Journal of Antimicrobial Chemotherapy, Vol 42, 621-628, Copyright © 1998 by The British Society for Antimicrobial Chemotherapy
B Yang, H Koga, H Ohno, K Ogawa, M Fukuda, Y Hirakata, S Maesaki, K Tomono, T Tashiro and S Kohno
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 < or = 16 mg/L were
susceptible to rifabutin and KRM-1648 with MICs < or = 1 mg/L.
Seventy-six of 81 strains resistant to rifampicin with MICs > or = 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 (< or = 1 mg/L),
while rifabutin was more active than KRM-1648 against organisms with high
MICs (> or = 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.
ORIGINAL ARTICLES
Relationship between antimycobacterial activities of rifampicin, rifabutin and KRM-1648 and rpoB mutations of Mycobacterium tuberculosis
The Second Department of Internal Medicine, Nagasaki University School of Medicine, Japan.
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