High rates of acquired resistance to fluoroquinolones, bedaquiline, and linezolid in patients failing treatment against drug-resistant tuberculosis in the Republic of Moldova.

OBJECTIVES: Mycobacterium tuberculosis with rifampicin resistance ranks among the four critical antimicrobial-resistant pathogens needing priority attention as identified by the World Health Organization (WHO) in 2024. Our objective was to identify the causes of treatment failure in patients diagnosed with multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) in a nationwide cohort in the Republic of Moldova, a WHO high-burden country of MDR/RR-TB.

METHODS: A retrospective cohort study analysed national tuberculosis surveillance data (2021-2022) on patients diagnosed with MDR/RR-TB with available baseline and follow-up drug susceptibility testing for WHO group A drugs. Treatment failure was defined as the absence of sputum culture conversion after 6 months. Logistic regression was used to identify risk factors associated with treatment failure.

RESULTS: Of 1034 patients initiating MDR/RR-TB treatment, 55 (5.3%) experienced treatment failure, whereas 693 (67.1%) were successfully treated. Baseline resistance to WHO group A drugs was significantly higher in patients with treatment failure than in those with successful outcomes: fluoroquinolones (32/48 [66.7%] vs. 86/471 [18.3%]; p < 0.0001), bedaquiline (6/42 [12.5%] vs. 3/468 [0.6%]; p < 0.0001), and linezolid (12/48 [25.0%] vs. 3/468 [0.6%]; p < 0.0001). Acquired resistance occurred in 19 of 48 (39.6%) of those failing treatment, but none with successful outcomes, particularly to bedaquiline 13 of 42 (30.9%), linezolid 6 of 36 (16.7%), and fluoroquinolones 4 of 16 (25.0%). Baseline fluoroquinolone resistance (OR, 4.7; 95% CI, 2.0-11.2) and acquired resistance to any WHO group A drug (OR, 63.5; 95% CI, 7.7-8311.7) were associated with treatment failure.

DISCUSSION: Although frequencies of treatment failure in MDR/RR-TB are low on bedaquiline-containing treatment regimens, we find alarmingly high rates of baseline and acquired drug resistance to key second-line anti-TB drugs as a driver for treatment failure in MDR/RR-TB. Strengthening resistance monitoring, improving adherence, and optimizing individualized regimens are urgently needed to prevent the emergence of extensively drug-resistant TB in high-burden settings of MDR/RR-TB.