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1.
BMC Infect Dis ; 20(1): 587, 2020 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-32770954

RESUMEN

BACKGROUND: Tuberculosis (TB) is transmitted in bioaerosols containing Mycobacterium tuberculosis (Mtb). Despite being central to ongoing TB transmission, no routine diagnostic assay exists to measure Mtb in bioaerosols. Furthermore, published studies of Mtb in bioaerosol samples have been limited to individuals with sputum-positive pulmonary TB. Notably, TB diagnosis is based on clinical symptoms and sputum laboratory findings. This is despite the fact that approximately half of all patients commencing TB treatment are sputum-negative, resulting in a high proportion of presumptive treatments. Here, we propose to use a sensitive air sampling protocol to investigate the prevalence of Mtb-containing bioaerosols in both sputum-positive and sputum-negative TB suspects, at the same time evaluating the potential to identify unrecognized transmitters of TB. METHODS: Our parallel-group design will identify viable Mtb in bioaerosols produced by individuals attending a TB clinic in South Africa. Sampling will be performed on eligible individuals presenting with symptoms indicative of TB and repeated at 14 days if initially positive. Participants will be prospectively classified into three distinct groups based on National TB Control Program (NTBCP) criteria: Group A, TB notification with sputum-based laboratory confirmation; Group B, TB notification with empiric diagnosis; and Group C, individuals not notified. Group C individuals with detectable Mtb bioaerosol will be monitored until resolution of clinical and laboratory status. Collection of bioaerosol specimens will be via two consecutive sampling modalities: (1) direct sampling following a specific respiratory manoeuvre; and (2) indirect sampling during passive respiratory activity. Bioaerosol specimens will be analyzed for viable Mtb using DMN-trehalose staining and live-cell fluorescence microscopy. Mtb genomes and mycobacterial and host lipids will be detected using droplet digital PCR and mass spectrometry analyses, respectively. The primary objective is to determine the prevalence of Mtb bioaerosols in all TB clinic attendees and in each of the groups. Secondary objectives are to investigate differences in prevalence of Mtb bioaerosol by HIV status and current isoniazid preventive therapy (IPT) use; we will also determine the impact of anti-TB chemotherapy on Mtb-containing bioaerosol production. DISCUSSION: Respiratory bioaerosol has a potential role in non-invasive TB diagnosis, infectivity measurement and treatment monitoring. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04241809 . Date of Registration: 27/1/2020.


Asunto(s)
Aerosoles/análisis , Manejo de Especímenes/métodos , Tuberculosis Pulmonar/diagnóstico , Adulto , ADN Bacteriano/química , ADN Bacteriano/metabolismo , Femenino , Humanos , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/aislamiento & purificación , Reacción en Cadena de la Polimerasa , Sudáfrica , Esputo/microbiología
2.
BMC Infect Dis ; 20(1): 556, 2020 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-32736602

RESUMEN

BACKGROUND: There is a general dearth of information on extrapulmonary tuberculosis (EPTB). Here, we investigated Mycobacterium tuberculosis (Mtb) drug resistance and transmission patterns in EPTB patients treated in the Tshwane metropolitan area, in South Africa. METHODS: Consecutive Mtb culture-positive non-pulmonary samples from unique EPTB patients underwent mycobacterial genotyping and were assigned to phylogenetic lineages and transmission clusters based on spoligotypes. MTBDRplus assay was used to search mutations for isoniazid and rifampin resistance. Machine learning algorithms were used to identify clinically meaningful patterns in data. We computed odds ratio (OR), attributable risk (AR) and corresponding 95% confidence intervals (CI). RESULTS: Of the 70 isolates examined, the largest cluster comprised 25 (36%) Mtb strains that belonged to the East Asian lineage. East Asian lineage was significantly more likely to occur within chains of transmission when compared to the Euro-American and East-African Indian lineages: OR = 10.11 (95% CI: 1.56-116). Lymphadenitis, meningitis and cutaneous TB, were significantly more likely to be associated with drug resistance: OR = 12.69 (95% CI: 1.82-141.60) and AR = 0.25 (95% CI: 0.06-0.43) when compared with other EPTB sites, which suggests that poor rifampin penetration might be a contributing factor. CONCLUSIONS: The majority of Mtb strains circulating in the Tshwane metropolis belongs to East Asian, Euro-American and East-African Indian lineages. Each of these are likely to be clustered, suggesting on-going EPTB transmission. Since 25% of the drug resistance was attributable to sanctuary EPTB sites notorious for poor rifampin penetration, we hypothesize that poor anti-tuberculosis drug dosing might have a role in the development of resistance.


Asunto(s)
Farmacorresistencia Bacteriana/genética , Mycobacterium tuberculosis/genética , Tuberculosis/transmisión , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Genotipo , Humanos , Lactante , Isoniazida/uso terapéutico , Aprendizaje Automático , Masculino , Persona de Mediana Edad , Mutación , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/patogenicidad , Filogenia , Rifampin/uso terapéutico , Sudáfrica , Tuberculosis/tratamiento farmacológico , Tuberculosis/microbiología , Tuberculosis Pulmonar/microbiología , Adulto Joven
3.
BMC Infect Dis ; 20(1): 570, 2020 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-32758165

