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Introduction: tuberculosis remains a major public health problem, with continuing high levels of prevalence, and mortality. In Niger, the incidence of tuberculosis remains high. This study aims to investigate the epidemiology of pulmonary tuberculosis at the National Anti-Tuberculosis Center of Niamey in Niger. Methods: this study used a quantitative approach with a retrospective and descriptive design. Data were obtained from positive pulmonary tuberculosis cases detected by microscopy on Ziehl-Neelsen stained sputum at the National Anti-Tuberculosis Center (NATC) in Niamey, Niger covered the period between June 2017 and January 2020. 955 pulmonary TB patients were recorded whose diagnosis was based either on clinical-radiological arguments (thus negative microscopy) or positive microscopy. This form was used to collect data recorded in the clinical case registers, registers, and Excel files of the GeneXpert platform of the NATC laboratory. Results: eighty-nine-point eleven percent (89.11%) of the patients were microscopy-positive. Among the study population, men were the most affected by tuberculosis with 80.03%. The 25-34 age group, representing 23.77%, was the most affected. 6.93% of patients were co-infected with tuberculosis and HIV. All patients were put on treatment, with a therapeutic success rate of 72.38% and a therapeutic failure rate of 10.95%. Among the cases of therapeutic failure, 80.90% had Mycobacterium tuberculosis complex detected and 27.14% were resistant to Rifampicin. Conclusion: Niger continues to have a tuberculosis epidemic which requires monitoring. Improving the diagnostic system for more effective management of the disease is important for appropriate diagnosis and treatment.
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Antituberculosos , Mycobacterium tuberculosis , Tuberculosis Pulmonar , Humanos , Estudios Retrospectivos , Masculino , Niger/epidemiología , Femenino , Adulto , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis Pulmonar/epidemiología , Tuberculosis Pulmonar/diagnóstico , Antituberculosos/farmacología , Antituberculosos/administración & dosificación , Adulto Joven , Persona de Mediana Edad , Mycobacterium tuberculosis/aislamiento & purificación , Mycobacterium tuberculosis/efectos de los fármacos , Adolescente , Resultado del Tratamiento , Niño , Infecciones por VIH/epidemiología , Infecciones por VIH/tratamiento farmacológico , Preescolar , Anciano , Tuberculosis Resistente a Múltiples Medicamentos/epidemiología , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/diagnóstico , Esputo/microbiología , Prevalencia , Coinfección/epidemiología , Coinfección/tratamiento farmacológico , Lactante , IncidenciaRESUMEN
BACKGROUND: Rifampicin resistant tuberculosis remains a global health problem with almost half a million new cases annually. In high-income countries patients empirically start a standardized treatment regimen, followed by an individualized regimen guided by drug susceptibility test (DST) results. In most settings, DST information is not available or is limited to isoniazid and fluoroquinolones. Whole genome sequencing could more accurately guide individualized treatment as the full drug resistance profile is obtained with a single test. Whole genome sequencing has not reached its full potential for patient care, in part due to the complexity of translating a resistance profile into the most effective individualized regimen. METHODS: We developed a treatment recommender clinical decision support system (CDSS) and an accompanying web application for user-friendly recommendation of the optimal individualized treatment regimen to a clinician. RESULTS: Following expert stakeholder meetings and literature review, nine drug features and 14 treatment regimen features were identified and quantified. Using machine learning, a model was developed to predict the optimal treatment regimen based on a training set of 3895 treatment regimen-expert feedback pairs. The acceptability of the treatment recommender CDSS was assessed as part of a clinical trial and in a routine care setting. Within the clinical trial setting, all patients received the CDSS recommended treatment. In 8 of 20 cases, the initial recommendation was recomputed because of stock out, clinical contra-indication or toxicity. In routine care setting, physicians rejected the treatment recommendation in 7 out of 15 cases because it deviated from the national TB treatment guidelines. A survey indicated that the treatment recommender CDSS is easy to use and useful in clinical practice but requires digital infrastructure support and training. CONCLUSIONS: Our findings suggest that global implementation of the novel treatment recommender CDSS holds the potential to improve treatment outcomes of patients with RR-TB, especially those with 'difficult-to-treat' forms of RR-TB.
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Antituberculosos , Sistemas de Apoyo a Decisiones Clínicas , Aprendizaje Automático , Rifampin , Tuberculosis Resistente a Múltiples Medicamentos , Humanos , Rifampin/uso terapéutico , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Antituberculosos/uso terapéutico , Antituberculosos/administración & dosificación , Mycobacterium tuberculosis/efectos de los fármacos , Medicina de Precisión/métodos , Pruebas de Sensibilidad Microbiana , Masculino , Femenino , AdultoRESUMEN
Introduction. Proper management of multidrug-resistant tuberculosis is a prioritized strategy for tuberculosis control worldwide. Objective. To evaluate differences concerning demographic and clinical characteristics and programmatic indicators of Buenaventura patient cohort with confirmed diagnosis of multidrug-resistant tuberculosis, compared to those of the other municipalities from Valle del Cauca, Colombia, 2013-2016. Materials and methods. We conducted an analytical cohort study to compare records of patients older than 15 years with multidrug-resistant tuberculosis included in the Programa de Tuberculosis de Buenaventura (with para-aminosalicylic acid) versus the other municipalities of Valle del Cauca (without para-aminosalicylic). Results. Ninety-nine cases were recorded with a median age of 40 years (IQR = 26 - 53); in Buenaventura, 56% of the patients were women, while in the other municipalities, men predominated with 67%; 95% had health insurance. The most common comorbidity was diabetes (14%). Adverse reactions to antituberculosis medications in Buenaventura were 1.3 times more frequent than in the other municipalities (OR = 2.3; 95% CI = 0.993 - 5.568; p = 0.04). In Buenaventura, the mortality rate was 5% compared to the 15% reported in the other municipalities. Treatment failures were not reported in Buenaventura, but 35% did not continue with the follow-up. Treatment success was higher in Buenaventura (56 %). Conclusion. A strengthened program in Buenaventura presented better programmatic results than those from the other municipalities of Valle del Cauca. Access to molecular tests, availability of shortened treatments, and continuous monitoring to identify adverse reactions to antituberculosis medications are routes for all other control programs.
