Progress in the chemotherapy of leprosy: Status, issues and prospects

Bacteremic infection caused by organisms of the Mycobacterium avium complex (MAC) is common in patients with AIDS. We evaluated both clarithromycin and dapsone alone and in combination for the treatment and prevention of disseminated MAC disease in beige mice. In the therapeutic model, C57BL/6 beige mice were infected intravenously with strain 101 of MAC (serovar 1). After 1 week postinfection, mice were given clarithromycin (200 mg/kg of body weight per day) and dapsone (15 mg/kg of body weight per day) alone or in combination by gavage. Treatment with clarithromycin resulted in a significant reduction in bacteremia and the numbers of CFU of MAC in the liver and spleen. Treatment with dapsone had no effect on the mycobacterial counts in blood, liver, or spleen, and the combination of dapsone with clarithromycin was no better than clarithromycin as a single agent. Clarithromycin and dapsone were used to prevent systemic disease in beige mice infected orally with MAC 101. Clarithromycin prophylaxis was associated with a significant reduction in the numbers of bacteria in the liver, spleen, and appendix compared with those in controls. Prophylaxis with dapsone resulted in a mild reduction in the numbers of MAC in the spleen but not in the other tissues. Clarithromycin both treats and prevents MAC disease in beige mice. Dapsone has no therapeutic effect, but it does have a slight prophylactic eflect, and in combination with clarithromycin it does not abrogate the effect of clarithromycin.Organisms of the Mycobacterium avium complex (MAC) are the most common cause of bacterial infection in patients with AIDS. Autopsy studies in AIDS patients have shown a large number of acid-fast bacilli in the liver, spleen, bone marrow, and intestines (17,20,28). Current observations suggest that most of the cases of MAC infection in AIDS patients are acquired by the gastrointestinal tract, and colonization of the gut appears to precede the onset of bacteremia (5,8).MAC is resistant to many of the standard antituberculosis antimicrobial agents, but some strains may be susceptible in vitro and in vivo to agents such as ethambutol, amikacin, rifabutin, macrolides, and azalides (clarithromycin, roxithromycin, and azithromycin), clofazimine, and certain fluoroquinolones (9, 10, 12-14, 22, 23). Clarithromycin, a new macrolide that is structurally related to erythromycin, is active in vitro (19,(25)(26)(27), inhibiting 90% of MAC strains (MICs, 1 to 8 ,ug/ml). Clarithromycin concentrates within macrophages and tissues (2), and it has also been shown to be active in experimental animals (12, 24) and AIDS patients with MAC infection, as shown in clinical trials (7, 9-11). The development of MAC resistance to clarithromycin has been observed in patients taking the antibiotic (18). For instance, in a recent compassionate-use study, resistance following clarithromycin therapy developed in 33% of patients (9).Dapsone is a synthetic antifolate that has activity against Mycobacterium leprae (15) vitro activity against MAC (16). We now report o...

mentioning

confidence: 99%

Clarithromycin, dapsone, and a combination of both used to treat or prevent disseminated Mycobacterium avium infection in beige mice

Bermudez

Inderlied

Kolonoski

et al. 1994

“…Even though the World Health Organization first recommended the use of multidrug therapy with dapsone, clofazimine, and rifampin in 1981 (21), Mycobacterium leprae resistance to dapsone and rifampin is still widely encountered and is of considerable concern (15). Thus, there is an urgent need for new antimycobacterial agents to treat leprosy (1,14). De Zwart and associates (3)(4)(5) have reported a new class of compounds, 2,2'-bipyridyl analogs, exhibiting potent antimycoplasmal properties.…”

mentioning

confidence: 99%

In vitro activities of 2,2'-bipyridyl analogs against Mycobacterium leprae

Dhople

Ibáñez

Dhople

1994

In vitro susceptibility ofMycobacterium leprae to two bipyridyl analogs was studied by using two biochemical parameters to measure the metabolic activity of the organism. VUF-8514 at 0.16 ,uglml, but not VUF-8842, completely inhibited the metabolic activity of M. keprae, and the action was bactericidal. When compared to rifampin (MIC 0.3 ,ug/ml), VUF-8514 was equally bactericidal against M. keprae. The aim of the present study was to evaluate the activities of these analogs, in comparison to that of rifampin, against M. leprae in an in vitro culture system. Antimicrobial agents. The 2,2'-bipyridyl analogs, VUF-8514 (isoquinoline derivative) and VUF-8842 (1,10-phenanthroline derivative) were obtained from H. Timmerman of Free University, Amsterdam, The Netherlands. The structural formulae and chemistry of these compounds have been described earlier (3)(4)(5) (7). ATP determinations were carried out by the firefly bioluminescent technique described earlier (8), while the procedure of Khanolkar and coworkers (17) was followed for the measurement of thymidine uptake.The effect of drug on M. leprae in primary culture was evaluated after incubating cultures for 4 weeks at 34°C. To determine if the effects were bacteriostatic or bactericidal, the cells from 4-week-old primary cultures were washed twice with fresh DH medium and then suspended in fresh DH medium without the drug and incubated at 34°C for four more weeks. At this time, ATP and [3H]thymidine uptake assays were again performed.Sampling for the assays from primary and subcultures was done as described previously. The results presented here were derived from three separate experiments, using different M. leprae strain in each experiment. In each experiment, triplicate assays were done for each concentration of every drug including rifampin.Susceptibility of M. leprae to bipyridyls. In the control cultures (without drugs), metabolic activity of M. leprae in primary cultures at 4 weeks was 143% of that at zero hour (Table 1). When the cells from these primary cultures were transferred to fresh DH medium, the activity in subcultures was 134% of the original at zero hour of these subcultures (143% increase in primary cultures was adjusted to 100% at zero hour for subcultures). With VUF-8514 at concentrations of 0.08 ,ug/ml and below, the metabolic activity of M. keprae in primary cultures as well as in subcultures was the same in control cultures. However, when the concentration of VUF-8514 in primary cultures was 0.16 ,ug/ml and higher, no metabolic activity could be detected, suggesting the MIC of VUF-8514 against M. leprae was 0.16 ,ug/ml. When these cells from primary cultures were transferred to fresh drug-free DH medium, cells failed to exhibit any metabolic activity, even after 4 weeks. This suggests the bactericidal activity of VUF-8514 on M leprae. On the other hand, VUF-8842 had no inhibitory effect on the metabolic activity of M leprae even at 0.32 ,ug/ml-the highest concentration tested to compare against rifampin, whose MIC against M leprae has been ...

“…Erythromycin and azithromycin were inactive, while both roxithromycin and clarithromycin were found to be consistently active and, in fact, bactericidal. By both methods, clarithromycin was found to be superior to roxithromycin, a finding which, at least in part, may be a consequence of the higher levels of clarithromycin at the site of infection.The World Health Organization (23) estimates that there are 10 million patients with leprosy, and yet there remains a compelling need for new antimicrobial agents to treat leprosy (2,14). At present, only dapsone, rifampin, and clofazimine are available to treat patients with leprosy.…”

mentioning

confidence: 99%

“…In 1960, Shepard (20) demonstrated that M. leprae multiplies locally when it is injected into the footpads of mice: an inoculum of 5 x 10i M. leprae per footpad generally results in a plateau of 1 x 106 M. leprae per footpad in 6 months. For the past three decades, this animal model has proved extremely useful for evaluating the efficacy of antimicrobial agents against M. leprae; and in general, antimicrobial agents active in the mouse footpad model at clinically achievable levels, including dapsone, rifampin, clofazimine, ethionamide, and streptomycin, have proved to be effective clinically (2,14).For the initial studies of antimicrobial agents in this model, we used continuous therapy from the time of infection and did not distinguish between bacteriostatic and bactericidal activity. To avoid this problem in these studies, we used the kinetic method of Shepard et al (22) footpads were infected with 5,000 M. leprae.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Activities of various macrolide antibiotics against Mycobacterium leprae infection in mice

Gelber¹,

Siu²,

Tsang³

et al. 1991

We evaluated the activities of several macrolide antibiotics against M. leprae infections in mouse footpads. Erythromycin and azithromycin were inactive, while both roxithromycin and clarithromycin were found to be consistently active and, in fact, bactericidal. By both methods, clarithromycin was found to be superior to roxithromycin, a finding which, at least in part, may be a consequence of the higher levels of clarithromycin at the site of infection.The World Health Organization (23) estimates that there are 10 million patients with leprosy, and yet there remains a compelling need for new antimicrobial agents to treat leprosy (2,14). At present, only dapsone, rifampin, and clofazimine are available to treat patients with leprosy. Because (i) Mycobacterium leprae resistance to dapsone and rifampin is encountered and is of considerable concern (18), (ii) toxicities and unacceptable side effects from each of these agents are not uncommon, and (iii) there is general consensus that lepromatous patients require multidrug therapy (25), other antimicrobial agents are certainly required to treat leprosy (2,14). A number of studies (9-11, 17, 19) performed with cell-free and macrophage in vitro culture systems demonstrated that many macrolide antibiotics inhibit the metabolic activity of M. leprae. However, to date there has been only one study that has confirmed that any macrolide has activity against the actual growth of M. leprae in vivo (11). In that study, clarithromycin, but not erythromycin or roxithromycin, was found to be effective against M. leprae in infected mice. Here we report results of studies on the activities of several macrolides against M. leprae-infected mice and findings that, while erythromycin and azithromycin were inactive, roxithromycin and clarithromycin were consistently active and, indeed, bactericidal.Unfortunately, M. leprae cannot be grown on artificial medium. In 1960, Shepard (20) demonstrated that M. leprae multiplies locally when it is injected into the footpads of mice: an inoculum of 5 x 10i M. leprae per footpad generally results in a plateau of 1 x 106 M. leprae per footpad in 6 months. For the past three decades, this animal model has proved extremely useful for evaluating the efficacy of antimicrobial agents against M. leprae; and in general, antimicrobial agents active in the mouse footpad model at clinically achievable levels, including dapsone, rifampin, clofazimine, ethionamide, and streptomycin, have proved to be effective clinically (2,14).For the initial studies of antimicrobial agents in this model, we used continuous therapy from the time of infection and did not distinguish between bacteriostatic and bactericidal activity. To avoid this problem in these studies, we used the kinetic method of Shepard et al. (22) footpads were infected with 5,000 M. leprae. At day 150 and intervals thereafter, the number of M. leprae in four feet (two mice) was assessed microscopically. The activity of a drug was determined by measuring the delay in the appearance of the bacterial p...