Drug-susceptible Tuberculosis Research Articles

Effectiveness and safety of available preventive tuberculosis treatment regimens for children and adolescents: protocol for a systematic review and network meta-analysis

IntroductionApproximately 5%–10% of individuals with untreated latent tuberculosis infection (LTBI) will progress to active tuberculosis (TB). Children are at a higher risk for progression to TB disease than adults. Isoniazid...

Hidden loss to follow-up among tuberculosis patients managed by public–private mix institutions in South Korea

In South Korea, public–private mix (PPM) was launched in 2011. This retrospective cohort study sought to determine the rate of loss to follow-up (LTFU) among drug-susceptible tuberculosis (DS-TB) patients in all nationwide PPM institutions, and the risk factors for LTFU. National notification data for DS-TB patients diagnosed between August 2011 and July 2014 in PPM institutions were analysed. Determination of LTFU included detection of instances where patients were transferred out, but when they did not attend at other TB centres in the following two months. Univariable and multivariable competing risk models were used to determine risk factors for LTFU. 73,046 patients with 78,485 records were enrolled. Nominally, 3426 (4.4%) of records were LTFU. However, after linking the multiple records in each patient, the percentage of LTFU was 12.3% (9004/73,046). Risk factors for LTFU were: being foreign-born (3.13 (95% CI 2.77–3.53)), prior LTFU (2.31 (2.06–2.59)) and greater distance between the patient’s home and the TB centre (4.27 (4.03–4.53)). ‘Transfer-out’ was a risk factor in patients managed by treatment centres close to home (1.65 (1.49–1.83)), but protective for those attending centres further (0.77 (0.66–0.89)) or far-away (0.52 (0.46–0.59)) from home. By considering the complete picture of a patient’s interactions with healthcare, we identified a much higher level of LTFU than previously documented. This has implications for how outcomes of treatment are reported and argues for a joined-up national approach for the management and surveillance of TB patients, in nations with similar healthcare systems.

Global trends, regional differences and age distribution for the incidence of HIV and tuberculosis co-infection from 1990 to 2019: results from the global burden of disease study 2019

Background People living with human immunodeficiency virus (HIV) are more likely to develop tuberculosis (TB), and their co-infection (HIV-TB) increases the risk of death. We aimed to describe the global trends, regional differences and age distribution of HIV-TB. Methods Annual new cases, age-standardized incidence rates (ASRs) and age-specific incidence rates with 95% uncertainty intervals (UIs) of HIV-infected drug-susceptible tuberculosis (HIV-DS-TB), HIV-infected multidrug-resistant tuberculosis without extensive drug resistance (HIV-MDR-TB) and HIV-infected extensively drug-resistant tuberculosis (HIV-XDR-TB) during 1990–2019 were collected from the Global Burden of Disease Study 2019. To reveal the trends of HIV-TB by region and age, the percentage change of new cases and estimated annual percentage change (EAPC) of ASRs were calculated. Results The ASR of HIV-XDR-TB increased significantly by an average of 14.77% (95% CI: 11.05%–18.62%) per year during 1990–2019 worldwide, while the ASRs of HIV-DS-TB and HIV-MDR-TB decreased after 2005. HIV-XDR-TB was a great threat to Eastern Europe for the largest number of new cases (792, 95% UI: 487–1167) and the highest ASR (0.34 per 100,000 population, 95% UI: 0.21–0.50). In addition, Oceania had the largest rise in ASRs of HIV-MDR-TB (EAPC = 22.56, 95% CI: 18.62–26.64) and HIV-XDR-TB (EAPC = 32.95, 95% CI: 27.90–38.20) during 1990–2019. Recently, age-specific incidence rates of HIV-XDR-TB increased in all age groups, especially in the 50–69 age groups among high, low-middle and low Socio-Demographic Index regions. Additionally, the proportion of patients aged <15 years was nearly 10% of new cases in sub-Saharan Africa in 2019, which was higher than in other regions. Conclusions HIV-infected drug-resistant TB is common in Oceania and Eastern Europe. Moreover, HIV-XDR-TB among elderly people became increasingly prevalent. In the future, the collaboration of management for HIV and TB should be intensified in Oceania and Eastern Europe, and more concerns need to be paid in elderly people.

