- Acquired Resistance to Antituberculosis Drugs in England, Wales, and Northern Ireland, 2000-2015. [Journal Article]
- EIEmerg Infect Dis 2018; 24(3):524-533
- Among tuberculosis (TB) patients, acquired resistance to anti-TB drugs represents a failure in the treatment pathway. To improve diagnosis and care for patients with drug-resistant TB, we examined th...
Among tuberculosis (TB) patients, acquired resistance to anti-TB drugs represents a failure in the treatment pathway. To improve diagnosis and care for patients with drug-resistant TB, we examined the epidemiology and risk factors associated with acquired drug resistance during 2000-2015 among TB patients in England, Wales, and Northern Ireland. We found acquired resistance in 0.2% (158/67,710) of patients with culture-confirmed TB. Using multivariate logistic regression, we identified the following factors associated with acquired drug resistance: having pulmonary disease; initial resistance to isoniazid, rifampin, or both; a previous TB episode; and being born in China or South Africa. Treatment outcomes were worse for patients with than without acquired resistance. Although acquired resistance is rare in the study area, certain patient groups are at higher risk. Identifying these patients and ensuring that adequate resources are available for treatment may prevent acquisition of resistance, thereby limiting transmission of drug-resistant strains of mycobacteria.
- A case of renal granulomatosis with polyangiitis following intravesical bacillus Calmette-Guérin therapy. [Case Reports]
- SJSaudi J Kidney Dis Transpl 2018 Jan-Feb; 29(1):185-188
- Various adverse reactions may occur after intravesical bacillus Calmette-Guérin (BCG) therapy. Although the virulence of attenuated BCG is low, serious complications such as bacterial cystitis, bladd...
Various adverse reactions may occur after intravesical bacillus Calmette-Guérin (BCG) therapy. Although the virulence of attenuated BCG is low, serious complications such as bacterial cystitis, bladder contractures, granulomatous prostatitis, epididymitis, orchitis, and systemic reactions such as fever and malaise have been described. Disseminated granulomatosis such as hepatitis and pneumonitis have also been described, but are rare. We report here the case of a 67-year-old patient who presented with renal granulomatosis with polyangiitis following intravesical BCG therapy for superficial bladder tumor. The biological evaluation revealed the presence of perinuclear anti-neutrophil cytoplasmic antibodies with specificity for antimyeloperoxidase. Renal biopsy specimen revealed pauci-immune crescentic glomerulonephritis with segmental glomerular necrosis, presence of granulomas and no evidence of any caseating necrosis. He received antituberculosis drugs in addition to corticosteroids and cyclophosphamide without any improvement of the renal function.
- Successful drug desensitization in patients with delayed-type allergic reactions to anti-tuberculosis drugs. [Journal Article]
- IJInt J Infect Dis 2018 Feb 02; 68:61-68
- CONCLUSIONS: The desensitization protocol for anti-tuberculosis drugs was associated with a high success rate, and the individuals who failed desensitization experienced mild allergic reactions.
- Evaluation of genotype MTBDRplus line probe assay in detection of rifampicin and isoniazid resistance in comparison to solid culture drug susceptibility testing in a tertiary care centre of western Uttar Pradesh. [Journal Article]
- IJIndian J Med Microbiol 2017 Oct-Dec; 35(4):568-574
- CONCLUSIONS: GenoType® MTBDRplus has good sensitivity and specificity in detecting MDR-TB cases with a significantly lesser turnaround time as compared to conventional DST method and simultaneous detection of Rif and INH resistance. This technique saves several weeks of time required for culture and DST.
- The Methylerythritol Phosphate Pathway: Promising Drug Targets in the Fight against Tuberculosis. [Journal Article]
- AIACS Infect Dis 2018 Feb 08
- Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a severe infectious disease in need of new chemotherapies especially for drug-resistant cases. To meet the urgent requirement of new ...
