Download the Free Unbound MEDLINE PubMed App to your smartphone or tablet.
Available for iPhone, iPad, iPod touch, and Android.
Mycobacterium tuberculosis AND drug use and [keywords]
- Genotypic susceptibility testing of Mycobacterium tuberculosis for Amikacin and Kanamycin resistance using a rapid Sloppy Molecular Beacon based assay identifies more cases of low level drug resistance than phenotypic Lowenstein-Jensen testing. [JOURNAL ARTICLE]
- J Clin Microbiol 2014 Oct 22.
Resistance to Amikacin (AMK) and Kanamycin (KAN) in clinical Mycobacterium tuberculosis (M.tb) strains is largely determined by specific mutations in the rrs gene and eis gene promoter. We developed a rapid, multiplexed Sloppy Molecular Beacon (SMB) assay to identify these mutations and then evaluated assay performance on 603 clinical M.tb DNA samples collected in South Korea. Assay performance was compared to gold-standard phenotypic drug susceptibility tests including Lowenstein-Jensen (LJ) absolute concentration, Mycobacterial Growth Indicator Tubes (MGIT) and TREK Sensititre® MYCOTB MIC plate (MYCOTB) methods. Target amplicons were also tested for mutations by Sanger sequencing. The SMB assay correctly detected 115/116 mutant and mixed sequences and 487/487 wild type sequences (sensitivity and specificity 99.1 and 100% respectively). Using LJ as the reference, sensitivity and specificity for AMK resistance was 92.2% and 100% respectively; and for KAN resistance was 87.7% and 95.6% respectively. Mutations in the rrs gene were unequivocally associated with high level cross-resistance to AMK and KAN in all three conventional drug susceptibility testing methods. However, eis promoter mutations were associated with KAN resistance using only the MGIT or MYCOTB methods but not the LJ method. No testing method associated eis promoter mutations with AMK resistance. Among the discordant samples with AMK and/or KAN resistance but wild type sequence at the target genes, we discovered four new mutations in the whiB7 5' untranslated (UTR) region in 6/22 samples. All the six samples were resistant to only KAN suggesting the possible role of these whiB7 5' UTR mutations in KAN resistance.
- Development of a biocompatible nanodelivery system for tuberculosis drugs based on isoniazid-Mg/Al layered double hydroxide. [Journal Article]
- Int J Nanomedicine 2014.:4749-62.
The primary challenge in finding a treatment for tuberculosis (TB) is patient non-compliance to treatment due to long treatment duration, high dosing frequency, and adverse effects of anti-TB drugs. This study reports on the development of a nanodelivery system that intercalates the anti-TB drug isoniazid into Mg/Al layered double hydroxides (LDHs). Isoniazid was found to be released in a sustained manner from the novel nanodelivery system in humans in simulated phosphate buffer solutions at pH 4.8 and pH 7.4. The nanodelivery formulation was highly biocompatible compared to free isoniazid against human normal lung and 3T3 mouse fibroblast cells. The formulation was active against Mycobacterium tuberculosis and gram-positive bacteria and gram-negative bacteria. Thus results show significant promise for the further study of these nanocomposites for the treatment of TB.
- Tuberculous pleuritis secondary to Mycobacterium bovis in a veterinarian. [JOURNAL ARTICLE]
- Clin Respir J 2014 Oct 22.
Mycobacterium bovis is a rare cause of tuberculosis in humans, but should be considered in individuals at risk secondary to medical co-morbidities (notably immunocompromise) or occupational exposure. Most cases are secondary to re-activation of latent infection in elderly individuals although cases of primary infection still occur, usually involving animal-to-human transmission. Pleural fluid culture in the context of suspected tuberculous pleuritis is frequently negative and pleural biopsy significantly increases the likelihood of confirming the diagnosis histologically and microbiologically. Although thoracoscopic biopsies are the reference standard, closed pleural biopsies are an appropriate and more accessible alternative in the majority of cases - these should be done under direct ultrasound guidance to maximise diagnostic yield. Treatment for M.bovis infection is with prolonged combination anti-tuberculous therapy, using an alternative to pyrazinamide as the organism is inherently resistant to this drug.
- Alarming Levels of Drug-Resistant Tuberculosis in HIV-Infected Patients in Metropolitan Mumbai, India. [JOURNAL ARTICLE]
- PLoS One 2014; 9(10):e110461.
