RESUMEN
Cutaneous mycobacterial infections cause substantial morbidity and are challenging to diagnose and treat. An improved understanding of the dermal immune response to mycobacteria may inspire new therapeutic approaches. We conducted a controlled human infection study with 10 participants who received 2 × 106 CFUs of Mycobacterium bovis bacillus Calmette-Guérin (Tice strain) intradermally and were randomized to receive isoniazid or no treatment. Peripheral blood was collected at multiple time points for flow cytometry, bulk RNA sequencing (RNA-seq), and serum Ab assessments. Systemic immune responses were detected as early as 8 d postchallenge in this M. bovis bacillus Calmette-Guérin-naive population. Injection-site skin biopsies were performed at days 3 and 15 postchallenge and underwent immune profiling using mass cytometry and single-cell RNA-seq, as well as quantitative assessments of bacterial viability and burden. Molecular viability testing and standard culture results correlated well, although no differences were observed between treatment arms. Single-cell RNA-seq revealed various immune and nonimmune cell types in the skin, and communication between them was inferred by ligand-receptor gene expression. Day 3 communication was predominantly directed toward monocytes from keratinocyte, muscle, epithelial, and endothelial cells, largely via the migration inhibitory factor pathway and HLA-E-KLRK1 interaction. At day 15, communication was more balanced between cell types. These data reveal the potential role of nonimmune cells in the dermal immune response to mycobacteria and the utility of human challenge studies to augment our understanding of mycobacterial infections.
Asunto(s)
Mycobacterium bovis , Piel , Humanos , Mycobacterium bovis/inmunología , Piel/inmunología , Piel/microbiología , Piel/patología , Masculino , Adulto , Isoniazida/uso terapéutico , Isoniazida/farmacología , Femenino , Tuberculosis/inmunología , Tuberculosis/microbiología , Adulto Joven , Antituberculosos/uso terapéuticoRESUMEN
Tuberculosis is a global public health concern. Earlier reports suggested the emergence of high rates of drug resistant tuberculosis in Egypt. This study included 102 isolates of Mycobacterium tuberculosis collected from two reference laboratories in Cairo and Alexandria. All clinical isolates were sub-cultured on Löwenstein-Jensen medium and analyzed using both BD BACTEC MGIT 960 SIRE Kit and standard diffusion disk assays to identify the antibiotic sensitivity profile. Extracted genomic DNA was subjected to whole genome sequencing (WGS) using Illumina platform. Isolates that belong to lineage 4 represented > 80%, while lineage 3 represented only 11% of the isolates. The percentage of drug resistance for the streptomycin, isoniazid, rifampicin and ethambutol were 31.0, 17.2, 19.5 and 20.7, respectively. Nearly 47.1% of the isolates were sensitive to the four anti-tuberculous drugs, while only one isolate was resistant to all four drugs. In addition, several new and known mutations were identified by WGS. High rates of drug resistance and new mutations were identified in our isolates. Tuberculosis control measures should focus on the spread of mono (S, I, R, E)- and double (S, E)-drug resistant strains present at higher rates throughout the whole Nile Delta, Egypt.
Asunto(s)
Antituberculosos , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis , Tuberculosis Resistente a Múltiples Medicamentos , Secuenciación Completa del Genoma , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/aislamiento & purificación , Egipto/epidemiología , Humanos , Antituberculosos/farmacología , Secuenciación Completa del Genoma/métodos , Tuberculosis Resistente a Múltiples Medicamentos/microbiología , Tuberculosis Resistente a Múltiples Medicamentos/epidemiología , Mutación , Adulto , Genoma Bacteriano , Masculino , Femenino , Farmacorresistencia Bacteriana/genética , Farmacorresistencia Bacteriana Múltiple/genética , Isoniazida/farmacología , Variación Genética , Persona de Mediana Edad , Estreptomicina/farmacologíaRESUMEN
BACKGROUND: Tuberculosis (TB) is a leading cause of death in patients with human immunodeficiency virus (HIV)/AIDS. About 60% of HIV-positive individuals with latent TB infection (LTBI) develop active TB. Isoniazid preventive therapy (IPT) is recommended by the World Health Organization to prevent the progression of active TB in people living with HIV/AIDS (PLWHA). However, IPT implementation has been limited in some countries like Indonesia. The objective of this study was to assess the effect of IPT administration on the incidence of active TB in HIV patients with latent TB. METHODS: This was a quasi-experimental prospective cohort study conducted in an academic hospital in Indonesia. Interferon-gamma release assay-positive HIV-TB patients were randomly divided into an IPT group (received 6 months of IPT) and a non-IPT group. The incidence of active pulmonary TB was compared between the two groups after 6 months of follow-up. RESULTS: Of the 23 eligible patients, 22 were enrolled (10 in the IPT group, 12 in the non-IPT group). The incidence of active pulmonary TB was 0% in both groups. Factors associated with the absence of TB in both groups were the use of antiretroviral therapy for >4 years and a CD4+ T lymphocyte count >200 cells/µL. IPT was found to be safe with minimal adverse effects. CONCLUSIONS: In this setting, the use of long-term antiretroviral therapy and higher CD4+ counts, rather than just IPT, were the key factors associated with preventing active TB in latent HIV-TB patients. These findings suggest that comprehensive HIV management may be more important than IPT alone for TB control in PLWHA. Further research is needed to optimize TB prevention strategies in this high-risk population.
