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1.
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
2.
Am J Respir Crit Care Med ; 204(6): 713-722, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34107231

RESUMO

Rationale: Until 2020, extensively drug-resistant tuberculosis (XDR-TB) was defined as TB with resistance to rifampicin and isoniazid (multidrug-resistant TB [MDR-TB]), any fluoroquinolone (FQ), and any second-line injectable drug (SLID). In 2019, the World Health Organization issued new recommendations for treating patients with drug-resistant TB, substantially limiting the role of SLIDs in MDR-TB treatment and thus putting the definition of XDR-TB into question. Objectives: To propose an up-to-date definition for XDR-TB. Methods: We used a large data set to assess treatment outcomes for patients with MDR-TB exposed to any type of longer regimen. We included patients with bacteriologically confirmed MDR-TB and known FQ and SLID resistance results. We performed logistic regression to estimate the adjusted odds ratios (aORs) for an unfavorable treatment outcome (failure, relapse, death, loss to follow-up), and estimates were stratified by the resistance pattern (FQ and/or SLID) and group A drug use (moxifloxacin/levofloxacin, linezolid, and/or bedaquiline). Measurements and Main Results: We included 11,666 patients with MDR-TB; 4,653 (39.9%) had an unfavorable treatment outcome. Resistance to FQs increased the odds of an unfavorable treatment outcome (aOR, 1.91; 95% confidence interval [CI], 1.63-2.23). Administration of bedaquiline and/or linezolid improved treatment outcomes regardless of resistance to FQs and/or SLIDs. Among patients with XDR-TB, compared with persons receiving no group A drug, aORs for an unfavorable outcome were 0.37 (95% CI, 0.20-0.69) with linezolid only, 0.40 (95% CI, 0.21-0.77) with bedaquiline only, and 0.21 (95% CI, 0.12-0.38) with both. Conclusions: Our study supports a new definition of XDR-TB as MDR-TB and additional resistance to FQ plus bedaquiline and/or linezolid and helps assess the adequacy of this definition for surveillance and treatment choice.


Assuntos
Antituberculosos/uso terapêutico , Tuberculose Extensivamente Resistente a Medicamentos/diagnóstico , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Adulto , Idoso , Bases de Dados Factuais , Diarilquinolinas/uso terapêutico , Esquema de Medicação , Farmacorresistência Bacteriana Múltipla , Quimioterapia Combinada , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Feminino , Fluoroquinolonas/uso terapêutico , Humanos , Isoniazida/uso terapêutico , Linezolida/uso terapêutico , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Rifampina/uso terapêutico , Resultado do Tratamento
3.
Sci Rep ; 11(1): 9493, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33947918

RESUMO

Peru has the highest burden of multidrug-resistant tuberculosis in the Americas region. Since 1999, the annual number of extensively drug-resistant tuberculosis (XDR-TB) Peruvian cases has been increasing, becoming a public health challenge. The objective of this study was to perform genomic characterization of Mycobacterium tuberculosis strains obtained from Peruvian patients with XDR-TB diagnosed from 2011 to 2015 in Peru. Whole genome sequencing (WGS) was performed on 68 XDR-TB strains from different regions of Peru. 58 (85.3%) strains came from the most populated districts of Lima and Callao. Concerning the lineages, 62 (91.2%) strains belonged to the Euro-American Lineage, while the remaining 6 (8.8%) strains belonged to the East-Asian Lineage. Most strains (90%) had high-confidence resistance mutations according to pre-established WHO-confident grading system. Discordant results between microbiological and molecular methodologies were caused by mutations outside the hotspot regions analysed by commercial molecular assays (rpoB I491F and inhA S94A). Cluster analysis using a cut-off ≤ 10 SNPs revealed that only 23 (34%) strains evidenced recent transmission links. This study highlights the relevance and utility of WGS as a high-resolution approach to predict drug resistance, analyse transmission of strains between groups, and determine evolutionary patterns of circulating XDR-TB strains in the country.


