RESUMO
INTRODUCTION: Very few studies have been devoted to extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis (TB) in Gabon. AIM: The aim of the present study is to present the epidemiology of pre-XDR and XDR TB and the evolution over time of patients with multidrug-resistant TB. METHODS: This retrospective study covered the activities from 2019 to 2022 of the Nkembo anti-tuberculosis center. RESULTS: Fifteen patients were eligible, including 11 (73.3%) pre-XDR patients and 4 (26.7%) XDR-TB patients. Three (20.0%) patients had HIV/TB co-infection. The sample consisted of 7 men (46.7%) and 8 women (53.3%), a sex ratio (M/F) of 0.87. The average age was 35.6 years, and the median 34 years, with extremes of 23 and 60 years. Eight patients (53.3%) represented new cases of pre-XDR or XDR-TB tuberculosis. The majority (60%; n=9) came from deprived neighborhoods with widespread promiscuity. The therapeutic success rate among pre-XDR patients was 4 (36.4%) versus 2 (50.0%) among XDR-TB patients. Reported mortality occurred 5 (33.3%) patients during treatment, including 3 pre-XDR and 2 XDR-TB patients. In all cases, they died before the end of the first trimester of follow-up. CONCLUSION: The high frequency of primary pre-extensively drug-resistant tuberculosis underscores the pervasiveness of resistance to anti-tuberculosis drugs and underlines a pressing need for detection of contact cases and early treatment.
Assuntos
Antituberculosos , Tuberculose Extensivamente Resistente a Medicamentos , Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Gabão/epidemiologia , Feminino , Masculino , Tuberculose Extensivamente Resistente a Medicamentos/epidemiologia , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Adulto , Estudos Retrospectivos , Pessoa de Meia-Idade , Adulto Jovem , Antituberculosos/uso terapêutico , Mycobacterium tuberculosis/isolamento & purificação , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Infecções por HIV/epidemiologia , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Coinfecção/epidemiologia , Coinfecção/microbiologiaRESUMO
BACKGROUND: Whole-genome sequencing (WGS)-based prediction of drug resistance in Mycobacterium tuberculosis has the potential to guide clinical decisions in the design of optimal treatment regimens. METHODS: We utilized WGS to investigate drug resistance mutations in a 32-year-old Tanzanian male admitted to Kibong'oto Infectious Diseases Hospital with a history of interrupted multidrug-resistant tuberculosis treatment for more than three years. Before admission, he received various all-oral bedaquiline-based multidrug-resistant tuberculosis treatment regimens with unfavourable outcomes. RESULTS: Drug susceptibility testing of serial M. tuberculosis isolates using Mycobacterium Growth Incubator Tubes culture and WGS revealed resistance to first-line anti-TB drugs, bedaquiline, and fluoroquinolones but susceptibility to linezolid, clofazimine, and delamanid. WGS of serial cultured isolates revealed that the Beijing (Lineage 2.2.2) strain was resistant to bedaquiline, with mutations in the mmpR5 gene (Rv0678. This study also revealed the emergence of two distinct subpopulations of bedaquiline-resistant tuberculosis strains with Asp47f and Glu49fs frameshift mutations in the mmpR5 gene, which might be the underlying cause of prolonged resistance. An individualized regimen comprising bedaquiline, delamanid, pyrazinamide, ethionamide, and para-aminosalicylic acid was designed. The patient was discharged home at month 8 and is currently in the ninth month of treatment. He reported no cough, chest pain, fever, or chest tightness but still experienced numbness in his lower limbs. CONCLUSION: We propose the incorporation of WGS in the diagnostic framework for the optimal management of patients with drug-resistant and extensively drug-resistant tuberculosis.
Assuntos
Antituberculosos , Tuberculose Extensivamente Resistente a Medicamentos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis , Sequenciamento Completo do Genoma , Humanos , Masculino , Adulto , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Antituberculosos/uso terapêutico , Antituberculosos/farmacologia , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Farmacorresistência Bacteriana Múltipla/genética , Tanzânia , Mutação , Diarilquinolinas/uso terapêutico , Diarilquinolinas/farmacologia , Genoma Bacteriano , Linezolida/uso terapêutico , Linezolida/farmacologiaRESUMO
Fluoroquinolone resistance is a major challenge in treating Multidrug-Resistant Tuberculosis globally. The GenoType MTBDRsl Ver 2.0, endorsed by the WHO, was used to characterize fluoroquinolone resistance. The fluoroquinolone resistance rates in the MDR-TB, Rifampicin-Resistant TB, and non-MDR-TB were 33%, 16.5%, and 5.4%, respectively. The most common mutation found in fluoroquinolone-resistant isolates was D94G (49.5%) in the gyrA gene. Of the 150 MDR-TB isolates, the prevalence of Extensively Drug-Resistant Tuberculosis and pre-XDR-TB was 1.33% and 30%, respectively. Among the 139 RR-TB isolates, pre-XDR-TB prevalence was 15.8%. The fluoroquinolone resistance rates were 5.12% among the 1230 isoniazid-monoresistant isolates. The study found that MDR-TB and RR-TB have higher risk of fluoroquinolone resistance than non-MDR tuberculosis. Rifampicin-resistant isolates with a mutation at codon S450L have a higher risk (RR = 12.96; 95%CI: 8.34-20.13) of developing fluoroquinolone resistance than isolates with mutations at other codons in the rpoB gene. Isoniazid-resistant isolates with a mutation at codon S315T have a higher risk (RR = 2.09; 95%CI: 1.25-3.50) of developing fluoroquinolone resistance. The study concludes that rapid diagnosis of fluoroquinolone resistance before starting treatment is urgently needed to prevent the spread and increase of resistance and to achieve better treatment outcomes in areas where it is higher.
