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Unexpected high prevalence of resistance-associated Rv0678 variants in MDR-TB patients without documented prior use of clofazimine or bedaquiline
Resistance-associated variants (RAVs) in Rv0678 , a regulator of the MmpS5-MmpL5 efflux pump, have been shown to lead to increased MICs of bedaquiline (2- to 8- fold) and clofazimine (2- to 4-fold). The prevalence of these Rv0678 RAVs in clinical isolates and their impact on treatment outcomes are i...
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| Published in: | Journal of antimicrobial chemotherapy 2017-03, Vol.72 (3), p.684-690 |
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| cited_by | cdi_FETCH-LOGICAL-c383t-70f81413e12582a33088da002f0cf99968320475eaa2c6ef8201c06b1ce6c1743 |
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| cites | cdi_FETCH-LOGICAL-c383t-70f81413e12582a33088da002f0cf99968320475eaa2c6ef8201c06b1ce6c1743 |
| container_end_page | 690 |
| container_issue | 3 |
| container_start_page | 684 |
| container_title | Journal of antimicrobial chemotherapy |
| container_volume | 72 |
| creator | Villellas, Cristina Coeck, Nele Meehan, Conor J Lounis, Nacer de Jong, Bouke Rigouts, Leen Andries, Koen |
| description | Resistance-associated variants (RAVs) in Rv0678 , a regulator of the MmpS5-MmpL5 efflux pump, have been shown to lead to increased MICs of bedaquiline (2- to 8- fold) and clofazimine (2- to 4-fold). The prevalence of these Rv0678 RAVs in clinical isolates and their impact on treatment outcomes are important factors to take into account in bedaquiline treatment guidelines.
Baseline isolates from two bedaquiline MDR-TB clinical trials were sequenced for Rv0678 RAVs and corresponding bedaquiline MICs were determined on 7H11 agar. Rv0678 RAVs were also investigated in non-MDR-TB sequences of a population-based cohort.
Rv0678 RAVs were identified in 23/347 (6.3%) of MDR-TB baseline isolates. Surprisingly, bedaquiline MICs for these isolates were high (> 0.24 mg/L, n = 8), normal (0.03-0.24 mg/L, n = 11) or low ( |
| doi_str_mv | 10.1093/jac/dkw502 |
| format | article |
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Baseline isolates from two bedaquiline MDR-TB clinical trials were sequenced for Rv0678 RAVs and corresponding bedaquiline MICs were determined on 7H11 agar. Rv0678 RAVs were also investigated in non-MDR-TB sequences of a population-based cohort.
Rv0678 RAVs were identified in 23/347 (6.3%) of MDR-TB baseline isolates. Surprisingly, bedaquiline MICs for these isolates were high (> 0.24 mg/L, n = 8), normal (0.03-0.24 mg/L, n = 11) or low (< 0.03 mg/L, n = 4). A variant at position -11 in the intergenic region mmpS5 - Rv0678 was identified in 39 isolates (11.3%) and appeared to increase the susceptibility to bedaquiline. In non-MDR-TB isolates, the frequency of Rv0678 RAVs was lower (6/852 or 0.7%). Competition experiments suggested that rifampicin was not the drug selecting for Rv0678 RAVs.
