RESUMO
The prolonged treatment duration for multidrug-resistant tuberculosis (MDR-TB) makes linezolid dosing difficult because of adverse effects associated with long-term use. We sought to find the optimal dosing regimen for linezolid across different MIC values. Pharmacokinetic (PK) data from TB patients were included from Brazil, Georgia, and two U.S. sites. Population PK modeling and simulation were performed. We used an fAUC (area under the unbound drug concentration-time curve)/MIC ratio of >119 as the PK/pharmacodynamic (PD) target and minimum (trough) concentrations of drug (Cmins) of 2 and 7 mg/liter as thresholds for toxicity. The PK/PD breakpoint was defined as the highest MIC at which the probability of target attainment is >90%. A total of 104 patients with pulmonary TB were included, with a median age and weight of 37 years and 60 kg. Eighty-one percent had drug-resistant TB. The PK data were best described by a one-compartment model. The PK/PD breakpoint was 0.125 mg/liter for a total daily dose of 300 mg, while daily doses of 450 to 600 mg and 900 to 1,200 mg had PK/PD breakpoints of 0.25 and 0.50 mg/liter, respectively. The probability of achieving a Cmin of ≤2 mg/liter was higher when the dose was given at once than when dividing it into 2 doses. Linezolid at a daily dose of 300 mg may not be optimal. We predicted an excellent and comparable efficacy of linezolid using total daily doses of 900 and 1,200 mg for MICs of ≤0.5 mg/liter but with the potential for more toxicity than with 600 mg daily. The increase in Cmin was noticeable when the daily dose was divided and may incur greater toxicity.
Assuntos
Tuberculose Resistente a Múltiplos Medicamentos , Tuberculose , Antibacterianos/uso terapêutico , Brasil , Georgia , Humanos , Linezolida , Testes de Sensibilidade Microbiana , Método de Monte Carlo , Tuberculose/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológicoRESUMO
Multidrug-resistant (MDR) tuberculosis (TB) emerged shortly after introduction of rifamycins in the 1960s; isoniazid resistance had already emerged by the mid-1950s. Without these two drugs, tuberculosis is very difficult and costly to treat, with unacceptably high rates of treatment failure, death, loss to follow-up, and no known preventive treatment. Global attention first focused on MDR TB in the early 1990s when nosocomial outbreaks with high case fatality rates were reported in many countries. Prevalence data for MDR TB on a global scale first became available in 1997. In 2016, about 4.1% of estimated ~10.4 million new TB patients plus 19% of ~1 million previously treated patients, that is ~600,000 people develop MDR TB or rifampicin resistant TB; 250,000 die annually. Ten years ago, <5% of them were diagnosed and enrolled on treatment, increasing to about 21.6% in 2016, leaving much room for improvement. Over that same period of time, momentum has been building to combat MDR TB, including advances in diagnostics, therapeutics, and care; decentralizing patient-centered care coupled with social support; growing improvements in prevention of transmission; increasing use of highly effective antiretroviral treatment; communications, advocacy, and social mobilization; leadership and updated policy guidance. Taking into account long-term epidemiological trends, all of these factors coupled with funding from the Global Fund and other major donors, suggest we may be on the verge of accelerating declines in MDR TB morbidity and mortality. Extreme poverty, which allows tuberculosis to flourish, has actually decreased by about one billion people over the past 25 years. What is needed now is political will on the part of national governments to apply these advances diligently and further reductions in poverty, pushing epidemiological trends past the inflection point to the downward slope. All these can be accelerated with increased support for science leading to better diagnosis, treatment and an effective vaccine to sustain and accelerate the meager declines reported thus far.
