Extemporaneously compounded liquid formulations of clofazimine.

BACKGROUND: Clofazimine (CFZ) is routinely used worldwide for the treatment of leprosy and TB. However, no liquid or dispersible tablet formulations of CFZ are currently available commercially for patients with challenges ingesting soft gelatin capsules or solid formulations. The aim of this research was to develop stable extemporaneous liquid formulations of CFZ that can be stored at room temperature for several weeks to enable practical dosing in the field. METHODS: Two formulations were prepared in syrup and sugar-free vehicles with CFZ tablets using a simple method that can be used in a routine pharmacy. Suspensions were stored at room temperature and at 30°C for 30 days. Formulation aliquots were tested on Days 0, 15 and 30 for appearance, pH, potency and microbial counts. RESULTS: Appearance remained unchanged during storage. The pH of both formulations was between 4.0 and 6.0. Potency was between 90% and 110% for 30 days in the syrup formulation and for 15 days in the sugar-free formulation. Microbial counts met United States Pharmacopeia 1111 limits for oral aqueous liquids and specific organisms were absent. CONCLUSIONS: A simple field-friendly method was successfully developed for the preparation of CFZ liquid formulations using commonly available ingredients. This will permit practical dosing and titration for children and other patients with swallowing challenges.

Validation study of HLA-B*13:01 as a biomarker of dapsone hypersensitivity syndrome in leprosy patients in Indonesia.

Leprosy is a stigmatizing, chronic infection which degenerates the nervous system and often leads to incapacitation. Multi-drug therapy which consists of dapsone, rifampicin and clofazimine has been effective to combat this disease. In Indonesia, especially in Papua Island, leprosy is still a problem. Furthermore, there had been higher reports of Dapsone Hypersensitivity Syndrome (DHS) which also challenges leprosy elimination in certain aspects. Globally, DHS has a prevalence rate of 1.4% and a fatality rate up to 13%. The aim of this study is to validate HLA-B*13:01, a previously discovered biomarker for DHS in the Chinese population, as a biomarker for DHS in the Papua population.This is a case-control study of 34 leprosy patients who presented themselves with DHS (case subjects) and 52 leprosy patients without DHS (control subjects). Patients were recruited from 2 provinces: Papua and West Papua. DNA was extracted from 3 ml blood specimens. HLA-B alleles were typed using the gold-standard sequence based typing method. Results were then analysed using logistic regression and risk assessment was carried out. The results of HLA-typing showed that HLA-B*13:01 was the most significant allele associated with DHS, with odds ratio = 233.64 and P-value = 7.11×10-9, confirming the strong association of HLA-B*13:01 to DHS in the Papua population. The sensitivity of this biomarker is 91.2% and specificity is 96.2%, with an area under the curve of 0.95. HLA-B*13:01 is validated as a biomarker for DHS in leprosy patients in Papua, Indonesia, and can potentially be a good predictor of DHS to help prevent this condition in the future.

Clofazimine, a Promising Drug for the Treatment of Babesia microti Infection in Severely Immunocompromised Hosts.

BACKGROUND: Persistent and relapsing babesiosis caused by Babesia microti often occurs in immunocompromised patients, and has been associated with resistance to antimicrobial agents such as atovaquone. Given the rising incidence of babesiosis in the United States, novel drugs are urgently needed. In the current study, we tested whether clofazimine (CFZ), an antibiotic used to treat leprosy and drug-resistant tuberculosis, is effective against B. microti. METHODS: Mice with severe combined immunodeficiency were infected with 107B. microti-infected erythrocytes. Parasites were detected by means of microscopic examination of Giemsa-stained blood smears or nested polymerase chain reaction. CFZ was administered orally. RESULTS: Uninterrupted monotherapy with CFZ curtailed the rise of parasitemia and achieved radical cure. B. microti parasites and B. microti DNA were cleared by days 10 and 50 of therapy, respectively. A 7-day administration of CFZ delayed the rise of parasitemia by 22 days. This rise was caused by B. microti isolates that did not carry mutations in the cytochrome b gene. Accordingly, a 14-day administration of CFZ was sufficient to resolve high-grade parasitemia caused by atovaquone-resistant B. microti parasites. CONCLUSIONS: Clofazimine is effective against B. microti infection in the immunocompromised host. Additional preclinical studies are required to identify the minimal dose and dosage of CFZ for babesiosis.

