RESUMEN
Drug-resistant tuberculosis (DR-TB) is a growing public health problem, and for the first time in decades, new drugs for the treatment of this disease have been developed. These new drugs have prompted strengthened efforts in DR-TB clinical trials research, and there are now multiple ongoing and planned DR-TB clinical trials. To facilitate comparability and maximise policy impact, a common set of core research definitions is needed, and this paper presents a core set of efficacy and safety definitions as well as other important considerations in DR-TB clinical trials work. To elaborate these definitions, a search of clinical trials registries, published manuscripts and conference proceedings was undertaken to identify groups conducting trials of new regimens for the treatment of DR-TB. Individuals from these groups developed the core set of definitions presented here. Further work is needed to validate and assess the utility of these definitions but they represent an important first step to ensure there is comparability in clinical trials on multidrug-resistant TB.
Asunto(s)
Antituberculosos/administración & dosificación , Ensayos Clínicos como Asunto , Proyectos de Investigación/normas , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Adulto , Antituberculosos/uso terapéutico , Humanos , Mycobacterium tuberculosis/efectos de los fármacosRESUMEN
Several new classes of anti-tuberculosis agents are likely to become available in the coming decade. Ensuring prompt access to these drugs for patients without other treatment options is an important medical and public health issue. This article reviews the current state of 'compassionate use' and 'expanded access' programs for these new drugs, and identifies several shortcomings that will limit patient access to the drugs. A series of five steps is outlined that will need to be taken by national health bodies, international agencies and non-governmental organizations to prevent undue delays in access to new tuberculosis drugs for patients who could benefit from them. Following these steps can ensure that patients will be able to benefit from access to these drugs, while minimizing the risk of emergence of resistance to the drug.
Asunto(s)
Antituberculosos/uso terapéutico , Ensayos de Uso Compasivo/métodos , Drogas en Investigación , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , HumanosRESUMEN
The 2-year follow-up results for a randomized placebo-controlled study of 47 patients with multidrug-resistant pulmonary tuberculosis treated with either the new diarylquinoline TMC207, recently renamed bedaquiline, or placebo, added to the first 8 weeks of a background regimen, are presented. Bedaquiline significantly reduced the time to culture conversion over 24 weeks (hazard ratio, 2.253; 95% confidence interval, 1.08 to 4.71; P = 0.031). With the exception of nausea reported in 26% of patients receiving bedaquiline and none receiving placebo, adverse events occurred at similar frequencies in both groups of patients: bilateral hearing impairment, extremity pain, acne, and noncardiac chest pain occurred in 13 and 21%, 17 and 13%, 9 and 17%, and 4 and 17% of patients, respectively, receiving bedaquiline or placebo. Excluding resistance to ethambutol and ethionamide, only one patient receiving bedaquiline acquired resistance to companion drugs, but five patients receiving placebo (4.8% versus 21.7%; P = 0.18) acquired resistance to companion drugs, and resistance to ofloxacin was acquired in four patients receiving placebo and none receiving bedaquiline (0% versus 22%; 0 = 0.066). In all, 23 patients (49%), including 13 receiving placebo (54%) and 10 receiving bedaquiline (44%), discontinued the study prior to its completion, 12 during the first 24 weeks of treatment. Eight subjects were withdrawn for noncompliance or default, and seven withdrew consent, citing the rigorous program of investigations for safety and pharmacokinetic monitoring. Bedaquiline may contribute to the management of multidrug-resistant tuberculosis by effecting more rapid sputum culture negativity and by preventing acquired resistance to companion drugs.
