THE CLINICAL SIGNIFICANCE OF THE CRITICAL DRUG CONCENTRATION OF RIFAMPICIN

Abstract

Following the study mentioned in Report 1, clinical investigations were made on the emergence and reversion of resistance to rifampicin (RFP), and the results were summarized as follows:
1) The previous study showed that the bacillary growth of 1 to 10% on 10 mcg RFP medium was 112 cases (6.9%) among 1, 779 cases, the growth of 11 to 50% was 5 cases (0.3%) and only 1 case (0.06%) grew over 50%. During the course of RFP treatment for 366 cases, 97 cases became resistant to RFP, and all these cases except 2 showed growth of 1% or more on 10 mcg as well as on 50 mcg RFP medium (Table 1). This fact leads us to believe that the error might be less to take the bacillary growth of either over 50% on 10 mcg or 1% or more on 50 mcg RFP medium for the clinical significance of RFP resistance than the criteria mentioned in the previous report.
2) The following characteristics were found when bacilli became resistant to RFP.
a) The amount of bacilli decreased or disappeared rapidly after starting RFP treatment, and the appearance of resistance to RFP coincided with the reappearance of bacilli or increase of bacilli amount (Fig. 1).
b) Among cases became resistant, 65% appeared within the first 3 months after starting RFP treatment, and if once it became resistant, it reached to the high grade of resistance at once (Table 1).
c) The appearance of resistance to the combined drugs was usually delayed except EB (Fig. 2). The emergence of resistance to RFP and EB among cases treated by the combination of RFP and EB, the number of cases showing resistance to RFP faster than to EB was 4 times more than that showing resistance to EB faster than to RFP. There were no other drugs except INH which became resistant faster than RFP. In the case of INH, all INH-sensitive cases converted to negative by the combined therapy with RFP until now.
d) The combined drugs remained sensitive for a long period after RFP became resistant. This indicates that RFP inhibits the growth of bacilli stronger than other drugs, and the rank of efficacy of other combined drugs can be determined by the length of time during which combined drugs remain sensitive.
3) There were 7 cases which remained bacilli positive and sensitive to RFP. Detailed analysis was made on 3 of them, and the above fact might be explained partly by the lower dose of drugs, as some cases like No.3 continuously discharging bacilli under RFP 0.3g and EB 1.0g twice weekly regimen converted to negative after changing the regimen to RFP 0.45g and EB 1.0g daily.
4) There were 4 cases in which resistance to 50mcg RFP returned to sensitive to 10mcg RFP. The frequency of this reversion of resistance was 4.2% among 95 bacteriologically relapsed cases and 9.3% among 43 cases in which bacilli were examined 6 months after the suspension of RFP. One example was shown in Fig. 3, and it was difficult to explain the reason of this reversion, as the number of cases was too small. These 4 cases were treated for the second time by RFP after RFP resistance reverted to sensitive, but all failed to convert to negative and became resistant again. This might be explained by the lack of sufficiently intensive combined drugs.