Mycobacterium tuberculosis AND drug use and [keywords]
- Loperamide Restricts Intracellular Growth of Mycobacterium tuberculosis in Lung Macrophages. [JOURNAL ARTICLE]
- Am J Respir Cell Mol Biol 2016 Jul 28.
New approaches for improving tuberculosis control using adjunct host-directed cellular and repurposed drug therapies are needed. Autophagy plays a crucial role in the response to tuberculosis, and a variety of autophagy-inducing drugs that are currently available for various medical conditions may serve as an adjunct treatment in pulmonary tuberculosis. Here, We evaluated the potential of loperamide, carbamazepine, valproic acid, verapamil and rapamycin to enhance the antimicrobial immune response to M. tuberculosis. Human monocyte-derived macrophages (MDMs) and murine alveolar cells (MACs) were infected with Mtb and treated with loperamide, carbamazepine, valproic acid, verapamil and rapamycin in vitro. Balb/c mice were intraperitoneally administered loperamide, valproic acid and verapamil, and MACs were infected in vitro with Mtb. The induction of autophagy, the containment of Mtb within autophagosomes and the intracellular Mtb burden were determined. Autophagy was induced by all of the drugs in human and mouse macrophages, and loperamide significantly increased the co-localization of LC3 with Mtb in MDMs. Carbamazepine, loperamide and valproic acid induced LC3 and ATG16L1 gene expression in MDMs and in MACs. Loperamide also induced a reduction in TNF-α production. Loperamide and verapamil induced autophagy, which was associated with a significant reduction in the intracellular growth of Mtb in MACs and alveolar macrophages (AMs). The intraperitoneal administration of loperamide and valproic acid induced autophagy in freshly isolated MACs. The anti-mycobacterial activity in MACs was higher after loperamide treatment and was associated with the degradation of p62. In conclusion, loperamide shows potential as an adjunctive therapy for the treatment of tuberculosis.
- Mycobacterium tuberculosis lineages and anti-tuberculosis drug resistance in reference hospitals across Viet Nam. [Journal Article]
- BMC Microbiol 2016; 16(1):167.
Mycobacterium tuberculosis, the tuberculosis (TB) pathogen, despite a low level of genetic diversity, has revealed a high variety of biological and epidemiological characteristics linked to their lineages, such as transmissibility, fitness and propensity to acquire drug resistance. This has important implications for the epidemiology of TB. We conducted this first countrywide cross-sectional study to identify the prevalent M. tuberculosis lineages and to assess their epidemiological associations and their relation to drug resistance. The study was conducted among isolates acquired in reference hospitals across Vietnam. Isolates with drug susceptibility testing profiles were identified for their lineages by spoligotyping. Logistic regression was used to investigate the association of M. tuberculosis lineages with location, age and sex of the patients and drug resistance levels.Results showed that the most prevalent lineage was Beijing (55.4 %), followed by EAI (27.5 %), T (6.4 %), LAM (1.3 %), Haarlem (1 %) and Zero type (0.3 %). The proportion of Beijing isolates in the North (70.4 %) and the South (68 %) was higher than in the Centre (28 %) (OR = 1.7 [95 % CI: 1.4-2.0], p < 0.0001), whereas the proportion of EAI isolates in the North (7.1 %) and the South (17 %) was much lower compared with the Centre (59 %) (OR = 0.5 [95 % CI: 0.4-0.6], p < 0.0001). Overall, Beijing isolates were the most likely to be drug-resistant and EAI isolates were the least likely to be drug-resistant, except in the South of Vietnam where EAI is also highly drug-resistant. The proportion of Beijing isolates was significantly higher (p < 0.01), and the proportion of EAI isolates was significantly lower (p < 0.05) in younger patients. The proportion of drug-resistance was higher in isolates collected from male patients and from patients in the middle age groups.The findings suggest ongoing replacement of EAI lineage, which is mainly more drug-susceptible with highly drug-resistant Beijing lineage in all studied regions of Vietnam. Male patients of working ages should be the focus for better control to prevent the emergence of drug-resistant TB.
- Genotypic characterization of drug resistant Mycobacterium tuberculosis in Quebec, 2002-2012. [Journal Article]
- BMC Microbiol 2016; 16(1):164.
The increasing emergence of drug-resistant tuberculosis presents a threat to the effective control of tuberculosis (TB). Rapid detection of drug-resistance is more important than ever to address this scourge. The purpose of this study was to genotypically characterize the first-line antitubercular drug-resistant isolates collected over 11 years in Quebec.The main mutations found in our resistant strains collection (n = 225) include: the S315T substitution in katG (50.2 %), the -15 C/T mutation in the inhA promoter (29 %); the S531L substitution in rpoB (43 %); the deletion 8 bp 446 / + R140S in pncA (72.9 %); the M306I (35.7 %) and M306V (21.4 %) substitutions in embB. Ten of the mutations in katG and 4 mutations identified in pncA were previously undescribed.Screening of mutations conferring resistance to first-line antituberculous drugs using DNA-sequencing approach seems to be feasible and would drastically shorten the time to determine the resistance profile compared to the proportion method.
