RESUMEN
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.
Asunto(s)
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
Introduction: neuromeningeal tuberculosis (NMT) is a significant public health challenge in Morocco because of its acute severity and high mortality rates. This study aims to comprehensively evaluate the epidemiological, clinical, therapeutic, and disease progression characteristics of NMT in the Kenitra province. Methods: a retrospective analysis was conducted on the medical records of patients diagnosed with NMT at the Diagnostic Center of Tuberculosis and Respiratory Diseases in Kenitra from 2014 to 2017. Results: among the 33 identified NMT cases, predominantly males (57.6%) were affected, with an age range of 4-76 years and a median age of 25 years. Extrapulmonary manifestations were prevalent, constituting 78.8% (n=26) of all cases, with meningeal localization in 45.5% (n=15) of confirmed cases. Furthermore, 9.1% (n=3) of cases were associated with unconfirmed cerebral tuberculosis (TB), and 12% (n=4) exhibited miliary TB. Familial transmission and comorbidities were identified as significant factors in disease progression. More than half of the patients received standardized antibacillary treatment during hospitalization, which lasted between 9 and 12 months. Treatment outcomes were generally positive (73%), but a 12% case fatality rate and 15% loss to follow-up were observed. Conclusion: this study highlights the complex clinical and public health challenges posed by NMT in Morocco. It emphasizes the need for improved health strategies that not only increase public awareness but also enhance the accessibility and quality of diagnostic services and treatment options.
Asunto(s)
Antituberculosos , Progresión de la Enfermedad , Índice de Severidad de la Enfermedad , Tuberculosis Meníngea , Humanos , Marruecos/epidemiología , Masculino , Femenino , Estudios Retrospectivos , Adolescente , Persona de Mediana Edad , Adulto , Niño , Adulto Joven , Anciano , Tuberculosis Meníngea/epidemiología , Tuberculosis Meníngea/diagnóstico , Tuberculosis Meníngea/tratamiento farmacológico , Preescolar , Antituberculosos/administración & dosificación , Resultado del Tratamiento , Hospitalización/estadística & datos numéricos , Tuberculosis Miliar/diagnóstico , Tuberculosis Miliar/epidemiología , Tuberculosis Miliar/tratamiento farmacológicoRESUMEN
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.
Asunto(s)
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
Tuberculosis (TB) is a common infectious disease that most often affects the lungs, but it can also affect any other organ with a wide range of clinical manifestations. There are three forms of hepatic involvement: diffuse hepatic tuberculosis combined with pulmonary tuberculosis; diffuse hepatic tuberculosis without pulmonary involvement; and nodular or focal/local hepatic tuberculosis, which is a very rare form and presents a diagnostic challenge. We here report the case of a young Moroccan man presenting with biliary colic that had been evolving for a month, associated with a forme fruste of tuberculous impregnation. CT scan and magnetic resonance imaging (MRI) of the liver showed nodular hepatic lesions. The diagnosis of focal hepatic tuberculosis was confirmed based on anatomopathological examination of biopsies obtained during laparoscopy. The patient received antitubercular treatment with good clinical-biological outcome.
