Clinical trial of ofloxacin alone and in combination with dapsone plus clofazimine for treatment of lepromatous leprosy

Abstract

Twenty-four patients with newly diagnosed lepromatous leprosy were allocated randomly to three groups and treated for 56 days with 400 mg of ofloxacin daily, 800 mg of ofloxacin daily, or 400 mg of ofloxacin, 100 mg of dapsone, and 50 mg of clofazimine daily plus 300 mg of clofazimine once every 28 days. Development and implementation of multidrug therapy (13) are the most important achievements in the history of leprosy control (12). However, the duration of the treatment is too long, especially the minimal duration for multibacillary leprosy therapy, which is 2 years, which causes serious operational difficulties in certain areas (5). Of the three components of the multidrug regimen for multibacillary leprosy, rifampin is the only drug that displays powerful bactericidal activity against Mycobacterium leprae; the other two drugs, dapsone and clofazimine, show only a modest degree of bactericidal activity. Without the introduction of new, more powerful bactericidal drugs to the regimens, it is unlikely that the duration may be substantially shortened (5).Among the major commercially available fluoroquinolones, ofloxacin is by far the most active compound against M. leprae (2). A clinical trial with patients with lepromatous leprosy demonstrated that 400 mg of ofloxacin daily was highly effective, producing very remarkable clinical improvement and killing an average of 99.99% (4 orders of magnitude) of M. leprae organisms after only 22 doses of treatment (3). This observation represented the first lead to an important new antileprosy drug since the introduction of rifampin more than 20 years ago.The current trial was carried out with several objectives in mind. First, because the number of spontaneously arising rifampin-resistant mutants in an untreated lepromatous patient is estimated to be no more than 104 (3, 5), it was necessary to confirm the killing of 99.99% of M. leprae by a short course of ofloxacin treatment. Second, because the activity of ofloxacin against M. leprae (2) and Mycobacterium tuberculosis (11) in mice is dose related, it was important to compare the therapeutic effects of and adverse reactions to 400 mg of ofloxacin daily with those of 800 mg of ofloxacin daily in the treatment of * Corresponding author.human leprosy. The third objective was to determine the usefulness of combining ofloxacin with dapsone and clofazimine in a new multidrug regimen. The bactericidal activities of the treatments were monitored by inoculation into mouse footpads of organisms recovered from skin biopsy specimens taken before and at intervals during treatment (3, 5). Because we already knew that 22 doses of ofloxacin alone killed about 99.99% of the viable organisms, nearly the limit of sensitivity of the technique even with nude mice (3, 5), the duration of the trial was set at 56 days. MATERIALS AND METHODSPatients. Twenty-four newly diagnosed leprosy patients (19 men and 5 women) with a mean age of 38 years (range, 18 to 60 years) who demonstrated large bacterial populations and active skin lesions were sele...

In vitro and in vivo activities of levofloxacin against Mycobacterium tuberculosis

“…Therefore, it is very difficult to identify the optimal dosage of LVFX for the treatment of human tuberculosis by extrapolating the results of the mouse experiment. However, because preliminary studies indicated that the pharmacokinetic properties of LVFX in healthy volunteers and presumably also in mice were very similar to those of OFLO (14) and because there is no evidence that the adverse reactions to fluoroquinolones are correlated with their anti-DNA gyrase activities, it is likely that the maximal clinically tolerated dosage of LVFX is similar to that of OFLO, i.e., 800 mg per day (5,9). Since the half-life of OFLO in humans (2,8,24) is significantly longer than that in mice (19), there is a very significant accumulation effect after multiple doses in healthy human volunteers (8) but probably not in mice; therefore, to extrapolate the results of the mouse experiments for the treatment of humans, it is appropriate to take into account the pharmacokinetic data for OFLO and LVFX in humans after multiple doses.…”

“…The activity of OFLO in mice was dosage related: a dosage of 150 mg/kg of body weight six times weekly displayed only a modest degree of activity against M. tuberculosis, whereas the activity of a dosage of 300 mg/kg six times weekly was moderate (12,19). The pharmacokinetic studies that will be discussed below estimated that doses of OFLO at 150 and 300 mg/kg in mice are equivalent, respectively, to 400-and 800-mg doses of OFLO in humans, with the latter dose being the maximal clinically tolerated dose (5,9). Because OFLO at 150 or 300 mg/kg daily in mice showed only a modest or moderate degree of activity against M. tuberculosis, it is understandable that the maximal clinically tolerated dosage of OFLO displayed no more than a marginal degree of therapeutic effect against human tuberculosis (20).…”

The Continuing Challenges of Leprosy

“…Clofazimine [3-(p-chloroanilino)-10-(p-chlorophenyl)-2,10-dihydro-2-(isopropylimino)phenazine] is a substituted iminophenazine with antimycobacterial activity for which the mechanism has not been fully elucidated (175). Clofazimine attains high intracellular levels in mononuclear phagocytic cells, its metabolic elimination is slow, it has an anti-inflammatory effect, and the incidence of resistance to it in M. leprae is low.…”

“…In addition, several investigators have identified multidrug-resistant strains of M. leprae (reviewed in reference 434). Ofloxacin and minocycline have been added to the drug arsenal for the treatment of leprosy (126,172,175,176; see also http://www.who.int/lep /romfaq3.htm). Current treatment recommendations in the United States have been summarized elsewhere (276a, 349), and Lockwood has provided a rigorous evidence-based discussion of the treatment of leprosy (234).…”

“…Ofloxacin (4-fluoroquinolone) is a fluorinated carboxyquinolone that has moderate anti-M. leprae activity (175,176). The mechanism of action of ofloxacin on M. leprae is unknown, but in other bacteria it appears to inhibit DNA replication by inhibiting the DNA gyrase, a tetramer containing two A-subunits (GyrA) and two B-subunits (GyrB) (99).…”