Introducción. El manejo adecuado de la tuberculosis multirresistente es una estrategia priorizada para el control de la tuberculosis en el mundo. Objetivo. Evaluar las diferencias entre las características demográficas y clínicas, y los indicadores programáticos de los pacientes con diagnóstico confirmado de tuberculosis pulmonar resistente a rifampicina o multirresistente en Buenaventura, frente a la cohorte de los demás municipios del Valle del Cauca entre 2013 y 2016. Materiales y métodos. Se desarrolló un estudio analítico de cohortes para comparar los registros de pacientes mayores de 15 años con tuberculosis multirresistente, del Programa de Tuberculosis de Buenaventura (con ácido paraaminosalicílico), frente a los demás municipios del Valle del Cauca (sin ácido paraaminosalicílico). Resultados. Se registraron 99 casos con una mediana de edad de 40 años (RIC = 26- 53); en Buenaventura, el 56 % eran mujeres; en los demás municipios, predominaron los hombres (67 %); el 95 % de los evaluados tenía aseguramiento en salud. La comorbilidad más frecuente fue diabetes (14 %). Las reacciones adversas a medicamentos antituberculosos en Buenaventura fueron 1,3 veces más frecuentes que en los demás municipios (OR = 2,3; IC95 %: 0,993 - 5,568; p = 0,04). En Buenaventura falleció el 5 % de los casos frente al 15 % reportado en los demás municipios. No hubo fracasos con el tratamiento en Buenaventura, pero se reportó un 35 % de pérdida del seguimiento. El éxito del tratamiento fue mayor en Buenaventura en el 56 %. Conclusión. El programa fortalecido de Buenaventura presentó mejores resultados programáticos que los demás municipios del Valle del Cauca. El acceso a pruebas moleculares, la disponibilidad de tratamientos acortados y el seguimiento continuo para identificar reacciones adversas a medicamentos antituberculosos son un derrotero para todos los programas de control.
Asunto(s)
Rifampin , Tuberculosis Resistente a Múltiples Medicamentos , Humanos , Colombia/epidemiología , Adulto , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/epidemiología , Rifampin/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Antituberculosos/uso terapéutico , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis Pulmonar/epidemiología , Estudios de Cohortes , Ácido Aminosalicílico/uso terapéutico , Adulto Joven , Antibióticos Antituberculosos/uso terapéuticoRESUMEN
Most phase III trials in drug-resistant tuberculosis have either been underpowered to quantify differences in microbiological endpoints or have taken up to a decade to complete. Composite primary endpoints, dominated by differences in treatment discontinuation and regimen changes, may mask important differences in treatment failure and relapse. Although new regimens for drug-resistant tuberculosis appear very effective, resistance to new drugs is emerging rapidly. There is a need for shorter, safer and more tolerable regimens, including those active against bedaquiline-resistant tuberculosis. Transitioning from multiple regimen A versus regimen B trials to a single large phase III platform trial would accelerate the acquisition of robust estimates of relative efficacy and safety. Further efficiencies could be achieved by adopting modern adaptive platform designs. Collaboration among trialists, affected community representatives, funders and regulators is essential for developing such a phase III platform trial for drug-resistant tuberculosis treatment regimens.
La majorité des essais de phase III relatifs à la tuberculose pharmacorésistante soit n'étaient pas assez puissants pour quantifier les fluctuations au niveau des critères microbiologiques, soit étaient trop longs, se poursuivant parfois pendant dix ans. Les critères primaires composites, dominés par des différences dans l'interruption du traitement et les changements de schéma, pourraient dissimuler d'importantes variations en termes d'échec thérapeutique et de rechute. Bien que les nouveaux traitements contre la tuberculose pharmacorésistante semblent très efficaces, la résistance aux nouveaux médicaments évolue rapidement. Il est donc nécessaire d'opter pour des traitements plus courts, plus sûrs et mieux tolérés, y compris ceux actifs contre la tuberculose résistant à la bédaquiline. Délaisser la multitude d'essais opposant un schéma de traitement A à un schéma de traitement B pour se diriger vers un unique essai plateforme de phase III de grande envergure permettrait d'obtenir plus vite des estimations solides concernant l'innocuité et l'efficacité relative. En outre, adopter des modèles de plateforme modernes et adaptatifs contribuerait à de meilleures performances. Enfin, la collaboration entre investigateurs, représentants des communautés concernées, bailleurs de fonds et organismes de réglementation est essentielle à l'élaboration de ce type d'essai plateforme de phase III sur les traitements contre la tuberculose pharmacorésistante.