Single Crystal FLIM Characterization of Clofazimine Loaded in Silica-Based Mesoporous Materials and Zeolites.

Clofazimine (CLZ) is an effective antibiotic used against a wide spectrum of Gram-positive bacteria and leprosy. One of its main drawbacks is its poor solubility in water. Silica based materials are used as drug delivery carriers that can increase the solubility of different hydrophobic drugs. Here, we studied how the properties of the silica framework of the mesoporous materials SBA-15, MCM-41, Al-MCM-41, and zeolites NaX, NaY, and HY affect the loading, stability, and distribution of encapsulated CLZ. Time-correlated single-photon counting (TCSPC) and fluorescence lifetime imaging microscopy (FLIM) experiments show the presence of neutral and protonated CLZ (1.3-3.8 ns) and weakly interacting aggregates (0.4-0.9 ns), along with H- and J-type aggregates (<0.1 ns). For the mesoporous and HY zeolite composites, the relative contribution to the overall emission spectra from H-type aggregates is low (<10%), while for the J-type aggregates it becomes higher (~30%). For NaX and NaY the former increased whereas the latter decreased. Although the CLZ@mesoporous composites show higher loading compared to the CLZ@zeolites ones, the behavior of CLZ is not uniform and its dynamics are more heterogeneous across different single mesoporous particles. These results may have implication in the design of silica-based drug carriers for better loading and release mechanisms of hydrophobic drugs.

Evaluation of Prospective HLA-B*13:01 Screening to Prevent Dapsone Hypersensitivity Syndrome in Patients With Leprosy.

Importance: Dapsone hypersensitivity syndrome (DHS) is the most serious adverse reaction associated with dapsone administration and one of the major causes of death in patients with leprosy, whose standard treatment includes multidrug therapy (MDT) with dapsone, rifampicin, and clofazimine. Although the HLA-B*13:01 polymorphism has been identified as the genetic determinant of DHS in the Chinese population, no studies to date have been done to evaluate whether prospective HLA-B*13:01 screening could prevent DHS by identifying patients who should not receive dapsone. Objective: To evaluate the clinical use of prospective HLA-B*13:01 screening for reduction of the incidence of DHS by excluding dapsone from the treatment for patients with HLA-B*13:01-positive leprosy. Design, Setting, and Participants: A prospective cohort study was conducted from February 15, 2015, to April 30, 2018, in 21 provinces throughout China. A total of 1539 patients with newly diagnosed leprosy were enrolled who had not received dapsone previously. After excluding patients who had a history of allergy to sulfones or glucose-6-phosphate dehydrogenase deficiency, 1512 individuals underwent HLA-B*13:01 genotyping. All of the patients were followed up weekly for the first 8 weeks after treatment to monitor for adverse events. Exposures: Patients who were HLA-B*13:01 carriers were instructed to eliminate dapsone from their treatment regimens, and noncarrier patients received standard MDT. Main Outcomes and Measures: The primary outcome was the incidence of DHS. The historical incidence rate of DHS (1.0%) was used as a control. Results: Among 1512 patients (1026 [67.9%] men, 486 [32.1%] women; mean [SD] age, 43.1 [16.2] years), 261 (17.3%) were identified as carriers of the HLA-B*13:01 allele. A total of 714 adverse events in 384 patients were observed during the follow-up period. Dapsone hypersensitivity syndrome did not develop in any of the 1251 patients who were HLA-B*13:01-negative who received dapsone, while approximately 13 patients would be expected to experience DHS, based on the historical incidence rate of 1.0% per year (P = 2.05 × 10-5). No significant correlation was found between other adverse events, including dermatologic or other events, and HLA-B*13:01 status. Conclusions and Relevance: Prospective HLA-B*13:01 screening and subsequent elimination of dapsone from MDT for patients with HLA-B*13:01-positive leprosy may significantly reduce the incidence of DHS in the Chinese population.

A new therapeutic combination for osteosarcoma: Gemcitabine and Clofazimine co-loaded liposomal formulation.

