Multidrug Therapy Regimens Research Articles

Leprosy in Taiwan, 2002–2011

The rate of leprosy has been significantly reduced through the implementation of intensified control strategies. Of particular note is the free multidrug therapy (MDT) regimen provided by the World Health Organization (WHO) since 1995, in which three standard first-line drugs, namely diaminodiphenylsulfone (dapsone), rifampicin, and clofazimine, are available for use in multidrug regimens of fixed duration. As a result, leprosy has been successfully eliminated from 119 of 122 countries in 2010. Leprosy is considered eliminated when the leprosy prevalence rate is less than 1 in a population of 10,000. The enhanced global strategy for further reducing the disease burden due to leprosy (plan period: 2011e2015) has been carried out in endemic countries. The prevalence of leprosy in the WHO western Pacific region, where Taiwan is located, is 0.05 and that of the southeast Asian region is 0.64 in the first quarter of 2012. Leprosy is caused by Mycobacterium leprae, an acid-fast bacillus bacterium. The bacterium has an incubation period ranging from several months to several decades after infection. Leprosy causes severe disfiguring skin sores and nerve damage in the arms and legs. The skin becomes stiff and dry, and the lesions show erythematous plaques

Fixed-duration therapy in leprosy: limitations and opportunities.

Leprosy has been considered a curable disease after the implementation of multidrug therapy (MDT), which has been proven to be safe and effective, by bringing about a significant change in the global and national scenario of leprosy by upgrading the control of leprosy to the next stage of eradication. Since its introduction, the MDT regimens for the treatment of leprosy have undergone several changes especially with regard to the duration of treatment. The advantages of shortened duration of treatment need to be balanced against the risk of relapse and a lot of controversies exist pertaining to this aspect. The fixed-duration (FD) therapy is not popular among academicians and private practitioners who prefer precise diagnosis and treatment with superior MDT regimens and for a longer duration. On the contrary, from a public health-care point of view, precise diagnosis and a longer treatment schedule are not cost effective and not feasible to be implemented in elimination programs. Hence, a fine balance needs to be maintained between achieving a cure for the patient and protecting the society at risk, and this review discusses the various limitations and opportunities of FD therapy with a note on the newer MDT regimens.

A Germline Mutation in Cathepsin B in a Child with ALL Points towards a Key Role for This Enzyme in L-Asparaginase Pharmacokinetics.

AbstractAbstract 2458▪▪This icon denotes a clinically relevant abstractThe bacterially derived enzyme L-Asparaginase (ASNase) is a key component in the multidrug therapy regimens used worldwide to treat pediatric and adult patients with acute lymphoblastic leukemia (ALL), however little is known about the molecular mechanisms that control the pharmacokinetics of this therapeutic protein. As a result, many patients who receive a standardized dose either exceed or do not reach the desired serum concentration. While elevated serum levels are associated with an increase in treatment related morbidity, underexposure seriously compromises therapeutic benefits.In search of molecular factors that determine ASNase turnover in vivo, we investigated a patient with strongly aberrant clearance kinetics. This 3-year old female diagnosed with common ALL suffered from severe ASNase-induced adverse events upon treatment with ErwiniaSNase as a result of strongly elevated serum ASNase levels. Pharmacokinetics data showed a severely delayed ASNase clearance. As a result, serum ASNase levels accumulated to intolerable levels upon repeated administration of the drug. We isolated DNA from peripheral blood mononuclear cells and buccal cells of this patient and performed targeted sequencing on genes suggested to be involved in ASNase clearance. We identified a novel heterozygous mutation in the gene encoding Cathepsin B in the germline of this patient. The mutant allele shows a deletion of a single codon, leading to a deletion of a lysine residue in the C terminus of the protein. We generated an EBV LCL cell line from this patients which showed a 75% reduction in Cathepsin B activity, relative to controls, indicating that this heterozygous mutation has a profound effect on the total Cathepsin B activity.Cathepsin B is normally synthesized as a 37 kD pre-pro enzyme and is processed in a two step process into a mature 2-chain active form. During this process, the protein is transported to the lysosome where it exerts its primary function. Using a combination of biochemical and imaging experiments we show that the mutant Cathepsin B cannot be processed into the mature form and is retained in the endoplasmatic reticulum. ASNase degradation assays demonstrate that this mutant form of Cathepsin B shows a diminished protease activity towards both E.coli and Erwinia ASNase, consistent with the reduced clearance observed in our patient.Cathepsin B and other cellular proteases are either actively secreted or released into the serum as a result of cell lysis. Although we find a variable low but detectable activity of Cathepin B in serum samples, all tested preparations of ASNase were stable upon prolonged incubation in serum, suggesting that serum components are not contributing to ASNase clearance in vivo. Hence, we propose that cellular uptake and subsequent proteolytic degradation of ASNase is the primary mechanism of clearance.In conclusion, we have identified a mutation in protease Cathepsin B and provide evidence that this mutation results in a loss of protease function towards ASNase, which can explain the strongly delayed clearance of ASNase in the patient. Our data suggest that differences in Cathepsin B activity may contribute to the large inter-patient variability in ASNase pharmacokinetics. Furthermore, given the role of Cathepsin proteases in antigen presentation, Cathepsin B may not only provide a target for predicting or controlling ASNase clearance kinetics but inhibition of Cathepsin may also prevent or delay the formation of inhibitory antibodies. Disclosures:Boos:European Erwinase Providers (EUSAPharm): Speakers Bureau; Medac: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lanvers-Kaminsky:Medac: Speakers Bureau.