Asunto(s)
Antituberculosos/uso terapéutico , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Claritromicina/uso terapéutico , Cicloserina/uso terapéutico , Dapsona/uso terapéutico , Diarilquinolinas , Eritromicina/uso terapéutico , Femenino , Humanos , Isoxazoles/uso terapéutico , Masculino , Ofloxacino/uso terapéutico , Oxazolidinonas/uso terapéutico , Quinolinas/uso terapéuticoRESUMEN
Evaluation of early bactericidal activity (EBA) by the determination of a fall in viable colony-forming units (CFU) of Mycobacterium tuberculosis in sputum is a first step in the clinical study of new antituberculosis agents. The time to detection (TTD) of growth in liquid media is more sensitive and could substitute for CFU counting on solid media. Overnight sputum samples collected during the evaluation of the novel agent TMC207 in comparison to isoniazid and rifampicin were studied. For the determination of CFU, we incubated 10-fold dilutions of homogenized sputum on selective 7H10 agar. The TTD was measured by incubating decontaminated sputum in the BACTEC MGIT 960 system. The fall in bacillary load over 7 days determined by CFU counting closely matched the prolongation of the TTD in the BACTEC MGIT 960 system. The CFU counts correlated significantly with the TTD. While the ranking of agents and different dosages of TMC207 was similar, the highest dose of TMC207 showed markedly better activity when measured by the TTD than CFU counting when compared to the activity of isoniazid. Automated TTD could augment, or, in future, replace, CFU counting to determine sputum bacillary load in EBA clinical trials pending a more formal evaluation of the correlation of the measurements.
Asunto(s)
Antituberculosos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/crecimiento & desarrollo , Quinolinas/farmacología , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis Pulmonar/microbiología , Adolescente , Adulto , Antituberculosos/administración & dosificación , Recuento de Colonia Microbiana , Medios de Cultivo , Diarilquinolinas , Femenino , Humanos , Isoniazida/administración & dosificación , Isoniazida/farmacología , Masculino , Persona de Mediana Edad , Quinolinas/administración & dosificación , Rifampin/administración & dosificación , Rifampin/farmacología , Esputo/microbiología , Factores de Tiempo , Resultado del Tratamiento , Tuberculosis Pulmonar/diagnóstico , Adulto JovenRESUMEN
Tibotec Medicinal Compound 207 (TMC207) is a novel diarylquinoline with a unique mode of action that targets mycobacterial ATP synthase. TMC207 exhibits high in vitro activity against mycobacterial strains either susceptible or resistant to all first-line and many second-line drugs, including fluoroquinolones, and has shown exceptional in vivo activity against several mycobacterial species in different animal models. In this early bactericidal activity study, 75 treatment-naïve patients with smear-positive pulmonary tuberculosis were randomized to once-daily oral TMC207 (25 mg, 100 mg, or 400 mg), 600 mg rifampin (RIF), or 300 mg isoniazid (INH) for 7 days. Sixteen-hour overnight sputum collected at baseline and on each treatment day was plated in serial dilutions on selective agar plates. The bactericidal activity was expressed as the log(10) decrease in CFU/ml sputum/day. Pharmacokinetic sampling was performed on day 7 of TMC207 administration up to 24 h postdose. The decreases in log(10) CFU counts (+/- standard deviation) from baseline to day 7 were 0.04 +/- 0.46 for 25 mg TMC207 (n = 14), 0.26 +/- 0.64 for 100 mg TMC207 (n = 14), 0.77 +/- 0.58 for 400 mg TMC207 (n = 14), 1.88 +/- 0.74 for INH (n = 11), and 1.70 +/- 0.71 for RIF (n = 14). Significant bactericidal activity of 400 mg TMC207 was observed from day 4 onward and was similar in magnitude to those of INH and RIF over the same period. The pharmacokinetics of TMC207 were linear across the dose range. In summary, TMC207 demonstrated bactericidal activity with a delayed onset and was well tolerated, and no study drug-related serious adverse events occurred.
