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K V Shur, M V Zaychikova, N E Mikheecheva, K M Klimina, O B Bekker, S N Zhdanova, O B Ogarkov, V N Danilenko
We report a draft genome sequence of Mycobacterium tuberculosis strain B9741 belonging to Beijing B0/W lineage isolated from a HIV patient from Siberia, Russia. This clinical isolate showed MDR phenotype and resistance to isoniazid, rifampin, streptomycin and pyrazinamide. We analyzed SNPs associated with virulence and resistance. The draft genome sequence and annotation have been deposited at GenBank under the accession NZ_LVJJ00000000.
December 2016: Genomics Data
Pooja Gopal, Michelle Yee, Jickky Sarathy, Jian Liang Low, Jansy P Sarathy, Firat Kaya, Véronique Dartois, Martin Gengenbacher, Thomas Dick
Pyrazinamide (PZA) is a critical component of first- and second-line treatments of tuberculosis (TB), yet its mechanism of action largely remains an enigma. We carried out a genetic screen to isolate Mycobacterium bovis BCG mutants resistant to pyrazinoic acid (POA), the bioactive derivative of PZA, followed by whole genome sequencing of 26 POA resistant strains. Rather than finding mutations in the proposed candidate targets fatty acid synthase I and ribosomal protein S1, we found resistance conferring mutations in two pathways: missense mutations in aspartate decarboxylase panD, involved in the synthesis of the essential acyl carrier coenzyme A (CoA), and frameshift mutations in the vitro nonessential polyketide synthase genes mas and ppsA-E, involved in the synthesis of the virulence factor phthiocerol dimycocerosate (PDIM)...
September 9, 2016: ACS Infectious Diseases
Devyani Deshpande, Shashikant Srivastava, Eric Nuermberger, Jotam G Pasipanodya, Soumya Swaminathan, Tawanda Gumbo
BACKGROUND:  The regimen of linezolid and moxifloxacin was found to be efficacious in the hollow fiber system model of pediatric intracellular tuberculosis. However, its kill rate was slower than the standard 3-drug regimen of isoniazid, rifampin, and pyrazinamide. We wanted to examine the effect of adding a third oral agent, faropenem, to this dual combination. METHODS:  We performed a series of studies in the hollow fiber system model of intracellular Mycobacterium tuberculosis, by mimicking pediatric pharmacokinetics of each antibiotic...
November 1, 2016: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Devyani Deshpande, Shashikant Srivastava, Eric Nuermberger, Jotam G Pasipanodya, Soumya Swaminathan, Tawanda Gumbo
BACKGROUND:  No treatment regimens have been specifically designed for children, in whom tuberculosis is predominantly intracellular. Given their activity as monotherapy and their ability to penetrate many diseased anatomic sites that characterize disseminated tuberculosis, linezolid and moxifloxacin could be combined to form a regimen for this need. METHODS:  We examined microbial kill of intracellular Mycobacterium tuberculosis (Mtb) by the combination of linezolid and moxifloxacin multiple exposures in a 7-by-7 mathematical matrix...
November 1, 2016: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Soumya Swaminathan, Jotam G Pasipanodya, Geetha Ramachandran, A K Hemanth Kumar, Shashikant Srivastava, Devyani Deshpande, Eric Nuermberger, Tawanda Gumbo
BACKGROUND:  The role of drug concentrations in clinical outcomes in children with tuberculosis is unclear. Target concentrations for dose optimization are unknown. METHODS:  Plasma drug concentrations measured in Indian children with tuberculosis were modeled using compartmental pharmacokinetic analyses. The children were followed until end of therapy to ascertain therapy failure or death. An ensemble of artificial intelligence algorithms, including random forests, was used to identify predictors of clinical outcome from among 30 clinical, laboratory, and pharmacokinetic variables...
November 1, 2016: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Gouranga Santra, Rudrajit Paul, Avik Karak, Somnath Mukhopadhay
A 22 year-old lady with multi-drug-resistant pulmonary tuberculosis was on Kanamycin, Cycloserine, Ethionamide, Pyrazinamide and Moxifloxacin since more than two months. She presented with muscle cramps and carpopedal spasm. Investigation revealed hypokalemia and metabolic alkalosis. She also had hypomagnesemia, hypochloremia and hypocalciuria. Serum urea and creatinine levels were normal. Patient was treated with intravenous and oral potassium chloride. Kanamycin was stopped. Metabolic alkalosis and hypokalemia improved gradually over one month...
May 2016: Journal of the Association of Physicians of India
Bella Devaleenal D, Geetha Ramachandran, Soumya Swaminathan
Inter-individual variations in the pharmacokinetics (PK) of anti-TB drugs are known to occur, which could have important therapeutic implications in patient management. Areas covered: We compiled factors responsible for PK variability of anti-TB drugs reported from different settings that would give a better understanding about the challenges of PK variability of anti-TB medications. We searched PubMed data base and Google scholar from 1976 to the present using the key words "Pharmacokinetics", "pharmacokinetic variability", "first-line anti-TB therapy", "Rifampicin", "Isoniazid", "Ethambutol", "Pyrazinamide", "food", "nutritional status", "HIV", "diabetes", "genetic polymorphisms" and "pharmacokinetic interactions"...
