Impact of pyrazinamide usage on serious adverse events in elderly tuberculosis patients: A multicenter cohort study.

BACKGROUND: Pyrazinamide (PZA) usage has been associated with adverse drug reactions, prompting its avoidance in treating elderly tuberculosis (TB) patients. This study aims to examine whether the administration of PZA is associated with poor outcomes during TB treatment among elderly individuals. METHODS: A retrospective analysis was undertaken on data collected from a prospective cohort conducted between July 2019 and June 2023, which involved tuberculosis patients from 18 institutions across the Republic of Korea. The study aimed to assess the impact of PZA on the incidence of serious adverse events (SAEs), medication interruptions, and becoming loss to follow-up (LTFU) during standard short courses of TB treatment in elderly (≥65 years old) patients. RESULTS: PZA was administered to 356 of 390 elderly patients (91.3%), and 98 of the 390 (25.1%) experienced SAEs. Treatment success was significantly lower in patients not treated with PZA compared to those who received PZA (64.7% vs 89.9%, p < 0.001). The incidence of SAEs, medication interruption, or LTFU was higher in patients not given PZA compared those who received PZA (52.9% vs. 27.2%, p = 0.002). A multivariate logistic regression analysis, factoring in covariates such as age, comorbidities, and baseline laboratory data, revealed that PZA was not a risk factor for SAEs, medication interruption, or LTFU in TB treatment (odds ratio [OR] 0.457, 95% confidence interval [CI] 0.201-1.041). CONCLUSION: Treating elderly TB patients with PZA did not increase the incidence of SAEs, medication interruptions, or LTFU during the standard short course of TB treatment. Therefore, considering its potential advantages, incorporating PZA into the treatment regimen for elderly TB patients may be advisable.

The impact of alcohol and illicit substance use on the pharmacokinetics of first-line TB drugs.

BACKGROUND: In South Africa, an estimated 11% of the population have high alcohol use, a major risk factor for TB. Alcohol and other substance use are also associated with poor treatment response, with a potential mechanism being altered TB drug pharmacokinetics. OBJECTIVES: To investigate the impact of alcohol and illicit substance use on the pharmacokinetics of first-line TB drugs in participants with pulmonary TB. METHODS: We prospectively enrolled participants ≥15 years old, without HIV, and initiating drug-susceptible TB treatment in Worcester, South Africa. Alcohol use was measured via self-report and blood biomarkers. Other illicit substances were captured through a urine drug test. Plasma samples were drawn 1 month into treatment pre-dose, and 1.5, 3, 5 and 8 h post-dose. Non-linear mixed-effects modelling was used to describe the pharmacokinetics of rifampicin, isoniazid, pyrazinamide and ethambutol. Alcohol and drug use were tested as covariates. RESULTS: The study included 104 participants, of whom 70% were male, with a median age of 37 years (IQR 27-48). Alcohol use was high, with 42% and 28% of participants having moderate and high alcohol use, respectively. Rifampicin and isoniazid had slightly lower pharmacokinetics compared with previous reports, whereas pyrazinamide and ethambutol were consistent. No significant alcohol use effect was detected, other than 13% higher ethambutol clearance in participants with high alcohol use. Methaqualone use reduced rifampicin bioavailability by 19%. CONCLUSION: No clinically relevant effect of alcohol use was observed on the pharmacokinetics of first-line TB drugs, suggesting that poor treatment outcome is unlikely due to pharmacokinetic alterations. That methaqualone reduced rifampicin means dose adjustment may be beneficial.

[Efficacy and safety of first-line anti-tuberculosis drugs combined with Linezolid for the treatment of pediatric tuberculous meningitis in real-word practice].

