indicates that about 2540 men in the sentenced prison population injected drugs in the six months before arrest.45 If we assume from our data that 8% of them were HIV positive that gives an estimated total of 203 HIV Patients, methods, and results Eight consenting adults (seven men and one woman) with lepromatous leprosy (five patients) or borderline lepromatous leprosy (three) who had been previously untreated (six) or whose leprosy had relapsed (two) were treated with 100 mg minocycline alone once daily for three months.After one week's treatment we observed improvement in either skin erythema or induration in six patients and improvement in both manifestations in two. After three months' treatment skin lesions had noticeably improved in all patients, six patients having complete resolution of all erythema and induration. One patient had mild transient vertigo, which resolved spontaneously without discontinuing treatment. No other adverse reaction was noted. Unexpectedly, none of the patients developed a lepra reaction.Before treatment and at one week and one, two, and three months after starting treatment skin biopsies were performed, from which 5 x 103 M leprae were inoculated into the hind feet of BALB/c mice. If more than 10' acid fast bacilli per foot pad were found in pooled foot pads (four) harvested eight and 12 months subsequently or in one foot pad or more of those (generally 10) counted individually 12 months after infection, viable bacilli were considered to have been present in the inoculum.All of the pretreatment skin biopsy specimens consistently resulted in growth of the bacilli in mice when evaluated by both methods. According to the findings of pooled harvests of foot pads no patient harboured any viable M leprae at either two or three months after starting treatment (table). Harvests of individual foot pads were more sensitive in detecting any viable M leprae; in six instances these results were positive and those of pooled harvests were negative, and in none was the opposite true (table). Viable bacilli were consistently absent from the skin in only one patient at one week after treatment. At one and two months respectively three and six of the patients had lost detectable viable leprosy bacilli, and by three months none of the eight patients harboured any viable bacilli.Serum minocycline concentrations determined by an agar disc diffusion method2 were at the peak (two hours after treatment) 1 84 (SD 0 48) mg/l (range 1 07-2-66 mg/i) and at the trough (24 hours after treatment) 0-43 (0 11) mg/l (range 0 33-0 58 mg/i), well above that (0-17 mg/i) previously found to inhibit consistently growth ofM leprae in mice.23 CommentThe consistent rapidity of the patients' clinical response to minocycline is unique in our experience. The clearance of viable M leprae from the skin by minocycline was faster than that reported for dapsone or clofazimine,4 slower than that for rifampicin,' and similar to that for pefloxacin and ofloxacin.5Hansen's Disease Research Program,

Previously, pefloxacin and ofloxacin were found to be active against Mycobacterium leprae in vitro, in experimental animals, and in clinical trials of lepromatous leprosy patients. In this study, we compared certain more recently developed fluoroquinolones (lomefloxacin, PD 124816, WIN 57273, temafloxacin, and sparfloxacin) with pefloxacin and ofloxacin in M. leprae-infected mice at doses of 50, 150, and 300 mg/kg given five times weekly. All seven of the fluoroquinolones studied were active against M. leprae; temafloxacin and sparfloxacin were the most active, being fuly bactericidal at all three dosage schedules. Additionally, sparfloxacin was found to be fully bactericidal at 15 and 30 mg/kg given five times weekly.Unfortunately, the presently recommended drugs for general treatment of multibacillary leprosy in humans have been limited to only a few antimicrobial agents: dapsone, rifampin, and clofazimine (38). Because (i) multidrug therapy is generally recommended for the treatment of leprosy (38), (ii) resistance, particularly to dapsone and rifampin, has occurred, resulting in clinical relapse (18), and (iii) significant side effects and toxicities precluding the use of each of these drugs in certain patients occurs, it is imperative that new bactericidal drugs which work in a novel manner be developed and incorporated into the existing therapeutic arsenal to treat this disease. Fluoroquinolones act at a heretofore unexplored locus for the treatment of Mycobacterium leprae infections, the DNA gyrase (32). Furthermore, they accumulate severalfold in resident macrophages (3, 25, 37), the obligate site of M. leprae infection.Previous studies of the activities of ciprofloxacin (1, 15), pefloxacin (15,26), and ofloxacin (13, 26, 31) against M. leprae-infected mice found that while ciprofloxacin was ineffective (owing to weak activity in vitro [5] and/or demonstrably poor gastrointestinal absorption in mice [15]), both pefloxacin and ofloxacin were found to be bactericidal. Furthermore, both pefloxacin (14, 24) and ofloxacin (14) have proved extremely promising for treatment of lepromatous leprosy patients. However, more recently developed fluoroquinolones have demonstrated even greater activity against gram-positive organisms; M. leprae is gram positive and shares certain similar antimicrobial susceptibilities with gram-positive bacteria. Therefore, we initiated this study to compare the relative activities against M. leprae of certain of these newer quinolones with those of pefloxacin and ofloxacin.We compared the activities of the newer quinolones sparfloxacin, temafloxacin, lomefloxacin, PD 124816, and WIN 57273 with those of pefloxacin and ofloxacin against M. leprae in infected mice. We utilized the kinetic method of of the quinolones five times weekly by gavage at doses of 50, 150, and 300 mg/kg. Additionally, because sparfloxacin previously had been found to inhibit the growth of M. leprae in nude mice at 15 mg/kg (36), in the present study, sparfloxacin was also evaluated at 15 and 30 mg/kg given five ...