Drug-susceptible tuberculosis treatment outcomes and its associated factors among inmates in prison settings in Bauchi State, Nigeria, 2014-2018.

Tuberculosis (TB) is a contagious disease and its transmissibility is increased in congregate settings. TB incidence rates are five-to-fifty times higher among inmates in prison settings than the general population which has a direct impact on the outcome of TB treatment. There is paucity of information on TB treatment outcomes and its associated factors in Nigerian prison settings. We therefore assessed TB treatment outcomes among inmates in prison settings in Bauchi State, Nigeria. We conducted a retrospective data analysis of inmates with TB in the five-main prison settings in Bauchi State. We extracted socio-demographic, clinical and treatment outcome characteristics from TB treatment register of inmates treated for TB between January 2014 and December 2018, using a checklist. We calculated the TB treatment success rate (TSR) and explored the relationship between the TSR and socio-demographic and clinical characteristics. Related variables were modelled in multiple logistic regression to identify factors associated with TSR at 5% level of significance. All 216 inmates were male with mean (SD) age of 37.6±11.4 years. Seventy-six (35.2%) were cured, 61 (28.2%) completed treatment, 65 (30.1%) were transferred-out without evaluation and 14 (6.5%) died. Overall TSR was 72.9%. Factors associated with successful-treatment-outcome were age, weight, imprisonment duration and HIV status. The results indicate that inmates who are 20–29 years are at least ten times more likely to be successful (aOR = 10.5; 95%CI: 3.2–35.1) than inmates who are 55 years or older. Inmates who are 30–39 years are about four times more likely to be successful than inmates who are 55 years or older (aOR = 4.2; 95% CI: 1.3–13.1). In general, the younger an inmate, the more successful he is. Inmates with pretreatment-weight; 55kg or more are 13 times more likely to be successful (aOR = 13.3; 95%CI: 6.0–29.6) than inmates with weight below 55kg. Inmates who were imprisoned for 2 years or less are about three times more likely to be successful (aOR = 2.6; 95%CI: 1.3–5.4) than inmates who were imprisoned for more than 2 years and HIV negative inmates were three times more likely to succeed (aOR = 3.3; 95%CI:1.4–7.8) than inmates who were HIV positive. We recommended that to improve TB treatment outcome among inmates; age, duration-of-imprisonment, weight and TB/HIV co-infection should be the major consideration during pretreatment, psychological and nutritional counselling and a tracking-system be developed by the authority to follow-up inmates transferred-out to other health facilities to ensure they complete the treatment and outcomes evaluated.

The circulating immune complexes as a biomarker of the endogenous intoxication in pulmonary tuberculosis

The aim of the study was to establish the concentration of the circulating immune complexes (CICs) with high (CIC 2,5%), medium (CIC 4,2%) and low (CIC 8.0%) molecular weights in patients with pulmonary tuberculosis (TB) as biomarkers of the endogenous intoxication and the degree of severity. We investigated 56 patients diagnosed with pulmonary TB and 36 healthy persons (control group). The patients were assigned to 2 groups: the study group 1 (I SG) included 29 patients in which the test established the drug susceptible TB and in the study group 2 (II SG) that included 27 patients with multidrug-resistant TB (MDR-TB). The inclusion criteria were: primary detected pulmonary TB, age older than 18 years, confirmed drug susceptibility (I SG) and confirmed MDR-TB (II SG). The exclusion criteria were: anti-TB treatment in anamnesis, extrapulmonary TB, age below 18 years, HIV infection, severe somatic diseases. The method of CIC quantification consisted in placing 50 l serum into 3 tubes followed by adding 100 l borate buffer and solution of 2.5%, 4.2% and 8.0% polyethylene glycol. The tubes were incubated 15 minutes at 25C and the optical density was assessed at the wavelength 340 nm. The results were compared with the general blood count and leucocital intoxication index Kalf-Kalif (LIIKK) as an alternative method to identify endogenous intoxication. As the results of the research we established that the peak level was observed for CICs with high and medium molecular weight, wrereas less pronounced it was for CICs with low molecular weight. The high severity of the endogenous intoxication predominated in the I SG and middle degree in the IISG, without achieving the statistical significance. LIIKK was lower in study groups comparing with the control healthy subjects due to increased count of eosinophils.