Asunto(s)
Antituberculosos/uso terapéutico , Mycobacterium tuberculosis/efectos de los fármacos , Quinolinas/uso terapéutico , Tuberculosis Pulmonar/tratamiento farmacológico , Administración Oral , Adolescente , Adulto , Antituberculosos/administración & dosificación , Antituberculosos/farmacocinética , Área Bajo la Curva , Diarilquinolinas , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Quinolinas/administración & dosificación , Quinolinas/farmacocinética , Esputo/efectos de los fármacos , Esputo/microbiología , Resultado del Tratamiento , Tuberculosis Pulmonar/microbiologíaAsunto(s)
Serodiagnóstico del SIDA/métodos , Infecciones por VIH/diagnóstico , Tamizaje Masivo , Fármacos Anti-VIH/uso terapéutico , Femenino , Infecciones por VIH/prevención & control , Humanos , Recién Nacido , New York , Atención Perinatal , Embarazo , Factores de Riesgo , Zidovudina/uso terapéuticoAsunto(s)
Antiinfecciosos/farmacología , Enterococcus faecalis/efectos de los fármacos , Enterococcus faecium/efectos de los fármacos , Fluoroquinolonas , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Ampicilina/farmacología , Antibacterianos/farmacología , Preescolar , Ciprofloxacina/farmacología , Farmacorresistencia Microbiana , Enterococcus faecalis/aislamiento & purificación , Infecciones por Bacterias Grampositivas/microbiología , Humanos , Lactante , Recién Nacido , Naftiridinas/farmacología , Penicilinas/farmacología , Vancomicina/farmacologíaRESUMEN
Despite the use of highly active antiretroviral therapy (HAART) and the success of protocol PACTG-076 in decreasing perinatal transmission of HIV infection in many industrialized countries, a total of 5,600,000 new cases of HIV infection were diagnosed worldwide in 1999. Of those cases, more than 10% are children under 15 years of age. The vast majority of pediatric HIV infection is due to perinatal transmission. More than 95% of HIV-infected people live in the developing world. Different studies are currently being conducted with modifications of the original PACTG-076, especially shorter courses of zidovudine (ZDV), combinations of antiretrovirals (ZDV and 3TC), or comparison of a modified version of the standard ZDV course vs. a single dose of nevirapine for the mother intrapartum and also for the newborn. The results of these studies may provide more affordable, alternative regimens to prevent maternal-to-child HIV-1 transmission for developing countries than the PACTG-076 protocol. It is very important that physicians and physician extenders (nurse practitioners and physician assistants) caring for infants born to HIV-infected mothers have an understanding of the pathophysiology of vertical HIV-1 infection transmission. They should be familiar with the conditions associated with an increased risk of transmission, interventions available to decrease this risk, current medications, and laboratory resources.
Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Infecciones por VIH/transmisión , VIH-1 , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Terapia Antirretroviral Altamente Activa , Esquema de Medicación , Femenino , Infecciones por VIH/prevención & control , Humanos , Recién Nacido , Lamivudine/administración & dosificación , Nevirapina/administración & dosificación , Embarazo , Zidovudina/administración & dosificaciónRESUMEN
New advances in the diagnosis and treatment of HIV infection continue to propel changes in public understanding of HIV infection and the administration of public health law. Over the past decade, New York State has moved from a policy of blind newborn screening for seroprevalence data to mandatory HIV testing as part of the statewide Newborn Screening (NBS) Program. A new statewide program of expedited HIV testing (48-hr turnaround results) of pregnant women and newborns (whose HIV status is unknown at the time of delivery) began in the summer of 1999. To better understand the impact this program might have on the patients who receive health care at Lincoln Medical and Mental Health Center (Lincoln Hospital), we evaluated our experience with the current NBS program prior to inauguration of the new expedited testing program. We evaluated the NBS program from February 1, 1997, to January 31, 1999, including total number of HIV-exposed/infected infants born, mother's HIV status (if known) at the time of delivery, amount of time between blood sampling and return of the test results to the Hospital, and medical follow-up of infants with positive newborn screening test results. This was a retrospective study of the NBS registry and the medical records of patients who receive primary health care from the Pediatric Immunology Service of the Department of Pediatrics at Lincoln Hospital. One hundred and four newborns were identified with positive-HIV antibody (HIV-Ab-positive), and 13 (12.5%) were confirmed to be HIV-infected by positive polymerase chain reaction (PCR) test of viral DNA. Sixty-five (62.5%) of the newborns with positive NBS screening test results were born to mothers who were known to be HIV-infected prior to delivery; 39 (37.5%) were unanticipated. Four (30%) of the 13 