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a severe infectious disease in need of new chemotherapies especially for drug-resistant cases. To meet the urgent requirement of new TB drugs with novel modes of action, the TB research community has been validating numerous targets from several biosynthetic pathways. The methylerythritol phosphate (MEP) pathway is utilized by Mtb for the biosynthesis of isopentenyl pyrophosphate (IPP) and its isomer dimethylallyl pyrophosphate (DMAPP), the universal five-carbon building blocks of isoprenoids. While being a common biosynthetic pathway in pathogens, the MEP pathway is completely absent in humans. Due to its unique presence in pathogens as well as the essentiality of the MEP pathway in Mtb, the enzymes in this pathway are promising targets for the development of new drugs against tuberculosis. In this Review, we discuss three enzymes in the MEP pathway: 1-deoxy-d-xylulose-5-phosphate synthase (DXS), 1-deoxy-d-xylulose-5-phosphate reductoisomerase (IspC/DXR), and 2C-methyl-d-erythritol 2,4-cyclodiphosphate synthase (IspF), which appear to be the most promising antitubercular drug targets. Structural and mechanistic features of these enzymes are reviewed, as well as selected inhibitors that show promise as antitubercular agents.
- Mycobacterium tuberculosis Molecular Determinants of Infection, Survival Strategies, and Vulnerable Targets. [Review]
- PPathogens 2018 Feb 01; 7(1)
- Mycobacterium tuberculosis is the causative agent of tuberculosis, an ancient disease which, still today, represents a major threat for the world population. Despite the advances in medicine and the ...
Mycobacterium tuberculosis is the causative agent of tuberculosis, an ancient disease which, still today, represents a major threat for the world population. Despite the advances in medicine and the development of effective antitubercular drugs, the cure of tuberculosis involves prolonged therapies which complicate the compliance and monitoring of drug administration and treatment. Moreover, the only available antitubercular vaccine fails to provide an effective shield against adult lung tuberculosis, which is the most prevalent form. Hence, there is a pressing need for effective antitubercular drugs and vaccines. This review highlights recent advances in the study of selected M. tuberculosis key molecular determinants of infection and vulnerable targets whose structures could be exploited for the development of new antitubercular agents.
- A 25-year surveillance of disseminated Bacillus Calmette-Guérin disease treatment in children in Southern Iran. [Journal Article]
- MMedicine (Baltimore) 2017; 96(52):e9035
- Disseminated Bacillus Calmette-Guérin (BCG) disease is one of the most serious complications of BCG vaccination, mainly among immunocompromised children with high morbidity and mortality.Currently, t...
Disseminated Bacillus Calmette-Guérin (BCG) disease is one of the most serious complications of BCG vaccination, mainly among immunocompromised children with high morbidity and mortality.Currently, there is no any consensus with regard to the standard regimen of antituberculosis (anti-TB) agents and duration of treatment in healthy or immunocompromised host in children. The aim of this study is to investigate the effect of various combination treatment strategies for disseminated BCG disease in children.In this cross-sectional study, the outcome of 3 different combination protocols was investigated in 59 patients.All patients were younger than 6 years old. Both possible immunocompetent and proven immunodeficient children were included in a period of 25 years (1991-2014) in a Nemazee referral teaching hospital.The minimum age was 1 month and the maximum was 60 months. The average age of patients was 8 months (8.26 ± 9.73). Out of 59 cases, 32 (54.2%) were female and 27 (45.8%) were male. Based on the primary work up, 52.5% of cases were classified as definite immunodeficient and 47.5% were classified as possible immunocompetent. Overall mortality rate was 50.8%. Mortality rate of disseminated BCG disease in immunocompetent and immunodeficient children was 28.6% and 71%, respectively. The mortality rate was not statistically different between patients treated with different treatment protocols. These results were not affected by immune status and the type of immunodeficiency.More than 2 anti-TB drugs combination will not change outcome of patient with disseminated BCG disease.
- Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly 'Current Medicinal Chemistry - Anti-Inflammator. [Journal Article]
- AAAntiinflamm Antiallergy Agents Med Chem 2018 Jan 26
- The search of novel anti-inflammatory agent is not considered as an ending process, since most of the clinically used anti-inflammatory drugs such as NSAIDs, Coxibs and GCs are allied with considerab...
