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1.
Nat Commun ; 12(1): 7312, 2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34911948

RESUMO

Recent advances in bacterial whole-genome sequencing have resulted in a comprehensive catalog of antibiotic resistance genomic signatures in Mycobacterium tuberculosis. With a view to pre-empt the emergence of resistance, we hypothesized that pre-existing polymorphisms in susceptible genotypes (pre-resistance mutations) could increase the risk of becoming resistant in the future. We sequenced whole genomes from 3135 isolates sampled over a 17-year period. After reconstructing ancestral genomes on time-calibrated phylogenetic trees, we developed and applied a genome-wide survival analysis to determine the hazard of resistance acquisition. We demonstrate that M. tuberculosis lineage 2 has a higher risk of acquiring resistance than lineage 4, and estimate a higher hazard of rifampicin resistance evolution following isoniazid mono-resistance. Furthermore, we describe loci and genomic polymorphisms associated with a higher risk of resistance acquisition. Identifying markers of future antibiotic resistance could enable targeted therapy to prevent resistance emergence in M. tuberculosis and other pathogens.


Assuntos
Antituberculosos/farmacologia , Farmacorresistência Bacteriana Múltipla , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Tuberculose/microbiologia , Genoma Bacteriano , Genômica , Humanos , Isoniazida/farmacologia , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/isolamento & purificação , Filogenia , Rifampina/farmacologia
2.
Ann Clin Microbiol Antimicrob ; 20(1): 84, 2021 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-34920727

RESUMO

BACKGROUND: There is paucity of data on the prevalence and distribution of multidrug- Resistant-Tuberculosis (MDR-TB) in the Republic of Congo. Among the challenges resides the implementation of a robust TB resistance diagnostic program using molecular tools. In resource limited settings there is a need to gather data to enable prioritization of actions. The objective of this study was is to implement molecular tools as a best of diagnosing MDR and XDR-TB among presumptive tuberculosis patients referred to reference hospital of Makelekele in Brazzaville, Republic of the Congo. METHODS: We have conducted a cross-sectional study, including a total of 92 presumptive pulmonary tuberculosis patients and who had never received treatment recruited at the reference hospital of Makelekele from October 2018 to October 2019. The socio-demographic and clinical data were collected as well as sputum samples. Rifampicin resistance was investigated using Xpert (Cepheid) and second-line TB drugs Susceptibility testing were performed by the Brucker HAIN Line Probe Assay (GenoType MTBDRsl VER 2.0 assay) method. RESULTS: From the 92 recruited patients, 57 (62%) were found positive for the Mycobacterium tuberculosis complex. The prevalence of rifampicin-resistant tuberculosis (RR-TB) was 9.8% (9/92) and importantly 2.2% were pre-XDR/XDR. CONCLUSION: This study showed a high rate of rifampicin resistance and the presence of extensively drug-resistant tuberculosis in the study area in new patients. This study highlights the need for further studies of TB drug resistance in the country.


Assuntos
Antituberculosos/farmacologia , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Mycobacterium tuberculosis/efeitos dos fármacos , Escarro/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Adolescente , Adulto , Antituberculosos/uso terapêutico , Congo/epidemiologia , Estudos Transversais , Tuberculose Extensivamente Resistente a Medicamentos/diagnóstico , Tuberculose Extensivamente Resistente a Medicamentos/epidemiologia , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/isolamento & purificação , Rifampina/farmacologia , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Adulto Jovem
3.
PLoS One ; 16(12): e0261442, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34919559

RESUMO

A laboratory validation study was conducted to assess the equivalence of Xpert MTB/RIF Ultra testing on the GeneXpert System and the GeneXpert Omni System ('Omni') for tuberculosis and rifampicin resistance. High concordance of the two devices was demonstrated for well-characterized clinical samples as well as control materials, with controls tested on Omni at normal and challenging environmental conditions (i.e. 35°C, 90% relative humidity). Equivalence of the Cts for all probes was also shown. Equivalence was demonstrated for the Omni and GeneXpert devices for tuberculosis and rifampicin resistance detection for a diverse range of clinical specimens and environmental conditions.