La tuberculosis multidrogo resistente (TB-MDR) surgió poco después de la introducción de rifampicina en la década de 1960, cuando la resistencia a la isoniazida ya había emergido a mediados de la década de 1950. Sin estos dos medicamentos, la tuberculosis es muy difícil y costosa de tratar, con tasas inaceptablemente altas de fracaso del tratamiento, muertes, pérdidas durante el seguimiento y ningún tratamiento preventivo conocido. La atención global se centró por primera vez en la TB-MDR en la década de 1990 cuando se reportaron brotes hospitalarios con altas tasas de letalidad en muchos países. Los datos de prevalencia para TB-MDR a escala global estaban por primera vez disponibles en 1997. En 2016, 4,1% de aproximadamente 10,4 millones de pacientes nuevos más el 19% de un millón de pacientes tratados previamente, hacían un aproximado de 600 000 personas que desarrollaron TB-MDR o resistencia a la rifampicina; y 250 000 murieron dicho año. Hace diez años, menos del 5% de ellos fueron diagnosticados e iniciaron el tratamiento, aumentando a aproximadamente en 21,6% en 2016, dejando un amplio margen para mejorar. Durante ese mismo período de tiempo, se han fomentado avances para combatir la TB-MDR, incluidos los avances en diagnóstico, terapéutica y atención; descentralizando la atención en el paciente junto con el apoyo social; crecientes mejoras en la prevención de la transmisión; uso cada vez mayor de tratamientos antirretrovirales de alta efectividad; comunicación, abogacía y movilización social; liderazgo y actualización del enfoque de las políticas. Teniendo en cuenta las tendencias epidemiológicas a largo plazo, todos estos factores junto con el financiamiento del Fondo Mundial y otros donantes importantes, sugieren que podemos estar a punto de acelerar la disminución de la morbilidad y mortalidad por TB-MDR. La pobreza extrema, que permite el incremento de la tuberculosis ha disminuido en aproximadamente mil millones de personas en los últimos 25 años. Lo que se necesita ahora es voluntad política por parte de los gobiernos nacionales para aplicar estos avances con diligencia y buscar una mayor reducción de pobreza, empujando las tendencias epidemiológicas más allá del punto de inflexión hacia una pendiente descendente. Todo esto se puede acelerar con un mayor apoyo para la ciencia que conduzca a un mejor diagnóstico, tratamiento y una vacuna efectiva para sostener y acelerar las reducciones reportadas hasta el momento.
Assuntos
Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , HumanosRESUMO
RESUMEN La tuberculosis multidrogo resistente (TB-MDR) surgió poco después de la introducción de rifampicina en la década de 1960, cuando la resistencia a la isoniazida ya había emergido a mediados de la década de 1950. Sin estos dos medicamentos, la tuberculosis es muy difícil y costosa de tratar, con tasas inaceptablemente altas de fracaso del tratamiento, muertes, pérdidas durante el seguimiento y ningún tratamiento preventivo conocido. La atención global se centró por primera vez en la TB-MDR en la década de 1990 cuando se reportaron brotes hospitalarios con altas tasas de letalidad en muchos países. Los datos de prevalencia para TB-MDR a escala global estaban por primera vez disponibles en 1997. En 2016, 4,1% de aproximadamente 10,4 millones de pacientes nuevos más el 19% de un millón de pacientes tratados previamente, hacían un aproximado de 600 000 personas que desarrollaron TB-MDR o resistencia a la rifampicina; y 250 000 murieron dicho año. Hace diez años, menos del 5% de ellos fueron diagnosticados e iniciaron el tratamiento, aumentando a aproximadamente en 21,6% en 2016, dejando un amplio margen para mejorar. Durante ese mismo período de tiempo, se han fomentado avances para combatir la TB-MDR, incluidos los avances en diagnóstico, terapéutica y atención; descentralizando la atención en el paciente junto con el apoyo social; crecientes mejoras en la prevención de la transmisión; uso cada vez mayor de tratamientos antirretrovirales de alta efectividad; comunicación, abogacía y movilización social; liderazgo y actualización del enfoque de las políticas. Teniendo en cuenta las tendencias epidemiológicas a largo plazo, todos estos factores junto con el financiamiento del Fondo Mundial y otros donantes importantes, sugieren que podemos estar a punto de acelerar la disminución de la morbilidad y mortalidad por TB-MDR. La pobreza extrema, que permite el incremento de la tuberculosis ha disminuido en aproximadamente mil millones de personas en los últimos 25 años. Lo que se necesita ahora es voluntad política por parte de los gobiernos nacionales para aplicar estos avances con diligencia y buscar una mayor reducción de pobreza, empujando las tendencias epidemiológicas más allá del punto de inflexión hacia una pendiente descendente. Todo esto se puede acelerar con un mayor apoyo para la ciencia que conduzca a un mejor diagnóstico, tratamiento y una vacuna efectiva para sostener y acelerar las reducciones reportadas hasta el momento.