Model vaccines against leprosy bacilli have consisted of nonvirulent, live, attenuated Mycobacterium bovis BCG and irradiated, heat-killed, or autoclaved intact M. leprae. We report that immunization with various cell wall fractions of M. leprae, progressively depleted of lipids, carbohydrates, and soluble proteins, as well as a partially purified protein(s) derived from a pellet fraction of sonicated M. keprae, conferred significant protection against subsequent infection with live leprosy bacilli. Moreover, lymphocytes from regional lymph nodes and spleens of mice immunized with these M. leprae-derived subunits responded by proliferation when stimulated with M. leprae in vitro. Our results provide the first evidence that vaccination with M. leprae-derived fractions protects mice against leprosy bacilli.

In this study, we evaluated vaccination with a number of purified, as well as recombinant, Mycobacterium leprae proteins for protective efficacy in mice. BALB/c mice were immunized intradermally with various native somatic (purified) or recombinant M. leprae proteins and their synthetic polypeptides emulsified in Freund's incomplete adjuvant. The protective efficacy of these preparations was assessed by enumeration of bacilli in the footpads of mice challenged with viable M. leprae 1 to 2 months following immunization. Protection was afforded by the purified and recombinant 10-kDa M. leprae cytoplasmic heat shock protein, the recombinant cell wall-associated 65-kDa M. leprae heat shock protein, and to a lesser extent, the purified 28-kDa M. leprae cytoplasmic protein (superoxide dismutase). Vaccination with either the purified or recombinant 35-kDa M. leprae cell membrane protein, the synthetic 27-amino-acid N-terminal peptide of the 10-kDa protein, the recombinant 18-kDa M. leprae protein, or the purified 22-kDa cell membrane protein was ineffective. When the interval between immunization and challenge was increased to 6 months, the purified 10-kDa M. leprae protein and the recombinant 65-kDa M. leprae protein lost vaccine efficacy, while a sodium dodecyl sulfate-soluble protein fraction of the M. leprae cell wall (soluble proteins), as had been found previously, continued to protect, suggesting that multiple M. leprae protein epitopes are critical for solid vaccine protection.

It had previously been discovered that intradermal mouse vaccina tion with a protein fraction of My cobacterium leprae (called soluble proteins) in Freund's incomplete adjuvant (FIA) resulted in consistent and long-lived protection against M. leprae multiplication from subsequent viable fo otpad challenges. In this study certain density-gradient subfractions of this soluble protein, but not others, in FIA afforded vaccine protection. The results of this study suggest which M. leprae proteins may be involved in protective immunity, particularly 1-3 kD, 10kD, 65 kD, and those of higher molecular weight.