Assuntos
Farmacorresistência Bacteriana Múltipla/genética , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Genoma Bacteriano/genética , Mycobacterium tuberculosis/genética , Adolescente , Adulto , Antituberculosos/uso terapêutico , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana/métodos , Pessoa de Meia-Idade , Mutação/genética , Mycobacterium tuberculosis/efeitos dos fármacos , Peru , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Sequenciamento Completo do Genoma/métodos , Adulto Jovem
4.
Eur J Clin Microbiol Infect Dis ; 40(9): 1851-1861, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33792806

RESUMO

This study aims to evaluate the clinical value of PCR-fluorescent probes for detecting the mutation gene associated with extensively drug-resistant tuberculosis (XDR-TB). The molecular species identification of 900 sputum specimens was performed using polymerase chain reaction (PCR)-fluorescent probe. The mutations of the drug resistance genes rpoB, katG, inhA, embB, rpsL, rrs, and gyrA were detected. The conventional drug susceptibility testing (DST) and PCR-directed sequencing (PCR-DS) were carried out as control. DST demonstrated that there were 501 strains of rifampicin resistance, 451 strains of isoniazid resistance, 293 strains of quinolone resistance, 425 strains of streptomycin resistance, 235 strains of ethambutol resistance, and 204 strains of amikacin resistance. Furthermore, 427 (47.44%) or 146 (16.22%) strains were MDR-TB or XDR-TB, respectively. The mutations of the rpoB, katG, inhA, embB, rpsL, rrs, and gyrA genes were detected in 751 of 900 TB patients by PCR-fluorescent probe method, and the rate of drug resistance was 751/900 (83.44%). No mutant genes were detected in the other 149 patients. Compared with DST, the mutant rates of rpoB, katG/inhA, rpsL, rrs, embB, and gyrA of six drugs were higher than 88%; five of six drugs were higher than 90% except for SM (88.11%). The MDR and XDR mutant gene types were found in 398 (42.22%) and 137 (15.22%) samples. PCR-DS was also employed and confirmed the PCR-fluorescent probe method with the accordance rate of 100%. The PCR-fluorescent probe method is rapid and straightforward in detecting XDR-TB genotypes and is worthy of being applied in hospitals.


Assuntos
Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Corantes Fluorescentes/normas , Mutação , Mycobacterium tuberculosis/genética , Reação em Cadeia da Polimerase/normas , Antituberculosos/farmacologia , Proteínas de Bactérias/genética , Farmacorresistência Bacteriana Múltipla , Corantes Fluorescentes/metabolismo , Corantes Fluorescentes/farmacologia , Genótipo , Humanos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Reação em Cadeia da Polimerase/métodos , Análise de Sequência de DNA , Escarro/microbiologia
5.
Eur J Med Res ; 26(1): 31, 2021 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-33812390

RESUMO

BACKGROUND: The aim of this study was to assess the treatment outcomes of multidrug and extensively drug-resistant tuberculosis (M/XDR-TB) in Zhejiang, China and to evaluate possible risk factors associated with poor outcomes of M/XDR-TB. METHODS: Two-hundred-and-sixty-two patients having M/XDR-TB who received the diagnosis and treatment at nine referral hospitals from 1 January 2016 to 31 December 2016 in Zhejiang, China were included. All patients received second-line regimens recommended by WHO under the DOTS-Plus strategy. RESULTS: Among the 262 patients, the treatment success rate was 55.34% (n = 145) with 53.44% (n = 140) cured and 1.91% (n = 5) who completed treatment, 62 (23.66%) failed, 27 (10.31%) died, 16 (6.11%) defaulted and 12 (4.58%) transferred out. Forty (64.52%) of the 62 M/XDR-TB patients who failed treatment were due to adverse effects in the first 10 months of treatment. Eighteen patients (6.37%) had XDR-TB. Treatment failure was significantly higher among patients with XDR-TB at 50% than that among patients with non-XDR-TB at 21.72% (P = 0.006). Failure outcomes were associated with a baseline weight less than 50 kg (OR, 8.668; 95% CI 1.679-44.756; P = 0.010), age older than 60 years (OR, 9.053; 95% CI 1.606-51.027; P = 0.013), hemoptysis (OR, 8.928; 95% CI 1.048-76.923; P = 0.045), presence of cavitary diseases (OR, 10.204; 95% CI 2.032-52.631; P = 0.005), or treatment irregularity (OR, 47.619; 95% CI 5.025-500; P = 0.001). CONCLUSION: Treatment outcomes for M/XDR-TB under the DOTS-Plus strategy in Zhejiang, China were favorable but still not ideal. Low body weight (< 50 kg), old age (> 60 years), severe symptoms of TB including cavitary disease, hemoptysis and irregular treatment were independent prognostic factors for failure outcomes in patients with M/XDR-TB.


