High Prevalence of Primary Multidrug Resistant Tuberculosis in Persons with No Known Risk Factors

INTRODUCTION: In high multidrug resistant (MDR) tuberculosis (TB) prevalence areas, drug susceptibility testing (DST) at diagnosis is recommended for patients with risk factors for MDR. However, this approach might miss a substantial proportion of MDR-TB in the general population. We studied primary MDR in patients considered to be at low risk of MDR-TB in Lima, Peru. METHODS: We enrolled new sputum smear-positive TB patients who did not report any MDR-TB risk factor: known exposure to a TB patient whose treatment failed or who died or who was known to have MDR-TB; immunosuppressive co-morbidities, ex prison inmates; prison and health care workers; and alcohol or drug abuse. A structured questionnaire was applied to all enrolled participants to confirm the absence of these factors and thus minimize underreporting. Sputum from all participants was cultured on Lowenstein-Jensen media and DST for first line drugs was performed using the 7H10 agar method. RESULTS: Of 875 participants with complete data, 23.2% (203) had risk factors for MDR-TB elicited after enrolment. Among the group with no reported risk factors who had a positive culture, we found a 6.3% (95%CI 4.4-8.3) (37/584) rate of MDR-TB. In this group no epidemiological characteristics were associated with MDR-TB. Thus, in this group, multidrug resistance occurred in patients with no identifiable risk factors. CONCLUSIONS: We found a high rate of primary MDR-TB in a general population with no identifiable risk factors for MDR-TB. This suggests that in a high endemic area targeting patients for MDR-TB based on the presence of risk factors is an insufficient intervention

Classifying new anti-tuberculosis drugs: Rationale and future perspectives

The classification of anti-tuberculosis (TB) drugs is important as it helps the clinician to build an appropriate anti-TB regimen for multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB cases that do not fulfil the criteria for the shorter MDR-TB regimen. The World Health Organization (WHO) has recently approved a revision of the classification of new anti-TB drugs based on current evidence on each drug. In the previous WHO guidelines, the choice of drugs was based on efficacy and toxicity in a step-down manner, from group 1 first-line drugs and groups 2-5 second-line drugs, to group 5 drugs with potentially limited efficacy or limited clinical evidence. In the revised WHO classification, exclusively aimed at managing drug-resistant cases, medicines are again listed in hierarchical order from group A to group D. In parallel, a possible future classification is independently proposed. The aim of this viewpoint article is to describe the evolution in WHO TB classification (taking into account an independently proposed new classification) and recent changes in WHO guidance, while commenting on the differences between them. The latest evidence on the ex-group 5 drugs is also discussed

Social, Clinical and Microbiological Differential Characteristics of Tuberculosis among Immigrants in Spain

BACKGROUND: To identify the differential tuberculosis (TB) characteristics within the immigrant population with respect to natives in Spain. METHODOLOGY/PRINCIPAL FINDINGS: A prospective cohort study design was implemented to examine the TB cases diagnosed and starting standard antituberculous treatment in Spain, between January 1st 2006 and March 31st 2007. A logistic regression analysis was performed to determine differential characteristics. 1,490 patients were included in the study population, 1,048 natives and 442 (29.7%) immigrants. According to the multivariate analysis, the following variables were significantly associated with immigrant TB cases: younger age (OR = 3.79; CI:2.16-6.62), living in group situation (OR = 7.61; CI:3.38-12.12), lower frequency of disabled (OR:0.08; CI:0.02-0.26) and retired (OR:0.21; CI:0.09-0.48) employment status, lower frequency of pulmonary disease presentation (OR = 0.47; CI:0.24-0.92), primary or emergency care admission (OR = 1.80; CI:1.05-3.06 and OR = 2.16; CI:1.36-3.45), drug resistance (OR = 1.86; CI:1.01-3.46), treatment default (OR:2.12; CI:1.18-3.81), lower frequency of alcohol and cigarette consumption (OR = 2.10; CI:1.42-3.11 and OR = 2.85; CI:2.10-3.87 respectively), more directly observed treatment (OR = 1.68; CI:1.04-2.69), and poor understanding of TB disease and its treatment (OR = 3.11; CI:1.86-5.20). The low percentage of primary MDR-TB in the native population (0.1% vs. 2.2% of immigrants) should be noted. CONCLUSIONS/SIGNIFICANCE: The differences show the need to introduce specific strategies in the management of TB within the immigrant population, including the improvement of social and work conditions