RESUMEN

BACKGROUND: In sub-Saharan Africa (SSA), most prisons are overcrowded with poor ventilation and put prisoners disproportionally at risk of exposure to Mycobacterium tuberculosis (TB) and developing TB infection but are mostly missed due to poor access to healthcare. Active case-finding (ACF) of TB in prisons facilitates early diagnosis and treatment of inmates and prevent the spread. We explored literature and described evidence on TB ACF interventions and approaches for prisoners in SSA prisons. METHODS: Guided by the Arksey and O'Malley framework, we searched PubMed, Google Scholar, SCOPUS, Academic search complete, CINAHL and MEDLINE with full text via EBSCOhost for articles on prisoners and ACF from 2000 to May 2019 with no language restriction. Two investigators independently screened the articles at the abstract and full-text stages in parallel guided by the eligibility criteria as well as performed the methodological quality appraisal of the included studies using the latest mixed-method appraisal tool. We extracted all relevant data, organized them into themes and sub-themes, and presented a narrative summary of the results. RESULTS: Of the 391 eligible articles found, 31 met the inclusion criteria. All 31 articles were published between 2006 and 2019 with the highest six (19.4%) in 2015. We found evidence in 11 countries. That is, Burkina Faso, Cameroon, Coˆte d'Ivoire, the Democratic Republic of the Congo, Ethiopia, Ghana, Malawi, Nigeria, South Africa, Uganda, and Zambia with most 41.9% (13/31) recorded in Ethiopia. These intervention studies were conducted in 134 prisons between 2001 and 2018 using either a single or combination of mass, facility-led, entry, peer educators for routine screening, and exit ACF approaches. The majority (74%) of the studies utilized only a mass screening approach. The most (68%) reported study outcome was smear-positive TB cases only (68%). We found no evidence in 16 SSA countries although they are classified among the three high-burden country lists for TB TB/HIV and Multidrug resistant-TB group. CONCLUSION: Our review highlights a dearth of evidence on TB ACF interventions in most SSA countries prisons. Hence, there is the need to scaling-up ACF interventions in SSA prisons, particularly countries included in the three high-burden country lists for TB, TB/HIV, and MDR-TB.


Asunto(s)
Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/inmunología , Prisioneros , Tuberculosis Resistente a Múltiples Medicamentos/diagnóstico , Tuberculosis Resistente a Múltiples Medicamentos/epidemiología , África del Sur del Sahara/epidemiología , Antibióticos Antituberculosos/uso terapéutico , Farmacorresistencia Bacteriana Múltiple , Femenino , Humanos , Masculino , Tamizaje Masivo/métodos , Mycobacterium tuberculosis/aislamiento & purificación , Técnicas de Amplificación de Ácido Nucleico , Prevalencia , Rifampin/uso terapéutico , Esputo/microbiología , Prueba de Tuberculina , Tuberculosis Resistente a Múltiples Medicamentos/microbiología
4.
BMC Infect Dis ; 20(1): 593, 2020 Aug 12.
Artículo en Inglés | MEDLINE | ID: mdl-32787798

RESUMEN

BACKGROUND: Tuberculosis is a serious health risk, for people living with human immune deficiency virus worldwide, and the burden of TB/HIV infection is still high in Ethiopia in particular. Therefore, the aim of this study was to determine the predictors of tuberculosis infection among adults visiting anti-retroviral treatment center in East and West Gojjam, northwest, Ethiopia. METHODS: Institution based unmatched case-control study was employed to determine the predictors of tuberculosis infection among adults visiting anti-retroviral treatment center in east and west Gojjam, Northwest, Ethiopia from March 7-April 15, 2017. Just about 552 participants were participated in the study (139 Cases and 413 controls). Cases were confirmed with active TB and infected with HIV, and controls were HIV positive adults with non-TB. All cases in each health facility who confirmed by acid-fast bacilli, culture and gene expert were considered as TB positive. However, controls were selected by using simple random sampling technique through the above diagnostic criteria and the data were collected with Face to face interview as well as patient medical record were utilized, and the quality of the data were assured, checked, coded, cleaned and entered in EPI-Data version 3.1 and exported to SPSS version 20 for the analysis. RESULT: Of the total sample (556), just about 552(99.2%) were participated in the study. 47.5% were females and 58.9% were rural dweller. Behavioral and modifiable biological risk factors: alcohol users (AOR = 2.33; 95%CI:1.34,4.07), BMI < 18.5 kg/m2 (AOR = 3.03;95%CI:1.79,5.14), CD4 count ≤200 cells/µl (AOR = 2.34;95%CI:1.89,2.79) and between 201 and 499 cells/µl (AOR = 2.63; 95%CI: 1.01,6.84), bedridden and ambulatory (AOR = 3.3;95%CI:1.70,6.29 and AOR = 8.2;95%CI:4.34,15.64), respectively. TB history in the family (AOR = 3.00; 95%CI: 1.57, 5.74) were predictors for TB infection. Taking CPT (AOR = 0.36; 95%CI: 0.21, 0.62) and having early WHO clinical stage I or II (AOR = 0.34; 95%CI: 0.20, 0.56) had protective effect against TB infection. CONCLUSION: From this study, it has been concluded that alcohol users, BMI < 18.5 kg/m2, CD4 count < 499 cells/µl, bedridden and ambulatory and TB history were predictors for TB-HIV co-infected adults. Strengthen screening more frequently, CPT Prophlaxysis and treated promptly important to reduce TB co-morbidity.


Asunto(s)
Infecciones Oportunistas Relacionadas con el SIDA/tratamiento farmacológico , Antirretrovirales/uso terapéutico , Coinfección/epidemiología , VIH , Mycobacterium tuberculosis/genética , Tuberculosis Pulmonar/epidemiología , Adolescente , Adulto , Consumo de Bebidas Alcohólicas , Índice de Masa Corporal , Recuento de Linfocito CD4 , Estudios de Casos y Controles , Etiopía/epidemiología , Femenino , Humanos , Masculino , Mycobacterium tuberculosis/aislamiento & purificación , Pronóstico , Población Rural , Adulto Joven
5.
BMC Infect Dis ; 20(1): 594, 2020 Aug 12.
Artículo en Inglés | MEDLINE | ID: mdl-32787869