Objective: To evaluate the efficacy and safety of first-line anti-tuberculosis (TB) drugs combined with linezolid in treatment of children with tuberculous meningitis (TBM). Methods: A retrospective cohort study design was performed. Eight-nine Children diagnosed as TBM during January 1st 2016 and December 31st 2023 in Department of Infectious Disease, Children's Hospital of Chongqing Medical University were enrolled in the study. According to different treatment regimens, children were divided into a group of first-line anti-tuberculous drugs (isoniazid, rifampicin, pyrazinamide, ethambutol (HRZE)) and a group of HRZE and linezolid combination (HRZEL). The efficacy and safety of the 2 regimens were compared and the relationship between linezolid drug concentration and adverse reactions were analyzed. Comparisons between groups were performed using χ2 test and Mann-Whitney U test. Results: The 89 children with TBM included 53 males and 36 females with an onset age of 4.6 (1.4, 9.6) years. There were 27 cases in the HZREL group and 62 cases in the HRZE group. Before treatment, positive rate of interferon-gamma release assays (IGRA) in HRZEL group was lower than that in HRZE group (64% (16/25) vs.92% (55/60), χ2=9.82, P<0.05), but protein level of cerebrospinal fluid (CSF) was higher than that in HRZE group (1.2 (1.0, 2.0) vs.0.8 (0.4,1.4) g/L, Z=0.32, P<0.05). By the end of the intensive phase, there were no significant differences of rates of CSF improvement and etiology negativity between HRZEL group and HRZE group (both P>0.05).The 44 TBM children with high CSF protein (>1 g/L) included 25 males and 19 females with an onset age of 6.7 (3.0, 11.8) years. There were 21 cases in the HZREL group and 23 cases in the HRZE group accordingly. Before treatment, there were no significant differences of positive rate of IGRA test and CSF protein level between the 2 groups (62% (13/21) vs. 87% (20/23), 1.7 (1.1, 2.2) vs. 1.5 (1.2, 1.9) g/L, χ2=3.67, Z=0.23, both P>0.05). There were no significant differences in CSF indicators, etiology negativity or imaging remission between the two groups by the end of intensive phase (all P>0.05). Higher frequencies of granulocytopenia, gastrointestinal symptoms as well as withdrawal or change of drugs were found in HRZEL group when compared to those in HRZE group (44% (12/27) vs. 19% (12/62), 7% (2/27) vs. 0, 33% (9/27) vs. 3% (2/62), χ2=6.01, 4.70, 15.74, all P<0.05). Conclusions: The efficacy of HRZEL regimen is similar to conventional HRZE regimen in children with TBM, but with higher adverse effect. Prudentially evaluating the pros and cons of linezolid in the usage of drug-susceptible TB and carefully monitoring of linezolid associated adverse effects is suggested.

Efficacy and tolerability of a 4-month ofloxacin-containing regimen compared to a 6-month regimen in the treatment of patients with superficial lymph node tuberculosis: a randomized trial.

BACKGROUND: Tuberculosis (TB) lymphadenitis is the most common form of extra-pulmonary TB, and the treatment duration is six months. This non-inferiority based randomized clinical trial in South India evaluated the efficacy and safety of a four-month ofloxacin containing regimen in tuberculosis lymphadenitis (TBL) patients. METHODS: New, adult, HIV-negative, microbiologically and or histopathologically confirmed superficial lymph node TB patients were randomized to either four-month oflaxacin containing test regimen [ofloxacin (O), isoniazid (H), rifampicin (R), pyrazinamide (Z) -2RHZO daily/ 2RHO thrice-weekly] or a six-month thrice-weekly control regimen (2HRZ, ethambutol/4RH). The treatment was directly observed. Clinical progress was monitored monthly during and up to 12 months post-treatment, and thereafter every three months up to 24 months. The primary outcome was determined by response at the end of treatment and TB recurrence during the 24 months post-treatment. RESULTS: Of the 302 patients randomized, 298 (98.7%) were eligible for modified intention-to-treat (ITT) analysis and 294 (97%) for per-protocol (PP) analysis. The TB recurrence-free favourable response in the PP analysis was 94.0% (95% CI: 90.1-97.8) and 94.5% (95% CI: 90.8-98.2) in the test and control regimen respectively, while in the ITT analysis, it was 92.7% and 93.2%. The TB recurrence-free favourable response in the test regimen was non-inferior to the control regimen 0.5% (95% CI: -4.8-5.9) in the PP analysis based on the 6% non-inferiority margin. Treatment was modified for drug toxicity in two patients in the test regimen, while one patient had a paradoxical reaction. CONCLUSION: The 4-month ofloxacin containing regimen was found to be non-inferior and as safe as the 6-month thrice-weekly control regimen.