Assuntos
Antibióticos Antituberculose/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Testes Imediatos , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Pulmonar/diagnóstico , Proteínas de Bactérias/genética , RNA Polimerases Dirigidas por DNA/genética , Farmacorresistência Bacteriana Múltipla/genética , Humanos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/isolamento & purificação , Rifampina/farmacologia , Escarro/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Pulmonar/tratamento farmacológico
4.
PLoS One ; 16(12): e0261849, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34962960

RESUMO

BACKGROUND: Tuberculosis (TB) and COVID-19 pandemics are both diseases of public health threat globally. Both diseases are caused by pathogens that infect mainly the respiratory system, and are involved in airborne transmission; they also share some clinical signs and symptoms. We, therefore, took advantage of collected sputum samples at the early stage of COVID-19 outbreak in Ghana to conduct differential diagnoses of long-standing endemic respiratory illness, particularly tuberculosis. METHODOLOGY: Sputum samples collected through the enhanced national surveys from suspected COVID-19 patients and contact tracing cases were analyzed for TB. The sputum samples were processed using Cepheid's GeneXpert MTB/RIF assay in pools of 4 samples to determine the presence of Mycobacterium tuberculosis complex. Positive pools were then decoupled and analyzed individually. Details of positive TB samples were forwarded to the NTP for appropriate case management. RESULTS: Seven-hundred and seventy-four sputum samples were analyzed for Mycobacterium tuberculosis in both suspected COVID-19 cases (679/774, 87.7%) and their contacts (95/774, 12.3%). A total of 111 (14.3%) were diagnosed with SARS CoV-2 infection and six (0.8%) out of the 774 individuals tested positive for pulmonary tuberculosis: five (83.3%) males and one female (16.7%). Drug susceptibility analysis identified 1 (16.7%) rifampicin-resistant tuberculosis case. Out of the six TB positive cases, 2 (33.3%) tested positive for COVID-19 indicating a coinfection. Stratifying by demography, three out of the six (50%) were from the Ayawaso West District. All positive cases received appropriate treatment at the respective sub-district according to the national guidelines. CONCLUSION: Our findings highlight the need for differential diagnosis among COVID-19 suspected cases and regular active TB surveillance in TB endemic settings.


Assuntos
COVID-19/diagnóstico , COVID-19/epidemiologia , Coinfecção/diagnóstico , Coinfecção/epidemiologia , Mycobacterium tuberculosis/genética , Pandemias/prevenção & controle , SARS-CoV-2/genética , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/epidemiologia , Antibióticos Antituberculose/farmacologia , COVID-19/prevenção & controle , COVID-19/virologia , Coinfecção/virologia , Diagnóstico Diferencial , Farmacorresistência Bacteriana/efeitos dos fármacos , Feminino , Gana/epidemiologia , Humanos , Masculino , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Rifampina/farmacologia , Escarro/microbiologia , Tuberculose Pulmonar/microbiologia
5.
Front Immunol ; 12: 656419, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34745081

RESUMO

Tuberculosis (TB) is the global health problem with the second highest number of deaths from a communicable disease after COVID-19. Although TB is curable, poor health infrastructure, long and grueling TB treatments have led to the spread of TB pandemic with alarmingly increasing multidrug-resistant (MDR)-TB prevalence. Alternative host modulating therapies can be employed to improve TB drug efficacies or dampen the exaggerated inflammatory responses to improve lung function. Here, we investigated the adjunct therapy of natural immune-modulatory compound berberine in C57BL/6 mouse model of pulmonary TB. Berberine treatment did not affect Mtb growth in axenic cultures; however, it showed increased bacterial killing in primary murine bone marrow-derived macrophages and human monocyte-derived macrophages. Ad libitum berberine administration was beneficial to the host in combination with rifampicin and isoniazid. Berberine adjunctive treatment resulted in decreased lung pathology with no additive or synergistic effects on bacterial burdens in mice. Lung immune cell flow cytometry analysis showed that adjunctive berberine treatment decreased neutrophil, CD11b+ dendritic cell and recruited interstitial macrophage numbers. Late onset of adjunctive berberine treatment resulted in a similar phenotype with consistently reduced numbers of neutrophils both in lungs and the spleen. Together, our results suggest that berberine can be supplemented as an immunomodulatory agent depending on the disease stage and inflammatory status of the host.


