Bedaquiline Drug Resistance Emergence Assessment in Multidrug-Resistant Tuberculosis (MDR-TB): a 5-Year Prospective In Vitro Surveillance Study of Bedaquiline and Other Second-Line Drug Susceptibility Testing in MDR-TB Isolates

Abstract

Bedaquiline Drug Resistance Emergence Assessment in Multidrug-resistant tuberculosis (MDR-TB) (DREAM) was a 5-year (2015 to 2019) phenotypic drug resistance surveillance study across 11 countries. DREAM assessed the susceptibility of 5,036 MDR-TB isolates of bedaquiline treatment-naive patients to bedaquiline and other antituberculosis drugs by the 7H9 broth microdilution (BMD) and 7H10/7H11 agar dilution (AD) MIC methods. Bedaquiline AD MIC quality control (QC) range for the H37Rv reference strain was unchanged, but the BMD MIC QC range (0.015 to 0.12 μg/ml) was adjusted compared with ranges from a multilaboratory, multicountry reproducibility study conforming to Clinical and Laboratory Standards Institute Tier-2 criteria. Epidemiological cutoff values of 0.12 μg/ml by BMD and 0.25 μg/ml by AD were consistent with previous bedaquiline breakpoints. An area of technical uncertainty or intermediate category was set at 0.25 μg/ml and 0.5 μg/ml for BMD and AD, respectively. When applied to the 5,036 MDR-TB isolates, bedaquiline-susceptible, -intermediate, and -resistant rates were 97.9%, 1.5%, and 0.6%, respectively, for BMD and 98.8%, 0.8%, and 0.4% for AD. Resistance rates were the following: 35.1% ofloxacin, 34.2% levofloxacin, 33.3% moxifloxacin, 1.5% linezolid, and 2% clofazimine. Phenotypic cross-resistance between bedaquiline and clofazimine was 0.4% in MDR-TB and 1% in pre-extensively drug-resistant (pre-XDR-TB)/XDR-TB populations. Coresistance to bedaquiline and linezolid and clofazimine and linezolid were 0.1% and 0.3%, respectively, in MDR-TB and 0.2% and 0.4%, respectively, in pre-XDR-TB/XDR-TB populations. Resistance rates to bedaquiline appear to be low in the bedaquiline-treatment-naive population. No treatment-limiting patterns for cross-resistance and coresistance have been identified with key TB drugs to date.

Keywords: Mycobacterium tuberculosis; bedaquiline; drug resistance; drug susceptibility testing; tuberculosis; variants.

FIG 1

Bedaquiline MIC quality control ranges for H37Rv by the 7H9 broth microdilution (A) and agar (B) dilution methods. Dashed lines indicate the BDQ QC ranges established through Tier-3 studies. BDQ QC ranges determined in the Tier-2 studies were 0.015 to 0.06 for the 7H9 BMD MIC and 0.015 to 0.12 for the AD MIC (25).

FIG 2

Bedaquiline 7H9 broth microdilution MIC distribution for MDR-TB clinical isolates. Susceptible (S), area of technical uncertainty (ATU)/intermediate (I), and resistant (R) breakpoints are indicated by arrows.

FIG 3

Bedaquiline agar dilution MIC distribution for MDR-TB clinical isolates. Susceptible (S), area of technical uncertainty (ATU)/intermediate (I), and resistant (R) breakpoints are indicated by arrows.

FIG 4

Categorical analysis of bedaquiline breakpoints using the error-rate-bound method. CLSI* indicates guidelines acceptable discrepancy rates (37), NA, not applicable; R, resistant; S, susceptible; I, intermediate. BDQ broth MIC S and R categories are indicated below the lower horizontal line and above the upper horizontal line, respectively. The BDQ agar MIC S and R categories are indicated to the right of the right-hand vertical line and to the left of the left-hand vertical line, respectively. The very major error rates (false susceptible by the agar method) are calculated in the upper right quadrant, where category ≥I + 2 is highlighted in dark orange and category I + 1 to I − 1 is highlighted in light orange. The major error rates (false resistant by the agar method) are calculated in the lower left quadrant, where category I + 1 to I − 1 is highlighted in light green and category ≤I − 2 is highlighted in dark green. The minor error rates are calculated between the parallel lines, where category ≥I + 2 is highlighted in dark blue, category I + 1 to I − 1 is highlighted in light blue, and category ≤I − 2 is highlighted in pink.

FIG 5

Cross-resistance between bedaquiline and clofazimine. Pre-XDR-TB, pre-extensively drug-resistant tuberculosis (MDR-TB with resistance to any fluoroquinolone or second-line injectable); XDR-TB, extensively drug-resistant tuberculosis (MDR-TB with resistance to any fluoroquinolone and any second-line injectable).