Comparative evaluation of intensified short course regimen and standard regimen for adults TB meningitis: a protocol for an open label, multi-center, parallel arms, randomized controlled superiority trial (INSHORT trial).

BACKGROUND: Despite several incremental improvements in the management of tuberculous meningitis (TBM), the mortality rates remain high. In spite of national and international guidelines, variation in the choice, dose, and duration of drugs exist between countries and clinicians. We propose to evaluate a shorter and more effective regimen containing agents with augmented intracerebral drug exposure and anti-inflammatory approaches to improve disability-free survival among patients with TBM. Our strategy incorporates the various developments in the field of TBM over the last two decades and only few trials have evaluated a composite of these strategies in the overall outcomes of TBM. METHODS: An open label, parallel arms, randomized controlled superiority trial will be conducted among 372 participants across 6 sites in India. Eligible participants will be randomly allocated in 1:1:1 ratio into one of the three arms. The intervention arm consists of 2 months of high-dose rifampicin (25 mg/kg), moxifloxacin (400 mg), pyrazinamide, isoniazid, aspirin (150 mg), and steroids followed by rifampicin, isoniazid, and pyrazinamide for 4 months. The second intervention arm includes all the drugs as per the first arm except aspirin and the patients in the control arm will receive treatment according to the National TB Elimination Program guidelines. All participants will be followed up for 1 year after the treatment.  DISCUSSION: Current WHO regimens have agents with poor central nervous system drug exposure and is too long. It does not reflect the accumulating evidence in the field. We propose a comprehensive clinical trial incorporating the emerging evidence accrued over the last two decades to shorten the duration and improve the treatment outcomes. This multi-centric trial may generate crucial evidence with policy and practice implications in the treatment of TBM. TRIAL REGISTRATION: Clinical Trial Registry India CTRI/2023/05/053314. Registered on 31 May 2023 ( https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=ODYzMzg=&Enc=&userName=CTRI/2023/05/053314 ). CLINICALTRIALS: gov NCT05917340. Registered on 6 August 2023 ( https://classic. CLINICALTRIALS: gov/ct2/show/NCT05917340 ). PROTOCOL VERSION: Version 1.3 dated 12 July 2023.

Shorter Treatment for Nonsevere Tuberculosis in African and Indian Children.

BACKGROUND: Two thirds of children with tuberculosis have nonsevere disease, which may be treatable with a shorter regimen than the current 6-month regimen. METHODS: We conducted an open-label, treatment-shortening, noninferiority trial involving children with nonsevere, symptomatic, presumably drug-susceptible, smear-negative tuberculosis in Uganda, Zambia, South Africa, and India. Children younger than 16 years of age were randomly assigned to 4 months (16 weeks) or 6 months (24 weeks) of standard first-line antituberculosis treatment with pediatric fixed-dose combinations as recommended by the World Health Organization. The primary efficacy outcome was unfavorable status (composite of treatment failure [extension, change, or restart of treatment or tuberculosis recurrence], loss to follow-up during treatment, or death) by 72 weeks, with the exclusion of participants who did not complete 4 months of treatment (modified intention-to-treat population). A noninferiority margin of 6 percentage points was used. The primary safety outcome was an adverse event of grade 3 or higher during treatment and up to 30 days after treatment. RESULTS: From July 2016 through July 2018, a total of 1204 children underwent randomization (602 in each group). The median age of the participants was 3.5 years (range, 2 months to 15 years), 52% were male, 11% had human immunodeficiency virus infection, and 14% had bacteriologically confirmed tuberculosis. Retention by 72 weeks was 95%, and adherence to the assigned treatment was 94%. A total of 16 participants (3%) in the 4-month group had a primary-outcome event, as compared with 18 (3%) in the 6-month group (adjusted difference, -0.4 percentage points; 95% confidence interval, -2.2 to 1.5). The noninferiority of 4 months of treatment was consistent across the intention-to-treat, per-protocol, and key secondary analyses, including when the analysis was restricted to the 958 participants (80%) independently adjudicated to have tuberculosis at baseline. A total of 95 participants (8%) had an adverse event of grade 3 or higher, including 15 adverse drug reactions (11 hepatic events, all but 2 of which occurred within the first 8 weeks, when the treatments were the same in the two groups). CONCLUSIONS: Four months of antituberculosis treatment was noninferior to 6 months of treatment in children with drug-susceptible, nonsevere, smear-negative tuberculosis. (Funded by the U.K. Medical Research Council and others; SHINE ISRCTN number, ISRCTN63579542.).

