Treatment Of Tuberculosis Infection Research Articles

RETRACTED: A microporous roust La(III)-organic framework for cyanosilylation reactions and treatment effect on tuberculosis by activating the PI3K-AKT signaling pathway in immune cells

Abstract A novel metal–organic framework (MOF) based on La(III) ions as the metal nodes with the formula of {[LaL(H2O)2]·H2O}n (1) was prepared under the hydrothermal conditions by using 1-(4-carboxybenzyl)-1H-pyrazole-3,5-dicarboxylic acid (H3L) as the three connected ligand. Complex 1 shows excellent water stabilities as well as solvent-free conditions, and reveals microporous nature as established via the CO2 sorption at 195 K. The resulting activated 1a shows good heterogeneous catalytic activity for the cyanosilylation of the aromatic aldehydes, which could be reused for at least four times without losing the framework integrality. Furthermore, anti-bacterial activity of the compound was deep studied within the research. Firstly, the RT-PCR was utilized to determine pi3k and akt relative expression in macrophages after tuberculosis (TB) infection and compound treatment. And the ELISA detection was enrolled for IFN-γ and TNF-α detection. Next, the production of active nitrogen mediator (RNIs) was measured by the RNIs detection kit. Finally, compound protective function in vivo was assessed within the TB infected mice model, the bacterial colony numbers in the lung tissue was determined by diluting ager plate method, the pathological injury of lung was observed by HE staining. In this research, we aim to reveal a new candidate for the TB infection treatment.

Anti-tuberculous Effects of Statin Therapy: A Review of Literature

Tuberculosis (TB) is a chronic infection caused by Mycobacterium tuberculosis (M. TB). It is transmitted through respiratory droplets. Increased cholesterol level is a predisposing factor for TB. M. TB uses cholesterol in the host macrophage membranes to bind and enter the macrophages. Statins are the drugs that are prescribed to hyperlipidemic patients to maintain their lipid levels in the normal range, thereby reducing the risk of stroke and cardiovascular events. Moreover, statins aid in reducing the levels of cholesterol in human macrophages. Therefore, a reduction in the membrane cholesterol minimizes the entry of TB pathogen inside macrophages. Furthermore, acting as vitamin D3 analogs and positively influencing pancreatic beta-cell function in a chronic diabetic state, statins minimize the occurrence of M. TB infection among diabetic population as well. This review aims to provide a comprehensive detail of all in vitro, in vivo, and retrospective studies that investigated the effects of statins in relation to the prevention or treatment of TB infection.

Development and Evaluation of a Reconstitutable Dry Suspension Containing Isoniazid for Flexible Pediatric Dosing.

Tuberculosis (TB) is a major cause of childhood death. Despite the startling statistics, it is neglected globally as evidenced by treatment and clinical care schemes, mostly extrapolated from studies in adults. The objective of this study was to formulate and evaluate a reconstitutable dry suspension (RDS) containing isoniazid, a first-line anti-tubercular agent used in the treatment and prevention of TB infection in both children and adults. The RDS formulation was prepared by direct dispersion emulsification of an aqueous-lipid particulate interphase coupled with lyophilization and dry milling. The RDS appeared as a cream-white free-flowing powder with a semi-crystalline and microparticulate nature. Isoniazid release was characterized with an initial burst up to 5 minutes followed by a cumulative release of 67.88% ± 1.88% (pH 1.2), 60.18% ± 3.33% (pH 6.8), and 49.36% ± 2.83% (pH 7.4) over 2 h. An extended release at pH 7.4 and 100% drug liberation was achieved within 300 min. The generated release profile best fitted the zero order kinetics (R2 = 0.976). RDS was re-dispersible and remained stable in the dried and reconstituted states over 4 months and 11 days respectively, under common storage conditions.

Advancement of GyrB Inhibitors for Treatment of Infections Caused by Mycobacterium tuberculosis and Non-tuberculous Mycobacteria.

