Treatment failure in a case of extensively drug-resistant tuberculosis associated with selection of a GyrB mutant causing fluoroquinolone resistance

Objective — to study the effectiveness of treatment of MDR-TB (multidrug-resistant tuberculosis) and preXDR-TB/XDR-TB (pre-extensively and extensively drug resistant tuberculosis), depending on the composition of ITRs (individualized treatment regimens). Materials and methods. Тhe prospective observational study included 566 patients with MDR/preXDR-TB and XDR-TB during 2016—2020 on the scientific clinical bases of the SI «National Institute of Phthisiology and Pulmonology named after F.G. Yanovsky NAMS of Ukraine» and ME «Kryvyi Rih Anti-tuberculosis Dispensary» Dnipropetrovsk Regional Council Department. Patients were prescribed individualized treatment regimens in cases where short (standard or modified) regimens could not be prescribed. Patients were divided into comparison groups: 469 of them were treated with antimycobacterial therapy including bedaquiline and other effective antimycobacterial drugs groups A—C (without delamanid) — group 1. And 97 patients who were treated with the inclusion of both new antimycobacterial drugs (bedaquiline and delamanid) — group 2. Results and discussion. Regardless of whether the delamanid, in addition to bedaquiline and other drugs selected for the scheme according to WHO recommendations, «effective treatment» was found in 91.3 against 88.6 % of patients. In the remote period (6-month — 4-year follow-up period) there was no recurrence of the disease, regardless of the composition of the regime. The loss of treatment effectiveness was due to deaths from non-tuberculosis reasons and those lost for follow-up. Conclusions. For highly effective treatment, individualized regimens should include bedaquidine and linezolid from group A, and for previously ineffectively treated patients, clofazimine and carbapenems must be included (possibility to include 4 or more effective AMDs in ITR). For patients with fluoroquinolone resistance, treatment should include delamanid.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00900-17 ◽

2017 ◽

Vol 61 (10) ◽

Cited By ~ 37

Author(s):

Yu Pang ◽

Zhaojing Zong ◽

Fengmin Huo ◽

Wei Jing ◽

Yifeng Ma ◽

...

Keyword(s):

Drug Resistance ◽

Fluoroquinolone Resistance ◽

Cross Resistance ◽

Drug Resistant ◽

Drug Resistant Tuberculosis ◽

Genetic Characteristics ◽

Acquired Drug Resistance ◽

Resistant Tuberculosis ◽

Extensively Drug Resistant

ABSTRACT 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.

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