La mayoría de los ensayos en fase III sobre tuberculosis resistente a los fármacos no ha tenido la potencia suficiente para cuantificar diferencias en los criterios de valoración microbiológicos o ha tardado hasta una década en completarse. Los criterios de valoración principales compuestos, dominados por las diferencias en la interrupción del tratamiento y los cambios de régimen, pueden ocultar diferencias importantes en el fracaso del tratamiento y la recaída. Aunque los nuevos regímenes de tratamiento para la tuberculosis resistente a los fármacos parecen muy eficaces, la resistencia a los nuevos fármacos está apareciendo rápidamente. Se necesitan regímenes de tratamiento más cortos, seguros y tolerables, incluidos los activos contra la tuberculosis resistente a la bedaquilina. La transición de múltiples ensayos de régimen A frente a régimen B a un único gran ensayo de plataforma en fase III aceleraría la obtención de estimaciones sólidas de la eficacia y seguridad relativas. Podrían lograrse mayores eficiencias si se adoptaran diseños de plataforma adaptativos modernos. La colaboración entre los autores de los ensayos, los representantes de las comunidades afectadas, los financiadores y los reguladores es esencial para desarrollar un ensayo de plataforma en fase III de este tipo para los regímenes de tratamiento de la tuberculosis resistente a los fármacos.
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Antituberculosos , Ensayos Clínicos Fase III como Asunto , Tuberculosis Resistente a Múltiples Medicamentos , Humanos , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Antituberculosos/uso terapéutico , Diarilquinolinas/uso terapéuticoRESUMEN
Objective: Osteoarticular tuberculosis (OATB) is one of the most common forms of extrapulmonary tuberculosis; however, limited epidemiological data are available on this public health concern worldwide, especially in developing countries. This study aimed to analyze the clinical epidemiology and drug resistance characteristics of OATB cases in Hunan province which located in South-central China. Methods: We retrospectively enrolled OATB patients with Mycobacterium tuberculosis culture positive at Hunan Chest Hospital from January 2013 through March 31, 2022. The multiple demographic, clinical variables and drug susceptibility data of the patients were collected from the hospital's electronic patient records. Descriptive statistical methods, Chi-square test and logistic regression analysis were employed as statistical methods. Results: Of the 269 OATB cases, 197 (73.23%) were males, 206 (76.85%) were farmers; patients' ages ranged from 5 to 85 years, 57 (21.19%) aged at 20-29 years old and 52 (19.33%) aged at 60-69 years old. In terms of the disease, 177 (65.80%) had spinal TB with most occurrence in lumbar vertebrae (26.02%, 70/269), multiple spinal sites (18.96%, 51/269) and thoracic vertebrae (15.24%, 41/269). Outside of the spine, OATB mainly occurred in the lower limb (13.38%, 36/269). In terms of drug resistance, 40 (14.87%) and 72 (26.77%) were resistant to rifampicin (RFP) and isoniazid (INH) respectively; 38 (14.13%) were multi-drug resistant (MDR), and a total of 78 (29.00%) isolates were drug resistant. OATB patients aged 40-49 years old (compared to those aged ≥70 years) and from the west of Hunan province, China (compared to those from the center of Hunan) were at risk for developing RR/MDR (ORs were 5.057 and 4.942, respectively; 95% CIs were 1.009-25.342 and 1.458-16.750, respectively). Conclusion: In South-central China, OATB mainly affected males, farmers and those aged 20-29 and 60-69 years old. Spinal TB is prone to occur in the lumbar and multiple spinal sites. The resistance situation of OATB was serious, and people aged 40-49 years old and patients from the west of Hunan were risk factors of RR/MDR. All these findings will help to improve the prevention, diagnosis and treatment strategies of OATB.
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Antituberculosos , Mycobacterium tuberculosis , Tuberculosis Osteoarticular , Humanos , Masculino , Adulto , Persona de Mediana Edad , China/epidemiología , Femenino , Anciano , Adolescente , Niño , Estudios Retrospectivos , Tuberculosis Osteoarticular/epidemiología , Tuberculosis Osteoarticular/tratamiento farmacológico , Tuberculosis Osteoarticular/microbiología , Anciano de 80 o más Años , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/aislamiento & purificación , Preescolar , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Adulto Joven , Tuberculosis Resistente a Múltiples Medicamentos/epidemiología , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/microbiología , Farmacorresistencia BacterianaRESUMEN
A previously healthy man developed pulmonary symptoms 2 weeks after starting treatment with a tumour necrosis factor (TNF) inhibitor. A negative interferon-gamma release assay (IGRA) test was obtained prior to TNF inhibitor exposure, without consideration of the fact that the patient was already immunosuppressed and had a previous positive IGRA test 17 months earlier. The patient was treated for pneumonia twice but did not achieve remission. His physical health progressively deteriorated over the following months. Malignancy was suspected but not found. Eight months after the onset of symptoms, Mycobacterium tuberculosis was found in samples from mediastinal lymph nodes, and the patient was diagnosed with multidrug-resistant tuberculosis (MDR-TB).This case illustrates the diagnostic challenge of TB, the need to raise awareness of the increased risk of TB in patients treated with TNF inhibitors and the need to increase knowledge regarding the effect of immunosuppressive agents on IGRA tests.