The prospect of ever increasing antibiotic resistance eroding currently available treatment options for bacterial infections underscores the need to continue to identify new antibiotics, preferably those that act on novel targets or with novel mechanisms of action. Bacterial gyrase B subunit (GyrB), an essential component of bacterial gyrase required for successful DNA replication, represents such a target. We describe recent examples of GyrB inhibitors and point out their potential utility for treatment of mycobacterial diseases caused by Mycobacterium tuberculosis (TB) and non-tuberculous mycobacteria (NTM). Current therapeutic options for these diseases are often suboptimal due to resistance to current standard of care antibiotics. A future GyrB inhibitor-based antibiotic could offer a new and effective addition to the armamentarium for treatment of mycobacterial diseases and possibly for infections caused by other bacterial pathogens. One GyrB inhibitor, SPR720, has recently completed a first-in-human clinical trial and is in clinical development for the treatment of NTM and TB infections.

Strategies to reach and motivate migrant communities at high risk for TB to participate in a latent tuberculosis infection screening program: a community-engaged, mixed methods study among Eritreans

BackgroundIn the Netherlands, migrant populations with a high tuberculosis (TB) incidence are an important target group for TB prevention. However, there is a lack of insight in effective community-engaged strategies to reach and motivate these migrants to participate in latent TB infection (LTBI) screening and treatment programs.MethodsIn cocreation with Eritrean key figures and TB staff, we designed and executed six strategies to reach and motivate Eritrean communities to participate in LTBI programs, in five regions in the Netherlands. We registered participation in LTBI education and screening, and LTBI treatment uptake and completion. We used semi-structured group and individual interviews with Eritrean participants, key figures, and TB staff to identify facilitators and barriers.ResultsUptake of LTBI education (13–75%) and consequent screening (10–124%) varied between strategies. LTBI screening uptake > 100% resulted from educated participants motivating others to participate in screening. Two strategies, using face-to-face promotion and targeting smaller groups, were the most successful. The program resulted in high LTBI treatment initiation and completion (both 97%). Reported program barriers included: competing priorities in the target group, perceived good health, poor risk perception, and scepticism towards the program purpose. TB staff perceived the program as useful but demanding in terms of human resources.ConclusionsEritrean migrant communities can be successfully reached and motivated for LTBI screening and treatment programs, when sufficient (human) resources are in place and community members, well-connected to and trusted by the community, are engaged in the design and execution of the program.

Model-Based Assessment of Variability in Isoniazid Pharmacokinetics and Metabolism in Patients Co-Infected With Tuberculosis and HIV: Implications for a Novel Dosing Strategy.

Tuberculosis is the most common cause of death in HIV-infected patients. Isoniazid is used as a first-line drug to treat tuberculosis infection. However, variability in isoniazid pharmacokinetics can result in hepatotoxicity or treatment failure. Determination of clinical factors affecting isoniazid pharmacokinetics and metabolic pathways in HIV co-infected patients is therefore critical. Plasma levels of isoniazid, acetyl-isoniazid, and isonicotinic acid from 63 patients co-infected with tuberculosis and HIV were analyzed by liquid chromatography with tandem mass spectrometry followed by nonlinear mixed-effects modeling. Patients were genotyped to determine acetylator status. Patients were either on concomitant efavirenz-based antiretroviral therapy or HIV treatment naïve. Clearances of isoniazid were 1.3-fold and 2.3-fold higher in intermediate and rapid acetylators, respectively, compared with slow acetylators. Patients on concomitant efavirenz-based antiretroviral therapy had 64% and 80% higher population predicted clearances of acetyl-isoniazid and isonicotinic acid, respectively, compared with patients who were HIV treatment naïve. Both sex and CD4 cell count affected the bioavailability of isoniazid. Variability in isoniazid exposure could be reduced by dose adaptions based on acetylator type and sex in addition to the currently used weight bands. A novel dosing strategy that has the potential to reduce isoniazid-related toxicity and treatment failure is presented.