Asunto(s)
Antituberculosos , Infecciones por VIH , Isoniazida , Tuberculosis Latente , Tuberculosis Pulmonar , Humanos , Isoniazida/uso terapéutico , Isoniazida/administración & dosificación , Tuberculosis Latente/complicaciones , Masculino , Antituberculosos/uso terapéutico , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Adulto , Femenino , Estudios Prospectivos , Tuberculosis Pulmonar/prevención & control , Tuberculosis Pulmonar/complicaciones , Tuberculosis Pulmonar/tratamiento farmacológico , Indonesia/epidemiología , Incidencia , Persona de Mediana Edad , Ensayos de Liberación de Interferón gammaRESUMEN
BACKGROUND: Drug-resistant tuberculosis (DR-TB) poses a major global challenge to public health and therapeutics. It is an emerging global concern associated with increased morbidity and mortality mostly seen in the low- and middle-income countries. Molecular techniques are highly sensitive and offer timely and accurate results for TB drug resistance testing, thereby positively influencing patient management plan. METHODS: The study was carried out at the National Tuberculosis Reference Laboratory (NTRL) in Kenya in the period between January and October 2022. A total of 243 Mycobacterium tuberculosis (M.tb) clinical isolates were included in the study. These isolates comprised of 50 isolates with mutations in rpoB, 51 isolates with katG mutations, 51 isolates with mutations in inhA, and 91 M.tb isolates lacking mutations in these genes based on Genotype MTBDRplus results. DNA from the isolates was extracted using the FluoroLyse extraction kit. Real-time polymerase chain reaction targeting the rpoB, InhA, and katG genes was performed using the FluoroType MTBDR amplification mix. Isolates with discordant results between Genotype MTBDRplus and FluoroCycler® MTBDR assays underwent targeted sequencing for the respective genes, then, sequences were analyzed for mutations using Geneious version 11.0 software. RESULTS: The sensitivity of the Fluorocycler XT MTBDR assay for the detection of mutations that confer drug resistance was 86% (95% confidence interval [CI] 73.0-94.0) for rpoB, 96% (95% CI 87-100) for katG and 92% (95% CI 81-98) for inhA. The assay's specificity was 97% (95% CI 93-99) for rpoB, 98% (95% CI 96-100) for katG, and 97% (95% CI 93-99) for inhA. CONCLUSION: The diagnostic accuracy of FluoroType MTBDR for the detection of mutations conferring resistance to rifampicin and isoniazid was high compared with that of Genotype MTBDRplus and demonstrates its suitability as a replacement assay for Genotype MTBDRplus.