Assuntos
Antituberculosos/uso terapêutico , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Mycobacterium tuberculosis/efeitos dos fármacos , Adulto , Idoso , China/epidemiologia , Tuberculose Extensivamente Resistente a Medicamentos/epidemiologia , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Tuberculose Extensivamente Resistente a Medicamentos/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Resultado do Tratamento
6.
Transbound Emerg Dis ; 68(2): 896-906, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32737943

RESUMO

Different and contrasting trends related to human migration and the implementation of health control programmes influence the spread of drug-resistant tuberculosis (TB). We analysed the Mycobacterium tuberculosis population structure in Estonia, a high-priority EU country for TB control, to detect the dynamic changes and underlying factors. The study collection included 278 M. tuberculosis isolates recovered in 1999 and 2014-2015. The isolates were subjected to drug susceptibility testing, genotyping and analysis of sublineage/cluster-specific markers and drug resistance mutations. The Beijing genotype was the most prevalent, and its rate increased from 28.6% in 1999 to 38.5% in 2015 (p = .09). The non-Beijing strains represented Euro-American lineage (Latin American Mediterranean [LAM], Ural, Haarlem, T, X genotypes) and Indo-Oceanic lineage (one EAI-IND isolate). The proportion of isolates resistant to two or more drugs increased from 22.4% to 29.1% (p = .1). The pre-XDR/XDR isolates were identified only within the Beijing genotype. In contrast, the drug resistance rate decreased in the LAM genotype from 42.1% to 11.8% (p = .05). The Beijing B0/W148-cluster ('successful Russian strain') included only MDR, pre-XDR or XDR isolates. All B0/W148-cluster isolates were resistant to two or more drugs compared to 28% of the Beijing 94-32-cluster (p = .0002). The Beijing genotype was not identified in the isolates from patients born in Estonia before 1940 compared to its 35.2% rate among other patients. In summary, the circulation of the highly drug-resistant isolates of the Beijing B0/W148 subtype, the increased prevalence of the Beijing genotype among HIV-coinfected patients and the increased number of patients with alcohol abuse (47.5%) present major challenges of the current TB control in Estonia. The Beijing genotype was likely brought to Estonia after 1945 due to the massive human influx from the Soviet Union. In contrast, the main genotypes of the Euro-American lineage were likely endemic in Estonia during all 20th century.


Assuntos
Antituberculosos/farmacologia , Tuberculose Extensivamente Resistente a Medicamentos/epidemiologia , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Mycobacterium tuberculosis/efeitos dos fármacos , Animais , Farmacorresistência Bacteriana Múltipla/genética , Estônia/epidemiologia , Genótipo , Humanos , Testes de Sensibilidade Microbiana/veterinária , Mycobacterium tuberculosis/genética , Prevalência
7.
Tuberculosis (Edinb) ; 126: 102043, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33370646

RESUMO

Although treatable with antibiotics, tuberculosis is a leading cause of death. Mycobacterium tuberculosis antibiotic resistance is becoming increasingly common and disease control is challenging. Conventional drug susceptibility testing takes weeks to produce results, and treatment is often initiated empirically. Therefore, new methods to determine drug susceptibility profiles are urgent. Here, we used mass-spectrometry-based metabolomics to characterize the metabolic landscape of drug-susceptible (DS), multidrug-resistant (MDR) and extensively drug-resistant (XDR) M. tuberculosis. Direct infusion mass spectrometry data showed that DS, MDR, and XDR strains have distinct metabolic profiles, which can be used to predict drug susceptibility and resistance. This was later confirmed by Ultra-High-Performance Liquid Chromatography and High-Resolution Mass Spectrometry, where we found that levels of ions presumptively identified as isoleucine, proline, hercynine, betaine, and pantothenic acid varied significantly between strains with different drug susceptibility profiles. We then confirmed the identification of proline and isoleucine and determined their absolute concentrations in bacterial extracts, and found significantly higher levels of these amino acids in DS strains, as compared to drug-resistant strains (combined MDR and XDR strains). Our results advance the current understanding of the effect of drug resistance on bacterial metabolism and open avenues for the detection of drug resistance biomarkers.