Dynamic changes of interferon gamma release assay results with latent tuberculosis infection treatment

ObjectivesUsing QuantiFERON-TB Gold In-Tube (QFT-GIT) for monitoring tuberculosis (TB) and latent TB infection treatment effect is controversial. The present study aimed to evaluate the dynamic changes of interferon gamma (IFN-γ) levels along with latent TB infection treatment via a randomized controlled study. MethodsA total of 910 participants treated with 8 weeks of once-weekly rifapentine plus isoniazid (group A), 890 treated with 6 weeks of twice-weekly rifapentine plus isoniazid (group B) and 818 untreated controls (group C) were followed for 2 years to track active TB development. QFT-GIT tests were repeated three times for all groups: before treatment (T0), at completion of treatment (T1) and 3 months after completion of treatment (T2). ResultsSimilar rates of persistent QFT-GIT reversion were observed in groups A (19.0%, 173/910), B (18.5%, 165/890) and C (20.7%, 169/818) (p 0.512). The dynamic changes of IFN-γ levels were not statistically significant among the three groups. In treated participants, individuals with higher baseline IFN-γ levels showed increased TB occurrence (1.0%, 9/896) compared to those with lower baseline levels (0.2%, 2/904) (p 0.037). A similar but statistically insignificant trend was also observed in untreated controls (1.8% (7/400) vs. 0.5% (2/418), p 0.100). When TB cases were matched with non-TB cases on baseline IFN-γ levels, no significant differences were found with respect to the dynamic changes in IFN-γ levels with time, regardless of whether they received treatment. ConclusionsQFT-GIT reversion or decreased IFN-γ levels should not be used for monitoring host response to latent TB infection treatment.

Latent tuberculosis infection screening and treatment in congregate settings (TB FREE COREA): protocol for a prospective observational study in Korea

IntroductionSouth Korea regards tuberculosis (TB) incidence in congregate settings as a serious problem. To this end, systematic latent TB infection (LTBI) diagnosis and treatment were provided to approximately 1.2 million...

Effect of ventilation improvement during a tuberculosis outbreak in underventilated university buildings.

The role of ventilation in preventing tuberculosis (TB) transmission has been widely proposed in infection control guidance. However, conclusive evidence is lacking. Modeling suggested the threshold of ventilation rate to reduce effective reproductive ratio (ratio between new secondary infectious cases and source cases) of TB to below 1 is corresponding to a carbon dioxide (CO2) level of 1000 parts per million (ppm). Here, we measured the effect of improving ventilation rate on a TB outbreak involving 27 TB cases and 1665 contacts in underventilated university buildings. Ventilation engineering decreased the maximum CO2 levels from 3204 ± 50 ppm to 591‐603 ppm. Thereafter, the secondary attack rate of new contacts in university dropped to zero (mean follow‐up duration: 5.9 years). Exposure to source TB cases under CO2 >1000 ppm indoor environment was a significant risk factor for contacts to become new infectious TB cases (P < .001). After adjusting for effects of contact investigation and latent TB infection treatment, improving ventilation rate to levels with CO2 <1000 ppm was independently associated with a 97% decrease (95% CI: 50%‐99.9%) in the incidence of TB among contacts. These results show that maintaining adequate indoor ventilation could be a highly effective strategy for controlling TB outbreaks.

Recent Advances in the Treatment of Tuberculosis Infection

Tuberculosis (TB) is a centuries old disease which is quite prevalent throughout the world caused by Mycobacterium tuberculosis. This disease kills more people every year than other infectious diseases despite the existence of an effective treatment. This treatment has been available since 1940, which means its existence spans over more than fifty years now. The development of antimicrobial resistance is one of the challenges facing the struggle to stem the tide of this lethal outbreak. The wider range of this disease is linked to few functional factors which include lack of public awareness, patient monitoring and follow-up. The prevalence of great progress and advancement in medical technology and research calls for greater efforts. This review article considers trends prevailing all around the globe in the ailments from a comprehensive perspective.