Asunto(s)
Antituberculosos , Isoniazida , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis , Rifampin , Tuberculosis Resistente a Múltiples Medicamentos , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/aislamiento & purificación , Humanos , Isoniazida/farmacología , Kenia , Rifampin/farmacología , Tuberculosis Resistente a Múltiples Medicamentos/microbiología , Antituberculosos/farmacología , Proteínas Bacterianas/genética , Mutación , Sensibilidad y Especificidad , ARN Polimerasas Dirigidas por ADN/genética , Farmacorresistencia Bacteriana Múltiple/genética , Catalasa/genética , Genotipo , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Oxidorreductasas/genéticaRESUMEN
BACKGROUND: Tuberculosis (TB) is caused due to the infection of Mycobacterium tuberculosis (MTB) and it can infect the various parts of the human body. The disease is highly prevalent and is the second most common cause of death worldwide after COVID-19. Apart from sputum specimen, it is exceedingly difficult to diagnose due to its paucibacillary nature. The current study was intended to evaluate the accuracy of Smart Sure™ MTB and multidrug-resistant-TB (MDR-TB) kits (Genetix Biotech Asia Pvt. Ltd., India) with Xpert ultra and Mycobacterium growth indicator tube (MGIT) culture on nonsputum specimens from TB suspects. METHODS: A total of 205 nonsputum specimens were received between October 2023 and May 2024 at Intermediate Reference Laboratory, Department of Medicine, All India Institute of Medical Sciences, New Delhi, India. Xpert ultra and Smart Sure™ MTB and MDR-TB tests were done directly on samples. However, processed specimens were used for MGIT culture and drug-susceptibility testing (DST). Invalid and MGIT contaminated specimens were excluded from the final calculation. RESULTS: Overall, sensitivity and specificity of Smart Sure™ MTB screening kit was 71.59% and 98.28%, respectively, with Xpert ultra and 68.35% and 90.83%, respectively, with MGIT culture. While comparing with both Xpert ultra and MGIT-DST to detect rifampicin (RIF) resistant, Smart Sure™ MDR-TB kits showed sensitivity of 75.0% and 100% of specificity. However, for isoniazid (INH) resistance, Smart Sure™ MDR-TB kits showed 100% of sensitivity and specificity with MGIT-DST. CONCLUSION: For the detection of MTB and its drug-resistance patterns (RIF and INH) in the specimens other than sputum, Smart Sure™ MTB and MDR-TB kits could play a vital role in TB endemic countries. While comparing the set-ups and skilled staffs, it required almost same as compared with previously approved WHO diagnostics used in resource-limited countries.
Asunto(s)
Mycobacterium tuberculosis , Juego de Reactivos para Diagnóstico , Sensibilidad y Especificidad , Centros de Atención Terciaria , Tuberculosis Resistente a Múltiples Medicamentos , Humanos , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/aislamiento & purificación , India , Tuberculosis Resistente a Múltiples Medicamentos/diagnóstico , Tuberculosis Resistente a Múltiples Medicamentos/microbiología , Pruebas de Sensibilidad Microbiana/instrumentación , Pruebas de Sensibilidad Microbiana/métodos , Esputo/microbiología , Antituberculosos/farmacología , Rifampin/farmacología , Isoniazida/farmacologíaRESUMEN
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.
Asunto(s)
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: Tuberculosis (TB) is an airborne disease caused by Mycobacterium tuberculosis (M. tuberculosis). The world is currently facing challenges due to the spread of anti-tuberculosis drug-resistant of M. tuberculosis. Isoniazid-resistant (INH), is one of the first-line anti-tuberculosis agents that has a high resistance case. This study used Multiplex allele-specific Polymerase Chain Reaction (MAS-PCR) to detect the most common mutations associated with isoniazid resistance on inhA, katG, and ahpC gene. METHODS: This study used samples from clinical isolates of M. tuberculosis which had been tested for their antibiotic sensitivity of first-line anti-tuberculosis drugs. The DNA extraction process was carried out using the boiling method and then amplified with specific primers for inhA, katG, and ahpC genes using the MAS-PCR method. The results are then read on the electrophoretic gel with an interpretation of the mutation gene when the target gene DNA bands were absent according to the allele-specific fragments target. RESULTS: A total of 200 isolates were tested in this study consisting of isoniazid-resistant and susceptible with the largest distribution of Multi-Drug Resistant (MDR) isolates with a total of 146 isolates (73%). The most significant gene mutation was on the ahpC gene in 61 isolates (30,5%) and the combination mutation of the katG + ahpC gene in 52 isolates (26%) with sensitivity and specificity of the test reaching 87% and 42% for the detection of INH-resistant. CONCLUSION: Mutation on the ahpC gene has the highest percentage in this study. AhpC gene can be considered one of the essential genes to be tested for the cause of isoniazid-resistant. Using MAS-PCR for detecting gene mutation in isoniazid-resistant was simple and easy, it has the potential to be widely used as a rapid screening molecular test.
