LETTER

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From 1943 until 1982 the standard treatment for lepromatous leprosy was lifelong dapsone monotherapy. Though dapsone is bacteriostatic and lepromatous leprosy has the highest bacterial burden of all human diseases, as well as an impairment in protective cellular immunity, dapsone monotherapy proved surprisingly effective. Only 10% of patients developed resistance (19), and on cessation after 18 years of treatment only an additional 10% clinically relapsed (21). In the 1970s Freekson and Rosenfeld (3) in Malta treated leprosy patients, many treated previously with dapsone alone for many years, with a regimen of daily rifampin, prothionamide, dapsone, and isoniazid (not active against Mycobacterium leprae) for 2 years and found that patients were regularly cured. In 1982 the World Health Organization (WHO) (22, 23) recommended another 2-year regimen of multidrug therapy (MDT) (monthly rifampin, 600 mg, plus clofazimine, 300 mg, and daily dapsone, 100 mg, plus clofazimine, 50 mg). This regimen has been widely implemented, largely in patients previously treated with dapsone for prolonged periods, many of whom no longer harbored detectable M. leprae, and successfuly (20). However, the one clinical study in previously untreated lepromatous patients followed up for a sufficient time found an unacceptably high relapse rate of 20 to 40%, depending on the initial bacterial burden (12).

Having discovered that minocycline was bactericidal for M. leprae in mice (5) and in a clinical trial (7) and having conducted several studies of the three antimicrobials utilized by Ji et al. (16) in mice and patients, I was naturally interested in their findings and conclusions. Against an alternative view of the reliability of WHO MDT and the further desirability of a once-monthly supervised regimen, Ji et al. (16) report that in leprosy patients single doses of minocycline plus ofloxacin with and without rifampin are bactericidal and side effects are acceptable; thus, further clinical application of intermittent therapy (monthly) is indicated. I do not believe their results in fact merit these conclusions.

In their introduction the authors state that further applications of regimens to be used with rifampin must prove themselves to be bactericidal. However, the single dose of minocycline plus ofloxacin used was entirely inactive in 3 of the 10 studied patients, and 68 and 69% bactericidal in two others, considered by the authors moderately bactericidal. However, the prototype bacteriostatic agent dapsone was previously found by me (4) and others (1), by using these techniques in mice, to be 72 to 87% bactericidal, and thus, we would consider, 68 to 69% primarily bacteriostatic. In any case whether this regimen was bactericidal in 7 of 10 or 5 of 10 of patients, it certainly was not reliably so and also far less active in mice than daily dapsone-clofazimine, a combination which together with monthly rifampin appears inadequate to effect a cure in previously untreated lepromatous leprosy patients (12). Also, in the current studies, 4 of the 10 patients receiving rifampin, minocycline, and ofloxacin had gastrointestinal side effects; however mild, this is consequential and likely would preclude large-scale utilization of such therapy. Thus, I would conclude, single doses of ofloxacin plus minocycline both in mice and in a clinical trial are not reliably bactericidal, and side effects are significant.

Monthly therapy for bacterial disease would be unique if found effective against leprosy. Contrary to the opinion of Ji et al. (16), the literature does not support a case for intermittent therapy for each of three agents utilized, either in experimental mouse infections or in leprosy patients, particularly the monthly regimen they envisage.

(i) In an established mouse footpad infection monitored by subpassage of M. leprae in serial 10-fold dilutions in mice, Grosset et al. (10) found that daily treatment with rifampin was significantly more bactericidal than weekly, fortnightly, or monthly treatment. An analysis of relapse rates in lepromatous leprosy patients treated with finite chemotherapy regimens which included several different frequencies of rifampin administration found that equivalent amounts of rifampin daily resulted in significantly lower relapse rates than more intermittent rifampin therapy (18).

(ii) My colleagues and I (9) found in mice that once-monthly minocycline was unreliable, and in clinical trials we (8) (contrary to the interpretation of Ji et al. [16]) and others (2) found single doses to be without activity. Though Ji et al. (16) are correct in saying that we (8) found that in six of eight patients single doses of minocycline resulted in a fall of the proportion of viable M. leprae, only in one patient was this statistically significant, and two of these six had a higher proportion of viable bacilli after an additional week of daily minocycline than was found prior to the beginning of treatment. Our data thus hardly support the suggestion that single doses of minocycline afford bacterial killing.

(iii) Though pefloxacin in mice was active when administered three times weekly, it was inactive even twice weekly, as well weekly and monthly (17). A single dose of ofloxacin was entirely inactive in five of eight treated patients (11). Even the study of Ji et al. (16) itself provides evidence against monthly therapy: in mice, together with rifampin, daily dapsone plus clofazimine, which are each far less active than either minocycline and ofloxacin, were vastly superior to single doses of minocycline plus ofloxacin. Though I (6) have also suggested alternative methodological explanations, the Ji et al. (16) claim that their case for the bactericidal activity of a single monthly dose, not found by others, is a result of the more sensitive "titration" methods they used. However, several of these other studies (10, 11, 17) utilized just those methods, and as has been mentioned, titration results have the pitfall of labeling activity which is primarily bacteriostatic "bactericidal." In any event there appears to be a compelling case favoring daily, as opposed to intermittent, therapy of leprosy.

Studies of potential synergism or anatagonism of combined treatment against M. leprae are difficult to perform and interpret, and the limited results available provide mixed findings for the agents proposed by Ji et al. (16). It is noteworthy, however, that the authors' published literature on mice (15) and leprosy patients (14) suggests that ofloxacin anatagonizes the killing provided by minocycline plus clarithromycin.

Finally, Ji et al. (16) appear now to advocate a duration of monthly supervised rifampin, minocycline, and ofloxacin of 2 years, the major bactericidal activity being provided by rifampin. Such a regimen includes less rifampin than what was used by them previously in a 1-month regimen of daily rifampin plus ofloxacin, which resulted in a very high rate of clinical relapse (13).

An effective regimen for the cure of lepromatous leprosy is still needed. Combinations of daily rifampin and newer bactericidal drugs (minocycline, clarithromycin, and fluorquinolones), each having been demonstrated to be more active than dapsone and clofazimine, appear to be reasonable treatments.