Asunto(s)
Antituberculosos , Inmunocompetencia , Laparoscopía , Imagen por Resonancia Magnética , Tomografía Computarizada por Rayos X , Tuberculosis Hepática , Humanos , Masculino , Tuberculosis Hepática/diagnóstico , Tuberculosis Hepática/tratamiento farmacológico , Antituberculosos/administración & dosificación , Biopsia , Marruecos , AdultoRESUMEN
Despite developing new diagnostics, drugs, and vaccines, treating tuberculosis (TB) remains challenging. Monitoring inflammatory markers can contribute to more precise diagnostics of TB, identifying its active and latent forms, or monitoring its treatment success. We assessed alterations in plasma levels of 48 cytokines in 20 patients (17 males) with active pulmonary TB compared to age-matched healthy controls (n = 18). Blood samples were collected from individuals hospitalised with TB prior to commencing antibiotic therapy, after the first week, and following the third week. The majority of patients received treatment with a combination of four first-line antituberculosis drugs: rifampicin, isoniazid, ethambutol, and pyrazinamide. Plasmatic cytokine levels from patients three times and controls were analyzed using a Bio-Plex Pro Human Cytokine Screening Panel. The results showed significantly higher levels of 31 cytokines (p<0.05) than healthy controls. Three-week therapy duration showed significantly decreased levels of nine cytokines: interferon alpha-2 (IFN-α2), interleukin (IL) 1 alpha (IL-1α), IL-1 receptor antagonist (IL-1ra), IL-6, IL-10, IL-12 p40, IL-17, leukemia inhibitory factor (LIF), and tumor necrosis factor alpha (TNF-α). Out of these, only levels of IL-1α and IL-6 remained significantly elevated compared to controls. Moreover, we have found a negative correlation of 18 cytokine levels with BMI of the patients but no correlation with age. Our results showed a clinical potential for monitoring the levels of specific inflammatory markers after a short treatment duration. The reduction in cytokine levels throughout the course of therapy could indicate treatment success but should be confirmed in studies with more individuals involved and a longer observation period.
Asunto(s)
Antituberculosos , Citocinas , Humanos , Masculino , Citocinas/sangre , Femenino , Antituberculosos/uso terapéutico , Antituberculosos/administración & dosificación , Adulto , Persona de Mediana Edad , Estudios de Casos y Controles , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis Pulmonar/sangre , Tuberculosis Pulmonar/inmunología , Tuberculosis/tratamiento farmacológico , Tuberculosis/sangre , Adulto Joven , Biomarcadores/sangre , AncianoRESUMEN
Due to interindividual variability in drug metabolism and pharmacokinetics, traditional isoniazid fixed-dose regimens may lead to suboptimal or toxic isoniazid concentrations in the plasma of patients with tuberculosis, contributing to adverse drug reactions, therapeutic failure, or the development of drug resistance. Achieving precision therapy for isoniazid requires a multifaceted approach that could integrate various clinical and genomic factors to tailor the isoniazid dose to individual patient characteristics. This includes leveraging molecular diagnostics to perform the comprehensive profiling of host pharmacogenomics to determine how it affects isoniazid metabolism, such as its metabolism by N-acetyltransferase 2 (NAT2), and studying drug-resistant mutations in the Mycobacterium tuberculosis genome for enabling targeted therapy selection. Several other molecular signatures identified from the host pharmacogenomics as well as other omics-based approaches such as gut microbiome, epigenomic, proteomic, metabolomic, and lipidomic approaches have provided mechanistic explanations for isoniazid pharmacokinetic variability and/or adverse drug reactions and thereby may facilitate precision therapy of isoniazid, though further validations in larger and diverse populations with tuberculosis are required for clinical applications. Therapeutic drug monitoring and population pharmacokinetic approaches allow for the adjustment of isoniazid dosages based on patient-specific pharmacokinetic profiles, optimizing drug exposure while minimizing toxicity and the risk of resistance. Current evidence has shown that with the integration of the host pharmacogenomics-particularly NAT2 and Mycobacterium tuberculosis genomics data along with isoniazid pharmacokinetic concentrations in the blood and patient factors such as anthropometric measurements, comorbidities, and type and timing of food administered-precision therapy approaches in isoniazid therapy can be tailored to the specific characteristics of both the host and the pathogen for improving tuberculosis treatment outcomes.
