In Vitro Drug Susceptibility of Bedaquiline, Delamanid, Linezolid, Clofazimine, Moxifloxacin, and Gatifloxacin against Extensively Drug-Resistant Tuberculosis in Beijing, China.

Extensively drug-resistant tuberculosis (XDR-TB) is a deadly form of TB that can be incurable due to its extreme drug resistance. In this study, we aimed to explore the in vitro susceptibility to bedaquiline (BDQ), delamanid (DMD), linezolid (LZD), clofazimine (CLO), moxifloxacin (MFX), and gatifloxacin (GAT) of 90 XDR-TB strains isolated from patients in China. We also describe the genetic characteristics of XDR-TB isolates with acquired drug resistance. Resistance to MFX, GAT, LZD, CLO, DMD, and BDQ was found in 82 (91.1%), 76 (84.4%), 5 (5.6%), 5 (5.6%), 4 (4.4%), and 3 (3.3%) isolates among the XDR-TB strains, respectively. The most frequent mutations conferring fluoroquinolone resistance occurred in codon 94 of the gyrA gene (57.8%), and the strains with these mutations (69.2%) were associated with high-level MFX resistance compared to strains with mutations in codon 90 (25.0%) (P < 0.01). All 5 CLO-resistant isolates exhibited ≥4-fold upward shifts in the BDQ MIC, which were attributed to mutations of codons 53 (60.0%) and 157 (20.0%) in the Rv0678 gene. Additionally, mutation in codon 318 of the fbiC gene was identified as the sole mutation related to DMD resistance. In conclusion, our data demonstrate that the XDR-TB strains exhibit a strikingly high proportion of resistance to the current anti-TB drugs, whereas BDQ, DMD, LZD, and CLO exhibit excellent in vitro activity against XDR-TB in the National Clinical Center on TB of China. The extensive cross-resistance between OFX and later-generation fluoroquinolones indicates that MFX and GAT may have difficulty in producing the desired effect for XDR-TB patients.

Pang Y ，Zong Z ，Huo F ，Jing W ，Ma Y ，Dong L ，Li Y ，Zhao L ，Fu Y ，Huang H ... -  《-》

No in vitro synergistic effect of bedaquiline combined with fluoroquinolones, linezolid, and clofazimine against extensively drug-resistant tuberculosis.

We explored the potential synergistic effect of bedaquiline (BDQ) combined with moxifloxacin (MFX), gatifloxacin (GAT), clofazimine (CLO), and linezolid (LZD) for treatment of extensively drug-resistant tuberculosis (XDR-TB). Of 191 XDR-TB isolates, 20 exhibiting minimal inhibitory concentration (MIC) values ≥0.063 μg/mL for BDQ were selected to study potential synergistic, additive, or antagonistic drug effects using a checkerboard assay. Antagonism occurred in 14 (70.0%), 0 (0.0%), 13 (65.0%), and 4 (20.0%) XDR-TB isolates for BDQ-MFX, BDQ-GAT, BDQ-LZD, and BDQ-CLO combinations, respectively. Our in vitro data demonstrate no observed synergistic effects against XDR-TB for drug combinations that included BDQ in combination with MFX, GAT, LZD, or CLO.

Pang Y ，Jing W ，Lu J ，Zong Z ，Huo F ，Dong L ，Dai G ，Li Y ，Huang H ，Chu N ... -  《-》

Delamanid, Bedaquiline, and Linezolid Minimum Inhibitory Concentration Distributions and Resistance-related Gene Mutations in Multidrug-resistant and Extensively Drug-resistant Tuberculosis in Korea.

Delamanid, bedaquiline, and linezolid have recently been approved for the treatment of multidrug- and extensively drug-resistant (MDR and XDR, respectively) tuberculosis (TB). To use these drugs effectively, drug susceptibility tests, including rapid molecular techniques, are required for accurate diagnosis and treatment. Furthermore, mutation analyses are needed to assess the potential for resistance. We evaluated the minimum inhibitory concentrations (MICs) of these three anti-TB drugs for Korean MDR and XDR clinical strains and mutations in genes related to resistance to these drugs. MICs were determined for delamanid, bedaquiline, and linezolid using a microdilution method. The PCR products of drug resistance-related genes from 420 clinical Mycobacterium tuberculosis strains were sequenced and aligned to those of M. tuberculosis H37Rv. The overall MICs for delamanid, bedaquiline, and linezolid ranged from ≤0.025 to >1.6 mg/L, ≤0.0312 to >4 mg/L, and ≤0.125 to 1 mg/L, respectively. Numerous mutations were found in drug-susceptible and -resistant strains. We did not detect specific mutations associated with resistance to bedaquiline and linezolid. However, the Gly81Ser and Gly81Asp mutations were associated with resistance to delamanid. We determined the MICs of three anti-TB drugs for Korean MDR and XDR strains and identified various mutations in resistance-related genes. Further studies are needed to determine the genetic mechanisms underlying resistance to these drugs.

