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1.
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
2.
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
5.
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
6.
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
7.
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
8.
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
9.
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
10.
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
11.
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
12.
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
13.
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
14.
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
15.
Sheng Wu Gong Cheng Xue Bao ; 37(7): 2503-2512, 2021 Jul 25.
Artigo em Chinês | MEDLINE | ID: mdl-34327915

RESUMO

The purpose of this study is to provide a simple and reliable genetic typing approach for molecular drug susceptibility test of Mycobacterium tuberculosis, through the developing of fluorescence molecular marker of rifampicin resistance gene rpoB. Eleven fluorescent molecular markers of the rpoB gene were established by using the sequence difference between the amino acid positions 531, 526, 516, 511 and 513 of rpoB gene of rifampicin-resistant strains and the alleles of rifampicin-sensitive strains, combined with the PARMS technique (Penta-primer amplification refractory mutation system). We used 104 clinical isolates of Mycobacterium tuberculosis to validate this marker and it was verified by sequencing as 100% correct. These samples were also tested with proportional drug sensitivity test. The coincidence rate was 94.23%. The molecular markers had high reliability for genotyping of rpoB gene. It can also detect low-concentration drug-resistant samples (511/533 unit point mutations) whose phenotypic susceptibility cannot be detected. The eleven sets of fluorescent molecular markers could cover 92%-96% of rpoB gene mutation types of rifampicin-resistant strains, and provide new idea for rapid detection of rifampin-resistant Mycobacterium tuberculosis.


Assuntos
Mycobacterium tuberculosis , Rifampina , Proteínas de Bactérias/genética , RNA Polimerases Dirigidas por DNA/genética , Farmacorresistência Bacteriana/genética , Testes de Sensibilidade Microbiana , Mutação , Mycobacterium tuberculosis/genética , Reprodutibilidade dos Testes , Rifampina/farmacologia , Tecnologia
16.
Antimicrob Agents Chemother ; 65(9): e0104321, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34228545

RESUMO

Rifamycins are widely used for treating mycobacterial and staphylococcal infections. Drug-drug interactions (DDI) caused by rifampicin (RIF) are a major issue. We used a model-based approach to predict the magnitude of DDI with RIF and rifabutin (RBT) for 217 cytochrome P450 (CYP) substrates. On average, DDI caused by low-dose RIF were twice as potent as those caused by RBT. Contrary to RIF, RBT appears unlikely to cause severe DDI, even with sensitive CYP substrates.


Assuntos
Preparações Farmacêuticas , Rifamicinas , Interações Medicamentosas , Rifabutina/farmacologia , Rifampina/farmacologia
17.
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
18.
Antimicrob Agents Chemother ; 65(9): e0050421, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34228548

RESUMO

Antimicrobial resistance (AMR) poses a threat to global health and the economy. Rifampicin-resistant Mycobacterium tuberculosis accounts for a third of the global AMR burden. Gaining the upper hand on AMR requires a deeper understanding of the physiology of resistance. AMR often results in a fitness cost in the absence of drug. Identifying the molecular mechanisms underpinning this cost could help strengthen future treatment regimens. Here, we used a collection of M. tuberculosis strains that provide an evolutionary and phylogenetic snapshot of rifampicin resistance and subjected them to genome-wide transcriptomic and proteomic profiling to identify key perturbations of normal physiology. We found that the clinically most common rifampicin resistance-conferring mutation, RpoB Ser450Leu, imparts considerable gene expression changes, many of which are mitigated by the compensatory mutation in RpoC Leu516Pro. However, our data also provide evidence for pervasive epistasis-the same resistance mutation imposed a different fitness cost and functionally distinct changes to gene expression in genetically unrelated clinical strains. Finally, we report a likely posttranscriptional modulation of gene expression that is shared in most of the tested strains carrying RpoB Ser450Leu, resulting in an increased abundance of proteins involved in central carbon metabolism. These changes contribute to a more general trend in which the disruption of the composition of the proteome correlates with the fitness cost of the RpoB Ser450Leu mutation in different strains.


