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Shengyuan Wu, Liai Lan, Jingjing Jiang, Xianting Ding, Chih-Ming Ho, Yuefen Lou, Guorong Fan
Tuberculosis is one of the top concerns in the world and acutely threatens human health. A new potent candidate regimen containing pyrazinamide (PZA), ethambutol (EMB), protionamide (PTO) and clofazimine (CFZ) was proposed by Parabolic Response Surface/Feedback System Control (FSC/PRS) system and showed excellent outcomes in vitro and vivo studies. Here, a convenient liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneously determination of four compounds in beagle dog plasma...
February 6, 2019: Journal of Pharmaceutical and Biomedical Analysis
Nargis Khan, Laura Mendonca, Achal Dhariwal, Ghislaine Fontes, Dick Menzies, Jianguo Xia, Maziar Divangahi, Irah L King
Current treatments for tuberculosis (TB) are effective in controlling Mycobacterium tuberculosis (Mtb) growth, yet have significant side effects and do not prevent reinfection. Therefore, it is critical to understand why our host defense system is unable to generate permanent immunity to Mtb despite prolonged anti-tuberculosis therapy (ATT). Here, we demonstrate that treatment of mice with the most widely used anti-TB drugs, rifampicin (RIF) or isoniazid (INH) and pyrazinamide (PYZ), significantly altered the composition of the gut microbiota...
February 19, 2019: Mucosal Immunology
Yu Wang, Xi Xiang, Wei-Wei Huang, Andrew J Sandford, Shou-Quan Wu, Miao-Miao Zhang, Ming-Gui Wang, Guo Chen, Jian-Qing He
A combination therapy of multiple drugs including isoniazid, rifampicin, ethambutol and pyrazinamide has been proven to be an effective option for the vast majority of tuberculosis (TB) patients. However, various adverse drug reactions (ADRs) limit its merit, with anti-TB drug-induced hepatotoxicity (ATDH) being a common and sometimes severe ADR. This study aimed to investigate the association between polymorphisms in two nuclear receptor genes, pregnane X receptor (PXR) and constitutive androstane receptor (CAR), and the risk of ATDH in a Chinese population...
February 18, 2019: Scientific Reports
Aryadne L de Almeida, Katiany R Caleffi-Ferracioli, Regiane B de L Scodro, Vanessa P Baldin, Débora C Montaholi, Luiza F Spricigo, Sandra S Nakamura-Vasconcelos, Laíse A Hegeto, Eloísa G Sampiron, Giovana F Costacurta, Diego A Dos S Yamazaki, Gisele de F Gauze, Vera Ld Siqueira, Rosilene F Cardoso
AIM:  To evaluate (i) the in vitro activity of eugenol (EUG) and three derivatives against Mycobacterium tuberculosis (Mtb), nontuberculous mycobacteria (NTM) and other bacteria, (ii) the EUG and antituberculosis drugs combinatory effect and (iii) the EUG and its derivatives cytotoxicity. MATERIALS & METHODS:  Minimum inhibitory concentration of the compounds were determined by resazurin microtiter or broth microdilution assay and the drug interaction between EUG and antituberculosis drugs by resazurin drug combination microtiter...
February 13, 2019: Future Microbiology
Juliane Havlicek, Beatrice Dachsel, Peter Slickers, Sönke Andres, Patrick Beckert, Silke Feuerriegel, Stefan Niemann, Matthias Merker, Ines Labugger
Pyrazinamide (PZA) is a key antibiotic for the treatment of drug susceptible tuberculosis. PZA-resistance is mainly mediated by mutations in the pncA gene; however the current gold standard is a phenotypic drug susceptibility test requiring a well-adjusted pH-value for reliable results. Our melting curve assay detects a non-wild type genotype in selected pncA regions in at least 3750 gene copies/mL within 2.5 hours. The prototype assay was further evaluated by analyzing 271 Mycobacterium tuberculosis complex isolates from Swaziland originating from a previously published drug resistance survey and including 118 isolates with pncA mutations...
