Relationship between antimycobacterial activities of rifampicin, rifabutin and KRM-1648 and rpoB mutations of Mycobacterium tuberculosis

被引:117
作者
Yang, B [1 ]
Koga, H [1 ]
Ohno, H [1 ]
Ogawa, K [1 ]
Fukuda, M [1 ]
Hirakata, Y [1 ]
Maesaki, S [1 ]
Tomono, K [1 ]
Tashiro, T [1 ]
Kohno, S [1 ]
机构
[1] Nagasaki Univ, Sch Med, Dept Internal Med 2, Nagasaki 8528501, Japan
关键词
D O I
10.1093/jac/42.5.621
中图分类号
R51 [传染病];
学科分类号
100401 ;
摘要
We compared the in-vitro antimycobacterial activities of rifabutin and KRM-1648, two rifamycin derivatives, with that of rifampicin against 163 strains of Mycobacterium tuberculosis. We also evaluated the correlation between the level of resistance to rifampicin, rifabutin and KRM-1648 and genetic alterations in the rpoB gene. All 82 strains susceptible to rifampicin or resistant to rifampicin with MICs less than or equal to 16 mg/L were susceptible to rifabutin and KRM-1648 with MICs less than or equal to 1 mg/L. Seventy-six of 81 strains resistant to rifampicin with MICs greater than or equal to 32 mg/L were resistant to both rifabutin and KRM-1648, but with lower MICs than those of rifampicin. KRM-1648 showed more potent antimycobacterial activity than rifabutin against organisms with low MICs (less than or equal to 1 mg/L), while rifabutin was more active than KRM-1648 against organisms with high MICs (greater than or equal to 2 mg/L). A total of 96 genetic alterations around the 69 bp core region of the rpoB gene were detected in 92 strains. Alterations at codons 515, 521 and 533 in the rpoB gene did not influence the susceptibility to rifampicin, rifabutin and KRM-1648. Point mutations at codons 516 and 529, deletion at codon 518 and insertion at codon 514 influenced the susceptibility to rifampicin but not that to rifabutin or KRM-1648. With the exception of one strain, all alterations at codon 513 and 531 correlated with resistance to the three test drugs. The resistant phenotype of strains with an alteration at codon 526 depended on the type of amino acid substitution. Our results suggest that analysis of genetic alterations in the rpoB gene might be useful not only for predicting rifampicin susceptibility, but also for deciding when to use rifabutin for treating tuberculosis. Further studies may be required to determine the usefulness of KRM-1648.
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页码:621 / 628
页数:8
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