Drug exposure and susceptibility of second-line drugs correlate with treatment response in patients with multidrug-resistant tuberculosis: a multicentre prospective cohort study in China
Understanding the impact of drug exposure and susceptibility on treatment response of multidrug-resistant tuberculosis (MDR-TB) will help to optimise treatment. This study aimed to investigate the association between drug exposure, susceptibility and response to MDR-TB treatment. Drug exposure and s...
Saved in:
| Published in: | The European respiratory journal Vol. 59; no. 3 |
|---|---|
| Main Authors: | , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
England
01.03.2022
|
| ISSN: | 1399-3003, 1399-3003 |
| Online Access: | Get more information |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Abstract | Understanding the impact of drug exposure and susceptibility on treatment response of multidrug-resistant tuberculosis (MDR-TB) will help to optimise treatment. This study aimed to investigate the association between drug exposure, susceptibility and response to MDR-TB treatment.
Drug exposure and susceptibility for second-line drugs were measured for patients with MDR-TB. Multivariate analysis was applied to investigate the impact of drug exposure and susceptibility on sputum culture conversion and treatment outcome. Probability of target attainment was evaluated. Random Forest and CART (Classification and Regression Tree) analysis was used to identify key predictors and their clinical targets among patients on World Health Organization-recommended regimens.
Drug exposure and corresponding susceptibility were available for 197 patients with MDR-TB. The probability of target attainment was highly variable, ranging from 0% for ethambutol to 97% for linezolid, while patients with fluoroquinolones above targets had a higher probability of 2-month culture conversion (56.3%
28.6%; adjusted OR 2.91, 95% CI 1.42-5.94) and favourable outcome (88.8%
68.8%; adjusted OR 2.89, 95% CI 1.16-7.17). Higher exposure values of fluoroquinolones, linezolid and pyrazinamide were associated with earlier sputum culture conversion. CART analysis selected moxifloxacin area under the drug concentration-time curve/minimum inhibitory concentration (AUC
/MIC) of 231 and linezolid AUC
/MIC of 287 as best predictors for 6-month culture conversion in patients receiving identical Group A-based regimens. These associations were confirmed in multivariate analysis.
Our findings indicate that target attainment of TB drugs is associated with response to treatment. The CART-derived thresholds may serve as targets for early dose adjustment in a future randomised controlled study to improve MDR-TB treatment outcome. |
|---|---|
| AbstractList | Understanding the impact of drug exposure and susceptibility on treatment response of multidrug-resistant tuberculosis (MDR-TB) will help to optimise treatment. This study aimed to investigate the association between drug exposure, susceptibility and response to MDR-TB treatment.BACKGROUNDUnderstanding the impact of drug exposure and susceptibility on treatment response of multidrug-resistant tuberculosis (MDR-TB) will help to optimise treatment. This study aimed to investigate the association between drug exposure, susceptibility and response to MDR-TB treatment.Drug exposure and susceptibility for second-line drugs were measured for patients with MDR-TB. Multivariate analysis was applied to investigate the impact of drug exposure and susceptibility on sputum culture conversion and treatment outcome. Probability of target attainment was evaluated. Random Forest and CART (Classification and Regression Tree) analysis was used to identify key predictors and their clinical targets among patients on World Health Organization-recommended regimens.METHODSDrug exposure and susceptibility for second-line drugs were measured for patients with MDR-TB. Multivariate analysis was applied to investigate the impact of drug exposure and susceptibility on sputum culture conversion and treatment outcome. Probability of target attainment was evaluated. Random Forest and CART (Classification and Regression Tree) analysis was used to identify key predictors and their clinical targets among patients on World Health