Development of a Mouse Food Pad Model for Detection of Sub Clinical Leprosy

Early diagnosis of leprosy and a multi-drug therapy (MDT) regimen will block the trajectory of nerve damage, disability and deformity that are the hallmarks of this chronic disease. However, the diagnosis of leprosy is made solely by recognition of clinical signs and symptoms, requiring special expertise. These limitations also result in the under reporting of worldwide prevalence and incidence rates for leprosy. Sorely needed is an objective laboratory test for detecting early leprosy. As the antigenic burden of M. leprae can be virtually undetectable in early clinical leprosy, cell mediated immunity and antibody responses will likely be weak. So the sensitivity of new diagnostic tests is as important as specificity. Major efforts are underway employing recombinant M. leprae antigens and synthetic peptides, to develop diagnostic assays for early leprosy infection, using in vitro T cell reactivity or serological tests. We have used the initial phase of the mouse foot pad model as an 'early' model of leprosy infection to screen T cell responses against M. leprae specific antigens and synthetic peptides. Unlike human disease in animal models we can control infection progress and monitor bacillary growth relative to time course of development of T cell response to specific M. leprae antigens. The study employed splenic T cells instead of draining lymph node T cells to model the systemic response as opposed to a local one. We found that 10(5) live M. leprae is the minimum dose required for any meaningful and consistent in vitro splenic IFN-gamma response against M. leprae antigens 3 months after foot pad inoculation. Using this model we found that several M. leprae recombinant proteins, ML0840, ML2028, ML2307, ML2346, ML2478, and ML2532, induced significant levels of IFN-gamma secretion. By controlling for variables that can be confounding factors in the sensitivity of human testing, this mouse model provides an interface between M. leprae diagnostic antigen development and the screening of these antigens in humans under field conditions.

Multiplex PCR technique could be an alternative approach for early detection of leprosy among close contacts - a pilot study from India