Clinical standards for drug-susceptible pulmonary TB.

SUMMARYBACKGROUND:The aim of these clinical standards is to provide guidance on ‘best practice’ for diagnosis, treatment and management of drug-susceptible pulmonary TB (PTB).METHODS:A panel of 54 global experts in the field of TB care, public health, microbiology, and pharmacology were identified; 46 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all 46 participants.RESULTS:Seven clinical standards were defined: Standard 1, all patients (adult or child) who have symptoms and signs compatible with PTB should undergo investigations to reach a diagnosis; Standard 2, adequate bacteriological tests should be conducted to exclude drug-resistant TB; Standard 3, an appropriate regimen recommended by WHO and national guidelines for the treatment of PTB should be identified; Standard 4, health education and counselling should be provided for each patient starting treatment; Standard 5, treatment monitoring should be conducted to assess adherence, follow patient progress, identify and manage adverse events, and detect development of resistance; Standard 6, a recommended series of patient examinations should be performed at the end of treatment; Standard 7, necessary public health actions should be conducted for each patient. We also identified priorities for future research into PTB.CONCLUSION:These consensus-based clinical standards will help to improve patient care by guiding clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment for PTB.

Treatment outcomes and associated factors among patients with multidrug-resistant tuberculosis in Ashanti Region, Ghana: a retrospective, cross-sectional study

ObjectiveAlthough several studies have assessed treatment outcomes of drug-susceptible tuberculosis (TB) in Ghana, very little has been done in the area of multidrug-resistant TB (MDR-TB). The aim of this study...

Tuberculostearic Acid-Containing Phosphatidylinositols as Markers of Bacterial Burden in Tuberculosis.

One-fourth of the global human population is estimated to be infected with strains of the Mycobacterium tuberculosis complex (MTBC), the causative agent of tuberculosis (TB). Using lipidomic approaches, we show that tuberculostearic acid (TSA)-containing phosphatidylinositols (PIs) are molecular markers for infection with clinically relevant MTBC strains and signify bacterial burden. For the most abundant lipid marker, detection limits of ∼102 colony forming units (CFUs) and ∼103 CFUs for bacterial and cell culture systems were determined, respectively. We developed a targeted lipid assay, which can be performed within a day including sample preparation—roughly 30-fold faster than in conventional methods based on bacterial culture. This indirect and culture-free detection approach allowed us to determine pathogen loads in infected murine macrophages, human neutrophils, and murine lung tissue. These marker lipids inferred from mycobacterial PIs were found in higher levels in peripheral blood mononuclear cells of TB patients compared to healthy individuals. Moreover, in a small cohort of drug-susceptible TB patients, elevated levels of these molecular markers were detected at the start of therapy and declined upon successful anti-TB treatment. Thus, the concentration of TSA-containing PIs can be used as a correlate for the mycobacterial burden in experimental models and in vitro systems and may prospectively also provide a clinically relevant tool to monitor TB severity.

Barriers faced by patients in the diagnosis of multidrug-resistant tuberculosis in Brazil.

ABSTRACTOBJECTIVE To understand patients’ narratives about the barriers they faced in the diagnosis and treatment of multidrug-resistant tuberculosis, and their consequences in Rio de Janeiro State, Brazil.METHODS This is a qualitative cross-sectional study with non-probabilistic sampling. A theoretical saturation criterion was considered for composing the number of interviewees. Semi-structured interviews were conducted from August to December 2019 with 31 patients undergoing treatment for multidrug-resistant tuberculosis at an outpatient referral center in Rio de Janeiro. Data were transcribed and processed with the aid of the NVIVO software. Interviews were evaluated by content analysis, and their themes, cross-referenced with participants’ characterization data.RESULTS Our main findings were: a) participants show a high proportion of primary drug resistance, b) patients experience delays in the diagnosis and effective treatment of multidrug-resistant tuberculosis ; c) healthcare providers fail to value or seek the diagnosis of drug-resistant tuberculosis, thus beginning the inadequate treatment for drug-susceptible tuberculosis, d) primary health units show low report rates of active case-finding and contact monitoring, and e) patients show poor knowledge about the disease.CONCLUSIONS We need to improve referral systems, and access to the diagnosis and effective treatment of multidrug-resistant tuberculosis; conduct an active investigation of contacts; intensify the training of healthcare providers, in collaboration with medical and nursing schools, in both public and private systems; and promote campaigns to educate the population on tuberculosis signs and symptoms.

