults receiving once-daily linezolid 600 mg. Forty-eight children were included (mean age 5.9 years; range 0.6 to 15.3); 31 received a single dose of linezolid, and 17 received multiple doses. The final pharmacokinetic model consisted of a one-compartment model characterised by clearance (CL) and volume (V) parameters that included allometric scaling to account for weight; no other evaluated covariates contributed to the model. Linezolid exposures in this population were higher compared to exposures in adults who had received a 600 mg once-daily dose. Consequently simulated, weight-banded once-daily optimal doses for children were lower than those currently used for most weight bands. Ten of 17 children who were followed long term had a linezolid-related adverse event, including 5 with a grade 3 or 4 event, all anaemia. Adverse events resulted in linezolid dose reductions in 4, temporary interruptions in 5, and permanent discontinuation in 4 children. Limitations of the study include the lack of very young children (none below 6 months of age), the limited number who were HIV infected, and the modest number of children contributing to long-term safety data.Linezolid-related adverse effects were frequent and occasionally severe. Careful linezolid safety monitoring is required. Compared to doses currently used in children in many settings for MDR-TB treatment, lower doses may approximate current adult target exposures, might result in fewer adverse events, and should therefore be evaluated.CONCLUSIONSLinezolid-related adverse effects were frequent and occasionally severe. Careful linezolid safety monitoring is required. Compared to doses currently used in children in many settings for MDR-TB treatment, lower doses may approximate current adult target exposures, might result in fewer adverse events, and should therefore be evaluated. Using data from two cohorts, Anthony Garcia-Prats and colleagues model the appropriate dosing necessary to achieve target concentrations for linezolid to treat children with multidrug-resistant tuberculosis. BackgroundLinezolid is increasingly important for multidrug-resistant tuberculosis (MDR-TB) treatment. However, among children with MDR-TB, there are no linezolid pharmacokinetic data, and its adverse effects have not yet been prospectively described. We characterised the pharmacokinetics, safety, and optimal dose of linezolid in children treated for MDR-TB.Methods and findingsChildren routinely treated for MDR-TB in 2 observational studies (2011-2015, 2016-2018) conducted at a single site in Cape Town, South Africa, underwent intensive pharmacokinetic sampling after either a single dose or multiple doses of linezolid (at steady state). Linezolid pharmacokinetic parameters, and their relationships with covariates of interest, were described using nonlinear mixed-effects modelling. Children receiving long-term linezolid as a component of their routine treatment had regular clinical and laboratory monitoring. Adverse events were assessed for severity and attribution to linezolid. The final population pharmacokinetic model was used to derive optimal weight-banded doses resulting in exposures in children approximating those in adults receiving once-daily linezolid 600 mg. Forty-eight children were included (mean age 5.9 years; range 0.6 to 15.3); 31 received a single dose of linezolid, and 17 received multiple doses. The final pharmacokinetic model consisted of a one-compartment model characterised by clearance (CL) and volume (V) parameters that included allometric scaling to account for weight; no other evaluated covariates contributed to the model. Linezolid exposures in this population were higher compared to exposures in adults who had received a 600 mg once-daily dose. Consequently simulated, weight-banded once-daily optimal doses for children were lower than those currently used for most weight bands. Ten of 17 children who were followed long term had a linezolid-related adverse event, including 5 with a grade 3 or 4 event, all anaemia. Adverse events resulted in linezolid dose reductions in 4, temporary interruptions in 5, and permanent discontinuation in 4 children. Limitations of the study include the lack of very young children (none below 6 months of age), the limited number who were HIV infected, and the modest number of children contributing to long-term safety data.ConclusionsLinezolid-related adverse effects were frequent and occasionally severe. Careful linezolid safety monitoring is required. Compared to doses currently used in children in many settings for MDR-TB treatment, lower doses may approximate current adult target exposures, might result in fewer adverse events, and should therefore be evaluated. Linezolid is increasingly important for multidrug-resistant tuberculosis (MDR-TB) treatment. However, among children with MDR-TB, there are no linezolid pharmacokinetic data, and its adverse effects have not yet been prospectively described. We characterised the pharmacokinetics, safety, and optimal dose of