Assuntos
Antituberculosos/farmacologia , Tuberculose Extensivamente Resistente a Medicamentos/metabolismo , Metaboloma/fisiologia , Metabolômica/métodos , Mycobacterium tuberculosis/metabolismo , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Humanos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação
9.
Curr Pharm Biotechnol ; 22(4): 480-500, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32600226

RESUMO

Tuberculosis (TB) is a prominent infective disease and a major reason of mortality/ morbidity globally. Mycobacterium tuberculosis causes a long-lasting latent infection in a significant proportion of human population. The increasing burden of tuberculosis is mainly caused due to multi drug-resistance. The failure of conventional treatment has been observed in large number of cases. Drugs that are used to treat extensively drug-resistant tuberculosis are expensive, have limited efficacy, and have more side effects for a longer duration of time and are often associated with poor prognosis. To regulate the emergence of multidrug resistant tuberculosis, extensively drug-resistant tuberculosis and totally drug resistant tuberculosis, efforts are being made to understand the genetic/molecular basis of target drug delivery and mechanisms of drug resistance. Understanding the molecular approaches and pathology of Mycobacterium tuberculosis through whole genome sequencing may further help in the improvement of new therapeutics to meet the current challenge of global health. Understanding cellular mechanisms that trigger resistance to Mycobacterium tuberculosis infection may expose immune associates of protection, which could be an important way for vaccine development, diagnostics, and novel host-directed therapeutic strategies. The recent development of new drugs and combinational therapies for drug-resistant tuberculosis through major collaboration between industry, donors, and academia gives an improved hope to overcome the challenges in tuberculosis treatment. In this review article, an attempt was made to highlight the new developments of drug resistance to the conventional drugs and the recent progress in the development of new therapeutics for the treatment of drugresistant and non-resistant cases.


Assuntos
Antituberculosos/uso terapêutico , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Animais , Tuberculose Extensivamente Resistente a Medicamentos/genética , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Humanos , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Tuberculose Resistente a Múltiplos Medicamentos/genética , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia
10.
PLoS One ; 15(12): e0244829, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33382836

RESUMO

Drug resistance (DR) remains a major challenge for tuberculosis (TB) control. Whole-genome sequencing (WGS) provides the highest genetic resolution for genotypic drug-susceptibility tests (DST). We compared DST profiles of 60 Mycobacterium tuberculosis isolates which were drug resistant according to agar proportion tests (one poly DR-TB, 34 multidrug-resistant TB and 25 extensively drug-resistant TB). We additionally performed minimum inhibitory concentration (MIC) tests using Sensititre MYCOTBI plates (MYCOTB) and a WGS-based DST. Agreement between WGS-based DST and MYCOTB was high for all drugs except ethambutol (65%) and ethionamide (62%). Isolates harboring the -15 c/t inhA promoter mutation had a significantly lower MIC for isoniazid than did isolates with the katG Ser315Thr mutation (p < 0.001). Similar patterns were seen for ethambutol (embB Gly406Asp vs. embB Met306Ile), streptomycin (gid Gly73Ala vs. rpsL Lys43Arg), moxifloxacin (gyrA Ala90Val vs. gyrA Asp94Gly) and rifabutin (rpoB Asp435Phe/Tyr/Val vs. rpoB Ser450Leu). For genotypic heteroresistance, isolates with lower proportion of mapped read tended to has lower MIC of anti-TB drugs than those with higher proportion. These results emphasize the high applicability of WGS for determination of DR-TB and the association of particular mutations with MIC levels.