RESUMEN

BACKGROUND: Implementation of an effective Tuberculosis Routine Surveillance System in low-income countries like Tanzania is problematic, despite being an essential tool for the detection and effective monitoring of drug resistant tuberculosis. Long delays in specimen transportation from the facilities to reference laboratory and results dissemination back to the health facilities, result in poor patient management, particularly where multidrug-resistant tuberculosis disease is present. METHODS: Following a detailed qualitative study, a pilot intervention of a revised Tuberculosis Routine Surveillance System was implemented in Mwanza region, Tanzania. This included the use of rapid molecular methods for the detection of both tuberculosis and drug resistance using Xpert MTB/RIF in some Mwanza sites, the use of Xpert MTB/RIF and Line Probe Assay at the Central Tuberculosis Reference Laboratory, a revised communication strategy and interventions to address the issue of poor form completion. A before and after comparison of the intervention on the number of drug resistant tuberculosis cases identified and the time taken for results feedback to the requesting site was reported. RESULTS: The revised system for previously treated cases tested at the Central Reference Laboratory was able to obtain the following findings; the number of cases tested increased from 75 in 2016 to 185 in 2017. The times for specimen transportation from health facilities to the reference laboratory were reduced by 22% (from 9 to 7 days). The median time for the district to receive results was reduced by 36% (from 11 to 7 days). Overall the number of drug resistant tuberculosis cases starting treatment increased by 67% (from 12 to 20). CONCLUSION: Detection of drug resistance could significantly be enhanced, and delays reduced by introduction of new technologies and improved routine surveillance system, including better communication using mobile applications such as 'WhatsApp' and close follow-ups. A larger scale study is now merited to ascertain if these benefits are robust across different contexts.


Asunto(s)
Diagnóstico Tardío/prevención & control , Pruebas Diagnósticas de Rutina/métodos , Monitoreo Epidemiológico , Mycobacterium tuberculosis/genética , Tuberculosis Resistente a Múltiples Medicamentos/diagnóstico , Tuberculosis Resistente a Múltiples Medicamentos/epidemiología , Antibióticos Antituberculosos/uso terapéutico , Comunicación , Farmacorresistencia Bacteriana Múltiple , Instituciones de Salud , Humanos , Laboratorios , Mycobacterium tuberculosis/aislamiento & purificación , Técnicas de Amplificación de Ácido Nucleico/métodos , Proyectos Piloto , Estudios Prospectivos , Investigación Cualitativa , Rifampin/uso terapéutico , Manejo de Especímenes/métodos , Tanzanía/epidemiología , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico
6.
BMC Infect Dis ; 20(1): 462, 2020 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-32611396

RESUMEN

BACKGROUND: At present, there are few studies on polymorphism of Mycobacterium tuberculosis (Mtb) gene and how it affects the TB epidemic. This study aimed to document the differences of polymorphisms between tuberculosis hot and cold spot areas of Guangxi Zhuang Autonomous Region, China. METHODS: The cold and hot spot areas, each with 3 counties, had been pre-identified by TB incidence for 5 years from the surveillance database. Whole genome sequencing analysis was performed on all sputum Mtb isolates from the detected cases during January and June 2018. Single nucleotide polymorphism (SNP) of each isolate compared to the H37Rv strain were called and used for lineage and sub-lineage identification. Pairwise SNP differences between every pair of isolates were computed. Analyses of Molecular Variance (AMOVA) across counties of the same hot or cold spot area and between the two areas were performed. RESULTS: As a whole, 59.8% (57.7% sub-lineage 2.2 and 2.1% sub-lineage 2.1) and 39.8% (17.8% sub-lineage 4.4, 6.5% sub-lineage 4.2 and 15.5% sub-lineage 4.5) of the Mtb strains were Lineage 2 and Lineage 4 respectively. The percentages of sub-lineage 2.2 (Beijing family strains) are significantly higher in hot spots. Through the MDS dimension reduction, the genomic population structure in the three hot spot counties is significantly different from those three cold spot counties (T-test p = 0.05). The median of SNPs distances among Mtb isolates in cold spots was greater than that in hot spots (897 vs 746, Rank-sum test p < 0.001). Three genomic clusters, each with genomic distance ≤12 SNPs, were identified with 2, 3 and 4 consanguineous strains. Two clusters were from hot spots and one was from cold spots. CONCLUSION: Narrower genotype diversity in the hot area may indicate higher transmissibility of the Mtb strains in the area compared to those in the cold spot area.


Asunto(s)
Frío , Epidemias , Calor/efectos adversos , Mycobacterium tuberculosis/genética , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/epidemiología , China/epidemiología , Análisis por Conglomerados , Genotipo , Humanos , Incidencia , Mycobacterium tuberculosis/aislamiento & purificación , Filogenia , Polimorfismo de Nucleótido Simple , Esputo/microbiología , Tuberculosis Pulmonar/transmisión , Secuenciación Completa del Genoma
7.
BMC Infect Dis ; 20(1): 543, 2020 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-32711457

RESUMEN

BACKGROUND: The main advantage of GeneXpert MTB/RIF® (Xpert) molecular diagnostic technology is the rapid detection of M.tuberculosis DNA and mutations associated with rifampicin (RIF) resistance for timely initiation of appropriate treatment and, consequently, preventing further transmission of the disease. We assessed time to treatment initiation and treatment outcomes of RIF-resistant and RIF-susceptible TB patients diagnosed and treated in Vladimir TB Dispensary, Russia in 2012, before and after implementation of GeneXpert MTB/RIF® diagnostic technology. METHODS: All adult patients suspected of having TB during February-December 2012 underwent a clinical examination, chest x-ray, microscopy, culture, and phenotypic drug susceptibility testing (DST). Starting August 2012 Xpert diagnostic technology became available in the facility. We used logistic regression to compare treatment outcomes in pre-Xpert and post-Xpert periods. Kaplan-Meier curves and log-rank test were used to compare the time to treatment initiation between the groups. RESULTS: Of 402 patients screened for TB during February-December 2012, 338 were diagnosed with TB (280 RIF-susceptible, 58 RIF-resistant). RIF-resistant patients in the post-Xpert group started treatment with second-line drugs (SLD) earlier than those in pre-Xpert group (median 11 vs. 37 days, Log-rank p = 0.02). The hazard ratio for time to SLD treatment initiation was significantly higher in post-Xpert group (HR:2.06; 95%CI:1.09,3.89) compared to pre-Xpert group. Among the 53/58 RIF-resistant TB patients with available treatment outcome, 28 (53%) had successful outcomes (cured/completed treatment) including 15/26 (58%) in post-Xpert group versus 13/27 (48%) in pre-Xpert group. The observed difference, however, was not statistically significant (OR:0.69; 95%CI:0.23,2.06). Among RIF-susceptible TB cases time to treatment initiation was not significantly different between the groups (2 vs. 3 days, Log-rank p = 0.73). Of 252/280 RIF-susceptible TB cases with treatment outcome, 199 (79%) cases had successful outcome including 94/114 (82%) in post-Xpert group versus 105/138 (76%) in pre-Xpert group (OR:0.68; 95%CI:0.36,1.26). CONCLUSION: We observed that availability of Xpert for initial diagnosis significantly reduced the time to SLD treatment for RIF-resistant patients in the Vladimir TB Dispensary. Although implementation of rapid diagnostics did not improve treatment outcomes, early diagnosis of MDR-TB is important for selection of appropriate treatment regimen and prevention of transmission of drug-resistant strains of TB.