December 30, 2018: Diagnostic Microbiology and Infectious Disease
Saumu Pazia Juma, Athanasia Maro, Suporn Pholwat, Stellah G Mpagama, Jean Gratz, Alphonse Liyoyo, Eric R Houpt, Gibson S Kibiki, Blandina T Mmbaga, Scott K Heysell
BACKGROUND: Tuberculosis (TB) is the leading cause of death from an infectious disease and the roll-out of rapid molecular diagnostics for rifampin resistance has resulted in a steady rise in the number of patients with multidrug-resistant (MDR)-TB referred for treatment. Pyrazinamide is used in susceptible TB treatment for 6 months when used in combination with rifampin, isoniazid and ethambutol and is an important companion drug in novel MDR-TB trials. This study was undertaken to determine the prevalence of pyrazinamide resistance by either phenotypic or pncA testing among patients admitted to a referral hospital in Tanzania for drug-susceptible and MDR-TB treatment...
February 7, 2019: BMC Infectious Diseases
N Sweetline Anne, B S M Ronald, T M A Senthil Kumar, A Thangavelu
This study was aimed out to explore the presence of drug resistance among M. tuberculosis and M. bovis isolates (n = 51) of bovine origin by conventional broth microdilution method and molecular methods. By broth microdilution method, 16 isolates were found to be resistant to isoniazid, 08 isolates were resistant to pyrazinamide, 09 isolates were resistant to rifampicin and 07 isolates were found to be resistant for ethambutol. Two isolates showed resistance to rifampicin and pyrazinamide, one isolate showed resistance to pyrazinamide and ethambutol and 03 isolates showed resistance to isoniazid and ethambutol...
January 2019: Tuberculosis
Ga-Young Ban, Yoon-Jeong Jeong, So-Hee Lee, Seung-Soo Shin, Yoo-Seob Shin, Hae-Sim Park, Seung-Hyun Kim, Young-Min Ye
BACKGROUND: Delayed drug hypersensitivity to first-line anti-tuberculosis medication is a major challenge in tuberculosis treatment. OBJECTIVE: This study was performed to investigate the efficacy/tolerability of desensitization therapy in treatment of first-line anti-tuberculosis medication hypersensitivity and the usefulness of immunologic evaluation therein. METHODS: This study was conducted as a prospective, observational cohort study...
February 2019: Respiratory Medicine
Qiqi Wang, Jiadan Xue, Zhi Hong, Yong Du
Vibrational modes of pyrazinamide (PZA), 3-hydroxybenzoic acid (3-hBA), and their cocrystal were characterized using terahertz time-domain (THz-TDS) and Raman vibrational spectroscopic techniques. In experimental THz spectra, the cocrystal has characteristic absorption bands at around 0.81, 1.47, and 1.61 THz, respectively, meanwhile the raw materials are absolutely different in this region. Raman spectra also show similar results about differences between the cocrystal and corresponding starting parent materials...
January 30, 2019: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Timothy M Walker, A Sarah Walker, Daniel J Wilson, Timothy E A Peto, Derrick W Crook, Farah Shamout, Tingting Zhu, David A Clifton
Motivation: Resistance co-occurrence within first-line anti-tuberculosis (TB) drugs is a common phenomenon. Existing methods based on genetic data analysis of Mycobacterium tuberculosis (MTB) have been able to predict resistance of MTB to individual drugs, but have not considered the resistance co-occurrence and cannot capture latent structure of genomic data that corresponds to lineages. Methods: We used a large cohort of TB patients from 16 countries across six continents where whole-genome sequences for each isolate and associated phenotype to anti-TB drugs were obtained using drug susceptibility testing recommended by the World Health Organization...