Assuntos
Antituberculosos/farmacologia , Farmacorresistência Bacteriana/genética , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Mycobacterium tuberculosis/genética , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Adulto , Antituberculosos/uso terapêutico , Etambutol/farmacologia , Etambutol/uso terapêutico , Etionamida/farmacologia , Etionamida/uso terapêutico , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Feminino , Humanos , Isoniazida/farmacologia , Isoniazida/uso terapêutico , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Mutação , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Sequenciamento Completo do Genoma
11.
Sci Rep ; 10(1): 20433, 2020 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-33235225

RESUMO

Molecular epidemiology of circulating clinical isolates is crucial to improve prevention strategies. The Spanish Working Group on multidrug resistant tuberculosis (MDR-TB) is a network that monitors the MDR-TB isolates in Spain since 1998. The aim of this study was to present the study of the MDR-TB and extensively drug-resistant tuberculosis (XDR-TB) patterns in Spain using the different recommended genotyping methods over time by a national coordinated system. Based on the proposed genotyping methods in the European Union until 2018, the preservation of one method, MIRU-VNTR, applied to selected clustered strains permitted to maintain our study open for 20 years. The distribution of demographic, clinical and epidemiological characteristics of clustered and non-clustered cases of MDR/XDR tuberculosis with proportion differences as assessed by Pearson's chi-squared or Fisher's exact test was compared. The differences in the quantitative variables using the Student's-t test and the Mann-Whitney U test were evaluated. The results obtained showed a total of 48.4% of the cases grouped in 77 clusters. Younger age groups, having a known TB case contact (10.2% vs 4.7%) and XDR-TB (16.5% vs 1.8%) were significantly associated with clustering. The largest cluster corresponded to a Mycobacterium bovis strain mainly spread during the nineties. A total of 68.4% of the clusters detected were distributed among the different Spanish regions and six clusters involving 104 cases were grouped in 17 and 18 years. Comparison of the genotypes obtained with those European genotypes included in The European Surveillance System (TESSy) showed that 87 cases had become part of 20 European clusters. The continuity of MDR strain genotyping in time has offered a widespread picture of the situation that allows better management of this public health problem. It also shows the advantage of maintaining one genotyping method over time, which allowed the comparison between ancient, present and future samples.


Assuntos
Técnicas de Genotipagem/métodos , Mycobacterium bovis/classificação , Mycobacterium tuberculosis/classificação , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Adolescente , Adulto , Fatores Etários , Criança , Pré-Escolar , Análise por Conglomerados , Farmacorresistência Bacteriana Múltipla , Tuberculose Extensivamente Resistente a Medicamentos/epidemiologia , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Repetições Minissatélites , Epidemiologia Molecular , Mycobacterium bovis/genética , Mycobacterium bovis/isolamento & purificação , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/isolamento & purificação , Filogenia , Vigilância da População , Espanha/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Adulto Jovem
12.
Emerg Microbes Infect ; 9(1): 2632-2641, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33205698

RESUMO

Tuberculosis disease (TB), caused by Mycobacterium tuberculosis, is a major public health issue in Thailand. The high prevalence of modern Beijing (Lineage 2.2.1) strains has been associated with multi- and extensively drug-resistant infections (MDR-, XDR-TB), complicating disease control. The impact of rarer proto-Beijing (L2.1) strains is less clear. In our study of thirty-seven L2.1 clinical isolates spanning thirteen years, we found a high prevalence of XDR-TB cases (32.4%). With ≤ 12 pairwise SNP distances, 43.2% of L2.1 patients belong to MDR-TB or XDR-TB transmission clusters suggesting a high level of clonal expansion across four Thai provinces. All XDR-TB (100%) were likely due to transmission rather than inadequate treatment. We found a 47 mutation signature and a partial deletion of the fadD14 gene in the circulating XDR-TB cluster, which can be used for surveillance of this rare and resilient M. tuberculosis strain-type that is causing increasing health burden. We also detected three novel deletion positions, a deletion of 1285 bp within desA3 (Rv3230c), large deletions in the plcB, plcA, and ppe38 gene which may play a role in the virulence, pathogenesis or evolution of the L2.1 strain-type.


Assuntos
Proteínas de Bactérias/genética , Tuberculose Extensivamente Resistente a Medicamentos/epidemiologia , Mutação , Mycobacterium tuberculosis/classificação , Pequim , Evolução Clonal , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Genótipo , Humanos , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/isolamento & purificação , Mycobacterium tuberculosis/patogenicidade , Filogenia , Filogeografia , Tailândia/epidemiologia , Virulência
13.
Sci Rep ; 10(1): 17518, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33060737