Asunto(s)
Antituberculosos , Isoniazida , Mycobacterium tuberculosis , Medicina de Precisión , Tuberculosis , Humanos , Antituberculosos/farmacocinética , Antituberculosos/administración & dosificación , Antituberculosos/efectos adversos , Medicina de Precisión/métodos , Isoniazida/farmacocinética , Isoniazida/administración & dosificación , Isoniazida/efectos adversos , Tuberculosis/tratamiento farmacológico , Tuberculosis/microbiología , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/genética , Monitoreo de Drogas/métodos , Arilamina N-Acetiltransferasa/genética , Arilamina N-Acetiltransferasa/metabolismo , Farmacogenética , Farmacorresistencia Bacteriana/genéticaRESUMEN
TBI-223, a novel oxazolidinone for tuberculosis, is designed to provide improved efficacy and safety compared to linezolid in combination with bedaquiline and pretomanid (BPaL). We aim to optimize the dosing of TBI-223 within the BPaL regimen for enhanced therapeutic outcomes. TBI-223 is investigated in preclinical monotherapy, multidrug therapy, and lesion penetration experiments to describe its efficacy and safety versus linezolid. A translational platform incorporating linezolid and BPaL data from preclinical experiments and 4 clinical trials (NCT00396084, NCT02333799, NCT03086486, NCT00816426) is developed, enabling validation of the framework. TBI-223 preclinical and Phase 1 data (NCT03758612) are applied to the translational framework to predict clinical outcomes and optimize TBI-223 dosing in combination with bedaquiline and pretomanid. Results indicate that daily doses of 1200-2400 mg TBI-223 may achieve efficacy comparable to the BPaL regimen, with >90% of patients predicted to reach culture conversion by two months.
Asunto(s)
Antituberculosos , Diarilquinolinas , Linezolid , Oxazolidinonas , Linezolid/administración & dosificación , Linezolid/uso terapéutico , Humanos , Antituberculosos/administración & dosificación , Antituberculosos/uso terapéutico , Oxazolidinonas/administración & dosificación , Oxazolidinonas/uso terapéutico , Diarilquinolinas/administración & dosificación , Diarilquinolinas/uso terapéutico , Animales , Femenino , Masculino , Mycobacterium tuberculosis/efectos de los fármacos , Quimioterapia Combinada , Adulto , Tuberculosis/tratamiento farmacológico , Resultado del Tratamiento , Persona de Mediana Edad , Ratones , Relación Dosis-Respuesta a Droga , NitroimidazolesRESUMEN
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
A 78-year-old woman with rheumatoid arthritis, who was started on baricitinib five or six months earlier, was referred to our hospital due to a subcutaneous abscess in her right axilla. Contrast-enhanced chest, abdomen, and pelvis computed tomography showed subcutaneous abscesses in her right axilla and lymphadenopathy with calcification. Cultures from the subcutaneous abscess and skin biopsy specimens were positive for Mycobacterium tuberculosis. These findings led to the diagnosis of scrofuloderma associated with tuberculous lymphadenitis. She was started on an antitubercular regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol as the initial phase treatment (first 2 months), followed by isoniazid and rifampicin for 4 months (total 6 months). After 6 months of antitubercular treatment, the abscesses and lymphadenitis disappeared. Although cases of tuberculosis during JAK inhibitor treatment are rare, they are serious adverse events that require caution.
