Abstract:

Objective The results of in vitro drug sensitivity test (drug sensitivity test) of drug-resistant MTB isolates against different combinations of anti-tuberculosis drugs (different combinations of drugs) were analyzed to evaluate the minimum inhibitory concentration (MIC) of different combinations of drugs and the anti-MTB synergistic effect on drug-resistant strains. Methods One hundred and forty-eight first retreatment tuberculosis patients participating in the “twelfth five-year” national science and technology key projects undertaken by the Shanghai Pulmonary Hospital affiliated to Tongji University were collected, and 167 MTB isolates were obtained via culturing of sputum samples from patients by BACTEC MGIT 960 and modified Roche separation method. Ninety-two resistant strains (including 36 of MDR-MTB, 54 of XDR-MTB, and 2 of single H resistant strains) from 75 patients identified by the above two methods of drug susceptibility test were used to perform the in vitro susceptibility tests of 4 types of drug combinations, including H-R, Mfx-Pa, Mfx-Pa-Rfb and Mfx-Pa-Rft, respectively, through three-dimensional chessboard MIC detection, and the synergistic rates of different drug combinations were calculated. Results The median (quartile) (M(Q₁,Q₃)) of the MIC values of H, R, Rfb, Rft, and Pa before drug combination were 4 (1,8), 24 (2,64), 0.5 (0.125,1),4 (4,4), and 8 (4,8) mg/L, respectively, which were significantly higher than that of H (2 (1,4) mg/L), R (1 (0.25,16) mg/L), and Rfb (0.125 (0.03125,0.125) mg/L) after Mfx-Pa combination, Rft (1 (1,1) mg/L) after Mfx-Pa combination, Pa (0.0075 (0.0075, 0.875) mg/L, 0.0075 (0.0075, 0.125) mg/L, and 0.0225 (0.0075,0.5) mg/L) combined with Mfx/Mfx-Rfb/Mfx-Rft, respectively (Z=-4.855, -6.908, -8.386, -8.632, -8.094, -8.335, -7.771, all P values <0.001).The synergic rates of H-R, Mfx-Pa, Mfx-Pa-Rfb and Mfx-Pa-Rft were 12.0% (11/92), 5.4% (5/92), 17.4% (16/92) and 23.9% (22/92), respectively. The difference of the synergic rates between H-R and Mfx-Pa combination to Mfx-Pa-Rfb and Mfx-Pa-Rft combination, respectively, were statistically significant (χ ²=12.670, P=0.002;χ ²=19.420, P<0.001;χ ²=18.640, P<0.001;χ ²=28.500, P<0.001). Conclusion The MIC values of H, R, Rfb, Rft and Pa in the combined drugs are lower than those before combination, indicating that the sensitivities to the combined drugs of drug-resistant strains are enhanced. The synergy rates of the three drug combinations are better than that of the two drug combinations, and Mfx-Pa-Rft showed better synergy than Mfx-Pa-Rfb combination.

Key words: Tuberculosis,multi-drug resistant, Extensively drug-resistant tuberculosis, Drug therapy,combination, Microbial sensitivity tests, In vitro, Drug synergism, Comparative study