Recurrent pneumothorax in a human immunodeficiency virus-positive patient with multidrug-resistant tuberculosis: a rare case of bronchopleural fistula: a case report

BackgroundHuman immunodeficiency virus/tuberculosis coinfections have amplified the multidrug-resistant tuberculosis pandemic in many countries in Sub-Saharan Africa, and multidrug-resistant tuberculosis has become a major public health threat. There is a paucity of data on severe complications of multidrug-resistant tuberculosis in the context of human immunodeficiency virus coinfection despite the increasing prevalence of multidrug-resistant tuberculosis/human immunodeficiency virus coinfection and the complexity of multidrug-resistant tuberculosis treatment. This report describes a rare case of complicated multidrug-resistant tuberculosis in a human immunodeficiency virus-positive individual.Case presentationA 39-year-old human immunodeficiency virus-positive Ugandan male on anti-retroviral therapy for 6 years, who had recently completed treatment for drug-susceptible tuberculosis from a public hospital, presented to the tuberculosis ward of Mulago National Referral Hospital with worsening respiratory symptoms including persistent cough with purulent sputum, fever, right chest pain, and shortness of breath. On admission, a diagnosis of drug-resistant tuberculosis was made following a positive sputum Xpert MTB/Rif test with rifampicin resistance. Culture-based tuberculosis tests and line probe assay confirmed multidrug-resistant tuberculosis. The patient was given multidrug-resistant tuberculosis treatment that included bedaquiline, isoniazid, prothionamide, clofazimine, ethambutol, levofloxacin, and pyrazinamide and switched to second-line anti-retroviral therapy that included tenofovir/lamivudine/lopinavir/ritonavir. Chest X-ray revealed a hydro-pneumothorax, following which a chest tube was inserted. With persistent bubbling from the chest tube weeks later and a check chest X-ray that showed increasing pleural airspace (pneumothorax) and appearance of a new air–fluid level, chest computed tomography scan was performed, revealing a bronchopleural fistula in the right hemithorax. The computed tomography scan also revealed a pyo-pneumothorax and lung collapse involving the right middle and lower lobes as well as a thick-walled cavity in the right upper lobe. With the pulmonary complications, particularly the recurrent pneumothorax, bronchopleural fistula, and empyema thoracis, cardiothoracic surgeons were involved, who managed the patient conservatively and maintained the chest tube. The patient continued to be ill with recurrent pneumothorax despite the chest tube, until relatives opted for discharge against medical advice.ConclusionsComplicated human immunodeficiency virus-related multidrug-resistant tuberculosis is not uncommon in settings of high human immunodeficiency virus/tuberculosis prevalence and is often associated with significant morbidity and mortality. Early diagnosis and treatment of multidrug-resistant tuberculosis, with rigorous monitoring for human immunodeficiency virus-positive individuals, is necessary to prevent debilitating complications.