linezolid in children treated for MDR-TB. Children routinely treated for MDR-TB in 2 observational studies (2011-2015, 2016-2018) conducted at a single site in Cape Town, South Africa, underwent intensive pharmacokinetic sampling after either a single dose or multiple doses of linezolid (at steady state). Linezolid pharmacokinetic parameters, and their relationships with covariates of interest, were described using nonlinear mixed-effects modelling. Children receiving long-term linezolid as a component of their routine treatment had regular clinical and laboratory monitoring. Adverse events were assessed for severity and attribution to linezolid. The final population pharmacokinetic model was used to derive optimal weight-banded doses resulting in exposures in children approximating those in adults receiving once-daily linezolid 600 mg. Forty-eight children were included (mean age 5.9 years; range 0.6 to 15.3); 31 received a single dose of linezolid, and 17 received multiple doses. The final pharmacokinetic model consisted of a one-compartment model characterised by clearance (CL) and volume (V) parameters that included allometric scaling to account for weight; no other evaluated covariates contributed to the model. Linezolid exposures in this population were higher compared to exposures in adults who had received a 600 mg once-daily dose. Consequently simulated, weight-banded once-daily optimal doses for children were lower than those currently used for most weight bands. Ten of 17 children who were followed long term had a linezolid-related adverse event, including 5 with a grade 3 or 4 event, all anaemia. Adverse events resulted in linezolid dose reductions in 4, temporary interruptions in 5, and permanent discontinuation in 4 children. Limitations of the study include the lack of very young children (none below 6 months of age), the limited number who were HIV infected, and the modest number of children contributing to long-term safety data. Linezolid-related adverse effects were frequent and occasionally severe. Careful linezolid safety monitoring is required. Compared to doses currently used in children in many settings for MDR-TB treatment, lower doses may approximate current adult target exposures, might result in fewer adverse events, and should therefore be evaluated. |
| Audience | Academic |
| Author | Savic, Rada M. Garcia-Prats, Anthony J. Garcia-Cremades, Maria Wiesner, Lubbe Hesseling, Anneke C. Draper, Heather R. Schaaf, H. Simon Winckler, Jana |
| AuthorAffiliation | 3 Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa 2 Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, United States of America 1 Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa FIND, SWITZERLAND |
| AuthorAffiliation_xml | – name: 3 Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa – name: 1 Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa – name: 2 Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, United States of America – name: FIND, SWITZERLAND |
| Author_xml | – sequence: 1 givenname: Anthony J. orcidid: 0000-0002-9280-1950 surname: Garcia-Prats fullname: Garcia-Prats, Anthony J. – sequence: 2 givenname: H. Simon surname: Schaaf fullname: Schaaf, H. Simon – sequence: 3 givenname: Heather R. surname: Draper fullname: Draper, Heather R. – sequence: 4 givenname: Maria orcidid: 0000-0002-3369-1210 surname: Garcia-Cremades fullname: Garcia-Cremades, Maria – sequence: 5 givenname: Jana orcidid: 0000-0003-1218-468X surname: Winckler fullname: Winckler, Jana – sequence: 6 givenname: Lubbe orcidid: 0000-0002-9070-8699 surname: Wiesner fullname: Wiesner, Lubbe – sequence: 7 givenname: Anneke C. surname: Hesseling fullname: Hesseling, Anneke C. – sequence: 8 givenname: Rada M. orcidid: 0000-0003-3143-5579 surname: Savic fullname: Savic, Rada M. |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/31039153$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
| Copyright | COPYRIGHT 2019 Public Library of Science 2019 Garcia-Prats et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. 2019 Garcia-Prats et al 2019 Garcia-Prats et al |
| Copyright_xml | – notice: COPYRIGHT 2019 Public Library of Science – notice: 2019 Garcia-Prats et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. – notice: 2019 Garcia-Prats et al 2019 Garcia-Prats et al |
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| DOI | 10.1371/journal.pmed.1002789 |
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| Discipline | Medicine |
| DocumentTitleAlternate | Linezolid PK and safety in children with MDR-TB |