Asunto(s)
Antibióticos Antituberculosos/uso terapéutico , Pruebas de Sensibilidad Microbiana/métodos , Mycobacterium tuberculosis/genética , Técnicas de Amplificación de Ácido Nucleico/métodos , Rifampin/uso terapéutico , Tiempo de Tratamiento , Tuberculosis Resistente a Múltiples Medicamentos/diagnóstico , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Adolescente , Adulto , Anciano , ADN Bacteriano/genética , Farmacorresistencia Bacteriana/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Estudios Prospectivos , Federación de Rusia , Resultado del Tratamiento , Tuberculosis Resistente a Múltiples Medicamentos/microbiología , Adulto Joven
8.
BMC Infect Dis ; 20(1): 495, 2020 Jul 10.
Artículo en Inglés | MEDLINE | ID: mdl-32650727

RESUMEN

BACKGROUND: Tuberculosis is a disease that may affect any organ of the body. Multifocal tuberculosis involving multiple systems with associated symptoms are rare, which makes the diagnosis challenging. Distinguishing multifocal tuberculosis from lesions metastatic from system malignancy is difficult. Single detection method is difficult to make a diagnosis. A combination of multiple methods is essential. CASE PRESENTATION: A 17-year-old male presented with a 20 days weakness of lower limbs, which aggravated for 6 days. The PET/CT showed increased metabolism of ileocecal intestinal and terminal ileum wall, multiple enlarged lymph node (LNs), multiple osteolytic bone lesions, and soft tissue intensity belong T7 and T8 vertebrae. To confirm the diagnosis of the disease, a biopsy of the mediastinum lymph nodes was carried out. Polymerase chain reaction (PCR) test of the specimen was positive for the Mycobacterium tuberculosis, the T-SPOT and Xpert MTB/RIF test were also positive, which suggested the presence of Mycobacterium tuberculosis. The final diagnosis was multifocal tuberculosis, the patients received the resection of the mass in the spine. Anti-tuberculosis drugs were given. The myodynamia and muscle tension of the patients recovered following the therapy. CONCLUSIONS: Our results indicated that Multifocal tuberculosis should also be taken into consideration when lesions metastatic from system malignancy were suspected from images results even without the clinical symptoms of tuberculosis, and combination of multiple diagnosis methods were essential for the diagnosis of multifocal disease.


Asunto(s)
Ganglios Linfáticos/patología , Tuberculosis/diagnóstico , Adolescente , Antituberculosos/uso terapéutico , Humanos , Ganglios Linfáticos/microbiología , Linfadenopatía/microbiología , Linfadenopatía/patología , Masculino , Mycobacterium tuberculosis/genética , Reacción en Cadena de la Polimerasa , Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias de la Columna Vertebral/patología , Tuberculosis/tratamiento farmacológico
9.
BMC Infect Dis ; 20(1): 548, 2020 Jul 29.
Artículo en Inglés | MEDLINE | ID: mdl-32727388

RESUMEN

BACKGROUND: Bacteriological confirmation (BC) proportion among notified pulmonary TB patients in China is among the lowest in the world. This study was to understand the yield of BC using different testing strategies and patient-level factors associated with BC among pulmonary TB patients in Tianjin, China during 2017-2018. METHODS: A retrospective study was conducted, enrolling pulmonary TB patients reported to National TB Information Management System (TBIMS) in Tianjin during 2017-2018. BC was defined as a positive result by any of the followings: smear microscopy, culture, or nucleic acid amplification test. Individual characteristics were compared between patients with positive and negative bacteriological results using contingency tables and χ2 test. Multivariable logistic regression was applied to analyze factors associated with BC, calculating adjusted odds ratios (aOR) and 95% confidence intervals (CI) (α = 0.05). RESULTS: Of 6364 reported patients, 4181 (65.7%) were bacteriologically confirmed. Positivity proportion was 43.1% (2746/6364) for smear microscopy, 57.7% (3380/5853) for culture, 61.7% (1608/2605) for Xpert® MTB/RIF assay (Xpert) and 73.4% (1824/2484) for combination of the three. The unemployed (aOR = 1.5, 95% CI: 1.0-2.2) and farmers (aOR = 1.7, 95% CI: 1.1-2.8) compared with students; diagnosis by inpatient hospitals compared with TB clinics (aOR = 3.4, 95% CI: 2.6-4.4); having symptoms for ≥2 weeks (aOR = 1.4, 95% CI: 1.1-1.8); cough (aOR = 2.2, 95% CI: 1.8-2.8); blood sputum (aOR = 1.5, 95% CI: 1.0-2.2); cavitation on chest X-ray (aOR = 3.3, 95% CI: 2.5-4.3); bilateral lung lobes affected (aOR = 1.7, 95% CI: 1.4-2.2) were factors associated with BC. CONCLUSIONS: Combination test was an effective way to improve BC among pulmonary TB patients. Being unemployed, farmers, having prolonged symptoms, and more severe in TB condition were factors associated with BC. We recommend combination of tests to improve BC for pulmonary TB patients, especially who are in early stage of the disease or with conditions tend to be bacteriologically negative.