Synthesis, antitubercular activity and mechanism of resistance of highly effective thiacetazone analogues

Defining the pharmacological target(s) of currently used drugs and developing new analogues with greater potency are both important aspects of the search for agents that are effective against drug-sensitive and drug-resistant Mycobacterium tuberculosis. Thiacetazone (TAC) is an anti-tubercular drug that was formerly used in conjunction with isoniazid, but removed from the antitubercular chemotherapeutic arsenal due to toxic side effects. However, several recent studies have linked the mechanisms of action of TAC to mycolic acid metabolism and TAC-derived analogues have shown increased potency against M. tuberculosis. To obtain new insights into the molecular mechanisms of TAC resistance, we isolated and analyzed 10 mutants of M. tuberculosis that were highly resistant to TAC. One strain was found to be mutated in the methyltransferase MmaA4 at Gly101, consistent with its lack of oxygenated mycolic acids. All remaining strains harbored missense mutations in either HadA (at Cys61) or HadC (at Val85, Lys157 or Thr123), which are components of the bhydroxyacyl-ACP dehydratase complex that participates in the mycolic acid elongation step. Separately, a library of 31 new TAC analogues was synthesized and evaluated against M. tuberculosis. Two of these compounds, 15 and 16, exhibited minimal inhibitory concentrations 10-fold lower than the parental molecule, and inhibited mycolic acid biosynthesis in a dose-dependent manner. Moreover, overexpression of HadAB HadBC or HadABC in M. tuberculosis led to high level resistance to these compounds, demonstrating that their mode of action is similar to that of TAC. In summary, this study uncovered new mutations associated with TAC resistance and also demonstrated that simple structural optimization of the TAC scaffold was possible and may lead to a new generation of TAC-derived drug candidates for the potential treatment of tuberculosis as mycolic acid inhibitors

Prevalence of Drug-Resistant Tuberculosis in Mainland China: Systematic Review and Meta-Analysis

Background: The spread of drug-resistant tuberculosis (TB) is one of the major public health problems in the world. Surveillance of anti-TB drug resistance is important for monitoring TB control strategies. However, the status of drugresistant TB in China has been reported inconsistently. Methods: We systematically reviewed published studies on drug-resistant TB in China until March 31, 2011, and quantitatively summarized prevalence and patterns of anti-TB drug resistance among new cases and previously treated cases, respectively. Results: Ninety-five eligible articles, published during 1993–2011, were included in this review. The meta-analyses showed that the prevalence of drug-resistant TB in new cases was 27.9 % (95 % CI, 25.6%–30.2%) (n/N = 27360/104356) and in previously treated cases was 60.3 % (95 % CI, 56.2%–64.2%) (n/N = 30350/45858). Furthermore, in these two study populations, the prevalence of multiple drug resistance was found to be 5.3 % (95 % CI, 4.4%–6.4%) (n/N = 8810/101718) and 27.4 % (95 % CI, 24.1%–30.9%) (n/N = 10486/44530) respectively. However, the results were found to be frequently heterogeneous (p for Q tests,0.001). The most common resistance was observed for isoniazid among both study populations. Different patterns of drug resistance were observed in the subgroup analysis with respect to geographic areas, drug susceptibility testing methods and subject enrollment time

Systematic Analysis of Cell Cycle Effects of Common Drugs Leads to the Discovery of a Suppressive Interaction between Gemfibrozil and Fluoxetine

Screening chemical libraries to identify compounds that affect overall cell proliferation is common. However, in most cases, it is not known whether the compounds tested alter the timing of particular cell cycle transitions. Here, we evaluated an FDA-approved drug library to identify pharmaceuticals that alter cell cycle progression in yeast, using DNA content measurements by flow cytometry. This approach revealed strong cell cycle effects of several commonly used pharmaceuticals. We show that the antilipemic gemfibrozil delays initiation of DNA replication, while cells treated with the antidepressant fluoxetine severely delay progression through mitosis. Based on their effects on cell cycle progression, we also examined cell proliferation in the presence of both compounds. We discovered a strong suppressive interaction between gemfibrozil and fluoxetine. Combinations of interest among diverse pharmaceuticals are difficult to identify, due to the daunting number of possible combinations that must be evaluated. The novel interaction between gemfibrozil and fluoxetine suggests that identifying and combining drugs that show cell cycle effects might streamline identification of drug combinations with a pronounced impact on cell proliferation