BackgroundImplementation of Multi drug Therapy (MDT) regimen has resulted in the decline of the total number of leprosy cases in the world. Though the prevalence rate has been declining, the incidence rate remains more or less constant and high in South East Asian countries particularly in India, Nepal, Bangladesh, Pakistan and Srilanka. Leprosy, particularly that of multibacillary type spreads silently before it is clinically detected. An early detection and treatment would help to prevent transmission in the community. Multiplex PCR (M-PCR) technique appears to be promising towards early detection among contacts of leprosy cases.MethodsA total of 234 paucibacillary (PB) and 205 multibacillary (MB) leprosy cases were studied in a community of an endemic area of Bankura district of West Bengal (Eastern India). They were assessed by smear examination for acid-fast bacilli (AFB) and M-PCR technique. These patients were treated with Multidrug Therapy (MDT) as prescribed by WHO following detection. A total of 110 MB and 72 PB contacts were studied by performing M-PCR in their nasal swab samples.Results83.4% of MB patients were observed to be positive by smear examination for AFB and 89.2% by M-PCR. While 22.2% of PB patients were found to be positive by smear examination for AFB, 80.3% of these patients were positive by M-PCR. Among leprosy contacts (using M-PCR), 10.9% were found to be positive among MB contacts and 1.3% among PB contacts. Interestingly, two contacts of M-PCR positive MB cases developed leprosy during the period of two years follow up.ConclusionThe M-PCR technique appears to be an efficient tool for early detection of leprosy cases in community based contact tracing amongst close associates of PB and MB cases. Early contact tracing using a molecular biology tool can be of great help in curbing the incidence of leprosy further.

Treatment of leprosy in India

Introduction of multi-drug therapy (MDT) into the National Leprosy Eradication Program (NLEP) of India has brought a decline in both the burden of the disease and the detection of new cases in the country. Despite this success, MDT has had many problems like remarkable relapse rate, non-adherence to the MDT and the emergence of drug resistance associated with it. Moreover, there is no new MDT regimen at present, which could solve all these problems. The current situation suggests that we should look for alternative solutions in the delivery of leprosy-related services. With the introduction of Accredited Social Health Activists under the National Rural Health Mission, there is an opportunity to control some of these problems associated with MDT. Besides, District Nucleus should take initiatives and actively participate in establishment of coordination between departments of Health, Social welfare and justice, education and various non-governmental agencies working in the field of leprosy and disability in order to deliver the best of services to the persons affected by leprosy.

Association Between Human Immunodeficiency Virus Infection and Cerebral Malaria in Children Below 12 Years Attending Mulago Hospital, Uganda: A Case-Control Study

Tuberculosis (TB) continues to be a major worldwide health problem and kills millions of people around the world. Lack of compliance to the strenuous multi-drug therapy regimen has resulted in multidrug-resistant TB. Hence novel drug targets are urgently needed to prevent and treat this killer disease. Mycobacterium tuberculosis, the causative agent of tuberculosis, requires iron for essential metabolic pathways. Because iron is not freely available in the host, pathogens must actively acquire this metal to establish an infection but they must also carefully regulate iron acquisition as excess free iron can be extremely toxic to the bacteria. Recent studies have demonstrated that failure to control iron uptake or to assemble the iron acquisition machinery has lethal effects for M. tuberculosis. In M. tuberculosis Iron dependent regulator-IdeR-regulates the expression of genes in response to intracellular iron levels. Loss of IdeR mediated repression leads to iron overload and oxidative damage. In contrast, enhanced IdeR repression at low iron levels attenuates M. tuberculosis virulence in mice. Sequence comparison shows that orthologs of IdeR are present in all the sequenced genomes of mycobacteria. We have used a bioinformatics approach to characterize structure, function and evolution of the iron dependent regulator protein (IdeR) sequence identified from 16 genomes. Our study shows different levels of sequence conservation in different functional domains of the IdeR molecules. Our study reveals how IdeR selects its DNA targets, how IdeR dimerizes and how Iron controls IdeR activity. This study will help in understanding the basis for different transcriptional responses of pathogenic and non -pathogenic mycobacteria in iron stress, which, in turn, may help in designing better drugs against pathogenic mycobacteria.