Asunto(s)
Antituberculosos , Proteínas Bacterianas , Catalasa , Isoniazida , Mutación , Mycobacterium tuberculosis , Tuberculosis Resistente a Múltiples Medicamentos , Humanos , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/aislamiento & purificación , Indonesia , Isoniazida/farmacología , Isoniazida/uso terapéutico , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Proteínas Bacterianas/genética , Tuberculosis Resistente a Múltiples Medicamentos/microbiología , Catalasa/genética , Oxidorreductasas/genética , Pruebas de Sensibilidad Microbiana , Femenino , Masculino , Adulto , Reacción en Cadena de la Polimerasa Multiplex , Farmacorresistencia Bacteriana Múltiple/genéticaRESUMEN
BACKGROUND: Among chronic condition problems, tuberculosis still represents a serious public health problem globally. OBJECTIVE: To investigate latent tuberculosis infection in patients with Crohn's disease. Retrospective, descriptive cross-sectional study of quantitative analysis. METHODS: The research was conducted on diagnosed cases of Crohn's disease at the University Hospital located in a city in Northeastern Brazil. All cases of patients with Crohn's disease undergoing isoniazid or rifampicin therapy for latent tuberculosis (LTBI) were included in the study. The data obtained were subsequently subjected to statistical analysis using the Statistical Package for the Social Sciences (SPSS) program. RESULTS: We analyzed 235 medical records, and it was observed that 56% were male, with a mean age of 42.7. Among these, 54% declared themselves as brown, 31% had completed high school, and 47% were residents of the city of Teresina. Regarding the clinical and epidemiological characteristics of the studied patients classified as having ILTB, 34% of the medical records were diagnosed by tuberculin test, 48.51% were investigated by x-ray examination, and the recent location affected the colon with 27%. CONCLUSION: Overall, the health profile of the participants in this study aligns with findings previously established in the literature, particularly studies conducted in other Brazilian states, as well as in other developing countries.
Asunto(s)
Enfermedad de Crohn , Hospitales Universitarios , Tuberculosis Latente , Humanos , Masculino , Estudios Retrospectivos , Enfermedad de Crohn/complicaciones , Femenino , Adulto , Estudios Transversales , Tuberculosis Latente/epidemiología , Tuberculosis Latente/complicaciones , Tuberculosis Latente/diagnóstico , Brasil/epidemiología , Hospitales Universitarios/estadística & datos numéricos , Persona de Mediana Edad , Adulto Joven , Adolescente , Rifampin/uso terapéutico , Anciano , Isoniazida/uso terapéutico , Antituberculosos/uso terapéuticoRESUMEN
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
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
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 & dosificaciónRESUMEN
Tuberculosis (TB) preventive treatment (TPT) effectively prevents the progression from TB infection to TB disease. This study explores factors associated with TPT non-completion in Cambodia using 6-years programmatic data (2018-2023) retrieved from the TB Management Information System (TB-MIS). Out of 14,262 individuals with latent TB infection (LTBI) initiated with TPT, 299 (2.1%) did not complete the treatment. Individuals aged between 15-24 and 25-34 years old were more likely to not complete the treatment compared to those aged < 5 years old, with aOR = 1.7, p = 0.034 and aOR = 2.1, p = 0.003, respectively. Individuals initiated with 3-month daily Rifampicin and Isoniazid (3RH) or with 6-month daily Isoniazid (6H) were more likely to not complete the treatment compared to those initiated with 3-month weekly Isoniazid and Rifapentine (3HP), with aOR = 2.6, p < 0.001 and aOR = 7, p < 0.001, respectively. Those who began TPT at referral hospitals were nearly twice as likely to not complete the treatment compared to those who started the treatment at health centers (aOR = 1.95, p = 0.003). To improve TPT completion, strengthen the treatment follow-up among those aged between 15 and 34 years old and initiated TPT at referral hospitals should be prioritized. The national TB program should consider 3HP the first choice of treatment.