Asunto(s)
Antituberculosos , Artritis Reumatoide , Inhibidores de las Cinasas Janus , Pirazoles , Sulfonamidas , Tuberculosis Ganglionar , Humanos , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/complicaciones , Femenino , Anciano , Inhibidores de las Cinasas Janus/efectos adversos , Antituberculosos/efectos adversos , Antituberculosos/administración & dosificación , Sulfonamidas/efectos adversos , Sulfonamidas/administración & dosificación , Pirazoles/efectos adversos , Tuberculosis Ganglionar/tratamiento farmacológico , Tuberculosis Ganglionar/diagnóstico , Purinas/efectos adversos , Purinas/administración & dosificación , Azetidinas/efectos adversos , Azetidinas/administración & dosificación , Tuberculosis Cutánea/diagnóstico , Tuberculosis Cutánea/tratamiento farmacológico , Resultado del Tratamiento , Mycobacterium tuberculosis/aislamiento & purificación , Quimioterapia Combinada , Isoniazida/efectos adversos , Isoniazida/administración & dosificaciónAsunto(s)
Tuberculosis de los Genitales Masculinos , Humanos , Masculino , Tuberculosis de los Genitales Masculinos/diagnóstico , Tuberculosis de los Genitales Masculinos/tratamiento farmacológico , Tuberculosis de los Genitales Masculinos/patología , Enfermedades de la Próstata/diagnóstico , Enfermedades de la Próstata/microbiología , Enfermedades de la Próstata/patología , Enfermedades de la Próstata/diagnóstico por imagen , Persona de Mediana Edad , Antituberculosos/administración & dosificaciónRESUMEN
BACKGROUND: Isoniazid preventive therapy (IPT) decreases risk of tuberculosis (TB) disease; impact on long-term infant growth is unknown. In a recent randomized trial (RCT), we assessed IPT effects on infant growth without known TB exposure. METHODS: The infant TB Infection Prevention Study (iTIPS) trial was a non-blinded RCT among HIV-exposed uninfected (HEU) infants in Kenya. Inclusion criteria included age 6-10 weeks, birthweight ≥2.5 kg, and gestation ≥37 weeks. Infants in the IPT arm received 10 mg/kg isoniazid daily for 12 months, while the control trial received no intervention; post-trial observational follow-up continued through 24 months of age. We used intent-to-treat linear mixed-effects models to compare growth rates (weight-for-age z-score [WAZ] and height-for-age z-score [HAZ]) between trial arms. RESULTS: Among 298 infants, 150 were randomized to IPT, 47.6% were females, median birthweight was 3.4 kg (interquartile range [IQR] 3.0-3.7), and 98.3% were breastfed. During the 12-month intervention period and 12-month post-RCT follow-up, WAZ and HAZ declined significantly in all children, with more HAZ decline in male infants. There were no growth differences between trial arms, including in sex-stratified analyses. In longitudinal linear analysis, mean WAZ (ß = 0.04 [95% CI:-0.14, 0.22]), HAZ (ß = 0.14 [95% CI:-0.06, 0.34]), and WHZ [ß = -0.07 [95% CI:-0.26, 0.11]) z-scores were similar between arms as were WAZ and HAZ growth trajectories. Infants randomized to IPT had higher monthly WHZ increase (ß to 24 months 0.02 [95% CI:0.01, 0.04]) than the no-IPT arm. CONCLUSION: IPT administered to HEU infants did not significantly impact growth outcomes in the first two years of life.
Asunto(s)
Antituberculosos , Infecciones por VIH , Isoniazida , Tuberculosis , Humanos , Isoniazida/uso terapéutico , Isoniazida/administración & dosificación , Femenino , Lactante , Masculino , Antituberculosos/uso terapéutico , Antituberculosos/administración & dosificación , Infecciones por VIH/prevención & control , Tuberculosis/prevención & control , Kenia , Preescolar , Recién NacidoRESUMEN
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
Multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) continue as public health concerns. Inhaled drug therapy for TB has substantial benefits in combating the causal agent of TB (Mycobacterium tuberculosis). Pretomanid is a promising candidate in an optional combined regimen for XDR-TB. Pretomanid has demonstrated high potency against M. tuberculosis in both the active and latent phases. Conventional spray drying was used to formulate pretomanid as dry powder inhalers (DPIs) for deep lung delivery using a proliposomal system with a trehalose coarse excipient to enhance the drug solubility. Co-spray drying with L-leucine protected hygroscopic trehalose in formulations and improved powder aerosolization. Higher amounts of L-leucine (40-50 % w/w) resulted in the formation of mesoporous particles with high percentages of drug content and entrapment efficiency. The aerosolized powders demonstrated both geometric and median aerodynamic diameters < 5 µm with > 90 % emitted dose and > 50 % fine particle fraction. Upon reconstitution in simulated physiological fluid, the proliposomes completely converted to liposomes, exhibiting suitable particle sizes (130-300 nm) with stable colloids and improving drug solubility, leading to higher drug dissolution compared to the drug alone. Inhalable pretomanid showed higher antimycobacterial activity than pretomanid alone. The formulations were safe for all broncho-epithelial cell lines and alveolar macrophages, thus indicating their potential suitability for DPIs targeting pulmonary TB.