Interim Guidance: 4-Month Rifapentine-Moxifloxacin Regimen for the Treatment of Drug-Susceptible Pulmonary Tuberculosis - United States, 2022.

On May 5, 2021, CDC's Tuberculosis Trials Consortium and the National Institutes of Health (NIH)-sponsored AIDS Clinical Trials Group (ACTG) published results from a randomized controlled trial indicating that a 4-month regimen containing rifapentine (RPT), moxifloxacin (MOX), isoniazid (INH), and pyrazinamide (PZA) was as effective as the standard 6-month regimen for tuberculosis (TB) treatment (1). On the basis of these findings, CDC recommends the 4-month regimen as a treatment option for U.S. patients aged ≥12 years with drug-susceptible pulmonary TB and provides implementation considerations for this treatment regimen.

Early phase of effective treatment induces distinct transcriptional changes in Mycobacterium tuberculosis expelled by pulmonary tuberculosis patients.

Effective treatment reduces a tuberculosis patient's ability to infect others even before they test negative in sputum or culture. Currently, the basis of reduced infectiousness of the Mycobacterium tuberculosis (Mtb) with effective treatment is unclear. We evaluated changes in aerosolized bacteria expelled by patients through a transcriptomic approach before and after treatment initiation (up to 14 days) by RNA sequencing. A distinct change in the overall transcriptional profile was seen post-treatment initiation compared to pretreatment, only when patients received effective treatment. This also led to the downregulation of genes associated with cellular activities, cell wall assembly, virulence factors indicating loss of pathogenicity, and a diminished ability to infect and survive in new host cells. Based on this, we identified genes whose expression levels changed with effective treatment. The observations of the study open up avenues for further evaluating the changes in bacterial gene expression during the early phase of treatment as biomarkers for monitoring response to tuberculosis treatment regimens and provide means of identifying better correlates of Mtb transmission.

INTENSIVE TREATMENT OF A CAPTIVE BORNEAN ELEPHANT (ELEPHAS MAXIMUS BORNEENSIS) INFECTED WITH MYCOBACTERIUM CAPRAE IN JAPAN.

In 2015, an estimated 17-year-old female Bornean elephant (Elephas maximus borneensis) at Fukuyama Zoo in Japan exhibited anorexia and significant weight loss. Pan-susceptible Mycobacterium tuberculosis complex (MTBC) was isolated from vaginal discharge, oral mucus, urine, and fecal samples by culture. The isolate was identified as Mycobacterium caprae by genetic analysis. Isoniazid, pyrazinamide, and levofloxacin were administered rectally. Body weight increased to normal, but subsequently decreased again. Elevation of liver enzymes occurred, likely related to the increase in isoniazid dosage. After recovery from side effects, the elephant's weight increased further. However, isoniazid-resistant M. caprae was isolated from oral mucus after anti-tuberculosis drug treatment for 9 mo. The regimen was changed to rifampicin, pyrazinamide, ethambutol, and levofloxacin, administered orally or rectally. The 18-mo treatment was completed in October 2018. This elephant has shown no clinical sign since. No MTBC-positive sample had been obtained as of March 2020.