The search of novel anti-inflammatory agent is not considered as an ending process, since most of the clinically used anti-inflammatory drugs such as NSAIDs, Coxibs and GCs are allied with considerable toxicity. However, numerous approaches were used to overcome the toxicity level such as co-administration with suitable agent/substance which provides protection against toxicity as well to synthesise new potent and safe anti-inflammatory drug. Although the drug treatment has been improved steadily but yet, it is still a challenge for the medicinal chemists to identify more potent therapeutic agents to treat or reduce the symptoms of inflammatory diseases. A variety of N-heterocyclic analogs are known to exhibit a wide range of interesting biological activities like antioxidant, anti-inflammatory, anticonvulsant, analgesic, antimicrobial, anticancer, antiprotozoal, antioxidant, antiparasitic, antiplatelet, cardioprotective, anthelmintic, antidiabetic, antitubercular, trypanocidal and anti-HIV. The present review summarizes the synthetic methodology and therapeutic potential of some N-heterocyclic analogs as potent anti-inflammatory agents.
- Genome-wide analysis of multi- and extensively drug-resistant Mycobacterium tuberculosis. [Journal Article]
- NGenNat Genet 2018; 50(2):307-316
- To characterize the genetic determinants of resistance to antituberculosis drugs, we performed a genome-wide association study (GWAS) of 6,465 Mycobacterium tuberculosis clinical isolates from more t...
To characterize the genetic determinants of resistance to antituberculosis drugs, we performed a genome-wide association study (GWAS) of 6,465 Mycobacterium tuberculosis clinical isolates from more than 30 countries. A GWAS approach within a mixed-regression framework was followed by a phylogenetics-based test for independent mutations. In addition to mutations in established and recently described resistance-associated genes, novel mutations were discovered for resistance to cycloserine, ethionamide and para-aminosalicylic acid. The capacity to detect mutations associated with resistance to ethionamide, pyrazinamide, capreomycin, cycloserine and para-aminosalicylic acid was enhanced by inclusion of insertions and deletions. Odds ratios for mutations within candidate genes were found to reflect levels of resistance. New epistatic relationships between candidate drug-resistance-associated genes were identified. Findings also suggest the involvement of efflux pumps (drrA and Rv2688c) in the emergence of resistance. This study will inform the design of new diagnostic tests and expedite the investigation of resistance and compensatory epistatic mechanisms.
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- A human xenobiotic nuclear receptor contributes to nonresponsiveness of Mycobacterium tuberculosis to the antituberculosis drug rifampicin. [Journal Article]
- JBJ Biol Chem 2018 Jan 22
- Mycobacterium tuberculosis is the causative agent of tuberculosis (TB). It acquires phenotypic drug resistance inside macrophages, and this resistance mainly arises from host-induced stress. However,...
Mycobacterium tuberculosis is the causative agent of tuberculosis (TB). It acquires phenotypic drug resistance inside macrophages, and this resistance mainly arises from host-induced stress. However, whether cellular drug efflux mechanisms in macrophages contribute to nonresponsiveness of M. tuberculosis to anti-TB drugs is unclear. Here, we report that xenobiotic nuclear receptors mediate TB drug nonresponsiveness by modulating drug efflux transporters in macrophages. This was evident from expression analysis of drug efflux transporters in macrophages isolated from TB patients. Among patients harboring rifampicin-susceptible M. tuberculosis, we observed increased intracellular survival of M. tuberculosis upon rifampicin treatment of macrophages isolated from patients not responding to anti-TB drugs compared with macrophages from patients who did respond. Of note, M. tuberculosis infection and rifampicin exposure synergistically modulated macrophage drug-efflux transporters in vitro. We also found that the xenobiotic nuclear receptor pregnane X receptor (PXR) modulates macrophage drug efflux transporter expression and activity, which compromised the anti-TB efficacy of rifampicin. We further validated this finding in a TB mouse model in which use of the PXR antagonist ketoconazole rescued rifampicin anti-TB activity. We conclude that PXR activation in macrophages compromises the efficacy of the anti-TB drug rifampicin. Alternative therapeutic strategies, such as use of the rifampicin derivatives rifapentine and rifabutin, which do not activate PXR, or of a PXR antagonist, may be effective for tackling drug nonresponsiveness of M. tuberculosis that arises from drug efflux systems of the host.