Asunto(s)
Microscopía/métodos , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/aislamiento & purificación , Técnicas de Amplificación de Ácido Nucleico/métodos , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/epidemiología , Adulto , Anciano , China/epidemiología , Agricultores , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Sensibilidad y Especificidad , Índice de Severidad de la Enfermedad , Esputo/microbiología , Tuberculosis Pulmonar/microbiología , Desempleo , Adulto Joven
10.
PLoS Pathog ; 16(6): e1008621, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32544188

RESUMEN

During tuberculosis, lung myeloid cells have two opposing roles: they are an intracellular niche occupied by Mycobacterium tuberculosis, and they restrict bacterial replication. Lung myeloid cells from mice infected with yellow-fluorescent protein expressing M. tuberculosis were analyzed by flow cytometry and transcriptional profiling to identify the cell types infected and their response to infection. CD14, CD38, and Abca1 were expressed more highly by infected alveolar macrophages and CD11cHi monocyte-derived cells compared to uninfected cells. CD14, CD38, and Abca1 "triple positive" (TP) cells had not only the highest infection rates and bacterial loads, but also a strong interferon-γ signature and nitric oxide synthetase-2 production indicating recognition by T cells. Despite evidence of T cell recognition and appropriate activation, these TP macrophages are a cellular compartment occupied by M. tuberculosis long-term. Defining the niche where M. tuberculosis resists elimination promises to provide insight into why inducing sterilizing immunity is a formidable challenge.


Asunto(s)
Antígenos CD11/inmunología , Macrófagos Alveolares , Monocitos , Mycobacterium tuberculosis/inmunología , Tuberculosis/inmunología , ADP-Ribosil Ciclasa 1/genética , ADP-Ribosil Ciclasa 1/inmunología , Transportador 1 de Casete de Unión a ATP/genética , Transportador 1 de Casete de Unión a ATP/inmunología , Animales , Antígenos CD11/genética , Macrófagos Alveolares/inmunología , Macrófagos Alveolares/microbiología , Macrófagos Alveolares/patología , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/inmunología , Ratones , Ratones Noqueados , Monocitos/inmunología , Monocitos/microbiología , Monocitos/patología , Mycobacterium tuberculosis/genética , Linfocitos T/inmunología , Linfocitos T/microbiología , Linfocitos T/patología , Tuberculosis/genética , Tuberculosis/patología
11.
Artículo en Inglés | MEDLINE | ID: mdl-32520211

RESUMEN

Simple, low-cost and effective diagnostic tests for tuberculosis (TB) are needed especially in TB-high burden settings. The present study evaluated the performance of an in-house loop-mediated isothermal amplification (LAMP) for diagnosing TB by comparing it to Xpert MTB/RIF, microscopy and culture. In Thailand, a total of 204 excess sputum samples volume after the processing of cultures were used for Mycobacterium tuberculosis (MTB) detection by Xpert MTB/RIF and LAMP. Based on culture results as the gold standard, the overall sensitivity of LAMP and Xpert MTB/RIF were 82.1% (126/153; 95% confidential interval [CI]: 75.4-88.98%) and 86.9 % (133/153; 95% CI: 80.5-90.8%) respectively, and the specificity of both tests was 100% (51/51; 95% CI: 93.0-100.0%). In comparison with Xpert MTB/RIF, the sensitivity and specificity of LAMP were 94.7% (126/133; 95% CI: 89.5-97.9%), and 100.0% (73/73; 95% CI: 94.9-100.0%), respectively. The average threshold cycle (Ct) of Xpert MTB/RIF detection for positive and negative LAMP results was statistically different, of 18.4 and 27.0, respectively (p < 0.05). In comparison with the acid-fast staining technique, and analyzing LAMP and Xpert MTB/RIF in smear-negative/culture-positive specimens, there was an increase of the detection rate by 47.7% (21/44) and 54.6% (24/44). The diagnostic sensitivity and specificity of LAMP appeared to be comparable to those of Xpert MTB/RIF. We claim that this LAMP has potential to provide a sensitive diagnostic test for the rapid TB diagnosis. It allowed a fast detection of MTB before the cultures and it could be used in resource-limited laboratory settings.


Asunto(s)
Mycobacterium tuberculosis/aislamiento & purificación , Esputo/microbiología , Tuberculosis/diagnóstico , ADN Bacteriano/análisis , ADN Bacteriano/genética , Pruebas Diagnósticas de Rutina , Humanos , Técnicas de Diagnóstico Molecular/métodos , Mycobacterium tuberculosis/genética , Reacción en Cadena de la Polimerasa , Sensibilidad y Especificidad , Tailandia
12.
Artículo en Inglés | MEDLINE | ID: mdl-32520212

RESUMEN

Drug resistant tuberculosis (DR-TB) is challenging particularly in developing countries. As such, a previous investigation gave the first insight into the mutational status of the Rifampicin Resistance Determining Region (RRDR) of rpoB gene among a restricted number of MTB patients' residents in the Northern Morocco. The purpose of this study was to investigate rpoB mutation types and frequencies associated with resistance to Rifampicin in a larger panel of MTB patients and to evaluate the usefulness of these mutations to improve the diagnosis of resistance to Rifampicin. A panel of 301 consecutive sputum samples belonging to patients suscpected of having TB from Northern Morocco was collected at the Pasteur Institute of Tangier between 2014-2017. Samples were subjected to conventionel microbiological tests. Evaluation of rpoB muational status was assessed by PCR amplification and sequencing of the RRDR of the rpoB gene. DST results showed that 26.4% of strains were MDR. Sequencing results reported single point mutations in 36 of 65 RIFR isolates of which two had two mutations. Aminoacid substitutions in the codon Ser531Leu occurred at the highest frequency (34.46%). Overall, 10 aminoacid substitutions have been registered, and the H526S substitution was reported for the first time. The present study highlighted that resistance to RIF is a reliable marker of MDR-TB, the common mutations successfully detected in the rpoB 531, rpoB526 and rpoB516 codons provide a foundation for the implementation of molecular approaches such as Hain and GeneXpert as a routine tests to detect DR-TB. However, considerable work is still necessary to identify extensive mutations associated with DR-TB.