Utilization of Bedaquiline among Drug Resistant-Tuberculosis patients

Background: India has one of the highest burdens of drug-resistant tuberculosis (DR-TB) globally. The persistent spread of DR-TB is one of the most daunting problems the world is witnessing. Current regimens for DR-TB are complicated, lengthy, and expensive compared to those used to treat drug-susceptible TB, leaving patients with much less effective treatment options. Bedaquiline (BDQ) is a novel drug that has strong bactericidal and sterilizing activities against Mycobacterium tuberculosis. The WHO recommends BDQ for the treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB). The objective of the study is to evaluate the utilization of BDQ among drug-resistant tuberculosis patients in a tertiary care hospital. Materials and Methods: A hospital-based retrospective observational study was conducted at the Government General and Chest Hospital in Erragadda, Hyderabad, Telangana, where suspected Tuberculosis cases are referred. All patients who were prescribed bedaquiline regimen were included in the study. Results: 23 Patients were prescribed BDQ during the study duration. The mean age of the patients was 41± 14.24 years and most of them were in the age group of 21-40 years. 15 patients (65.21%) were Males. Diabetes mellitus was the most common co-morbid condition. Two patients (8.70%) successfully completed the treatment, 3 patients (13.04%) died during treatment and 18 patients (78.26%) were still receiving the treatment during the study period. Adverse effects were documented in 12 patients and the most common adverse events were related to gastrointestinal tract. Conclusion: Bedaquiline containing regimen was well tolerated with less number of manageable adverse effects.

Assessment of Adverse Drug Events, Their Risk Factors, and Management Among Patients Treated for Multidrug-Resistant TB: A Prospective Cohort Study From Pakistan.

Background: Multidrug-resistant tuberculosis (MDR-TB) is a growing public health problem. Treatment regimens used against MDR-TB are costly, prolonged, and associated with more side effects as compared with the drug-susceptible tuberculosis. This study was framed to determine the incidence of adverse drug events, risk factors, and their management in MDR-TB patients. Methods: This prospective follow-up cohort study was conducted at the site of programmatic management of drug-resistant TB located at the Pakistan Institute of Medical Sciences, Islamabad. All patients, irrespective of their age, gender, and ethnicity, were included in the study. Adverse drug events were observed in patients at different time points during the study. Patients enrolled for the treatment from January 2018 were prospectively followed till December 2020 up to their end treatment outcomes. Results: Out of 126 MDR-TB patients enrolled for treatment, 116 met the inclusion criteria and were included in the final analysis. Most patients (50.9%) were between 18 and 45 years of age. A minimum of one adverse event was experienced by (50.9%) patients. Of all the adverse events, gastrointestinal disorders were more frequent (47.4%), followed by arthralgia (28.4%) and psychiatric disturbance (20.6%). Furthermore, multivariate analysis showed a significant association with the incidence of adverse events in patients with age group above 60 years (odds ratio (OR) 4.50; 95% CI 1.05-19.2), active smokers (OR 4.20; 95% CI 1.31-13.4), delayed reporting to the TB center (OR 4.03; 95% CI 1.34-12.1), and treatment without bedaquiline regime (OR 3.54; 95% CI 1.23-10.1). Most of the patients (94.6%), counseled by the pharmacist, were found to be satisfied with the information provided and looked for more pharmacist counseling opportunities in the management of MDR-TB. Conclusion: Current findings recommend that ADEs might be well managed by timely identification and reporting. Bedaquiline coupled with other active medications lowered the chance of ADEs in MDR-TB patients. Elderly patients, active smoking behavior, and those who have a delay in the treatment initiation are more prone to ADEs. Clinical pharmacist’s contribution to TB control programs may help caregivers and patients concerning the rational use of medication, early detection, and management of ADEs.

Systematic TB screening using WHO radiograph categorisation and care outcomes.

BACKGROUND: An appropriate screening approach and quality care are crucial for TB programmes in prisons. This study assessed crude TB prevalence, accuracy of the screening methods and treatment outcomes in a Thai prison.METHOD: This was a retrospective analysis of findings from a mass CXR screening conducted among incarcerated people in July 2017. Digital radiographs were forwarded to a chest physician to read and classify in six categories using WHO categorisation. CXR with significant Categories 3 (no active TB), 4 (not TB), 5 (TB) and 6 (unclassified) abnormalities were eligible for sputum microscopy and Xpert testing. A screening questionnaire locally known as TB-P1 was used for case management. Patients with TB received care in the prison.RESULTS: Of 2,382 prisoners screened, 6.3% had CXR Categories 3-6. Crude prevalence of bacteriologically confirmed TB was 1,133/100,000 (95% CI 748.3-1644.9). The screening´s sensitivity was 96.3% based on CXR Category 5 and 22.2% using TB-P1. Treatment success rates in drug-susceptible and drug-resistant TB patients were respectively 66.7% and 33.3%.CONCLUSION: The WHO radiograph categorisation could be used to screen for TB in the field and may be applied in artificial intelligence for interpreting CXR; screening questionnaires are not effective in prison environments. Nonetheless, low treatment success rates remained a challenge.