Histoid leprosy: a retrospective study of 40 cases from India

Rare variants of leprosy pose a diagnostic challenge even to astute clinicians and histoid leprosy is one such form of disease with unique clinical and histopathological features. There are very few large series on this entity, mainly reported from India. To study the epidemiological and clinical characteristics of patients with histoid leprosy. We undertook this retrospective study including patients registered with the leprosy clinic of our tertiary care referral centre from January 1991 to December 2006. Data regarding demographic details, clinical features, treatment, complications and course following treatment were extracted from the records of the leprosy clinic. The incidence of histoid leprosy among the registered patients of our clinic was 1.8% (40 of 2150). There was a significant male preponderance with a male/female ratio of 5.7 : 1. The anatomical areas of involvement were thighs/buttocks (67.5%), arms (62.5%), back (52.5%), face (47.5%), forearms (47.5%) and legs (35%) in descending order of frequency. This variety of leprosy was found most commonly in patients with a primary diagnosis of lepromatous leprosy (40%). De novo histoid lesions, i.e. lesions of histoid leprosy developing without evidence of lesions of other types of leprosy in the Ridley-Jopling classification, appeared in 12.5% of patients only. Only three patients had received antileprosy treatment before presentation. Episodes of erythema nodosum leprosum (ENL) had occurred in 40% of patients, although only one patient manifested ENL after the diagnosis of histoid leprosy. The disease responded satisfactorily to the respective World Health Organization multidrug therapy regimens in all except in one patient who relapsed with borderline lepromatous leprosy. As the bacillary load is very high in these patients, they can form a potential reservoir of the infection in the community especially in the postleprosy elimination era. Contrary to the earlier belief in the dapsone era, most of our patients manifested disease without any history of inadequate or incomplete antileprosy therapy.

Targeting Iron Acquisition by Mycobacterium tuberculosis

Tuberculosis (TB) caused by the pathogen Mycobacterium tuberculosis continues to be a major worldwide health problem. Lack of compliance to the complex, multi-drug therapy regimen has resulted in multidrug-resistant TB and a need for new drug targets. Siderophore molecules used for iron acquisition are good targets because pathogen survival and virulence is directly related to iron availability. Indeed, a key host defense mechanism is the production of siderocalins that sequester iron-laden siderophores and M. tuberculosis replicates poorly in the absence of these siderophores. A number of investigators have recently targeted siderophores or their synthesis for the development of novel anti-tubercular therapeutics. For example, one group has synthesized 'dominant negative' mycobactin siderophore analogues that significantly inhibit bacterial growth. Several other groups have developed agents that directly inhibit enzymes involved in siderophore synthesis. A profoundly different approach is to target the iron dependent regulator protein (IdeR) that represses siderophore synthesis genes and virulence factors when sustainable iron levels have been achieved. Loss of the repression leads to iron overload and oxidative damage. In contrast, enhanced IdeR repression at low iron levels attenuates M. tuberculosis virulence in mice. The structural basis for iron activation and IdeR binding to DNA has been recently reported and these insights have enabled the structure-based design of agents that target IdeR function. Small peptides that either enhance IdeR repression or inhibit IdeR dimerization demonstrate that IdeR activity can be rationally modulated.

Leprosy situation in South Sulawesi, Indonesia

Since the World Health Organization (WHO) set the global goal of leprosy elimination in 2000, many countries have successfully achieved elimination. Indonesia has achieved elimination at a national level, but several provinces and areas still have a high prevalence rate. South Sulawesi is one of 6 provinces on Sulawesi Island, and 5 of these provinces still have many leprosy patients with a prevalence rate of more than 1.1 per 10, 000 population and new cases are detected every year. The leprosy control program has not been successful in reducing the prevalence of this disease and 22 out of 27 regencies have, on average, a prevalence rate of 2.3 cases per 10, 000 population, of which child cases account for more than 5%, indicating that there are many more leprosy cases in the community. The leprosy control program has been helped by the multi drug therapy (MDT) regimen based on the WHO recommendation and several research studies carried out in the area. However, we as yet do not have a clear idea how to eliminate leprosy in South Sulawesi and further research is required.

