Yuhong Liu1, Jingtao Gao1, Jian Du1, Wei Shu1, Lu Wang2, Yufeng Wang3, Zhongtan Xue3, Liang Li4, Shaofa Xu5, Yu Pang6. 1. Clinical Center on TB, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, P.R. China. 2. Department of Bacteriology and Immunology, Beijing Key Laboratory on Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, P.R. China. 3. Department of Laboratory Quality Control, Innovation Alliance on Tuberculosis Diagnosis and Treatment (Beijing), Beijing, 101149, P.R. China. 4. Clinical Center on TB, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, P.R. China. Electronic address: liliang69@tb123.org. 5. Clinical Center on TB, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, P.R. China. Electronic address: xushaofa@263.net. 6. Department of Bacteriology and Immunology, Beijing Key Laboratory on Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, P.R. China. Electronic address: pangyupound@163.com.
Abstract
OBJECTIVES: The aim of this study was to describe the prevalence of clofazimine (CFZ) resistance in a cohort of patients with multidrug-resistant tuberculosis (MDR-TB) in China. A further aim was to identify dynamic changes in CFZ susceptibility and its molecular mechanism after exposure to bedaquiline (BDQ) and/or CFZ. METHODS: The experimental setting was based on an MDR-TB cohort receiving BDQ-containing regimens. Sequential isolates were obtained from these patients. The CFZ and BDQ susceptibility of isolates were determined using the minimum inhibitory concentration (MIC) method. The fragments of Rv0678 and pepQ were sequenced. RESULTS: A total of 277 patients infected with MDR-TB were included in this study. CFZ resistance was noted in 23 isolates (23/277, 8.3%). The rate of acquired CFZ resistance (12/189, 6.3%) was significantly greater than that of primary resistance (11/88, 12.5%, p = 0.028). Out of 23 CFZ-resistant isolates, five (5/23) were BDQ-resistant and the other 18 (18/23) were susceptible to BDQ. Of note, nine out of 23 CFZ-resistant isolates had mutations within either of the target genes. Kaplan-Meier analysis demonstrated that the baseline CFZ resistance had no influence on time to culture conversion in this cohort (p = 0.828). Acquired CFZ resistance emerged in eight patients (8/94, 8.5%) during treatment for MDR-TB, including three patients receiving regimens without CFZ. CONCLUSIONS: The study results demonstrated a high rate of CFZ resistance among MDR-TB patients in China. Patients treated with BDQ-containing regimens achieved a comparable culture conversion rate regardless of baseline CFZ susceptibility. The presence of acquired CFZ resistance following BDQ treatment without a known mutation indicates that other mechanisms conferring cross-resistance to these two compounds may exist.
OBJECTIVES: The aim of this study was to describe the prevalence of clofazimine (CFZ) resistance in a cohort of patients with multidrug-resistant tuberculosis (MDR-TB) in China. A further aim was to identify dynamic changes in CFZ susceptibility and its molecular mechanism after exposure to bedaquiline (BDQ) and/or CFZ. METHODS: The experimental setting was based on an MDR-TB cohort receiving BDQ-containing regimens. Sequential isolates were obtained from these patients. The CFZ and BDQ susceptibility of isolates were determined using the minimum inhibitory concentration (MIC) method. The fragments of Rv0678 and pepQ were sequenced. RESULTS: A total of 277 patientsinfected with MDR-TB were included in this study. CFZ resistance was noted in 23 isolates (23/277, 8.3%). The rate of acquired CFZ resistance (12/189, 6.3%) was significantly greater than that of primary resistance (11/88, 12.5%, p = 0.028). Out of 23 CFZ-resistant isolates, five (5/23) were BDQ-resistant and the other 18 (18/23) were susceptible to BDQ. Of note, nine out of 23 CFZ-resistant isolates had mutations within either of the target genes. Kaplan-Meier analysis demonstrated that the baseline CFZ resistance had no influence on time to culture conversion in this cohort (p = 0.828). Acquired CFZ resistance emerged in eight patients (8/94, 8.5%) during treatment for MDR-TB, including three patients receiving regimens without CFZ. CONCLUSIONS: The study results demonstrated a high rate of CFZ resistance among MDR-TB patients in China. Patients treated with BDQ-containing regimens achieved a comparable culture conversion rate regardless of baseline CFZ susceptibility. The presence of acquired CFZ resistance following BDQ treatment without a known mutation indicates that other mechanisms conferring cross-resistance to these two compounds may exist.
Authors: Jupiter Marina Kabahita; Joel Kabugo; Francis Kakooza; Isa Adam; Ocung Guido; Henry Byabajungu; Joanitah Namutebi; Maria Magdalene Namaganda; Pius Lutaaya; James Otim; Fredrick Elishama Kakembo; Stephen Kanyerezi; Patricia Nabisubi; Ivan Sserwadda; George William Kasule; Hasfah Nakato; Kenneth Musisi; Denis Oola; Moses L Joloba; Gerald Mboowa Journal: Antimicrob Resist Infect Control Date: 2022-05-12 Impact factor: 6.454