Dry powder inhalation formulation of chitosan nanoparticles for co-administration of isoniazid and pyrazinamide.

Co-loaded isoniazid and pyrazinamide chitosan nanoparticles were formulated using the ionic gelation method. The formulations were adjusted to five mass ratios of tripolyphosphate (TPP) and chitosan at three TPP concentrations. Particle size, polydispersity index, zeta potential, and encapsulation efficiency were used to evaluate all formulations. The results revealed that the ratio of TPP to chitosan had the highest impact in generating chitosan nanoparticles. The selected nanoparticle formulations were freeze-dried, and the obtained dry powders were characterized using scanning electron microscopy, differential scanning calorimetry, X-ray diffraction, and Fourier-transform infrared spectroscopy to confirm the interaction of loaded drug and formulation excipients. The aerosolized performance of dry powders was also evaluated using the Andersen cascade impactor. A mass median aerodynamic diameter of 3.3-3.5 µm, % fine particle fraction of 30-44%, and 92-95% emitted dose were obtained from all formulations. The dry powder formulations were not toxic to the respiratory tract cell lines. Furthermore, they did not provoke alveolar macrophages into producing inflammatory cytokines or nitric oxides, indicating that the formulations are safe and could potentially be used to deliver to respiratory tract for tuberculosis treatment.

Tuberculosis in the intensive care unit: alternative treatment regimens and association with mortality.

OBJECTIVES: Adequate anti-tuberculosis (TB) treatment is an important factor that can affect the patient's outcome. Higher mortality is found in patients who do not receive optimal treatment that includes isoniazid and rifampicin. The objective of this study is to evaluate the association of use of alternative TB treatment regimens (without rifampicin and isoniazid) and mortality among patients requiring intensive care. METHODS: Retrospective cohort study, from January 2010 to December 2018. Patients aged > 18 years with a TB diagnosis, admitted to the ICU of a general, tertiary care, university-affiliated hospital (Hospital de Clínicas de Porto Alegre - HCPA) were included. Data on TB treatment used and outcomes of treatment were collected. RESULTS: 462 patients met the inclusion criteria and were included in the analysis; 284 used the usual treatment regimen (rifampicin, isoniazid, pyrazinamide and ethambutol - all orally), and 178 used alternative treatment regimens (IV levofloxacin plus oral ethambutol plus IM streptomycin or IV amikacin, without rifampicin and isoniazid). The mortality was higher among users of alternative treatment regimens (63.5%) than among usual treatment regimen users (51.4%) (P = 0.011). In a multivariate analysis, age, albumin and death were independently associated with alternative treatment regimens use. CONCLUSIONS: TB programmes in which IV rifampicin is not widely available should consider including it, especially for critically ill TB patients, for whom there may be improved survival.