De-escalation therapy in ventilator-associated pneumonia

To describe the use of a 'de-escalation' strategy to deliver appropriate empiric therapy for ventilator-associated pneumonia, without the overuse of antibiotics. Initial empiric therapy can be appropriate in 80-90% of ventilator-associated pneumonia patients, if it is selected on the basis of local microbiologic data or individual patient surveillance cultures. Following initial empiric therapy, de-escalation means using microbiologic and clinical data to change from an initial broad-spectrum, multidrug empiric therapy regimen to a therapy with fewer antibiotics and agents of narrower spectrum. In spite of early success with this approach there is an opportunity to de-escalate more often, particularly in patients with negative pretherapy cultures, and in those whose cultures show multidrug-resistant organisms, including Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus. In addition, it is possible to reduce the total duration of therapy, particularly when the initial therapy is accurate. When de-escalation has been employed, it has led to less antibiotic usage, shorter durations of therapy, fewer episodes of secondary pneumonia and reduced mortality, without increasing the frequency of antibiotic resistance. De-escalation is a promising strategy for optimizing the responsible use of antibiotics while allowing the delivery of prompt and appropriate empiric therapy of ventilator-associated pneumonia.

Leprosy in an endemic focus in the Sudan

Objectives: The objectives of this study were active case detection, provision of multidrug treatment in primary health care settings and evaluation of the accuracy of the clinical system of classification that was adopted by the Leprosy Control Program of Sudan. Design: The whole population of two villages in a remote area in eastern Sudan were examined initially and then followed up for three years in this prospective study. Patients from the surrounding villages, who were self reporting were also included in the study. Setting: The study was conducted in a primary health care setting, which was the only available form of health care facility in the study area. Subjects: Communal consent was obtained following explanation and discussion with the Sheikhs. The population of the two villages were interviewed and examined clinically with particular reference to skin lesions. Informed consents to participate in the study were obtained from individuals with skin lesions. Interventions: Skin biopsies were taken under local anaesthesia and aseptic conditions from suspicious lesions. Multi-drug therapy regimen (MDT) was given to those with proven disease. Out come measures: Response was measured by improvement in skin lesions and sensations every six months. Results: Compliance was around 90 %. According to the clinical classification 68.4% and 31.6% of the patients were multi-bacillary and pauci-bacillary respectively. There was 100 % agreement between the clinical classification and Ridley & Jopling classification where all Tuberculoid (TT) patients were correctly diagnosed as pauci-bacillary and borderline Lepromatous (BL) and Lepromatous (LL) patients were correctly diagnosed as multibacillary. Seventy BT patients were misclassified as multi-bacillary disease. Conclusions: The clinical classification is adequate for the diagnosis and treatment of leprosy patients in remote areas of eastern Sudan. Sudanese Journal of Dermatology Vol. 3(2) 2005: 73-79

Association of asthma therapy and churg-strauss syndrome: An analysis of postmarketing surveillance data

Background: Churg-Strauss syndrome (CSS), also known as allergic granulomatous angiitis (AGA), is a rare vasculitis that occurs in patients with bronchial asthma. The nature of the association of CSS with various asthma therapies is unclear.Objective: This study investigated the associations of different multidrug asthma therapy regimens and the reporting of AGA (the preferred code for CSS in the coding dictionary for the Adverse Event Reporting System [AERS]) by applying an iterative method of disproportionally analysis to th AERS database maintained by the US Food and Drug Administration.Methods: The public-release version of the AERS database was used to identify reports of AGA in patients receiving asthma therapy. Reporting of AGA was examined using iterative disproportionality methods in patients receiving ≥1 of the following drug classes: inhaled corticosteroid (ICS), leukotriene receptor antagonist (LTRA), short-acting β2-agonist (SABA), or long-acting β2-agonist (LABA). The Bayesian data-mining algorithm known as the multi-item gamma poisson shrinker was used to determine the relative reporting rates by calculation of the empirical Bayes geometric mean (EBGM) and its 90% CI (EB05 = lower limit and EB95 = upper limit) for each drug. Subset analyses were performed for each drug with different medication combinations to differentiate the relative reporting of AGA for each.Results: A strong association was found between LTRA use and AGA (EBGM = 104.0, EB05 = 95.0, EB95 = 113.8) that persisted with all combinations of therapy studied. AGA was also associated with the ICS, SABA and LABA classes (EBGM values of 27.8, 14.6 and 40.4, respectively). However, the latter associations were mostly dependent on the presence of concurrent LTRA and, to a lesser extemt, oral corticosteroid therapy and became negligible (ie, EB05 < 2) for patients who were not receiving these concurrent treatments.Conclusions: Differences based on relative reporting were observed in the patterns of association of AGA with LTRA, ICS, and β2-agonist therapies. A strong association between LTRA use and AGA was present regardless of the use of other asthma drugs.