Organization-recommended regimens.Drug exposure and corresponding susceptibility were available for 197 patients with MDR-TB. The probability of target attainment was highly variable, ranging from 0% for ethambutol to 97% for linezolid, while patients with fluoroquinolones above targets had a higher probability of 2-month culture conversion (56.3% versus 28.6%; adjusted OR 2.91, 95% CI 1.42-5.94) and favourable outcome (88.8% versus 68.8%; adjusted OR 2.89, 95% CI 1.16-7.17). Higher exposure values of fluoroquinolones, linezolid and pyrazinamide were associated with earlier sputum culture conversion. CART analysis selected moxifloxacin area under the drug concentration-time curve/minimum inhibitory concentration (AUC0-24h/MIC) of 231 and linezolid AUC0-24h/MIC of 287 as best predictors for 6-month culture conversion in patients receiving identical Group A-based regimens. These associations were confirmed in multivariate analysis.RESULTSDrug exposure and corresponding susceptibility were available for 197 patients with MDR-TB. The probability of target attainment was highly variable, ranging from 0% for ethambutol to 97% for linezolid, while patients with fluoroquinolones above targets had a higher probability of 2-month culture conversion (56.3% versus 28.6%; adjusted OR 2.91, 95% CI 1.42-5.94) and favourable outcome (88.8% versus 68.8%; adjusted OR 2.89, 95% CI 1.16-7.17). Higher exposure values of fluoroquinolones, linezolid and pyrazinamide were associated with earlier sputum culture conversion. CART analysis selected moxifloxacin area under the drug concentration-time curve/minimum inhibitory concentration (AUC0-24h/MIC) of 231 and linezolid AUC0-24h/MIC of 287 as best predictors for 6-month culture conversion in patients receiving identical Group A-based regimens. These associations were confirmed in multivariate analysis.Our findings indicate that target attainment of TB drugs is associated with response to treatment. The CART-derived thresholds may serve as targets for early dose adjustment in a future randomised controlled study to improve MDR-TB treatment outcome.CONCLUSIONSOur findings indicate that target attainment of TB drugs is associated with response to treatment. The CART-derived thresholds may serve as targets for early dose adjustment in a future randomised controlled study to improve MDR-TB treatment outcome. Understanding the impact of drug exposure and susceptibility on treatment response of multidrug-resistant tuberculosis (MDR-TB) will help to optimise treatment. This study aimed to investigate the association between drug exposure, susceptibility and response to MDR-TB treatment. Drug exposure and susceptibility for second-line drugs were measured for patients with MDR-TB. Multivariate analysis was applied to investigate the impact of drug exposure and susceptibility on sputum culture conversion and treatment outcome. Probability of target attainment was evaluated. Random Forest and CART (Classification and Regression Tree) analysis was used to identify key predictors and their clinical targets among patients on World Health Organization-recommended regimens. Drug exposure and corresponding susceptibility were available for 197 patients with MDR-TB. The probability of target attainment was highly variable, ranging from 0% for ethambutol to 97% for linezolid, while patients with fluoroquinolones above targets had a higher probability of 2-month culture conversion (56.3% 28.6%; adjusted OR 2.91, 95% CI 1.42-5.94) and favourable outcome (88.8% 68.8%; adjusted OR 2.89, 95% CI 1.16-7.17). Higher exposure values of fluoroquinolones, linezolid and pyrazinamide were associated with earlier sputum culture conversion. CART analysis selected moxifloxacin area under the drug concentration-time curve/minimum inhibitory concentration (AUC /MIC) of 231 and linezolid AUC /MIC of 287 as best predictors for 6-month culture conversion in patients receiving identical Group A-based regimens. These associations were confirmed in multivariate analysis. Our findings indicate that target attainment of TB drugs is associated with response to treatment. The CART-derived thresholds may serve as targets for early dose adjustment in a future randomised controlled study to improve MDR-TB treatment outcome. |