Osteosarcoma is the most common cancer in bone. Drug resistance is a challenge of current treatments that needs to be improved with novel treatment strategies. In this research, a new dual drug delivery system was developed with Gemcitabine (GEM) and Clofazimine (CLF) co-loaded liposome formulations. GEM is a well-known anticancer agent and CLF is a leprostatic and anti-inflammatory drug recently recognized as effective on cancer. GEM and CLF co-loaded liposomal formulation was achieved with compartmentalization as hydrophilic GEM being in core and lipophilic CLF sequestering in lipid-bilayer. Liposomes had high encapsulation efficiency (above 90%, GEM and above 80%, CLF). CLF release was enhanced while GEM release was slowed down in co-loaded liposomes compared to single cases. GEM/CLF co-loaded liposomes significantly enhanced cytotoxicity than GEM or CLF loaded liposomes on osteosarcoma cell line. CLF and GEM had synergistic effect (CI < 1). Results of flow cytometry showed higher apoptotic cell ratio, caspase-3 activity, mitochondrial membrane depolarized cells' ratio for GEM/CLF co-loaded liposome treatments than other liposomes. Cytotoxicity of CLF on bone cancer cells and also its synergistic effect with GEM on osteosarcoma is reported for the first time with this study. CLF's loading with GEM into liposome was also a new approach for enhancement of anticancer effect on Saos-2 cells. Therefore, GEM/CLF co-loaded liposomal delivery system is proposed as a novel approach for treatment of osteosarcoma.

Evaluating the safety, tolerability, pharmacokinetics and efficacy of clofazimine in cryptosporidiosis (CRYPTOFAZ): study protocol for a randomized controlled trial.

BACKGROUND: Cryptosporidium infection and diarrhea (cryptosporidiosis) is a life-threatening infection in persons with HIV and also in children of 6-18 months of age in the developing world. To date, only nitazoxanide is licensed for treatment of cryptosporidiosis, and only in persons after the first year of life and with healthy immune systems. Clofazimine (CFZ: Lamprene®), an established drug that has been used for leprosy for more than 50 years, recently has been described as effective against Cryptosporidium in vitro and in mouse infections. The efficacy and pharmacokinetics of CFZ in vivo, in HIV-infected patients with cryptosporidial diarrhea are not known. METHODS: CRYPTOFAZ includes a randomized, double-blind, placebo-controlled study of the safety, tolerability and Cryptosporidium inhibitory activity of orally administered CFZ in subjects with HIV infection and chronic diarrhea with Cryptosporidium. An additional open label aspect of the study will compare the pharmacokinetics (PK) of orally administered CFZ in HIV-infected individuals with and without Cryptosporidium-associated diarrhea. The study will recruit a total of 66 subjects. Study participants will be given either CFZ or a placebo for 5 days while in hospital and will be followed up after discharge. Cryptosporidium will be diagnosed by quantitative PCR as the definitive test and by stool ELISA, which will also be used to quantify the shedding of Cryptosporidium in stool. PK will be studied on plasma and stool samples. Primary endpoints include reduction in the number of Cryptosporidium shed in stools over a 5-day period and compared to placebo recipients and the PK of CFZ in plasma assessed by area under the curve, peak plasma concentration, and half-life (T ½) determined after the last dose. DISCUSSION: This study provides an opportunity to explore a possible treatment option for HIV-infected patients with cryptosporidial diarrhea, who, as of now in Malawi and most of sub-Saharan Africa, do not have a definitive treatment apart from supportive care. The strength of this study lies in it being a randomized, double-blind, placebo-controlled trial. If shown to be effective and safe, the findings will also lay a foundation for a future study of the use of CFZ in children 6-18 months of age. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03341767 . Registered on 14 November 2017.

Mycobacterium leprae-Specific Antibodies in Multibacillary Leprosy Patients Decrease During and After Treatment With Either the Regular 12 Doses Multidrug Therapy (MDT) or the Uniform 6 Doses MDT.

