RESUMEN
OBJECTIVE: To compare the occurrence, duration and severity of ENL in leprosy patients treated with either 12 or 24 months of standard multi-drug therapy (MDT). STUDY POPULATION: 296 patients treated with MDT for 2 years, between 1985 and 1992 and followed up as part of a relapse study; and 293 patients, treated between 1998 and 2004, with MDT for 1 year and also followed up as part of a relapse study. The Chi squared test and multiple logistic regression analysis were used to test for statistical significance. RESULTS: ENL was not significantly more common, but it was longer-lasting and more severe in patients receiving only 12 months of MDT, as compared with those receiving 24 months treatment. A high BI at the start of treatment significantly increased the risk of severe ENL by a factor of between 6 and 12, while treatment with 12 instead of 24 months of MDT significantly increased the risk by a factor of between 3 and 10. CONCLUSIONS: This study provides further evidence that a high initial BI is the key risk factor for ENL. It also suggests that the difference between these two cohorts in their experience of ENL as demonstrated in this study, may be related to the different amounts of clofazimine which the two cohorts were given in the early years of their treatment. Further studies are needed to determine whether clofazimine could be used more specifically to reduce the severity of ENL in the small group of patients at high risk for the condition.
Asunto(s)
Clofazimina/uso terapéutico , Eritema Nudoso/prevención & control , Leprostáticos/uso terapéutico , Lepra Lepromatosa/tratamiento farmacológico , Adolescente , Adulto , Distribución por Edad , Anciano , Niño , Quimioterapia Combinada , Eritema Nudoso/tratamiento farmacológico , Eritema Nudoso/epidemiología , Femenino , Estudios de Seguimiento , Humanos , India/epidemiología , Lepra Lepromatosa/diagnóstico , Lepra Lepromatosa/epidemiología , Masculino , Persona de Mediana Edad , Mycobacterium leprae/efectos de los fármacos , Mycobacterium leprae/aislamiento & purificación , Recurrencia , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del Tratamiento , Organización Mundial de la Salud , Adulto JovenRESUMEN
INTRODUCTION: Moxifloxacin, rifampicin, rifapentine, linezolid, and PA 824, alone and in combination, have been previously administered, as single doses and five times daily doses, to M. leprae infected mice during lag phase multiplication and were each found to have some bactericidal activity. DESIGN: The fluroquinolones, ofloxacin, moxifloxacin and gatifloxacin, (50 mg/kg, 150 mg/kg and 300 mg/kg) and the rifamycins (5 mg/kg, 10 mg/kg, and 20 mg/kg), rifampicin and rifapentine, were evaluated alone and in combination for bactericidal activity against M. leprae using the mouse footpad model during logarithmic multiplication. Linezolid and PA 824 were similarly evaluated alone and linezolid in combination with rifampicin, minocycline and ofloxacin. RESULTS: The three fluroquinolones and rifamycins were found alone and in combination to be bactericidal at all dosage schedules. PA 824 had no activity against M. leprae, while linezolid at a dose of 25 mg/kg was bacteriostatic, and progressively more bactericidal at doses of 50 mg/kg and 100 mg/kg. No antagonisms were detected between any of these drugs when used in combinations. CONCLUSION: Moxifloxacin, gatifloxacin, rifapentine and linezolid were found bactericidal against rapidly multiplying M. leprae.
Asunto(s)
Antiinfecciosos/uso terapéutico , Fluoroquinolonas/administración & dosificación , Lepra/tratamiento farmacológico , Mycobacterium leprae/efectos de los fármacos , Quinolinas/administración & dosificación , Animales , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Lepra/microbiología , Ratones , Ratones Endogámicos CBA , Pruebas de Sensibilidad Microbiana , Mycobacterium leprae/crecimiento & desarrolloRESUMEN
OBJECTIVES: To compare the efficacy of a 4-week ofloxacin-containing regimen and the standard WHO-MDT regimen for PB leprosy, in terms of the rate and timing of relapse after treatment completion. DESIGN: 124 PB patients were enrolled in a randomised, double-blind trial. Of these, 66 received the standard 6-month WHO-MDT regimen, whereas 58 received 28 daily supervised doses of rifampicin 600mg + ofloxacin 400 mg, plus 5 months of placebo. Patients were regularly monitored for clinical response and for signs of relapse after treatment completion. RESULTS: Patients enrolled in the ofloxacin group had a mean follow-up of 10.8 years (628 patient-years) with 1 early relapse at 3 years after treatment completion. On relapse, this patient remained smear negative but was reclassified by current WHO criteria (> or =6 skin lesions) as multibacillary (MB). Patients on the WHO-MDT regimen had a mean follow-up of 11.3 years (749 patient-years) with two late relapses at 8 and 12 years, both still classified as PB on relapse. CONCLUSION: In conclusion, both regimens appeared generally efficacious, and, in particular, resulted in few relapses.