Prospects of contezolid (MRX-I) against multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis.

Tuberculosis has become a great global public health threat. Compared with drug-susceptible tuberculosis (TB), the treatment regimens for multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) involve more severe adverse events and poorer treatment outcomes. Linezolid (LZD) is the first oxazolidinones used for TB. Thanks to its potent activity against Mycobacterium tuberculosis, LZD has become one of the key agents in the regimens against MDR/XDR-TB. However, this drug may cause intolerability and other adverse events. Contezolid, another novel oxazolidinone, can also inhibit M. tuberculosis, still with fewer adverse effects compared with LZD. This paper is to prospect the potentials of contezolid in the treatment of MDR/XDR-TB, with focus on its efficacy and possible adverse effects.

Post-tuberculosis lung disease: a comparison of Brazilian, Italian, and Mexican cohorts.

ABSTRACTObjective:To evaluate lung function in a cohort of patients with a history of pulmonary tuberculosis in Brazil, as well as to evaluate the decline in lung function over time and compare it with that observed in similar cohorts in Mexico and Italy. Methods:The three cohorts were compared in terms of age, smoking status, pulmonary function test results, six-minute walk test results, and arterial blood gas results. In the Brazilian cohort, pulmonary function test results, six-minute walk test results, and arterial blood gas results right after the end of tuberculosis treatment were compared with those obtained at the end of the follow-up period. Results:The three cohorts were very different regarding pulmonary function test results. The most common ventilatory patterns in the Brazilian, Italian, and Mexican cohorts were an obstructive pattern, a mixed pattern, and a normal pattern (in 58 patients [50.9%], in 18 patients [41.9%], and in 26 patients [44.1%], respectively). Only 2 multidrug-resistant tuberculosis cases were included in the Brazilian cohort, whereas, in the Mexican cohort, 27 cases were included (45.8%). Mean PaO2 and mean SaO2 were lower in the Mexican cohort than in the Brazilian cohort (p < 0.0001 and p < 0.002 for PaO2 and SaO2, respectively). In the Brazilian cohort, almost all functional parameters deteriorated over time. Conclusions:This study reinforces the importance of early and effective treatment of drug-susceptible tuberculosis patients, because multidrug-resistant tuberculosis increases lung damage. When patients complete their tuberculosis treatment, they should be evaluated as early as possible, and, if post-tuberculosis lung disease is diagnosed, they should be managed and offered pulmonary rehabilitation because there is evidence that it is effective in these patients.

Time Trend Analysis of Tuberculosis Treatment While Using Digital Adherence Technologies-An Individual Patient Data Meta-Analysis of Eleven Projects across Ten High Tuberculosis-Burden Countries.

Worldwide, non-adherence to tuberculosis (TB) treatment is problematic. Digital adherence technologies (DATs) offer a person-centered approach to support and monitor treatment. We explored adherence over time while using DATs. We conducted a meta-analysis on anonymized longitudinal adherence data for drug-susceptible (DS) TB (n = 4515) and drug-resistant (DR) TB (n = 473) populations from 11 DAT projects. Using Tobit regression, we assessed adherence for six months of treatment across sex, age, project enrolment phase, DAT-type, health care facility (HCF), and project. We found that DATs recorded high levels of adherence throughout treatment: 80% to 71% of DS-TB patients had ≥90% adherence in month 1 and 6, respectively, and 73% to 75% for DR-TB patients. Adherence increased between month 1 and 2 (DS-TB and DR-TB populations), then decreased (DS-TB). Males displayed lower adherence and steeper decreases than females (DS-TB). DS-TB patients aged 15–34 years compared to those >50 years displayed steeper decreases. Adherence was correlated within HCFs and differed between projects. TB treatment adherence decreased over time and differed between subgroups, suggesting that over time, some patients are at risk for non-adherence. The real-time monitoring of medication adherence using DATs provides opportunities for health care workers to identify patients who need greater levels of adherence support.