ABSTRACT Multidrug-resistant (MDR) tuberculosis (TB) emerged shortly after introduction of rifamycins in the 1960s; isoniazid resistance had already emerged by the mid-1950s. Without these two drugs, tuberculosis is very difficult and costly to treat, with unacceptably high rates of treatment failure, death, loss to follow-up, and no known preventive treatment. Global attention first focused on MDR TB in the early 1990s when nosocomial outbreaks with high case fatality rates were reported in many countries. Prevalence data for MDR TB on a global scale first became available in 1997. In 2016, about 4.1% of estimated ~10.4 million new TB patients plus 19% of ~1 million previously treated patients, that is ~600,000 people develop MDR TB or rifampicin resistant TB; 250,000 die annually. Ten years ago, <5% of them were diagnosed and enrolled on treatment, increasing to about 21.6% in 2016, leaving much room for improvement. Over that same period of time, momentum has been building to combat MDR TB, including advances in diagnostics, therapeutics, and care; decentralizing patient-centered care coupled with social support; growing improvements in prevention of transmission; increasing use of highly effective antiretroviral treatment; communications, advocacy, and social mobilization; leadership and updated policy guidance. Taking into account long-term epidemiological trends, all of these factors coupled with funding from the Global Fund and other major donors, suggest we may be on the verge of accelerating declines in MDR TB morbidity and mortality. Extreme poverty, which allows tuberculosis to flourish, has actually decreased by about one billion people over the past 25 years. What is needed now is political will on the part of national governments to apply these advances diligently and further reductions in poverty, pushing epidemiological trends past the inflection point to the downward slope. All these can be accelerated with increased support for science leading to better diagnosis, treatment and an effective vaccine to sustain and accelerate the meager declines reported thus far.
ABSTRACT Multidrug-resistant (MDR) tuberculosis (TB) emerged shortly after introduction of rifamycins in the 1960s; isoniazid resistance had already emerged by the mid-1950s. Without these two drugs, tuberculosis is very difficult and costly to treat, with unacceptably high rates of treatment failure, death, loss to follow-up, and no known preventive treatment. Global attention first focused on MDR TB in the early 1990s when nosocomial outbreaks with high case fatality rates were reported in many countries. Prevalence data for MDR TB on a global scale first became available in 1997. In 2016, about 4.1% of estimated ~10.4 million new TB patients plus 19% of ~1 million previously treated patients, that is ~600,000 people develop MDR TB or rifampicin resistant TB; 250,000 die annually. Ten years ago, <5% of them were diagnosed and enrolled on treatment, increasing to about 21.6% in 2016, leaving much room for improvement. Over that same period of time, momentum has been building to combat MDR TB, including advances in diagnostics, therapeutics, and care; decentralizing patient-centered care coupled with social support; growing improvements in prevention of transmission; increasing use of highly effective antiretroviral treatment; communications, advocacy, and social mobilization; leadership and updated policy guidance. Taking into account long-term epidemiological trends, all of these factors coupled with funding from the Global Fund and other major donors, suggest we may be on the verge of accelerating declines in MDR TB morbidity and mortality. Extreme poverty, which allows tuberculosis to flourish, has actually decreased by about one billion people over the past 25 years. What is needed now is political will on the part of national governments to apply these advances diligently and further reductions in poverty, pushing epidemiological trends past the inflection point to the downward slope. All these can be accelerated with increased support for science leading to better diagnosis, treatment and an effective vaccine to sustain and accelerate the meager declines reported thus far.