Asunto(s)
Antituberculosos , Isoniazida , Tuberculosis Latente , Rifampin , Humanos , Cambodia/epidemiología , Adolescente , Adulto , Femenino , Masculino , Adulto Joven , Antituberculosos/uso terapéutico , Estudios Retrospectivos , Isoniazida/uso terapéutico , Rifampin/uso terapéutico , Rifampin/análogos & derivados , Niño , Tuberculosis Latente/tratamiento farmacológico , Tuberculosis Latente/epidemiología , Tuberculosis Latente/prevención & control , Preescolar , Tuberculosis/prevención & control , Tuberculosis/epidemiología , Tuberculosis/tratamiento farmacológico , Persona de Mediana Edad , LactanteRESUMEN
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
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
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: The whole-genome sequencing (WGS) is becoming an increasingly effective tool for rapid and accurate detection of drug resistance in Mycobacterium tuberculosis complex (MTBC). This approach, however, has still been poorly evaluated on strains from Central and Eastern European countries. The purpose of this study was to assess the performance of WGS against conventional drug susceptibility testing (DST) for the detection of multi-drug resistant (MDR) phenotypes among MTBC clinical strains from Poland and Lithuania. METHODS: The study included 208 MTBC strains (130 MDR; 78 drug susceptible), recovered from as many tuberculosis patients in Lithuania and Poland between 2018 and 2021. Resistance to rifampicin (RIF) and isoniazid (INH) was assessed by Critical Concentration (CC) and Minimum Inhibitory Concentration (MIC) DST as well as molecular-based techniques, including line-probe assay (LPA) and WGS. The analysis of WGS results was performed using bioinformatic pipeline- and software-based tools. RESULTS: The results obtained with the CC DST were more congruent with those by LPA compared to pipeline-based WGS. Software-based tools showed excellent concordance with pipeline-based analysis in prediction of RIF/INH resistance. The RIF-resistant strains demonstrated a relatively homogenous MIC distribution with the mode at the highest tested MIC value. The most frequent RIF-resistance conferring mutation was rpoB S450L. The mode MIC for INH was two-fold higher among double katG and inhA mutants than among single katG mutants. The overall rate of discordant results between all methods was calculated at 5.3%. Three strains had discordant results by both genotypic methods (LPA and pipeline-based WGS), one strain by LPA only, three strains by MIC DST, two strains by both MIC DST and pipeline-based WGS, and the remaining two strains showed discordant results with all three methods, compared to CC DST. CONCLUSIONS: Considering MIC DST results, current CCs of the first-line anti-TB drugs might be inappropriately high and may need to be revised. Both molecular methods demonstrated 100% specificity, while pipeline-based WGS had slightly lower sensitivity for RIF and INH than LPA, compared to CC DST.
Asunto(s)
Antituberculosos , Proteínas Bacterianas , Farmacorresistencia Bacteriana Múltiple , Isoniazida , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis , Fenotipo , Rifampin , Tuberculosis Resistente a Múltiples Medicamentos , Secuenciación Completa del Genoma , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/genética , Humanos , Pruebas de Sensibilidad Microbiana/métodos , Antituberculosos/farmacología , Farmacorresistencia Bacteriana Múltiple/genética , Tuberculosis Resistente a Múltiples Medicamentos/microbiología , Isoniazida/farmacología , Rifampin/farmacología , Proteínas Bacterianas/genética , Polonia , Lituania , ARN Polimerasas Dirigidas por ADN/genética , Oxidorreductasas/genética , Catalasa/genética , MutaciónRESUMEN
BACKGROUND: Personalized medicine is a rapidly revolving field that offers new opportunities for tailoring disease treatment to individual patients. The main idea behind this approach is to carefully select safe and effective medications and treatment plant based on each patient's unique pharmacokinetic profile. Isoniazid is a first-line anti-tuberculosis drug that has interindividual variability in its metabolic processing, leading to significant differences in plasma concentrations among patients receiving equivalent doses. This variability necessitates the creation of individualized treatment regimens as part of personalized medicine to achieve more effective therapy. RESULTS: In this work, a deep eutectic solvent-based liquid-liquid microextraction approach for the separation and determination of isoniazid in human plasma by high-performance liquid chromatography with UV-Vis detection was developed for the first time. A new natural deep eutectic solvent based on thymol as a hydrogen bond donor and 4-methoxybenzaldehyde as a hydrogen bond acceptor was proposed as the extraction solvent. The developed microextraction procedure assumed two simultaneous processes during the mixing of the sample and extraction solvent: the derivatization of the polar analyte in the presence of 4-methoxybenzaldehyde (component of the natural deep eutectic solvent) with the formation of a hydrophobic Schiff base (1); mass transfer of the Schiff base from the sample phase to the extraction solvent phase (2). Under optimal conditions, the limits of detection and quantification were 20 and 60 µg L-1, respectively. The RSD value was <10 %, the extraction recovery was 95 %. SIGNIFICANCE: In this work, the possibility of isoniazid derivatization in the natural deep eutectic solvent phase with the formation of the Schiff base was presented for the first time. The approach provided the separation and preconcentration of polar isoniazid without the use of expensive derivatization agents and solid-phase extraction cartridges. The formation of the Schiff base was confirmed by mass spectrometry.