| Author | Hu, Yi Zheng, Xubin Xie, Yan Schön, Thomas Davies Forsman, Lina Bao, Ziwei Alffenaar, Jan-Willem Bruchfeld, Judith Ning, Zhu Xu, Biao |
| Author_xml | – sequence: 1 givenname: Xubin surname: Zheng fullname: Zheng, Xubin organization: Dept of Epidemiology, School of Public Health and Key Laboratory of Public Health Safety, Fudan University, Shanghai, China – sequence: 2 givenname: Lina surname: Davies Forsman fullname: Davies Forsman, Lina organization: Dept of Infectious Disease, Karolinska University Hospital, Stockholm, Sweden – sequence: 3 givenname: Ziwei surname: Bao fullname: Bao, Ziwei organization: The Fifth People's Hospital of Suzhou, Suzhou, China – sequence: 4 givenname: Yan surname: Xie fullname: Xie, Yan organization: Zigong Centre for Disease Control and Prevention, Zigong, China – sequence: 5 givenname: Zhu surname: Ning fullname: Ning, Zhu organization: Zigong Centre for Disease Control and Prevention, Zigong, China – sequence: 6 givenname: Thomas surname: Schön fullname: Schön, Thomas organization: Division of Inflammation and Infectious Diseases, Dept of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden – sequence: 7 givenname: Judith surname: Bruchfeld fullname: Bruchfeld, Judith organization: Dept of Infectious Disease, Karolinska University Hospital, Stockholm, Sweden – sequence: 8 givenname: Biao surname: Xu fullname: Xu, Biao organization: Dept of Epidemiology, School of Public Health and Key Laboratory of Public Health Safety, Fudan University, Shanghai, China – sequence: 9 givenname: Jan-Willem surname: Alffenaar fullname: Alffenaar, Jan-Willem organization: J-W. Alffenaar and Y. Hu contributed equally – sequence: 10 givenname: Yi surname: Hu fullname: Hu, Yi email: yhu@fudan.edu.cn organization: J-W. Alffenaar and Y. Hu contributed equally |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/34737224$$D View this record in MEDLINE/PubMed |
| BookMark | eNpNkMtKAzEUhoNU7EWfQJAs3YzmNp2JO6lXENzoumQmpzYyk4y5qH01n86UVnCVw8d3_hz-KRpZZwGhU0ouKK35JeVSckL4BaGSlQUjjB6gyZYWWzz6N4_RNIR3QuhccHqExlxUvGJMTNDPjU9vGL4HF5IHrKzGIYUWhmga05m4wW6FA7TO6qIzFrDOfsCt8x46FQF_mbjG0YOKPdiIPYTB2QDYWDyoaDILO6dPXTTb7SI7JkSV7Zga8G3qXAZXWO2cNu_kUwbvwgBtNJ-Qv1s7H3GISW-2yYu1seoYHa5UF-Bk_87Q693ty-KheHq-f1xcPxWtqGkseMNY1RLN6hWp6wbKpgJJMpiLFaNQzpmSVAOtRa1FA2LOVe5VlaLSIBsm2Qyd73LzRR8JQlz2JjfUdcqCS2HJSimYzNl1Vs_2amp60MvBm175zfKvb_YLbz6Krw |
| CitedBy_id | crossref_primary_10_3389_fphar_2022_1063453 crossref_primary_10_1128_aac_01700_22 crossref_primary_10_3390_pharmaceutics16050677 crossref_primary_10_1093_pcmedi_pbaf008 crossref_primary_10_3389_fphar_2023_1022090 crossref_primary_10_3390_biomedicines10102592 crossref_primary_10_1016_j_ijantimicag_2023_106914 crossref_primary_10_3389_fphar_2022_1032674 crossref_primary_10_1002_sscp_70051 crossref_primary_10_1016_j_cmi_2022_10_002 crossref_primary_10_1016_j_ijantimicag_2022_106620 crossref_primary_10_1097_FTD_0000000000001164 crossref_primary_10_1093_jac_dkae309 crossref_primary_10_1016_j_ijid_2024_01_001 crossref_primary_10_1093_jac_dkae404 crossref_primary_10_3390_pharmaceutics16010144 crossref_primary_10_1183_13993003_01108_2023 crossref_primary_10_1007_s40262_023_01220_y crossref_primary_10_1016_j_jchromb_2025_124470 crossref_primary_10_1093_cid_ciae329 crossref_primary_10_1136_bmjopen_2023_075383 crossref_primary_10_1183_13993003_00149_2022 crossref_primary_10_1093_jac_dkae041 |
| ContentType | Journal Article |
| Copyright | Copyright ©The authors 2022. |
| Copyright_xml | – notice: Copyright ©The authors 2022. |
| DBID | NPM 7X8 |
| DOI | 10.1183/13993003.01925-2021 |
| DatabaseName | PubMed MEDLINE - Academic |
| DatabaseTitle | PubMed MEDLINE - Academic |
| DatabaseTitleList | MEDLINE - Academic PubMed |
| Database_xml | – sequence: 1 dbid: NPM name: PubMed url: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed sourceTypes: Index Database – sequence: 2 dbid: 7X8 name: MEDLINE - Academic url: https://search.proquest.com/medline sourceTypes: Aggregation Database |
| DeliveryMethod | no_fulltext_linktorsrc |
| Discipline | Medicine |
| EISSN | 1399-3003 |
| ExternalDocumentID | 34737224 |
| Genre | Journal Article |
