Immigration from areas of high incidence is thought to have fueled the resurgence of tuberculosis (TB) in areas of low incidence. To reduce the risk of disease in low-incidence areas, the main countermeasure has been the screening of immigrants on arrival. This measure is based on the assumption of a prompt decline in the incidence of TB in immigrants during their first few years of residence in a country with low overall incidence. We have documented that this assumption is not true for 619 Somali immigrants reported in Denmark as having TB. The annual incidence of TB declined only gradually during the first 7 years of residence, from an initial 2,000 per 100,000 to 700 per 100,000. The decline was described by an exponential function with a half-time of 5.7 (95% confidence interval 4.0 to 9.7) years. This finding seriously challenges the adequacy of the customary practice of screening solely on arrival.

As countries approach the elimination phase of tuberculosis, specific problems and challenges emerge, due to the steadily declining incidence in the native population, the gradually increasing importance of the importation of latent tuberculosis infection and tuberculosis from other countries and the emergence of groups at particularly high risk of tuberculosis. Therefore, a Working Group of the World Health Organization (WHO), the International Union Against Tuberculosis and Lung Disease (IUATLD) and the Royal Netherlands Tuberculosis Association (KNCV) have developed a new framework for low incidence countries based on concepts and definitions consistent with those of previous recommendations from WHO/IUATLD Working Groups. In low-incidence countries, a broader spectrum of interventions is available and feasible, including: 1) a general approach to tuberculosis which ensures rapid detection and treatment of all the cases and prevention of unnecessary deaths; 2) an overall control strategy aimed at reducing the incidence of tuberculosis infection (risk-group management and prevention of transmission of infection in institutional settings) and 3) a tuberculosis elimination strategy aimed at reducing the prevalence of tuberculosis infection (outbreak management and provision of preventive therapy for specified groups and individuals). Government and private sector commitment towards elimination, effective case detection among symptomatic individuals together with active case finding in special groups, standard treatment of disease and infection, access to tuberculosis diagnostic and treatment services, prevention (e.g. through screening and bacille Calmette-Guéria immunization in specified groups), surveillance and treatment outcome monitoring are prerequisites to implementing the policy package recommended in this new framework document.

Infliximab is a humanized antibody against tumor necrosis factor alpha (TNF-alpha) that is used in the treatment of Crohn's disease and rheumatoid arthritis. Approximately 147,000 patients throughout the world have received infliximab. Excess TNF-alpha in association with tuberculosis may cause weight loss and night sweats, yet in animal models it has a protective role in the host response to tuberculosis. There is no direct evidence of a protective role of TNF-alpha in patients with tuberculosis.

Does immigration from a high-prevalence area contribute to an increased risk of tuberculosis in a low-incidence country? The tuberculosis incidence in Somalia is among the highest ever registered. Due to civil war and starvation, nearly half of all Somalis have been forced from their homes, causing significant migration to low-incidence countries. In Denmark, two-thirds of all tuberculosis patients are immigrants, half from Somalia. To determine the magnitude of Mycobacterium tuberculosis transmission between Somalis and Danes, we analyzed DNA fingerprint patterns of isolates collected in Denmark from 1992 to 1999, comprising >97% of all culture-positive patients (n = 3,320). Of these, 763 were Somalian immigrants, 55.2% of whom shared identical DNA fingerprint patterns; 74.9% of these were most likely infected before their arrival in Denmark, 23.3% were most likely infected in Denmark by other Somalis, and 1.8% were most likely infected by Danes. In the same period, only 0.9% of all Danish tuberculosis patients were most likely infected by Somalis. The Somalian immigrants in Denmark could be distributed into 35 different clusters with possible active transmission, of which 18 were retrieved among Somalis in the Netherlands. This indicated the existence of some internationally predominant Somalian strains causing clustering less likely to represent recent transmission. In conclusion, M. tuberculosis transmission among Somalis in Denmark is limited, and transmission between Somalis and Danes is nearly nonexistent. The higher transmission rates between nationalities found in the Netherlands do not apply to the situation in Denmark and not necessarily elsewhere, since many different factors may influence the magnitude of active transmission.