Assuntos
Antituberculosos/uso terapêutico , Berberina/uso terapêutico , Fatores Imunológicos/uso terapêutico , Isoniazida/uso terapêutico , Rifampina/uso terapêutico , Tuberculose Pulmonar/tratamento farmacológico , Animais , Antituberculosos/farmacologia , Berberina/farmacologia , Citocinas/imunologia , Células Dendríticas/efeitos dos fármacos , Quimioterapia Combinada , Feminino , Humanos , Fatores Imunológicos/farmacologia , Isoniazida/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/crescimento & desenvolvimento , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Rifampina/farmacologia , Baço/efeitos dos fármacos , Baço/imunologia , Baço/microbiologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologia
7.
Int J Tuberc Lung Dis ; 25(11): 911-916, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34686233

RESUMO

BACKGROUND: Recommended by the World Health Organization as an initial diagnostic test for TB in children, Xpert® MTB/RIF is widely implemented in many countries, including Kenya.METHODS: Three hundred HIV-positive and negative children (<5 years) were enrolled in Kisumu County, Kenya, from October 2013 to August 2015. Multiple specimen types were collected from each child and tested using Xpert, liquid culture, and phenotypic drug susceptibility testing (DST). Samples positive for rifampin (RIF) resistance on Xpert were tested using line-probe assay and sequencing.RESULTS: Of 32 children with bacteriologically confirmed TB, 27 had positive Xpert results. Of these, 3/27 (11%, 95% CI 4-28) had RIF resistance detected on Xpert, but not by phenotypic DST, line-probe assay, or sequencing. For these three children, five Xpert tests showed RIF resistance; all five tests had semi-quantitative "very low" results and delay or absence of probe D signal, whereas no Xpert results with higher semi-quantitative results showed RIF resistance. All three children responded well to standard TB treatment.CONCLUSIONS: False RIF resistance may be detected in pediatric specimens. Further study is needed to determine if false RIF resistance is associated with low bacterial load.


Assuntos
Antibióticos Antituberculose , Mycobacterium tuberculosis , Tuberculose Pulmonar , Antibióticos Antituberculose/uso terapêutico , Criança , Farmacorresistência Bacteriana , Humanos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/genética , Rifampina/farmacologia , Sensibilidade e Especificidade , Tuberculose Pulmonar/tratamento farmacológico
8.
Int J Tuberc Lung Dis ; 25(10): 832-838, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34615580

RESUMO

BACKGROUND: South Africa´s diagnostic algorithm for TB diagnosis from 2011 to 2017 employed the Xpert® MTB/RIF assay as the initial screening test for TB diagnosis and rifampicin (RIF) susceptibility, followed by submission of a specimen for GenoType® MTBDRplus. This study aimed to determine the concordance between the two assays in terms of RIF susceptibility and explore reasons for discordance.METHODS: This was a retrospective laboratory-based study that included all MTBDRplus results of tests performed at the Braamfontein Mycobacteriology Referral Laboratory between 1 September 2014 and 31 August 2015. The patient´s Xpert RIF result was linked with the MTBDRplus result.RESULTS: The overall concordance between RIF susceptibility results was 96.4%. There were 68 discordant RIF results. The most common reasons for discordance identified were possible false Xpert RIF-resistant results (22%), mixed infection/heteroresistance (16%), transcription errors (7%) and erroneous manual interpretation of the MTBDRplus strip (7%). Xpert RIF resistance detected using delayed hybridisation was associated with discordance.CONCLUSIONS: The overall concordance between the MTBDRplus and Xpert RIF results were very good. Management of discordance should include repeat specimens for Xpert and MTBDRplus and rpoB sequencing. All variables should then be considered before treatment regimens are altered.


Assuntos
Antibióticos Antituberculose , Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Antibióticos Antituberculose/farmacologia , Antibióticos Antituberculose/uso terapêutico , Farmacorresistência Bacteriana , Humanos , Mycobacterium tuberculosis/genética , Estudos Retrospectivos , Rifampina/farmacologia , Sensibilidade e Especificidade , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico
10.
Pan Afr Med J ; 39: 128, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34527144

