eprintid: 10144637 rev_number: 20 eprint_status: archive userid: 699 dir: disk0/10/14/46/37 datestamp: 2022-03-04 11:04:52 lastmod: 2023-03-20 15:22:30 status_changed: 2022-03-04 11:04:52 type: article metadata_visibility: show sword_depositor: 699 creators_name: CRyPTIC Consortium, . creators_name: Walker, Ann Sarah title: Epidemiological cutoff values for a 96-well broth microdilution plate for high-throughput research antibiotic susceptibility testing of M. tuberculosis ispublished: pub divisions: UCL divisions: J38 divisions: D65 divisions: B02 note: This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions. abstract: Drug susceptibility testing of M. tuberculosis is rooted in a binary susceptible/resistant paradigm. Whilst there are considerable advantages in measuring the minimum inhibitory concentrations (MICs) of a panel of drugs for an isolate it is necessary to measure the epidemiological cutoff values (ECOFF/ECVs) to permit comparison with qualitative data. Here we present ECOFF/ECVs for 13 anti-TB compounds, including bedaquiline and delamanid, derived from 20 637 clinical isolates collected by 14 laboratories based in 11 countries on five continents. Each isolate was incubated for 14 days on a dry 96-well broth microdilution plate and then read. Resistance to most of the drugs due to prior exposure is expected and the MIC distributions for many of the compounds are complex and therefore a phenotypically wild-type population could not be defined. Since a majority of samples also underwent genetic sequencing, we defined a genotypically wild-type population and measured the MIC of the 99th percentile by direct measurement and via fitting a Gaussian using interval regression. The proposed ECOFF/ECV values were then validated by comparing to the MIC distributions of high-confidence genetic variants that confer resistance and to qualitative drug susceptibility tests obtained via Mycobacterial Growth Indicator Tube and the Microscopic-Observation Drug-Susceptibility assay. These ECOFF/ECV values will inform and encourage the more widespread adoption of broth microdilution – this is a cheap culture-based method that tests the susceptibility of 12–14 antibiotics on a single 96-well plate and so could help personalise the treatment of tuberculosis. date: 2022-10-01 date_type: published publisher: European Respiratory Society official_url: https://doi.org/10.1183/13993003.00239-2022 oa_status: green full_text_type: other language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 1942927 doi: 10.1183/13993003.00239-2022 lyricists_name: Walker, Ann lyricists_id: ASWAL40 actors_name: Walker, Ann actors_id: ASWAL40 actors_role: owner full_text_status: public publication: European Respiratory Journal volume: 60 number: 4 article_number: 2200239 issn: 0903-1936 citation: CRyPTIC Consortium, .; Walker, Ann Sarah; (2022) Epidemiological cutoff values for a 96-well broth microdilution plate for high-throughput research antibiotic susceptibility testing of M. tuberculosis. European Respiratory Journal , 60 (4) , Article 2200239. 10.1183/13993003.00239-2022 <https://doi.org/10.1183/13993003.00239-2022>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10144637/2/Walker_Epidemiological%20cutoff%20values%20for%20a%2096-well%20broth%20microdilution%20plate%20for%20high-throughput%20research%20antibiotic%20susceptibility%20testing%20of%20M.%20tuberculosis_AAM.pdf document_url: https://discovery.ucl.ac.uk/id/eprint/10144637/4/Walker_Epidemiological%20cutoff%20values%20for%20a%2096-well%20broth%20microdilution%20plate%20for%20high-throughput%20research%20antibiotic%20susceptibility%20testing%20of%20M.%20tuberculosis_SuppM.pdf document_url: https://discovery.ucl.ac.uk/id/eprint/10144637/5/Walker_Epidemiological%20cutoff%20values%20for%20a%2096-well%20broth%20microdilution%20plate%20for%20high-throughput%20research%20antibiotic%20susceptibility%20testing%20of%20M.%20tuberculosis_SuppM2.tsv