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Tuberculosis Resistente a Múltiples Medicamentos , Humanos , Masculino , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Mycobacterium tuberculosis/aislamiento & purificación , Ensayos de Liberación de Interferón gamma , Inhibidores del Factor de Necrosis Tumoral/efectos adversos , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Diagnóstico Erróneo , Antituberculosos/uso terapéutico , Persona de Mediana Edad , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Huésped InmunocomprometidoRESUMEN
BACKGROUND: Drug-resistant tuberculosis (DR-TB) poses a significant threat to global TB control and remains a major public health issue. This study aims to evaluate treatment outcomes and identify risk factors for unfavorable outcomes in patients with multi-DR-TB (MDR-TB) treated at a major reference hospital in Istanbul. METHODS: We conducted a retrospective analysis of 413 patients with rifampicin-resistant and MDR-TB who received treatment between January 1, 2013, and December 31, 2023, at the University of Health Sciences Süreyyapasa Chest Diseases Training and Research Hospital. Patients were treated following the World Health Organization and national guidelines, with regimens tailored to individual drug resistance profiles and side effect management. Demographic data, comorbidities, microbiological follow-up, drug resistance patterns, treatment regimens, and radiological findings were analyzed. RESULTS: Treatment success was achieved in 350 patients (84.74%). Thirty-two patients (7.74%) were lost to follow-up, and 32 patients (7.74%) died. Logistic regression analysis identified several factors associated with unfavorable treatment outcomes: comorbidities (odds ratio [OR]: 7.555, P = 0.001), quinolone resistance (OR: 3.695, P = 0.030), and bronchiectasis (OR: 4.126, P = 0.013). Additional significant factors included male gender (P = 0.007), foreign-born status (P = 0.013), age over 35 years (P = 0.002), previous treatment history (P = 0.058), and drug side effects (P = 0.012). CONCLUSION: The long-term regimen for MDR-TB was found to be highly successful, with an 84.74% treatment success rate. Effective treatment regimens, close patient follow-up, early recognition of side effects, and comprehensive management are crucial for achieving successful outcomes. Identifying and addressing risk factors such as comorbidities, drug resistance, and specific patient demographics can further improve treatment success rates. This study underscores the importance of tailored treatment strategies and robust patient management in combating MDR-TB.
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Antituberculosos , Rifampin , Tuberculosis Resistente a Múltiples Medicamentos , Humanos , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Masculino , Femenino , Rifampin/uso terapéutico , Estudios Retrospectivos , Adulto , Persona de Mediana Edad , Resultado del Tratamiento , Factores de Riesgo , Antituberculosos/uso terapéutico , Antituberculosos/efectos adversos , Mycobacterium tuberculosis/efectos de los fármacos , Adulto Joven , Anciano , Turquía , Farmacorresistencia Bacteriana Múltiple , AdolescenteRESUMEN
Antibiotic tolerance in Mycobacterium tuberculosis reduces bacterial killing, worsens treatment outcomes, and contributes to resistance. We studied rifampicin tolerance in isolates with or without isoniazid resistance (IR). Using a minimum duration of killing assay, we measured rifampicin survival in isoniazid-susceptible (IS, n=119) and resistant (IR, n=84) isolates, correlating tolerance with bacterial growth, rifampicin minimum inhibitory concentrations (MICs), and isoniazid-resistant mutations. Longitudinal IR isolates were analyzed for changes in rifampicin tolerance and genetic variant emergence. The median time for rifampicin to reduce the bacterial population by 90% (MDK90) increased from 1.23 days (IS) and 1.31 days (IR) to 2.55 days (IS) and 1.98 days (IR) over 15-60 days of incubation, indicating fast and slow-growing tolerant sub-populations. A 6 log10-fold survival fraction classified tolerance as low, medium, or high, showing that IR is linked to increased tolerance and faster growth (OR = 2.68 for low vs. medium, OR = 4.42 for low vs. high, p-trend = 0.0003). High tolerance in IR isolates was associated with rifampicin treatment in patients and genetic microvariants. These findings suggest that IR tuberculosis should be assessed for high rifampicin tolerance to optimize treatment and prevent the development of multi-drug-resistant tuberculosis.
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Antituberculosos , Farmacorresistencia Bacteriana , Isoniazida , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis , Rifampin , Rifampin/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/genética , Isoniazida/farmacología , Estudios Longitudinales , Humanos , Antituberculosos/farmacología , Farmacorresistencia Bacteriana/genética , Tuberculosis Resistente a Múltiples Medicamentos/microbiología , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis/microbiología , Tuberculosis/tratamiento farmacológicoRESUMEN
BACKGROUND: Respiratory microbiota is closely related to tuberculosis (TB) initiation and progression. However, the dynamic changes of respiratory microbiota during treatment and its association with TB progression remains unclear. METHODS: A total of 16 healthy individuals and 16 TB patients (10 drug-sensitive TB (DS-TB) and 6 drug-resistant TB (DR-TB)) were recruited. Sputum samples were collected at baseline for all anticipants and after anti-TB treatment at Month-6 for TB patients. High throughput 16 S RNA sequencing was used to characterize the respiratory microbiota composition. RESULTS: Compared to the healthy individuals, TB patients exhibited lower respiratory microbiota diversity (p < 0.05). This disruption was alleviated after anti-TB treatment, especially for DS-TB patients. Parvimonas spp. numbers significantly increased after six months of anti-TB treatment in both DS-TB and DR-TB patients (p < 0.05). Rothia spp. increase during treatment was associated with longer sputum-culture conversion time and worse pulmonary lesion absorption (p < 0.05). Besides, Moraxella spp. prevalence was associated with longer sputum-culture conversion time, while Gemella spp. increase was associated with worsening resolving of pulmonary lesions (p < 0.05). CONCLUSION: Dynamic changes of respiratory microbiota during anti-TB treatment is closely related to TB progression. The involvement of critical microorganisms, such as Parvimonas spp., Rothia spp., Moraxella, and Gemella spp., appears to be associated with pulmonary inflammatory conditions, particularly among DR-TB. These microorganisms could potentially serve as biomarkers or even as targets for therapeutic intervention to enhance the prognosis of tuberculosis patients.