The whole-genome fingerprinting technique, fluorescent amplified-fragment length polymorphism (FAFLP) analysis, was applied to Mycobacterium tuberculosis. Sixty-five clinical isolates were analyzed to determine the value of FAFLP as a stand-alone genotyping technique and to compare it with the well-established IS6110 typing system. The genome sequence of M. tuberculosis strain H37Rv (S. T. Cole et al., Nature 393:537-544, 1998) was used to model computer-generated informative primer combination(s), and the precision and reproducibility of FAFLP were evaluated by comparing the results of in vitro and computer-generated experiments. Multiplex FAFLP was used to increase resolving power in a predictable and systematic fashion. FAFLP analysis was broadly congruent with IS6110 typing for those strains with multiple IS6110 copies. It was also able to resolve an epidemiologically unlinked group of strains with only one copy of IS6110; up to 10% of clinical isolates may fall into this category. For certain epidemiological investigations, it was concluded that a combination of FAFLP and IS6110 typing would give higher resolution than would either alone. FAFLP data were digital, precise, reproducible, and suitable for rapid electronic dissemination, manipulation, interlaboratory comparison, and storage in national or international epidemiological databases. Because FAFLP samples and analyzes base substitution across the genome as a whole, FAFLP could generate new information about the microevolution of the M. tuberculosis complex.

To estimate the risk and prevalence of Mycobacterium tuberculosis (MTB) infection and tuberculosis (TB) incidence, prevalence, and mortality, including disease attributable to human immunodeficiency virus (HIV), for 212 countries in 1997.

The present study is based on notified cases of tuberculosis (TB) in the National tbc. register 1972-1996. A decline in Tb incidence was seen from 1972 and until the mid-1980's. Subsequently the trend has reversed due to an increasing number of TB cases in foreigners. In 1996, 60% of all cases of TB in Denmark were found in foreigners reflecting the rising number of refugees and their families arriving in Denmark from highly endemic areas, mainly Somalia. Among native Danes the TB incidence fell from 14 per 100,000 in 1972 to 4 per 100,000 in the 1980's and stabilized at this very low level. The unchanged incidence in Danes covers a falling incidence in the older and a rising incidence in the younger and middle-aged adult population, mainly in the capital. Approximately half of the cases occur in high-risk groups. The TB-epidemic is close to elimination in the indigenous Danish population, but the disease is maintained at a low level probably due to increased patient and doctor delay and resulting microepidemics primarily in high-risk populations.

G. Qader, M.K. Seddiq, K.M. Rashid, A. Hami, M.H. Akhgar, B. Ahma, S. Drye, A. Somj, M. Meles, P.G. Suarez

Bruce D Agins, Daniel J Ikeda, Michael J A Reid, Eric Goosby, Madhukar Pai, Adithya Cattamanchi

Tuberculosis is preventable, treatable, and curable, yet it has the highest mortality rate of infectious diseases worldwide. Over the past decade, services to prevent, screen, diagnose, and treat tuberculosis have been developed and scaled up globally, but progress to end the disease as a public health threat has been slow, particularly in low-income and middle-income countries. In these settings, low-quality tuberculosis prevention, diagnostic, and treatment services frustrate efforts to translate use of existing tools, approaches, and treatment regimens into improved individual and public health outcomes.