RESUMO

Recently, paradoxical combinations of colistin with anti-Gram-positive bacterial agents were introduced as a treatment alternative for multidrug-resistant Acinetobacter baumannii (MDRAB) infection. We assessed the therapeutic efficacy of the colistin-linezolid combination regimen in vitro and in a murine model of Acinetobacter baumannii pneumonia. A multidrug-resistant clinical strain (MDRAB31) and an extensively drug-resistant clinical strain (XDRAB78) were used in this study. The survival rates of mice and bacterial counts in lung tissue were used to assess the effects of colistin-linezolid combination. The survival rates of colistin-linezolid combination groups significantly increased compared with colistin groups for MDRAB31 (72% versus 32%, P = 0.03) and for XDRAB78 (92% versus 68%, P = 0.031). The colistin-linezolid combination groups significantly reduced the bacterial counts in lung tissue compared with colistin groups for MDRAB31 and for XDRAB78 (P < 0.05). The colistin-linezolid combination had a bactericidal and synergistic effect compared with colistin alone in time-kill assay and in murine model of pneumonia. Our data demonstrated the synergistic effect of colistin-linezolid combination regimen as a treatment alternative for the severe pulmonary infection caused by MDRAB and XDRAB.


Assuntos
Infecções por Acinetobacter/tratamento farmacológico , Antituberculosos/uso terapêutico , Colistina/administração & dosagem , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Linezolida/administração & dosagem , Pneumonia Bacteriana/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Acinetobacter baumannii/metabolismo , Animais , Modelos Animais de Doenças , Sinergismo Farmacológico , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Feminino , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , Pneumonia Bacteriana/microbiologia , Fatores de Tempo , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia
14.
Folia Med (Plovdiv) ; 62(3): 444-452, 2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-33009738

RESUMO

Tuberculosis is a severe, infectious disease caused by Mycobacterium tuberculosis. The aim of this review was to present the efficacy of linezolid as an agent against multidrug and extensively drug-resistant tuberculosis as gathered from many recent research studies. Linezolid seems to have strongly the potential of being used as an anti-tuberculosis agent because it blocks bacterial ribosomal protein synthesis. Nevertheless caution is required because of the adverse effects it causes, especially when the linezolid daily dosage exceeds 600 mg. The most severe adverse effects include anemia, peripheral neuropathy, optic neuropathy and thrombocytopenia. Still, more trials and research need to be done in order to gather more information and value the cost-benefit dosage of the treatment.


Assuntos
Antituberculosos , Tuberculose Extensivamente Resistente a Medicamentos , Linezolida , Mycobacterium tuberculosis/efeitos dos fármacos , Antituberculosos/efeitos adversos , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Humanos , Linezolida/efeitos adversos , Linezolida/farmacologia , Linezolida/uso terapêutico
15.
PLoS One ; 15(10): e0240564, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33052983

RESUMO

BACKGROUND: Drug-Resistant Tuberculosis (DR-TB) is a rising threat of the TB control program caused mainly by treatment interruption in Ethiopia. The success of the current treatment regimen for DR-TB is poor partly due to a high treatment interruption rate. Thus, this study assessed treatment interruption and associated factors among DR-TB patients. METHODS: An institution-based cross-sectional study was conducted among 550 DR-TB patients who have initiated treatment from September 2010 to December 2017. Data were entered using Epi Data version 4.200 and exported to STATA version 14 for analysis. A bi-variable logistic regression model was first fitted, and variables having a p-value < 0.2 in the bi-variable analysis were entered into the multivariable logistic regression model. Crude and Adjusted Odds Ratios (COR and AOR) with 95% confidence interval (CI) were used to determine the strength of association between the treatment interruption and independent variables. Variables with p-value <0.05 in the multi-variable model were considered as statistically significant predictors of treatment interruption. RESULTS: In this study, the prevalence of treatment interruption among patients registered on DR-TB treatment was 14.55% (95% CI: 11.83, 17.76). Of the interrupters, the treatment interruption during the intensive and continuation phase of treatment was reported as 45% and 71.25%, respectively. Similarly, about 15% of patients had treatment interruption both during the intensive and continuation phase of treatment. The average duration of treatment interruption was 12 (±2.03 SD) and 6 (±1.2 SD) days during the intensive and continuation phase of treatment, respectively. Patients who had no treatment supporter [AOR = 1.45; 95% CI: 1.23-3.66] and developed adverse drug events [AOR = 1.60; 95% CI: 1.22-2.85] were statistically significant predictors of treatment interruption. CONCLUSIONS: Treatment interruption was low in the study setting. The presence of treatment supporter and absence of drug side effects was significantly associated with decreased occurrence of treatment interruption. Thus, patient linkage to treatment supporter and excellent pharmacovigilance are highly recommended in the study setting.


