Low Rate of Acquired Linezolid Resistance in Multidrug-Resistant Tuberculosis Treated With Bedaquiline-Linezolid Combination

Jian Du; Jingtao Gao; Yanhong Yu; Qingfeng Li; Guanghong Bai; Wei Shu; Mengqiu Gao; Yuhong Liu; Lu Wang; Yufeng Wang; Zhongtan Xue; Fengmin Huo; Liang Li; Yu Pang

doi:10.3389/fmicb.2021.655653

Low Rate of Acquired Linezolid Resistance in Multidrug-Resistant Tuberculosis Treated With Bedaquiline-Linezolid Combination

Front Microbiol. 2021 May 3:12:655653. doi: 10.3389/fmicb.2021.655653. eCollection 2021.

Authors

Jian Du¹, Jingtao Gao¹, Yanhong Yu², Qingfeng Li³, Guanghong Bai⁴, Wei Shu¹, Mengqiu Gao⁵, Yuhong Liu¹, Lu Wang⁶, Yufeng Wang⁷, Zhongtan Xue⁷, Fengmin Huo⁶, Liang Li¹, Yu Pang⁶

Affiliations

¹ Clinical Center on TB, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China.
² Tuberculosis Laboratory, Shenyang Tenth People's Hospital (Shenyang Chest Hospital), Shenyang, China.
³ Department of Laboratory, Public Health and Clinical Center of Chengdu, Chengdu, China.
⁴ Department of Laboratory, Shaanxi Provincial Tuberculosis Institute, Xi'an, China.
⁵ Department of Tuberculosis, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China.
⁶ Beijing Key Laboratory on Drug-Resistant Tuberculosis Research, Department of Bacteriology and Immunology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China.
⁷ Department of Laboratory Quality Control, Innovation Alliance on Tuberculosis Diagnosis and Treatment (Beijing), Beijing, China.

Abstract

In this retrospective study in China, we aimed to: (1) determine the prevalence of linezolid (LZD) resistance among multidrug-resistant tuberculosis (MDR-TB)-infected patients; (2) monitor for dynamic LZD susceptibility changes during anti-TB treatment; and (3) explore molecular mechanisms conferring LZD resistance. A total of 277 MDR-TB patients receiving bedaquiline (BDQ)-containing regimens in 13 TB specialized hospitals across China were enrolled in the study. LZD and BDQ susceptibility rates were determined using the minimum inhibitory concentration (MIC) method, then DNA sequences of patient isolates were analyzed using Sanger sequencing to detect mutations conferring LZD resistance. Of 277 patients in our cohort, 115 (115/277, 41.5%) with prior LZD exposure yielded 19 (19/277, 6.9%) isolates exhibiting LZD resistance. The LZD resistance rate of LZD-exposed group isolates significantly exceeded the corresponding rate for non-exposed group isolates (P = 0.047). Genetic mutations were observed in 10 (52.6%, 10/19) LZD-resistant isolates, of which a Cys154Arg (36.8%, 7/19) substitution within ribosomal protein L3 was most prevalent. Analysis of sequential positive cultures obtained from 81 LZD-treated patients indicated that cultured organisms obtained from most patients (85.2%, 69/81) retained original LZD MIC values; however, organisms cultured later from two patients exhibited significantly increased MIC values that were attributed to the rplC substitution T460C. Overall, LZD resistance was detected in 6.9% of patients of an MDR-TB cohort in China. Low rate of acquired LZD resistance was noted in MDR-TB treated with BDQ-LZD combination.

Keywords: bedaquiline; linezolid; multidrug-resistant; susceptibility; tuberculosis.