Assuntos
Humanos , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológicoRESUMO
BACKGROUND: Human immunodeficiency virus (HIV)-associated tuberculosis deaths have decreased worldwide over the past decade. We sought to evaluate the effect of HIV status on tuberculosis mortality among patients undergoing treatment for tuberculosis in Lima, Peru, a low HIV prevalence setting. METHODS: We conducted a prospective cohort study of patients treated for tuberculosis between 2005 and 2008 in two adjacent health regions in Lima, Peru (Lima Ciudad and Lima Este). We constructed a multivariate Cox proportional hazards model to evaluate the effect of HIV status on mortality during tuberculosis treatment. RESULTS: Of 1701 participants treated for tuberculosis, 136 (8.0%) died during tuberculosis treatment. HIV-positive patients constituted 11.0% of the cohort and contributed to 34.6% of all deaths. HIV-positive patients were significantly more likely to die (25.1 vs. 5.9%, P < 0.001) and less likely to be cured (28.3 vs. 39.4%, P = 0.003). On multivariate analysis, positive HIV status (hazard ratio [HR] = 6.06; 95% confidence interval [CI], 3.96-9.27), unemployment (HR = 2.24; 95% CI, 1.55-3.25), and sputum acid-fast bacilli smear positivity (HR = 1.91; 95% CI, 1.10-3.31) were significantly associated with a higher hazard of death. CONCLUSIONS: We demonstrate that positive HIV status was a strong predictor of mortality among patients treated for tuberculosis in the early years after Peru started providing free antiretroviral therapy. As HIV diagnosis and antiretroviral therapy provision are more widely implemented for tuberculosis patients in Peru, future operational research should document the changing profile of HIV-associated tuberculosis mortality.
Assuntos
Infecções por HIV/complicações , Tuberculose/mortalidade , Adulto , Feminino , Infecções por HIV/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Peru/epidemiologia , Prevalência , Modelos de Riscos Proporcionais , Estudos Prospectivos , Tuberculose/epidemiologia , Tuberculose/etiologia , Adulto JovemRESUMO
OBJETIVOS: Evaluamos una estrategia para la prevención de la tuberculosis en las comunidades más afectadas por esta enfermedad. MÉTODOS: En 1996, trazamos un mapa de los casos de tuberculosis notificados (1985-1995) y de las personas con reacción positiva a la prueba de la tuberculina (1993-1995) en el condado de Smith, Texas, Estados Unidos de América. Definimos los dos conglomerados de mayor tamaño y densidad, identificando los dos vecindarios con mayor incidencia (180 manzanas y 3 153 residentes). Tras una preparación intensiva de la comunidad, personal sanitario capacitado ofreció a todos los residentes, de vivienda en vivienda, la posibilidad de hacerse la prueba de la tuberculina, a menos que estuviera contraindicado. A las personas con resultados positivos en esta prueba se las acompañó a un consultorio móvil para realizarles ahí radiografías, una evaluación clínica y, según fuera pertinente, proceder con el tratamiento preventivo con isoniazida. Para evaluar las repercusiones a largo plazo, trazamos un mapa de todos los casos de tuberculosis que se registraron en el condado de Smith durante el período equivalente después del proyecto. RESULTADOS: De las 2 258 personas que cumplían los requisitos para participar, 1 291 (57,1%) se sometieron a la prueba de la tuberculina, 229 (17,7%) presentaron resultados positivos en dicha prueba y 147 fueron tratadas. De 1996 al 2006, no se registró ningún caso de tuberculosis en ninguno de los vecindarios del proyecto, a diferencia de lo ocurrido en el decenio anterior a la intervención y en el resto del condado de Smith, donde aparecieron continuamente casos de tuberculosis. CONCLUSIONES: Dirigirse a los vecindarios con una incidencia alta para realizar el tamizaje activo en la comunidad y aplicar tratamiento preventivo con isoniazida puede acelerar la eliminación de la tuberculosis en los Estados Unidos.