Abstract Background Although the incidence of tuberculosis (TB) has decreased in South Korea, the mortality rate remains high. TB mortality is a key indicator for TB control interventions. The purpose of this study was to assess early and TB-related mortality during anti-TB treatment and describe the associated clinical characteristics. Methods A multicenter cross-sectional study was performed across South Korea. Patients with pulmonary TB who died during anti-TB treatment and whose records were submitted to the national TB surveillance system between 2015 and 2017 were enrolled. All TB deaths were categorized based on cause (TB-related or non-TB-related) and timing (early or late). We identified statistical associations using the frequency table, chi-square test, and binary logistic regression. Results Of 5595 notifiable mortality cases, 3735 patients with pulmonary TB were included in the analysis. There were 2541 (68.0%) male patients, and 2935 (78.6%) mortality cases were observed in patients older than 65 years. There were 944 (25.3%) cases of TB-related death and 2545 (68.1%) cases of early death. Of all cases, 187 (5.0%) patients were diagnosed post-mortem and 38 (1.0%) patients died on the first day of treatment. Low body mass index (adjusted odds ratio (aOR) = 1.26; 95% confidence interval (CI) = 1.08–1.48), no reported illness (aOR = 1.36; 95% CI = 1.10–1.68), bilateral disease on chest X-ray (aOR = 1.30; 95% CI = 1.11–1.52), and positive acid-fast bacilli smear result (aOR = 1.30; 95% CI = 1.11–1.52) were significantly associated with early death, as well as TB-related death. Acute respiratory failure was the most common mode of non-TB-related death. Malignancy was associated with both late (aOR = 0.71; 95% CI = 0.59–0.89) and non-TB-related (aOR = 0.35; 95% CI = 0.26–0.46) death. Conclusions A high proportion of TB death was observed in elderly patients and attributed to non-TB-related causes. Many TB-related deaths occurred during the intensive phase, particularly within the first month. Further studies identifying risk factors for different causes of TB death at different phases of anti-TB treatment are warranted for early targeted intervention in order to reduce TB mortality.…

Abstract Background Isoniazid resistant tuberculosis is the most prevalent type of resistance in Swaziland and over two-thirds of the isoniazid resistant tuberculosis patients are tuberculosis and human immunodeficiency virus co-infected. The study aimed to determine risk factors associated with isoniazid resistant tuberculosis among human immunodeficiency virus positive patients in Swaziland. Methods This was a case-control study conducted in nine healthcare facilities across Swaziland. Cases were patients with isoniazid resistant tuberculosis (including 78 patients with isoniazid mono-resistant tuberculosis, 42 with polydrug-resistant tuberculosis, and 77 with multidrug-resistant tuberculosis). Controls were presumed drug-susceptible tuberculosis patients (n = 203). Multinomial logistic regression was used to determine related factors. Results The median time lag from diagnosis to tuberculosis treatment initiation was 50 days for isoniazid mono or poly drug-resistant tuberculosis, 17 days for multidrug-resistant tuberculosis compared to 1 day for drug-susceptible tuberculosis patients. History of previous tuberculosis treatment was positively associated with either isoniazid mono or poly drug-resistant tuberculosis (OR = 7.91, 95% CI: 4.14–15.11) and multidrug-resistant tuberculosis (OR = 12.20, 95% CI: 6.07–24.54). Isoniazid mono or poly resistant tuberculosis patients were more likely to be from rural areas (OR = 2.05, 95% CI: 1.23–3.32) and current heavy alcohol drinkers compared to the drug-susceptible tuberculosis group. Multi drug-resistant tuberculosis patients were more likely to be non-adherent to tuberculosis treatment compared to drug-susceptible tuberculosis group (OR = 3.01, 95% CI: 1.56–5.82). Conclusion To prevent and control isoniazid resistant tuberculosis among HIV-positive patients in Swaziland, the tuberculosis program should strengthen the use of rapid diagnostic tests, detect resistance early, promptly initiate supervised tuberculosis treatment and decentralize quality tuberculosis services to the rural areas. Adherence to tuberculosis treatment should be improved.…

Xiao, S., Guo, H., Weiner, W. S., Maddox, C., Mao, C., Gunosewoyo, H., Pelly, S., White, E. L., Rasmussen, L., Schoenen, F. J., Aube, J., Bishai, W. R., Lun, S.