October 11, 2016: Expert Review of Clinical Pharmacology
Denis S Tikhonov, Dmitry I Sharapa, Jan Schwabedissen, Vladimir V Rybkin
In this study, we investigate the ability of classical molecular dynamics (MD) and Monte-Carlo (MC) simulations for modeling the intramolecular vibrational motion. These simulations were used to compute thermally-averaged geometrical structures and infrared vibrational intensities for a benchmark set previously studied by gas electron diffraction (GED): CS2, benzene, chloromethylthiocyanate, pyrazinamide and 9,12-I2-1,2-closo-C2B10H10. The MD sampling of NVT ensembles was performed using chains of Nose-Hoover thermostats (NH) as well as the generalized Langevin equation thermostat (GLE)...
October 12, 2016: Physical Chemistry Chemical Physics: PCCP
Meenu Pichholiya, Arvind Kumar Yadav, S K Luhadia, Jameela Tahashildar, M L Aseri
OBJECTIVES: To compare the efficacy and safety of febuxostat and allopurinol in pyrazinamide (PZA)-induced hyperuricemia in patients taking antitubercular therapy (ATT). METHODS: This randomized controlled study was conducted at a tertiary care teaching institute of Rajasthan in all the sputum-positive tubercular patients aged between 18 and 65 years of either sex. Serum uric acid level was monitored at 0(th), 2(nd), 4(th), 6(th), and 8(th) week of ATT. Patients whose uric acid level was found to be increased at 2(nd) week were finally recruited in the study...
September 2016: Indian Journal of Pharmacology
Yang-Mu Huang, Qi-Peng Zhao, Qiao-Meng Ren, Dan-Lu Peng, Yan Guo
BACKGROUND: Tuberculosis (TB) is a major infectious disease globally. Adequate and proper use of anti-TB drugs is essential for TB control. This study aims to study China's production capacity and sales situation of anti-TB drugs, and to further discuss the potential for China to contribute to global TB control. METHODS: The production data of anti-TB drugs in China from 2011 to 2013 and the sales data from 2010 to 2014 were extracted from Ministry of Industry and Information Technology database of China and IMS Health database, respectively...
October 4, 2016: Infectious Diseases of Poverty
Neha S Shah, S Y Grace Lin, Pennan M Barry, Yi-Ning Cheng, Gisela Schecter, Ed Desmond
Background.  Data from international settings suggest that isolates of Mycobacterium tuberculosis with rpoB mutations testing phenotypically susceptible to rifampin (RIF) may have clinical significance. We analyzed treatment outcomes of California patients with discordant molecular-phenotypic RIF results. Methods.  We included tuberculosis (TB) patients, during 2003-2013, whose specimens tested RIF susceptible phenotypically but had a rpoB mutation determined by pyrosequencing. Demographic data were abstracted from the California TB registry...
September 2016: Open Forum Infectious Diseases
Bintou A Ahidjo, Mariama C Maiga, Elizabeth A Ihms, Mamoudou Maiga, Alvaro A Ordonez, Laurene S Cheung, Sarah Beck, Bruno B Andrade, Sanjay Jain, William R Bishai
Pirfenidone is a recently approved antifibrotic drug for the treatment of idiopathic pulmonary fibrosis (IPF). Because tuberculosis (TB) is characterized by granulomatous inflammation in conjunction with parenchymal destruction and replacement fibrosis, we sought to determine whether the addition of pirfenidone as an adjunctive, host-directed therapy provides a beneficial effect during antimicrobial treatment of TB. We hypothesized that pirfenidone's antiinflammatory and antifibrotic properties would reduce inflammatory lung damage and increase antimicrobial drug penetration in granulomas to accelerate treatment response...
September 8, 2016: JCI Insight
Yun Zhang, Kechun Liu, Hozeifa M Hassan, Hongli Guo, Pingping Ding, Liwen Han, Qiuxia He, Weiyun Chen, Chung-Der Hsiao, Luyong Zhang, Zhenzhou Jiang
Pyrazinamide (PZA) is an essential antitubercular drug, but still little is known about its hepatotoxicity potential. This study examined the effects of PZA exposure on zebrafish (Danio rerio) larvae and the mechanisms underlying its hepatotoxicity. The transgenic line of zebrafish larvae that expressed enhanced green fluorescent protein (EGFP) in the liver were incubated with 1, 2.5 and 5 mM of PZA from 72 hours post fertilization (hpf). Different endpoints such as mortality, morphology changes in size and shape of the liver, histological changes, transaminase analysis and apoptosis, markers of oxidative and genetic damage, as well as certain genes expression were selected to evaluate PZA-induced hepatotoxicity...
October 3, 2016: Antimicrobial Agents and Chemotherapy
Ira Shah, Forum Shah
BACKGROUND: The prevalence of drug-resistant (DR) tuberculosis (TB) in children is increasing. Although, in India, multi-drug-resistant (MDR) TB rates have been relatively stable, the number of children with pre-extensively drug-resistant and extensively drug-resistant (XDR) TB is increasing. AIM: To determine whether the prevalence of DR TB in children in Mumbai is changing and to study the evolving patterns of resistance. METHODS: A retrospective study was undertaken in 1311 paediatric patients referred between April 2007 and March 2013 to the Paediatric TB clinic at B...