1882. Tuberculosis in the Department of Veterans Affairs: Missed Opportunities for Prevention

BackgroundUS and global elimination of tuberculosis (TB) is an important goal. Despite decreased incidence, CDC predicts elimination of TB in the US will not occur in the 21st century without improved detection and treatment of latent TB infection (LTBI). We describe the current burden of active TB infection and LTBI testing and treatment among patients within the Department of Veterans Affairs (VA).MethodsUsing the 2009 CDC case definition for laboratory-confirmed TB, we queried VA data sources from January 2010 to December 2018 for Mycobacterium tuberculosis detected via culture or nucleic acid amplification test (NAAT) from specimens from all body sites. For all TB patients, we extracted demographic, ICD-9 and ICD-10 risk factor, and LTBI testing and treatment data.ResultsBetween 2010 and 2018, the average annual incidence of TB was 1.7 cases per 100,000 unique users of VA care (ranging from a high of 2.8 in 2010 to low of 0.8 in 2018). For 899 identified cases, demographic factors associated with highest TB rates were age between 45 and 64, Asian race, and residence in District of Columbia (Table 1). The most frequently occurring risk factors were substance abuse, diabetes, and homelessness. Of 90 patients with susceptibility documentation, 14 (15%) had resistance to 1 or more anti-TB drug (1 with multi-drug-resistant TB). Fifteen patients (1.7%) died within 7 days of their TB diagnosis; in all but 2 cases, TB was the primary cause of death (Table 2). Figure 1 depicts screening and treatment for LTBI among patients with TB. Only 228/899 (25.4%) TB patients had LTBI screening ≥ 3 months prior to diagnosis. Of the 347 TB patients never screened for LTBI, 264 (76%) had ≥ 1 documented TB risk factor. Among 228 patients screened for LTBI >3 months prior to active disease, 69 (30%) screened positive; however, only 24 (35%) had LTBI treatment initiated.ConclusionAlthough rates of TB infection are decreasing, VHA providers would benefit from education on recognizing patients with risk factors which place them at high risk for TB who should be screened for LTBI. CDC recommends preventive treatment of patients who screen positive for LTBI, and provider collaboration with local public health departments to provide directly observed therapy in cases where adherence may be in question. Disclosures All Authors: No reported Disclosures.

Long-term Prognosis of Tuberculosis Infection and Disease in Swedish Children

Reports of the outcome of treatment of tuberculosis (TB) disease and infection (TBI) in children are scarce. Since 2010, we routinely use interferon-gamma release assays in addition to clinical history for the exclusion of TBI, although the safety of this approach has been questioned. We present the frequency of recurrent TB or progression to TB after treatment for TB disease or TB infection, respectively, and progression to disease in children considered TB uninfected at our pediatric TB clinic. We included 4707 patients from 1990 to 2017. At the initial assessment, 96 (2.0%) had previously received TB treatment, 253 (5.4%) had TB disease, 1625 (35%) had TBI and 2733 (58%) children were considered uninfected. Patients were passively followed at our clinic, at the adult TB clinics in Stockholm and at the Swedish national TB registry. During a median follow-up time of 8.4 years, we found 36 cases of TB disease, with true relapses in 3/243 (1.2%) successfully treated TB patients. Preventive treatment of TBI reduced the risk of progression to TB by 85%, from 4.3% (15/349) to 0.6% (8/1262). In children considered uninfected, the risk of later developing TB was 0.07% (2/2733). The effectiveness of TB management was acceptable. Our routine procedures for the exclusion of TBI appear safe.

An Overview on the Potential Antimycobacterial Agents Targeting Serine/Threonine Protein Kinases from Mycobacterium tuberculosis.

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), still remains an urgent global health issue, mainly due to the emergence of multi-drug resistant strains. Therefore, there is a pressing need to develop novel and more efficient drugs to control the disease. In this context, targeting the pathogen virulence factors, and particularly signal mechanisms, seems to be a promising approach. An important transmembrane signaling system in Mtb is represented by receptor-type Serine/ Threonine protein kinases (STPKs). Mtb has 11 different STPKs, two of them, PknA and PknB, are essential. By contrast PknG and PknH are involved in Mtb virulence and adaptation, and are fundamental for the pathogen growth in infection models. Therefore, STPKs represent a very interesting group of pharmacological targets in M. tuberculosis. In this work, the principal inhibitors of the mycobacterial STPKs will be presented and discussed. In particular, medicinal chemistry efforts have been focused on discovering new antimycobacterial compounds, targeting three of these kinases, namely PknA, PknB and PknG. Generally, the inhibitory effect on these enzymes do not correlate with a significant antimycobacterial action in whole-cell assays. However, compounds with activity in the low micromolar range have been obtained, demonstrating that targeting Mtb STPKs could be a new promising strategy for the development of drugs to treat TB infections.