The sub-optimal effectiveness of β-lactam antibiotics against Mycobacterium tuberculosis has hindered the utility of this compound class for tuberculosis treatment. However, treatment with a second-line regimen containing meropenem plus a β-lactamase inhibitor was found to be encouraging in an extensively drug-resistant tuberculosis case study (M.C. Payen et al, Int J Tuberc Lung Dis 2012. 16:558–60). We hypothesized that the innate resistance of M. tuberculosis to β-lactams is mediated in part by the non-canonical accessory proteins that are not considered as the classical targets of β-lactams, and that small-molecule inhibitors of these accessory targets may sensitize M. tuberculosis to β-lactams. In this study, we screened an NIH small-molecule library for their abilities to sensitize M. tuberculosis to meropenem. We identified six hit compounds that belong to either N-arylindole or benzothiophene chemotype. Verification studies confirmed the synthetic lethality phenotype for three of the N-arylindoles and one benzothiophene derivative. The latter was demonstrated to be partially bioavailable via oral administration in mouse. Structure-activity relationship studies on both structural classes identified analogs with potent antitubercular activity, alone or in combination with meropenem. Transcriptional profiling revealed that the oxidoreductases, the MmpL family proteins, and the 27-kDa benzoquinone methyltransferase could be the targets of the N-arylindole potentiator. In conclusion, our compound-compound synthetic lethality screening revealed novel small molecules that are capable of potentiating the action of meropenem, presumably via inhibition of the innate resistance conferred by the β-lactams accessory proteins. β-lactam compound-compound synthetic lethality may be an alternate approach for drug-resistant tuberculosis.…

Tanner, L., Evans, J. C., Seldon, R., Jordaan, A., Warner, D. F., Haynes, R. K., Parkinson, C. J., Wiesner, L.

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), remains a leading infectious killer globally, demanding the urgent development of faster-acting drugs with novel mechanisms of action. Riminophenazines such as clofazimine are clinically efficacious against both drug-susceptible and drug-resistant strains of Mtb. We determined the in vitro anti-Mtb activities; absorption, distribution, metabolism, and excretion properties; and in vivo mouse pharmacokinetics of a series of structurally related phenoxazines. One of these, PhX1, displayed promising drug-like properties and potent in vitro efficacy, supporting its further investigation in an Mtb-infected animal model.…

Riou C, Jhilmeet N, Rangaka M, et al.

AbstractThe reconstitution of Mycobacterium tuberculosis (Mtb)-antigen-specific CD4 T cells in a cohort of HIV-infected persons starting antiretroviral treatment (ART) in high TB endemic area is described. Restoration of the antigen-specific CD4 T cell subsets mirrored the overall CD4 T cell compartment. Activation (assessed by HLA-DR expression) decreased during ART but remained elevated compared to HIV-uninfected persons. Despite known Mtb sensitisation determined by IGRA, 12/23 participants had no Mtb-specific CD4 T cells detectable by flow cytometry, combined with overall elevated T cell activation and memory differentiation, suggesting heightened turnover. Our data suggest early ART initiation to maintain polyfunctional immune memory responses.

Zelner J.

Weiner J, 3rd, Domaszewska T, Donkor S, et al.

AbstractBackgroundStrategies to prevent Mycobacterium tuberculosis (Mtb) infection are urgently required. This study aimed to identify correlates of protection against early Mtb infection.MethodsTwo groups of Mtb-exposed contacts of TB patients were recruited and classified according to their Mtb infection status using Tuberculin skin test (TST; cohort 1) or QuantiFERON (QFT; cohort 2. A negative reading at baseline with a positive reading at follow-up classified TST or QFT converters and a negative reading at both time-points classified TST or QFT non-converters. RNA-sequencing, Mtb proteome arrays (IgG and IgA) and metabolic profiling was performed.ResultsSeveral genes were found to be differentially expressed at baseline between converters and non-converters prior to any signs of infection by current tests. Gene set enrichment analysis revealed a distinct B cell gene signature in TST non-converters compared to converters. When infection status was defined by QFT, enrichment of Type I IFN and antiviral gene signatures was observed. A remarkable AUC of 1.0 was observed for IgA reactivity to Rv0134 and an AUC of 0.98 for IgA reactivity to both Rv0629c and Rv2188c. IgG reactivity to Rv3223c resulted in an AUC of 0.96 and was markedly higher compared to TST non-converters. We also identified several differences in metabolite profiles, including changes in biomarkers of inflammation, fatty acid metabolism, and bile acids. Pantothenate (Vitamin B5) was significantly increased in TST non-converters compared to converters at baseline (q=0.0060).ConclusionsThese data provide new insights into the early protective response to Mtb infection and possible avenues to interfere with Mtb infection including Vitamin B5 supplementation.