Yang JS ，Kim KJ ，Choi H ，Lee SH ... -  《-》

In vitro interaction profiles of the new antitubercular drugs bedaquiline and delamanid with moxifloxacin against clinical Mycobacterium tuberculosis isolates.

The emergence of drug-resistant tuberculosis (TB) poses a serious challenge to existing anti-TB therapies. Hence, there is a direct need for identification of new drugs and effective combination regimens. In this study, minimum inhibitory concentrations (MICs) of the anti-TB drugs bedaquiline (BDQ), delamanid (DEL) and moxifloxacin (MFX) were evaluated using a resazurin microtiter assay (REMA) against five drug-resistant clinicalMycobacterium tuberculosis (MTB) isolates as well as the drug-susceptible reference strain H37Rv. In addition, their fractional inhibitory concentration indices (FICIs) were evaluated using a REMA-based calorimetric chequerboard assay to assess their interaction profiles against the MTB isolates. The FICI indicated that BDQ acted synergistically with DEL against isoniazid (INH)-monoresistant, rifampicin (RIF)-monoresistant and extensively drug-resistant (XDR) clinical MTB isolates. In addition, the combination of DEL acted synergistically with MFX against INH-monoresistant, RIF-monoresistant and XDR clinical MTB isolates. Moreover, the combination of BDQ and MFX showed a synergistic effect against RIF-monoresistant and pre-XDR clinical MTB isolates. DEL at 0.125×MIC (i.e. 0.015μg/mL) used in combination with BDQ at 0.25×MIC (i.e. 0.015μg/mL) had a stronger bactericidal effect against the XDR-TB clinical isolate than DEL alone at 1×MIC (i.e. 0.125μg/mL). Synergistic and additive effects between these two-drug combinations offer an attractive chemotherapeutic regimen against drug-resistant clinical MTB isolates.

Chandramohan Y ，Padmanaban V ，Bethunaickan R ，Tripathy S ，Swaminathan S ，Ranganathan UD ... -  《-》

Prevalence of extensively drug-resistant tuberculosis in a Chinese multidrug-resistant TB cohort after redefinition.

Recently, the definition of extensively drug-resistant TB (XDR-TB) has been revised. In this study, we conducted a descriptive and retrospective study to determine the prevalence of XDR-TB in a Chinese multidrug-resistant TB (MDR-TB) cohort. Broth microdilution method was performed to determine in vitro susceptibilities of Mycobacterium tuberculosis (MTB) isolates to (FQs), bedaquiline (BDQ) and linezolid (LZD). The putative drug target genes conferring drug resistance were screened by DNA sequencing. A total of 425 MDR-TB isolates were included from 13 pilots in China. LZD and BDQ resistance were noted in 30 (7.1%) and 10 (2.4%) isolates. On the basis of latest definitions, 114 (26.8%) were MDR-TB, 282 (66.4%) were pre-XDR-TB, and 29 (6.8%) were XDR-TB. Among 311 FQ-resistant isolates, 265 harbored genetic mutations within QRDRs. The most common mutations were observed at codon 94 of gyrA, accounting for 47.2% of FQ-resistant MTB isolates. Only mutations within the Rv0678 gene were found to confer BDQ resistance in our cohort, conferring 40.0% of BDQ resistance. For LZD resistance, 53.3% of LZD-resistant isolates carried genetic mutations in rplC or 23S rRNA. The most frequent mutation was Cys154Arg in the rplC gene. In addition, we recorded two MDR-TB patients with resistance to both BDQ and LZD, of which one patient experienced continuous positive culture of MTB despite inclusion of efficacious moxifloxacin. Our results demonstrate that the low prevalence of XDR-TB holds great promise for MDR-TB treatment with WHO-endorsed regimens containing BDQ-LZD combination, whereas the high prevalence of FQ-resistance in MDR-TB patients warrants national attention.

Yao C ，Guo H ，Li Q ，Zhang X ，Shang Y ，Li T ，Wang Y ，Xue Z ，Wang L ，Li L ，Pang Y ... -  《Antimicrobial Resistance and Infection Control》