Asunto(s)
Antituberculosos/farmacología , Mutación/genética , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/genética , Rifampin/farmacología , Tuberculosis Resistente a Múltiples Medicamentos/microbiología , Adulto , Femenino , Genotipo , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Reacción en Cadena de la Polimerasa
13.
Rev Soc Bras Med Trop ; 53: e20190404, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32578701

RESUMEN

INTRODUCTION: We aimed to estimate the prevalence and transmission of drug-resistant tuberculosis in a high-burden Brazilian setting under directly observed therapy short-course strategy. METHODS: Isolates of culture-confirmed pulmonary tuberculosis patients from Guarulhos, Brazil, diagnosed in October 2007-2011 were subjected to drug susceptibility and IS6110-restriction fragment length polymorphism testing. RESULTS: The overall resistance prevalence was 11.5% and the multi-drug resistance rate was 4.2%. Twenty-six (43.3%) of 60 drug-resistant isolates were clustered. Epidemiological relationships were identified in 11 (42.3%) patients; 30.8% of the cases were transmitted in households. CONCLUSIONS: Drug-resistant tuberculosis was relatively low and transmitted in households and the community.


Asunto(s)
Terapia por Observación Directa/métodos , Mycobacterium tuberculosis/efectos de los fármacos , Tuberculosis Resistente a Múltiples Medicamentos/epidemiología , Adolescente , Adulto , Brasil/epidemiología , Estudios Transversales , Femenino , Humanos , Masculino , Mycobacterium tuberculosis/genética , Polimorfismo de Longitud del Fragmento de Restricción , Prevalencia , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/transmisión , Adulto Joven
14.
J Med Microbiol ; 69(7): 979-985, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32579099

RESUMEN

Introduction. Childhood tuberculosis meningitis is a severe form of tuberculosis with high morbidity and mortality. The diagnosis is frequently missed and delayed due to lack of sensitive tests like acid-fast bacilli (AFB) smear and delayed results by culture.Aims. To compare the role of IS6110 and protein antigen b PCR in cerebrospinal fluid (CSF) for rapid diagnosis of tuberculous meningitis (TBM) in children.Methodology. Forty-five cases of TBM and 20 controls were enrolled in this prospective study.Results. The mean ages of cases and controls were 4.2±0.5 years and 4.5±0.7 years, respectively. In the TBM group, two-thirds of the children were <4 years of age, and 62 % were males. Sensitivities of AFB smear examination, Löwenstein-Jensen (LJ) medium and bactenecin (BACTEC) culture in cases were 4.4, 0 and 2.2%, respectively. The protein antigen b PCR was most sensitive as it was positive in 35 (77.8 %) of TBM patients; IS6110 PCR was positive in 27 (60 %) patients. Both PCR-based tests had higher positivity than conventional tests and BACTEC culture. No significant difference was seen between the PCR tests. Excellent agreement was observed between both PCR-based tests as they were concordant for 26 positive samples and 35 negative samples.Conclusion. Protein b PCR is a sensitive and rapid method for the diagnosis of TBM (sensitivity 77.8 %). Both PCRs were more sensitive than smear, LJ and BACTEC. The specificity of both PCR was 100 %.


Asunto(s)
Mycobacterium tuberculosis/genética , Reacción en Cadena de la Polimerasa/métodos , Tuberculosis Meníngea/diagnóstico , Antígenos Bacterianos/genética , Líquido Cefalorraquídeo , Preescolar , Elementos Transponibles de ADN/genética , ADN Bacteriano , Femenino , Humanos , Masculino , Estudios Prospectivos , Sensibilidad y Especificidad , Tuberculosis Meníngea/líquido cefalorraquídeo
15.
J Med Microbiol ; 69(7): 1013-1019, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32579102

RESUMEN

Introduction. Multidrug-resistant tuberculosis (MDR-TB) is a major public health problem globally, including in Indonesia. Whole-genome sequencing (WGS) analysis has rarely been used for the study of TB and MDR-TB in Indonesia.Aim. We evaluated the use of WGS for drug-susceptibility testing (DST) and to investigate the population structure of drug-resistant Mycobacterium tuberculosis in Java, Indonesia.Methodology. Thirty suspected MDR-TB isolates were subjected to MGIT 960 system (MGIT)-based DST and to WGS. Phylogenetic analysis was done using the WGS data. Results obtained using MGIT-based DST and WGS-based DST were compared.Results. Agreement between WGS and MGIT was 93.33 % for rifampicin, 83.33 % for isoniazid and 76.67 % for streptomycin but only 63.33 % for ethambutol. Moderate WGS-MGIT agreement was found for second-line drugs including amikacin, kanamycin and fluoroquinolone (73.33-76.67 %). MDR-TB was more common in isolates of the East Asian Lineage (63.3%). No evidence of clonal transmission of DR-TB was found among members of the tested population.Conclusion. Our study demonstrated the applicability of WGS for DST and molecular epidemiology of DR-TB in Java, Indonesia. We found no transmission of DR-TB in Indonesia.


