Acquired bedaquiline resistance during the treatment of drug-resistant tuberculosis: a systematic review

Abstract

Background Drug-resistant tuberculosis (DR-TB) is considered to be a public health threat and is difficult to cure, requiring a lengthy treatment with potent, potentially toxic drugs. The novel antimicrobial agent bedaquiline has shown promising results for patients with DR-TB, improving the rate of culture conversion and reducing TB-related mortality. However, increasing numbers of cases with acquired bedaquiline resistance (ABR) have been reported in recent years. Methods This systematic review aimed to assess the frequency of ABR and characteristics of patients acquiring it. Studies showing data on sequential bedaquiline drug-susceptibility testing in patients treated with a bedaquiline-containing regimen were included. The databases CENTRAL, PubMed and Embase were manually searched, and 866 unique records identified, eventually leading to the inclusion of 13 studies. Phenotypic ABR was assessed based on predefined MIC thresholds and genotypic ABR based on the emergence of resistance-associated variants. Results The median (IQR) frequency of phenotypic ABR was 2.2% (1.1%–4.6%) and 4.4% (1.8%–5.8%) for genotypic ABR. Among the studies reporting individual data of patients with ABR, the median number of likely effective drugs in a treatment regimen was five, in accordance with WHO recommendations. In regard to the utilization of important companion drugs with high and early bactericidal activity, linezolid was included in the regimen of most ABR patients, whereas the usage of other group A (fluoroquinolones) and former group B drugs (second-line injectable drugs) was rare. Conclusions Our findings suggest a relevant frequency of ABR, urging for a better protection against it. Therefore, treatment regimens should include drugs with high resistance-preventing capacity through high and early bactericidal activity.

Evaluation of Xpert®MTB/XDR test for susceptibility testing ofMycobacterium tuberculosisto first and second-line drugs in Uganda

“…The sensitivity and specificity, n (%; 95%Confidence Interval, CI) of the Xpert ® MTB/XDR test for; INH were 58 (89.2; 79.1-95.5) and 30 (88.2; 72. 5 [15]. In some areas over 30% of the RR-TB patients are already resistant to FQ, pre-XDR, at the start of the treatment [16].…”

Bedaquiline resistance in Mycobacterium tuberculosis during antimycobacterial therapy and its impact on clinical outcomes (clinical cases)

“…Liu Y. et al [3], studying the dynamics of the MBT isolates sensitivity to Bdq during AMBT, have obtained, that these patients were at greater risk of AMBT failure compared to initially resistant to Bdq MDR-TB cases. Mallick J. S. et al in a systematic review [2] have determined that in order to prevent the development of acquired resistance in MBT isolates to Bdq during AMBT, treatment regimens should include drugs with high and early bactericidal activity.…”

“…Regarding the reasons for the development of acquired drug resistance to Bdq, the second clinical case, as examples of other authors, has demonstrated low adherence to treatment. Mallick J. S. et al [2], Liu Y. et al [3], Guglielmetti L. et al [4] indicate the reasons of this outcome: the prescription of Bdq to patients with initially low adherence to treatment, a high frequency of self-discontinuation of AMBT by patients.…”

Predicting MmpR-based bedaquiline resistance using sequence- and structure-based features

“…Although rare, variants in the mmpL5 gene have been shown to override Rv0678-mediated BDQ resistance, resulting in BDQ hypersusceptibility [37]. Similarly, variants in pepQ and Rv1979c have been observed in BDQ resistant isolates, although evidence for their role in clinical BDQ resistance is very scarce [38,39]. Third, many isolates with variants had to be excluded.…”