Asunto(s)
Antituberculosos , Inhaladores de Polvo Seco , Leucina , Liposomas , Tamaño de la Partícula , Tuberculosis Pulmonar , Administración por Inhalación , Antituberculosos/administración & dosificación , Antituberculosos/química , Antituberculosos/farmacología , Antituberculosos/farmacocinética , Tuberculosis Pulmonar/tratamiento farmacológico , Humanos , Leucina/química , Leucina/administración & dosificación , Trehalosa/química , Trehalosa/administración & dosificación , Aerosoles , Solubilidad , Excipientes/química , Polvos , Liberación de Fármacos , Secado por Pulverización , Composición de Medicamentos/métodos , Química Farmacéutica/métodos , Mycobacterium tuberculosis/efectos de los fármacos , NitroimidazolesRESUMEN
Central nervous system tuberculosis (CNS-TB) is a severe form of extra-pulmonary tuberculosis with high mortality and morbidity rates. The standard treatment regimen for CNS-TB parallels that of pulmonary TB, despite the challenge posed by the blood-brain barrier (BBB), which limits the efficacy of first-line anti-TB drugs (ATDs). Nose-to-brain (N2B) drug delivery offers a promising solution for achieving high ATD concentrations directly at infection sites in the brain while bypassing the BBB. This study aimed to develop chitosan nanoparticles encapsulating ATDs, specifically isoniazid (INH) and rifampicin (RIF). These nanoparticles were further processed into micro-sized chitosan nano-aggregates (NA) via spray drying. Both INH-NA and RIF-NA showed strong mucoadhesion and significantly higher permeation rates across RPMI 2650 cells compared to free ATDs. Intranasal administration of these NAs to TB-infected mice for four weeks resulted in a significant reduction of mycobacterial load by approximately â¼2.86 Log 10 CFU compared to the untreated group. This preclinical data highlights the efficacy of intranasal chitosan nano-aggregates in treating CNS-TB, demonstrating high therapeutic potential, and addressing brain inflammation challenges. To our knowledge, this study is the first to show nasal delivery of ATD nano-formulations for CNS-TB management.
Asunto(s)
Antituberculosos , Quitosano , Isoniazida , Nanopartículas , Rifampin , Tuberculosis del Sistema Nervioso Central , Animales , Ratones , Tuberculosis del Sistema Nervioso Central/tratamiento farmacológico , Barrera Hematoencefálica , Quitosano/administración & dosificación , Quitosano/química , Nanopartículas/administración & dosificación , Nanopartículas/química , Administración Intranasal , Células Epiteliales/efectos de los fármacos , Antituberculosos/administración & dosificación , Antituberculosos/química , Ratones Endogámicos BALB C , Adhesivos/administración & dosificación , Adhesivos/química , Mucinas/química , Encéfalo/efectos de los fármacos , Encéfalo/patología , Humanos , Línea Celular , Isoniazida/administración & dosificación , Rifampin/administración & dosificación , Sistemas de Liberación de MedicamentosRESUMEN
Liposomal formulations of antibiotics for inhalation offer the potential for the delivery of high drug doses, controlled drug release kinetics in the lung, and an excellent safety profile. In this study, we evaluated the in vivo performance of a liposomal formulation for the poorly soluble, antituberculosis agent, bedaquiline. Bedaquiline was encapsulated within monodisperse liposomes of â¼70 nm at a relatively high drug concentration (â¼3.6 mg/mL). Formulations with or without fucose residues, which bind to C-type lectin receptors and mediate a preferential binding to macrophage mannose receptor, were prepared, and efficacy was assessed in an in vivo C3HeB/FeJ mouse model of tuberculosis infection (H37Rv strain). Seven intranasal instillations of 5 mg/kg bedaquiline formulations administered every second day resulted in a significant reduction in lung burden (â¼0.4-0.6 Δlog10 CFU), although no differences between fucosylated and nonfucosylated formulations were observed. A pharmacokinetic study in healthy, noninfected Balb/c mice demonstrated that intranasal administration of a single dose of 2.5 mg/kg bedaquiline liposomal formulation (fucosylated) improved the lung bioavailability 6-fold compared to intravenous administration of the same formulation at the same dose. Importantly, intranasal administration reduced systemic concentrations of the primary metabolite, N-desmethyl-bedaquiline (M2), compared with both intravenous and oral administration. This is a clinically relevant finding as the M2 metabolite is associated with a higher risk of QT-prolongation in predisposed patients. The results clearly demonstrate that a bedaquiline liposomal inhalation suspension may show enhanced antitubercular activity in the lung while reducing systemic side effects, thus meriting further nonclinical investigation.
