title: Determination of MIC Breakpoints for Second-Line Drugs Associated with Clinical Outcomes in Multidrug-Resistant Tuberculosis Treatment in China.
abstract: Our study aims to identify the clinical breakpoints (CBPs) of second-line drugs (SLDs) above which standard therapy fails in order to improve multidrug-resistant tuberculosis (MDR-TB) treatment. MICs of SLDs were determined for M. tuberculosis isolates cultured from 207 MDR-TB patients in a prospective cohort study in China between January 2010 and December 2012. Classification and regression tree (CART) analysis was used to identify the CBPs predictive of treatment outcome. Of the 207 MDR-TB isolates included in the present study, the proportion of isolates above the critical concentration recommended by WHO ranged from 5.3% in pyrazinamide to 62.8% in amikacin. By selecting pyrazinamide as the primary node (CBP, 18.75 mg/liter), 72.1% of sputum culture conversions at month four could be predicted. As for treatment outcome, pyrazinamide (CBP, 37.5 mg/liter) was selected as the primary node to predict 89% of the treatment success, followed by ofloxacin (CBP, 3 mg/liter), improving the predictive capacity of the primary node by 10.6%. Adjusted by identified confounders, the CART-derived pyrazinamide CBP remained the strongest predictor in the model of treatment outcome. Our findings indicate that the critical breakpoints of some second-line drugs and PZA need to be reconsidered in order to better indicate MDR-TB treatment outcome.
authors.affiliation: Department of Epidemiology, School of Public Health, Fudan University, and Key Laboratory of Public Health Safety (Fudan University), Ministry of Education, Shanghai, China.
authors.forename: Xubin
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Xiamen Center for Disease Control and Prevention, Fujian Province, China.
authors.forename: Rongrong
authors.initials: R
authors.lastname: Zheng
authors.affiliation: Department of Epidemiology, School of Public Health, Fudan University, and Key Laboratory of Public Health Safety (Fudan University), Ministry of Education, Shanghai, China Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Solna, Sweden yhu@fudan.edu.cn.
authors.forename: Yi
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Microbiology, the Public Health Agency of Sweden, Solna, Sweden.
authors.forename: Jim
authors.initials: J
authors.lastname: Werngren
authors.affiliation: Unit of Infectious Diseases, Department of Medicine, Karolinska Institutet, Stockholm, Sweden Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Lina Davies
authors.identifier: 0000-0001-8885-3320
authors.initials: LD
authors.lastname: Forsman
authors.affiliation: Department of Microbiology, the Public Health Agency of Sweden, Solna, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Mansjö
authors.affiliation: Department of Epidemiology, School of Public Health, Fudan University, and Key Laboratory of Public Health Safety (Fudan University), Ministry of Education, Shanghai, China.
authors.forename: Biao
authors.initials: B
authors.lastname: Xu
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Solna, Sweden Department of Microbiology, the Public Health Agency of Sweden, Solna, Sweden.
authors.forename: Sven
authors.initials: S
authors.lastname: Hoffner
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000583:Amikacin / Q000627:therapeutic use; D000995:Antitubercular Agents / Q000627:therapeutic use*; D002681:China; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests / Q000379:methods; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D015242:Ofloxacin / Q000627:therapeutic use; D011446:Prospective Studies; D011718:Pyrazinamide / Q000627:therapeutic use; D016896:Treatment Outcome; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy* / Q000382:microbiology; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000382:microbiology; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D011718:Pyrazinamide; D000583:Amikacin; D015242:Ofloxacin