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| References_xml | – year: 2017 ident: ref27 article-title: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events publication-title: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events – year: 2018 ident: ref18 article-title: Linezolid pharmacokinetics in MDR-TB: a systematic review, meta-analysis and Monte Carlo simulation publication-title: Journal of Antimicrobial Chemotherapy – volume: 21 start-page: 1223 issue: 10 year: 2015 ident: ref37 article-title: The association between sterilizing activity and drug distribution into tuberculosis lesions publication-title: Nature Medicine doi: 10.1038/nm.3937 – year: 2011 ident: ref23 article-title: Guidelines for the programmatic management of drug-resistant tuberculosis– 2011 update – ident: ref7 – volume: 16 start-page: 1193 issue: 10 year: 2016 ident: ref12 article-title: Global burden of drug-resistant tuberculosis in children: a mathematical modelling study publication-title: Lancet Infectious Diseases doi: 10.1016/S1473-3099(16)30132-3 – volume: 15 start-page: 93 issue: 2 year: 2013 ident: ref15 article-title: Pharmacokinetics of antibacterial agents in the CSF of children and adolescents publication-title: Paediatric Drugs doi: 10.1007/s40272-013-0017-5 – year: 2018 ident: ref6 article-title: Rapid Communication: Key changes to treatment of multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB) – volume: 42 start-page: 329 issue: 4 year: 2013 ident: ref16 article-title: Plasma exposure of free linezolid and its ratio to minimum inhibitory concentration varies in critically ill patients publication-title: International Journal of Antimicrobial Agents doi: 10.1016/j.ijantimicag.2013.06.015 – volume: 392 start-page: 821 issue: 10150 year: 2018 ident: ref5 article-title: Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis publication-title: Lancet doi: 10.1016/S0140-6736(18)31644-1 – volume: 13 start-page: 152 year: 2013 ident: ref29 article-title: Restricted mean survival time: an alternative to the hazard ratio for the design and analysis of randomized trials with a time-to-event outcome publication-title: BMC Medical Research Methodology doi: 10.1186/1471-2288-13-152 – volume: 2 start-page: 643 issue: 5 year: 2011 ident: ref32 article-title: Flip-flop pharmacokinetics—delivering a reversal of disposition: challenges and opportunities during drug development publication-title: Therapeutic Delivery doi: 10.4155/tde.11.19 – volume: 74 start-page: 413 issue: 5 year: 2003 ident: ref38 article-title: Impact of ontogeny on linezolid disposition in neonates and infants publication-title: Clinical Pharmacology and Therapeutics doi: 10.1016/S0009-9236(03)00226-1 – year: 2013 ident: ref24 article-title: Management of Drug-Resistant Tuberculosis: Policy Guidelines publication-title: Management of Drug-Resistant Tuberculosis: Policy Guidelines – year: 2016 ident: ref22 article-title: WHO Treatment guidelines for drug-resistant tuberculosis: 2016 update – volume: 358 start-page: 1975 issue: 9297 year: 2001 ident: ref2 article-title: Oxazolidinone antibiotics publication-title: Lancet doi: 10.1016/S0140-6736(01)06964-1 – volume: 383 start-page: 1572 issue: 9928 year: 2014 ident: ref11 article-title: Incidence of multidrug-resistant tuberculosis disease in children: systematic review and global estimates publication-title: Lancet doi: 10.1016/S0140-6736(14)60195-1 – volume: 22 start-page: S153 issue: 9 year: 2003 ident: ref19 article-title: Linezolid pharmacokinetics in pediatric patients: an overview publication-title: Pediatric Infectious Disease Journal doi: 10.1097/01.inf.0000086954.43010.63 – volume: 121 start-page: 303 issue: 4 year: 2017 ident: ref17 article-title: A 10-Year Experience of therapeutic drug monitoring (TDM) of linezolid in a hospital-wide population of patients receiving conventional dosing: is there enough evidence for suggesting TDM in the majority of patients? publication-title: Basic & Clinical Pharmacology & Toxicology doi: 10.1111/bcpt.12797 – volume: 17 start-page: 407 issue: 4 year: 1998 ident: ref28 article-title: British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood publication-title: Statistics in Medicine doi: 10.1002/(SICI)1097-0258(19980228)17:4<407::AID-SIM742>3.0.CO;2-L – year: 2009 ident: ref25 article-title: Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events publication-title: Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events – volume: 13 start-page: 16 issue: 1 year: 2013 ident: ref4 article-title: Linezolid for multidrug-resistant tuberculosis publication-title: Lancet Infectious Diseases doi: 10.1016/S1473-3099(12)70299-2 – volume: 94 start-page: 93 issue: 2 year: 2014 ident: ref9 article-title: Linezolid for the treatment of drug-resistant tuberculosis in children: A review and recommendations publication-title: Tuberculosis (Edinburgh, Scotland) doi: 10.1016/j.tube.2013.10.003 – year: 2017 ident: ref35 article-title: Linezolid dose that maximizes sterilizing effect while minimizing toxicity and resistance emergence for tuberculosis publication-title: Antimicrobial Agents and Chemotherapy – volume: 2 start-page: 1627 issue: 11 year: 2015 ident: ref31 article-title: Linezolid trough concentrations correlate with mitochondrial toxicity-related adverse events in the treatment of chronic extensively drug-resistant tuberculosis publication-title: EBioMedicine doi: 10.1016/j.ebiom.2015.09.051 – volume: 2 start-page: 1568 issue: 11 year: 2015 ident: ref20 article-title: Linezolid for treating tuberculosis: a delicate balancing act publication-title: EBioMedicine doi: 10.1016/j.ebiom.2015.10.014 – volume: 198 start-page: 684 issue: 5 year: 2018 ident: ref30 article-title: An Alternative approach for the analysis of time-to-event and survival outcomes in pulmonary medicine publication-title: American Journal of Respiratory and Critical Care Medicine doi: 10.1164/rccm.201801-0189LE – volume: 61 issue: 10 year: 2017 ident: ref34 article-title: Systematic therapeutic drug monitoring for linezolid: variability and clinical impact publication-title: Antimicrobial Agents and Chemotherapy doi: 10.1128/AAC.00687-17 – volume: 29 start-page: 827 issue: 9 year: 2010 ident: ref14 article-title: Pharmacokinetics and distribution of linezolid in cerebrospinal fluid in children and adolescents publication-title: Pediatric Infectious Disease Journal doi: 10.1097/INF.0b013e3181df4b9a – volume: 6 start-page: e01741 issue: 6 year: 2015 ident: ref36 article-title: Preclinical evaluations to identify optimal linezolid regimens for tuberculosis therapy publication-title: MBio doi: 10.1128/mBio.01741-15 – year: 2018 ident: ref1 article-title: Global tuberculosis report 2018 – year: 2017 ident: ref8 article-title: 2017 Pipeline Report: HIV, TB & HCV. Drugs, diagnostics, vaccines, preventive technologies, cure research, and immune-based and gene therapies in development – volume: 51 start-page: ii17 issue: Suppl 2 year: 2003 ident: ref13 article-title: Pharmacokinetic and pharmacodynamic profile of linezolid in healthy volunteers and patients with gram-positive infections publication-title: Journal of Antimicrobial Chemotherapy – volume: 38 start-page: 573 issue: 5 year: 2016 ident: ref33 article-title: Variable linezolid exposure in intensive care unit patients: possible role of drug-drug interactions publication-title: Therapeutic Drug Monitoring doi: 10.1097/FTD.0000000000000324 – volume: 42 start-page: 288 issue: 1 year: 2013 ident: ref3 article-title: Linezolid to treat extensively drug-resistant TB: retrospective data are confirmed by experimental evidence publication-title: European Respiratory Journal doi: 10.1183/09031936.00191712 – ident: ref10 – volume: 367 start-page: 1508 issue: 16 year: 2012 ident: ref21 article-title: Linezolid for treatment of chronic extensively drug-resistant tuberculosis publication-title: New England Journal of Medicine doi: 10.1056/NEJMoa1201964 – year: 2014 ident: ref26 article-title: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events publication-title: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events |
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| Snippet | Linezolid is increasingly important for multidrug-resistant tuberculosis (MDR-TB) treatment. However, among children with MDR-TB, there are no linezolid... Background Linezolid is increasingly important for multidrug-resistant tuberculosis (MDR-TB) treatment. However, among children with MDR-TB, there are no... Using data from two cohorts, Anthony Garcia-Prats and colleagues model the appropriate dosing necessary to achieve target concentrations for linezolid to treat... BackgroundLinezolid is increasingly important for multidrug-resistant tuberculosis (MDR-TB) treatment. However, among children with MDR-TB, there are no... Background Linezolid is increasingly important for multidrug-resistant tuberculosis (MDR-TB) treatment. However, among children with MDR-TB, there are no... |
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| SubjectTerms | Adolescent Adults Adverse drug reactions Analysis Anemia Antimicrobial agents Antitubercular Agents - administration & dosage Antitubercular Agents - adverse effects Antitubercular Agents - pharmacokinetics Bedaquiline Bioengineering Chemotherapy Child Child health Child, Preschool Children Children & youth Childrens health Complications and side effects Computer simulation Dosage Dosage and administration Dose-Response Relationship, Drug Drug dosages Drug Monitoring Drug resistance Drug therapy Exposure Female Funding Health sciences HIV Human immunodeficiency virus Humans Infant Infectious diseases Linezolid Linezolid - administration & dosage Linezolid - adverse effects Linezolid - pharmacokinetics Male Medicine Microbial drug resistance Multidrug resistance Multidrug resistant organisms Observational studies Patients Pediatrics Peripheral neuropathy Pharmacokinetics Population-based studies Prospective Studies Risk factors Safety Safety and security measures Safety regulations Scaling Side effects South Africa Supervision Systematic review Treatment Outcome Tuberculosis Tuberculosis, Multidrug-Resistant - drug therapy Tuberculosis, Multidrug-Resistant - metabolism Tutu, Desmond |
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| Title | Pharmacokinetics, optimal dosing, and safety of linezolid in children with multidrug-resistant tuberculosis: Combined data from two prospective observational studies |
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