Assuntos
Antituberculosos/uso terapêutico , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Adulto , Antituberculosos/efeitos adversos , Etiópia/epidemiologia , Tuberculose Extensivamente Resistente a Medicamentos/epidemiologia , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Feminino , Instalações de Saúde , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/patogenicidade , Resultado do Tratamento , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia
16.
Pan Afr Med J ; 36: 165, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32952809

RESUMO

Pre-extensively drug resistant tuberculosis (pre-XDR-TB) has been an area of growing concern, and posing a threat to global efforts of TB control. We report a case of PreXDR-TB spondylodiscitis with resistance to a Fluoroquinolone, in an immunocompetent patient under antibacillary treatment for pleural tuberculosis, managed with drug sensitivity-based second-line antituberculous drug regimen. Our case shows the challenges of the diagnostic and management of Drug-resistant TB spondylodiscitis.


Assuntos
Antituberculosos/farmacologia , Discite/tratamento farmacológico , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Tuberculose Pleural/tratamento farmacológico , Adulto , Discite/diagnóstico , Discite/microbiologia , Farmacorresistência Bacteriana Múltipla , Tuberculose Extensivamente Resistente a Medicamentos/diagnóstico , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Fluoroquinolonas/farmacologia , Humanos , Masculino , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Tuberculose Pleural/microbiologia
17.
Indian J Tuberc ; 67(3): 340-342, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32825862

RESUMO

Tuberculosis is one of the top ten causes of death and the leading cause from a single infectious agent. Drug-resistant Tuberculosis continues to be a public health crisis. Urgent action is required to improve the coverage and quality of diagnosis, treatment and care for people with drug-resistant Tuberculosis. Patients with pulmonary Tuberculosis can spread the disease by coughing, sneezing, or simply talking. For that reason, it is important to diagnosis Tuberculosis in order to start treatment as soon as possible. In the present manuscript we present the case of a 25-year-old Indian HIV-negative female, no comorbidity, with a history of drug susceptible tuberculosis diagnosed in 2015 which advanced in extensively drug-resistant tuberculosis after two years of treatment. This case report highlights the risk of mismanagement of patient affected by Tuberculosis and the consequences related which could harm the patient's health.


Assuntos
Antituberculosos/uso terapêutico , Substituição de Medicamentos , Duração da Terapia , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Tuberculose Pulmonar/microbiologia , Adulto , Progressão da Doença , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Tuberculose Extensivamente Resistente a Medicamentos/fisiopatologia , Feminino , Humanos , Índia , Testes de Sensibilidade Microbiana , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/fisiopatologia
18.
Am J Trop Med Hyg ; 103(3): 1067-1071, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32700662

RESUMO

Stigma is an important social determinant of health-seeking behavior; however, the nature and extent of its association with depression among people living with multidrug-resistant tuberculosis (MDR-TB) are not well-understood. We enrolled 200 microbiologically confirmed MDR-TB inpatients at a TB specialist hospital in KwaZulu-Natal Province, an area considered the epicenter for MDR-TB coinfection in South Africa. Four aspects of stigma and their association with major depression were assessed through individual interviews: 1) community and 2) patient perspectives toward TB, and 3) community and 4) patient perspectives toward HIV. A major depressive episode (MDE), HIV coinfection, and low income were significantly associated with greater stigma subscales. Based on an adjusted regression model, the MDE was the only factor independently associated with (all aspects of) stigma. These results indicate the potential utility of addressing stigma associated with the MDE as an important step in improving health-seeking behavior to promote adherence and retention in care.