HIV-infected babies were born to mothers who were known to be HIV-infected prior to delivery, and 9 (70%) were born to mothers whose HIV status was unknown at the time of delivery. Eighty percent (80%) of HIV-Ab-positive infants continued to receive follow-up care at Lincoln Hospital. Relocation to other health-care facilities occurred as a result of parental choice or due to foster care placement. No babies were "lost" from the NBS program. The average time between sampling and receipt of results for all blood tests was 16 days (range 10 to 141). Nearly 40% of newborns who acquired HIV infection from their mothers were unanticipated because the mother's HIV status was unknown at the time of delivery. These unanticipated HIV-infected infants represent missed opportunities for prevention of maternal-to-child transmission of HIV infection and early therapeutic intervention for HIV-infected infants. The new expedited HIV-testing program for New York State will facilitate early diagnosis, prevention and treatment of the HIV-exposed/infected infant for whom maternal HIV status is unknown at the time of delivery.
Asunto(s)
Infecciones por VIH/diagnóstico , Infecciones por VIH/transmisión , Política de Salud/legislación & jurisprudencia , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Tamizaje Neonatal/organización & administración , Femenino , Humanos , Recién Nacido , Masculino , Ciudad de Nueva York , Embarazo , Desarrollo de Programa , Evaluación de Programas y Proyectos de Salud , Salud Pública , Sistema de Registros , Estudios Retrospectivos , Población UrbanaAsunto(s)
Infección Hospitalaria/tratamiento farmacológico , Casas de Salud , Infecciones Neumocócicas/tratamiento farmacológico , Vacunas Bacterianas/uso terapéutico , Infección Hospitalaria/prevención & control , Farmacorresistencia Microbiana , Humanos , Ciudad de Nueva York , Infecciones Neumocócicas/prevención & controlRESUMEN
BACKGROUND: The transmission of malaria has increased in recent years in many countries where it was once eradicated or under control, and malaria remains a major cause of morbidity and mortality throughout the developing world. Imported cases of malaria have been increasing in New York City and throughout the United States during the past decade. The New York City Department of Health has modified its malaria surveillance program in order to improve the assessment of diagnosis and treatment of malaria in New York City residents and to provide appropriate advice to health professionals who treat these patients. OBJECTIVES: To describe the epidemiologic and clinical characteristics of laboratory-confirmed cases of malaria diagnosed in New York City residents from January 1, 1991, through December 31, 1996. METHODS: The retrospective study of case reports was carried out by the Malaria Surveillance Program of the Bureau of Communicable Diseases, New York City Department of Health, New York City, NY. It included the laboratory diagnosis of malaria and the species involved, and included also descriptive epidemiologic information of patients with malaria (age, sex, race/ethnicity, date and place of onset of illness, travel history, immigration status, previous history of malaria, history of blood transfusion, drugs used for treatment or prophylaxis), as well as a record of clinical complications of the infection (thrombocytopenia, hemolysis, anemia, cerebral malaria, renal failure, respiratory distress syndrome, fatal outcome). RESULTS: Malaria was diagnosed in 988 residents of New York City during the 5-year period from January 1, 1991, through December 31, 1995. The largest number of cases, 254 (26%), occurred in 1996, with the majority of these cases (76%) observed between the months of May and October. Sixty-four percent (627) of these cases were males. The age range of cases was from newborn (first day of life) to 83 years (median, 31 years). Of the 962 cases of whom the racial/ethnic identity was known, 580 (59%) were black/non-Hispanic and 255 (26%) were Asian/Pacific Islander. Travel outside of the United States was reported by 958 patients, the majority to Africa (569/958, 59%). Only 139 patients (14%) claimed the use of malaria prophylaxis during travel. Plasmodium falciparum was identified in 505 (51%) and P. vivax in 356 (36%) of the cases. Clinical complications included hemolysis with severe anemia, thrombocytopenia, cerebral malaria, renal failure, and respiratory distress syndrome. All four fatal cases involved infections with P. falciparum, either alone or in combination with another plasmodia species. CONCLUSIONS: Imported cases of malaria occur frequently in New York City and may be associated with serious complications. Health care providers should consider this diagnosis in patients who have recently travelled or arrived from abroad, presenting with headache, fever, and other constitutional symptoms. There are many missed opportunities for the use of malaria prophylaxis, and physicians should familiarize themselves with current recommendations for malaria prophylaxis for travel to areas of the world where people are at risk for the transmission of malaria.