Mycobacterium tuberculosis as a Cause of Periprosthetic Joint Infection After Total Knee Arthroplasty: A Review of the Literature.

Total knee arthroplasty (TKA) has become one of the most popular and successful surgeries performed in the world. Infection remains one of the most dreaded complications following TKA, and while rare, tuberculosis as a microbial etiology remains difficult to both diagnose and treat. A review was performed using PubMed, the Cochrane Database of Systematic Reviews, and EMBASE to identify literature pertinent to Mycobacterium tuberculosis infection, TKAs, periprosthetic joint infections, and any combination of the three. The diagnosis of tuberculosis infection after TKA is difficult due to nonspecific signs and symptoms and diagnostic testing. The surgeon should use a comprehensive approach to incorporate the patient’s medical history, physical exam, and blood and imaging diagnostics. Among these, bacterial culture and histopathological examination remain the gold standard of diagnosis, but Polymerase chain reaction technology offers another, more sensitive and rapid option. Treatment strategy centers around on the cornerstone of anti-tuberculosis medical therapy and surgery depending on the clinical situation. While there is a lack of primary literature and standardized guidelines for the diagnosis and treatment of tuberculosis infection after TKA, the overarching principles of the treatment of tuberculosis and the treatment of the periprosthetic infection can be implemented together. There remains room for original research and improvements in both diagnostic testing and treatment.

Moving toward Tuberculosis Elimination. Critical Issues for Research in Diagnostics and Therapeutics for Tuberculosis Infection.

Tuberculosis (TB) has surpassed HIV to become the leading infectious killer of adults globally, causing almost 2 million deaths annually. Although this airborne disease has been treatable since 1948, global rates of TB have dropped less than two percent per year; an estimated 10 million incident cases continue to occur annually, including one million in children. While transmission of active disease is an important driver of the epidemic, the seedbed that feeds the epidemic is the more than two billion people estimated to have TB infection, five to ten percent of whom will progress to active disease during their lifetime. While any successful strategy aimed at TB elimination needs to address this reservoir of TB infection worldwide, much remains to be understood about host and pathogen factors that can be used to identify increased risk for progression to disease, and intervened upon to prevent progression from occurring. The Division of AIDS of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA, and the Harvard Medical School Center for Global Health Delivery-Dubai convened a group of scientists and stakeholders on September 28 and 29, 2017, to address knowledge gaps that affect our ability to rapidly find and treat individuals infected with Mycobacterium tuberculosis who are most likely to progress to active disease. The meeting identified a number of efforts underway to address this important gap in the collective ability to stop the global TB epidemic. Here, we review and outline the priority areas for research, diagnosis and treatment of TB infection that emerged from the meeting (Table 1), building on recent reviews in this area.

Time-Lapse Atomic Force Microscopy Reveals New End Take Off (Neto) Dynamics in Mycobacteria

Tuberculosis is a lung infection caused by Mycobacterium tuberculosis. One third of the world population is thought to be infected. Antibiotic treatment with antibiotics lasts 6 month, which is difficult to achieve in low-income countries. The uncommon ability of tuberculosis bacteria to persist during long periods is linked to various factors, one of which potentially being cell growth asymmetry. However, growth symmetry or asymmetry of mycobacteria remains a controversial topic as opposing descriptions have been reported in the literature. Observing bacterial growth at the single cell level is inherently challenging due to the diffraction limit of optical microscopes and the small size of the cells. We built a new dedicated platform for long-term, correlated Atomic Force Microscopy (AFM) and fluorescence microscopy and obtained time-lapses of bacterial growth at an unprecedented resolution. Surprisingly, the AFM high-resolution time-lapses did not match any of the two previously reported models of pure symmetry and pure asymmetry. Mycobacterial pole growth dynamics was rather an intermediate between the two, reminiscent of the well-known “new end take off” mechanism for fission yeast. Using AFM nanomanipulation we show that growth asymmetry is not a physical occlusion phenomenon, but is inherent to mycobacterial growth. Finally, using fluorescent photoconversion microscopy we identify biomolecular mechanisms linked to growth asymmetry, which in the future could be used to develop novel treatments for tuberculosis infection.