Abstract Background Nucleic acid amplification tests (NAAT) have been used as a diagnostic tool for pulmonary tuberculosis (PTB) in Taiwan for many years. In accordance with Taiwanese legislation, health care personnel are required to notify the Centers for Disease Control and Prevention (CDC) in case of suspected PTB. This study aimed to investigate the impact of NAAT(Gen-Probe) on the notification system for PTB and anti-tuberculosis treatments in Taiwan. Methods A retrospective study on the impact of NAAT (Enhanced Amplified Mycobacterium tuberculosis Direct Test [E-MTD], Gen-Probe, San Diego, CA, USA) [NAAT(Gen-Probe)] was carried out at Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation from March 2011 to December 2017. During the study period, microscopic acid-fast-bacilli smears and mycobacterial cultures were available for PTB diagnosis. NAAT(Gen-Probe) was first introduced at the hospital in January 2014 for use as a diagnostic method for PTB. Positive sputum culture was considered as the gold standard for PTB diagnosis. We excluded clinically-diagnosed PTB cases. Results When NAAT(Gen-Probe) was applied, the rate of error notification to CDC decreased from 64.3 to 7.0% (P 

Abstract Background Multidrug-resistant tuberculosis (MDR-TB) in HIV endemic settings is a major threat to public health. MDR-TB is a substantial and underreported problem in Sub-Saharan Africa (SSA), with recognised cases projected to increase with advancement in diagnostic technology. There is paucity of review evidence on treatment outcomes and antiretroviral (ART) uptake among MDR-TB patients with HIV in SSA. To address this gap a review of treatment outcomes in HIV patients co-infected with MDR-TB in the SSA region was undertaken. Methods Three databases (Medline, Web of Science, CINHAL), Union on Lung Heath conference proceedings and grey literature were searched for publications between January 2004 and May 2018. Records were assessed for eligibility and data extracted. Random effect meta-analysis was conducted using STATA and Cochrane’s review manager. Results A total of 271 publications were identified of which nine fulfilled the inclusion criteria. Data was collected from 3368 MDR-TB and HIV co-infected patients from four SSA countries; South Africa (6), Lesotho (1), Botswana (1) and Ethiopia (1). The most common outcome was cure (34.9% cured in the pooled analysis), this was followed by death (18.1% in pooled analysis). ART uptake was high, at 83% in the pooled analysis. Cure ranged from 28.6 to 54.7% among patients on ART and from 22.2 to 57.7%  among those not on ART medication. MDR-TB and HIV co-infected patients were less likely to be successfully treated than HIV negative MDR-TB patients (Risk Ratio = 0.87, 95% CI 0.97, 0.96). Conclusion Treatment outcomes for MDR-TB and HIV co-infected patients do not vary widely from those reported globally. However, treatment success was lower among HIV positive MDR-TB patients compared to HIV negative MDR-TB patients. Prompt antiretroviral initiation and interventions to improve treatment adherence are necessary.…

Michael S. Niederman, Girish Balachandran Nair, Ulrich Matt, Susanne Herold, Kelly Pennington, Kristina Crothers, Matthew Cummings, Neil W. Schluger

American Journal of Respiratory and Critical Care Medicine, Volume 200, Issue 4, Page 414-422, August 15, 2019. …

Katharina Kranzer, Barbara Kalsdorf, Jan Heyckendorf, Sönke Andres, Matthias Merker, Sabine Hofmann-Thiel, Guido V. Bloemberg, Harald Hoffmann, Stefan Niemann, Christoph Lange, Florian P. Maurer

American Journal of Respiratory and Critical Care Medicine, Volume 200, Issue 4, Page 514-515, August 15, 2019. …

Wu Q, Hossfeld A, Gerberick A, et al.