Asunto(s)
Malaria/epidemiología , Adolescente , Adulto , Anciano , Animales , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Malaria/etiología , Malaria/prevención & control , Masculino , Persona de Mediana Edad , Ciudad de Nueva York/epidemiología , Plasmodium/aislamiento & purificación , Vigilancia de la Población , Estudios Retrospectivos , ViajeRESUMEN
BACKGROUND: Between 1990 to 1992 and 1993 to 1995 there was a >5-fold increase (16.7% to 89.8%) in vancomycin-resistant Enterococcus faecium isolates as a percentage of all isolates of vancomycin-resistant enterococci on the pediatric units of The New York Hospital-Cornell Medical Center (NYH-CMC). A molecular epidemiologic investigation was undertaken to determine the extent to which this increase was associated with the spread of a vanA-containing clone of vancomycin-resistant E. faecium that had been previously defined in adults hospitalized at NYH-CMC or with the spread of another vanA clone that had been defined in children hospitalized on the pediatric service at Memorial Sloan-Kettering Cancer Center, which shares a common pediatric intensive care unit and pediatric house staff with NYH-CMC. METHODS: Molecular genotyping of vancomycin-resistant E. faecium isolates obtained from pediatric patients from 1993 to 1995 was performed by pulsed field gel electrophoresis of chromosomal SmaI digests. Southern hybridization was performed using vanA- and vanB-specific probes. Medical records of patients were reviewed for pertinent clinical and demographic information. RESULTS: A single vanB clone of vancomycin-resistant E. faecium was responsible for 17 (77.3%) of 22 isolates in the neonatal intensive care unit (NICU) of NYH-CMC. Two other vanB strains of vancomycin-resistant E. faecium and 2 vanA strains were identified among the 5 remaining NICU isolates. Vancomycin-resistant E. faecium isolates from the other pediatric units represented a heterogeneous population of primarily vanA strains, but vanA clonal strains previously identified from patients on adult services at NYH-CMC and from children hospitalized at Memorial Sloan-Kettering Cancer Center were not detected. CONCLUSION: A newly identified vanB clone was responsible for the increase in vancomycin-resistant E. faecium isolates in the NICU of NYH-CMC. The increase of vancomycin-resistant E. faecium among children hospitalized at NYH-CMC was unrelated to the spread of vancomycin-resistant E. faecium among adults in the same hospital or among children at an affiliated facility cared for by the same house staff and sharing a common pediatric intensive care unit.