Assuntos
Antituberculosos , Fluoroquinolonas , Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Fluoroquinolonas/farmacologia , Fluoroquinolonas/uso terapêutico , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/efeitos dos fármacos , Estudos Retrospectivos , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/transmissão , Tuberculose Resistente a Múltiplos Medicamentos/genética , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Masculino , Feminino , Tuberculose Pulmonar/epidemiologia , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/microbiologia , Adulto , Mutação , Medição de Risco , Pessoa de Meia-Idade , Testes de Sensibilidade Microbiana , Rifampina/farmacologia , Rifampina/uso terapêutico , Tuberculose Extensivamente Resistente a Medicamentos/epidemiologia , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Farmacorresistência Bacteriana Múltipla/genética , Isoniazida/farmacologia , Isoniazida/uso terapêutico , IdosoRESUMO
This report documents the case of a Ukrainian patient infected with an extensively drug-resistant (XDR) lineage 2 Mycobacterium tuberculosis strain harbouring the rifampicin resistance mutation RpoB I491F. This mutation is not detected by routine molecular WHO-recommended rapid diagnostics, complicating the detection and treatment of these strains. The occurrence of such mutations underscores the need for enhanced diagnostic techniques and tailored treatment regimens, especially in eastern Europe where lineage 2 strains and XDR-tuberculosis are prevalent.
Assuntos
Antituberculosos , Proteínas de Bactérias , RNA Polimerases Dirigidas por DNA , Tuberculose Extensivamente Resistente a Medicamentos , Mutação , Mycobacterium tuberculosis , Rifampina , Adulto , Humanos , Antituberculosos/uso terapêutico , Proteínas de Bactérias/genética , RNA Polimerases Dirigidas por DNA/genética , Tuberculose Extensivamente Resistente a Medicamentos/diagnóstico , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Alemanha , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/isolamento & purificação , Mycobacterium tuberculosis/efeitos dos fármacos , Rifampina/uso terapêutico , Ucrânia , FemininoRESUMO
Rising cases of drug resistance of mycobacterium species are one of the biggest concerns when the goal is to eradicate TB (Tuberculosis) from the world by the year 2030. A limited number of treatment options as MTB (Mycobacterium tuberculosis) is getting resistant to anti-mycobacterial drugs either due to a patient's non-compliance towards treatment regimen or if a patient is infected by drug-resistant species of MTB. This review aims to assess the effectiveness of pretomanid, a recently approved drug for the treatment of extensively drug-resistant TB. A thorough search of databases like PubMed, Cochrane library, CDC, Research Gate, and Google scholar was used in order to find case reports and clinical trials providing data on the efficacy of pretomanid in different drug regimens. According to research trials conducted, the drug appears to be efficacious, safe, and well-tolerable. Only headache was the most frequently observed adverse drug event, and a high dose-related increase in serum creatinine level was seen, which came to normal after the drug was discontinued.
Assuntos
Antituberculosos , Tuberculose Extensivamente Resistente a Medicamentos , Humanos , Antituberculosos/uso terapêutico , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Nitroimidazóis/uso terapêutico , Resultado do Tratamento , Mycobacterium tuberculosis/efeitos dos fármacosRESUMO
BACKGROUND & OBJECTIVES: The purpose of present study is to analyse the distribution and pattern of genetic mutations in PRE-XDR-TB and extensive drug resistant Mycobacterium tuberculosis (XDR-TB) using second-line line probe assay and to compare them with different parameters. METHOD: Sputum, Lymph node aspirate and cold accesses from patients with rifampicin resistant Tuberculosis were subjected to first line and second line Probe Assay (Genotype MTBDRsl by Hain Life Science, Germany) to assess additional drug resistance to fluroquinolones (Levofloxacin & Moxifloxacin) and Aminoglycosides (Amikacin, Ofloxacin and Kanamycin). The genetic mutation pattern was analysed and compared with demographic, clinical and other parameters. RESULTS: The final study population included 123 fluoroquinolone resistant isolates including 14 isolates with additional second line aminoglycosides drug resistance. The most frequent mutation observed among Gyr A drug resistance mutation was D94G (Gyr A MUT3C, 50/123,40%) corresponding to high level resistance to levofloxacin and moxifloxacin. The most frequent wild type mutant among Gyr A gene locus was WT 3 (85/123,69%). The most common mutation among second line aminoglycoside resistant isolates was at eis WT2 (7/14,50%) followed by rrs MUT 2 (4/14,29%). CONCLUSIONS: GyrA MUT3C (Asp94Gly) was the most common mutation in Gyr A gene locus in M. tuberculosis causing high level levofloxacin and moxifloxacin resistance. Patients with Asp94Gly mutation was significantly associated with underweight body mass index (p = 0.026). This study also observed that history of anti-tuberculosis therapy is a risk factor for FQ drug resistance mutations (p < 0.001).