Drug-resistant tuberculosis (DR-TB) is a looming threat to tuberculosis control in India. However, no countrywide prevalence data are available. The burden of DR-TB in HIV-co-infected patients is likewise unknown. Undiagnosed and untreated DR-TB among HIV-infected patients is a major cause of mortality and morbidity. We aimed to assess the prevalence of DR-TB (defined as resistance to any anti-TB drug) in patients attending public antiretroviral treatment (ART) centers in greater metropolitan Mumbai, India.A cross-sectional survey was conducted among adults and children ART-center attendees. Smear microscopy, culture and drug-susceptibility-testing (DST) against all first and second-line TB-drugs using phenotypic liquid culture (MGIT) were conducted on all presumptive tuberculosis patients. Analyses were performed to determine DR-TB prevalence and resistance patterns separately for new and previously treated, culture-positive TB-cases.Between March 2013 and January 2014, ART-center attendees were screened during 14135 visits, of whom 1724 had presumptive TB. Of 1724 attendees, 72 (4%) were smear-positive and 202 (12%) had a positive culture for Mycobacterium tuberculosis. Overall DR-TB was diagnosed in 68 (34%, 95% CI: 27%-40%) TB-patients. The proportions of DR-TB were 25% (29/114) and 44% (39/88) among new and previously treated cases respectively. The patterns of DR-TB were: 21% mono-resistant, 12% poly-resistant, 38% multidrug-resistant (MDR-TB), 21% pre-extensively-drug-resistant (MDR-TB plus resistance to either a fluoroquinolone or second-line injectable), 6% extensively drug-resistant (XDR-TB) and 2% extremely drug-resistant TB (XDR-TB plus resistance to any group-IV/V drug). Only previous history of TB was significantly associated with the diagnosis of DR-TB in multivariate models.The burden of DR-TB among HIV-infected patients attending public ART-centers in Mumbai was alarmingly high, likely representing ongoing transmission in the community and health facilities. These data highlight the need to promptly diagnose drug-resistance among all HIV-infected patients by systematically offering access to first and second-line DST to all patients with 'presumptive TB' rather than 'presumptive DR-TB' and tailor the treatment regimen based on the resistance patterns.
- In vitro and in vivo activity against M. tuberculosis of the nitroimidazole TBA-354. [JOURNAL ARTICLE]
- Antimicrob Agents Chemother 2014 Oct 20.
Nitroimidazoles are a promising new class of anti-tubercular agents. The nitroimidazo-oxazole delamanid (OPC-67683, Deltyba) is in Phase III trials for treatment of multi-drug resistant tuberculosis while the nitroimidazo-oxazine PA-824 is entering Phase III for drug sensitive and drug resistant tuberculosis. TBA-354 (a.k.a SN31354[(S)-2-nitro-6-((6-(4-trifluoromethoxy)phenyl)pyridine-3-yl)methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine]) is a pyridine-containing biaryl compound with exceptional efficacy against chronic murine tuberculosis and favorable bioavailability in preliminary rodent studies. It was selected as a potential next generation anti-tuberculosis nitroimidazole following an extensive medicinal chemistry effort. Here, we further evaluate the pharmacokinetic properties and activity against Mycobacterium tuberculosis of TBA-354. TBA-354 is narrow spectrum and bactericidal in vitro against replicating and non-replicating Mycobacterium tuberculosis, with potency similar to that of delamanid and greater than that of PA-824. Addition of serum protein or albumin does not significantly alter this activity. TBA-354 maintains activity against Mycobacterium tuberculosis H37Rv-isogenic mono-resistant strains and clinical drug-sensitive and drug-resistant isolates. Spontaneous resistant mutants appear at a frequency of 3 × 10(-7). In vitro studies and in vivo studies in mice confirm that TBA-354 has high bioavailability and a long elimination half-life. In vitro studies suggest a low risk of drug-drug interactions. Low dose aerosol infection models of acute and chronic murine tuberculosis reveal time and dose-dependent in vivo bactericidal activity that is at least as potent to delamanid and more potent than PA-824. Its superior potency and pharmacokinetic profile that predicts suitability for once daily oral dosing suggest that TBA-354 be studied further for potential as a next generation nitroimidazole.
- Verapamil Increases the Bactericidal Activity of Bedaquiline Against Mycobacterium tuberculosis in the Mouse Model. [JOURNAL ARTICLE]
- Antimicrob Agents Chemother 2014 Oct 20.
Bedaquiline is a newly approved drug for multidrug resistant tuberculosis with concerns about its safety in humans. We found that co-administration of verapamil with sub-inhibitory doses of bedaquiline gave the same bactericidal effect in mice as full human-bioequivalent bedaquiline dosing. Adding verapamil to bedaquiline monotherapy also protected from development of resistant mutants in vivo. Adjunctive use of verapamil may permit use of lower doses of bedaquiline and thereby reduce its dose-related toxicities in tuberculosis patients.