OBJECTIVES: We evaluated a strategy for preventing tuberculosis (TB) in communities most affected by it. METHODS: In 1996, we mapped reported TB cases (1985-1995) and positive tuberculin skin test (TST) reactors (1993-1995) in Smith County, Texas. We delineated the 2 largest, densest clusters, identifying 2 highest-incidence neighborhoods (180 square blocks, 3153 residents). After extensive community preparation, trained health care workers went door-to-door offering TST to all residents unless contraindicated. TST-positive individuals were escorted to a mobile clinic for radiography, clinical evaluation, and isoniazid preventive treatment (IPT) as indicated. To assess long-term impact, we mapped all TB cases in Smith County during the equivalent time period after the project. RESULTS: Of 2258 eligible individuals, 1291 (57.1%) were tested, 229 (17.7%) were TST positive, and 147 were treated. From 1996 to 2006, there were no TB cases in either project neighborhood, in contrast with the preintervention decade and the continued occurrence of TB in the rest of Smith County. CONCLUSIONS: Targeting high-incidence neighborhoods for active, community-based screening and IPT may hasten TB elimination in the United States.
Assuntos
Tuberculose/diagnóstico , Tuberculose/prevenção & controle , Tuberculose/transmissãoRESUMO
The Objective of this analysis was to identify predictors of death, failure, and default among MDR-TB patients treated with second-line drugs in DOTS-plus projects in Estonia, Latvia, Philippines, Russia, and Peru, 2000-2004. Risk ratios (RR) with 95% confidence intervals (CI) were calculated using multivariable regression. Of 1768 patients, treatment outcomes were: cure/completed - 1156 (65%), died - 200 (11%), default - 241 (14%), failure - 118 (7%). Independent predictors of death included: age>45 years (RR = 1.90 (95%CI 1.29-2.80), HIV infection (RR = 4.22 (2.65-6.72)), extrapulmonary disease (RR = 1.54 (1.04-2.26)), BMI<18.5 (RR = 2.71 (1.91-3.85)), previous use of fluoroquinolones (RR = 1.91 (1.31-2.78)), resistance to any thioamide (RR = 1.59 (1.14-2.22)), baseline positive smear (RR = 2.22 (1.60-3.10)), no culture conversion by 3rd month of treatment (RR = 1.69 (1.19-2.41)); failure: cavitary disease (RR = 1.73 (1.07-2.80)), resistance to any fluoroquinolone (RR = 2.73 (1.71-4.37)) and any thioamide (RR = 1.62 (1.12-2.34)), and no culture conversion by 3rd month (RR = 5.84 (3.02-11.27)); default: unemployment (RR = 1.50 (1.12-2.01)), homelessness (RR = 1.52 (1.00-2.31)), imprisonment (RR = 1.86 (1.42-2.45)), alcohol abuse (RR = 1.60 (1.18-2.16)), and baseline positive smear (RR = 1.35 (1.07-1.71)). Patients with biomedical risk factors for treatment failure or death should receive heightened medical attention. To prevent treatment default, management of patients who are unemployed, homeless, alcoholic, or have a prison history requires extra measures to insure treatment completion.
Assuntos
Antituberculosos/administração & dosagem , Terapia Diretamente Observada , Soropositividade para HIV/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Adulto , Fatores Etários , Índice de Massa Corporal , Estônia/epidemiologia , Feminino , Soropositividade para HIV/tratamento farmacológico , Soropositividade para HIV/mortalidade , Humanos , Letônia/epidemiologia , Masculino , Razão de Chances , Avaliação de Resultados em Cuidados de Saúde , Peru/epidemiologia , Filipinas/epidemiologia , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Risco , Federação Russa/epidemiologia , Fatores Socioeconômicos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/mortalidadeRESUMO
The Peruvian National Tuberculosis Control Program issued guidelines in 2006 specifying criteria for culture and drug-susceptibility testing (DST), including district-level rapid DST. All patients referred for culture and DST in 2 districts of Lima, Peru, during January 2005-November 2008 were monitored prospectively. Of 1,846 patients, 1,241 (67.2%) had complete DST results for isoniazid and rifampin; 419 (33.8%) patients had multidrug-resistant (MDR) TB at the time of referral. Among patients with new smear-positive TB, household contact and suspected category I failure were associated with MDR TB, compared with concurrent regional surveillance data. Among previously treated patients with smear-positive TB, adult household contact, suspected category II failure, early relapse after category I, and multiple previous TB treatments were associated with MDR TB, compared with concurrent regional surveillance data. The proportion of MDR TB detected by using guidelines was higher than that detected by a concurrent national drug-resistance survey, indicating that the strategy effectively identified patients for DST.
