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Mycobacterium tuberculosis AND drug use and [keywords]
- Tubercular spondylitis in children. [REVIEW]
- Indian J Orthop 2014 3; 48(2):136-144.
Spine of the child has unique anatomy and growth potential to grow to adult size. Tuberculosis (TB) spine results in bone loss as well as disturbed growth potential, hence spinal deformities may progress as the child grows. The growth potential is also disturbed when the disease focus is surgically intervened. Surgery is indicated for complications such as deformity, neurological deficit, instability, huge abscess, diagnostic dilemma and in suspected drug resistance to mycobacterium tuberculosis. The child on antitubercular treatment needs to be periodically evaluated for weight gain and drug dosages need to be adjusted accordingly. The severe progressive kyphotic deformity should be surgically corrected. Mild to moderate cases should be followed up until maturity to observe progression/improvement of spinal deformity. The surgical correction of kyphotic deformity in active disease is less hazardous than in a healed kyphosis. The internal kyphectomy by extra pleural approach allows adequate removal of internal salient in paraplegic patients with healed kyphotic deformity.
- Surgical treatment of nontuberculous mycobacterial lung disease. [JOURNAL ARTICLE]
- Gen Thorac Cardiovasc Surg 2014 Apr 17.
While the prevalence of pulmonary tuberculosis has been decreasing, the prevalence of nontuberculous mycobacterial lung disease has been increasing. Unlike tuberculosis, nontuberculous mycobacterial disease is not communicable. However, their indolent nature may result in extensive parenchymal destruction, causing respiratory failure and vulnerability to airway infection. Nontuberculous mycobacterial lung disease, therefore, has been becoming a significant health problem. According to the 2007 American Thoracic Society/Infectious Diseases Society of America statement on nontuberculous mycobacterial diseases, the primary treatment is a multidrug treatment regimen. However, its efficacy is less than satisfactory for Mycobacterium avium complex lung disease, which is the most common type of nontuberculous mycobacterial lung diseases, and for Mycobacterium abscessus lung disease, which is notoriously resistant to chemotherapeutic drugs. The statement, therefore, has proposed a multidisciplinary treatment approach for these types of nontuberculous mycobacterial lung diseases: a combination of multidrug treatment regimen and adjuvant resectional surgery. This review covers the rationale, indication, procedure, and outcome of surgical treatment of nontuberculous mycobacterial lung disease. The rationale of surgery is to prevent disease progressing by removing the areas of lung most affected, harboring the largest amounts of mycobacteria. The indications for surgery include a poor response to drug therapy, the development of macrolide-resistant disease, or the presence of a significant disease-related complication such as hemoptysis. The surgical procedures of choice are various types of pulmonary resections, including wedge resection, segmentectomy, lobectomy, or pneumonectomy. The reported series have achieved favorable treatment outcomes in surgically treated patients with acceptable morbidity and mortality rates.
- Profiling of rpoB Mutations and MICs to Rifampicin and Rifabutin in Mycobacterium tuberculosis. [JOURNAL ARTICLE]
- J Clin Microbiol 2014 Apr 16.
Resistance to rifampicin (RIF) and rifabutin (RFB) in Mycobacterium tuberculosis is associated with mutations within an 81 bp region of the rpoB gene (RIF resistance-determining region, RRDR). Previous studies have shown that certain mutations in this region are more likely to confer high levels of RIF resistance, while others may be found in phenotypically susceptible isolates. In this study we sought to determine the relationship between MIC of RIF and RFB and rpoB-RRDR mutations in 32 multidrug resistant (MDR), 4 RIF mono-resistant and 5 susceptible M. tuberculosis clinical isolates. MICs were determined using the MGIT 960 system. Mutations in the rpoB-RRDR were determined by Sanger sequencing.S531L, S531W, H526Y, H526D and D516A-R529Q RpoB substitutions were associated with high MICs to RIF and RFB. Five isolates carrying the mutations L511P, H526L, H526N, and D516G/S522L were found to be susceptible to RIF. Several mutations were associated with resistance to RIF and susceptibility to RFB (F514FF, D516V, S522L). Whole genome sequencing of two MDR isolates without rpoB-RRDR mutations revealed a mutation outside of the RRDR (V146F, RIF MIC 50 μg/ml). The implications of polymorphisms identified in the second isolate and RIF resistance need to be further explored.Our study further establishes a correlation between mutations and MIC levels for RIF and also RFB in M. tuberculosis. Several rpoB mutations were identified in RIF and RFB susceptible isolates. The clinical significance of these findings requires further exploration. Until then, a combination of phenotypic and molecular testing for drug susceptibility testing is advisable.
- [Multiple drug resistance of Mycobacterium tuberculosis isolated from new cases of respiratory tract tuberculosis]. [English Abstract, Journal Article]
- Antibiot Khimioter 2013; 58(11-12):23-5.
Resistance of Mycobacterium tuberculosis isolated from new cases registered during a period from 2007 to 2012 was estimated. High rate of the M.tuberculosis multiple drug resistance increase was observed: from 28% in 2007 to 64% in 2012. Low efficacy of the treatment of such patients requires revision of the tuberculosis control strategy and search for new pharmacological agents groups.