Assuntos
Antituberculosos , Mutação , Mycobacterium tuberculosis , Humanos , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Masculino , Feminino , Adulto , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/microbiologia , Pessoa de Meia-Idade , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Testes de Sensibilidade Microbiana , Fluoroquinolonas/farmacologia , Fluoroquinolonas/uso terapêutico , Farmacorresistência Bacteriana Múltipla/genética , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Levofloxacino/farmacologia , Levofloxacino/uso terapêutico , Moxifloxacina/uso terapêutico , Moxifloxacina/farmacologia , Adulto JovemRESUMO
BACKGROUND: A variety of factors influence adherence to the lengthy duration of anti-tuberculosis treatment, making it a complicated and dynamic problem. The objective of this study was to investigate the treatment interruption patterns using pre-defined criteria among a cohort of pulmonary tuberculosis patients and to elicit the associated factors. METHODS: This prospective, observational study was conducted between October 2016 to May 2018. All smear and culture positive pulmonary tuberculosis patients (age ≥ 14 years) enrolled between October 1, 2016 to March 31, 2017 across 3 Designated Microscopy Centers (DMCs) were included and followed up till end of treatment for outcome in drug-sensitive, and till interim outcome at 6 months for drug-resistant TB patients. Patterns and reasons for interruptions were recorded as per the study protocol. RESULTS: 171 patients were enrolled in this study, of which 135 (78.94 %) were on Category-I and Category-II treatment (drug-sensitive tuberculosis), 23 (13 %) were multidrug-resistant (MDR) and 13 (8 %) were extensively drug resistant (XDR) tuberculosis patients. Among the drug-sensitive group, 65 (48 %) patients completed their treatment without any interruption while 70 (52 %) patients interrupted with at least one missed dose. Among the 36 MDR/XDR patients, 19 (53 %) patients did not interrupt treatment, but 17 (47 %) patients interrupted with at least one missing dose. The 87 patients in both sub-groups interrupted for 232 times/episodes of which 140 were short and 84 were long interruptions. The main reasons for interruption were found to be busy schedule in 63 (29 %) patients, adverse drug reactions in 40 (18.4 %) and comorbidities in 43 (19.8 %) patients. Feeling of early improvement/no improvement in 23 (10.5 %) patients, addictions in 27 (12.4 %) patients, lack of family support in 14 (6.4 %), unawareness of dosage and duration of treatment in 7 (3.20 %) patients were other common reasons. CONCLUSION: The plurality of patients studied were found to be in the younger age group i.e., 14-25 years (n = 75), constituting nearly 44 % of all the patients included and male treatment interrupters (62 %) outnumbered the females (38 %), possibly owing to work schedule or addictions. The majority of interruptions were related to patient related factors (93.5 %), followed by DOTS provided factors (6.40 %) and system related factors (3.01 %). Further studies should be conducted to classify the factors of treatment interruptions in detail and also to study the impact of these interruptions' patterns on final outcomes.
Assuntos
Antituberculosos , Adesão à Medicação , Tuberculose Resistente a Múltiplos Medicamentos , Tuberculose Pulmonar , Humanos , Índia , Masculino , Antituberculosos/uso terapêutico , Antituberculosos/administração & dosagem , Feminino , Adulto , Tuberculose Pulmonar/tratamento farmacológico , Fatores de Risco , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Estudos Prospectivos , Pessoa de Meia-Idade , Adesão à Medicação/estatística & dados numéricos , Adulto Jovem , Adolescente , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológicoRESUMO
This study aimed to reinforce the importance of the epidemiological surveillance of multidrug-resistant tuberculosis (MDR-TB) in Rio de Janeiro State (RJ). Here, we reviewed seven articles we published between 2018 and 2022. This study had two phases. The quantitative phase where frequency was used to describe patient characteristics and regressions were used to evaluate the relationship between treatment outcomes and covariates. The qualitative phase where content analysis of the narratives was performed. Secondary (electronic systems) and primary (semi-structured interviews) data were used. We analyzed 2,269 MDR-TB, 58.1% MDR-TB, and 18.6% extensively drug-resistant TB (XDR-TB) cases, of which 44.3% exhibited unfavorable outcomes. Among the 140 patients with XDR-TB, 29.3% had not undergone prior treatment for MDR-TB. The primary resistance rate in MDR-TB cases was 14.7%, revealing significant demographic and clinical disparities, particularly among women, Caucasians, and those with higher education levels. The number of cases increased from 7.69% in 2000 to 38.42% in 2018, showing an increasing trend (AAPC = 9.4; 95% CI 1.4-18.0, p < 0.001), with 25.4% underreporting. A qualitative study confirmed a high proportion of primary resistance (64.5%) and delayed diagnosis of MDR-TB. In RJ, the diagnostic and therapeutic cascade of MDR-TB must be improved using molecular tests to achieve an early diagnosis of resistance and immediate initiation of appropriate treatment, promote social protection for MDR/XDR-TB patients and their families, enhance TB contact tracing, establish and monitor hospital surveillance centers integrated with Primary Care, and unify various information systems through interoperability for better integration.
Assuntos
Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Brasil/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Antituberculosos/uso terapêutico , Antituberculosos/farmacologia , Adulto Jovem , Tuberculose Extensivamente Resistente a Medicamentos/epidemiologia , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Adolescente , Monitoramento EpidemiológicoRESUMO
Drug-resistant tuberculosis (TB) poses a significant public health concern in South Africa due to its complexity in diagnosis, treatment, and management. This study assessed the diagnostic performance of the Xpert MTB/XDR test for detecting drug resistance in patients with TB by using archived sputum sediments. This study analyzed 322 samples collected from patients diagnosed with TB between 2016 and 2019 across South Africa, previously characterized by phenotypic and genotypic methods. The Xpert MTB/XDR test was evaluated for its ability to detect resistance to isoniazid (INH), ethionamide (ETH), fluoroquinolones (FLQ), and second-line injectable drugs (SLIDs) compared with phenotypic drug susceptibility testing (pDST) and whole-genome sequencing (WGS). Culture, Xpert MTB/RIF Ultra, and Xpert MTB/RIF (G4) tests were performed to determine sensitivity and agreement with this test for TB detection. The sensitivities using a composite reference standard, pDST, and sequencing were >90% for INH, FLQ, amikacin (AMK), kanamycin (KAN), and capreomycin (CAP) resistance, meeting the WHO target product profile criteria for this class. A lower sensitivity of 65.9% (95% CI: 57.1-73.6) for ETH resistance was observed. The Xpert MTB/XDR showed a sensitivity of 98.3% (95% CI: 96.1-99.3) and specificity of 100% (95% CI: 86.7-100) compared with culture, a positive percent agreement (PPA) of 98.8% (95% CI: 93.7-99.8) and negative percent agreement (NPA) of 100.0% (95% CI: 78.5-100.0) compared with G4, and a PPA of 99.5% (95% CI: 97.3-99.9) and NPA of 100.0% (95% CI: 78.5-100.0) compared with Xpert MTB/RIF Ultra for detecting Mycobacterium tuberculosis. The test offers a promising solution for the rapid detection of drug-resistant TB and could significantly enhance control efforts in this setting.
Assuntos
Antituberculosos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis , Sensibilidade e Especificidade , Humanos , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , África do Sul , Antituberculosos/farmacologia , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Extensivamente Resistente a Medicamentos/diagnóstico , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Escarro/microbiologia , Sequenciamento Completo do Genoma , Técnicas de Diagnóstico Molecular/métodos , Farmacorresistência Bacteriana MúltiplaRESUMO
BACKGROUND: Tuberculosis is a highly contagious disease caused by Mycobacterium tuberculosis, and the increase in antibiotic resistance threatens humankind. Therefore, there is an urgent need to develop new anti-tuberculosis drugs that can overcome the limitations of existing drugs. Here, we report the anti-tuberculosis effect of microbiome therapeutic PMC205, a strain of Bacillus subtilis. METHODS: The anti-tuberculosis activity of probiotics was evaluated in mouse models of lethal and latent pulmonary tuberculosis induced by high or low-dose infection of the extensively drug-resistant strain. Probiotics were administered by inhalation, and the burden of M. tuberculosis in the lungs, along with mortality and clinical observations, were monitored for 12 weeks and 8 months, respectively. For an in-depth understanding, analysis of the microbiome and inflammatory profile of the lung microenvironment and induction of autophagy in vitro were explored. RESULTS: After inhalation administration of PMC205 for 3 months, the survival rate was 100%, unlike all deaths in the saline-treated group, and the burden of M. tuberculosis in the lungs was reduced by log 1.3 in the 8-month latent tuberculosis model. Moreover, PMC205 induced recovery of disrupted lung microflora, increased butyric acid, and suppressed excessive inflammation. It also promoted autophagy. CONCLUSIONS: These results confirm PMC205's anti-tuberculosis effect, suggesting that it can be developed as an adjuvant to current antibiotic therapy to solve the drug-resistant tuberculosis problem.
Assuntos
Antituberculosos , Modelos Animais de Doenças , Tuberculose Extensivamente Resistente a Medicamentos , Pulmão , Microbiota , Mycobacterium tuberculosis , Probióticos , Tuberculose Pulmonar , Animais , Camundongos , Mycobacterium tuberculosis/efeitos dos fármacos , Probióticos/uso terapêutico , Probióticos/administração & dosagem , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Antituberculosos/uso terapêutico , Antituberculosos/farmacologia , Pulmão/microbiologia , Pulmão/patologia , Microbiota/efeitos dos fármacos , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/microbiologia , Bacillus subtilis/efeitos dos fármacos , Feminino , Autofagia/efeitos dos fármacos , Camundongos Endogâmicos C57BL , HumanosRESUMO
BACKGROUND: Tuberculosis (TB), one of the deadliest infectious diseases globally, is increasingly exacerbated in China by the emergence of resistant Mycobacterium tuberculosis (MTB) strains. Drug-resistant TB, including mono-drug-resistant TB, multidrug-resistant TB (MDR-TB), and extensively drug-resistant TB (XDR-TB), presents significant public health challenges. METHODS: We conducted a systematic literature review from January 2010 to February 2024 using databases such as PubMed, Embase, Web of Science, and Google Scholar. Our focus was on empirical data related to drug resistance patterns in newly diagnosed TB cases. Non-empirical studies were excluded through meticulous filtering. For the meta-analysis, we used Review Manager (RevMan) 5.2 and assessed evidence quality using the Newcastle-Ottawa Scale (NOS). RESULTS: Our search strategy identified 40 studies that met the inclusion criteria, encompassing a total sample size of 87,667 participants. Among new TB cases, the estimated prevalence of MDR-TB in China was 6.9% (95% CI: 5.6-8.1%). Prevalence rates for mono-drug resistance to first-line anti-TB medications were as follows: isoniazid at 18.2% (95% CI: 16.4-20.6%), rifampicin at 10.5% (95% CI: 8.6-12.8%), and ethambutol at 5.7% (95% CI: 4.1-7.3%). The prevalence of streptomycin resistance, a former first-line anti-TB drug, was 17.1% (95% CI: 14.6-19.1%). The prevalence of other types of mono-drug resistance was 15.2% (95% CI: 13.9-17.3%), and for XDR-TB, it was 0.9% (95% CI: 0.6-1.4%). CONCLUSIONS: The high prevalence of drug-resistant TB in China poses a significant public health challenge. There is an urgent need for targeted interventions and continued surveillance to combat the spread of drug-resistant TB.
Assuntos
Antituberculosos , Tuberculose Extensivamente Resistente a Medicamentos , Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , China/epidemiologia , Farmacorresistência Bacteriana Múltipla , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Tuberculose Extensivamente Resistente a Medicamentos/epidemiologia , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Prevalência , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/microbiologiaRESUMO
Despite available global efforts and funding, Tuberculosis (TB) continues to affect a considerable number of patients worldwide. Policy makers and stakeholders set clear goals to reduce TB incidence and mortality, but the emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) complicate the reach of these goals. Drug-resistance TB needs to be diagnosed rapidly and accurately to effectively treat patients, prevent the transmission of MDR-TB, minimise mortality, reduce treatment costs and avoid unnecessary hospitalisations. In this narrative review, we provide a comprehensive overview of laboratory methods for detecting drug resistance in MTB, focusing on phenotypic, molecular and other drug susceptibility testing (DST) techniques. We found a large variety of methods used, with the BACTEC MGIT 960 being the most common phenotypic DST and the Xpert MTB/RIF being the most common molecular DST. We emphasise the importance of integrating phenotypic and molecular DST to address issues like resistance to new drugs, heteroresistance, mixed infections and low-level resistance mutations. Notably, most of the analysed studies adhered to the outdated definition of XDR-TB and did not consider the pre-XDR definition, thus posing challenges in aligning diagnostic methods with the current landscape of TB resistance.
Assuntos
Antituberculosos , Tuberculose Extensivamente Resistente a Medicamentos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis , Fenótipo , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Antituberculosos/uso terapêutico , Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Testes de Sensibilidade Microbiana/métodos , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Tuberculose Extensivamente Resistente a Medicamentos/diagnóstico , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Farmacorresistência Bacteriana Múltipla/genética , Técnicas de Diagnóstico Molecular/métodos , Valor Preditivo dos TestesRESUMO
Based on the assessment of new evidence, the World Health Organization (WHO) updated its guidelines for the treatment of drug-resistant tuberculosis (TB) in December 2022. The new recommendations and the latest study data made it necessary to update the existing guideline on the treatment of at least rifampicin-resistant TB (RR-TB) for the German-speaking countries, replacing the respective chapters of the treatment guidelines published in 2022. A shortened treatment of proven RR-TB and multidrug-resistant TB for at least 6 months using the fixed and non-modifiable drug combination of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) is now also recommended for Austria, Germany, and Switzerland under certain conditions considering the existing barriers for the implementation of the new treatment regimen. For the treatment of pre-extensively drug-resistant (pre-XDR-) TB, an individualized treatment for 18 months continues to be the primary recommendation. The non-modifiable drug combination of bedaquiline, pretomanid, and linezolid (BPaL) may be used alternatively in selected pre-XDR-TB cases, provided that all prerequisites are met. The necessary requirements for using BPaLM and BPaL are presented in detail in this amendment to the consensus-based TB treatment guideline for adult patients.
Assuntos
Antituberculosos , Tuberculose Extensivamente Resistente a Medicamentos , Rifampina , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Áustria , Diarilquinolinas/farmacologia , Diarilquinolinas/uso terapêutico , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Alemanha , Linezolida/farmacologia , Linezolida/uso terapêutico , Moxifloxacina/farmacologia , Moxifloxacina/uso terapêutico , Rifampina/farmacologia , Rifampina/uso terapêutico , Suíça , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológicoRESUMO
BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB), characterized by isoniazid and rifampicin resistance, is caused by chromosomal mutations that restrict treatment options and complicate tuberculosis management. This study sought to investigate the prevalence of pre-extensively drug-resistant (pre-XDR) and extensively drug-resistant (XDR) tuberculosis, as well as mutation pattern, in Nepalese patients with MDR/rifampicin-resistant (RR)-TB strains. METHODS: A cross-sectional study was conducted on MDR/RR-TB patients at the German Nepal Tuberculosis Project from June 2017 to June 2018. The MTBDRsl line probe assay identified pre-XDR-TB and XDR-TB. Pre-XDR-TB included MDR/RR-TB with resistance to any fluoroquinolone (FLQ), while XDR-TB included MDR/RR-TB with resistance to any FLQ and at least one additional group A drug. Mutation status was determined by comparing bands on reaction zones [gyrA and gyrB for FLQ resistance, rrs for SILD resistance, and eis for low-level kanamycin resistance, according to the GenoType MTBDRsl VER 2.0, Hain Lifescience GmbH, Nehren, Germany definition of pre-XDR and XDR] to the evaluation sheet. SPSS version 17.0 was used for data analysis. RESULTS: Out of a total of 171 patients with MDR/RR-TB, 160 had (93.57%) had MTBC, of whom 57 (35.63%) had pre-XDR-TB and 10 (6.25%) had XDR-TB. Among the pre-XDR-TB strains, 56 (98.25%) were FLQ resistant, while 1 (1.75%) was SLID resistant. The most frequent mutations were found at codons MUT3C (57.14%, 32/56) and MUT1 (23.21%, 13/56) of the gyrA gene. One patient had SLID resistant genotype at the MUT1 codon of the rrs gene (100%, 1/1). XDR-TB mutation bands were mostly detected on MUT1 (30%, 3/10) of the gyrA and rrs, MUT3C (30%, 3/10) of the gyrA, and MUT1 (30%, 3/10) of the rrs. CONCLUSIONS: Pre-XDR-TB had a significantly higher likelihood than XDR-TB, with different specific mutation bands present in gyrA and rrs genes.
Assuntos
Antituberculosos , Tuberculose Extensivamente Resistente a Medicamentos , Mutação , Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Nepal/epidemiologia , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Masculino , Feminino , Adulto , Estudos Transversais , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Tuberculose Extensivamente Resistente a Medicamentos/epidemiologia , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Pessoa de Meia-Idade , Antituberculosos/uso terapêutico , Antituberculosos/farmacologia , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Testes de Sensibilidade Microbiana , Rifampina/uso terapêutico , Rifampina/farmacologia , Isoniazida/uso terapêutico , Isoniazida/farmacologia , Farmacorresistência Bacteriana Múltipla/genética , Adulto Jovem , Fluoroquinolonas/farmacologia , Fluoroquinolonas/uso terapêutico , Adolescente , IdosoRESUMO
BACKGROUND: Pre-extensively drug-resistant tuberculosis (pre-XDR-TB), defined as multidrug-resistant TB (MDR-TB) with additional resistance to any fluoroquinolone (FQ) is difficult to treat. We assessed whether the use of new or repurposed drugs (bedaquiline, delamanid, linezolid, carbapenem, clofazimine, pretomanid) mitigated treatment failure of pre-XDR-TB. METHODS: MDR-TB patients managed in the Taiwan MDR-TB consortium between July 2009-December 2019 were eligible. Treatment outcomes at 30 months were assessed. Logistic regression models were constructed to investigate factors associated with treatment outcomes. RESULTS: 109 patients with FQ-resistant MDR-TB and 218 patients with FQ-susceptible MDR-TB were included. 60 (55.1%) patients with FQ-resistant MDR-TB and 63 (28.9%) patients with FQ-susceptible MDR-TB have been treated with new or repurposed drugs (p < 0.01). Of the 218 patients with FQ-susceptible MDR-TB, 187 (85.8%) had treatment success, 30 (13.8%) died, no treatment failure, and 1 (0.5%) was loss-to-follow-up; of the 109 patients with FQ-resistant MDR-TB, 78 (71.6%) had treatment success, 21 (19.3%) died, 9 (8.3%) had treatment failure, and 1 (0.9%) was loss-to-follow-up (p < 0.01). The use of new or repurposed drugs was not associated with treatment outcomes among patients with FQ-susceptible MDR-TB. No patients with FQ-resistant MDR-TB treated with ≥2 new or repurposed drugs within 6 months of treatment initiation had treatment failure (p = 0.03). Patients with FQ-resistant MDR-TB treated with 1 new or repurposed drugs was more likely to have treatment failure as compared with patients not treated with new or repurposed drugs (adjOR 7.06, 95% CI 1.72-29.06). CONCLUSIONS: Proper use of new or repurposed anti-TB drugs can mitigate treatment failure in FQ-resistant MDR-TB.
Assuntos
Antituberculosos , Falha de Tratamento , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Masculino , Antituberculosos/uso terapêutico , Feminino , Pessoa de Meia-Idade , Adulto , Taiwan , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Reposicionamento de Medicamentos , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Estudos Retrospectivos , Idoso , Farmacorresistência Bacteriana Múltipla , Tuberculose Pulmonar/tratamento farmacológico , Mycobacterium tuberculosis/efeitos dos fármacos , Fluoroquinolonas/uso terapêutico , Resultado do TratamentoRESUMO
Treatment decisions for tuberculosis (TB) in the absence of full drug-susceptibility data can result in amplifying resistance and may compromise treatment outcomes. Genomics of Mycobacterium tuberculosis (M.tb) from clinical samples enables detection of drug resistance to multiple drugs. We performed whole-genome sequencing (WGS) for 600 clinical samples from patients with tuberculosis to identify the drug-resistance profile and mutation spectrum. We documented the reasons reported by clinicians for referral. WGS identified a high proportion (51%) of pre-extensively drug-resistant (pre-XDR) cases followed by multidrug-resistant tuberculosis (MDR-TB) (15.5%). This correlates with the primary reason for referral, as non-response to the first-line treatment (67%) and treatment failure or rifampicin resistance (14%). Multivariate analysis indicated that all young age groups (P < 0.05), male gender (P < 0.05), and Beijing strain (P < 0.01) were significant independent predictors of MDR-TB or MDR-TB+ [pre-extensively drug-resistant tuberculosis (XDR-TB) and XDR-TB]. Ser315Thr (72.5%) in the inhA gene and Ser450Leu in the rpoB gene (65.5%) were the most prevalent mutations, as were resistance-conferring mutations to pyrazinamide (41%) and streptomycin (61.33%). Mutations outside the rifampicin resistance-determining region (RRDR), Ile491Phe and Val170Phe, were seen in 1.3% of cases; disputed mutations in rpoB (Asp435Tyr, His445Asn, His445Leu, and Leu430Pro) were seen in 6% of cases, and mutations to newer drugs such as bedaquiline and linezolid in 1.0% and 7.5% of cases, respectively. This study on clinical samples highlights that there is a high proportion of pre-XDR cases and emerging resistance to newer drugs; ongoing transmission of these strains can cause serious threat to public health; and whole-genome sequencing can effectively identify and support precision medicine for TB. IMPORTANCE: The current study is based on real-world data on the TB drug-resistance profile by whole-genome sequencing of 600 clinical samples from patients with TB in India. This study indicates the clinicians' reasons for sending samples for WGS, which is for difficult-to-treat cases and/or relapse and treatment failure. The study reports a significant proportion of cases with pre-XDR-TB strains that warrant policy makers' attention. It reflects the current iterative nature of the diagnostic tests under programmatic conditions that leads to delays in appropriate diagnosis and empirical treatment. India had an estimated burden of 2.95 million TB cases in 2020 and 135,000 multidrug-resistant cases. However, WGS profiles of M.tb from India remains disproportionately poorly represented. This study adds a significant body of data on the mutation profiles seen in M.tb isolated from patients with TB in India, mutations outside the RRDR, disputed mutations, and resistance-conferring mutations to newer drugs such as bedaquiline and linezolid.
Assuntos
Antituberculosos , RNA Polimerases Dirigidas por DNA , Farmacorresistência Bacteriana Múltipla , Tuberculose Extensivamente Resistente a Medicamentos , Testes de Sensibilidade Microbiana , Mutação , Mycobacterium tuberculosis , Oxirredutases , Tuberculose Resistente a Múltiplos Medicamentos , Sequenciamento Completo do Genoma , Humanos , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Índia/epidemiologia , Masculino , Feminino , Adulto , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Pessoa de Meia-Idade , Farmacorresistência Bacteriana Múltipla/genética , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Proteínas de Bactérias/genética , Adulto Jovem , Adolescente , Idoso , Rifampina/farmacologia , Rifampina/uso terapêuticoAssuntos
Antituberculosos , Diarilquinolinas , Linezolida , Nitroimidazóis , Oxazóis , Refugiados , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Linezolida/uso terapêutico , Refugiados/estatística & dados numéricos , Antituberculosos/uso terapêutico , Diarilquinolinas/uso terapêutico , Alemanha , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Somália , Masculino , Ucrânia/epidemiologia , Feminino , Adulto , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Oxazolidinonas/uso terapêutico , Pessoa de Meia-IdadeRESUMO
Tuberculosis, caused by infection with Mycobacterium tuberculosis (MTB), remains a global public health challenge. Multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) strains make tuberculosis more difficult to control. New tools to study the biology of MTB can identify novel targets for drug discovery. Recently, the Clustered Regularly Interspaced Short Palindromic Repeats interference (CRISPRi) combined with next-generation sequencing has provided many novel insights into the physiology and genetics of MTB. This review summarizes the application and optimization of CRISPRi in MTB biology.
Assuntos
Tuberculose Extensivamente Resistente a Medicamentos , Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Mycobacterium tuberculosis/genética , Antituberculosos/uso terapêutico , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Biologia , Testes de Sensibilidade MicrobianaRESUMO
Tuberculosis (TB) remains the foremost cause of death by an infectious disease globally. Multidrug-resistant or rifampicin-resistant TB (MDR/RR-TB; resistance to rifampicin and isoniazid, or rifampicin alone) is a burgeoning public health challenge in several parts of the world, and especially Eastern Europe, Russia, Asia and sub-Saharan Africa. Pre-extensively drug-resistant TB (pre-XDR-TB) refers to MDR/RR-TB that is also resistant to a fluoroquinolone, and extensively drug-resistant TB (XDR-TB) isolates are additionally resistant to other key drugs such as bedaquiline and/or linezolid. Collectively, these subgroups are referred to as drug-resistant TB (DR-TB). All forms of DR-TB can be as transmissible as rifampicin-susceptible TB; however, it is more difficult to diagnose, is associated with higher mortality and morbidity, and higher rates of post-TB lung damage. The various forms of DR-TB often consume >50% of national TB budgets despite comprising <5-10% of the total TB case-load. The past decade has seen a dramatic change in the DR-TB treatment landscape with the introduction of new diagnostics and therapeutic agents. However, there is limited guidance on understanding and managing various aspects of this complex entity, including the pathogenesis, transmission, diagnosis, management and prevention of MDR-TB and XDR-TB, especially at the primary care physician level.
Assuntos
Tuberculose Extensivamente Resistente a Medicamentos , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Tuberculose Extensivamente Resistente a Medicamentos/diagnóstico , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Tuberculose Extensivamente Resistente a Medicamentos/epidemiologia , Rifampina/uso terapêutico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Isoniazida/uso terapêuticoRESUMO
Multidrug-resistant tuberculosis (MDR-TB) has imposed a significant economic and health burden worldwide, notably in China. Using whole genome sequence, we sought to understand the mutation and transmission of MDR-TB in Shandong. A retrospective study of patients diagnosed with pulmonary tuberculosis in Shandong from 2009 to 2018 was conducted. To explore transmission patterns, we performed whole genome sequencing on MDR-TB isolates, identified genomic clusters, and assessed the drug resistance of TB isolates. Our study analyzed 167 isolates of MDR-TB, finding that 100 were clustered. The predominant lineage among MDR-TB isolates was lineage 2, specifically with a notable 88.6% belonging to lineage 2.2.1. Lineage 4 constituted a smaller proportion, accounting for 4.2% of the isolates. We discovered that Shandong has a significant clustering percentage for MDR-TB, with Jining having the highest percentage among all Shandong cities. The clustering percentages of MDR-TB, pre-extensively drug-resistant tuberculosis, and extensively drug-resistant tuberculosis were 59.9%, 66.0%, and 71.4%, respectively, and the clustering percentages increased with the expansion of the anti-TB spectrum. Isolates from genomic clusters 1 and 3 belonged to lineage 2.2.1 and showed signs of cross-regional transmission. The distribution of rrs A1401G and katG S315T mutations in lineage 2.2.1 and 2.2.2 strains differed significantly (Pâ <â .05). MDR-TB isolates with rpoB I480V, embA-12Câ >â T, and rrs A1401G mutations showed a higher likelihood of clustering (Pâ <â .05). Our findings indicate a significant problem of local transmission of MDR-TB in Shandong, China. Beijing lineage isolates and some drug-resistant mutations account for the MDR-TB transmission in Shandong.