RAVs in Rv0678 occur more frequently in MDR-TB patients than previously anticipated, are not associated with prior use of bedaquiline or clofazimine, and in the majority of cases do not lead to bedaquiline MICs above the provisional breakpoint (0.24 mg/L). Their origin remains unknown. Given the variety of RAVs in Rv0678 and their variable effects on the MIC, only phenotypic drug-susceptibility methods can currently be used to assess bedaquiline susceptibility.</description><identifier>ISSN: 0305-7453</identifier><identifier>EISSN: 1460-2091</identifier><identifier>DOI: 10.1093/jac/dkw502</identifier><identifier>PMID: 28031270</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Anti-Inflammatory Agents - pharmacology ; Antibiotics, Antitubercular - therapeutic use ; Antitubercular Agents - pharmacology ; Antitubercular Agents - therapeutic use ; Clinical Trials as Topic ; Clofazimine - pharmacology ; Clofazimine - therapeutic use ; Diarylquinolines - pharmacology ; Diarylquinolines - therapeutic use ; Humans ; Microbial Sensitivity Tests ; Mycobacterium tuberculosis - drug effects ; Mycobacterium tuberculosis - genetics ; Original Research ; Prevalence ; Rifampin - therapeutic use ; Sequence Analysis, DNA ; Tuberculosis, Multidrug-Resistant - epidemiology ; Tuberculosis, Multidrug-Resistant - microbiology</subject><ispartof>Journal of antimicrobial chemotherapy, 2017-03, Vol.72 (3), p.684-690</ispartof><rights>The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c383t-70f81413e12582a33088da002f0cf99968320475eaa2c6ef8201c06b1ce6c1743</citedby><cites>FETCH-LOGICAL-c383t-70f81413e12582a33088da002f0cf99968320475eaa2c6ef8201c06b1ce6c1743</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28031270$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Villellas, Cristina</creatorcontrib><creatorcontrib>Coeck, Nele</creatorcontrib><creatorcontrib>Meehan, Conor J</creatorcontrib><creatorcontrib>Lounis, Nacer</creatorcontrib><creatorcontrib>de Jong, Bouke</creatorcontrib><creatorcontrib>Rigouts, Leen</creatorcontrib><creatorcontrib>Andries, Koen</creatorcontrib><title>Unexpected high prevalence of resistance-associated Rv0678 variants in MDR-TB patients without documented prior use of clofazimine or bedaquiline</title><title>Journal of antimicrobial chemotherapy</title><addtitle>J Antimicrob Chemother</addtitle><description>Resistance-associated variants (RAVs) in Rv0678 , a regulator of the MmpS5-MmpL5 efflux pump, have been shown to lead to increased MICs of bedaquiline (2- to 8- fold) and clofazimine (2- to 4-fold). The prevalence of these Rv0678 RAVs in clinical isolates and their impact on treatment outcomes are important factors to take into account in bedaquiline treatment guidelines.
Baseline isolates from two bedaquiline MDR-TB clinical trials were sequenced for Rv0678 RAVs and corresponding bedaquiline MICs were determined on 7H11 agar. Rv0678 RAVs were also investigated in non-MDR-TB sequences of a population-based cohort.
Rv0678 RAVs were identified in 23/347 (6.3%) of MDR-TB baseline isolates. Surprisingly, bedaquiline MICs for these isolates were high (> 0.24 mg/L, n = 8), normal (0.03-0.24 mg/L, n = 11) or low (< 0.03 mg/L, n = 4). A variant at position -11 in the intergenic region mmpS5 - Rv0678 was identified in 39 isolates (11.3%) and appeared to increase the susceptibility to bedaquiline. In non-MDR-TB isolates, the frequency of Rv0678 RAVs was lower (6/852 or 0.7%). Competition experiments suggested that rifampicin was not the drug selecting for Rv0678 RAVs.
