In vitro synergistic activity of clofazimine and other antituberculous drugs against multidrug-resistant Mycobacterium tuberculosis isolates

• The prevalence of CLO-resistant isolates among XDR group is significantly higher than that of MDR group.
• The combination of CLO and EMB shows better synergism than the other combinations containing CLO.
• The CLO-MOX combination is more likely to show synergy against MDR isolates than the CLO-LEV combination.

Clofazimine (CLO) is a promising candidate drug for use in the management of multidrug-resistant tuberculosis (MDR-TB) patients. In this study, the minimum inhibitory concentration (MIC) method was used to investigate drug susceptibility to CLO as well as potential synergies between CLO and other antituberculous drugs, including ethambutol (EMB), levofloxacin (LEV), moxifloxacin (MOX), amikacin (AMK) and capreomycin (CAP), among MDR-TB isolates from China. A total of 195 MDR-TB isolates were collected from the national drug resistance survey conducted in China. Of the 195 MDR-TB isolates, 54 (27.7%) were classified as CLO-resistant, whilst 141 (72.3%) were CLO-susceptible with MICs of ≤1 μg/mL. In addition, the prevalence of CLO-resistant isolates among the extensively drug-resistant (XDR)-TB group was 61.5% (8/13), which was significantly higher than that of the MDR-TB group (23.0%) (P = 0.006). When fractional inhibitory concentration indexes (FICIs) were calculated for 24 isolates, synergy was found in 11 isolates (45.8%) against the CLO/EMB combination, 6 (25.0%) against the CLO/LEV combination, 8 (33.3%) against the CLO/MOX combination, 4 (16.7%) against the CLO/AMK combination and 5 (20.8%) against the CLO/CAP combination. In addition, <15% of MDR-TB isolates showed antagonistic effects against these five combinations. In conclusion, these findings demonstrate that the combination of CLO and EMB shows better synergism than the other combinations containing CLO. The CLO/MOX combination is more likely to show synergy against MDR-TB isolates than the CLO/LEV combination. Taken together, we suggest that CLO, in combination with EMB or MOX, may be a promising drug regimen for the treatment of MDR-TB.