AbstractBackgroundTuberculosis (TB) is caused by Mycobacterium tuberculosis (M.tb). Recent emergence of MDR-TB strains seriously threatens TB control and prevention. However the role of macrophage multi drug resistance gene MDR1 on intracellular M.tb survival during anti-TB drug treatment is not known.MethodsWe employed the human monocyte derived macrophages to study the role of M.tb on regulation of MDR1 and drug resistance.ResultsWe discovered that M.tb infection increases the expression of macrophage MDR-1 to extrude various chemical substances, including TB drugs, resulting in enhanced survival of intracellular M.tb. The pathway of regulation involves M.tb infection of macrophages, and suppression of the heat shock factor1 (HSF1), a transcriptional regulator of MDR1 through the up regulation of miR-431. Notably, nonpathogenic Mycobacterium smegmatis did not increase MDR1 expression, indicating active secretion of virulence factor(s) in pathogenic M.tb contributing to this phenotype. Finally, inhibition of MDR1 improves antibiotic-mediated killing of M.tb.ConclusionWe report a novel finding that M.tb up regulates MDR1 during infection, which limits the exposure of M.tb to sub-lethal concentrations of antimicrobials. This condition promotes M.tb survival and potentially enhances the emergence of resistant variants.

Abstract Background Despite rapid scale up of antiretroviral therapy (ART), Tuberculosis (TB) remains the commonest opportunistic infection and cause of death among HIV infected individuals in resource limited settings like India. Incidence of TB in individuals on ART in private healthcare sector in India is infrequently studied. Methods This retrospective cohort study conducted between 1st March 2009 and 1st March 2017 aimed to evaluate rate of incident TB in individuals initiated on ART at 3 private sector ART clinics in Pune, India. Individuals more than 12 years of age with ART duration of atleast 6 months were included. Patients were classified as having prevalent TB if they had a TB episode within the year prior to ART initiation or if they developed TB within 6 months of starting ART. Individuals who were diagnosed with TB after 6 months of starting ART were classified as incident TB cases. A recurrent episode of TB after treatment completion or cure of prevalent TB was also regarded as incident TB. Patients were classified as definitive TB if Mycobacterium tuberculosis was grown in culture from a biological sample or a positive rapid molecular test. Patients were classified as probable TB if there was radiologic evidence of TB in absence of confirmatory culture or PCR. Results 1904 patients with a median duration of follow up on ART of 57 (IQR = 32.0, 84.0) months were included. Of these, 182 developed incident TB (22% definitive TB, 38% recurrent cases). TB incidence at 6–12 months, 13–24 months, 25–60 months and > 60 months of ART was 24.32, 5.46, 2.54 and 0.75 cases per 100 person years respectively. Current time updated CD4 count

Wang, Q., Modongo, C., Allender, C., Engelthaler, D. M., Warren, R. M., Zetola, N. M., Shin, S. S.

Multidrug-resistant tuberculosis is an alarming threat and targeted deep sequencing (DS) may be an effective method for rapid identification of drug-resistant profiles, including detection of heteroresistance. We evaluated sensitivity and specificity of targeted DS vs. phenotypic drug susceptibility testing (pDST) among patients starting first-line anti-TB therapy in Botswana. Overall, we found high concordance between DS and pDST. Lower sensitivity of DS, which targets established high-confidence resistance variants, was observed for detecting isoniazid-resistance among HIV-infected patients.…

Hussein Chalhoub, Sarah V. Harding, Paul M. Tulkens, Françoise Van Bambeke

Burkholderia pseudomallei, Yersinia pestis, and Francisella tularensis are facultative intracellular bacteria causing life-threatening infections. We have (i) compared the activity of finafloxacin (fluoroquinolone in development showing improved activity at acidic pH) with that of ciprofloxacin, levofloxacin, and imipenem against the extracellular and intracellular (THP-1 monocytes) forms of infection by attenuated surrogates of these species (B. thailandensis, Y. pseudotuberculosis, F. philomiragia) (ii) assessed finafloxacin cellular pharmacokinetics (accumulation, distribution, efflux).