- Failure of the Amikacin, Cefoxitin, and Clarithromycin Combination Regimen for Pulmonary Mycobacterium abscessus. [JOURNAL ARTICLE]
- Antimicrob Agents Chemother 2016 Jul 25.
In the hollow-fiber model, we mimicked the drug exposures achieved in the lungs of humans treated with standard amikacin, clarithromycin and cefoxitin combination therapy for Mycobacterium abscessus At optimal dosing, a kill rate of -0.09 (95% CI -0.04- 0.03) log10 colony forming units (CFU) per ml/day was achieved over the first 14 days, after which there was regrowth due to acquired drug resistance. Thus, the standard regimen quickly failed. A new regimen is needed.
- Convergence of a diabetes mellitus, protein energy malnutrition, and TB epidemic: the neglected elderly population. [Journal Article, Review]
- BMC Infect Dis 2016; 16(1):361.
On a global scale, nearly two billion persons are infected with Mycobacterium tuberculosis. From this vast reservoir of latent tuberculosis (TB) infection, a substantial number will develop active TB during their lifetime, with some being able to transmit TB or Multi-drug- resistant (MDR) TB to others. There is clinical evidence pointing to a higher prevalence of infectious diseases including TB among individuals with Diabetes Mellitus (DM). Furthermore, ageing and diabetes mellitus may further aggravate protein-energy malnutrition (PEM), which in turn impairs T-lymphocyte mediated immunologic defenses, thereby increasing the risk of developing active TB and compromising TB treatment. This article aims to a) highlight synergistic mechanisms associated with immunosenescence, DM and PEM in relation to the development of active TB and b) identify nutritional, clinical and epidemiological research gaps.To explore the synergistic relationship between ageing, DM, tuberculosis and PEM, a comprehensive review was undertaken. The MEDLINE and the Google Scholar databases were searched for articles published from 1990 to March 2015, using different MESH keywords in various combinations.Ageing and DM act synergistically to reduce levels of interferon gamma (IFN- γ), thereby increasing susceptibility to TB, for which cell mediated immunity (CMI) plays an instrumental role. These processes can set in motion a vicious nutritional cycle which can predispose to PEM, further impairing the CMI and consequently limiting host defenses. This ultimately transforms the latent TB infection into active disease. A clinical diagnostic algorithm and clinical guidelines need to be established for this population.Given the increase in ageing population with DM and PEM, especially in resource-poor settings, these synergistic tripartite interactions must be examined if a burgeoning TB epidemic is to be averted. Implementation of a comprehensive, all-encompassing approach to curb transmission is clearly indicated. To this end, clinical, nutritional and epidemiological research gaps must be addressed without a delay.
- [Analysis on drug resistance of Mycobacterium tuberculosis and influencing factors in six provinces of China]. [English Abstract, Journal Article]
- Zhonghua Liu Xing Bing Xue Za Zhi 2016 Jul; 37(7):945-8.
To analyze the drug-resistance of clinical Mycobacterium tuberculosis strains isolated from the tuberculosis(TB)patients in six provinces in China and related risk factors, and provide evidences for the effective prevention and treatment of drug resistant TB.Six provinces were selected from China. The background information of the TB patients was investigated with questionnaire survey, and the drug susceptibilities of the clinical M. tuberculosis strains to isoniazid, rifampin, ethambutol and streptomycin were tested by means of the proportional drug susceptibility test. Then the results and related risk factors were analyzed with software SPSS 20.0.The overall drug resistant rate and multi drug-resistant(MDR)rate were 23.42% and 13.51% respectively. The overall drug resistant rate and MDR rate in Beijing, Jilin, Hunan, Henan, Shaanxi, Xinjiang were 21.50%, 12.24%, 36.27%, 42.86%, 27.78%, 24.39% and 4.67%, 8.16%, 24.51%, 26.53%, 15.28%, 14.15%, respectively. The χ(2) analysis results showed that the differences in single drug-resistant rate, overall drug resistant rate and MDR rate in these provinces had significant differences(P=0.000). The univariate statistical analysis results showed that the retreatment for TB and TB treatment history were the risk factors associated with drug resistance(P<0.05).The drug resistance of TB was very serious in China, but the TB drug resistance varied with province. The preventive intervention should be strengthened against all the major risk factors associated with the drug resistance for the better prevention and control of TB.
- Development of potent chemical antituberculosis agents targeting Mycobacterium tuberculosis acetohydroxyacid synthase. [JOURNAL ARTICLE]
- Int J Antimicrob Agents 2016 Jul 6.