Asunto(s)
Administración Intranasal , Antituberculosos , Diarilquinolinas , Liposomas , Ratones Endogámicos BALB C , Mycobacterium tuberculosis , Animales , Diarilquinolinas/farmacocinética , Diarilquinolinas/administración & dosificación , Diarilquinolinas/química , Diarilquinolinas/farmacología , Liposomas/química , Antituberculosos/administración & dosificación , Antituberculosos/farmacocinética , Antituberculosos/farmacología , Antituberculosos/química , Ratones , Mycobacterium tuberculosis/efectos de los fármacos , Femenino , Pulmón/metabolismo , Pulmón/efectos de los fármacos , Fucosa/química , Tuberculosis/tratamiento farmacológico , Modelos Animales de Enfermedad , Ratones Endogámicos C3HRESUMEN
Asunto(s)
Antituberculosos , Diabetes Mellitus , Tuberculosis , Humanos , Antituberculosos/farmacocinética , Antituberculosos/administración & dosificación , Diabetes Mellitus/metabolismo , Isoniazida/farmacocinética , Isoniazida/administración & dosificación , Pirazinamida/farmacocinética , Rifampin/farmacocinética , Rifampin/administración & dosificación , Tuberculosis/tratamiento farmacológicoRESUMEN
BACKGROUND: Despite the introduction of bedaquiline (Bdq) containing all-oral regimens for treating patients with rifampicin resistant/multidrug resistant tuberculosis (MDR/RR-TB) in 2019, data on its effectiveness in Pakistan, which has the fifth highest MDR-TB burden, is lacking. This study evaluates treatment outcomes and identifies factors associated with unsuccessful outcomes among MDR/RR-TB patients treated with an all-oral longer treatment regimen (LTR). METHODS: This retrospective record review included all microbiologically confirmed pulmonary MDR/RR-TB patients treated with an all-oral LTR between August 2019 and February 2021 across nine PMDT centres in Pakistan. Sociodemographic and clinical data were retrieved from the Electronic Nominal Recording and Reporting System. Treatment outcomes, defined by WHO criteria, were analysed using SPSS and multivariate binary logistic regression to identify factors associated with unsuccessful outcomes. A p-value < 0.05 was considered statistically significant. RESULTS: The final analysis included 644 MDR/RR-TB patients (mean age 37.9 ± 17.6 years), mostly male (53.0 %), underweight (68.0 %), with TB treatment history (66.1 %), MDR-TB (84.9 %), lung cavitation (71.0 %), and no comorbidities (86.4 %). Fluoroquinolone resistance was found in 41.9 %, 16 % had used second-line drugs, and 9.8 % had previous MDR-TB treatment. A total of 400 (62.1 %) patients were declared cured, 53 (8.2 %) treatment completed, 117 (18.2 %) died, 37 (5.7 %) lost to follow-up (LTFU), and 37 (5.7 %) treatment failures. Overall treatment success rate was 70.3 % (n = 453). In multivariate analysis, history of TB treatment (OR:1.63, 95 %CI:1.09-2.64, p = 0.023), previous SLD use (OR:2.09, 95 %CI: 1.20-3.37, p = 0.012), resistance to Z (OR:0.43, 95 %CI: 0.20-0.81, p = 0.023), and resistance to > 5 drugs (OR:3.12, 95 %CI:1.36-11.64, p = 0.013) were significantly associated with death and treatment failure. Whereas, lung cavitation had statistically significant association with LTFU (OR:2.66, 95 %CI:1.10-7.32, p = 0.045). CONCLUSION: Treatment success rate (70.3 %) in this study fell below the WHO recommended target success rate (>90 %). Enhanced clinical management, coupled with special attention to patients exhibiting identified risk factors could improve treatment outcomes.