Asunto(s)
Antibacterianos/farmacología , Infección Hospitalaria/tratamiento farmacológico , Farmacorresistencia Microbiana , Enterococcus faecium/efectos de los fármacos , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Vancomicina/farmacología , Adolescente , Niño , Preescolar , Infección Hospitalaria/epidemiología , ADN Bacteriano/análisis , Electroforesis en Gel de Campo Pulsado , Enterococcus faecium/genética , Infecciones por Bacterias Grampositivas/epidemiología , Humanos , Lactante , Recién Nacido , Unidades de Cuidado Intensivo Neonatal , Unidades de Cuidado Intensivo PediátricoRESUMEN
BACKGROUND: Enterococci can cause serious infections in the newborn. The increased number of these infections since the late 1970s and the increased isolation of organisms resistant to many commonly used antimicrobials prompted review of our experience with enterococcal bacteremia in the neonatal intensive care unit. This review was aimed at defining the character of illness of newborns who had these infections during a 20-year period. METHODS: This was a retrospective review of the medical records of newborns with enterococci isolated from blood. RESULTS: Between January, 1974, and December, 1993, 138 episodes of enterococcal bacteremia occurred in newborns hospitalized in the neonatal intensive care unit. Thirty-four episodes occurred during the first decade and 104 episodes during the second decade. One hundred of the 138 episodes were reviewed. In 64% of these episodes other microorganisms were also isolated from blood. Comparison of clinical characteristics associated with these episodes in the first and second decade demonstrated that episodes occurring in the more recent decade occurred in older infants (mean age of onset, 44.7 vs. 16.1 days; episodes occurring after 14 days, 73% vs. 41%). Common characteristics associated with enterococcal bacteremia included the presence of a central vascular catheter (77%), necrotizing enterocolitis (33%) and abdominal distension (21%). Vancomycin-resistant enterococci caused bacteremia in 6 infants and caused illnesses indistinguishable from those caused by susceptible organisms. CONCLUSIONS: In the more recent decade there were three times the number of episodes of enterococcal bacteremia in our neonatal intensive care unit than there were in the previous decade. The characteristics associated with these infections were similar to those occurring with other nosocomial bacterial infections in the neonate and did not change during the period reviewed. Most recent episodes occurred as part of polymicrobial infections in newborns hospitalized for more than 1 month. Infections caused by vancomycin-resistant enterococci occurred in older patients but were clinically indistinguishable from infections caused by sensitive organisms.
Asunto(s)
Bacteriemia/etiología , Enterococcus , Infecciones por Bacterias Grampositivas/etiología , Factores de Edad , Enterococcus/efectos de los fármacos , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Estudios Retrospectivos , Vancomicina/farmacologíaRESUMEN
To document the occurrence of transplacental transmission of microfilariae and to determine how frequently it occurred, umbilical cord blood samples and placental tissues were collected from 22 microfilaria-positive women in an area with endemic Wuchereria bancrofti. Microfilaria (mf) counts in the women ranged from 1 to 3,820 mf/ml. Microfilariae were detected in 2 placenta samples and a single cord blood sample. The positive cord blood sample and 1 of the positive placenta samples came from the same woman; no microfilariae were found in a finger prick sample taken from the infant 3 wk after delivery. Our results suggest that microfilariae cross the placenta in less than 10% of pregnancies of microfilaria-positive mothers. Furthermore, the microfilaria count of the mother does not seem to influence directly whether microfilariae are present in the placental blood pool. Although actual transfer of microfilariae to the fetus may occur infrequently, exposure to parasite antigens occurs with much greater frequency. The effect of in utero exposure to either microfilariae or parasite antigens may render newborns tolerant and explain why children born to infected mothers are almost 3 times more likely to become infected than are children born to uninfected women.