- Increase in Nontuberculous Mycobacteria Isolated in Shanghai, China: Results from a Population-Based Study. [JOURNAL ARTICLE]
- PLoS One 2014; 9(10):e109736.
In China, the prevalence of nontuberculous mycobacteria (NTM) in isolates from mycobacterial culture-positive patients with pulmonary tuberculosis (TB) is largely unknown.We used conventional biochemical and 16S rRNA gene sequencing to identify species of mycobacteria in specimens from patients suspected of having TB. Drug-susceptibility testing was performed on NTM isolates using the proportion method. We also determined the independent risk factors associated with infection with NTM compared with infection with Mycobacterium tuberculosis.The overall rate of NTM isolated from mycobacterial culture-positive patients was 5.9% in this population, with a significantly increasing trend from 3.0% in 2008 to 8.5% in 2012 (P for trend <0.001). The organism most frequently identified was M. kansasii (45.0%), followed by M. intracellulare (20.8%) and M. chelonae/abscessus (14.9%). The overall proportion of isolates resistant to the four first-line anti-TB agents were 64.6% for isoniazid, 77.6% for streptomycin, 63.3% for rifampicin and 75.1% for ethambutol. The risk factors most often associated with NTM infection were older age (P for trend <0.001), being a resident of Shanghai (adjusted odds ratio [aOR], 1.48; 95% CI, 1.10-2.00), having been treated for tuberculosis (aOR, 1.64; 95% CI, 1.18-2.29), having a cavity on chest X-ray (aOR, 1.51; 95% CI, 1.16-1.96), and being sputum smear-negative (aOR, 1.59; 95% CI, 1.16-2.18).The prevalence of NTM isolated in Shanghai increased between 2008 and 2012, thus clinicians should consider NTM as a possible cause of TB-like disease. Accurate species identification is imperative so that proper treatment can be administered for diseases caused by the diversity of NTM species.
- Lessons learned in TB drug discovery: an industrial chemist's perspective. [JOURNAL ARTICLE]
- Future Med Chem 2014 Aug; 6(12):1377-1380.
- Improved understanding of pathogenesis from protein interactions in Mycobacterium tuberculosis. [JOURNAL ARTICLE]
- Expert Rev Proteomics 2014 Oct 18.:1-11.
Comprehensive mapping and analysis of protein-protein interactions provide not only systematic approaches for dissecting the infection and survival mechanisms of pathogens but also clues for discovering new antibacterial drug targets. Protein interaction data on Mycobacterium tuberculosis have rapidly accumulated over the past several years. This review summarizes the current progress of protein interaction studies on M. tuberculosis, the causative agent of tuberculosis. These efforts improve our knowledge on the stress response, signaling regulation, protein secretion and drug resistance of the bacteria. M. tuberculosis-host protein interaction studies, although still limited, have recently opened a new door for investigating the pathogenesis of the bacteria. Finally, this review discusses the importance of protein interaction data on identifying and screening new anti-tuberculosis targets and drugs, respectively.
- Delamanid when other anti-tuberculosis-treatment regimens failed due to resistance or tolerability. [JOURNAL ARTICLE]
- Expert Opin Pharmacother 2014 Oct 18.:1-9.
Introduction: The limited availability of effective drugs causes difficulties in the management of multidrug-resistant tuberculosis (MDR-TB) and novel therapeutic agents are needed. Delamanid , a new nitro-hydro-imidazooxazole derivative, inhibits mycolic acid synthesis. This review covers the efficacy and safety of delamanid for MDR-TB. Area covered: This paper reviews the pharmacological profile of delamanid and the results of clinical trials evaluating its efficacy for treating MDR-TB in combination with other anti-TB drugs. The drug's safety and tolerability profiles are also considered. Expert opinion: Delamanid showed potent activity against drug-susceptible and -resistant Mycobacterium tuberculosis in both in vitro and in vivo studies. In clinical trials, the drug showed significant early bactericidal activity in pulmonary TB patients, and increased culture conversion after 2 months of treatment in combination with an optimized background regimen in MDR-TB patients. In addition, decreased mortality was observed in MDR-TB patients who received > 6 months of delamanid treatment. The drug was generally tolerable, but QT prolongation should be monitored carefully using electrocardiograms and potassium levels. Therefore, delamanid could be used as part of an appropriate combination regimen for pulmonary MDR-TB in adult patients when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability.