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1.
Arq Neuropsiquiatr ; 78(11): 700-707, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33331464

RESUMO

BACKGROUND: The timely diagnosis of tuberculous meningitis (TBM) is challenging. Molecular diagnostic tools are necessary for TBM, particularly in low- and middle-income countries. OBJECTIVES: We aimed to calculate the diagnostics characteristics of Xpert MTB/RIF for the detection of Mycobacterium tuberculosis in the cerebrospinal fluid (CSF) and the frequency of rifampicin (RIF)-resistance in the CSF samples. METHODS: A total of 313 consecutive CSF samples were studied and categorized into TBM definite, probable, possible, or not TBM cases based on the clinical, laboratory, and imaging data. RESULTS: For the definite TBM cases (n=7), the sensitivity, specificity, efficiency, and positive likelihood ratio were 100, 97, 97, and 38%, respectively. However, for the TBM definite associated with the probable cases (n=24), the sensitivity decreased to 46%. All CSF samples that were Xpert MTB/RIF-positive were RIF susceptible. CONCLUSION: Xpert MTB/RIF showed high discriminating value among the microbiology-proven TBM cases, although the values for the probable and possible TBM cases were reduced. Xpert MTB/RIF contributes significantly to the diagnosis of TBM, mainly when coupled with the conventional microbiological tests and clinical algorithms.


Assuntos
Mycobacterium tuberculosis , Tuberculose Meníngea , Brasil , Humanos , Mycobacterium tuberculosis/genética , Rifampina/farmacologia , Sensibilidade e Especificidade , Tuberculose Meníngea/diagnóstico , Tuberculose Meníngea/tratamento farmacológico
2.
PLoS One ; 15(11): e0242542, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33212470

RESUMO

BACKGROUND: Tuberculosis is one of the major causes of death globally. The problems become even more complicated with the rise in prevalence of multidrug resistant tuberculosis (MDR-TB). Many diseases have been reported to occur with tuberculosis making it more difficult to manage. Candida spp., which are yeast-like fungi and a constituent of normal flora in humans, are notoriously reported to be one of the most common opportunistic nosocomial infections. This study aimed to measure the proportion of presumptive MDR-TB patients colonized with Candida spp. and to characterize its susceptibility against azole group antifungal agents. METHODS: Sputum from presumptive MDR-TB patients were collected and examined for the presence of Mycobacterium tuberculosis and its rifampicin resistant status using GeneXpert. It was further cultured on Sabouroud's Dextrose Agar (SDA) to isolate the Candida spp. The Candida species were determined using HiCrome™ Candidal Differential Agar. Antifungal susceptibility was tested using microbroth dilution methods. Checkerboard microdilution assays were performed to measure the interaction between rifampicin and fluconazole to C. albicans. RESULTS: There were 355 presumptive MDR-TB patients enrolled. A total of 101 (28.4%) patients were confirmed to have M. tuberculosis. There were 113 (31.8%) sputum positive for Candida spp., which corresponded to 149 Candida spp. isolates. Candida albicans was the most frequent (53.7%) species isolated from all patients. The susceptibility of Candida spp. against fluconazole, itraconazole, and ketoconazole were 38.3%, 1.3%, and 10.7% respectively. There was significant association between rifampicin exposure history and susceptibility of Candida albicans against fluconazole (Odds Ratio: 9.96; 95% CI: 1.83-54.19; p <0.01), but not for ketoconazole and itraconazole. The checkerboard microdilution assays showed that rifampicin decreased the fungicidal activity of fluconazole to C. albicans in a dose-dependent manner. CONCLUSION: There was high frequency of azole resistant Candida spp. isolates colonizing the respiratory tract of presumptive MDR-TB patients. This presence might indicate the association of chronic exposure to rifampicin, the main drug for tuberculosis therapy, with the induction of azole resistance.


Assuntos
Antifúngicos/farmacologia , Antituberculosos/farmacologia , Candida/efeitos dos fármacos , Candidíase/complicações , Farmacorresistência Fúngica Múltipla , Fluconazol/farmacologia , Rifampina/farmacologia , Tuberculose Resistente a Múltiplos Medicamentos/complicações , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antituberculosos/uso terapêutico , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Criança , Interações Medicamentosas , Feminino , Humanos , Itraconazol/farmacologia , Cetoconazol/farmacologia , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Rifampina/uso terapêutico , Especificidade da Espécie , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Adulto Jovem
3.
PLoS One ; 15(11): e0240361, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33147218

RESUMO

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) continues to be a global health problem. Data on rifampicin resistance MTB using Xpert- MTB/RIF assay in Ethiopia, particularly in the study area is limited. The aim of this study was to determine the frequency of MTB and rifampicin resistant-MTB among presumptive tuberculosis patients in Tigray, Northern Ethiopia. METHODS: A multicenter retrospective study was conducted among presumptive TB patients from five governmental hospitals and one comprehensive specialized teaching hospital in Tigray regional state. Records of sputum sample results of presumptive MTB patients with Xpert-MTB/RIF assay from January 2016 to December 2019 were investigated. Data extraction tool was used to collect data from registration books and analyzed using SPSS ver.21 statistical software. Statistical significance was set at p-value ≤ 0.05. RESULTS: Of the 30,935 presumptive adult TB patients who have provided specimens for TB diagnosis from January 2016 to December 2019, 30,300 (98%) had complete data and were included in this study. More than half, 17,471 (57.7%) were males, and the age of the patients ranged from 18-112 years, with a median age of 40.65 (interquartile 29.4-56.5 years). Majority, 28,996 (95.7%) of the participants were treatment naïve, and 23,965 (79.1%) were with unknown HIV status. The overall frequency of MTB was 2,387 (7.9% (95% CI: 7.6-8.2%); of these, 215 (9% (95% CI: 7.9-10.2%) were rifampicin resistant-MTB. Age (18-29 years), HIV positive and previous TB treatment history were significantly associated with high MTB (p < 0.001), whereas gender (being female) was associated with low MTB (p < 0.001). Likewise, rifampicin resistant-MTB was more prevalent among relapse (p < 0.001) and failure cases (p = 0.025); while age group 30-39 years was significantly associated with lower frequency of rifampicin resistant-MTB (p = 0.008). CONCLUSION: Frequency of MTB among tuberculosis presumptive patients was low; however, the problem of rifampicin resistant-MTB among the tuberculosis confirmed patients was high. The high frequency of MTB and RR-MTB among previously treated and HIV positive patients highlights the need for more efforts in TB treatment and monitoring program in the study area.


Assuntos
Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Rifampina/farmacologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antituberculose/farmacologia , Bioensaio/métodos , Estudos Transversais , Etiópia/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/fisiologia , Estudos Retrospectivos , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Adulto Jovem
4.
J Assoc Physicians India ; 68(11): 33-36, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33187034

RESUMO

Introduction: India has the highest number of TB (27%) and MDR/RR-TB (24%) cases among the notified TB patients. Xpert MTB/ RIF assay is a fully automated cartridge-based real-time PCR to detect MTB and resistance to rifampicin within two hours using three specific primers and five unique molecular probes to target the rpoB gene. This study was done to detect RR-TB cases and frequency of missing probes, which target mutations in rpoB gene, in the different groups of study population in Sirmaur district of Himachal Pradesh. Methods: All, pulmonary and extrapulmonary specimens, were processed for AFB microscopy and Xpert MTB/RIF assay to diagnose TB and RR-TB. Results: Xpert detected MTBC in 721 patients. Using AFB microscopy, only 284 samples were positive. Of these MTB positive patients, 671 had pulmonary TB and 50 were EPTB cases. Resistance to RIF was detected in 31 (4.29%) cases of which resistance in presumptive tuberculosis group and presumptive drug resistant tuberculosis was 1.51% and 9.30% respectively. Twentyeight (4.17%) PTB cases and three (6%) EP-TB cases were resistant to RIF. The frequency of probe E was highest (77.41%) and mutation combination of probes C and D and E and D was 3.22%. Conclusion: Drug resistance in the MTBC is mainly conferred through point mutations in specific gene targets in the bacterial genome. Molecular assays like Genexpert gives rapid diagnosis and Rifampicin resistance. This study helps to provide baseline data of mutations with in the 81 bp of rpoB gene and stresses the need to further evaluate the mutation patterns in this part of the country.


Assuntos
Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Farmacorresistência Bacteriana/genética , Humanos , Índia , Mycobacterium tuberculosis/genética , Rifampina/farmacologia , Sensibilidade e Especificidade , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico
5.
J Vis Exp ; (164)2020 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-33191927

RESUMO

Due to the global threat of rising antimicrobial resistance, novel antibiotics are urgently needed. We investigate natural products from Myxobacteria as an innovative source of such new compounds. One bottleneck in the process is typically the elucidation of their mode-of-action. We recently established isothermal microcalorimetry as part of a routine profiling pipeline. This technology allows for investigating the effect of antibiotic exposure on the total bacterial metabolic response, including processes that are decoupled from biomass formation. Importantly, bacteriostatic and bactericidal effects are easily distinguishable without any user intervention during the measurements. However, isothermal microcalorimetry is a rather new approach and applying this method to different bacterial species usually requires pre-evaluation of suitable measurement conditions. There are some reference thermograms available of certain bacteria, greatly facilitating interpretation of results. As the pool of reference data is steadily growing, we expect the methodology to have increasing impact in the future and expect it to allow for in-depth fingerprint analyses enabling the differentiation of antibiotic classes.


Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Produtos Biológicos/farmacologia , Calorimetria/métodos , Metabolômica/métodos , Acinetobacter/efeitos dos fármacos , Acinetobacter/crescimento & desenvolvimento , Acinetobacter/metabolismo , Bactérias/crescimento & desenvolvimento , Bactérias/metabolismo , Cloranfenicol/farmacologia , Ciprofloxacino/farmacologia , Testes de Sensibilidade Microbiana , Rifampina/farmacologia , Tetraciclina/farmacologia
6.
PLoS One ; 15(10): e0240257, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33017455