OBJECTIFS: Un traitement antituberculeux (TB) adéquat est un facteur important pouvant influencer les résultats du patient. Une mortalité plus élevée est observée chez les patients qui ne reçoivent pas un traitement optimal comprenant de l'isoniazide et de la rifampicine. L'objectif de cette étude est d'évaluer l'association entre l'utilisation d'autres schémas thérapeutiques anti-TB (sans rifampicine ni isoniazide) et la mortalité chez les patients nécessitant des soins intensifs. MÉTHODES: Etude de cohorte rétrospective, de janvier 2010 à décembre 2018. Les patients âgés de >18 ans avec un diagnostic de TB, admis à l'unité de soins intensifs d'un hôpital général, avec des soins tertiaires, affilié à l'Université (Hôpital de Clínicas de Porto Alegre-HCPA) ont été inclus. Des données sur le traitement anti-TB utilisé et les résultats du traitement ont été collectés. RÉSULTATS: 462 patients répondaient aux critères d'inclusion et ont été inclus dans l'analyse; 284 ont utilisé le schéma thérapeutique habituel (rifampicine, isoniazide, pyrazinamide et éthambutol - tous par voie orale) et 178 ont utilisé des schémas thérapeutiques alternatifs (lévofloxacine IV plus éthambutol oral plus streptomycine IM ou amikacine IV, sans rifampicine ni isoniazide). La mortalité était plus élevée chez les utilisateurs de schémas thérapeutiques alternatifs (63,5%) que chez les utilisateurs de schémas thérapeutiques habituels (51,4%) (P = 0,011). Dans l'analyse multivariée, l'âge, l'albumine et le décès ont été indépendamment associés à l'utilisation de schémas thérapeutiques alternatifs. CONCLUSIONS: Les programmes de lutte contre la TB dans lesquels la rifampicine IV n'est pas largement disponible devraient envisager de l'inclure, en particulier pour les patients atteints de TB et sévèrement malades, pour lesquels la survie peut être améliorée.

Effect of interval between food intake and drug administration at fasting condition on the plasma concentrations of first-line anti-tuberculosis drugs in Chinese population.

We aimed to investigate the effect of interval between food intake and drug administration at fasting condition on the plasma concentrations of first-line anti- tuberculosis (TB) drugs in Chinese population. Newly diagnosed TB patients administered the anti-TB drugs under fasting conditions orally, and then had prepared breakfast at 30 minutes and 120 min after dosing, respectively. Blood sampling was also performed 120  minutes after dosing for the detection of Cmax purpose. Overall, twenty-five participants were included in our analysis. The Cmaxs of 30  minutes interval and 120  minutes interval were 21.8 ±â€Š2.0 and 19.2 ±â€Š2.0 µg/mL for rifampin, 1.6 ±â€Š0.2 and 2.1 ±â€Š0.2 µg/mL for isoniazid (INH), 1.5 ±â€Š0.1and 1.5 ±â€Š0.2 µg/mL for ethambutol (EMB), and 49.2 ±â€Š3.7 and 41.5 ±â€Š3.9 µg/mL for pyrazinamide, respectively. Statistical analysis revealed that there was no statistical difference between 2 groups. Additionally, 88.0% and 72.0% of the 25 participants at 2-hour interval group had peak concentrations less than the lower limit of the reference range for INH and EMB, respectively. The Cmaxs of INH were 0.9 ±â€Š0.4 µg/ml for rapid acetylator, which was significantly lower than those of intermediate (1.4 ±â€Š1.0 µg/mL), and slow acetylator (2.5 ±â€Š1.0 µg/mL), respectively (P < .01). In conclusion, our data demonstrate that early food intake at 30 minutes after drug administration had no significant influence on the plasma concentrations. In addition, a high proportion of patients receiving first-line anti-TB regimen fail to achieve the expected plasma drug ranges of INH and EMB (P > .05).

Management of isoniazid-monoresistant tuberculosis (Hr-TB) in Queensland, Australia: a retrospective case series.

OBJECTIVES: Drug-resistance represents a major threat in the fight against tuberculosis. Globally, isoniazid-monoresistant tuberculosis (Hr-TB) is twice as common as multidrug/rifampicin-resistant (MDR/RR)-TB. Recently updated WHO guidelines now recommend treatment of Hr-TB with rifampicin, ethambutol, pyrazinamide and levofloxacin for at least six months. Our primary objective was to define the frequency, treatment and outcomes for Hr-TB in Queensland, Australia. We also sought to determine the frequency of fluoroquinolone use and whether its inclusion improved outcomes. METHODS: Retrospective case series of tuberculosis notifications in Queensland between 2000 and 2017 with at least low-level isoniazid resistance and preserved susceptibility to other first-line oral agents. RESULTS: Hr-TB was identified in 7.2% of all notifications. Where outcomes were assessable (163/198), 76.1% were treated with first-line agents only and 11.0% received at least six months of a fluoroquinolone-containing regimen (consistent with recent WHO guidelines). Favourable outcomes were achieved in 95.7%, comparable to fully susceptible disease (94.9%). Inclusion of a fluoroquinolone did not significantly improve outcomes compared with a regimen containing first-line agents only, although these cases were more likely to have high-level resistance. Previous treatment made an unfavourable outcome more likely. CONCLUSIONS: Hr-TB is prevalent in Queensland. Treatment outcomes in our cohort were comparable to fully susceptible disease. The current WHO-recommended regimen did not confer advantage over an appropriately constructed regimen containing first-line agents only. Our findings suggest that, in a well-resourced setting with good programmatic management, the addition of a fluoroquinolone may not substantially improve outcomes - potentially allowing these agents to be reserved for more extensively resistant disease.