Assuntos
RNA Polimerases Dirigidas por DNA , Mycobacterium tuberculosis , Proteínas de Bactérias/genética , RNA Polimerases Dirigidas por DNA/genética , Farmacorresistência Bacteriana/genética , Testes de Sensibilidade Microbiana , Mutação , Mycobacterium tuberculosis/genética , Filogenia , Proteômica , Rifampina/farmacologia
19.
J Glob Antimicrob Resist ; 26: 207-218, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34214698

RESUMO

OBJECTIVES: Globally, the incidence and mortality of tuberculosis (TB) are declining; however, low detection of drug-resistant disease threatens to reverse current progress toward global TB control. Multiple rapid molecular diagnostic tests have recently been developed to detect genetic mutations in Mycobacterium tuberculosis (Mtb) known to confer drug resistance. However, their utility depends on the frequency and distribution of resistance-associated mutations in the pathogen population. This review aimed to assess the prevalence of gene mutations associated with rifampicin (RIF)- and isoniazid (INH)-resistant Mtb in Ethiopia. METHODS: We searched the literature in PubMed/MEDLINE, Web of Science, Scopus and Cochrane Library. Data analysis was conducted in Stata 11. RESULTS: Totally, 909 (95.8%) of 949 INH-resistant Mtb isolates had detectable gene mutations: 95.8% in katG315 and 5.9% in the inhA promoter region. Meta-analysis resulted in an estimated pooled prevalence of katGMUT1(S315T1) of 89.2% (95% CI 81.94-96.43%) and a pooled prevalence of inhAMUT1(C15T) of 77.5% (95% CI 57.84-97.13%). Moreover, 769 (90.8%) of 847 RIF-resistant strains had detectable rpoB gene mutations. Meta-analysis resulted in a pooled prevalence of rpoBMUT3(S531L) of 74.2% (95% CI 66.39-82.00%). CONCLUSION: RIF-resistant Mtb were widespread, particularly those harbouring rpoB(S531L) mutation. Similarly, INH-resistant Mtb with katG(S315T1) and inhA(C15T) mutations were common. Tracking S531L, S315T1 and C15T mutations among RIF- and INH-resistant isolates, respectively, would be diagnostically and epidemiologically valuable. Rapid diagnosis of RIF- and INH-resistant Mtb would expedite modification of TB treatment regimens, and proper timely infection control interventions could reduce the risk of development and transmission of multidrug-resistant TB.


Assuntos
Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Resistência a Medicamentos , Etiópia/epidemiologia , Humanos , Isoniazida/farmacologia , Testes de Sensibilidade Microbiana , Mutação , Mycobacterium tuberculosis/genética , Prevalência , Rifampina/farmacologia , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia
20.
Colloids Surf B Biointerfaces ; 206: 111976, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34280682

RESUMO

The main objective of this study was to investigate polyethylene imine (PEI) based stereocomplexed nanomiceles for intracellular delivery of rifampicin against Mycobacterium bovis (M. bovis) and their in vitro-in vivo evaluation. The formation of Rifampicin (Rif) loaded isotactic (PEI-g-PLLA and PEI-g-PDLA) and stereocomplexed nanomicelles (StM) of PEI conjugated poly l- and poly d-lactic acid via self-assembly was thoroughly explored. Synthesis of polymer graft was confirmed via FTIR and NMR. A 2-fold reduction in CMC of StM was observed along with decreased particle size in comparison to isotactic nanomicelles. In vitro, StM exhibited a higher encapsulation efficiency and 84 % of drug release in 48 h. at pH 5 with minimal initial burst release in comparison to isotactic nanomicelles. Minimum inhibitory concentration (MIC) of StM was found to be four folds lower in contrast to isotactic nanomicelles. Ex vivo studies exhibited a better uptake of StM and minimum cytotoxicity in murine alveolar macrophages. Following oral administration in mice, drug loaded StM exhibited highest distribution in macrophage rich organs, longer half-life, AUC, AUMC and MRT in comparison to isotactic nanomicelles indicating maximum bioavailability and efficacy of StM. In vivo antimycobacterial activity also demonstrated a higher reduction (2.38fold) in M. bovis CFU at reduced dosing frequency by drug loaded StM in comparison to control group. Thus, StM can be regarded as a simple, stable, efficient, and biocompatible carrier system for delivery of rifampicin to intracellular M. bovis with added advantage of reduced dosing frequency and improved patient compliance.


Assuntos
Mycobacterium bovis , Rifampina , Animais , Portadores de Fármacos , Liberação Controlada de Fármacos , Camundongos , Micelas , Polietilenoimina , Rifampina/farmacologia
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