RAVs in Rv0678 occur more frequently in MDR-TB patients than previously anticipated, are not associated with prior use of bedaquiline or clofazimine, and in the majority of cases do not lead to bedaquiline MICs above the provisional breakpoint (0.24 mg/L). Their origin remains unknown. Given the variety of RAVs in Rv0678 and their variable effects on the MIC, only phenotypic drug-susceptibility methods can currently be used to assess bedaquiline susceptibility.</description><subject>Anti-Inflammatory Agents - pharmacology</subject><subject>Antibiotics, Antitubercular - therapeutic use</subject><subject>Antitubercular Agents - pharmacology</subject><subject>Antitubercular Agents - therapeutic use</subject><subject>Clinical Trials as Topic</subject><subject>Clofazimine - pharmacology</subject><subject>Clofazimine - therapeutic use</subject><subject>Diarylquinolines - pharmacology</subject><subject>Diarylquinolines - therapeutic use</subject><subject>Humans</subject><subject>Microbial Sensitivity Tests</subject><subject>Mycobacterium tuberculosis - drug effects</subject><subject>Mycobacterium tuberculosis - genetics</subject><subject>Original Research</subject><subject>Prevalence</subject><subject>Rifampin - therapeutic use</subject><subject>Sequence Analysis, DNA</subject><subject>Tuberculosis, Multidrug-Resistant - epidemiology</subject><subject>Tuberculosis, Multidrug-Resistant - microbiology</subject><issn>0305-7453</issn><issn>1460-2091</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><recordid>eNpVkd1u1DAQhS0EotvCDQ-AfImQQsd24jg3SLSUH6kIqWqvrVln0nVJ4tROtsBb8MZ42VLBlXXGn88c-TD2QsAbAY06vkF33H67q0A-YitRaigkNOIxW4GCqqjLSh2ww5RuAEBX2jxlB9KAErKGFft1NdL3idxMLd_46w2fIm2xp9ERDx2PlHyaMasCUwrO4w682IKuDd9i9DjOifuRf3l_UVye8AlnT7vRnZ83YZl5G9wy5El-NUUfIl_SH2PXhw5_-sGPWUa-phZvF99n-Yw96bBP9Pz-PGJXH84uTz8V518_fj59d144ZdRc1NAZUQpFQlZGolJgTIsAsgPXNU2jjZJQ1hUhSqepMxKEA70WjrQTdamO2Nu977SsB2pdDhmxtznlgPGHDejt_zej39jrsLVVmT_S1Nng1b1BDLcLpdkOPjnqexwpLMkKU5UCdGlMRl_vURdDSpG6hzUC7K5Dmzu0-w4z_PLfYA_o39LUbwDCmzo</recordid><startdate>20170301</startdate><enddate>20170301</enddate><creator>Villellas, Cristina</creator><creator>Coeck, Nele</creator><creator>Meehan, Conor J</creator><creator>Lounis, Nacer</creator><creator>de Jong, Bouke</creator><creator>Rigouts, Leen</creator><creator>Andries, Koen</creator><general>Oxford University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20170301</creationdate><title>Unexpected high prevalence of resistance-associated Rv0678 variants in MDR-TB patients without documented prior use of clofazimine or bedaquiline</title><author>Villellas, Cristina ; Coeck, Nele ; Meehan, Conor J ; Lounis, Nacer ; de Jong, Bouke ; Rigouts, Leen ; Andries, Koen</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c383t-70f81413e12582a33088da002f0cf99968320475eaa2c6ef8201c06b1ce6c1743</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Anti-Inflammatory Agents - pharmacology</topic><topic>Antibiotics, Antitubercular - therapeutic use</topic><topic>Antitubercular Agents - pharmacology</topic><topic>Antitubercular Agents - therapeutic use</topic><topic>Clinical Trials as Topic</topic><topic>Clofazimine - pharmacology</topic><topic>Clofazimine - therapeutic use</topic><topic>Diarylquinolines - pharmacology</topic><topic>Diarylquinolines - therapeutic use</topic><topic>Humans</topic><topic>Microbial Sensitivity Tests</topic><topic>Mycobacterium tuberculosis - drug effects</topic><topic>Mycobacterium tuberculosis - genetics</topic><topic>Original Research</topic><topic>Prevalence</topic><topic>Rifampin - therapeutic use</topic><topic>Sequence Analysis, DNA</topic><topic>Tuberculosis, Multidrug-Resistant - epidemiology</topic><topic>Tuberculosis, Multidrug-Resistant - microbiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Villellas, Cristina</creatorcontrib><creatorcontrib>Coeck, Nele</creatorcontrib><creatorcontrib>Meehan, Conor