| GroupedDBID | --- .55 .GJ 18M 1OC 2WC 31~ 3O- 53G 5GY 5RE 5VS 8-1 AADJU AAFWJ AAZMJ ABCQX ABJNI ABOCM ABSQV ACEMG ACGFO ACPRK ACXQS ADBBV ADDZX ADMOG AENEX AFFNX AFHIN AFZJQ AIZTS AJAOE ALMA_UNASSIGNED_HOLDINGS BAWUL BTFSW CAG COF CS3 DIK E3Z EBS EJD F5P F9R GX1 H13 INIJC J5H KQ8 L7B LH4 LW6 NPM OK1 P2P PQQKQ R0Z RHF RHI TER TR2 W8F WOQ X7M ZE2 ZGI ZXP ~02 7X8 ADYFA |
| ID | FETCH-LOGICAL-c481t-3b227c0d28f088be5b7e90c0d64f21e562a91de1848d4be463a993a547de9b292 |
| IEDL.DBID | 7X8 |
| ISICitedReferencesCount | 29 |
| ISICitedReferencesURI | http://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=Summon&SrcAuth=ProQuest&DestLinkType=CitingArticles&DestApp=WOS_CPL&KeyUT=000792497500018&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D |
| ISSN | 1399-3003 |
| IngestDate | Thu Sep 04 17:02:49 EDT 2025 Wed Feb 19 02:26:29 EST 2025 |
| IsDoiOpenAccess | false |
| IsOpenAccess | true |
| IsPeerReviewed | true |
| IsScholarly | true |
| Issue | 3 |
| Language | English |
| License | Copyright ©The authors 2022. |
| LinkModel | DirectLink |
| MergedId | FETCHMERGED-LOGICAL-c481t-3b227c0d28f088be5b7e90c0d64f21e562a91de1848d4be463a993a547de9b292 |
| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
| OpenAccessLink | https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-185300 |
| PMID | 34737224 |
| PQID | 2594290888 |
| PQPubID | 23479 |
| ParticipantIDs | proquest_miscellaneous_2594290888 pubmed_primary_34737224 |
| PublicationCentury | 2000 |
| PublicationDate | 2022-03-01 |
| PublicationDateYYYYMMDD | 2022-03-01 |
| PublicationDate_xml | – month: 03 year: 2022 text: 2022-03-01 day: 01 |
| PublicationDecade | 2020 |
| PublicationPlace | England |
| PublicationPlace_xml | – name: England |
| PublicationTitle | The European respiratory journal |
| PublicationTitleAlternate | Eur Respir J |
| PublicationYear | 2022 |
| References | 35332091 - Eur Respir J. 2022 Mar 24;59(3) |
| References_xml | – reference: 35332091 - Eur Respir J. 2022 Mar 24;59(3): |
| SSID | ssj0016431 |
| Score | 2.5144973 |
| Snippet | Understanding the impact of drug exposure and susceptibility on treatment response of multidrug-resistant tuberculosis (MDR-TB) will help to optimise... |
| SourceID | proquest pubmed |
| SourceType | Aggregation Database Index Database |
| Title | Drug exposure and susceptibility of second-line drugs correlate with treatment response in patients with multidrug-resistant tuberculosis: a multicentre prospective cohort study in China |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/34737224 https://www.proquest.com/docview/2594290888 |
| Volume | 59 |
| WOSCitedRecordID | wos000792497500018&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D |
| hasFullText | |
| inHoldings | 1 |
| isFullTextHit | |
| isPrint | |
| link | http://cvtisr.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwpV1Lb9swDBa2phh66Z5t0z3AAbtqsWXZlnsZhm3BDkuQwzbkFkiWVBQI7NSOi_Wv9deVlJ3mNGDALj4QlGGLFPVJ_CQy9kHJRKUuNVwqgQsUG3lelE7yTJkI4azL4sB2__0jn8_Vclkshg23dqBV7mJiCNS2LmmPfIIwHUMnjgn1aXPNqWoUZVeHEhqP2ShBKEOUrny5zyLgbNsvuArK70fJcOsQevGEZCT6SBAnRV8R8d8xZphrpk__9yufseMBZcLn3i2es0euesGezIY8-kt297XpLsH92dS0QQi6stB2bWC4BLLsLdQeWlorW044FCzqt1BSKY81olOg7Vt4IKlD0zNtHVxVMNzU2vY6gbBIrTnqEFZF7W1nXFN26xoFF6B7ncASdYD_uzv8CVS8t9lCuAGX3hxqfb9iv6bffn75zocqDryUKt7yxAiRl5EVymO_GPSL3BURCjLpRewQf-kitg5XmspK42SWaDSNTmVuXWFEIU7YQVVX7oyB8jqmimnYw0ZqrZW3nowoU58mJtNj9n5nlRWOEkp96MrVXbva22XMTnvTrjb9dR6rRFKpHiHP_6H1a3Yk6PxDIKG9YSOPMcK9ZYflzfaqbd4F98PnfDG7B5SP6TM |
| linkProvider | ProQuest |
| openUrl | ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Drug+exposure+and+susceptibility+of+second-line+drugs+correlate+with+treatment+response+in+patients+with+multidrug-resistant+tuberculosis%3A+a+multicentre+prospective+cohort+study+in+China&rft.jtitle=The+European+respiratory+journal&rft.au=Zheng%2C+Xubin&rft.au=Davies+Forsman%2C+Lina&rft.au=Bao%2C+Ziwei&rft.au=Xie%2C+Yan&rft.date=2022-03-01&rft.issn=1399-3003&rft.eissn=1399-3003&rft.volume=59&rft.issue=3&rft_id=info:doi/10.1183%2F13993003.01925-2021&rft.externalDBID=NO_FULL_TEXT |
| thumbnail_l | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=1399-3003&client=summon |
| thumbnail_m | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=1399-3003&client=summon |
| thumbnail_s | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=1399-3003&client=summon |