1991 Volume 66 Issue 10 Pages 679-685
The Standard Initial Chemotherapy, chemotherapeutic activity of which depends mostly on the two potent bactericidal drugs, INH and RFP, has made a remarkable progress in the treatment of tuberculosis.
However, certain difficult situations still remain in the treatment of resistant diseases, mostly in retreatment cases especially resistant to INH and/or RFP, and of the patients who are not able to continue the Standard Regimens because of side effects and/or severe complications with various organ dysfunctions.
It is evident that presently available antituberculosis drugs are not potent enough to deal satisfactorily with the above situations, and besides, there has been unsatisfactory chemotherapeutic efficacy against infections caused by Mycobacterium avium complex.
The above matters strongly urge our effort to develop new antimycobacterial agents. In the present review, in vitro and in vivo activities of newly synthesized rifamycin derivatives (3'-hydroxy-5'-akylpiperazinyl-benzoxazinorifamycins, KRMs) were discussed.
Of a total of 158 newly synthesized compounds, five (KRM-1648, KRM-1657, KRM-1668, KRM-1674, KRM-2312) were selected due to significantly lower MICs than those of RFP against M. tuberculosis H37Rv and M. intracellulare 31F093T. The MIC90s of these compounds were 16 to 32 times lower than MIC90 of RFP against RFP-susceptible clinical isolates (20 strains) of M. tuberculosis, and 100 times or more lower than MIC90s of RFP against 20 disease-associated M. avium complex strains. Daily oral single administration (10mg/kg) of all these compounds demonstrated 100% survival of 20 ddY male mice infected with an intravenous lethal dose of M. tuberculosis H37Rv for 40 days, while only 40% or less of the mice treated with 10mg/kg/day of RFP survived at 40 days of infection. All of the untreated mice died within 22 days of infection. Consecutive viable counts of bacilli in lung and spleen of the female beige mice infected intravenously with ca. 108 cfu of M. intracellulare 31F093T were significantly lower in the KRM-1648-treated (20mg/kg/day) group than the untreated, although KRM-1648 could not eradicate the disease in single usage. There was no significant difference between RFP-treated and untreated groups.
Preliminary data also suggest superior bactericidal activity of KRM-1648 against H37Rv to that of RFP in vitro, and in vivo chemotherapeutic superiority of KRM-1648 to RFP in murine tuberculosis is being confirmed by the administration of smaller doses. In experimental murine M. intracellulare model, an encouraging result was obtained for the usefulness of KRM-1648 in combination chemotherapy of M. intracellulare infections.
The above results all suggest that KRM-1648 could be a promising drug of both M. tuberculosis and M. intracellulare infections in humans, and future plans for further evaluations were discussed.
