Epidemiological cut-off values for a 96-well broth microdilution plate for high-throughput research antibiotic susceptibility testing of M. tuberculosis

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Fowler, Philip W. ; Barilar, Ivan ; Battaglia, Simone ; Borroni, Emanuele ; Brandao, Angela Pires ; Brankin, Alice ; Cabibbe, Andrea Maurizio ; Carter, Joshua ; Cirillo, Daniela Maria ; Claxton, Pauline ; Clifton, David A. ; Cohen, Ted ; Coronel, Jorge ; Crook, Derrick W. ; Dreyer, Viola ; Earle, Sarah G. ; Escuyer, Vincent ; Ferrazoli, Lucilaine ; Gao, George Fu ; Gardy, Jennifer ; Gharbia, Saheer ; Ghisi, Kelen Teixeira ; Ghodousi, Arash ; Gibertoni Cruz, Ana Luiza ; Grandjean, Louis ; Grazian, Clara ; Groenheit, Ramona ; Guthrie, Jennifer L. ; He, Wencong ; Hoffmann, Harald ; Hoosdally, Sarah J. ; Hunt, Martin ; Iqbal, Zamin ; Ismail, Nazir Ahmed ; Jarrett, Lisa ; Joseph, Lavania ; Jou, Ruwen ; Kambli, Priti ; Khot, Rukhsar ; Knaggs, Jeff ; Koch, Anastasia ; Kohlerschmidt, Donna ; Kouchaki, Samaneh ; Lachapelle, Alexander S. ; Lalvani, Ajit ; Lapierre, Simon Grandjean ; Laurenson, Ian F. ; Letcher, Brice ; Lin, Wan-Hsuan ; Liu, Chunfa ; Liu, Dongxin ; Malone, Kerri M. ; Mandal, Ayan ; Mansjo, Mikael ; Matias, Daniela ; Meintjes, Graeme ; Mendes, Flavia de Freitas ; Merker, Matthias ; Mihalic, Marina ; Millard, James ; Miotto, Paolo ; Mistry, Nerges ; Moore, David ; Musser, Kimberlee A. ; Ngcamu, Dumisani ; Nhung, Hoang Ngoc ; Niemann, Stefan ; Nilgiriwala, Kayzad Soli ; Nimmo, Camus ; Okozi, Nana ; Oliveira, Rosangela Siqueira ; Omar, Shaheed Vally ; Paton, Nicholas ; Peto, Timothy E. A. ; Watanabe Pinhata, Juliana Maira ; Plesnik, Sara ; Puyen, Zully M. ; Rabodoarivelo, Marie Sylvianne ; Rakotosamimanana, Niaina ; Rancoita, Paola M., V ; Rathod, Priti ; Robinson, Esther ; Rodger, Gillian ; Rodrigues, Camilla ; Rodwell, Timothy C. ; Roohi, Aysha ; Santos-Lazaro, David ; Shah, Sanchi ; Kohl, Thomas Andreas ; Smith, Grace ; Solano, Walter ; Spitaleri, Andrea ; Supply, Philip ; Surve, Utkarsha ; Tahseen, Sabira ; Thuong, Nguyen Thuy ; Thwaites, Guy ; Todt, Katharina ; Trovato, Alberto ; Utpatel, Christian ; Van Rie, Annelies ; Vijay, Srinivasan ; Walker, Timothy M. ; Walker, A. Sarah ; Warren, Robin ; Werngren, Jim ; Wijkander, Maria ; Wilkinson, Robert J. ; Wilson, Daniel J. ; Wintringer, Penelope ; Xiao, Yu-Xin ; Yang ; Zhao Yanlin ; Yao, Shen-Yuan ; Zhu, Baoli ; CRyPTIC Consortium

• Document type: Journal article
• Source: European Respiratory Journal; v. 60, n. 4, p. 22-pg., 2022-10-01.

Abstract

Drug susceptibility testing of M. tuberculosis is rooted in a binary susceptible/resistant paradigm. While 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 cut-off values (ECOFF/ECVs) to permit comparison with qualitative data. Here we present ECOFF/ECVs for 13 anti-tuberculosis 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/ECVs were then validated by comparing with the MIC distributions of high-confidence genetic variants that confer resistance and with qualitative drug susceptibility tests obtained via the Mycobacterial Growth Indicator Tube (MGIT) system or Microscopic-Observation Drug Susceptibility (MODS) assay. These ECOFF/ECVs 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. (AU)

• FAPESP's process: 17/16082-7 - Characterization of mutations in clinical isolates of Mycobacterium tuberculosis resistant to 1st and 2nd line drugs and the relationship between mutations and phenotypic resistance levels to isoniazid.
• Grantee: Rosangela Siqueira de Oliveira
• Support Opportunities: Regular Research Grants
• FAPESP's process: 12/51756-5 - Performance of methods for diagnosis of multidrug-resistant tuberculosis and Extensively Resistant. Applicability in a Reference Laboratory
• Grantee: Lucilaine Ferrazoli
• Support Opportunities: Research Grants - Research in Public Policies for the National Health Care System (PP-SUS)