Electronic pillbox-enabled self-administered therapy versus standard directly observed therapy for tuberculosis medication adherence and treatment outcomes in Ethiopia (SELFTB): protocol for a multicenter randomized controlled trial.

BACKGROUND: To address the multifaceted challenges associated with tuberculosis (TB) in-person directly observed therapy (DOT), the World Health Organization recently recommended that countries maximize the use of digital adherence technologies. Sub-Saharan Africa needs to investigate the effectiveness of such technologies in local contexts and proactively contribute to global decisions around patient-centered TB care. This study aims to evaluate the effectiveness of pillbox-enabled self-administered therapy (SAT) compared to standard DOT on adherence to TB medication and treatment outcomes in Ethiopia. It also aims to assess the usability, acceptability, and cost-effectiveness of the intervention from the patient and provider perspectives. METHODS: This is a multicenter, randomized, controlled, open-label, superiority, effectiveness-implementation hybrid, mixed-methods, two-arm trial. The study is designed to enroll 144 outpatients with new or previously treated, bacteriologically confirmed, drug-sensitive pulmonary TB who are eligible to start the standard 6-month first-line anti-TB regimen. Participants in the intervention arm (n = 72) will receive 15 days of HRZE-isoniazid, rifampicin, pyrazinamide, and ethambutol-fixed-dose combination therapy in the evriMED500 medication event reminder monitor device for self-administration. When returned, providers will count any remaining tablets in the device, download the pill-taking data, and refill based on preset criteria. Participants can consult the provider in cases of illness or adverse events outside of scheduled visits. Providers will handle participants in the control arm (n = 72) according to the standard in-person DOT. Both arms will be followed up throughout the 2-month intensive phase. The primary outcomes will be medication adherence and sputum conversion. Adherence to medication will be calculated as the proportion of patients who missed doses in the intervention (pill count) versus DOT (direct observation) arms, confirmed further by IsoScreen urine isoniazid test and a self-report of adherence on eight-item Morisky Medication Adherence Scale. Sputum conversion is defined as the proportion of patients with smear conversion following the intensive phase in intervention versus DOT arms, confirmed further by pre-post intensive phase BACTEC MGIT TB liquid culture. Pre-post treatment MGIT drug susceptibility testing will determine whether resistance to anti-TB drugs could have impacted culture conversion. Secondary outcomes will include other clinical outcomes (treatment not completed, death, or loss to follow-up), cost-effectiveness-individual and societal costs with quality-adjusted life years-and acceptability and usability of the intervention by patients and providers. DISCUSSION: This study will be the first in Ethiopia, and of the first three in sub-Saharan Africa, to determine whether electronic pillbox-enabled SAT improves adherence to TB medication and treatment outcomes, all without affecting the inherent dignity and economic wellbeing of patients with TB. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04216420. Registered on 2 January 2020.

Bile acids, lipid and purine metabolism involved in hepatotoxicity of first-line anti-tuberculosis drugs.