Cost-effectiveness of a medication event monitoring system for tuberculosis management in Morocco.

BackgroundDigital health technologies have been used to enhance adherence to TB medication, but the cost-effectiveness remains unclear.MethodsWe used the real data from the study conducted from April 2014 to December 2020 in Morocco using a smart pillbox with a web-based medication monitoring system, called Medication Event Monitoring Systems (MEMS). Cost-effectiveness was evaluated using a decision analysis model including Markov model for Multi-drug resistant (MDR) TB from the health system perspective. The primary outcome was the incremental cost-effectiveness ratio (ICER) per disability adjusted life-year (DALY) averted. Two-way sensitive analysis was done for the treatment success rate between MEMS and standard of care.ResultsThe average total per-patient health system costs for treating a new TB patient under MEMS versus standard of care were $398.70 and $155.70, respectively. The MEMS strategy would reduce the number of drug-susceptible TB cases by 0.17 and MDR-TB cases by 0.01 per patient over five years. The ICER of MEMS was $434/DALY averted relative to standard of care, and was most susceptible to the TB treatment success rate of both strategies followed by the managing cost of MEMS.ConclusionMEMS is considered cost-effective for managing infectious active TB in Morocco.

Evaluation of a novel inhibitor of aspartate semialdehyde dehydrogenase as a potent antitubercular agent against Mycobacterium tuberculosis.

The in vitro activity of IMB-XMA0038, a novel inhibitor targeting Mycobacterial tuberculosis (Mtb) aspartate semialdehyde dehydrogenase, was evaluated. Minimum inhibitory concentrations (MICs) of IMB-XMA0038 were against 20 Mtb isolates, including H37Rv (ATCC 27294), ten clinical pan-sensitive isolates, and nine clinical multidrug-resistant (MDR) isolates. In addition, minimum bactericidal concentrations (MBCs) were also determined against the H37Rv and 6 MDR isolates (the background information is same as above in order). A model was generated to evaluate IMB-XMA0038 activity against dormant Mtb. The post-antibiotic effect (PAE), an important indicator of antimicrobial drug dosing schedules to obtain efficacy, was determined based on time required for regrowth of Mtb to 50% of the OD600max value after treatment with various concentrations of IMB-XMA0038 and INH. In addition, interactions between IMB-XMA0038 and other anti-tuberculosis drugs, measured using a checkerboard assay, revealed that IMB-XMA0038 MICs of 0.5-1 μg/mL could be achieved in combinations. Synergistic effects were observed for IMB-XMA0038 when used together with almost all other anti-tuberculosis drugs against most Mtb isolates. IMB-XMA0038 exhibited greater activity than rifampin against Mtb under hypoxic conditions, as reflected by CFU decreases of 1.1-log-unit versus 0.8-log-unit, respectively, for IMB-XMA0038 and rifampin concentrations of 4 × MIC. IMB-XMA0038-induced PAEs (9, 10, 11 days) were comparable to INH PAEs (10, 11, 12 days). These findings suggest that addition of IMB-XMA0038 to current therapeutic regimens could be useful to improve the efficacy of treatments for drug-resistant and drug-susceptible TB.

Effects of Bedaquiline on Antimicrobial Activity and Cytokine Secretion of Macrophages Infected with Multidrug-Resistant Mycobacterium tuberculosis Strains.