RESUMO

Tuberculous meningitis (TBM) is the most severe form of Mycobacterium tuberculosis (Mtb) infection in humans and is a public health concern worldwide. We evaluated the performance of GeneXpert MTB/RIF (GeneXpert) for the diagnosis of TBM. In addition, genetic diversity and drug susceptibility profiling of Mtb strains isolated from TBM patients were also investigated. A total of 293 TBM suspected cerebrospinal fluid (CSF) samples were collected and subjected to GeneXpert and Mycobacterial Growth Indicator Tube (MGIT 960) culture, respectively. Sensitivity and specificity of GeneXpert was 72.7% and 98.5%, respectively by using MGIT 960 as a gold standard (GeneXpert (n = 20, 6.8%) vs MGIT 960 (n = 22, 7.5%)). All Mtb positive cultures were subjected to 24-locus Mycobacterial Interspersed Repetitive Unit Variable Number Tandem Repeat (MIRU-VNTR) typing, Line probe assay (LPA) and MGIT 960- Drug Susceptibility Testing (DST). The rpoB gene was amplified and sequenced for selected isolates. Among our TBM patients, East African Indian (EAI) lineage (n = 16, 72.7%) was most predominant followed by Beijing (n = 3, 13.6%), S-family (n = 2, 9.1%) and Delhi/CAS (n = 1, 4.5%). Three Mtb strains were found to be Isoniazid (INH) resistant by MGIT 960; however LPA revealed that two strains were INH resistant and one strain was multi drug resistant (MDR) (Resistant to Isoniazid and Rifampicin (RIF)). We identified rifampicin resistant isolate with the mutation D516F in rifampicin resistance-determining region (RRDR) and observed discordant results between LPA, GeneXpert and MGIT 960. In addition, GeneXpert showing false RIF resistance was identified (no mutation in RRDR). We conclude that GeneXpert is useful for the diagnostic confirmation of TBM; however a GeneXpert negative sample should be subjected to MGIT 960 culture or LPA to rule out TBM. EAI lineage was the most predominant among TBM patients in South India and associated with drug resistance. The discordance between GeneXpert, MGIT 960 and LPA with respect to rifampicin resistance has to be ruled out to avoid TB treatment failure or relapse.


Assuntos
Patologia Molecular/métodos , Tuberculose Meníngea/microbiologia , Antituberculosos/farmacologia , Proteínas de Bactérias/genética , RNA Polimerases Dirigidas por DNA/genética , Variação Genética/genética , Humanos , Índia , Isoniazida/farmacologia , Testes de Sensibilidade Microbiana , Reação em Cadeia da Polimerase Multiplex , Rifampina/farmacologia , Centros de Atenção Terciária/estatística & dados numéricos
7.
PLoS One ; 15(9): e0239328, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32966321

RESUMO

BACKGROUND: Pakistan is among top five high burden countries for tuberculosis and drug resistant TB. Among rifampicin sensitive new pulmonary TB (PTB), prevalence of isoniazid resistance is 8.3% (95%CI: 7.0-10.7) and resistance to fluoroquinolone is higher (11·1%, 95%CI: 7·8-14·3) than isoniazid resistance. METHOD: Five year retrospective data (2015-2019) of drug susceptibility testing (DST) for Mycobacterium tuberculosis isolates, performed using recommended phenotypic (pDST) and/or genotypic (gDST) methods was analyzed stratified by rifampicin results for isoniazid resistance profiles and associated levofloxacin and pyrazinamide resistance. FINDINGS: DST data was analyzed from 11045 TB patients. Isolates were tested using pDST (87%), gDST (92%) and both methods (79.5%). For both rifampicin and isoniazid, a significant difference (P < .001) was noted between resistance detected by pDST and gDST. Among isolates, tested by both methods (8787), 49% were resistant to rifampicin and 51.7% to isoniazid with discordance in resistant results of 15.8% for each, with 13.2% (570) of rifampicin resistance reported sensitive by pDST and 14.2% (660) of isoniazid resistance missed by gDST. Estimated isoniazid resistance among rifampicin sensitive new PTB, extrapulmonary TB and previously treated PTB was 9.8% (95%CI: 8.7-11.1), 6.8% (95%CI: 5.4-8.5) and 14.6% (95%CI: 11.8-17.9) respectively. Significant differences were reported between the genotypic profile of isoniazid resistance associated with rifampicin-resistant and sensitive isolates including detectable mutations (87% vs 71.6%), frequency of inhA (7.6% and 30.2%) and katG mutations (76.1% vs 41.2%) respectively. Among rifampicin resistant and sensitive isolates, a significantly higher level of resistance to levofloxacin and pyrazinamide was seen associated with isoniazid resistance. CONCLUSION: There are risks and many challenges in implementing WHO recommended treatment for isoniazid resistant tuberculosis. The laboratory based surveillance can complement random surveys in country specific planning for TB diagnostics and appropriate treatment regimens.


Assuntos
Farmacorresistência Bacteriana/efeitos dos fármacos , Monitoramento Epidemiológico , Isoniazida/farmacologia , Levofloxacino/farmacologia , Pirazinamida/farmacologia , Rifampina/farmacologia , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Adolescente , Adulto , Antituberculosos/farmacologia , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Lactente , Laboratórios , Masculino , Testes de Sensibilidade Microbiana , Paquistão , Fenótipo , Estudos Retrospectivos , Tuberculose Resistente a Múltiplos Medicamentos/genética , Adulto Jovem
8.
PLoS One ; 15(8): e0238016, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32866193