Leprosy serology reflects the bacillary load of patients and multidrug therapy (MDT) reduces Mycobacterium leprae-specific antibody titers of multibacillary (MB) patients. The Clinical Trial for Uniform Multidrug Therapy Regimen for Leprosy Patients in Brazil (U-MDT/CT-BR) compared outcomes of regular 12 doses MDT/R-MDT and the uniform 6 doses MDT/U-MDT for MB leprosy, both of regimens including rifampicin, clofazimine, and dapsone. This study investigated the impact of R-MDT and U-MDT and the kinetic of antibody responses to M. leprae-specific antigens in MB patients from the U-MDT/CT-BR. We tested 3,400 serum samples from 263 MB patients (R-MDT:121; U-MDT:142) recruited at two Brazilian reference centers (Dona Libânia, Fortaleza, Ceará; Alfredo da Matta Foundation, Manaus, Amazonas). Enzyme-linked immunosorbent assays with three M. leprae antigens [NT-P-BSA: trisaccharide-phenyl of phenollic glycolipid-I antigen (PGL-I); LID-1: Leprosy Infectious Disease Research Institute Diagnostic 1 di-fusion recombinant protein; and ND-O-LID: fusion complex of disaccharide-octyl of PGL-I and LID-1] were performed using around 13 samples per patient. Samples were collected at baseline/M0, during MDT (R-MDT:M1-M12 months, U-MDT:M1-M6 months) and after MDT discontinuation (first, second year). Statistical significance was assessed by the Mann-Whitney U test for comparison between groups (p values < 0.05). Mixed effect multilevel regression analyses were used to investigate intraindividual serological changes overtime. In R-MDT and U-MDT groups, males predominated, median age was 41 and 40.5 years, most patients were borderline lepromatous and lepromatous leprosy (R-MDT:88%, U-MDT: 90%). The bacilloscopic index at diagnosis was similar (medians: 3.6 in the R-MDT and 3.8 in the U-MDT group). In R-MDT and U-MDT groups, a significant decline in anti-PGL-I positivity was observed from M0 to M5 (p = 0.035, p = 0.04, respectively), from M6 to M12 and at the first and second year posttreatment (p < 0.05). Anti-LID-1 antibodies declined from M0 to M6 (p = 0.024), M7 to M12 in the R-MDT; from M0 to M4 (p = 0.003), M5 to M12 in the U-MDT and posttreatment in both groups (p > 0.0001). Anti-ND-O-LID antibodies decreased during and after treatment in both groups, similarly to anti-PGL-I antibodies. Intraindividual serology results in R-MDT and U-MDT patients showed that the difference in serology decay to all three antigens was dependent upon time only. Our serology findings in MB leprosy show that regardless of the duration of the U-MDT and R-MDT, both of them reduce M. leprae-specific antibodies during and after treatment. In leprosy, antibody levels are considered a surrogate marker of the bacillary load; therefore, our serological results suggest that shorter U-MDT is also effective in reducing the patients' bacillary burden similarly to R-MDT. Clinical Trial Registration: ClinicalTrials.gov, NCT00669643.

Clinical pilot study: Clarithromycin efficacy in multibacillary leprosy therapy.

Background: Rifampicin is one of the important components in the multidrug therapy (MDT)-World Health Organization regimen for leprosy. Clarithromycin is one of the alternative therapies of rifampicin. Methods: This clinical pilot study was to compare the efficacy of 2,000 mg clarithromycin to 600 mg rifampicin in combination with dapsone and clofazimine for 3 months in multibacillary (MB) leprosy patients. They were divided into an MDT-MB regimen group that consists of rifampicin-dapsone-clofazimine and clarithromycin-dapsone-clofazimine (CDC) regimen group, each group consisted of seven patients. Results: The morphological index (MI) was reduced insignificantly after 3 months therapy in MDT-MB group (P = 0.248). While in the CDC group, the MI decrement showed a significant result (P = 0.004). The comparison of MI reduction in MDT-MB and CDC groups showed an insignificant difference (P = 0.130). Skin discoloration was occurred in both groups, whereas mild-nausea was presented in the CDC group, in addition, red-colored urine was developed in the MDT-MB group. Conclusion: We concluded that 2,000 mg clarithromycin is as effective as 600 mg rifampicin in combination with dapsone and clofazimine regimen in MB leprosy patients. Hence, clarithromycin can be considered as an alternative therapy for leprosy patients who resistance and/or allergy to rifampicin.

Clinical trial for uniform multidrug therapy for leprosy patients in Brazil (U-MDT/CT-BR): adverse effects approach.