Assuntos
Transtorno Depressivo Maior/epidemiologia , Tuberculose Extensivamente Resistente a Medicamentos/epidemiologia , Infecções por HIV , Estigma Social , Tuberculose Resistente a Múltiplos Medicamentos/patologia , Adulto , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Feminino , Humanos , Pacientes Internados , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Retenção nos Cuidados , África do Sul/epidemiologia , Adulto Jovem
19.
Int J Antimicrob Agents ; 56(2): 106036, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32485278

RESUMO

The Mycobacterium tuberculosis Beijing genotype is a clinically and epidemiologically important lineage that is subdivided into ancient/ancestral and modern strains. In our previous study in western Siberia, we identified variable number of tandem repeats (VNTR)-based clusters within the early ancient sublineage of the Beijing genotype characterized by an unexpectedly high rate of extensive drug resistance (XDR). In the current study, next generation sequencing data were analysed to gain insight into genomic signatures underlying drug resistance of these strains. A total of 184 genomes of the Beijing early ancient sublineage from Russia (16), China (15), Japan (36), Korea (25), Vietnam (18), Thailand (73), and the USA (1) were used for phylogenetic analysis. The drug-resistant profile was deduced genotypically. The Russian isolates were distributed into two clusters and were all drug resistant, mainly pre-XDR and XDR. The largest of these clusters included only Russian isolates from remote locations in both Asian and European parts of the country. All its isolates had a quadruple drug resistance (to isoniazid, rifampin, ethambutol and streptomycin) due to the 6-mutation signature (KatG Ser315Thr, KatG Ile335Val, RpoB Ser450Leu, RpoC Asp485Asn, EmbB Gln497Arg, and RpsL Lys43Arg). In most samples, it was complemented with additional and different pncA, gyrA and rrs mutations leading to the pre-XDR/XDR genotype. Phylogenomic analysis indicates a distant origin of this Russian resistant cluster in the early 1970s but location and circumstances are yet to be clarified.


Assuntos
Farmacorresistência Bacteriana Múltipla/genética , Tuberculose Extensivamente Resistente a Medicamentos/epidemiologia , Mutação , Mycobacterium tuberculosis/genética , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Pequim/epidemiologia , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Genoma Bacteriano , Genótipo , Técnicas de Genotipagem , Humanos , Japão/epidemiologia , Epidemiologia Molecular , Mycobacterium tuberculosis/classificação , Filogenia , Polimorfismo de Nucleotídeo Único , República da Coreia/epidemiologia , Federação Russa/epidemiologia , Tailândia/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Estados Unidos/epidemiologia , Vietnã/epidemiologia , Sequenciamento Completo do Genoma
20.
Sci Rep ; 10(1): 8957, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32488120

RESUMO

Tuberculosis treatment includes broad-spectrum antibiotics such as rifampicin, streptomycin and fluoroquinolones, which are also used against other pathogenic bacteria. We developed Drug Resistance Associated Genes database (DRAGdb), a manually curated repository of mutational data of drug resistance associated genes (DRAGs) across ESKAPE (i.e. Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) pathogens, and other bacteria with a special focus on Mycobacterium tuberculosis (MTB). Analysis of mutations in drug-resistant genes listed in DRAGdb suggested both homoplasy and pleiotropy to be associated with resistance. Homoplasy was observed in six genes namely gidB, gyrA, gyrB, rpoB, rpsL and rrs. For these genes, drug resistance-associated mutations at codon level were conserved in MTB, ESKAPE and many other bacteria. Pleiotropy was exemplified by a single nucleotide mutation that was associated with resistance to amikacin, gentamycin, rifampicin and vancomycin in Staphylococcus aureus. DRAGdb data also revealed that mutations in some genes such as pncA, inhA, katG and embA,B,C were specific to Mycobacterium species. For inhA and pncA, the mutations in the promoter region along with those in coding regions were associated with resistance to isoniazid and pyrazinamide respectively. In summary, the DRAGdb database is a compilation of all the major MTB drug resistance genes across bacterial species, which allows identification of homoplasy and pleiotropy phenomena of DRAGs.


Assuntos
Antituberculosos/farmacologia , Bases de Dados Genéticas , Farmacorresistência Bacteriana Múltipla/genética , Mycobacterium tuberculosis/genética , Proteínas de Bactérias/genética , DNA Bacteriano/genética , Curadoria de Dados/métodos , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Fluoroquinolonas/uso terapêutico , Isoniazida/uso terapêutico , Testes de Sensibilidade Microbiana , Mutação/efeitos dos fármacos , Pirazinamida/uso terapêutico , Rifampina/uso terapêutico , Análise de Sequência de DNA/métodos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico
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