RESUMO

BACKGROUND: Since a meta-analysis showed little or no effect of second-line injectables on treatment success, and using injectables may induce ototoxicity, injectable-free rifampicin-resistant tuberculosis (RR-TB) treatment regimens are recommended. However, acquired resistance preventing activity was overlooked. No previous study assessed the effect of shortening the duration of kanamycin administration to 2 months during the intensive phase of the RR-TB shorter treatment regimen (STR). METHODS: Retrospective cohort study of the effect of using 2 months of kanamycin instead of the standard 4(+) months (extension if lack of smear conversion at 4 months) on recurrence (either treatment failure or relapse) and fluoroquinolone acquired drug resistance, in patients treated with a gatifloxacin-based STR in Damien Foundation supported clinics in Bangladesh. Logistic regression was used to estimate associations. RESULTS: Five of 52 (9.6%) treated with a STR containing two months of kanamycin had recurrence, compared to 21 of 738 (2.8%) patients treated with the standard STR containing 4(+) months of kanamycin (OR 3.7; 95%CI:1.5-10.3). In those with initially fluoroquinolone-susceptible TB, acquired resistance to fluoroquinolone was detected in none of 639 patients treated with 4(+) months of kanamycin and two (4.5%) of 44 treated with two months of kanamycin (OR 75.2; 95%CI:3.6-1592.1). CONCLUSION: Two months of kanamycin was insufficient to prevent recurrence with acquired resistance to gatifloxacin, the core drug of the most effective RR-TB STR. Injectable mediated resistance prevention is important to reach high effectiveness, to safeguard all treatment options after recurrence, and to prevent the spread of resistant TB. Studies on all-oral regimens should also assess the effect of regimen composition on resistance acquisition. Until evidence shows that other drugs can assure at least the same strong resistance preventing activity of the injectables, it seems wise to continue using this group of drugs, and adapt the regimen if any ototoxicity is detected.


Assuntos
Farmacorresistência Bacteriana/efeitos dos fármacos , Rifampina/farmacologia , Tuberculose/tratamento farmacológico , Adolescente , Adulto , Estudos de Coortes , Feminino , Humanos , Injeções , Canamicina/administração & dosagem , Canamicina/farmacologia , Canamicina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
9.
Int J Biol Macromol ; 163: 1787-1797, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32950529

RESUMO

The pandemic prevalence of COVID-19 has become a very serious global health issue. Scientists all over the world have been seriously attempting in the discovery of a drug to combat SARS-CoV-2. It has been found that RNA-dependent RNA polymerase (RdRp) plays a crucial role in SARS-CoV-2 replication, and thus could be a potential drug target. Here, comprehensive computational approaches including drug repurposing and molecular docking were employed to predict an effective drug candidate targeting RdRp of SARS-CoV-2. This study revealed that Rifabutin, Rifapentine, Fidaxomicin, 7-methyl-guanosine-5'-triphosphate-5'-guanosine and Ivermectin have a potential inhibitory interaction with RdRp of SARS-CoV-2 and could be effective drugs for COVID-19. In addition, virtual screening of the compounds from ZINC database also allowed the prediction of two compounds (ZINC09128258 and ZINC09883305) with pharmacophore features that interact effectively with RdRp of SARS-CoV-2, indicating their potentiality as effective inhibitors of the enzyme. Furthermore, ADME analysis along with analysis of toxicity was also undertaken to check the pharmacokinetics and drug-likeness properties of the two compounds. Comparative structural analysis of protein-inhibitor complexes revealed that the amino acids Y32, K47, Y122, Y129, H133, N138, D140, T141, S709 and N781 are crucial for drug surface hotspot in the RdRp of SARS-CoV-2.


Assuntos
Antivirais/química , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos , Pneumonia Viral/tratamento farmacológico , /antagonistas & inibidores , Betacoronavirus/enzimologia , Infecções por Coronavirus/virologia , Fidaxomicina/química , Fidaxomicina/farmacologia , Humanos , Ivermectina/química , Ivermectina/farmacologia , Simulação de Acoplamento Molecular , Pandemias , Pneumonia Viral/virologia , Rifabutina/química , Rifabutina/farmacologia , Rifampina/análogos & derivados , Rifampina/química , Rifampina/farmacologia , Replicação Viral/efeitos dos fármacos
10.
Arch Biochem Biophys ; 692: 108522, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32781051

RESUMO

About one quarter of people worldwide are infected with tuberculosis, and multi-drug resistant tuberculosis (MDR-TB) remains a health threat. It is known that two-Component Signal Transduction Systems (TCSs) of Mycobacterium tuberculosis are closely related to tuberculosis resistance, but the mechanism by which orphan response protein Rv3143 regulates strain sensitivity to drug is still unclear. This study found that Rv3143 overexpression resulted in approximately two-fold increase in Mycobacterium smegmatis antibiotic sensitivity. Transcriptome sequencing indicated that 198 potential genes were regulated by Rv3143, affecting the sensitivity of the strain to rifampicin (RIF). MSMEG_4740 promoter binding with Rv3143, was screened out by surface plasmon resonance (SPR). Rv1524, the homologous gene of MSMEG_4740, belonging to the glycosyltransferase (Gtf) family, was related to cell wall modification. By measuring ethidium bromide (EB) accumulation, we found when Rv3143 or MSMEG_4740, or Rv1524 was overexpressed, the cell wall permeability of Mycobacterium smegmatis was increased. In addition, a combination of Rv3143 and RIF was observed. Our findings provide a new strategy for treating drug-resistant tuberculosis by increasing the expression of Rv3143 to enhance the strain sensitivity to antibiotics.


Assuntos
Proteínas de Bactérias/metabolismo , Parede Celular/metabolismo , Farmacorresistência Bacteriana , Mycobacterium smegmatis/metabolismo , Proteínas de Bactérias/genética , Parede Celular/genética , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Mycobacterium smegmatis/genética , Permeabilidade/efeitos dos fármacos , Rifampina/farmacologia , Transcriptoma/efeitos dos fármacos
11.
Int J Mol Sci ; 21(17)2020 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-32824985