BACKGROUND: The Clinical Trial for Uniform Multidrug Therapy for Leprosy Patients in Brazil (U-MDT/CT-BR), designed to evaluate the effectiveness of a six-months regimen, assessed the adverse effects caused by the drugs. OBJECTIVE: Describe adverse effects due to MDT in U-MDT/CT-BR, comparing the uniform regimen (U-MDT) to the current WHO regimen (R-MDT). PATIENTS AND METHODS: After operational classification, patients were randomly allocated to the study groups. U-MDT PB and U-MDT MB groups, received the U-MDT regimen, six doses of MB-MDT (rifampicin, dapsone and clofazimine). R-MDT PB and R-MDT MB groups, received the WHO regimens: six doses (rifampicin and dapsone) for PB and 12 doses (rifampicin, dapsone and clofazimine) for MB. During treatment, patients returned monthly for clinical and laboratorial evaluation. Patients with single lesion were not included in this trial. RESULTS: Skin pigmentation (21.7%) and xerosis (16.9%) were the most frequent complaints among 753 patients. Laboratory exams showed hemoglobin concentration lower than 10g/dL in 23.3% of the patients, glutamic oxaloacetic transaminase (GOT) above 40U/L in 29.5% and glutamic pyruvic transaminase (GPT) above 40U/L in 28.5%. Twenty-four patients (3.2%) stopped dapsone intake due to adverse effects, of whom 16.6% due to severe anemia. One case of sulfone syndrome was reported. STUDY LIMITATIONS: Loss of some monthly laboratory sample collection. CONCLUSIONS: There was no statistical difference regarding adverse effects in the R-MDT and U-MDT groups but anemia was greater in patients from R-MDT/MB group, therefore adverse effects do not represent a constraint to recommend the six-month uniform regimen of treatment for all leprosy patients.

Clinical trial for uniform multidrug therapy for leprosy patients in Brazil (U-MDT/CT-BR): adverse effects approach

Abstract: BACKGROUND: The Clinical Trial for Uniform Multidrug Therapy for Leprosy Patients in Brazil (U-MDT/CT-BR), designed to evaluate the effectiveness of a six-months regimen, assessed the adverse effects caused by the drugs. OBJECTIVE: Describe adverse effects due to MDT in U-MDT/CT-BR, comparing the uniform regimen (U-MDT) to the current WHO regimen (R-MDT). Patients and methods: After operational classification, patients were randomly allocated to the study groups. U-MDT PB and U-MDT MB groups, received the U-MDT regimen, six doses of MB-MDT (rifampicin, dapsone and clofazimine). R-MDT PB and R-MDT MB groups, received the WHO regimens: six doses (rifampicin and dapsone) for PB and 12 doses (rifampicin, dapsone and clofazimine) for MB. During treatment, patients returned monthly for clinical and laboratorial evaluation. Patients with single lesion were not included in this trial. RESULTS: Skin pigmentation (21.7%) and xerosis (16.9%) were the most frequent complaints among 753 patients. Laboratory exams showed hemoglobin concentration lower than 10g/dL in 23.3% of the patients, glutamic oxaloacetic transaminase (GOT) above 40U/L in 29.5% and glutamic pyruvic transaminase (GPT) above 40U/L in 28.5%. Twenty-four patients (3.2%) stopped dapsone intake due to adverse effects, of whom 16.6% due to severe anemia. One case of sulfone syndrome was reported. STUDY LIMITATIONS: Loss of some monthly laboratory sample collection. CONCLUSIONS: There was no statistical difference regarding adverse effects in the R-MDT and U-MDT groups but anemia was greater in patients from R-MDT/MB group, therefore adverse effects do not represent a constraint to recommend the six-month uniform regimen of treatment for all leprosy patients.

Uniform multidrug therapy for leprosy patients in Brazil (U-MDT/CT-BR): Results of an open label, randomized and controlled clinical trial, among multibacillary patients.