Asunto(s)
Filariasis Linfática/transmisión , Sangre Fetal/parasitología , Placenta/parasitología , Complicaciones Parasitarias del Embarazo/parasitología , Wuchereria bancrofti/fisiología , Animales , Filariasis Linfática/parasitología , Femenino , Estudios de Seguimiento , Haití , Humanos , Recién Nacido , Microfilarias/fisiología , Embarazo , Wuchereria bancrofti/aislamiento & purificaciónRESUMEN
To compare the efficacy and tolerability of various combinations of low- and high-dose ivermectin and diethylcarbamazine (DEC), 59 persons with Wuchereria bancrofti microfilaremia were enrolled in a double-blinded six-arm clinical trial in Leogane, Haiti. On day 1, study participants were treated with low clearing doses of ivermectin, DEC, or placebo; on day 5 they received 200-400 micrograms/kg of ivermectin or 6 mg/kg of DEC. Adverse reactions, which were generally mild, occurred more frequently with ivermectin than with DEC. One year after treatment, the geometric mean microfilarial density returned to 0.9% of pretreatment levels for persons who received a total of 420 micrograms/kg of ivermectin. This rate was significantly lower than 5.6% for persons who were treated with 220 micrograms/kg of ivermectin (P = 0.02) and 9.3% for those receiving 6 or 7 mg/kg of DEC (P = 0.006). Persons treated with a clearing dose of ivermectin followed by 6 mg/kg of DEC also had low microfilarial densities (1.7% of pretreatment levels), suggesting an additive or synergistic effect of the two drugs. The addition of a clearing dose neither reduced the severity of adverse reactions nor improved the efficacy of high-dose ivermectin. Community-based intervention trials are now warranted to determine the feasibility and effectiveness of mass chemotherapy with single high-dose ivermectin for the prevention and control of lymphatic filariasis.
Asunto(s)
Dietilcarbamazina/uso terapéutico , Filariasis Linfática/tratamiento farmacológico , Ivermectina/uso terapéutico , Wuchereria bancrofti/efectos de los fármacos , Adolescente , Adulto , Anciano , Animales , Ritmo Circadiano , Dietilcarbamazina/administración & dosificación , Dietilcarbamazina/efectos adversos , Dietilcarbamazina/farmacología , Método Doble Ciego , Esquema de Medicación , Sinergismo Farmacológico , Quimioterapia Combinada , Tolerancia a Medicamentos , Filariasis Linfática/sangre , Femenino , Humanos , Ivermectina/administración & dosificación , Ivermectina/efectos adversos , Ivermectina/farmacología , Masculino , Microfilarias/efectos de los fármacos , Persona de Mediana EdadRESUMEN
Lymphatic filariasis has been difficult to control until recently because of the lack of a suitable drug for treatment. Ivermectin has proven safe and effective at reducing levels of circulating microfilariae. However, the apparent need to administer the drug every 6 to 9 months to keep microfilaraemia levels sufficiently suppressed to reduce transmission has been a major drawback to using ivermectin in community-based intervention programmes. In a study conducted in Haiti, we have found that high doses of ivermectin suppress microfilaraemia levels for 2 years. Our findings suggest that a single dose of ivermectin can reduce transmission of lymphatic filariasis for extended periods of time, thus eliminating the need for costly biannual treatment.
Asunto(s)
Filariasis Linfática/tratamiento farmacológico , Ivermectina/uso terapéutico , Adolescente , Adulto , Anciano , Animales , Filariasis Linfática/sangre , Humanos , Ivermectina/administración & dosificación , Microfilarias/aislamiento & purificación , Persona de Mediana Edad , Distribución Aleatoria , Factores de Tiempo , Resultado del Tratamiento , Wuchereria bancrofti/aislamiento & purificaciónRESUMEN
The presence of circulating microfilariae has been associated with alterations in B and T cell functions. In this study, we compared the influence of diethylcarbamazine (DEC) and ivermectin on filarial antigen-specific immune responses in a Haitian population. Both drugs were effective at reducing microfilaremia levels to less than 10% of pretreatment levels for up to one year. This reduction in microfilaremia was associated with two phases of altered cellular responsiveness monitored with in vitro assays. Five days post-treatment, cellular proliferation in response to both filarial and nonfilarial antigens was significantly increased, as was the background response in the absence of any antigen. At both nine months and one year post-treatment, the filarial antigen-specific reactivity of both DEC- and ivermectin-treated patients was significantly increased over baseline levels. No differences were observed between the two treatment groups in terms of humoral or cellular reactivity to filarial antigens, despite evidence suggesting a role for DEC in adult worm killing. These results provide additional evidence that microfilariae modulate antifilarial immune reactivity.