Mycobacterium tuberculosis acetohydroxyacid synthase (MTB-AHAS) has been suggested as a crucial target for antibacterial agents. High-throughput screening of a chemical library was performed to identify potent new inhibitors of MTB-AHAS. Among the 6800 tested compounds, 15 were identified as potent inhibitors, exhibiting >80-90% inhibition of in vitro MTB-AHAS activity at a fixed concentration of 20 µM. Five compounds belonging to the triazolopyrimidine structural class showed greater inhibition potency, with a half-maximum inhibition concentration (IC50 value) in the low micromolar range (0.4-1.24 µM). Furthermore, potent inhibitors demonstrated non-competitive, uncompetitive or mixed-competitive inhibition. Molecular docking experiments with these potent chemicals using a homology model of MTB-AHAS indicated hydrophobic and hydrogen bond interactions with some key herbicide binding site residues with binding energies (ΔG) of -8.04 to -10.68 Kcal/mol, respectively. The binding modes were consistent with inhibition mechanisms, as the chemicals were oriented outside the active site. Importantly, these potent inhibitors demonstrated significant growth inhibition of various clinically isolated multidrug-resistant and extensively drug-resistant M. tuberculosis strains, with 50% minimum inhibitory concentrations (MIC50 values) ranging from 0.2 µg/mL to 0.8 µg/mL, which resemble the MICs of conventional drugs for tuberculosis (isoniazid, 0.1 µg/mL; rifampicin, 0.4 µg/mL). Thus, the identified potent inhibitors show potential as scaffolds for further in vivo studies and might provide an impetus for the development of strong antituberculosis agents targeting MTB-AHAS.
- Drug susceptibility testing of rapidly growing mycobacteria in extrapulmonary tuberculosis. [Journal Article]
- Indian J Tuberc 2016 Apr; 63(2):119-22.
There has been an increasing awareness of the rapidly growing mycobacteria (RGM), of which numerous species and phylogenetic groups are clearly established human pathogens. It is important to appropriately distinguish RGM from other mycobacteria, as first-line antituberculous drugs are ineffective for their treatment. Variability in susceptibility of RGM is seen in relation to species, different geographical areas, and time. Therefore, we conducted a study to speciate the isolates of RGM and perform antimicrobial susceptibility testing. The study was carried out in the department of microbiology of a tertiary care hospital. This study included 40 isolates of RGM obtained from clinical specimens from suspected cases of extrapulmonary tuberculosis. Forty isolates of RGM were speciated by phenotypic methods and drug susceptibility testing was done by broth microdilution method. Of the 40 isolates of RGM, 55% belonged to Mycobacterium fortuitum group, 35% were M. smegmatis group, and 10% were M. chelonae-abscessus group. In M. fortuitum group, sensitivity was seen to amikacin (13.63%), cefoxitin (18.18%), imipenem (31.81%), ceftriaxone (22.72%), and cotrimoxazole (31.81%). Only 14.28% and 7.14% of M. smegmatis were sensitive to cotrimoxazole and amikacin, respectively. M. chelonae-abscessus group was resistant to all the antibiotics tested and showed only intermediate sensitivity to amoxicillin-clavulanic acid (50%) and gatifloxacin (25%). A variability in sensitivity to different antimicrobials exists in all groups. Hence, it is advisable to perform antimicrobial susceptibility test before commencement of therapy.
- Detection and characterization of drug-resistant conferring genes in Mycobacterium tuberculosis complex strains: A prospective study in two distant regions of Ghana. [Journal Article]
- Tuberculosis (Edinb) 2016 Jul.:147-54.
We spoligotyped and screened 1490 clinical Mycobacterium tuberculosis complex strains from Northern and Greater Accra regions of Ghana against INH and RIF using the microplate alamar blue phenotypic assay. Specific drug resistance associated genetic elements of drug resistant strains were analyzed for mutations. A total of 111 (7.5%), 10 (0.7%) and 40 (2.6%) were mono-resistant to INH, RIF, and MDR, respectively. We found the Ghana spoligotype to be associated with drug resistance (INH: 22.1%; p = 0.0000, RIF: 6.2%; p = 0.0103, MDR: 4.6%; p = 0.0240) as compared to the Cameroon spoligotype (INH: 6.7%, RIF: 2.4%, MDR: 1.6%). The propensity for an isolate to harbour katG S315T mutation was higher in M. tuberculosis (75.8%) than Mycobacterium africanum (51.7%) (p = 0.0000) whereas the opposite was true for inhApro mutations; MAF (48.3%) compared to MTBSS (26.7%) (p = 0.0419). We identified possible novel compensatory INH resistance mutations in inhA (G204D) and ahpCpro (-88G/A and -142G/A) and a novel ndh mutation K32R. We detected two possible rpoC mutations (G332R and V483G), which occurred independently with rpoB S450L, respectively. The study provides the first evidence that associate the Ghana spoligotype with DR-TB and calls for further genome analyses for proper classification of this spoligotype and to explore for fitness implications and mechanisms underlying this observation.
- Prevalence of pyrazinamide resistance across the spectrum of drug resistant phenotypes of Mycobacterium tuberculosis. [Journal Article]
- Tuberculosis (Edinb) 2016 Jul.:128-30.
Pyrazinamide resistance is largely unknown in the spectrum of drug resistant phenotypes. We summarize data on PZA resistance in clinical isolates from South Africa. PZA DST should be performed when considering its inclusion in treatment of patients with rifampicin-resistant TB or MDR-TB.