RESUMO

The aim of this study is to examine the use of an inflammasome competitor as a preventative agent. Coronaviruses have zoonotic potential due to the adaptability of their S protein to bind receptors of other species, most notably demonstrated by SARS-CoV. The binding of SARS-CoV-2 to TLR (Toll-like receptor) causes the release of pro-IL-1ß, which is cleaved by caspase-1, followed by the formation and activation of the inflammasome, which is a mediator of lung inflammation, fever, and fibrosis. The NLRP3 (NACHT, LRR and PYD domains-containing protein 3) inflammasome is implicated in a variety of human diseases including Alzheimer's disease (AD), prion diseases, type 2 diabetes, and numerous infectious diseases. By examining the use of 4,4'-diaminodiphenyl sulfone (DDS) in the treatment of patients with Hansen's disease, also diagnosed as Alzheimer's disease, this study demonstrates the diverse mechanisms involved in the activation of inflammasomes. TLRs, due to genetic polymorphisms, can alter the immune response to a wide variety of microbial ligands, including viruses. In particular, TLR2Arg677Trp was reported to be exclusively present in Korean patients with lepromatous leprosy (LL). Previously, mutation of the intracellular domain of TLR2 has demonstrated its role in determining the susceptibility to LL, though LL was successfully treated using a combination of DDS with rifampicin and clofazimine. Of the three tested antibiotics, DDS was effective in the molecular regulation of NLRP3 inflammasome activators that are important in mild cognitive impairment (MCI), Parkinson's disease (PD), and AD. The specific targeting of NLRP3 itself or up-/downstream factors of the NLRP3 inflammasome by DDS may be responsible for its observed preventive effects, functioning as a competitor.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Dapsona/farmacologia , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pneumonia Viral/tratamento farmacológico , Doença de Alzheimer/patologia , Clofazimina/farmacologia , Disfunção Cognitiva/patologia , Humanos , Interleucina-1beta/metabolismo , Hanseníase/tratamento farmacológico , Hanseníase/genética , Pandemias , Transtornos Parkinsonianos/patologia , Rifampina/farmacologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Receptor 2 Toll-Like/genética
12.
Sci Rep ; 10(1): 14128, 2020 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-32839480

RESUMO

Long term multiple systemic antibiotics form the cornerstone in the treatment of bone and joint tuberculosis, often combined with local surgical eradication. Implanted carriers for local drug delivery have recently been introduced to overcome some of the limitations associated with conventional treatment strategies. In this study, we used a calcium sulphate hemihydrate (CSH)/nanohydroxyapatite (nHAP) based nanocement (NC) biomaterial as a void filler as well as a local delivery carrier of two standard of care tuberculosis drugs, Rifampicin (RFP) and Isoniazid (INH). We observed that the antibiotics showed different release patterns where INH showed a burst release of 67% and 100% release alone and in combination within one week, respectively whereas RFP showed sustained release of 42% and 49% release alone and in combination over a period of 12 weeks, respectively indicating different possible interactions of antibiotics with nHAP. The interactions were studied using computational methodology, which showed that the binding energy of nHAP with RFP was 148 kcal/mol and INH was 11 kcal/mol, thus varying substantially resulting in RFP being retained in the nHAP matrix. Our findings suggest that a biphasic ceramic based drug delivery system could be a promising treatment alternative to bone and joint TB.


Assuntos
Antituberculosos/farmacologia , Sulfato de Cálcio/farmacologia , Portadores de Fármacos/farmacologia , Durapatita/farmacologia , Isoniazida/farmacologia , Rifampina/farmacologia , Tuberculose Osteoarticular/tratamento farmacológico , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Regeneração Óssea/efeitos dos fármacos , Biologia Computacional , Preparações de Ação Retardada/farmacologia , Interações Medicamentosas , Quimioterapia Combinada , Testes de Sensibilidade Microbiana , Mycobacterium smegmatis/efeitos dos fármacos
13.
Niger J Clin Pract ; 23(8): 1172-1177, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32788498

RESUMO

Background: Multidrug-resistant tuberculosis (MDR-TB) is a global health challenge. The emergence of MDR TB has contributed remarkably to the spread of tuberculosis and also poses a threat, which if not effectively addressed may wipe out the achievements of previous efforts in controlling tuberculosis. Objective: This study was aimed at detecting MDR-TB among patients in a setting prevalent with tuberculosis and HIV in Southeast, Nigeria. Method: Sputum specimens collected from 740 suspected tuberculosis (TB) patients were screened for acid-fast bacilli (AFB). All the 111 AFB positive samples were subjected to culture on Lowenstein-Jensen (LJ) medium and Mycobacterium Growth Indicator Tube (MGIT) 960 TB system. The isolates were then confirmed as Mycobacterium tuberculosis using SD Bioline Rapid Diagnostic Tests before being subjected to drug susceptibility testing to first-line anti-TB drugs. MDR-TB was determined by isolates being resistant to both isoniazid and rifampicin. HIV testing was performed for participants included in the study using standard rapid diagnostic tests. Result: Out of the 111 AFB-positive sputum samples, 65 (58.6%) were culture-positive for Mycobacterium tuberculosis. MDR-TB was found in 2 ([3.1%] 95% CI = 0.0-7.3) of the culture-positive samples. The rate of TB and HIV coinfection was 7.7%. Maximum single-drug resistance was seen in ethambutol 12 ([18.5%] 95% CI = 9.0-27.9). Conclusion: The MDR-TB rate of 3.1% found in this study was relatively low and efforts should be intensified to keep it low.


