First-line anti-tuberculosis drug challenge reactions in DRESS in an HIV endemic setting.

BACKGROUND: In high HIV prevalence settings, first line anti-tuberculosis drug (FLTD)-associated DRESS poses therapeutic challenges. Sequential and additive drug challenge (SADC) of FLTDs best identifies offending drug(s), avoids unnecessary exclusions, and optimises re-initiation of non-offending drugs. However, SADC-associated reaction complexities limit its utility. OBJECTIVE: We aimed to describe characteristics of FLTD-associated DRESS patients, their treatment-limiting SADC reactions and related outcomes. METHODS: Patients hospitalized with FLTD-associated DRESS from 2013-2023 in a South African tertiary hospital and enrolled (retrospectively or prospectively) in an existing registry were eligible. RESULTS: SADC was undertaken in 41 patients. Overall, 47 classifiable reactions occurred, 34/47(72%) in 29/41(71%) patients, were treatment-limiting and 12/41(29%) reinitiated FLTDs uneventfully. Fifteen single and eight multiple drug-reactors were identified. Rifampicin, in 13/23(57%) reactors was the commonest individual offender. Ethambutol was most frequently involved in multiple drug-reactors. Median(IQR) time to a detectable reaction was 24(12-120) hours, 6/34(18%) being immediate (<6hours). Itch (65%), eosinophilia (56%), fever (41%), atypical lymphocytosis (41%), rash (38%), transaminitis (32%) and facial oedema (18%), singly or in combination were commonest features. Three reactions, one epidermal necrolysis and two liver derangements, were CTCAE grade 4 (life-threatening) events. No predictors of multiple drug-reactivity were identified, but multiple reactors were hospitalised significantly longer, 125(100-134) versus 60(45-80) days. CONCLUSIONS: SADC optimises FLTD reinitiation. However, timing, clinical presentation and severity of SADC-associated reactions following FLTD-associated DRESS is markedly heterogenous. Additionally, multiple drug-reactors are a complex group requiring longer hospitalisation, and without routine biomarkers to differentiate true multiple drug hypersensitivity from non-specific flare-ups and guide long-term drug avoidance strategies.

Incidence of side effects of antituberculosis drugs and their related factors in northern Iran: a retrospective cohort study.

Background: Antituberculosis drugs may cause mild, moderate or severe adverse drug reactions (ADR) leading to poor compliance. Description of the pattern of ADR and their related factors can help tuberculosis (TB) control program as part of the WHO programs. This study aims to investigate the incidence of ADR and associated factors among TB patients in northern Iran. Methods: This is a retrospective cohort study. The required information, including year of diagnosis, age, gender, residence area, nationality, HIV co-morbidity, history of anti TB treatment and ADR, was obtained from the Deputy of Health, Mazandaran University of Medical Sciences, Iran. All data were analyzed using SPSS version 21 software. Results: Out of 3903 TB patients, 136 (3.5%) experienced major ADR. The incidence of ADR for men and women as well as for those with and without previous treatment history were 3.9% vs. 3.3% and 5.3% vs. 3.4%, respectively (p>0.05). Multiple logistic regression models showed a higher chance of ADR among those aged over 59 compared with those aged under 29 (OR=2.63, 95% confidence interval: 1.54-4.49). Conclusions: Age over 59 can be considered a risk factor for ADR with anti-TB drug administration.

A QSPR analysis of physical properties of antituberculosis drugs using neighbourhood degree-based topological indices and support vector regression.

Topological indices are molecular descriptors used in QSPR modelling to predict the physicochemical properties of molecules. Topological indices are used in numerous applications in drug design. In this work, we compute the neighbourhood degree-based topological indices of 15 antituberculosis drugs, we studied the QSPR analysis of these drugs using support vector regression. The efficiency of support vector regression is determined by comparing it with the classical linear regression. Our QSPR model further shows the superiority of the SVR model as a better predictive model in QSPR analysis of the physical properties of antituberculosis drugs. The findings in this study are a further contribution to the field of chemical graph theory and drug design, providing a deeper understanding of neighbourhood degree-based topological indices and their predictive capabilities in QSPR model.