- A Systematic Follow-Up of Mycobacterium tuberculosis Drug-Resistance and Associated Genotypic Lineages in the French Departments of the Americas over a Seventeen-Year Period. [Journal Article]
- Biomed Res Int 2014.:689852.
THE POPULATION OF THE FRENCH DEPARTMENTS OF THE AMERICAS (FDA) IS HIGHLY INFLUENCED BY THE INTENSE MIGRATORY FLOWS WITH MAINLAND FRANCE AND SURROUNDING COUNTRIES OF THE CARIBBEAN AND LATIN AMERICA, SOME OF WHICH HAVE HIGH INCIDENCE RATES OF TUBERCULOSIS (HAITI: 230/100,000; Guyana: 111/100,000; and Suriname: 145/100,000) and drug resistance. Since the development of drug resistance to conventional antituberculous drugs has a major impact on the treatment success of tuberculosis, we therefore decided to review carefully Mycobacterium tuberculosis drug resistance and associated genotypic lineages in the FDA over a seventeen-year period (January 1995-December 2011). A total of 1239 cases were studied, including 153 drug-resistant and 26 multidrug-resistant- (MDR-) TB cases, representing 12.3% and 2.1% of the TB cases in our study setting. A significantly higher proportion of M. tuberculosis isolates among relapse cases showed drug resistance to isoniazid (22.5%, P = 0.002), rifampicin (20.0%, P < 0.001), or both (MDR-TB, 17.5%; P < 0.001). Determination of spoligotyping based phylogenetic clades showed that among the five major lineages observed-T family (30.1%); Latin-American and Mediterranean (LAM, 23.7%); Haarlem (H, 22.2%); East-African Indian (EAI, 7.2%); and X family (6.5%)-two lineages, X and LAM, were overrepresented in drug-resistant and MDR-TB cases, respectively. Finally, 19 predominant spoligotypes were identified for the 1239 isolates of M. tuberculosis in our study among which 4 were significantly associated with drug resistance corresponding to SIT20/LAM1, SIT64/LAM6, SIT45/H1, and SIT46/undefined lineage.
- A Trisubstituted Benzimidazole Cell Division Inhibitor with Efficacy against Mycobacterium tuberculosis. [Journal Article]
- PLoS One 2014; 9(4):e93953.
Trisubstituted benzimidazoles have demonstrated potency against Gram-positive and Gram-negative bacterial pathogens. Previously, a library of novel trisubstituted benzimidazoles was constructed for high throughput screening, and compounds were identified that exhibited potency against M. tuberculosis H37Rv and clinical isolates, and were not toxic to Vero cells. A new series of 2-cyclohexyl-5-acylamino-6-N, N-dimethylaminobenzimidazoles derivatives has been developed based on SAR studies. Screening identified compounds with potency against M. tuberculosis. A lead compound from this series, SB-P17G-A20, was discovered to have an MIC of 0.16 µg/mL and demonstrated efficacy in the TB murine acute model of infection based on the reduction of bacterial load in the lungs and spleen by 1.73±0.24 Log10 CFU and 2.68±Log10 CFU, respectively, when delivered at 50 mg/kg by intraperitoneal injection (IP) twice daily (bid). The activity of SB-P17G-A20 was determined to be concentration dependent and to have excellent stability in mouse and human plasma, and liver microsomes. Together, these studies demonstrate that SB-P17G-A20 has potency against M. tuberculosis clinical strains with varying susceptibility and efficacy in animal models of infection, and that trisubstituted benzimidazoles continue to be a platform for the development of novel inhibitors with efficacy.
- Strain Diversity of Mycobacterium tuberculosis Isolates from Pulmonary Tuberculosis Patients in Afar Pastoral Region of Ethiopia. [Journal Article]
- Biomed Res Int 2013.:238532.
Data on genotypic diversity of Mycobacterium tuberculosis complex (MTBC) is important to understand its epidemiology, human adaptation, clinical phenotypes, and drug resistance. This study aimed to characterize MTBC clinical isolates circulating in a predominantly pastoralist area in Ethiopia, a country where tuberculosis is the second leading cause of mortality. Culture of sputum samples collected from a total of 325 pulmonary TB suspects was done to isolate MTBC. Spoligotyping was used to characterize 105 isolates from culture positive slopes and the result was compared with an international database. Forty-four spoligotype patterns were observed to correspond to 35 shared-types (SITs) containing 96 isolates and 9 orphan patterns; 27 SITs containing 83 isolates matched a preexisting shared-type in the database, whereas 8 SITs (n = 13 isolates) were newly created. A total of 19 SITs containing 80 isolates were clustered within this study (overall clustering of 76.19%). Three dominant lineages (T, CAS, and Manu) accounted for 76.19% of the isolates. SIT149/T3-ETH was one of the two most dominant sublineages. Unlike previous reports, we show that Manu lineage strains not only constitute a dominant lineage, but are also associated with HIV infection in Afar region of Ethiopia. The high level of clustering suggests the presence of recent transmission that should be further studied using additional genotyping markers.
