Interactions of linezolid and second-line anti-tuberculosis agents against multidrug-resistant Mycobacterium tuberculosis in vitro and in vivo.
OBJECTIVE
The objectives of this study were to evaluate the interactions between linezolid (LZD) and second-line anti-tuberculosis (TB) agents in susceptible and multidrug-resistant (MDR) TB in vitro, and to validate the in vitro results in a murine TB model.


METHODS
The minimum inhibitory concentrations of LZD and seven second-line anti-TB drugs against H37Rv and three multidrug-resistant clinical isolates were determined by Alamar Blue assay, and the interaction patterns of LZD and the seven second-line anti-TB agents against the four isolates were studied using a dynamic checkerboard method. The activities of these combinations against Mycobacterium tuberculosis were evaluated in a murine model of TB.


RESULTS
The combination of LZD + capreomycin exhibited partial synergism for three of four isolates, LZD + para-aminosalicylic acid exhibited partial synergism for two of four isolates, and LZD + levofloxacin and LZD + amikacin exhibited partial synergism for one of four isolates; all other combinations showed indifference or an additive effect in vitro. The activities of six combinations and the standard regimen rifampicin + isoniazid + pyrazinamide were investigated in a murine model of TB (infection with H37Rv). Significant reductions in colony-forming units (CFU) were found in LZD + capreomycin and LZD + clofazimine groups when the CFU in the lungs on day 0 (the day of beginning treatment) was compared with the CFU in the lungs after 2 months of treatment.


CONCLUSIONS
These combinations of LZD and second-line anti-TB drugs were all active against MDR-TB with indifference or an additive effect, except LZD + capreomycin, which showed partial synergy.
Department of Pharmacology, Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute, Tongzhou District, Beijing, China.
Weijie
W
Zhao
Pharmacy of Beijing Chest Hospital affiliated to the Capital Medical University, No. 97 Beimachang, Tongzhou District, Beijing, China.
Meiqin
M
Zheng
Department of Pharmacology, Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute, Tongzhou District, Beijing, China.
Bin
B
Wang
Pharmacy of Beijing Chest Hospital affiliated to the Capital Medical University, No. 97 Beimachang, Tongzhou District, Beijing, China.
Xiaopan
X
Mu
Pharmacy of Beijing Chest Hospital affiliated to the Capital Medical University, No. 97 Beimachang, Tongzhou District, Beijing, China.
Peng
P
Li
Department of Pharmacology, Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute, Tongzhou District, Beijing, China.
Lei
L
Fu
Pharmacy of Beijing Chest Hospital affiliated to the Capital Medical University, No. 97 Beimachang, Tongzhou District, Beijing, China.
Shuo
S
Liu
Pharmacy of Beijing Chest Hospital affiliated to the Capital Medical University, No. 97 Beimachang, Tongzhou District, Beijing, China. Electronic address: guozhenyong0425@sina.com.
Zhenyong
Z
Guo
D010131:Aminosalicylic Acid / Q000627:therapeutic use; D000818:Animals; D000995:Antitubercular Agents / Q000627:therapeutic use*; D002207:Capreomycin / Q000627:therapeutic use; D004338:Drug Combinations; D004347:Drug Interactions; D006801:Humans; D007538:Isoniazid / Q000627:therapeutic use; D000069349:Linezolid / Q000627:therapeutic use*; D008297:Male; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000302:isolation & purification; D011718:Pyrazinamide / Q000627:therapeutic use; D012293:Rifampin / Q000627:therapeutic use; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy*
D000995:Antitubercular Agents; D004338:Drug Combinations; C087181:isoniazid, pyrazinamide, rifampin drug combination; D002207:Capreomycin; D011718:Pyrazinamide; D010131:Aminosalicylic Acid; D000069349:Linezolid; D007538:Isoniazid; D012293:Rifampin
Interaction; Linezolid; Multidrug-resistant; Mycobacterium tuberculosis; Second-line anti-TB