Fenômeno de Lúcio (eritema necrosante) na gestação

O fenômeno de Lúcio, variante do estado reacional hansênico tipo 2, provavelmente mediado por imunocomplexos, caracteriza-se por reação cutânea necrosante grave que ocorre principalmente em doentes portadores de hanseníase virchowiana não nodular. Os autores relatam o caso de uma paciente de 27 anos, do sexo feminino, gestante de 32 semanas, com quadro de lesões eritêmato-purpúricas nos membros, bem delimitadas, confluentes, encimadas por bolhas, algumas necróticas e ulceradas, com uma semana de evolução, acompanhadas de febre e intensa dor local. A baciloscopia da linfa evidenciou bacilos álcool-acidorresistentes formando globias, e a histopatologia da pele confirmou hanseníase virchowiana, compatível com fenômeno de Lúcio. Foi iniciada prednisona e poliquimioterapia multibacilar com rifampicina, clofazimina e sulfona, com boa evolução. A gravidez tem sido associada à elevada incidência de aparecimento dos primeiros sinais ou ao agravamento da hanseníase por alterações hormonais que levam ao desequilíbrio imunológico, sendo considerado crítico o período compreendido entre o último trimestre de gestação e os primeiros três meses da lactação, quando a imunossupressão atinge seu ápice. Apesar da recomendação de se restringir a ingestão de drogas na gestação, o tratamento da hanseníase deve ser realizado, visto que seus benefícios superam os riscos.

Effectiveness of multidrug therapy in multibacillary leprosy: a long-term follow-up of 34 multibacillary leprosy patients treated with multidrug regimens till skin smear negativity

The World Health Organization (WHO) Field Trials of multidrug therapy (MDT) started at Schieffelin Leprosy Research and Training Centre (SLR & IC), Karigiri, India in December 1981. The patients were treated with two MDT regimens. The first (regimen A) consisted of 600mg rifampicin and 300mg of clofazimine given under supervision on 2 consecutive days monthly, 225mg injection of acedapsone bimonthly and dapsone 100mg daily. The second regimen (regimen B) was the conventional MDT (WHO/MDT), rifampicin 600mg and clofazimine 300mg supervised once a month, dapsone 100mg and clofazimine 50mg daily, unsupervised. Both the regimens were administered for a minimum period of 2 years or until skin smear negativity, whichever occurred later. Thirty-four newly detected previously untreated MB patients, 16 of whom received regimen A and 18 regimen B, were reassessed. Both regimens were well accepted and well tolerated by the patients. Clofazimine discolouration was the only adverse effect of MDT seen in these patients. After completion of treatment with MDT, the patients were followed up for a total duration of 466 person-years with a mean of 13.7 +/- 1.4 years per patient. No relapse was seen.

Current World Health Organization-sponsored studies in the chemotherapy of leprosy

Until the early 1 980s, dapsone monotherapy administered to known patients was used for control of leprosy. Dapsone was usually administered in a dosage of 100 mg daily for a minimum of 5 years to patients with paucibacillary (PB) leprosy, and for life to patients with multibacillary (MB) leprosy. Because it was a weakly bactericidal and slowly acting drug, dapsone monotherapy led to poor patient compliance and the emergence of dapsone-resistant strains of Mycobacterium leprae. Since 1982, the multidrug therapy (MDT) regimens recommended by the World Health Organization (WHO), which include a combination of rifampicin, clofazimine and dapsone for MB leprosy and rifampicin plus dapsone for PB leprosy, have been applied in national leprosy control programmes in all of the leprosy endemic countries in the world. This therapy has proved to be a most reliable and practical method of treating leprosy. The introduction of MDT in 1982 has resulted in a dramatic reduction of the prevalence of leprosy, from 5 ·4 million registered cases in 1 985 to 0·8 million in 1999. By the end of 1999, more than 10 million patients had been cured by MDT. Follow-up of the large number of patients cured by MDT has revealed very low relapse rates after stopping treatment; the cumulative risk of relapse is less than 1 % over a period of 9 years for both MB and PB leprosy. Despite the success of the standard WHO MDT regimens, there is a need for more effective combined drug regimens. Several WHO-sponsored programmes of research in the chemotherapy of leprosy are currently in progress. The purpose of this report is briefly to describe the programmes and their current status.