Asunto(s)
Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/genética , Tuberculosis Resistente a Múltiples Medicamentos/genética , Adulto , Antituberculosos/farmacología , Evaluación Preclínica de Medicamentos/métodos , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Farmacorresistencia Bacteriana Múltiple/genética , Femenino , Genotipo , Humanos , Indonesia/epidemiología , Kanamicina/farmacología , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Epidemiología Molecular , Mutación , Fenotipo , Filogenia , Rifampin/farmacología , Estreptomicina/farmacología , Tuberculosis Resistente a Múltiples Medicamentos/microbiología , Secuenciación Completa del Genoma/métodos
16.
Thorax ; 75(7): 584-591, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32546574

RESUMEN

BACKGROUND: Understanding how pathogen genetic factors contribute to pathology in TB could enable tailored treatments to the most pathogenic and infectious strains. New strategies are needed to control drug-resistant TB, which requires longer and costlier treatment. We hypothesised that the severity of radiological pathology on the chest radiograph in TB disease was associated with variants arising independently, multiple times (homoplasies) in the Mycobacterium tuberculosis genome. METHODS: We performed whole genome sequencing (Illumina HiSeq2000 platform) on M. tuberculosis isolates from 103 patients with drug-resistant TB in Lima between 2010 and 2013. Variables including age, sex, HIV status, previous TB disease and the percentage of lung involvement on the pretreatment chest radiograph were collected from health posts of the national TB programme. Genomic variants were identified using standard pipelines. RESULTS: Two mutations were significantly associated with more widespread radiological pathology in a multivariable regression model controlling for confounding variables (Rv2828c.141, RR 1.3, 95% CI 1.21 to 1.39, p<0.01; rpoC.1040 95% CI 1.77 to 2.16, RR 1.9, p<0.01). The rpoB.450 mutation was associated with less extensive radiological pathology (RR 0.81, 95% CI 0.69 to 0.94, p=0.03), suggestive of a bacterial fitness cost for this mutation in vivo. Patients with a previous episode of TB disease and those between 10 and 30 years of age also had significantly increased radiological pathology. CONCLUSIONS: This study is the first to compare the M. tuberculosis genome to radiological pathology on the chest radiograph. We identified two variants significantly positively associated with more widespread radiological pathology and one with reduced pathology. Prospective studies are warranted to determine whether mutations associated with increased pathology also predict the spread of drug-resistant TB.


Asunto(s)
Proteínas Bacterianas/genética , ADN Bacteriano/genética , Mycobacterium tuberculosis/genética , Tuberculosis Resistente a Múltiples Medicamentos/metabolismo , Adolescente , Adulto , Anciano , Proteínas Bacterianas/metabolismo , Niño , Femenino , Estudios de Seguimiento , Genotipo , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Estudios Retrospectivos , Tuberculosis Resistente a Múltiples Medicamentos/genética , Tuberculosis Resistente a Múltiples Medicamentos/microbiología , Adulto Joven
17.
BMC Infect Dis ; 20(1): 390, 2020 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-32487030

RESUMEN

BACKGROUND: Fluoroquinolones are broad-spectrum antibiotics that are recommended, and increasingly important, for the treatment of multidrug-resistant tuberculosis (MDR-TB). Resistance to fluoroquinolones is caused by mutations in the Quinolone Resistance Determining Region (QRDR) of gyrA and gyrB genes of Mycobacterium tuberculosis. In this study, we characterized the phenotypic and genotypic resistance to fluoroquinolones for the first time in northeast Iran. METHODS: A total of 123 Mycobacterium tuberculosis isolates, including 111 clinical and 12 collected multidrug-resistant isolates were studied. Also, 19 WHO quality control strains were included in the study. The phenotypic susceptibility was determined by the proportion method on Löwenstein-Jensen medium. The molecular cause of resistance to the fluoroquinolone drugs ofloxacin and levofloxacin was investigated by sequencing of the QRDR region of the gyrA and gyrB genes. RESULTS: Among 123 isolates, six (4.8%) were fluoroquinolone-resistant according to phenotypic methods, and genotypically three of them had a mutation at codon 94 of the gyrA gene (Asp→ Gly) which was earlier reported to cause resistance. All three remaining phenotypically resistant isolates had a nucleotide change in codon 95. No mutations were found in the gyrB gene. Five of the 19 WHO quality control strains, were phenotypically fluoroquinolone-resistant, four of them were genotypically resistant with mutations at codon 90, 91 of the gyrA gene and one resistant strain had no detected mutation. CONCLUSIONS: Mutation at codon 94 of the gyrA gene, was the main cause of fluoroquinolone resistance among M. tuberculosis isolates in our region. In 3/6 fluoroquinolone-resistant isolates, no mutations were found in either gyrA or gyrB. Therefore, it can be concluded that various other factors may lead to fluoroquinolone resistance, such as active efflux pumps, decreased cell wall permeability, and drug inactivation.


Asunto(s)
Antituberculosos/farmacología , Farmacorresistencia Bacteriana/efectos de los fármacos , Fluoroquinolonas/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/genética , Codón , Farmacorresistencia Bacteriana/genética , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Farmacorresistencia Bacteriana Múltiple/genética , Femenino , Genotipo , Humanos , Irán , Levofloxacino/farmacología , Masculino , Pruebas de Sensibilidad Microbiana , Mutación , Mycobacterium tuberculosis/aislamiento & purificación , Ofloxacino/farmacología , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/microbiología
18.
PLoS Comput Biol ; 16(6): e1007533, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32542021

RESUMEN

Metabolism underpins the pathogenic strategy of the causative agent of TB, Mycobacterium tuberculosis (Mtb), and therefore metabolic pathways have recently re-emerged as attractive drug targets. A powerful approach to study Mtb metabolism as a whole, rather than just individual enzymatic components, is to use a systems biology framework, such as a Genome-Scale Metabolic Network (GSMN) that allows the dynamic interactions of all the components of metabolism to be interrogated together. Several GSMNs networks have been constructed for Mtb and used to study the complex relationship between the Mtb genotype and its phenotype. However, the utility of this approach is hampered by the existence of multiple models, each with varying properties and performances. Here we systematically evaluate eight recently published metabolic models of Mtb-H37Rv to facilitate model choice. The best performing models, sMtb2018 and iEK1011, were refined and improved for use in future studies by the TB research community.