RESUMO

Introduction: Zimbabwe is one of the 30 countries globally with a high burden of multidrug-resistant TB or rifampicin-resistant TB. The World Health Organization recommended that patients diagnosed with multidrug-resistant TB be treated with 20-24 month standardized second-line drugs since 2010. However, factors associated with mortality and treatment success have not been systematically evaluated in Zimbabwe. The Objective of the study was to assess factors associated with Mortality and treatment success among multidrug-resistant-TB patients registered and treated under the National Tuberculosis programme in Zimbabwe. Methods: the study was conducted using secondary data routinely collected from the National tuberculosis (TB) programme. Categorical variables were summarised using frequencies and a generalized linear model with a log-link function and a Poisson distribution was used to assess factors associated with mortality and treatment success. The level of significance was set at P-Value < 0.05. Results: patient antiretroviral therapy (ART) status was a significant associated factor of treatment success or failure (RRR = 3.92, p < 0.001). Patients who were not on ART had a high risk of death by 3.92 times compared to patients who were on ART. In the age groups 45 - 54 years (relative risk ratios (RRR) = 1.41, p = 0.048), the risk of death was increased by 1.41 times compared to other age groups. Patients aged 55 years and above (RRR = 1.55, p = 0.017), had a risk of dying increased by 1.55 times compared to other age groups. Diagnosis time duration of 8 - 30 days (RRR = 0.62, p = 0.022) was found to be protective, a shorter diagnosis time duration between 8 to 30 days reduced the risk of TB deaths by 0.62 times compared to longer periods. Missed TB doses of > 10% (RRR = 2.03, p < 0.001) increased the risk of MDR/RR-TB deaths by 2.03 times compared to missing TB doses of ≤ 10%. Conclusion: not being on ART when HIV positive was a major significant predictor of mortality. Improving ART uptake among those ART-naïve and strategies aimed at improving treatment adherence are important in improving treatment success rates.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Antituberculosos/administração & dosagem , Infecções por HIV/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Adolescente , Adulto , Fatores Etários , Antituberculosos/farmacologia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Rifampina/farmacologia , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/mortalidade , Adulto Jovem , Zimbábue
11.
Antimicrob Agents Chemother ; 65(11): e0065821, 2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34491807

RESUMO

Biofilm has recently been highlighted as a complicating feature of necrotizing soft tissue infections (NSTI) caused by Streptococcus pyogenes (i.e., group A Streptococcus [GAS]) contributing to a persistence of bacteria in tissue despite prolonged antibiotic therapy. Here, we assessed the standard treatment of benzylpenicillin and clindamycin with or without rifampin in a tissue-like setting. Antibiotic efficacy was evaluated by CFU determination in a human organotypic skin model infected for 24 or 48 h with GAS strains isolated from NSTI patients. Antibiotic effect was also evaluated by microcalorimetric metabolic assessment in in vitro infections of cellular monolayers providing continuous measurements over time. Adjunctive rifampin resulted in enhanced antibiotic efficacy of bacterial clearance in an organotypic skin tissue model, 97.5% versus 93.9% (P = 0.006). Through microcalorimetric measurements, adjunctive rifampin resulted in decreased metabolic activity and extended lag phase for all clinical GAS strains tested (P < 0.05). In addition, a case report is presented of adjunctive rifampin treatment in an NSTI case with persistent GAS tissue infection. The findings of this study demonstrate that adjunctive rifampin enhances clearance of GAS biofilm in an in vitro tissue infection model.


Assuntos
Infecções dos Tecidos Moles , Infecções Estreptocócicas , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Humanos , Rifampina/farmacologia , Infecções dos Tecidos Moles/tratamento farmacológico , Infecções Estreptocócicas/tratamento farmacológico , Streptococcus pyogenes
12.
PLoS One ; 16(9): e0257647, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34543329