Abstract Background In recent years, studies on the diagnostic accuracy of in-house real-time PCR (hRT-PCR) assay for the detection of Mycobacterium tuberculosis (Mtb) have been reported with unignorable discrepancies. To assess the overall accuracy of the hRT-PCR assay for Mtb diagnosis in different samples for individuals with active pulmonary and extra-pulmonary Mtb infection, a systematic review and meta-analysis were performed. Methods The PUBMED, EMBASE, Web of Science, and Cochrane databases were searched up to June 2017 for eligible studies that estimated diagnostic sensitivity and specificity with the hRT-PCR assay in respiratory and non-respiratory samples in pulmonary and extra-pulmonary Mtb infection patients, with Mtb culture as the reference standard. Bivariate random effect models were used to provide pooled estimation of diagnostic accuracy. Further, subgroup and meta-regression analyses were performed to explore sources of heterogeneity. The risk of bias was assessed by the QUADAS-2 tool. Results Of the 3589 candidate studies, 18 eligible studies met our inclusion criteria. Compared to Mtb culture data, the pooled sensitivity and specificity were 0.96 and 0.92, respectively. The diagnostic odds ratio (DOR) was 192.96 (95% CI 68.46, 543.90), and the area under the summary ROC curve (AUC) was 0.9791. There was significant heterogeneity in sensitivity and specificity among the enrolled studies (p 

Min-Chul Kim, Sung-Cheol Yun, Sang-Oh Lee, Sang-Ho Choi, Yang Soo Kim, Jun Hee Woo and Sung-Han Kim

Abstract. Statins have anti-inflammatory and immunomodulatory properties that may affect the development of tuberculosis (TB). We assessed the association between use of statins and the risk of active TB by propensity score matching. Furthermore, we analyzed the impact of statins on TB in patients according to the presence or absence of diabetes. The study was based on the National Health Insurance database and its subset database of the “medical checkup” population of South Korea. We identified 123,468 statin users and 439,546 non–statin users. After propensity score matching, 28,018 statin users and the same number of non–statin users were finally analyzed. The development of active TB was monitored in these matched pairs over 11 years. In the propensity score–matching analysis, the number of active TB cases was 30 in 30,303 person-years (0.99 per 1,000 person-years; 95% CI, 0.64–1.35) in the statin users and 235 in 167,857 person-years (1.40 per 1,000 person-years; 95% CI, 1.22–1.58) in the non–statin users. Statin users had a significantly lower risk of TB than non–statin users: hazard ratio (HR) 0.67 (95% CI, 0.46–0.98) (P = 0.04). A subgroup analysis showed that statin use reduced the risk of TB in subjects without diabetes, but not in patients with diabetes: HRs were, respectively, 0.28 (95% CI, 0.13–0.60) (P = 0.001) and 1.05 (95% CI, 0.66–1.67) (P = 0.84). There is epidemiologic evidence that statin decreases the risk of active TB. However, the protective effect of statins against TB is attenuated by diabetes.…

Park, Y., Ahn, Y.-M., Jonnala, S., Oh, S., Fisher, J. M., Goodwin, M. B., loerger, T. R., Via, L. E., Bayliss, T., Green, S. R., Ray, P. C., Wyatt, P. G., Barry, C. E., Boshoff, H. I.

Mechanisms of magnesium homeostasis in Mycobacterium tuberculosis are poorly understood. Herein we describe the characterization of a pyrimidinetrione amide scaffold that disrupts magnesium homeostasis in the pathogen by direct binding to the CorA Mg2+/Co2+ transporter. Mutations in domains of CorA that are predicted to regulate the pore opening in response to Mg2+ ions conferred resistance to this scaffold. The pyrimidinetrione amides were cidal against the pathogen under both actively replicating as well as non-replicating conditions in vitro and were efficacious against the organism during macrophage infection. However, the compound lacked efficacy in infected mice possibly due to limited exposure. Our results indicate that inhibition of Mg2+ homeostasis by CorA is an attractive target for tuberculosis drug discovery and encourage identification of improved CorA inhibitors.…