J</creatorcontrib><creatorcontrib>Lounis, Nacer</creatorcontrib><creatorcontrib>de Jong, Bouke</creatorcontrib><creatorcontrib>Rigouts, Leen</creatorcontrib><creatorcontrib>Andries, Koen</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of antimicrobial chemotherapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Villellas, Cristina</au><au>Coeck, Nele</au><au>Meehan, Conor J</au><au>Lounis, Nacer</au><au>de Jong, Bouke</au><au>Rigouts, Leen</au><au>Andries, Koen</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Unexpected high prevalence of resistance-associated Rv0678 variants in MDR-TB patients without documented prior use of clofazimine or bedaquiline</atitle><jtitle>Journal of antimicrobial chemotherapy</jtitle><addtitle>J Antimicrob Chemother</addtitle><date>2017-03-01</date><risdate>2017</risdate><volume>72</volume><issue>3</issue><spage>684</spage><epage>690</epage><pages>684-690</pages><issn>0305-7453</issn><eissn>1460-2091</eissn><abstract>Resistance-associated variants (RAVs) in Rv0678 , a regulator of the MmpS5-MmpL5 efflux pump, have been shown to lead to increased MICs of bedaquiline (2- to 8- fold) and clofazimine (2- to 4-fold). The prevalence of these Rv0678 RAVs in clinical isolates and their impact on treatment outcomes are important factors to take into account in bedaquiline treatment guidelines.
Baseline isolates from two bedaquiline MDR-TB clinical trials were sequenced for Rv0678 RAVs and corresponding bedaquiline MICs were determined on 7H11 agar. Rv0678 RAVs were also investigated in non-MDR-TB sequences of a population-based cohort.
Rv0678 RAVs were identified in 23/347 (6.3%) of MDR-TB baseline isolates. Surprisingly, bedaquiline MICs for these isolates were high (> 0.24 mg/L, n = 8), normal (0.03-0.24 mg/L, n = 11) or low (< 0.03 mg/L, n = 4). A variant at position -11 in the intergenic region mmpS5 - Rv0678 was identified in 39 isolates (11.3%) and appeared to increase the susceptibility to bedaquiline. In non-MDR-TB isolates, the frequency of Rv0678 RAVs was lower (6/852 or 0.7%). Competition experiments suggested that rifampicin was not the drug selecting for Rv0678 RAVs.
RAVs in Rv0678 occur more frequently in MDR-TB patients than previously anticipated, are not associated with prior use of bedaquiline or clofazimine, and in the majority of cases do not lead to bedaquiline MICs above the provisional breakpoint (0.24 mg/L). Their origin remains unknown. Given the variety of RAVs in Rv0678 and their variable effects on the MIC, only phenotypic drug-susceptibility methods can currently be used to assess bedaquiline susceptibility.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>28031270</pmid><doi>10.1093/jac/dkw502</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of antimicrobial chemotherapy, 2017-03, Vol.72 (3), p.684-690 |
| issn | 0305-7453 1460-2091 |
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| source | Oxford Journals Online |
| subjects | Anti-Inflammatory Agents - pharmacology Antibiotics, Antitubercular - therapeutic use Antitubercular Agents - pharmacology Antitubercular Agents - therapeutic use Clinical Trials as Topic Clofazimine - pharmacology Clofazimine - therapeutic use Diarylquinolines - pharmacology Diarylquinolines - therapeutic use Humans Microbial Sensitivity Tests Mycobacterium tuberculosis - drug effects Mycobacterium tuberculosis - genetics Original Research Prevalence Rifampin - therapeutic use Sequence Analysis, DNA Tuberculosis, Multidrug-Resistant - epidemiology Tuberculosis, Multidrug-Resistant - microbiology |
| title | Unexpected high prevalence of resistance-associated Rv0678 variants in MDR-TB patients without documented prior use of clofazimine or bedaquiline |
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