RESUMO

INTRODUCTION: Despite the exalted status of sputum mycobacterial load for gauging pulmonary tuberculosis treatment and progress, Chest X-rays supplement valuable information for taking instantaneous therapeutic decisions, especially during the COVID-19 pandemic. Even though literature on individual parameters is overwhelming, few studies have explored the interaction between radiographic parameters denoting severity with mycobacterial burden signifying infectivity. By using a sophisticated approach of integrating Chest X-ray parameters with sputum mycobacterial characteristics, evaluated at all the three crucial time points of TB treatment namely pre-treatment, end of intensive phase and completion of treatment, utilizing the interactive Cox Proportional Hazards model, we aimed to precisely deduce predictors of unfavorable response to TB treatment. MATERIALS AND METHOD: We extracted de-identified data from well characterized clinical trial cohorts that recruited rifampicin-sensitive Pulmonary TB patients without any comorbidities, taking their first spell of anti-tuberculosis therapy under supervision and meticulous follow up for 24 months post treatment completion, to accurately predict TB outcomes. Radiographic data independently obtained, interpreted by two experienced pulmonologists was collated with demographic details and, sputum smear and culture grades of participants by an independent statistician and analyzed using the Cox Proportional Hazards model, to not only adjust for confounding factors including treatment effect, but also explore the interaction between radiological and bacteriological parameters for better therapeutic application. RESULTS: Of 667 TB patients with data available, cavitation, extent of involvement, lower zone involvement, smear and culture grade at baseline were significant parameters predisposing to an unfavorable TB treatment outcome in the univariate analysis. Reduction in radiological lesions in Chest X-ray by at least 50% at 2 months and 75% at the end of treatment helped in averting unfavorable responses. Smear and Culture conversion at the end of 2 months was highly significant as a predictor (p<0.001). In the multivariate analysis, the adjusted hazards ratios (HR) for an unfavorable response to TB therapy for extent of involvement, baseline cavitation and persistence (post treatment) were 1.21 (95% CI: 1.01-1.44), 1.73 (95% CI: 1.05-2.84) and 2.68 (95% CI: 1.4-5.12) respectively. A 3+ smear had an HR of 1.94 (95% CI: 0.81-4.64). Further probing into the interaction, among patients with 3+ and 2+ smears, HRs for cavitation were 3.26 (95% CI: 1.33-8.00) and 1.92 (95% CI: 0.80-4.60) while for >2 zones, were 3.05 (95% CI: 1.12-8.23) and 1.92 (95% CI: 0.72-5.08) respectively. Patients without cavitation, zonal involvement <2, and a smear grade less than 2+ had a better prognosis and constituted minimal disease. CONCLUSION: Baseline Cavitation, Opacities occupying >2 zones and 3+ smear grade individually and independently forecasted a poorer TB outcome. The interaction model revealed that Zonal involvement confined to 2 zones, without a cavity and smear grade up to 2+, constituting "minimal disease", had a better prognosis. Radiological clearance >50% along with smear conversion at the end of intensive phase of treatment, observed to be a reasonable alternative to culture conversion in predicting a successful outcome. These parameters may potentially take up key positions as stratification factors for future trials contemplating on shorter TB regimens.


Assuntos
Mycobacterium tuberculosis/fisiologia , Rifampina/uso terapêutico , Escarro/microbiologia , Tuberculose Pulmonar/diagnóstico por imagem , Tuberculose Pulmonar/tratamento farmacológico , Adulto , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Análise Multivariada , Modelos de Riscos Proporcionais , Rifampina/farmacologia , Resultado do Tratamento , Tuberculose Pulmonar/microbiologia , Adulto Jovem
13.
Int J Pharm ; 608: 121097, 2021 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-34534632

RESUMO

Tuberculosis (TB) treatment has become a challenge because of the natural presence of multilayered cell wall rich in lipids which restrict antibiotic permeability within the bacteria. The development of mutations conferring resistance has aggravated the situation. Consequently, maximum pharmaceutical efforts are required to improve the treatment, and antimicrobial peptides (AMPs) with antimycobacterial activity can be exploited as a new treatment strategy against TB. The synergistic interaction between conventional antibiotics and AMPs has broadened its application landscape. To overcome peptide instability and bioavailability issues, encapsulation of these bioactive in biocompatible polymers was adopted. In this study, the effect of synthetic AMPs HHC-8 [KIWWWWRKR] and MM-10 [MLLKKLLKKM] encapsulated in poly (ε-caprolactone) nanoparticles (PCL-NPs) was evaluated against mycobacteria using REMA (Resazurin Microtiter Assay Plate) technique. PCL encapsulation allowed us to load the required amount of peptides, i.e. HHC-8 and MM-10, with an efficiency of âˆ¼ 18.9 ± 5.24 and âˆ¼ 21.1 ± 6.19 % respectively, and sphere size was around 376.5 ± 14.9 nm and 289.87 ± 17.98 nm for PCL-HHC-8-NPs and PCL-MM-10-NPs, respectively. Minimal degradation and sustained release of peptides from nanoparticles improved antimicrobial activity, decreasing the MIC50 from 75 µg/ml to 18.75 µg/ml against M. smegmatis and from 75 µg/ml to 9 µg/ml against M. tuberculosis, respectively. The combinatorial MIC assays of encapsulated AMP with rifampicin antibiotics against M. smegmatis showed synergism between AMP-PCL-NPs and antibiotics with fractional inhibitory concentrations (FICs) around âˆ¼ 0.09. The combinations of AMP NPs also demonstrated synergy against the mycobacteria. Our findings suggest that enhanced efficacy is due to protection offered by AMPs encapsulation resulting in augmentation of membrane permeation by AMPs and enhanced accumulation of antibiotics within mycobacteria resulting in synergy. The study findings might assist in the preclinical development of AMP for the fight against TB.