Asunto(s)
Dapsona/uso terapéutico , Leprostáticos/uso terapéutico , Lepra Paucibacilar/tratamiento farmacológico , Ofloxacino/uso terapéutico , Rifampin/uso terapéutico , Adulto , Método Doble Ciego , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recurrencia , Piel/microbiología , Factores de Tiempo , Resultado del Tratamiento , Organización Mundial de la SaludRESUMEN
INTRODUCTION: Previously we reported a 2-month clinical trial of moxifloxacin therapy in eight patients with MB leprosy (7 LL and 1 BL), finding both rapid killing of M. leprae and clinical improvement, without serious side effects or toxicities. Here we report the outcomes in two patients treated with moxifloxacin. DESIGN: Two previously untreated LL patients were treated with a single 400 mg dose of moxifloxacin, no therapy for 7 days and then daily 400 mg moxifloxacin for 48 days. Clinical response, viability of M. leprae in the skin, and side effects/toxicities were carefully monitored. RESULTS: In both patients a single dose of moxifloxacin resulted in significant killing of M. leprae (P < 0.001%). In both patients no viable M. leprae were found after 15 doses of moxifloxacin. Improvement in skin lesions occurred again remarkably rapidly and no untoward effects were noted. CONCLUSION: Loss of viable M. leprae was quite rapid, similar to that found previously only for rifampicin, patients improved rapidly, and moxifloxacin was well tolerated.
Asunto(s)
Compuestos Aza/uso terapéutico , Leprostáticos/uso terapéutico , Lepra Lepromatosa/tratamiento farmacológico , Viabilidad Microbiana/efectos de los fármacos , Mycobacterium leprae/efectos de los fármacos , Quinolinas/uso terapéutico , Adulto , Compuestos Aza/administración & dosificación , Fluoroquinolonas , Humanos , Leprostáticos/administración & dosificación , Lepra Lepromatosa/microbiología , Masculino , Persona de Mediana Edad , Moxifloxacino , Mycobacterium leprae/aislamiento & purificación , Quinolinas/administración & dosificación , Piel/microbiología , Piel/patología , Resultado del TratamientoRESUMEN
In a clinical trial of moxifloxacin in eight multibacillary leprosy patients, moxifloxacin proved highly effective. In all trial patients, a single 400-mg dose of moxifloxacin resulted in significant killing (P Asunto(s)
Antibacterianos/uso terapéutico
, Compuestos Aza/uso terapéutico
, Lepra/tratamiento farmacológico
, Mycobacterium leprae/efectos de los fármacos
, Quinolinas/uso terapéutico
, Adulto
, Animales
, Antibacterianos/administración & dosificación
, Antibacterianos/farmacología
, Compuestos Aza/administración & dosificación
, Compuestos Aza/farmacología
, Fluoroquinolonas
, Pie/microbiología
, Humanos
, Lepra/microbiología
, Lepra/patología
, Masculino
, Ratones
, Persona de Mediana Edad
, Moxifloxacino
, Mycobacterium leprae/crecimiento & desarrollo
, Mycobacterium leprae/patogenicidad
, Quinolinas/administración & dosificación
, Quinolinas/farmacología
, Piel/microbiología
, Piel/patología
, Resultado del Tratamiento
RESUMEN
The World Health Organization advocates 2 leprosy treatment regimens on the basis of disease classification (as multibacillary or paucibacillary) by skin lesion count. This method, which, in the Philippines, results in a high prevalence (78%) of patients with multibacillary leprosy, was directly compared with classification using standard histopathological and microbiological criteria in 264 currently untreated patients with leprosy. Of those whose leprosy was classified as paucibacillary, 38%-51% of patients had multibacillary leprosy according to classic criteria and were thus at risk of undertreatment according to World Health Organization recommendations.