Demanding an end to tuberculosis: treatment of tuberculosis infection among persons living with and without HIV.

More than two billion people are infected with Mycobacterium tuberculosis and few of them are ever offered therapy in spite of such treatment being associated with reduced rates of morbidity and mortality. This article reviews the current recommendations on the diagnosis and treatment of TB infection (or what is commonly referred to as 'prophylaxis' or 'preventive therapy' of latent TB) and discusses barriers to implementation that have led to low demand for this life-saving therapeutic intervention. Treatment of infection for both TB and drug-resistant TB is well tolerated and effective, and several new, shorter regimens - including rfiapenitine-based regimens of 1 month and 12 weeks duration - have been shown to be effective. Not all persons infected with TB go on to develop disease and the risk is the highest in the first 2 years after infection. Given this, additional work is needed to better identify those at the highest risk of developing active TB. Practitioners should offer newer, shorter regimens to persons who are infected with TB and at high risk of developing disease, including people living with HIV and household contacts of people living with TB who are age 5 years and under. This includes individuals who have been exposed to drug-resistant forms of disease. Socioeconomic risk factors may play a key role in the development of TB disease and should also be addressed.

Properties of Therapeutic Deep Eutectic Solvents of l-Arginine and Ethambutol for Tuberculosis Treatment.

The treatment for tuberculosis infection usually involves a prolonged regimen of multiple antibacterial drugs, which might lead to various secondary effects. For preventing drug resistance and side-effects of anti-tuberculosis drugs, new methods for improving the bioavailability of APIs were investigated. The strategy proposed consists of the preparation of therapeutic deep eutectic solvents (THEDES), that incorporate l-arginine and ethambutol. The eutectic mixtures were prepared by mixing the components at a certain molar ratio, until a clear liquid solution was formed. The prepared mixtures were characterized by differential scanning calorimetry (DSC), polarized optical microscopy (POM) and nuclear magnetic resonance spectroscopy (1H and 13C-NMR). The solubility and permeability of the drugs when they are in the THEDES form was evaluated at 37 °C, in phosphate buffered saline (PBS). Solubility studies showed an increase of the solubility of ethambutol when incorporated in the eutectic system. The cytotoxicity was evaluated using a model cell line (Caco-2), comparing the cytotoxicity of the API incorporated in the eutectic system. We observed that the cell viability in the THEDES was affected by the presence of citric acid, and higher cytotoxicity values were observed. Nonetheless, these findings do not compromise the possibility to use these systems as new delivery systems for ethambutol and arginine.

Determinants and characteristics of tuberculosis in liver transplant recipients

Solid organ transplant (SOT) recipients have increased risk of tuberculosis (TB). We aimed to investigate the prevalence and features of TB in liver transplant (LT) recipients at our transplantation canter. All patients who underwent LT between January 2004 and December 2013 and whose data were accessible were included in the study. Demographic features, tuberculin skin test (TST) results, and TB prevalence were recorded. Characteristics of LT recipients who developed TB were evaluated. A total of 403 patients underwent LT during this period. Mean age was 47.27 ± 11.04 years; 280 (69.47%) were males. The TST was administered to 108 (25.91%) and the QuantiFERON-TB test to 1 patient. TST positivity was determined in 28 (25.93%). Latent TB infection (LTBI) treatment was not recommended to any of the LT candidates. In the posttransplant period, 5 patients (1.24%) developed TB over a median duration of 14 (min: 7, max: 84) months, 2 of whom were found to have had LTBI in the pretransplant period. The prevalence of TB in LT recipients at our center was similar to that in the current literature. LTBI screening, including risk factor assessment and TST/QuantiFERON-TB testing, is necessary in the early diagnostic workup for TB in LT recipients.

Treatment of Multidrug-Resistant Tuberculosis Infection in Children.

Treatment of Multidrug-Resistant Tuberculosis Infection in Children.