Assuntos
Mycobacterium tuberculosis , Nanopartículas , Antibacterianos/farmacologia , Caproatos , Lactonas , Proteínas Citotóxicas Formadoras de Poros , Rifampina/farmacologia
14.
BMC Infect Dis ; 21(1): 891, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34465301

RESUMO

BACKGROUND: Determining factors affecting the transmission of rifampicin (RR) and multidrug-resistant (MDR) Mycobacterium tuberculosis complex strains under standardized tuberculosis (TB) treatment is key to control TB and prevent the evolution of drug resistance. METHODS: We combined bacterial whole genome sequencing (WGS) and epidemiological investigations for 37% (n = 195) of all RR/MDR-TB patients in Cameroon (2012-2015) to identify factors associated with recent transmission. RESULTS: Patients infected with a strain resistant to high-dose isoniazid, and ethambutol had 7.4 (95% CI 2.6-21.4), and 2.4 (95% CI 1.2-4.8) times increased odds of being in a WGS-cluster, a surrogate for recent transmission. Furthermore, age between 30 and 50 was positively correlated with recent transmission (adjusted OR 3.8, 95% CI 1.3-11.4). We found high drug-resistance proportions against three drugs used in the short standardized MDR-TB regimen in Cameroon, i.e. high-dose isoniazid (77.4%), ethambutol (56.9%), and pyrazinamide (43.1%). Virtually all strains were susceptible to fluoroquinolones, kanamycin, and clofazimine, and treatment outcomes were mostly favourable (87.5%). CONCLUSION: Pre-existing resistance to high-dose isoniazid, and ethambutol is associated with recent transmission of RR/MDR strains in our study. A possible contributing factor for this observation is the absence of universal drug susceptibility testing in Cameroon, likely resulting in prolonged exposure of new RR/MDR-TB patients to sub-optimal or failing first-line drug regimens.


Assuntos
Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Adulto , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Camarões/epidemiologia , Estudos Epidemiológicos , Genômica , Humanos , Isoniazida/farmacologia , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Mycobacterium tuberculosis/genética , Rifampina/farmacologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia
15.
BMC Infect Dis ; 21(1): 781, 2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34372793

RESUMO

BACKGROUND: Detection of tuberculosis disease (TB) and timely identification of Mycobacterium tuberculosis (Mtb) strains that are resistant to treatment are key to halting tuberculosis transmission, improving treatment outcomes, and reducing mortality. METHODS: We used 332,657 Xpert MTB/RIF assay results, captured as part of the Myanmar Data Utilization Project, to characterize Mtb test positivity and rifampicin resistance by both age and sex, and to evaluate risk factors associated with rifampicin resistance. RESULTS: Overall, 70% of individuals diagnosed with TB were males. Test positivity was higher among males (47%) compared to females (39%). The highest positivity by age occurred among individuals aged 16-20, with test positivity for females (65%) higher than for males (57%). Although a greater absolute number of males were rifampicin resistant, a greater proportion of females (11.4%) were rifampicin resistant as compared to males (9.3%). In the multivariate model, history of previous treatment, age less than 30, testing in the Yangon region, and female sex were significantly positively associated with rifampicin resistance after adjusting for HIV status and year test was performed. CONCLUSIONS: Our results indicate that young adults were more likely to test positive for TB and be identified as rifampicin resistant compared to older adults.


Assuntos
Antibióticos Antituberculose , Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Tuberculose Pulmonar , Tuberculose , Idoso , Antibióticos Antituberculose/farmacologia , Antibióticos Antituberculose/uso terapêutico , Farmacorresistência Bacteriana/efeitos dos fármacos , Feminino , Humanos , Masculino , Mianmar/epidemiologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Rifampina/farmacologia , Sensibilidade e Especificidade , Distribuição por Sexo , Tuberculose/tratamento farmacológico , Tuberculose/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Tuberculose Pulmonar/tratamento farmacológico , Adulto Jovem
16.
Braz J Biol ; 83: e244311, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34431905