Asunto(s)
Lepra/clasificación , Piel/patología , Clasificación/métodos , Humanos , Leprostáticos/uso terapéutico , Lepra/tratamiento farmacológico , Lepra/patología , Organización Mundial de la SaludAsunto(s)
Leprostáticos/historia , Leprostáticos/uso terapéutico , Lepra/tratamiento farmacológico , Lepra/historia , Mycobacterium leprae/efectos de los fármacos , Dapsona/uso terapéutico , Femenino , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Lepra/microbiología , Masculino , Pruebas de Sensibilidad Microbiana , Resultado del Tratamiento , Organización Mundial de la SaludRESUMEN
In 1982-1984 we conducted a six-month clinical trial in 50 previously untreated lepromatous leprosy patients randomly assigned to directly observed monotherapy with one of two thioamides, ethionamide or prothionamide, each given six times a week at doses of either 250 mg or 500 mg. The findings of this study have only recently been analyzed, and the potential for the use of these thioamides in leprosy patients placed in perspective. However, because of the small number of patients included in this study, the results must be interpreted with some caution. Clinical improvement was noted in 74% of the patients treated with ethionamide and in 83% of those treated with prothionamide. Therapy was well tolerated and drug-related hepatotoxicity did not require discontinuation of therapy. The 500-mg dose of both ethionamide and prothionamide resulted in loss in Mycobacterium leprae viability more rapidly than did the 250-mg dose, and prothionamide at both dose levels was superior to the equivalent dose of ethionamide. Overall killing of M. leprae in this study was found to be similar to that obtained previously with dapsone and clofazimine, but less than was obtained with rifampin, minocycline, clarithromycin, pefloxacin, and ofloxacin.
Asunto(s)
Etionamida/uso terapéutico , Leprostáticos/uso terapéutico , Lepra Lepromatosa/tratamiento farmacológico , Mycobacterium leprae/crecimiento & desarrollo , Protionamida/uso terapéutico , Adolescente , Adulto , Animales , Biopsia , Niño , Relación Dosis-Respuesta a Droga , Etionamida/efectos adversos , Femenino , Humanos , Leprostáticos/efectos adversos , Masculino , Ratones , Persona de Mediana Edad , Protionamida/efectos adversosRESUMEN
A 2-month clinical trial of pefloxacin and ofloxacin in previously untreated multibacillary patients was conducted at the Leonard Wood Memorial Leprosy Research Center, Cebu, the Philippines. Treatment with either pefloxacin or ofloxacin resulted in rapid clinical improvement, in this regard pefloxacin appearing somewhat superior. Reactions and side effects were minimal. Single doses of either agent did not result in significant killing of Mycobacterium leprae, but significant bactericidal activity was observed for all fluoroquinolone-treated patients by one week of daily therapy (n = 21), and either agent independently by 3 weeks of daily therapy. At the completion of therapy only two of 10 pefloxacin-treated patients and 0 of 11 ofloxacin-treated patients harboured any detectable viable M. leprae from active lesions, confirming previous work that these fluoroquinolones exhibit bactericidal activity in leprosy patients and more than that found previously for dapsone and clofazimine.
Asunto(s)
Lepra Lepromatosa/tratamiento farmacológico , Mycobacterium leprae/efectos de los fármacos , Ofloxacino/administración & dosificación , Pefloxacina/administración & dosificación , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Lepra Lepromatosa/diagnóstico , Masculino , Filipinas , Probabilidad , Estudios Prospectivos , Sensibilidad y Especificidad , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
We evaluated the incidence, severity, and duration of reactional states in 139 multibacillary (MB) leprosy patients in the first 2 years after the completion of the 1 year regimen of multidrug therapy (MDT) currently recommended by the World Health Organization (WHO) and compared those findings with 295 MB leprosy patients treated with the same regimen previously recommended for 2 years. During the first year after the completion of 1 year MDT, patients experienced 1 or more reactional states 27% of the time, the vast majority being lepra type 1 reactions (reversal reactions, RR), whereas patients who received 2 year MDT experienced a reactional state during that time period only 8% of the time (P < 0.001). Furthermore, during the first year after the completion of therapy, and during the first 2 years, both the number of reactional states and reversal reactions were significantly (P < or = 0.004) more frequent, severe, of longer duration, and more commonly associated with neuritis.