January 28, 2019: Bioinformatics
Myungsun Lee, Jeongha Mok, Deog Kyeom Kim, Tae Sun Shim, Won-Jung Koh, Doosoo Jeon, Taehoon Lee, Seung Heon Lee, Ju Sang Kim, Jae Seuk Park, Ji Yeon Lee, Song Yee Kim, Jae Ho Lee, Kyung-Wook Jo, Byung Woo Jhun, Young Ae Kang, Joong Hyun Ahn, Chang-Ki Kim, Soyoun Shin, Taeksun Song, Sung Jae Shin, Young Ran Kim, Heejung Ahn, Seokyung Hahn, Ho Jeong Won, Ji Yeon Jang, Sang Nae Cho, Jae-Joon Yim
BACKGROUND: Treatment success rates of multidrug-resistant tuberculosis (MDR-TB) remain unsatisfactory, and long-term use of second-line anti-TB drugs is accompanied by the frequent occurrence of adverse events, low treatment compliance, and high costs. The development of new efficient regimens with shorter treatment durations for MDR-TB will solve these issues and improve treatment outcomes. METHODS: This study is a phase II/III, multicenter, randomized, open-label clinical trial of non-inferiority design comparing a new regimen to the World Health Organization-endorsed conventional regimen for fluoroquinolone-sensitive MDR-TB...
January 16, 2019: Trials
Nabila Ismail, Remco P H Peters, Nazir A Ismail, Shaheed V Omar
Six in-vitro clofazimine-resistant spontaneous mutants obtained from a wild-type or pyrazinamide-resistant ATCC reference strain were selected to evaluate bedaquiline cross-resistance. The reverse was conducted for bedaquiline mutants. All clofazimine mutants harbouring an rv0678 mutation displayed phenotypic cross-resistance. We observed the same for rv0678 bedaquiline mutants, however atpE bedaquiline mutants showed no phenotypic cross-resistance. This confirms that upfront clofazimine usage may impact subsequent bedaquiline use due to a shared efflux resistance pathway...
January 14, 2019: Antimicrobial Agents and Chemotherapy
Pierre Mugabo, Mwila Mulubwa
BACKGROUND AND OBJECTIVES: Pyrazinamide, a drug used in the regimen for the treatment of drug-sensitive tuberculosis, is also used for the treatment of multidrug-resistant tuberculosis (MDR-TB). We aimed to describe the population pharmacokinetics of pyrazinamide and its major metabolite, pyrazinoic acid, in patients with MDR-TB and characterise the effects of demographic variables. METHODS: This was a non-randomised clinical study involving 51 adult patients admitted for the intensive phase of MDR-TB treatment...
January 8, 2019: European Journal of Drug Metabolism and Pharmacokinetics
Napoleón González Saldaña, Agustín Rafael De Colsa Ranero, Diego Mauricio Galvis Trujillo, Eduardo Arias De la Garza, Ana Isabel Quesada Tortoriello, Bárbara Varela Ruiz, Rodolfo Rodríguez Jurado, Hugo Juárez Olguín, Miroslava Lindoro Silva
RATIONALE: Osteitis corresponds to a rare but potentially serious complication reported in pediatric population after the application of the Bacillus Calmette-Guerin (BCG) vaccine. In the present study, 3 clinical cases associated with this entity are reported. PATIENT CONCERNS: The 1st case corresponds to a 1-year-old female patient who presented an increase in the volume of the right pelvic limb after BCG application. The second case is a 2-year-old male who began with an increase in volume, overactive gait and pain at the level of the left knee on walking that began after a trauma in the left low limb...
January 2019: Medicine (Baltimore)
A P-G Chua, L K-Y Lim, S-H Gan, C B-E Chee, Y-T Wang
BACKGROUND: Tuberculosis (TB) drug-induced liver injury (TB-DILI) usually occurs within 8 weeks of anti-tuberculosis drug initiation. In Singapore, we suspected that the onset of TB drug-induced transaminitis may be confounded with hepatitis C virus (HCV) and hepatitis B (HBV) virus co-infection. OBJECTIVE: To determine the impact of HCV/HBV co-infection on the course of treatment in patients with TB treatment interrupted due to transaminitis. DESIGN: TB patients with treatment interruption during 2013-2014 were identified through the Singapore national TB registry...
