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

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

doi:10.3389/fmicb.2021.655653

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.

Highlights

MATERIALS AND METHODSMultidrug-resistant tuberculosis (MDR-TB), defined as disease caused by Mycobacterium tuberculosis complex (MTBC) strains with rifampicin and isoniazid resistance, poses a major challenge to TB elimination worldwide (Dheda et al, 2017; World Health Organization, 2019)
Multidrug-resistant tuberculosis (MDR-TB), defined as disease caused by Mycobacterium tuberculosis complex (MTBC) strains with rifampicin and isoniazid resistance, poses a major challenge to TB elimination worldwide (Dheda et al, 2017; World Health Organization, 2019)
minimum inhibitory concentration (MIC) distributions are displayed as a histogram in Figure 2 and were stratified based on prior LZD exposure

Summary

Introduction

Multidrug-resistant tuberculosis (MDR-TB), defined as disease caused by Mycobacterium tuberculosis complex (MTBC) strains with rifampicin and isoniazid resistance, poses a major challenge to TB elimination worldwide (Dheda et al, 2017; World Health Organization, 2019). Due to initial drug resistance of MDR-TB bacilli to potent first-line anti-TB drugs, treatment of multidrug-resistant TB requires prolonged and complex administration of a limited number of second-line regimens that are associated with poorer treatment outcomes (Bastos et al, 2017; Dheda et al, 2017). Based on clinical trial results, in 2018 WHO endorsed the use of LZD as a preferred agent for administration to all patients with MDR-TB (World Health Organization, 2018). The accumulating body of clinical data demonstrating LZD treatment benefits warrants an increasingly greater role for LZD as a cornerstone anti-TB agent for combating drug-resistant TB in national TB treatment programs (Sharma et al, 2017; Sharma et al, 2020)

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Conclusion