Bilateral Endoscopic Debridement Combined with Local Antituberculosis Drugs for Thoracic Tuberculosis with Large Paravertebral Abscess: A Multicenter Study with 4-year Follow-Up.

BACKGROUND: Paravertebral abscess represents a prevalent manifestation of thoracic tuberculosis, often necessitating surgical intervention. In this study, we introduced a novel approach by employing bilateral endoscopic debridement (BED) to address large Paravertebral abscesses associated with thoracic tuberculosis, a method not previously proposed in the literature. The clinical efficacy was examined through a comprehensive 4-year follow-up. METHODS: We conducted a retrospective analysis on patients diagnosed with thoracic tuberculosis and paravertebral abscess who underwent BED combined with local antituberculosis drugs (BED + LAD) between February 2015 and February 2019. A total of 29 eligible patients (12 males and 17 females) with a median (interquartile ranges) of 59.0(16.5) years were included in the study. All patients received the BED + LAD treatment. After the surgery, the patients were treated with a 4-drug antituberculosis therapy (Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol). All relevant indicators were meticulously recorded and analyzed. RESULTS: The surgical procedures were successfully completed for all subjects, with an average intraoperative bleeding volume of (25.2 ± 8.9) ml, an average surgical time of (68.4 ± 14.0) minutes, an average fluoroscopy frequency of (21.7 ± 8.2) times, an average hospital stay of (14.2 ± 4.3) days, and an average medication period of (42.1 ± 9.6) weeks. All subjects completed at least a 4-year follow-up period. At the final follow-up, ESR and CRP levels returned to normal, and there was no significant increase in the Cobb angle (P>0.05). CONCLUSIONS: The application of BED + LAD in the treatment of thoracic tuberculosis and paravertebral abscess proved to be a safe, effective, and feasible approach.

Antituberculosis-Drugs Induced DRESS: A Multidrug Hypersensitivity or Drug Hypersensitivity Relapse? A Case Report.

DRESS related to first-line antituberculosis drugs (ATD) is a challenging diagnosis. With a long-lasting combined treatment of 4-concomitantly administrated drugs, identification of the culprit drug remains difficult and may expose patients to treatment interruption and affect their outcome. A 42-year-old female, treated with isoniazid, rifampicin, pyrazinamide and ethambutol for multifocal tuberculosis, developed, 40 days later, hyperthermia, facial edema, cervical lymphadenopathy and generalized exanthema. Biological test results revealed eosinophilia, atypical lymphocytes, and liver injury. DRESS was suspected, and ATD were withdrawn. As patch tests for the 4 ATD showed negative results, we decided to reintroduce pyrazinamide, ethambutol and rifampicin separately with a 3-day interval. Pyrazinamide and rifampicin were tolerated. However, after receiving ethambutol, she developed fever and generalized rash, with no biological abnormalities. Since ethambutol was claimed to be the culprit drug, isoniazid was added, and 10 hours later, the patient developed fever, facial edema, generalized rash, eosinophilia and liver injury. This clinical and biological pattern resolved 2 weeks later. This report suggests a hypersensitivity relapse to ethambutol after isoniazid-induced DRESS.

Clinical research progress of novel antituberculosis drugs on multidrug-resistant tuberculosis.

Multidrug-resistant tuberculosis (MDR-TB) has become a critical challenge to public health, and the prevention and treatment of MDR-TB are of great significance in reducing the global burden of tuberculosis. How to improve the effectiveness and safety of chemotherapy for MDR-TB is a pressing issue that needs to be addressed in tuberculosis control efforts. This article provides a comprehensive review of the clinical application of new antituberculosis drugs in MDR-TB, aiming to provide a scientific basis for the prevention and treatment strategy of MDR-TB.