Asunto(s)
Leprostáticos/efectos adversos , Lepra/tratamiento farmacológico , Adolescente , Adulto , Estudios de Cohortes , Quimioterapia Combinada , Femenino , Humanos , Leprostáticos/administración & dosificación , Leprostáticos/uso terapéutico , Masculino , Adulto JovenRESUMEN
As a participant in a multicenter trial, we evaluated the relapse rate in 189 multibacillary (MB) leprosy patients treated with four different regimens and followed-up for as many as 12 years after the initiation of treatment. Treatment regimens included 1 year of WHO MDT (a regimen including dapsone, clofazimine, and rifampin), 2 years of WHO MDT, 1 month of daily rifampin and daily ofloxacin, and 1 year of WHO MDT plus an initial 1 month of daily rifampin and daily ofloxacin. Relapse rates after 9 and 12 years from the initiation of therapy in the three regimens that included WHO MDT were 0-3%, whereas relapses occurred in those treated with the 1-month regimen alone at a significantly greater rate (P < 0.05): 11% at 9 years and 25% at 12 years. Relapses occurred late, beginning at 5 years after the initiation of therapy, and were confined to those patients histopathologically borderline lepromatous and polar lepromatous having a high bacterial burden. Prospects for an alternative effective short-course therapy of leprosy are presented.
Asunto(s)
Leprostáticos/administración & dosificación , Leprostáticos/uso terapéutico , Lepra/tratamiento farmacológico , Adolescente , Adulto , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia , Factores de Tiempo , Adulto JovenRESUMEN
Leprosy is a chronic and debilitating human disease caused by infection with the Mycobacterium leprae bacillus. Despite the marked reduction in the number of registered worldwide leprosy cases as a result of the widespread use of multidrug therapy, the number of new cases detected each year remains relatively stable. This indicates that M. leprae is still being transmitted and that, without earlier diagnosis, M. leprae infection will continue to pose a health problem. Current diagnostic techniques, based on the appearance of clinical symptoms or of immunoglobulin M (IgM) antibodies that recognize the bacterial phenolic glycolipid I, are unable to reliably identify early-stage leprosy. In this study we examine the ability of IgG within leprosy patient sera to bind several M. leprae protein antigens. As expected, multibacillary leprosy patients provided stronger responses than paucibacillary leprosy patients. We demonstrate that the geographic locations of the patients can influence the antigens they recognize but that ML0405 and ML2331 are recognized by sera from diverse regions (the Philippines, coastal and central Brazil, and Japan). A fusion construct of these two proteins (designated leprosy IDRI diagnostic 1 [LID-1]) retained the diagnostic activity of the component antigens. Upon testing against a panel of prospective sera from individuals who developed leprosy, we determined that LID-1 was capable of diagnosing leprosy 6 to 8 months before the onset of clinical symptoms. A serological diagnostic test capable of identifying and allowing treatment of early-stage leprosy could reduce transmission, prevent functional disabilities and stigmatizing deformities, and facilitate leprosy eradication.
Asunto(s)
Anticuerpos Antibacterianos/sangre , Antígenos Bacterianos , Lepra/diagnóstico , Lepra/inmunología , Mycobacterium leprae/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Antibacterianos/inmunología , Antígenos Bacterianos/inmunología , Niño , Diagnóstico Precoz , Femenino , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Inmunoglobulina M/sangre , Inmunoglobulina M/inmunología , Lepra/microbiología , Masculino , Persona de Mediana Edad , Proteínas Recombinantes de Fusión/inmunologíaRESUMEN
A group of multibacillary patients is clearly at high risk for relapse following 2-yr WHO-MDT. Relapse is largely confined to BL or LL patients with a high BI initially, and occurs long after the discontinuation of therapy. This important group of patients at risk for treatment failure presents several important issues: the need to identify those at risk and the operational requirements needed for their long term follow-up. Also, this group of patients might well benefit from an alternative antimicrobial regimen from the outset, as well as upon relapse.