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Antituberculosos , Microbiota , Esputo , Tuberculosis Resistente a Múltiples Medicamentos , Tuberculosis Pulmonar , Humanos , Esputo/microbiología , Masculino , Femenino , Antituberculosos/uso terapéutico , Microbiota/efectos de los fármacos , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis Pulmonar/microbiología , Adulto , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/microbiología , Persona de Mediana Edad , Resultado del Tratamiento , Bacterias/efectos de los fármacos , Bacterias/genética , Bacterias/clasificación , Bacterias/aislamiento & purificación , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/genética , ARN Ribosómico 16S/genéticaRESUMEN
BACKGROUND: Control of rifampicin-resistant tuberculosis (RR-MTB) requires novel technologies for restoring the anti-TB efficacy of priority drugs. We sought to evaluate the ability of nanotechnology application in the recovery of the anti-tuberculosis efficacy of rifampicin. METHODS: Nanocomposite- standard dose of rifampicin and 20 nm silver nanoparticles (AgNPs) suspension solution of 6 different concentrations: 0.25%; 0.5%; 1%; 2.5%; 5%; and 10%, were supplemented to 70 rifampicin-resistant mycobacterium tuberculosis (RR-MTB) isolates. The control arm consisted of 35 RR-MTB isolates and AgNPs suspension with identical concentrations. The inhibitory effect of nanocomposites was evaluated by MTB growth rate using the BACTECTM MGIT 960TM. The safety assessment of single-use AgNPs was conducted in experimental animals. RESULTS: The suppression process of AgNPs on RR-MTB isolates started with 2,5% nanocomposite solution application and full suppression was achieved in 5% and 10% nanocomposite solutions. A standard dose of rifampicin and a 2.5% solution of AgNPs increased the minimal inhibitory effect on RR-MTB by 10% (total 80%) vs the isolated use of a 2.5% solution of AgNPs (70%). An experiment on animals revealed the complete safety of a single injection of ultra-high doses of AgNPs. CONCLUSION: The study showed the potentiating effect of AgNPs in overcoming the resistance of MTB to rifampicin providing a scientific basis for further research.
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Nanopartículas del Metal , Mycobacterium tuberculosis , Nanocompuestos , Rifampin , Plata , Rifampin/farmacología , Plata/química , Plata/farmacología , Nanocompuestos/química , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/crecimiento & desarrollo , Nanopartículas del Metal/química , Nanopartículas del Metal/uso terapéutico , Animales , Humanos , Pruebas de Sensibilidad Microbiana , Farmacorresistencia Bacteriana/efectos de los fármacos , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/microbiología , Antituberculosos/farmacología , Antibióticos Antituberculosos/farmacologíaRESUMEN
Tuberculosis (T.B.) remains a prominent global cause of health challenges and death, exacerbated by drug-resistant strains such as multidrug-resistant tuberculosis MDR-TB and extensively drug-resistant tuberculosis XDR-TB. For an effective disease management strategy, it is crucial to understand the dynamics of T.B. infection and the impacts of treatment. In the present article, we employ AI-based machine learning techniques to investigate the immunity impact of medications. SEIPR epidemiological model is incorporated with MDR-TB for compartments susceptible to disease, exposed to risk, infected ones, preventive or resistant to initial treatment, and recovered or healed population. These masses' natural trends, effects, and interactions are formulated and described in the present study. Computations and stability analysis are conducted upon endemic and disease-free equilibria in the present model for their global scenario. Both numerical and AI-based nonlinear autoregressive exogenous NARX analyses are presented with incorporating immediate treatment and delay in treatment. This study shows that the active patients and MDR-TB, both strains, exist because of the absence of permanent immunity to T.B. Furthermore, patients who have recovered from tuberculosis may become susceptible again by losing their immunity and contributing to transmission again. This article aims to identify patterns and predictors of treatment success. The findings from this research can contribute to developing more effective tuberculosis interventions.