Assuntos
Antituberculosos/farmacologia , Isoniazida/uso terapêutico , Mycobacterium tuberculosis/isolamento & purificação , Rifampina/uso terapêutico , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Antituberculosos/uso terapêutico , Estudos Transversais , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Humanos , Isoniazida/farmacologia , Masculino , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Nigéria/epidemiologia , Valor Preditivo dos Testes , Prevalência , Rifampina/farmacologia , Escarro/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Adulto Jovem
14.
PLoS One ; 15(8): e0236054, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32750053

RESUMO

INTRODUCTION: Multi-drug resistance is a major challenge in the control of tuberculosis. Despite newer modalities for diagnosis and treatment, people are still suffering from this disease. Understanding the common gene mutations conferring rifampicin and isoniazid resistance is crucial for the implementation of effective molecular tools at local and national levels. Hence, this study aimed to evaluate the molecular detection of rifampicin and isoniazid-resistant gene mutations in M.tuberculosis isolates in Addis Ababa, Ethiopia. METHOD: Health Center-based cross-sectional study was conducted between January and September 2017 in Addis Ababa, Ethiopia. The collected sputum samples were processed for mycobacterial isolation and Region of difference 9 based polymerase chain reaction for species identification. To characterize the rifampicin and isoniazid-resistant M. tuberculosis isolates, a molecular genetic assay (GenoType MTBDRplus) was used; the assay is based on DNA-STRIP technology. RESULT: Culture positivity was confirmed in 82.6% (190/230) of smear-positive newly diagnosed pulmonary tuberculosis cases enrolled in the study. From 190 isolates 93.2% were sensitive for both rifampicin and isoniazid, and 6.8% of the isolates were resistant to at least one of the tested anti-TB drugs. Gene mutations were observed in all studied multidrug resistance-associated gene loci (rpoB, katG, and inhA). Two isolates exhibited heteroresistance, a mutated, as well as wild type sequences, were detected in the respective strains. MDR-TB case was observed in 1.1% (2/190) of the cases. All the MDR-TB cases were positive for HIV and found to have a history of prior hospital admission. CONCLUSION: In our finding a relatively high prevalence of any drug resistance was observed and the overall prevalence of multidrug-resistant tuberculosis was 1.1%.The majority of drug-resistant isolates demonstrated common mutations. Heteroresistant strains were detected, signaling the existence of an M.tuberculosis population with variable responses to anti-tuberculosis drugs or of mixed infections.


Assuntos
Antituberculosos/farmacologia , Farmacorresistência Bacteriana Múltipla/genética , Mycobacterium tuberculosis/genética , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Adolescente , Adulto , Antituberculosos/uso terapêutico , Estudos Transversais , Análise Mutacional de DNA , DNA Bacteriano/genética , DNA Bacteriano/isolamento & purificação , Etiópia , Feminino , Genes Bacterianos/genética , Loci Gênicos/genética , Humanos , Isoniazida/farmacologia , Isoniazida/uso terapêutico , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Mutação , Mycobacterium tuberculosis/isolamento & purificação , Reação em Cadeia da Polimerase , Rifampina/farmacologia , Rifampina/uso terapêutico , Escarro/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Adulto Jovem
15.
PLoS Pathog ; 16(7): e1008623, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32639986

RESUMO

Antibiotic treatment has emerged as a promising strategy to sterilize and kill filarial nematodes due to their dependence on their endosymbiotic bacteria, Wolbachia. Several studies have shown that novel and FDA-approved antibiotics are efficacious at depleting the filarial nematodes of their endosymbiont, thus reducing female fecundity. However, it remains unclear if antibiotics can permanently deplete Wolbachia and cause sterility for the lifespan of the adult worms. Concerns about resistance arising from mass drug administration necessitate a careful exploration of potential Wolbachia recrudescence. In the present study, we investigated the long-term effects of the FDA-approved antibiotic, rifampicin, in the Brugia pahangi jird model of infection. Initially, rifampicin treatment depleted Wolbachia in adult worms and simultaneously impaired female worm fecundity. However, during an 8-month washout period, Wolbachia titers rebounded and embryogenesis returned to normal. Genome sequence analyses of Wolbachia revealed that despite the population bottleneck and recovery, no genetic changes occurred that could account for the rebound. Clusters of densely packed Wolbachia within the worm's ovarian tissues were observed by confocal microscopy and remained in worms treated with rifampicin, suggesting that they may serve as privileged sites that allow Wolbachia to persist in worms while treated with antibiotic. To our knowledge, these clusters have not been previously described and may be the source of the Wolbachia rebound.


Assuntos
Brugia pahangi/microbiologia , Filariose/microbiologia , Filaricidas/farmacologia , Rifampina/farmacologia , Wolbachia/efeitos dos fármacos , Animais , Feminino , Gerbillinae
16.
Mikrobiyol Bul ; 54(2): 211-222, 2020 Apr.
Artigo em Turco | MEDLINE | ID: mdl-32723277