Assuntos
Antituberculosos/farmacologia , Farmacorresistência Bacteriana Múltipla , Programas de Rastreamento/métodos , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Humanos , Isoniazida/farmacologia , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/isolamento & purificação , Peru/epidemiologia , Vigilância da População/métodos , Guias de Prática Clínica como Assunto , Prevalência , Rifampina/farmacologia , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/microbiologiaRESUMO
BACKGROUND: Multi-drug resistant tuberculosis patients in resource-poor settings experience large delays in starting appropriate treatment and may not be monitored appropriately due to an overburdened laboratory system, delays in communication of results, and missing or error-prone laboratory data. The objective of this paper is to describe an electronic laboratory information system implemented to alleviate these problems and its expanding use by the Peruvian public sector, as well as examine the broader issues of implementing such systems in resource-poor settings. METHODS: A web-based laboratory information system "e-Chasqui" has been designed and implemented in Peru to improve the timeliness and quality of laboratory data. It was deployed in the national TB laboratory, two regional laboratories and twelve pilot health centres. Using needs assessment and workflow analysis tools, e-Chasqui was designed to provide for improved patient care, increased quality control, and more efficient laboratory monitoring and reporting. RESULTS: Since its full implementation in March 2006, 29,944 smear microscopy, 31,797 culture and 7,675 drug susceptibility test results have been entered. Over 99% of these results have been viewed online by the health centres. High user satisfaction and heavy use have led to the expansion of e-Chasqui to additional institutions. In total, e-Chasqui will serve a network of institutions providing medical care for over 3.1 million people. The cost to maintain this system is approximately US$0.53 per sample or 1% of the National Peruvian TB program's 2006 budget. CONCLUSION: Electronic laboratory information systems have a large potential to improve patient care and public health monitoring in resource-poor settings. Some of the challenges faced in these settings, such as lack of trained personnel, limited transportation, and large coverage areas, are obstacles that a well-designed system can overcome. e-Chasqui has the potential to provide a national TB laboratory network in Peru. Furthermore, the core functionality of e-Chasqui as been implemented in the open source medical record system OpenMRS http://www.openmrs.org for other countries to use.
Assuntos
Sistemas de Informação em Laboratório Clínico/organização & administração , Laboratórios/organização & administração , Desenvolvimento de Programas , Administração em Saúde Pública/normas , Garantia da Qualidade dos Cuidados de Saúde/métodos , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Sistemas de Informação em Laboratório Clínico/estatística & dados numéricos , Implementação de Plano de Saúde , Humanos , Laboratórios/normas , Área Carente de Assistência Médica , Avaliação das Necessidades , Peru , Fatores de Tempo , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológicoRESUMO
Evidence of successful management of multidrug-resistant tuberculosis (MDRTB) is mainly generated from referral hospitals in high-income countries. We evaluate the management of MDRTB in 5 resource-limited countries: Estonia, Latvia, Peru, the Philippines, and the Russian Federation. All projects were approved by the Green Light Committee for access to quality-assured second-line drugs provided at reduced price for MDRTB management. Of 1047 MDRTB patients evaluated, 119 (11%) were new, and 928 (89%) had received treatment previously. More than 50% of previously treated patients had received both first- and second-line drugs, and 65% of all patients had infections that were resistant to both first- and second-line drugs. Treatment was successful in 70% of all patients, but success rate was higher among new (77%) than among previously treated patients (69%). In resource-limited settings, treatment of MDRTB provided through, or in collaboration with, national TB programs can yield results similar to those from wealthier settings.