Asunto(s)
Antituberculosos , Diarilquinolinas , Rifampin , Tuberculosis Resistente a Múltiples Medicamentos , Humanos , Femenino , Masculino , Estudios Retrospectivos , Adulto , Pakistán , Antituberculosos/uso terapéutico , Antituberculosos/administración & dosificación , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Diarilquinolinas/uso terapéutico , Diarilquinolinas/administración & dosificación , Persona de Mediana Edad , Rifampin/uso terapéutico , Rifampin/administración & dosificación , Resultado del Tratamiento , Adulto Joven , Administración Oral , Adolescente , AncianoRESUMEN
Asunto(s)
Calidad de Vida , Espirometría , Tuberculosis Pulmonar , Humanos , Masculino , Femenino , Adulto , Tuberculosis Pulmonar/tratamiento farmacológico , Factores de Riesgo , Encuestas y Cuestionarios , Prevalencia , Adulto Joven , Pulmón/fisiopatología , Persona de Mediana Edad , Antituberculosos/administración & dosificación , Fumar/epidemiología , Estudios Transversales , Análisis MultivarianteRESUMEN
BACKGROUND: Tuberculosis remains a global health concern, and half of cured patients have permanent lung injury. N-acetylcysteine (NAC) has shown beneficial antimicrobial, antioxidant, and immunomodulatory effects in preclinical tuberculosis models. We examined its effects on tuberculosis treatment outcomes. METHODS: This prospective, randomized, controlled trial nested within the TB SEQUEL cohort study enrolled 140 adults with moderate or far-advanced tuberculosis. Participants were randomly assigned 1:1 to standard therapy with or without 1200 mg of oral NAC twice daily for days 1 to 112. Clinical evaluations, sputum culture, and spirometry were performed at specified intervals through day 168, after which participants returned to the TB SEQUEL cohort. The primary outcome was culture conversion. Secondary outcomes included whole-blood glutathione levels and lung function. RESULTS: Participants were predominantly young, male, and human immunodeficiency virus 1-negative and had heavy sputum Mycobacterium tuberculosis (MTB) infection burdens. NAC increased glutathione levels (NAC × day interaction, 8.48; 95% confidence interval [CI], 1.93 to 15.02) but did not increase stable culture conversion (hazard ratio, 0.84; 95% CI, 0.59 to 1.20; P=0.33). NAC treatment was associated with improved recovery of lung function (NAC × month, 0.49 [95% CI, 0.02 to 0.95] and 0.42 [95% CI, -0.06 to 0.91] for forced vital capacity and forced expiratory volume in the first second, respectively, as percentages of predicted values). The effects of NAC on lung function were greatest in participants with severe baseline lung impairment and appeared to persist beyond the period of NAC administration. Rates of serious or grade 3 to 4 nonserious adverse events did not differ between the groups. CONCLUSIONS: Despite increasing whole-blood glutathione levels, NAC did not affect eradication of MTB infection in adults with pulmonary tuberculosis that was moderate to far advanced. Secondary outcomes of lung function showed changes that merit further investigation. (Funded by TB SEQUEL grant 01KA1613 of the German Ministry for Education and Research, the Health Africa Project, and the German Center for Infection Research; ClinicalTrials.gov number, NCT03702738.).