OBJECTIVES: Rifampin (RIF), isoniazid (INH) and pyrazinamide (PZA) are essential components of the short-term first-line anti-tuberculosis (anti-TB) chemotherapy regimen and can cause hepatotoxicity. However, the mechanism of anti-TB drug-induced hepatotoxicity (ATDH) is currently unclear. We investigate the relevant contributions to liver injury and the pathway of the above-mentioned drugs administered alone or in combination. METHODS: UPLC-Q-TOF/MS-based metabolomics, bile acids (BAs) analysis and FXR/SHP detection were used to evaluate the toxicity of these drugs and clarify the underlying metabolism-related pathway. RESULTS: In C57BL/6 mice administered the corrected clinical doses, RIF, INH and PZA could induced hepatotoxicity; with less toxicity in the combination therapy than RIF. The pathological biochemistry, BAs concentration and metabolically regulated FXR/SHP gene expression analyzes in mice were consistent with the metabolomics results. FXR played a role in the hepatotoxicity of anti-tuberculosis drugs in the obeticholic acid treated and FXR-/- mice. Additionally, the purine and lipid metabolic pathways were involved in ATDH. CONCLUSION: ATDH was involved in bile acids and lipid and purine metabolism. The BAs metabolic pathway involvement in mice was validated in TB patients. The noninvasive metabolomics approach is more systemic than routine toxicity evaluation and can be used to assess compound toxicity and the underlying mechanism.

Diagnostic Challenges and Dilemmas in Tuberculous Meningitis.

Tuberculosis is a global burden with an unacceptably high mortality rate, especially in low- and middle-income countries. We reported the case of 34-year-old Somali female with no significant risk factors who initially presented with headache and blurred vision. The patient subsequently developed altered mental status and significant vision changes. Initial lumbar puncture showed lymphocytic pleocytosis with negative gram stain, acid-fast bacilli stain, and culture. Initial polymerase chain reaction for tuberculosis was negative. The patient worsened despite receiving broad-spectrum antibiotics. The patient had a prolonged hospital course and eventually required lumbar drain placement for hydrocephalus. Repeated polymerase chain reactions for Mycobacterium tuberculosis from the lumbar drain samples was positive, and the diagnosis of tuberculous meningitis was confirmed. The patient improved after lumbar drain placement and treatment with isoniazid, rifampin, pyrazinamide, ethambutol and steroid tapering. This case illustrated the challenge of diagnosing tuberculous meningitis.

Tuberculosis hepática simulando metástasis de cáncer colorrectal / Hepatic tuberculosis mimicking metastatic colorectal cancer

No disponible

Design and optimization of a child-friendly dispersible tablet containing isoniazid, pyrazinamide, and rifampicin for treating tuberculosis in pediatrics.

Objective: Develop a child-friendly Fixed Dose Combination (FDC) water-dispersible tablet for Tuberculosis (TB) treatment, with 50, 150, and 75 mg of isoniazid, pyrazinamide and rifampicin respectively. This new formulation must contain the lowest number of excipients accepted for pediatrics and fulfill all the pharmacopeia requirements.Significance: At present, there is no adequate market dosage form available for children. There is, however, one in a prequalification phase by the World Health Organization but its composition contains excipients which may not be suitable for pediatrics. Therefore, this new formulation would cover this therapeutic gap.Methods: A factorial design, based on three quantitative factors (compression force and concentration of AcDiSol® and Explosol®) at three levels each, was performed to elucidate their influence over disintegration time and friability. In addition, the influence of the press speed on disintegration time, friability, tensile strength, fineness of dispersion and content uniformity over the target tablet was tested. A stability test was done following ICH guideline for accelerated conditions.Results: Tablets developed with 9% w/w of Explosol® and a compression force of 16 kN disintegrated in less than 3 min and showed a friability below 1% when 15-mm punches were used. The tableting process could be done up to 25 and 50 cycles/minute ensuring good quality attributes when 15 and 12-mm punches were used, respectively. All APIs remained inside the limit of ± 5% of drug content till 6 months of storage.Conclusion: A high-quality child-friendly FDC water-dispersible tablet was developed improving the treatment of TB in pediatric.