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Antituberculosos , Aprendizaje Automático , Tuberculosis Resistente a Múltiples Medicamentos , Humanos , Antituberculosos/uso terapéutico , Antituberculosos/farmacología , Tuberculosis Resistente a Múltiples Medicamentos/inmunología , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis/inmunología , Tuberculosis/microbiología , Tuberculosis/tratamiento farmacológico , Mycobacterium tuberculosis/inmunología , Tuberculosis Extensivamente Resistente a Drogas/inmunologíaRESUMEN
BACKGROUND AND OBJECTIVES: Drug resistant tuberculosis (DR-TB) remains a global challenge with about a third of the cases are not detected. With the recent advances in the diagnosis and treatment follow-up of DR-TB, there have been improvements with treatment success rates. However, there is limited evidence on the successful models of care that have consistently registered good outcomes. Our aim was to assess Ethiopia's experience in scaling up an ambulatory, decentralized model of care while managing multiple regimen transition processes and external shocks. METHODS: This was a cross-sectional, mixed-method study. For the quantitative data, we reviewed routine surveillance data for the period 2009-2022 and collected additional data from publicly available reports. We then analyzed the data descriptively. Qualitative data were collected from program reports, quarterly presentations, minutes of technical working group meetings, and clinical review committee reports and analyzed thematically. RESULTS: The number of DR-TB treatment initiating centers increased from 1 to 67, and enrollment increased from 88 in 2010 to 741 in 2019, but declined to 518 in 2022. A treatment success rate (TSR) of over 70% was sustained. The decentralized and ambulatory service delivery remained the core service delivery model. The country successfully navigated multiple regimen transitions, including the recently introduced six-month short oral regimen. Several challenges remain, including the lack of strong and sustainable specimen transportation system, lack of established systems for timely tracing and linking of missed DR-TB cases, and data quality issues. CONCLUSIONS: Ethiopia scaled up a decentralized ambulatory model of care, kept up to date with recent developments in treatment regimens, and maintained a high TSR, despite the influence of multiple external challenges. The recent decline in case notification requires a deeper look into the underlying reasons. The feasibility of fully integrating DR-TB treatment and follow up at community level should be explored further.
Asunto(s)
Antituberculosos , Tuberculosis Resistente a Múltiples Medicamentos , Etiopía/epidemiología , Humanos , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/epidemiología , Antituberculosos/uso terapéutico , Estudios Transversales , Resultado del TratamientoRESUMEN
Fluoroquinolone resistance is a major challenge in treating Multidrug-Resistant Tuberculosis globally. The GenoType MTBDRsl Ver 2.0, endorsed by the WHO, was used to characterize fluoroquinolone resistance. The fluoroquinolone resistance rates in the MDR-TB, Rifampicin-Resistant TB, and non-MDR-TB were 33%, 16.5%, and 5.4%, respectively. The most common mutation found in fluoroquinolone-resistant isolates was D94G (49.5%) in the gyrA gene. Of the 150 MDR-TB isolates, the prevalence of Extensively Drug-Resistant Tuberculosis and pre-XDR-TB was 1.33% and 30%, respectively. Among the 139 RR-TB isolates, pre-XDR-TB prevalence was 15.8%. The fluoroquinolone resistance rates were 5.12% among the 1230 isoniazid-monoresistant isolates. The study found that MDR-TB and RR-TB have higher risk of fluoroquinolone resistance than non-MDR tuberculosis. Rifampicin-resistant isolates with a mutation at codon S450L have a higher risk (RR = 12.96; 95%CI: 8.34-20.13) of developing fluoroquinolone resistance than isolates with mutations at other codons in the rpoB gene. Isoniazid-resistant isolates with a mutation at codon S315T have a higher risk (RR = 2.09; 95%CI: 1.25-3.50) of developing fluoroquinolone resistance. The study concludes that rapid diagnosis of fluoroquinolone resistance before starting treatment is urgently needed to prevent the spread and increase of resistance and to achieve better treatment outcomes in areas where it is higher.
Asunto(s)
Antituberculosos , Fluoroquinolonas , Mycobacterium tuberculosis , Tuberculosis Resistente a Múltiples Medicamentos , Humanos , Fluoroquinolonas/farmacología , Fluoroquinolonas/uso terapéutico , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/efectos de los fármacos , Estudios Retrospectivos , Tuberculosis Resistente a Múltiples Medicamentos/epidemiología , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/microbiología , Tuberculosis Resistente a Múltiples Medicamentos/transmisión , Tuberculosis Resistente a Múltiples Medicamentos/genética , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Masculino , Femenino , Tuberculosis Pulmonar/epidemiología , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis Pulmonar/microbiología , Adulto , Mutación , Medición de Riesgo , Persona de Mediana Edad , Pruebas de Sensibilidad Microbiana , Rifampin/farmacología , Rifampin/uso terapéutico , Tuberculosis Extensivamente Resistente a Drogas/epidemiología , Tuberculosis Extensivamente Resistente a Drogas/microbiología , Tuberculosis Extensivamente Resistente a Drogas/tratamiento farmacológico , Farmacorresistencia Bacteriana Múltiple/genética , Isoniazida/farmacología , Isoniazida/uso terapéutico , AncianoRESUMEN
BACKGROUND: Children represent a particularly vulnerable demographic in the context of drug-resistant (DR) tuberculosis (TB) due to their increased likelihood of close contact with adults diagnosed with the disease. Approximately 25 000-30 000 children develop DR-TB annually. While treatment success rates for DR-TB in children surpass those in adults, children and adolescents encounter distinct challenges throughout the diagnosis and treatment of DR-TB (including MDR-TB, Pre-XDR TB, and XDR-TB). AIM: To identify current practices in drug administration to children diagnosed with DR-TB where appropriate dosage forms are not available in South Africa. METHOD: An observational study was carried out at the study site to determine how medication prescribed was manipulated and administered by nursing staff to paediatric patients in the wards. RESULTS: The observational study identified 8 drugs used in DR-TB at the study site, where some manipulation to the formulation was necessary to enable administration to paediatric patients. Linezolid and para-aminosalicylic acid are the only drugs available and registered in the South Africa in a formulation that is suitable for administration to paediatric patients. Activities carried out by nursing staff to enable the administration of DR-TB medication included cutting capsules and tablets and dissolving the tablet or capsule contents in distilled water to obtain the required suitable dose. DISCUSSION: Lack of availability of suitable dosage forms for paediatrics patients results in several challenges, such as additional time required for drug preparation, increased time duration of medication administration, and unpalatability of drugs. These challenges may subsequently affect compliance and therapeutic outcomes of the treatment of paediatric patients, especially as outpatients. CONCLUSION: Research needs to focus on the development of appropriate dosage forms for the paediatric population and focus on identifying cases of DR-TB in children. This will assist in building evidence to advocate for registration of child-friendly dosage forms thereby ensuring a sustainable supply of medication.