August 9, 2016: Paediatrics and International Child Health
A K Hemanth Kumar, V Chandrasekaran, T Kannan, A Lakshmi Murali, J Lavanya, V Sudha, Soumya Swaminathan, Geetha Ramachandran
PURPOSE: The aim of the study was to compare plasma concentrations of rifampicin (RMP), isoniazid (INH) and pyrazinamide (PZA) between tuberculosis (TB) patients with and without diabetes mellitus (DM). METHODS: Two-hour post-dosing concentrations of RMP, INH and PZA were determined in adult TB patients that were studied with (n = 452) and without DM (n = 1460), treated with a thrice-weekly regimen in India. Drug concentrations were estimated by HPLC. RESULTS: The median (IQR) INH [6...
September 20, 2016: European Journal of Clinical Pharmacology
Lindsey H M Te Brake, Jeroen J M W van den Heuvel, Aaron Ohene Buaben, Reinout van Crevel, Albert Bilos, Frans G Russel, Rob E Aarnoutse, Jan B Koenderink
INTRODUCTION: It is largely unknown if simultaneous administration of tuberculosis (TB) drugs and metformin leads to drug-drug interactions (DDIs). Disposition of metformin is determined by organic cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs). Thus any DDIs would primarily be mediated via these transporters. This study aimed to assess the in vitro inhibitory effects of TB drugs (rifampicin, isoniazid, pyrazinamide, ethambutol, amikacin, moxifloxacin and linezolid) on metformin transport, and whether TB drugs are also substrates themselves of OCTs and MATEs...
September 19, 2016: Antimicrobial Agents and Chemotherapy
Yolanda Cifuentes, Martha Isabel Murcia, Jorge Piar, Patricia Pardo
Tuberculosis is a serious public health problem worldwide. In 2012, the World Health Organization estimated 8.6 million new cases and 1.3 million deaths due to the disease. In 2011, the incidence in Colombia was 24 cases per 100,000 inhabitants. There is little information about tuberculosis in pregnant women, and congenital infection is considered a rare disease that is difficult to diagnose, leads to high mortality, and may be confused with tuberculosis acquired after birth. In addition, it has been associated with HIV infection in mothers and infants...
2016: Biomédica: Revista del Instituto Nacional de Salud
Majid Marjani, Parvaneh Baghaei, Mehdi Kazempour Dizaji, Pegah Gorji Bayani, Fanak Fahimi, Payam Tabarsi, Ali Akbar Velayati
Hepatic toxicity is the most serious adverse effect of anti-tuberculosis drugs. This study was performed to evaluate the efficacy of silymarin as a hepatoprotective herbal agent. In a randomized double blind clinical trial, 70 new cases of pulmonary tuberculosis were divided into two groups. The intervention group was assigned to receive silymarin and the control group received placebo. Tuberculosis was treated by classic regimen consisting isoniazid, rifampin, pyrazinamide and ethambutol. No statistically significant difference was found between the two groups concerning the frequency of drug induced liver injury or mild elevation of liver enzymes...
2016: Iranian Journal of Pharmaceutical Research: IJPR
Gustavo E Velásquez, Roger I Calderon, Carole D Mitnick, Mercedes C Becerra, Chuan-Chin Huang, Zibiao Zhang, Carmen C Contreras, Rosa M Yataco, Jerome T Galea, Leonid W Lecca, Megan B Murray
Phenotypic drug-susceptibility testing is the current gold standard for detecting Mycobacterium tuberculosis susceptibility to antituberculous drugs. Pyrazinamide is one antituberculous drug for which the correlation between in vitro resistance and clinical outcomes remains unclear. Here we performed latent class analysis (LCA) to develop a consensus gold standard definition of pyrazinamide resistance using three paired standard pyrazinamide resistance assays. We then compared this consensus measure to the two-month culture results for patients with multidrug-resistant tuberculosis (MDR-TB) who were treated for two months with first-line antituberculous drugs before their resistance results were known...
September 6, 2016: Antimicrobial Agents and Chemotherapy
Virginia Leiro-Fernández, Diana Valverde, Rafael Vázquez-Gallardo, Lucía Constenla-Caramés, Víctor Del Campo-Pérez, Alberto Fernández-Villar
AIMS: To evaluate the role of human leukocyte antigen (HLA) class II DQB1*0201 and DQA1*0102 in the risk of antituberculosis drug (ATD)-induced hepatotoxicity (ATDH) in a cohort of tuberculosis patients of Caucasian origin from Spain. METHODS: Matched case-control study including active tuberculosis (TB) patients from Spain (Caucasian) treated with first-line ATD (Isoniazid, Rifampin, and Pyrazinamide). Presence or absence of HLA class II DQB1*0201 and DQA1*0102 alleles were compared between cases and controls...
2016: Frontiers in Medicine
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