Asunto(s)
Leprostáticos/uso terapéutico , Lepra Dimorfa/tratamiento farmacológico , Lepra Dimorfa/prevención & control , Lepra Lepromatosa/tratamiento farmacológico , Lepra Lepromatosa/prevención & control , Quimioterapia Combinada , Estudios de Seguimiento , Humanos , Lepra , Lepra Dimorfa/epidemiología , Lepra Lepromatosa/epidemiología , Mycobacterium leprae , Filipinas , Recurrencia , Factores de Riesgo , Insuficiencia del Tratamiento , Organización Mundial de la SaludRESUMEN
Relapse rate estimates after 2 year WHO multiple drug therapy (MDT) in multi-bacillary (MB) leprosy vary. Between 1987 and 1994, 500 MB leprosy patients completing 2 year MDT were enrolled in a prospective relapse study. The majority of patients (N = 316) were treated and followed at the physician-staffed Cebu Skin Clinic (CSC), whereas others (N = 184) received therapy from government clinics and were followed by CSC technicians in the field. Relapse definition was an increased bacteriologic index (BI) and new skin lesions, supplemented with mouse footpad inoculations. Through 2002, follow-up was 5368 person-years, with a mean of 10.8 years per patient. The absolute relapse rate was 3% (15/498; 0.28/100 person-years), with a cumulative risk estimate of 3.9% at 15 yrs. For a subset of 217 patients followed for >or=12 yrs or until relapse, relapses occurred in 9% (13/142) attending the CSC, versus 3% (2/75) assessed in the field (p = 0.09). The rate for patients followed at CSC for >or=12 yrs and a pre-treatment BI >or=2.7+ was 13% (13/98). All relapses were BL or LL, with pre-treatment BI's of >or=2.7+. Relapses occurred long after completion of therapy, between 3 and 11 yrs from the midpoint of the examination without relapse to detection, or between 6 to 13 yrs to the actual year of detection, 7 occurring at >or=10 yrs. Lesion material from all relapses contained M. leprae that was rifampin and clofazimine sensitive, whereas 3 showed partial or full dapsone resistance. [Follow-up rigor and time], medical expertise, and pre-treatment bacterial load influence relapse rates after 2 yr MDT.
Asunto(s)
Leprostáticos/uso terapéutico , Lepra/tratamiento farmacológico , Adolescente , Adulto , Anciano , Animales , Niño , Estudios de Cohortes , Farmacorresistencia Bacteriana , Quimioterapia Combinada , Femenino , Humanos , Leprostáticos/farmacología , Lepra/prevención & control , Masculino , Ratones , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Mycobacterium leprae/efectos de los fármacos , Filipinas , Recurrencia , Factores de Tiempo , Organización Mundial de la SaludRESUMEN
No disponible
Asunto(s)
Humanos , Lepra/tratamiento farmacológico , Leprostáticos/uso terapéutico , Sulfonas/uso terapéutico , Lepra/historiaRESUMEN
Sequential monitoring of 724 sera for antibodies to a neoantigen based on phenolic glycolipid-I (PGL-I) and native lipoarabinomannan (LAM) in 90 leprosy patients undergoing therapy in San Francisco was conducted. Untreated lepromatous patients frequently (91%) had significant antibodies to both moieties. Antibodies were less frequently found in tuberculoid patients (74% to neoantigen and 37% to LAM). In the first 3 years of treatment, average serum antibodies to both moieties fell significantly. Antibodies to LAM fell during each of the first 4 years of therapy, but decreasing antibody levels to the PGL-I neoantigen did not appear to fall consistently after the third year of treatment. A wide variation in the rate of fall of serum antibodies was noted. Sequential changes in the amounts of serum antibodies to the neoantigen and LAM in general paralleled one another but were at times discrepant. Both in San Francisco and Malaysia, skin-smear negative, long-term treated, lepromatous leprosy patients frequently harbored significant antibodies to both PGL-I and LAM
Asunto(s)
Humanos , Anticuerpos Antibacterianos/fisiología , Anticuerpos Antibacterianos/inmunología , Antígenos Bacterianos/inmunología , Glucolípidos/inmunología , Lepra/terapiaRESUMEN
To measure the rate at which Mycobacterium leprae are killed in the course of the mouse footpad infection after the maximum of multiplication has been achieved, M. leprae were harvested shortly before and at intervals after multiplication had reached the level of 10(6) organisms per footpad, serially diluted, and inoculated into the footpads of passage mice. Beginning 1 year later, foot-by-foot harvests of M. leprae were performed from passage mice, and the proportion of viable organisms in the passage inocula was calculated by means of a most-probable-number calculation. In addition, the proportion of solidly staining M. leprae was measured in the passage inocula. The proportion of viable M. leprae in the passage inocula was found to decrease with the time after multiplication to 10(6) organisms per footpad of donor mice; the half-time of loss of viable M. leprae was 25 days. The proportion of solidly staining organisms appeared to be directly related to the proportion of viable organisms, as measured by mouse passage, and inversely proportional to the time after multiplication to 10(6) organisms per footpad.