Asunto(s)
Antituberculosos , Tuberculosis Resistente a Múltiples Medicamentos , Humanos , Sudáfrica , Niño , Administración Oral , Antituberculosos/administración & dosificación , Antituberculosos/uso terapéutico , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Adolescente , Formas de Dosificación , Linezolid/administración & dosificación , Linezolid/uso terapéutico , Preescolar , Masculino , Ácido Aminosalicílico/administración & dosificación , Ácido Aminosalicílico/uso terapéutico , FemeninoRESUMEN
Tuberculosis (TB) is a serious and fatal disease caused by Mycobacterium tuberculosis (Mtb). The World Health Organization reported an estimated 1.30 million TB-related deaths in 2022. The escalating prevalence of Mtb strains classified as being multi-, extensively, extremely, or totally drug resistant, coupled with the decreasing efficacies of conventional therapies, necessitates the development of novel treatments. As viruses that infect Mycobacterium spp., mycobacteriophages may represent a strategy to combat and eradicate drug-resistant TB. More exploration is needed to provide a comprehensive understanding of mycobacteriophages and their genome structure, which could pave the way toward a definitive treatment for TB. This review focuses on the properties of mycobacteriophages, their potential in diagnosing and treating TB, the benefits and drawbacks of their application, and their use in human health. Specifically, we summarize recent research on mycobacteriophages targeted against Mtb infection and newly developed mycobacteriophage-based tools to diagnose and treat diseases caused by Mycobacterium spp. We underscore the urgent need for innovative approaches and highlight the potential of mycobacteriophages as a promising avenue for developing effective diagnosis and treatment to combat drug-resistant Mycobacterium strains.
Asunto(s)
Micobacteriófagos , Mycobacterium tuberculosis , Tuberculosis , Micobacteriófagos/genética , Micobacteriófagos/fisiología , Humanos , Tuberculosis/tratamiento farmacológico , Tuberculosis/microbiología , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Antituberculosos/uso terapéutico , Antituberculosos/farmacologíaRESUMEN
The mycobacterial F-ATP synthase is responsible for the optimal growth, metabolism and viability of Mycobacteria, establishing it as a validated target for the development of anti-TB therapeutics. Herein, we report the discovery of an N-acyl phenothiazine derivative, termed PT6, targeting the mycobacterial F-ATP synthase. PT6 is bactericidal and active against the drug sensitive, Rifampicin-resistant as well as Multidrug-resistant tuberculosis strains. Compound PT6 showed noteworthy inhibition of F-ATP synthesis, exhibiting an IC50 of 0.788 µM in M. smegmatis IMVs and was observed that it could deplete intracellular ATP levels, exhibiting an IC50 of 30 µM. PT6 displayed a high selectivity towards mycobacterial ATP synthase compared to mitochondrial ATP synthase. Compound PT6 showed a minor synergistic effect in combination with Rifampicin and Isoniazid. PT6 demonstrated null cytotoxicity as confirmed by assessing its toxicity against VERO cell lines. Further, the binding mechanism and the activity profile of PT6 were validated by employing in silico techniques such as molecular docking, Prime MM/GBSA, DFT and ADMET analysis. These results suggest that PT6 presents an attractive lead for the discovery of a novel class of mycobacterial F-ATP synthase inhibitors.
Asunto(s)
Antituberculosos , Diseño de Fármacos , Inhibidores Enzimáticos , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis , Fenotiazinas , Fenotiazinas/farmacología , Fenotiazinas/química , Fenotiazinas/síntesis química , Antituberculosos/farmacología , Antituberculosos/síntesis química , Antituberculosos/química , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/enzimología , Relación Estructura-Actividad , Estructura Molecular , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Relación Dosis-Respuesta a Droga , Animales , Chlorocebus aethiops , Células Vero , Simulación del Acoplamiento Molecular , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológicoRESUMEN
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Mutación , Mycobacterium tuberculosis , Tuberculosis Resistente a Múltiples Medicamentos , Humanos , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/aislamiento & purificación , Antituberculosos/uso terapéuticoRESUMEN
Tuberculosis (TB) remains a leading cause of death, but antibiotic treatments for tuberculous meningitis, the deadliest form of TB, are based on those developed for pulmonary TB and not optimized for brain penetration. Here, we perform first-in-human dynamic 18F-pretomanid positron emission tomography (PET) in eight human subjects to visualize 18F-pretomanid biodistribution as concentration-time exposures in multiple compartments (NCT05609552), demonstrating preferential brain versus lung tissue partitioning. Preferential, antibiotic-specific partitioning into brain or lung tissues of several antibiotics, active against multidrug resistant (MDR) Mycobacterium tuberculosis strains, are confirmed in experimentally-infected mice and rabbits, using dynamic PET with chemically identical antibiotic radioanalogs, and postmortem mass spectrometry measurements. PET-facilitated pharmacokinetic modeling predicts human dosing necessary to attain therapeutic brain exposures. These data are used to design optimized, pretomanid-based regimens which are evaluated at human equipotent dosing in a mouse model of TB meningitis, demonstrating excellent bactericidal activity without an increase in intracerebral inflammation or brain injury. Importantly, several antibiotic regimens demonstrate discordant activities in brain and lung tissues in the same animal, correlating with tissue antibiotic exposures. These data provide a mechanistic basis for the compartmentalized activities of antibiotic regimens, with important implications for developing treatments for meningitis and other infections in compartments with unique antibiotic penetration.