December 1, 2018: International Journal of Tuberculosis and Lung Disease
Noura M Al-Mutairi, Suhail Ahmad, Eiman Mokaddas, Hanaa S Eldeen, Susan Joseph
BACKGROUND: Accurate drug susceptibility testing (DST) of Mycobacterium tuberculosis in clinical specimens and culture isolates to first-line drugs is crucial for diagnosis and management of multidrug-resistant tuberculosis (MDR-TB). Resistance of M. tuberculosis to rifampicin is mainly due to mutations in hot-spot region of rpoB gene (HSR-rpoB). The prevalence of disputed (generally missed by rapid phenotypic DST methods) rpoB mutations, which mainly include L511P, D516Y, H526N, H526L, H526S, and L533P in HSR-rpoB and I572F in cluster II region of rpoB gene, is largely unknown...
January 3, 2019: BMC Infectious Diseases
Kathleen F Walsh, Ariadne Souroutzidis, Stalz Charles Vilbrun, Miranda Peeples, Guy Joissaint, Sobieskye Delva, Pamphile Widmann, Gertrude Royal, Jake Pry, Heejung Bang, Jean W Pape, Serena P Koenig
Multidrug-resistant tuberculosis (MDR-TB) outcomes are poor partly because of the long treatment duration; the World Health Organization conditionally recommends a shorter course regimen to potentially improve treatment outcomes. Here, we describe the drug susceptibility patterns of a cohort of MDR-TB patients in Haiti and determine the number of likely effective drugs if they were treated with the recommended shorter course regimen. We retrospectively examined drug susceptibility patterns of adults initiating MDR-TB treatment between 2008 and 2015 at the Haitian Group for the Study of Kaposi's Sarcoma and Opportunistic Infections in Port-au-Prince, Haiti...
December 26, 2018: American Journal of Tropical Medicine and Hygiene
Jesper Sundell, Emile Bienvenu, Sofia Birgersson, Angela Äbelö, Michael Ashton, Kurt-Jürgen Hoffmann
Co-infection of tuberculosis in HIV-patients is a major health concern worldwide and especially so in Sub-Saharan Africa. To enhance the study of potential drug-drug interactions when simultaneously treating the two infections, a liquid chromatography tandem mass spectrometry method was developed for the quantitation of the four first line anti-tuberculosis drugs isoniazid, rifampicin, pyrazinamide, ethambutol and four of their major metabolites in human plasma. Analytes were extracted from 200 μL of plasma using a sequential liquid-liquid extraction with ethyl acetate at neutral and acidic pH...
October 31, 2018: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
L T Daum, O S Konstantynovska, O S Solodiankin, P I Poteiko, V I Bolotin, J D Rodriguez, A P Gerilovych, J P Chambers, G W Fischer
Multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis cases in the Ukraine are increasing. Pyrazinamide (PZA) is critically important for first- and second-line tuberculosis (TB) treatment regimes. However, PZA drug susceptibility testing is time consuming and technically challenging. The present study utilized Next-generation sequencing (NGS) to identify mutations in the pncA gene from clinical isolates and to assess the prevalence of pncA gene mutations in MDR/XDR-TB patients...
November 10, 2018: Diagnostic Microbiology and Infectious Disease
Feng Sun, Yang Li, Yu Chen, Wenlong Guan, Xiangao Jiang, Xiaomeng Wang, Pengfei Ren, Junlian Li, Jichan Shi, Guiqing He, Meiying Wu, Peijun Tang, Fei Wang, Yunfeng Sheng, Fuli Huang, Zumo Zhou, Heqing Huang, Liang Hong, Qihui Liu, Ying Zhang, Wenhong Zhang
The current treatment for multidrug-resistant tuberculosis (MDR-TB) takes a lengthy period of 18-24 months and has a poor cure rate of 50-60%. A multi-center, prospective cohort study was conducted to assess the role of molecular susceptibility testing to pyrazinamide (PZA) in optimising the treatment for MDR-TB.We assigned 76 patients in the molecular susceptibility optimised group and 159 patients in the regular treatment group where PZA susceptibility was not determined. One hundred and fifty-two patients were matched (76 in the optimised group and 76 in the regular group) after the propensity score matching...
December 21, 2018: European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology
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