Asunto(s)
Genoma Bacteriano , Redes y Vías Metabólicas , Mycobacterium tuberculosis/genética , Teorema de Bayes , Biomasa , Carbono/metabolismo , Colesterol/metabolismo , Medios de Cultivo , Reacciones Falso Positivas , Genotipo , Glicerol/metabolismo , Modelos Biológicos , Mycobacterium tuberculosis/metabolismo , Fenotipo , Valor Predictivo de las Pruebas , Programas Informáticos , Biología de Sistemas , Termodinámica
19.
PLoS One ; 15(6): e0233620, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32492022

RESUMEN

BACKGROUND: To reach WHO End tuberculosis (TB) targets, countries need a quality-assured laboratory network equipped with rapid diagnostics for tuberculosis diagnosis and drug susceptibility testing. Diagnostic network analysis aims to inform instrument placement, sample referral, staffing, geographical prioritization, integration of testing enabling targeted investments and programming to meet priority needs. METHODS: Supply chain modelling and optimization software was used to map Lesotho's TB diagnostic network using available data sources, including laboratory and programme reports and health and demographic surveys. Various scenarios were analysed, including current network configuration and inclusion of additional GeneXpert and/or point of care instruments. Different levels of estimated demand for testing services were modelled (current [30,000 tests/year], intermediate [41,000 tests/year] and total demand needed to find all TB cases [88,000 tests/year]). RESULTS: Lesotho's GeneXpert capacity is largely well-located but under-utilized (19/24 sites use under 50% capacity). The network has sufficient capacity to meet current and near-future demand and 70% of estimated total demand. Relocation of 13 existing instruments would deliver equivalent access to services, maintain turnaround time and reduce costs compared with planned procurement of 7 more instruments. Gaps exist in linking people with positive symptom screens to testing; closing this gap would require extra 11,000 tests per year and result in 1000 additional TB patients being treated. Closing the gap in linking diagnosed patients to treatment would result in a further 629 patients being treated. Scale up of capacity to meet total demand will be best achieved using a point-of-care platform in addition to the existing GeneXpert footprint. CONCLUSIONS: Analysis of TB diagnostic networks highlighted key gaps and opportunities to optimize services. Network mapping and optimization should be considered an integral part of strategic planning. By building efficient and patient-centred diagnostic networks, countries will be better equipped to meet End TB targets.


Asunto(s)
Redes Comunitarias , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/aislamiento & purificación , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/epidemiología , Antibióticos Antituberculosos/uso terapéutico , Servicios de Laboratorio Clínico , ADN Bacteriano/genética , Farmacorresistencia Bacteriana , Humanos , Lesotho/epidemiología , Pruebas de Sensibilidad Microbiana/métodos , Modelos Teóricos , Técnicas de Amplificación de Ácido Nucleico/métodos , Sistemas de Atención de Punto , Rifampin/uso terapéutico , Programas Informáticos , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis Pulmonar/microbiología
20.
PLoS One ; 15(5): e0232482, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32357366

RESUMEN

The study was designed to assess whether plant extracts / phytochemical (D-Pinitol) synergistically combine with antituberculosis drugs and act on Mycobacterium smegmatis (M. smegmatis) as well as assess their mode of action on Mycobacterium tuberculosis (M.tb) Filamenting temperature sensitive mutant Z (FtsZ) protein. Resazurin microtitre plate assay (Checker board) was performed to analyze the activity of plant extracts against M. smegmatis. Synergistic behaviour of plant extracts / D-Pinitol with Isoniazid (INH) and Rifampicin (RIF) were determined by time-kill and checker board assays. Elongation of M. smegmatis cells due to this treatment was determined by light microscopy. The effect of Hexane methanol extract (HXM) plant extracts on cell viability was determined using PI/SYTO9 dual dye reporter Live/Dead assay. Action of HXM plant extracts / D-Pinitol on inhibition of FtsZ protein was done using Guanosine triphosphatase (GTPase) light scattering assay and quantitative Polymerase Chain Reaction (qPCR). The Hexane-methanolic plant extract of Acacia nilotica, Aegle marmelos and Glycyrrhiza glabra showed antimycobacterial activity at 1.56 ± 0.03, 1.32 ± 0.02 and 1.25 ± 0.03 mg/mL respectively and that of INH and RIF were 4.00 ± 0.06 µg/mL and 2.00 ± 0.04 µg/mL respectively. These plant extracts and major phytochemical exudate D-Pinitol was found to act synergistically with antimycobacterial drugs INH and RIF with an FIC index ~ 0.20. Time-Kill kinetics studies indicate that, these plant extracts were bacteriostatic in nature. D-Pinitol in conjunction with INH and RIF exhibited a 2 Log reduction in the growth of viable cells compared to untreated. Attempt to elucidate their mode of action through phenotypic analysis indicated that these plant extracts and D-Pinitol was found to interfere in cell division there by leading to an abnormal elongated cellular morphology. HXM extracts and D-Pinitol synergistically combined with the first line tuberculosis drugs, INH and RIF, to act on M. smegmatis. The increase in the length of M. smegmatis cells on treatment with D-Pinitol and HXM extract of the plants indicated that they hinder the cell division mechanism thereby leading to a filamentous phenotype, and finally leading to cell death. In addition, the integrity of the bacterial cell membrane is also altered causing cell death. Further gene expression analysis showed that these plant extracts and D-Pinitol hampers with function of FtsZ protein which was confirmed through in vitro inhibition of FtsZ-GTPase enzymatic activity.


Asunto(s)
Proteínas Bacterianas/genética , Proteínas del Citoesqueleto/genética , Mycobacterium smegmatis/efectos de los fármacos , Mycobacterium smegmatis/genética , Plantas Medicinales , Antituberculosos/administración & dosificación , Proteínas Bacterianas/antagonistas & inhibidores , División Celular/efectos de los fármacos , Proteínas del Citoesqueleto/antagonistas & inhibidores , Sinergismo Farmacológico , Regulación Bacteriana de la Expresión Génica/efectos de los fármacos , Genes Bacterianos/efectos de los fármacos , Humanos , Técnicas In Vitro , Inositol/administración & dosificación , Inositol/análogos & derivados , Isoniazida/administración & dosificación , Pruebas de Sensibilidad Microbiana , Mutación , Mycobacterium smegmatis/citología , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/genética , Extractos Vegetales/administración & dosificación , Rifampin/administración & dosificación , Temperatura
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