Asunto(s)
Antituberculosos , Encéfalo , Pulmón , Mycobacterium tuberculosis , Adulto , Animales , Femenino , Humanos , Masculino , Ratones , Conejos , Antituberculosos/farmacocinética , Antituberculosos/uso terapéutico , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Pulmón/diagnóstico por imagen , Pulmón/metabolismo , Mycobacterium tuberculosis/efectos de los fármacos , Tomografía de Emisión de Positrones/métodos , Distribución Tisular , Tuberculosis Meníngea/diagnóstico por imagen , Tuberculosis Meníngea/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/diagnóstico por imagen , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológicoRESUMEN
BACKGROUND: The injectable shorter multi-drug resistant tuberculosis (MDR-TB) regimen, has been reported to be less costly and more effective in the treatment of MDR-TB compared to the longer regimen. Ethiopia introduced the injectable shorter regimen (SR) in April 2018 following official recommendation by the World Health Organization (WHO) in 2016. While the WHO recommendation was based on evidence coming from extensive programmatic studies in some Asian and African countries, there is paucity of information on patient outcomes in the Ethiopian context. Thus, we aimed to assess the treatment outcomes and identify factors associated with the outcomes of MDR-TB patients on injectable SR. METHODS: A multi-center facility-based retrospective cohort study was conducted in Ethiopia on 245 MDR-TB patients who were treated between April 2018 and March 2020. Data were collected from patients' medical records and analyzed using SPSS version 25. Descriptive statistics was used to summarize the results while inferential analysis was employed to investigate predictors of treatment outcomes and survival status. RESULTS: A total of 245 patients were included in the study, with 129 (52.7%) of them being female. Median age of the patients was 27 (IQR: 21-33). The overall treatment success rate was 87.8%, with 156 (63.7%) cured and 59 (24.1%) patients who completed treatment. The unfavorable outcomes accounted for 12.2%, with 16 (6.5%) treatment failure, 8 (3.3%) death and 6 (2.4%) lost to follow up. Majority of the unfavorable outcomes occurred during the early phase of therapy, with median time to event of 1.8 months (95% CI: 0.99-2.69). The use of khat (a green leafy shrub abused for its stimulant like effect) and being diagnosed with MDR-TB than rifampicin resistant only, were identified as independent factors associated with unfavorable outcomes. CONCLUSION: The injectable SR for MDR-TB was found to have positive treatment outcomes in the context of programmatic management in Ethiopia.
Asunto(s)
Antituberculosos , Inyecciones , Tuberculosis Resistente a Múltiples Medicamentos , Humanos , Estudios Retrospectivos , Femenino , Etiopía , Masculino , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Antituberculosos/administración & dosificación , Antituberculosos/uso terapéutico , Adulto , Resultado del Tratamiento , Adulto Joven , Persona de Mediana EdadRESUMEN
Thiopeptides are ribosomally biosynthesized and post-translationally modified peptides (RiPPs) that potently inhibit the growth of Gram-positive bacteria by targeting multiple steps in protein biosynthesis. The poor pharmacological properties of thiopeptides, particularly their low aqueous solubility, has hindered their development into clinically useful antibiotics. Antimicrobial activity screens of a library of Actinomycetota extracts led to discovery of the novel polyglycosylated thiopeptides persiathiacins A and B from Actinokineospora sp. UTMC 2448. Persiathiacin A is active against methicillin-resistant Staphylococcus aureus and several Mycobacterium tuberculosis strains, including drug-resistant and multidrug-resistant clinical isolates, and does not significantly affect the growth of ovarian cancer cells at concentrations up to 400 µM. Polyglycosylated thiopeptides are extremely rare and nothing is known about their biosynthesis. Sequencing and analysis of the Actinokineospora sp. UTMC 2448 genome enabled identification of the putative persiathiacin biosynthetic gene cluster (BGC). A cytochrome P450 encoded by this gene cluster catalyzes the hydroxylation of nosiheptide in vitro and in vivo, consistent with the proposal that the cluster directs persiathiacin biosynthesis. Several genes in the cluster encode homologues of enzymes known to catalyze the assembly and attachment of deoxysugars during the biosynthesis of other classes of glycosylated natural products. One of these encodes a glycosyl transferase that was shown to catalyze attachment of a D-glucose residue to nosiheptide in vitro. The discovery of the persiathiacins and their BGC thus provides the basis for the development of biosynthetic engineering approaches to the creation of novel (poly)glycosylated thiopeptide derivatives with enhanced pharmacological properties.