RESUMO

Tuberculosis is a communicable disease with high morbidity and mortality rates in developing countries. The study's primary objective is to compare conventional methods such as acid-fast bacillus (AFB) culture and microscopy with rapid diagnostic methods. The secondary objective is to compare histopathological and microbiological findings in suspected patients with tubercular lymphadenitis. A total of 111 samples (August 2018 to September 2019) of lymph nodes were processed for AFB microscopy, AFB cultures, drug-susceptibility testing (DST), histopathology, and Xpert Mycobacterium Tuberculosis (MTB)/resistance to Rifampin (RIF) assays. Out of 111 lymph node samples, 6 (5.4%) were positive for AFB smear microscopy, 84 (75.6%) were positive for AFB culture, 80 (70.7%) were positive on Gene Xpert, and 102 (91.8%) were indicative of tuberculosis for histopathology studies. Mycobacteria growth indicator tube (MGIT) culture positivity was 84 (75.6%) higher than solid Lowenstein-Jensen (LJ) culture 74 (66.6%). Positive cultures underwent phenotypic DST. Two cases were Multidrug-resistant (MDR) on DST, while three cases were Rifampicin resistant on Gene Xpert. The sensitivity of Genexpert was (62%) against the conventional AFB culture method. The poor performance of conventional lymphadenitis diagnostic methods requires early and accurate diagnostic methodology. Xpert MTB/RIF test can help in the treatment of multidrug-resistant TB cases. Nonetheless, rapid and conventional methods should be used for complete isolation of Mycobacterium tuberculosis.


Assuntos
Mycobacterium tuberculosis , Tuberculose dos Linfonodos , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Rifampina/farmacologia , Rifampina/uso terapêutico , Tuberculose dos Linfonodos/diagnóstico
17.
Sci Rep ; 11(1): 17387, 2021 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-34462504

RESUMO

Multi-drug (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) continues to be a global public health problem especially in high TB burden countries like Nigeria. Many of these cases are undetected and go on to infect high risk individuals. Clinical samples from positive rifampicin resistant Xpert®MTB/Rif assay were subjected to direct whole genome sequencing and bioinformatics analysis to identify the full antibiotics resistance and lineage profile. We report two (2) XDR TB samples also belonging to the East-Asian/Beijing family of lineage 2 Mycobacterium tuberculosis complex from clinical samples in Nigeria. Our findings further reveal the presence of mutations that confer resistance to first-line drugs (rifampicin, isoniazid, ethambutol and pyrazanimide), second-line injectables (capreomycin, streptomycin, kanamycin and/or amikacin) and at least one of the fluoroquinolones (ofloxacin, moxifloxacin, levofloxacin and/or ciprofloxacin) in both samples. The genomic sequence data from this study not only provide the first evidence of XDR TB in Nigeria and West Africa, but also emphasize the importance of WGS in accurately detecting MDR and XDR TB, to ensure adequate and proper management treatment regimens for affected individuals. This will greatly aid in preventing the spread of drug resistance TB in high burden countries.


Assuntos
Tuberculose Extensivamente Resistente a Medicamentos/diagnóstico , Mycobacterium tuberculosis/genética , Adulto , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Capreomicina/farmacologia , Capreomicina/uso terapêutico , DNA Bacteriano/química , DNA Bacteriano/metabolismo , Tuberculose Extensivamente Resistente a Medicamentos/complicações , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Feminino , Fluoroquinolonas/farmacologia , Fluoroquinolonas/uso terapêutico , Infecções por HIV/complicações , Infecções por HIV/diagnóstico , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Mycobacterium tuberculosis/classificação , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Nigéria , Filogenia , Rifampina/farmacologia , Rifampina/uso terapêutico , Sequenciamento Completo do Genoma , Adulto Jovem
18.
FEMS Microbiol Lett ; 368(14)2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34240144

RESUMO

The bacterial populations surviving in the presence of antibiotics contain cells that have gained genetic resistance, phenotypic resistance and tolerance to antibiotics. Isolation of live bacterial population, surviving against antibiotics, from the milieu of high proportions of dead/damaged cells will facilitate the study of the cellular/molecular processes used by them for survival. Here we present a Percoll gradient centrifugation based method for the isolation of enriched population of Mycobacterium smegmatis surviving in the presence of bactericidal concentrations of rifampicin and moxifloxacin. From the time of harvest, throughout the enrichment and isolation processes, and up to the lysis of the cells for total RNA preparation, we maintained the cells in the presence of the antibiotic to avoid changes in their metabolic status. The total RNA extracted from the enriched population of live antibiotic-surviving population showed structural integrity and purity. We analysed the transcriptome profile of the antibiotic-surviving population and compared it with the orthologue genes of Mycobacterium tuberculosis that conferred antibiotic tolerance on tubercle bacilli isolated from the tuberculosis patients under treatment with four antitubercular antibiotics. Statistically significant comparability between the gene expression profiles of the antibiotic tolerance associated genes of M. smegmatis and M. tuberculosis validated the reliability/utility of the method.