Asunto(s)
Disolventes Eutécticos Profundos , Isoniazida , Microextracción en Fase Líquida , Isoniazida/sangre , Isoniazida/química , Isoniazida/aislamiento & purificación , Humanos , Microextracción en Fase Líquida/métodos , Disolventes Eutécticos Profundos/química , Cromatografía Líquida de Alta Presión/métodos , Antituberculosos/sangre , Antituberculosos/aislamiento & purificación , Antituberculosos/químicaRESUMEN
Tuberculosis (TB) treatment becomes challenging due to the unique cell wall structure of Mycobacterium tuberculosis (M. tb). Among various components of the M.tb cell wall, mycolic acid (MA) is of particular interest because it is speculated to exhibit extremely low permeability for most of the drug molecules, thus helping M.tb to survive against medical treatment. However, no quantitative assessment of the thermodynamic barrier encountered by various well-known TB drugs in the mycolic acid monolayer has been performed so far using computational tools. On this premise, our present work aims to probe the permeability of some first and second line TB drugs, namely ethambutol, ethionamide, and isoniazid, through the modelled mycolic acid monolayer, using molecular dynamics (MD) simulation with two sets of force field (FF) parameters, namely GROMOS 54A7-ATB (GROMOS) and CHARMM36 (CHARMM) FFs. Our findings indicate that both FFs provide consistent results in terms of the mode of drug-monolayer interactions but significantly differ in the drug permeability through the monolayer. The mycolic acid monolayer generally exhibited a higher free energy barrier of crossing with CHARMM FF, while with GROMOS FF, better stability of drug molecules on the monolayer surface was observed, which can be attributed to the greater electrostatic potential at the monolayer-water interface, found for the later. Although both the FF parameters predicted the highest resistance against ethambutol (permeability values of 8.40 × 10-34 cm s-1 and 9.61 × 10-31 cm s-1 for the CHARMM FF and the GROMOS FF, respectively), results obtained using GROMOS were found to be consistent with the water solubility of drugs, suggesting it to be a slightly better FF for modelling drug-mycolic acid interactions. Therefore, this study enhances our understanding of TB drug permeability and highlights the potential of the GROMOS FF in simulating drug-mycolic acid interactions.
Asunto(s)
Antituberculosos , Simulación de Dinámica Molecular , Mycobacterium tuberculosis , Ácidos Micólicos , Permeabilidad , Ácidos Micólicos/química , Ácidos Micólicos/metabolismo , Antituberculosos/química , Antituberculosos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Termodinámica , Isoniazida/química , Etionamida/química , Etionamida/metabolismo , Etambutol/químicaRESUMEN
BACKGROUND: Tuberculosis (TB) is a leading cause of death among children living with HIV (CLHIV). Isoniazid preventive therapy (IPT) reduces the incidence of TB by 70% and mortality by 50% among CLHIV. However, in most developing countries including Tanzania, the uptake of IPT is suboptimal, below the 90% WHO-global uptake target. We assessed the factors associated with IPT uptake among CLHIV in Mwanza region, Tanzania. METHODS: This was a multicenter facility-based cross-sectional study among CLHIV aged 1 to 10 years in seven districts of Mwanza region, Tanzania from 1st November 2021 to 20th January 2022. Data were collected using a structured interview-administered questionnaire including information on children and caregivers' demographics, caregivers' health related information and children's clinical information. Our outcome variable was uptake of IPT, defined as initiation on IPT either during the time of the study or within past three years before this study We conducted modified Poisson regression to assess the association between IPT uptake and selected exposures in Stata version 15.0. RESULTS: A total of 415 CLHIV were enrolled, the median age of the children was 7 years (Interquartile range: 5-8). The uptake of IPT was 91% (n = 377). The majority of children's caregivers were HIV positive (86%, n = 387) and were aware about IPT (63.6%, n = 264). Factors associated with IPT uptake included; having an employed caregiver [Adjusted Prevalence Ratio (aPR): 1.06 95% Confidence Interval (CI): 1.00-1.13] and attending the ART clinic every month [aPR: 1.00; 95% CI: 0.87-1.00] . CONCLUSIONS: The uptake of IPT uptake among CLHIV in Mwanza, Tanzania exceeds the global WHO-target of ≥ 90%. Monthly ART clinic visits could be essential in promoting IPT uptake among CLHIV.