Background Bedaquiline (Bdq) exerts bactericidal effects against drug-susceptible and drug-resistant Mycobacterium tuberculosis strains, including multidrug-resistant M. tuberculosis strains (MDR-MTBs). However, few reported investigations exist regarding Bdq effects on MDR-MTBs-infected macrophages activities and cytokine secretion. Here, Bdq bactericidal activities against MDR-MTBs and related cellular immune mechanisms were explored. Methods Macrophages infected with MDR-MTBs or H37Rv received Bdq treatments (4 h/8 h/24 h/48 h) at 1 × the minimum inhibitory concentration (1 × MIC), 10 × MIC and 20 × MIC. Intracellular colony-forming units (CFUs) and culture supernatant IL-12/23 p40, TNF-α, IL-6, and IL-10 were determined using the Luminex® 200TM system. Normally distributed continuous data (mean ± standard deviation) were analyzed using t-test or F-test (SPSS 25.0, P < 0.05 deemed statistically significant). Results (1) 100% of Bdq-treated macrophages (all doses applied over 4–48 h) survived with 0% inhibition of proliferation observed. (2) Intracellular CFUs of Bdq-treated MDR-MTBs-infected macrophages decreased over 4–48 h of treatment, were lower than preadministration and control CFUs, decreased with increasing Bdq dose, and resembled H37Rv-infected group CFUs (48 h). (3) For MDR-MTBs-infected macrophages (various Bdq doses), IL-12/23 p40 levels resembled preadministration group levels and exceeded controls (4 h); TNF-α levels exceeded preadministration group levels (24 h/48 h) and controls (24 h); IL-12/23 p40 and TNF-α levels resembled H37Rv-infected group levels (4 h/8 h/24 h/48 h); IL-6 levels exceeded preadministration and H37Rv-infected group levels (24 h/48 h) and controls (24 h); IL-10 levels resembled preadministration and H37Rv-infected group levels (4 h/8 h/24 h/48 h) and were lower than controls (24 h/48 h); IL-12/23 p40 and IL-10 levels remained unchanged as intracellular CFUs changed, with IL-12/23 p40 levels exceeding controls (4 h) and IL-10 levels remaining lower than controls (24 h/48 h); TNF-α and IL-6 levels increased as intracellular CFUs decreased (24 h/48 h) and exceed controls (24 h). Conclusion Bdq was strongly bactericidal against intracellular MDR-MTBs and H37Rv in a time-dependent, concentration-dependent manner. Bdq potentially exerted immunomodulatory effects by inducing high-level Th1 cytokine expression (IL-12/23 p40, TNF-α) and low-level Th2 cytokine expression (IL-10).

Comparison of Disability-Adjusted Life Years (DALYs) and Economic Burden on People With Drug-Susceptible Tuberculosis and Multidrug-Resistant Tuberculosis in Korea.

In the future, tuberculosis (TB) will place a heavy burden on the aging population in Korea. To prepare for this crisis, it is important to analyze the disease burden trend of drug-susceptible tuberculosis (DS-TB) and multidrug-resistant tuberculosis (MDR-TB). Measuring disability-adjusted life years (DALYs) and economic burden on MDR-TB patients can help reduce the incidence of TB. Accordingly, in this study, we measured the DALYs and economic burden on DS-TB and MDR-TB patients in 2014–2017 using a combination of National Health Insurance claims data, Annual Report on the Notified TB data, and Statistics Korea's mortality data. The incidence-based DALY approach implemented involved the summation of years of life lost and years lived with disability. For measuring economic burden, direct and indirect costs incurred by patients were totaled. From 2014 to 2017, DALYs per 100,000 people with DS-TB were 56, 49, 46, and 40, respectively, and DALYs per 100,000 people with MDR-TB were 3, 2, 2, and 2, respectively. The economic burden for the DS-TB population from 2014 to 2017 was $143.89 million, $136.36 million, $122.85 million, and $116.62 million, respectively, while that for MDR-TB was $413.44 million, $380.25 million, $376.46 million and $408.14 million, respectively. The results showed a decreasing trend in DALYs and economic burden for DS-TB, whereas MDR-TB was still found to be burdensome without a specific trend. With respect to age, the economic burden for both DS-TB and MDR-TB was higher among men than among women till ≤ 79 years. Conversely, the economic burden for women aged ≥80 years was higher as compared to their male counterparts. In conclusion, the incidence and spread of TB in all areas of society must be suppressed through intensive management of MDR-TB in the older population. We hope that the national TB management project will proceed efficiently when the infectious disease management system is biased to one side due to the COVID-19 pandemic.