The new challenges for chemotherapy research.

Scientific knowledge is constantly expanding, and needs are changing; therefore, efforts must be made to adapt the treatment of leprosy and the manner in which it is implemented to the newly identified needs. Because an effective vaccine against leprosy remains to be identified, multidrug therapy (MDT) is the only tool available for leprosy control. At present, therefore, the priority is to make MDT available in all endemic countries for all patients, even those living in difficult-to-access areas. The remaining important issues in chemotherapy research are to improve the quality of leprosy case-finding, improve the quality of MDT, identify the areas in which leprosy patients are not receiving proper MDT, and find the means necessary to ensure delivery to all of appropriate MDT. The MDT regimens recommended by the World Health Organization are of too long duration, require correct classification of the patients as PB or MB, and rely upon the daily self-administration of dapsone and clofazimine to prevent selection of rifampicin resistant mutants among MB patients. Thus, research leading to the development of new drug regimens should be directed toward overcoming the shortcomings of the presently recommended regimens. The drugs required to permit use of regimens of shorter duration, that may be employed among both PB and MB patients, and that enable fully supervised drug administration may be already in hand, and the necessary clinical trials to confirm efficacy and acceptability should be carried out.

In vitro activity of epiroprim, a dihydrofolate reductase inhibitor, singly and in combination with brodimoprim and dapsone, against Mycobacterium leprae

The antimicrobial effects of a new dihydrofolate reductase inhibitor, epiroprim, alone and in combination with dapsone and brodimoprim against Mycobacterium leprae were evaluated in vitro in cell-free culture system. Two biochemical parameters were used to measure metabolic activity (and growth) of the organism. The minimal inhibitory activity of epiroprim against M. leprae was 10 mg/l and the action was bactericidal. When combined with dapsone, epiroprim exhibited a strong synergism; on the other hand, combination of epiroprim and brodimoprim provided only additive effects. The results suggest that epiroprim can be a component in multidrug therapy regimen in leprosy.

The activity of rifabutin against Mycobacterium leprae in armadillos

The activity of rifabutin (LM 427) against Mycobacterium leprae was evaluated in armadillos inoculated earlier with human-derived M. leprae. Rifabutin was administered daily at a dose of 6 mg/kg body weight/day. The effect of rifabutin on M. leprae harvested from armadillos was determined by measuring the intracellular levels of ATP (an indicator of metabolic activity) of M. leprae and also their ability to multiply in the mouse footpads and in vitro in DH medium. Within 2 weeks of initiating the treatment, ATP levels declined to 21% of the original (pre-treatment level) and these M. leprae failed to multiply in the footpads of mice as well as in the in vitro culture system. This suggests that rifabutin was able to kill all M. leprae within 2 weeks . After 8 weeks the treatment was terminated and results showed that M. leprae from the treated armadillos remained non-viable in the mouse footpad system as well as in the in vitro system, indicating bactericidal action of rifabutin. The results suggest that rifabutin can be a substitute for rifampin in the leprosy multi-drug therapy regimen.

Multidrug-resistance to dapsone, rifampicin, and ofloxacin in Mycobacterium leprae

Drug resistance in Mycobacterium leprae was reported in 1964 for dapsone and in 1976 for rifampicin, both successively used as monotherapy for leprosy.1 To prevent drug resistance resulting from the selection of resistant mutants present in multibacillary leprosy, WHO recommended multidrug therapy (MDT) regimens in 1981. Ofloxacin, a fluoroquinolone which is bactericidal against M leprae,2 has been proposed for new MDT combinations. Acquired resistance to fluoroquinolones, commonly observed for many bacterial species, has been also reported in M tuberculosis for patients with cavitary tuberculosis treated with ofloxacin monotherapy.