Asunto(s)
Antígenos Helmínticos/sangre , Dietilcarbamazina/uso terapéutico , Filariasis/tratamiento farmacológico , Filarioidea/inmunología , Ivermectina/uso terapéutico , Animales , Anticuerpos Antihelmínticos/sangre , Antígenos Helmínticos/inmunología , Dietilcarbamazina/farmacología , Método Doble Ciego , Femenino , Filariasis/sangre , Filariasis/inmunología , Filarioidea/efectos de los fármacos , Humanos , Inmunidad Celular , Ivermectina/farmacología , Estudios Longitudinales , Activación de Linfocitos , Masculino , Microfilarias/efectos de los fármacos , Microfilarias/inmunologíaRESUMEN
This three-phase study was designed to compare high dose ivermectin with a standard diethylcarbamazine (DEC) regimen for patient tolerability, potential to kill adult filaria, and duration of microfilarial suppression in 30 Haitian subjects with Wuchereria bancrofti microfilaremia. All were first given a 1-mg oral dose of ivermectin (phase 1) to reduce microfilaria densities. Participants were randomized into three groups: Group 1 received DEC (6mg/kg per day for 12 days), Group 2 received 200 mcg/kg of ivermectin, and Group 3 received 400 mcg/kg of ivermectin (200 mcg/kg per day for 2 days). All drug regimens were well tolerated with few adverse reactions. Most reactions occurred during phase I and consisted primarily of headache, fever, and myalgia. At the end of phase 1, 27 of 30 (90%) patients were microfilaria negative. During phase 2, four of the six men receiving DEC developed scrotal reactions suggesting killing adult worms; no such reactions were noted in 10 men receiving ivermectin (p less than 0.05). At one-year follow up (phase 3), all treatment groups had less than 10% return to pretreatment microfilaria levels. The mean percent of baseline microfilaria counts were for Group 1, 0.9% (range 0-5%); Group 2, 8.2% (range 0-31%); and Group 3, 3.8% (range 0-25%). Seven individuals in Group 1 were microfilaria-negative, while only one and three individuals were microfilaria-negative in Groups 2 and 3, respectively. These results suggest that DEC causes more damage to the adult worms and greater reduction in microfilaria densities than ivermectin, but that high doses of ivermectin may suppress microfilaremia in lymphatic filariasis for periods much longer than previously reported.
Asunto(s)
Dietilcarbamazina/uso terapéutico , Filariasis Linfática/tratamiento farmacológico , Ivermectina/uso terapéutico , Wuchereria bancrofti , Adolescente , Adulto , Animales , Método Doble Ciego , Tolerancia a Medicamentos , Filariasis Linfática/sangre , Femenino , Estudios de Seguimiento , Haití , Humanos , Masculino , Microfilarias/efectos de los fármacos , Microfilarias/crecimiento & desarrollo , Persona de Mediana Edad , Wuchereria bancrofti/efectos de los fármacos , Wuchereria bancrofti/crecimiento & desarrolloRESUMEN
To investigate the usage of antischistosomal drugs in the Nile Delta, an antischistosomal drug history was obtained by interview from a sample of inhabitants of the villages of Halaba (1,024, or every 4th household) and Kharkania (505, or every 20th household), south-central Nile Delta. Only 3% and 0.4% of participants, respectively, in the 2 villages reported receiving antischistosomal drugs during the previous 4 years. Most villagers received oral compounds (praziquantel and niridazole), and the treatment regimen was completed by 95%. This study reveals changes in antischistosomal drug usage since a study 8 years earlier in the village of Halaba, when most of the drugs were injectable compounds.