Assuntos
Técnicas Bacteriológicas/métodos , Moxifloxacina/farmacologia , Mycobacterium smegmatis/isolamento & purificação , Mycobacterium smegmatis/fisiologia , Rifampina/farmacologia , Antituberculosos/farmacologia , Tolerância a Medicamentos/genética , Perfilação da Expressão Gênica , Humanos , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Viabilidade Microbiana/genética , Infecções por Mycobacterium não Tuberculosas/microbiologia , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium smegmatis/genética , Reprodutibilidade dos Testes
19.
Clin Lab ; 67(7)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34258958

RESUMO

BACKGROUND: Xpert MTB/RIF is recommended by the World Health Organization (WHO) for a rapid and simultaneous detection of Mycobacterium tuberculosis (Mtb) and rifampicin resistance specific to patients who have symptoms and signs. METHODS: The aim of this study was to evaluate the diagnostic significance possessed by various assays specific to the detection of Mtb. This study included 345 suspected TB patients who received treatment at the Shandong Public Health Clinical Center during May 2019 and August 2019. Related data included demographics, gender, age, past medical history (PMH), country of birth, country of residence, clinical information and laboratory test outcomes. The smear method was performed three times, the BD960 method was conducted two times and the MTB/ RIF and Xpert Ultra (phlegm precipitation) assays were performed once. All methods were completed simultaneously. RESULTS: The Xpert Ultra MTB (phlegm precipitation) method exhibited the highest consistency and sensitivity, followed by the Xpert MTB, Mtb culture, and smear methods, respectively. The Xpert Ultra MTB method also exhibited a significantly higher detection rate relative to the smear method (X2 = 13.411, p < 0.001). CONCLUSIONS: Xpert MTB/RIF along with Xpert Ultra (phlegm precipitation) exhibited higher sensitivity specific for the diagnosis of TB and rifampicin-resistance. The combined effects of these four methods showed outstanding sensitivity compared with single methods alone.


Assuntos
Antibióticos Antituberculose , Mycobacterium tuberculosis , Tuberculose Pulmonar , Antibióticos Antituberculose/farmacologia , Antibióticos Antituberculose/uso terapêutico , Farmacorresistência Bacteriana , Humanos , Mycobacterium tuberculosis/genética , Rifampina/farmacologia , Sensibilidade e Especificidade , Escarro , Tuberculose Pulmonar/tratamento farmacológico
20.
J Infect Chemother ; 27(11): 1578-1583, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34244055

RESUMO

INTRODUCTION: Rifampicin (RIF) is one of the most effective anti-tuberculosis first-line drugs prescribed along with isoniazid. However, the emergence of RIF resistance Mycobacterium tuberculosis (MTB) isolates is a major issue towards tuberculosis (TB) control program in high MDR TB-burdened countries including Pakistan. Molecular data behind phenotypic resistance is essential for better management of RIF resistance which has been linked with mutations in rpoB gene. Since molecular studies on RIF resistance is limited in Pakistan, the current study was aimed to investigate the molecular data of mutations in rpoB gene behind phenotypic RIF resistance isolates in Pakistan. METHOD: A total of 322 phenotypically RIF-resistant isolates were randomly selected from National TB Reference Laboratory, Pakistan for sequencing while 380 RIF resistance whole-genome sequencing (WGS) of Pakistani isolates (BioProject PRJEB25972), were also analyzed for rpoB mutations. RESULT: Among the 702 RIF resistance samples, 675 (96.1%) isolates harbored mutations in rpoB in which 663 (94.4%) were detected within the Rifampicin Resistance Determining Region (RRDR) also known as a mutation hot spot region, including three novel. Among these mutations, 657 (97.3%) were substitutions including 603 (89.3%) single nucleotide polymorphism, 49 (7.25%) double and five (0.8%) triple. About 94.4% of Phenotypic RIF resistance strains, exhibited mutations in RRDR, which were also detectable by GeneXpert. CONCLUSION: Mutations in the RRDR region of rpoB is a major mechanism of RIF resistance in MTB circulating isolates in Pakistan. Molecular detection of drug resistance is a faster and better approach than phenotypic drug susceptibility testing to reduce the time for transmission of RIF resistance strains in population. Such insights will inform the deployment of anti-TB drug regimens and disease control tools and strategies in high burden settings, such as Pakistan.


Assuntos
Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Antituberculosos/farmacologia , Proteínas de Bactérias/genética , RNA Polimerases Dirigidas por DNA/genética , Humanos , Testes de Sensibilidade Microbiana , Mutação , Mycobacterium tuberculosis/genética , Paquistão , Rifampina/farmacologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico
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