Trials of daily, long-term minocycline and rifampin or clarithromycin and rifampin in the treatment of borderline lepromatous and lepromatous leprosy

International Journal of Leprosy and Other Mycobacterial Diseases, Jun 2000 by Rea, Thomas H

Trials of Daily, Long-Term Minocycline and Rifampin or Clarithromycin and Rifampin in the Treatment of Borderline Lepromatous and Lepromatous Leprosy'

In 1970 rifampin was the first antibiotic demonstrated to be strongly microbiocidal for Mycobacterium leprae in humans (18). In a short period of time in the 1990s, three additional antibiotics were recognized as also having potent bactericidal activity against M. leprae in humans, specifically minocycline (4, 9), clarithromycin (9), and several of the fluoroquinolone group (5), with ofloxacin receiving the most attention (10-12, 14). These sudden advances provided opportunities to explore new therapeutic regimens in the treatment of leprosy. The motivation for such exploration comes from several sources. For example, a shorter period of time for treatment would reduce noncompliance and perhaps costs as well. Also, the high relapse rate observed by Jamet, et al. (8) among heavily bacillary patients treated with the conventional combination of rifampin, dapsone and clofazimine suggested a need for alternative regimens. Finally, combinations of microbiocidal agents might be better than combinations of microbiocidal drugs which also include a bacteriostatic agent, reasoning a priori as well as by analogy with the treatment of human tuberculosis, for which the use of multiple bactericidal agents has become standard (6).

Reported in the present paper is the longterm experience with two combinations of bactericidal agents, minocycline and rifampin, or clarithromycin and rifampin, in the management of lepromatous (LL) and borderline lepromatous (BL) leprosy. To address questions of their safety, tolerance, and effect upon the reactional state frequency, patients receiving these combination bactericidal regimens were compared with those treated concurrently with dapsone and rifampin.

MATERIALS AND METHODS

Patients in the Hansen's Disease Clinic of the Los Angeles County/University of Southern California Medical Center, Los Angeles, California, U.S.A., were classified according the criteria and nomenclature of Ridley and his colleagues (19). Criteria for the diagnosis of reactional states were as previously reported for erythema nodosum leprosum (ENL) (19), delayed-type hypersensitivity (DTH) reactions (17), and the Lucio reaction (16).

Whatever the regimen used, patients were encouraged to stay on combination therapy for a period of 3-32 years, followed by single drug therapy indefinitely. However, each patient was offered the opportunity to cease drug treatment after 2 years. Of the patients reported in this study, none elected to stop treatment altogether after 2 years, but one did stop combined therapy after 2 years but chose to continue with a single agent.

The regimens employed consisted of 1 ) minocycline 100 mg daily and rifampin 600 mg daily, 2) clarithromycin 500 mg daily and rifampin 600 mg daily, and 3) dapsone 100 mg daily and rifampin 600 mg daily. In the event of a DTH reaction managed with corticosteroids, rifampin was sometimes reduced to 600 mg monthly or, if very severe, discontinued altogether. At its commencement dapsone therapy was initiated at 25 mg daily, increased by 25 mg increments at 7 day intervals, and monitored at weekly intervals for the first 4 weeks. Similarly, initial rifampin use was monitored at intervals of 1-2 weeks for the first 4 weeks. After 4 weeks, patients were routinely seen at 3-month intervals, more often if required by reactional states.

A blood count and blood chemistries were obtained before starting treatment and at each subsequent clinic visit. Normal values for leukocytes for men were 4.9-9.9 x 10^sup 3^/mm^sup 3^; for women, 4.2-12.3. The normal values for tests reflecting liver function were as follows: bilirubin, total 0.0-1.0 and direct 0.0-0.3 mg/dL; alkaline phosphates, 45-140 units/dL; lactic acid dehydrogenase (LDH), 90-220 units/dL; aspartate aminotransferase (AST), 10-40 units/dL; and alanine aminotransferase (ALT), 20-65 units/dL. Renal function was monitored by including creatinine and urea levels in the blood chemistries.

A leukopenia, if present for three consecutive counts, was considered to be "persistent," but if occurring less often, was considered to be "sporadic." An anemia of 10 g/dL of hemoglobin or less was considered to be a contraindication to starting dapsone and a reason to discontinue it, if occurring early in therapy and not associated with ENL.

Concerning possible adverse hepatic reactions, liver function tests were considered to be "normal" if no more than one abnormality occurred yearly, were judged to be "persistently abnormal" if abnormal on three consecutive visits, but were judged to be "sporadically abnormal" if more than one abnormality per year was seen but not on three consecutive visits.

No patients were enrolled in this study after 30 June 1999. All data considered in this study were recorded before 1 January 2000.

RESULTS

A total of 56 patients, in four different groups, received a combination microbiocidal regimen. Daily minocycline and rifampin was started in 24 previously untreated BL or LL patients for a total of 646 patient-months, an average of 26.9 months per patient. Daily clarithromycin and rifampin was started in eight previously untreated BL or LL patients for a total of 174 patient-months, an average of 21.8 months per patient. In addition, daily minocycline and rifampin was started in 12 BL or LL patients who had a bacteriologic relapse during dapsone therapy or after prolonged noncompliance, and in 12 BL or LL patients who were judged to be at risk of relapse, because of frequent failure to keep clinic appointments, for 379 and 354 patientmonths, an average of 32.5 and 29.5 months per patient, respectively. Concurrently with these four groups, a fifth group, consisting of 34 previously untreated BL or LL patients, received daily dapsone and rifampin for a total of 870 patient-months, an average of 25.6 months per patient.