RESUMO

Members of the Mycobacterium tuberculosis complex (MTBC) are the causative agents of tuberculosis (TB). Rifampin resistance in the clinical isolates of MTBC is an important indicator for multidrug resistant-TB (MDR-TB) cases. In this study, it was aimed to evaluate whether the Sensititre MycoTB plaque method is suitable for the routine use in determining drug susceptibility of rifampin resistant MTBC strains. Xpert MTBC/ RIF positive rifampin resistant 100 MTBC isolates were included in the study. Xpert MTBC/RIF (Cepheid, USA) test were performed after the samples were processed by homogenization and decontamination and acid-fast staining. Rifampin resistant clinical samples were cultured in automated MGIT/BACTEC 960 (Becton Dickinson, USA) system and acid fast bacteria (AFB) were investigated. The anti-TB drug susceptibility tests of all culture positive AFB and cord factor identified as MTBC by using a cart test (MPB64, Capilla TB-Neo, Tauns Laboratories, Inc., Numazu, Japan) were performed with the Löwenstein-Jensen proportion method (LJPM) and Sensititre MycoTB (Trek Diagnostic Systems, Cleveland, OH, USA) methods. For the comparison of the methods used, the tests were performed simultaneously. The standard LJPM was performed according to the previously described procedures by World Health Organization and the Sensititre MycoTB plate method was performed as defined by the manufacturer. The final concentrations of isoniazide, rifampin, rifabutin, ethambutol, ofloxacin, moxifloxacin amikacin, kanamycin, cycloserine, ethionamide and p-aminosalicylic acid in Löwenstein-Jensen media for LJPM were 0.2 µg/ml, 40.0 µg/ml, 20.0 µg/ml, 2.0 µg/ml, 2.0 µg/ml, 1.0 µg/ml, 4.0 µg/ml, 30.0 µg/ml, 30.0 µg/ml, 40.0 µg/ml, 40.0 µg/ml and 1.0 µg/ ml, respectively. The results were obtained in 14 days for all of the drugs in the Sensititre MycoTB plate method and in 28-42 days in the LJPM. In this study, the sensitivity and specificity percentages of the Sensititre MycoTB method and the categorical agreement between the two methods were calculated. The sensitivity and specificity percentages of the Sensititre MycoTB plate method were between 84.4-100% and 95.6- 100%, respectively. The categorical agreements between the two methods were 92-100% for the drugs tested in the study. Ethambutol was found to have the lowest sensitivity (84.4%) and specificity (95.6%). The sensitivities of isoniazide, ofloxacin, streptomycin, kanamycin, ethionamide and p-aminosalicylic acid were 98.8%, 90.0%, 94.3%, 87.5%, 91.7% and 95.6%, respectively, while rifampicin, rifabutin, moxifloxacin, amikacin, cycloserine were calculated as 100%. The specificities of isoniazid, rifampicin, rifabutin, ofloxacin, moxifloxacin, amikacin, kanamycin, and cycloserine were found to be 100%, streptomycin, ethionamide and p-aminosalicylic specificity were 96.9%, 97.4% and 98.9% respectively. The categorical agreement was 96-100% in all tested drugs except ethambutol (92%). As a result, although the cost is high, owing to the short incubation period, easy to perform, the possibility for evaluating both first and second line anti-TB drugs simultaneously, determination of minimum inhibitory concentration values of the drugs, long shelf life, high sensitivity, specificity and the categorical agreement values, the Sensititre MycoTB method was determined as an effective method that can be used especially in laboratories where the workload and the MDR-TB cases are high.


Assuntos
Antituberculosos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis , Rifampina , Tuberculose , Antituberculosos/farmacologia , Etambutol/farmacologia , Testes de Sensibilidade Microbiana/métodos , Mycobacterium tuberculosis/efeitos dos fármacos , Rifampina/farmacologia , Tuberculose/microbiologia
17.
PLoS Pathog ; 16(7): e1008700, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32687537

RESUMO

With antibiotic resistance rates on the rise, it is critical to understand how microbial species interactions influence the evolution of resistance. In obligate mutualisms, the survival of any one species (regardless of its intrinsic resistance) is contingent on the resistance of its cross-feeding partners. This sets the community antibiotic sensitivity at that of the 'weakest link' species. In this study, we tested the hypothesis that weakest link dynamics in an obligate cross-feeding relationship would limit the extent and mechanisms of antibiotic resistance evolution. We experimentally evolved an obligate co-culture and monoculture controls along gradients of two different antibiotics. We measured the rate at which each treatment increased antibiotic resistance, and sequenced terminal populations to question whether mutations differed between mono- and co-cultures. In both rifampicin and ampicillin treatments, we observed that resistance evolved more slowly in obligate co-cultures of E. coli and S. enterica than in monocultures. While we observed similar mechanisms of resistance arising under rifampicin selection, under ampicillin selection different resistance mechanisms arose in co-cultures and monocultures. In particular, mutations in an essential cell division protein, ftsI, arose in S. enterica only in co-culture. A simple mathematical model demonstrated that reliance on a partner is sufficient to slow the rate of adaptation, and can change the distribution of adaptive mutations that are acquired. Our results demonstrate that cooperative metabolic interactions can be an important modulator of resistance evolution in microbial communities.


Assuntos
Adaptação Fisiológica/efeitos dos fármacos , Resistência Microbiana a Medicamentos/fisiologia , Escherichia coli/fisiologia , Interações Microbianas/fisiologia , Salmonella enterica/fisiologia , Adaptação Fisiológica/genética , Ampicilina/farmacologia , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Técnicas de Cocultura , Escherichia coli/efeitos dos fármacos , Interações Microbianas/efeitos dos fármacos , Modelos Teóricos , Mutação , Rifampina/farmacologia , Salmonella enterica/efeitos dos fármacos
18.
J Pharmacol Exp Ther ; 375(1): 139-151, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32719071