- Prevalence and molecular characteristics of drug-resistant tuberculosis in Hunan, China. [JOURNAL ARTICLE]
- Antimicrob Agents Chemother 2014 Apr 14.
To determine the prevalence and molecular characteristics of drug-resistant tuberculosis in Hunan province, drug susceptibility testing and spoligotyping method were performed among 171 Mycobacterium tuberculosis (M. tuberculosis) isolates. In addition, the mutated characteristics of 12 loci including katG, inhA, rpoB, rpsL, rrs1, embB, pncA, tlyA, eis, rrs2, gyrA and gyrB among drug-resistant isolates were also analyzed by DNA sequencing. Our results indicated that the prevalence of isoniazid (INH), rifampin (RIF), streptomycin (SM), ethambutol (EMB), pyrazinamide (PZA), capreomycin (CAP), kanamycin (KAN), amikacin (AKM) and ofloxacin (OFX) resistance in Hunan province were 35.7%, 26.9%, 20.5%, 9.9% 15.2%, 2.3%, 1.8%, 1.2% and 10.5%, respectively. The previously treated patients presented significantly increased risks for developing drug resistance. The majority of M. tuberculosis isolates belonged to Beijing family. Almost all the drug resistance demonstrated no association with genotype. The most frequent mutations of drug-resistant isolates were katG315, inhA-15, rpoB531, 526 and 516, rpsL43, rrs1514, embB306, pncA96, rrs21401, gyrA94 and 90, respectively. These results contribute to the knowledge of the prevalence of drug resistance in Hunan and also expand the molecular characteristics of drug resistance in China.
- Reduced Virulence of an Extensively Drug-Resistant Outbreak Strain of Mycobacterium tuberculosis in a Murine Model. [Journal Article]
- PLoS One 2014; 9(4):e94953.
Bacterial drug resistance is often associated with a fitness cost. Large outbreaks of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB have been described that predominately affect persons with HIV infection. We obtained four closely-related Mycobacterium tuberculosis strains (genotype F15/LAM4/KZN) from an outbreak in KwaZulu-Natal (KZN), South Africa, including drug-sensitive, MDR, and XDR clinical isolates. We compared the virulence of these strains in a murine model of aerosol M. tuberculosis infection for four phenotypes: (1) competitive in vivo growth in lung and spleen, (2) non-competitive in vivo growth in lung and spleen, (3) murine survival time, and (4) lung pathology. When mixtures of sensitive, MDR, and XDR KZN strains were aerosolized (competitive model), lung CFUs were similar at 60 days after infection, and spleen CFUs were ordered as follows: sensitive > MDR > XDR. When individual strains were aerosolized (non-competitive model), modest differences in lung and spleen CFUs were observed with the same ordering. C57BL/6, C3H/FeJ, and SCID mice all survived longer after infection with MDR as compared to sensitive strains. SCID mice infected with an XDR strain survived longer than those infected with MDR or sensitive strains. Lung pathology was reduced after XDR TB infection compared to sensitive or MDR TB infection. In summary, increasing degrees of drug resistance were associated with decreasing murine virulence in this collection of KZN strains as measured by all four virulence phenotypes. The predominance of HIV-infected patients in MDR and XDR TB outbreaks may be explained by decreased virulence of these strains in humans.
- Mycobactericidal Activity of Sutezolid (PNU-100480) in Sputum (EBA) and Blood (WBA) of Patients with Pulmonary Tuberculosis. [Journal Article]
- PLoS One 2014; 9(4):e94462.
Sutezolid (PNU-100480) is a linezolid analog with superior bactericidal activity against Mycobacterium tuberculosis in the hollow fiber, whole blood and mouse models. Like linezolid, it is unaffected by mutations conferring resistance to standard TB drugs. This study of sutezolid is its first in tuberculosis patients.Sputum smear positive tuberculosis patients were randomly assigned to sutezolid 600 mg BID (N = 25) or 1200 mg QD (N = 25), or standard 4-drug therapy (N = 9) for the first 14 days of treatment. Effects on mycobacterial burden in sputum (early bactericidal activity or EBA) were monitored as colony counts on agar and time to positivity in automated liquid culture. Bactericidal activity was also measured in ex vivo whole blood cultures (whole blood bactericidal activity or WBA) inoculated with M. tuberculosis H37Rv.All patients completed assigned treatments and began subsequent standard TB treatment according to protocol. The 90% confidence intervals (CI) for bactericidal activity in sputum over the 14 day interval excluded zero for all treatments and both monitoring methods, as did those for cumulative WBA. There were no treatment-related serious adverse events, premature discontinuations, or dose reductions due to laboratory abnormalities. There was no effect on the QT interval. Seven sutezolid-treated patients (14%) had transient, asymptomatic ALT elevations to 173±34 U/L on day 14 that subsequently normalized promptly; none met Hy's criteria for serious liver injury.The mycobactericidal activity of sutezolid 600 mg BID or 1200 mg QD was readily detected in sputum and blood. Both schedules were generally safe and well tolerated. Further studies of sutezolid in tuberculosis treatment are warranted.ClinicalTrials.gov NCT01225640.