BACKGROUND: Leprosy control is based on early diagnosis and multidrug therapy. For treatment purposes, leprosy patients can be classified as paucibacillary (PB) or multibacillary (MB), according to the number of skin lesions. Studies regarding a uniform treatment regimen (U-MDT) for all leprosy patients have been encouraged by the WHO, rendering disease classification unnecessary. METHODOLOGY AND FINDINGS: An independent, randomized, controlled clinical trial conducted from 2007 to 2015 in Brazil, compared main outcomes (frequency of reactions, bacilloscopic index trend, disability progression and relapse rates) among MB patients treated with a uniform regimen/U-MDT (dapsone+rifampicin+clofazimine for six months) versus WHO regular-MDT/R-MDT (dapsone+rifampicin+clofazimine for 12 months). A total of 613 newly diagnosed, untreated MB patients with high bacterial load were included. There was no statistically significant difference in Kaplan-Meyer survival function regarding reaction or disability progression among patients in the U-MDT and R-MDT groups, with more than 25% disability progression in both groups. The full mixed effects model adjusted for the bacilloscopic index average trend in time showed no statistically significant difference for the regression coefficient in both groups and for interaction variables that included treatment group. During active follow up, four patients in U-MDT group relapsed representing a relapse rate of 2.6 per 1000 patients per year of active follow up (95% CI [0·81, 6·2] per 1000). During passive follow up three patients relapsed in U-MDT and one in R-MTD. As this period corresponds to passive follow up, sensitivity analysis estimated the relapse rate for the entire follow up period between 2·9- and 4·5 per 1000 people per year. CONCLUSION: Our results on the first randomized and controlled study on U-MDT together with the results from three previous studies performed in China, India and Bangladesh, support the hypothesis that UMDT is an acceptable option to be adopted in endemic countries to treat leprosy patients in the field worldwide. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00669643.

Uniform multidrug therapy for leprosy patients in Brazil (U-MDT/CT-BR): results of an open label, randomized and controlled clinical trial, among multibacillary patients

BACKGROUND: Leprosy control is based on early diagnosis and multidrug therapy. For treatment purposes, leprosy patients can be classified as paucibacillary (PB) or multibacillary (MB), according to the number of skin lesions. Studies regarding a uniform treatment regimen (U-MDT) for all leprosy patients have been encouraged by the WHO, rendering disease classification unnecessary. METHODOLOGY AND FINDINGS: An independent, randomized, controlled clinical trial conducted from 2007 to 2015 in Brazil, compared main outcomes (frequency of reactions, bacilloscopic index trend, disability progression and relapse rates) among MB patients treated with a uniform regimen/U-MDT (dapsone+rifampicin+clofazimine for six months) versus WHO regular-MDT/R-MDT (dapsone+rifampicin+clofazimine for 12 months). A total of 613 newly diagnosed, untreated MB patients with high bacterial load were included. There was no statistically significant difference in Kaplan-Meyer survival function regarding reaction or disability progression among patients in the U-MDT and R-MDT groups, with more than 25% disability progression in both groups. The full mixed effects model adjusted for the bacilloscopic index average trend in time showed no statistically significant difference for the regression coefficient in both groups and for interaction variables that included treatment group. During active follow up, four patients in U-MDT group relapsed representing a relapse rate of 2.6 per 1000 patients per year of active follow up (95% CI [0·81, 6·2] per 1000). During passive follow up three patients relapsed in U-MDT and one in R-MTD. As this period corresponds to passive follow up, sensitivity analysis estimated the relapse rate for the entire follow up period between 2·9- and 4·5 per 1000 people per year. CONCLUSION: Our results on the first randomized and controlled study on U-MDT together with the results from three previous studies performed in China, India and Bangladesh, support the hypothesis that UMDT is an acceptable option to be adopted in endemic countries to treat leprosy patients in the field worldwide.

A Traditional NSAID Aspirin along with Clofazimine in Erythema Nodosum Leprosum Reaction: Study of Six Cases.

Six male patients of lepromatous leprosy with erythema nodosum leprosum reaction (ENL) reactions diagnosed clinically and by slit skin smear were treated with aspirin and clofazimine. Aspirin was given in the daily dosage of 75mg/kg body weight up to a maximum of 2.8 grams in four divided doses, along with daily 300mg clofazimine in three divided doses and dapsone 100mg daily with rifampicin 600mg once a month. Aspirin was continued in the same dosage for a month before being tapered and stopped at the end of third month when clofazimine was also reduced to 50 mg daily. All the six cases had an excellent response in 15 days.

Treatment of leprosy.

Leprosy is a curable disease, having been eliminated from many countries, including India. This has been possible due to the wide availability of effective and safe drugs. Treatment of leprosy has undergone considerable changes over decades, from chaulmoogra oil in 1915 to dapsone monotherapy in 1946, then eventually to multidrug therapy (MDT) in 1982. In the last two decades, reports of resistance to all first-line drugs have appeared in the literature, with the need to conduct clinical trials using newer but highly bactericidal drugs and their combinations against Mycobacterium leprae.