RESUMO

Organic anion-transporting polypeptide (OATP) 1B induction is an evolving mechanism of drug disposition and interaction. However, there are contradictory reports describing OATP1B expression in hepatocytes and liver biopsies after administration of an inducer. This study investigated the in vivo effects of the common inducer rifampin (RIF) on the activity and expression of cynomolgus monkey OATP1B1 and OATP1B3 transporters, which are structurally and functionally similar their human OATP1B counterparts. Multiple doses of oral RIF (15 mg/kg) resulted in a steady 3.9-fold increase of CYP3A biomarker, 4ß-hydroxycholesterol (4ßHC), in the plasma samples collected before each RIF dose during the treatment period (i.e., predose). In contrast, the predose plasma levels of OATP1B biomarkers coproporphyrin (CP) I and CPIII did not change when compared with RIF treatment. The trough concentration, area under plasma concentration-time curve (AUC), and half-life of RIF decreased markedly during RIF treatment, suggesting that RIF induced its own clearance. Consequently, RIF treatment increased CPI and CPIII AUCs substantially after a single administration and, to a lesser extent, after multiple administrations compared with preadministration AUCs. In addition, OATP1B1 and OATP1B3 mRNA expressions were not modulated by RIF treatment (0.85-1.3-fold), whereas CYP3A8 expression was increased 3.7-5.0-fold, which correlated well with the predose levels of CP and 4ßHC. Rifampin treatment showed 2.0-3.3-fold increases in P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 2 (MRP2) expression in the small intestine. Collectively, these findings indicate that monkey OATP1B and OATP1B3 are not induced by RIF, and further investigation of OATP1B induction by RIF and other nuclear receptor activators in humans is warranted. SIGNIFICANCE STATEMENT: In this study, combined endogenous biomarker and gene expression data suggested that RIF did not induce OATP1B in cynomolgus monkeys. For the first time, the study determines transporter gene expression in the nonhuman primate liver, gut, and kidney tissues after administration of RIF for 7 days, leading to a better understanding of the induction of OATP1B and other major drug transporters. Finally, it provides evidence to strengthen the claim that coproporphyrin is a suitable endogenous probe of OATP1B activity.


Assuntos
Coproporfirinas/sangue , Expressão Gênica/efeitos dos fármacos , Rifampina/farmacologia , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/biossíntese , Animais , Biomarcadores/sangue , Feminino , Hidroxicolesteróis/sangue , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Macaca fascicularis , Masculino , Rifampina/administração & dosagem , Rifampina/sangue , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/genética
19.
Saudi Med J ; 41(7): 753-756, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32601645

RESUMO

Elizabethkingia meningoseptica (E. meningoseptica ) are Gram-negative bacteria commonly associated with nosocomial infections in neonates. This is a case study of E. meningoseptica, presented as meningitis and sepsis in a term baby. The female infant was born by vaginal delivery at 37 weeks gestational age. The case was peculiar because the baby was neither premature nor immuno-compromised, which are known risk factors for E. meningoseptica infection. The onset began on the second day of the neonate's life. On day 3, peripheral blood culture and cerebrospinal fluid findings isolated a gram-negative bacteria identified as E. meningoseptica. The first-line antibiotics therapy was changed to ciprofloxacin, vancomycin, and rifampicin, based on the laboratory determination of antimicrobial sensitivity. The patient's clinical condition improved, although post hemorrhagic ventricular dilatation was revealed by imaging studies. Clinicians should possess proper awareness of the antibiotic sensitivity of E. meningoseptica, as it is important in preventing high rates of morbidity and mortality.


Assuntos
Antibacterianos/administração & dosagem , Ciprofloxacino/administração & dosagem , Infecções por Flavobacteriaceae , Flavobacteriaceae , Meningites Bacterianas/tratamento farmacológico , Meningites Bacterianas/microbiologia , Rifampina/administração & dosagem , Sepse/tratamento farmacológico , Sepse/microbiologia , Vancomicina/administração & dosagem , Antibacterianos/farmacologia , Ciprofloxacino/farmacologia , Farmacorresistência Bacteriana , Quimioterapia Combinada , Feminino , Flavobacteriaceae/efeitos dos fármacos , Flavobacteriaceae/isolamento & purificação , Humanos , Recém-Nascido , Rifampina/farmacologia , Arábia Saudita , Resultado do Tratamento , Vancomicina/farmacologia
20.
PLoS Pathog ; 16(6): e1008567, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32574211

RESUMO

Efforts at host-directed therapy of tuberculosis have produced little control of the disease in experimental animals to date. This is not surprising, given that few specific host targets have been validated, and reciprocally, many of the compounds tested potentially impact multiple targets with both beneficial and detrimental consequences. This puts a premium on identifying appropriate molecular targets and subjecting them to more selective modulation. We discovered an aminopyrimidine small molecule, 2062, that had no direct antimycobacterial activity, but synergized with rifampin to reduce bacterial burden in Mtb infected macrophages and mice and also dampened lung immunopathology. We used 2062 and its inactive congeners as tool compounds to identify host targets. By biochemical, pharmacologic, transcriptomic and genetic approaches, we found that 2062's beneficial effects on Mtb control and clearance in macrophages and in mice are associated with activation of transcription factor EB via an organellar stress response. 2062-dependent TFEB activation led to improved autophagy, lysosomal acidification and lysosomal degradation, promoting bacterial clearance in macrophages. Deletion of TFEB resulted in the loss of IFNγ-dependent control of Mtb replication in macrophages. 2062 also targeted multiple kinases, such as PIKfyve, VPS34, JAKs and Tyk2, whose inhibition likely limited 2062's efficacy in vivo. These findings support a search for selective activators of TFEB for HDT of TB.


Assuntos
Antituberculosos/farmacologia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Mycobacterium tuberculosis/metabolismo , Rifampina/farmacologia , Tuberculose , Animais , Modelos Animais de Doenças , Feminino , Camundongos , Mycobacterium tuberculosis/patogenicidade , Tuberculose/tratamento farmacológico , Tuberculose/metabolismo , Tuberculose/patologia
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