In vitro optimization of crushed drug-sensitive antituberculosis medication when administered via a nasogastric tube.

IMPORTANCE: The incidence of tuberculosis (TB) in intensive care units (ICUs) can be as high as 3% in high-burden settings, translating to more than 7,500 patients admitted to the ICU annually. In resource-limited settings, the lack or absence of intravenous formulations of drug-sensitive antituberculosis medications necessitates healthcare practitioners to crush, dissolve, and administer the drugs to critically ill patients via a nasogastric tube (NGT). This off-label practice has been linked to plasma concentrations below the recommended target concentrations, particularly of rifampicin and isoniazid, leading to clinical failure and the development of drug resistance. Optimizing the delivery of crushed drug-sensitive antituberculosis medication via the NGT to critically ill patients is of utmost importance.

A pituitary mass is not always an adenoma: A rare case of pituitary tuberculoma in an adolescent.

INTRODUCTION AND IMPORTANCE: Tuberculosis of the central nervous system is unusual and accounts for 1 % of all cases of tuberculosis in the world. The pituitary location is even scarcer. CASE PRESENTATION: A 14-year-old girl presented with polyuria-polydipsia syndrome and menstrual irregularity. MRI showed an intrasellar lesion of the pituitary gland. She underwent transsphenoidal surgery for histopathological diagnosis and removal of the lesion. Histological findings were consistent with a tuberculoma. She was put on anti-tuberculosis drugs and is being followed up. CLINICAL DISCUSSION: In endemic areas, pituitary tuberculosis should be considered in the differential diagnosis of pituitary tumors. The histological examination will guide the diagnosis. Sometimes, other complementary examinations such as the tuberculin skin test can be of great help when the histology is not conclusive. Medical treatment can be curative, however, surgery can be necessary for decompression. CONCLUSION: In addition to being the first case of histologically proven primary pituitary tuberculosis in a child reported in Morocco, the present case is unique in the way that the extensive radiological examinations did not reveal any evidence of other systemic or pulmonary tuberculosis.

Case report: Successful treatment with contezolid in a patient with tuberculous meningitis who was intolerant to linezolid.

Tuberculous meningitis (TBM) is the most common form of central nervous system tuberculosis (TB) and the most severe form of extrapulmonary TB. It often presents with non-specific symptoms initially and has a high mortality and disability rate. With good central nervous system penetration, linezolid is recommended for treating drug-resistant, severe, or refractory tuberculous meningitis in China. Despite the benefits of linezolid on TBM treatment, the adverse effects of long-term therapy, such as myelosuppression, peripheral neuritis, and optic neuritis, are notable and can be severe and even life-threatening, leading to discontinuation and compromising treatment expectations. Contezolid is a novel oxazolidinone antibacterial agent approved by the National Medical Products Administration of China in 2021, which has a more favorable safety profile than linezolid in terms of myelosuppression and monoamine oxidase inhibition. Here we first report a case of TBM in a patient who was intolerant to antituberculosis treatment with linezolid and achieved good efficacy and safety results after the compassionate use of contezolid. Given the widespread use of linezolid in TB treatment and the potential risks for long-term use, multi-center prospective controlled clinical trials in TB and TBM patients are needed to investigate the appropriate use of contezolid further.

Serum Protein Electrophoresis Bands As Biomarkers for Drug-Sensitive Pulmonary Tuberculosis.

INTRODUCTION: India has the highest cases of tuberculosis worldwide. According to WHO (2022), the incidence of tuberculosis in India is 210 per 100,000 population. Their incidence of new positive smear cases is 75 per 100,000 population per year. In tuberculosis, the level of albumin decreases while globulin increases leading to a low albumin to globulin (A/G) ratio, and electrophoresis of serum proteins are good diagnostic approach and provides essential information for monitoring treatment outcomes. MATERIALS AND METHODS: The present study includes 50 cases of pulmonary tuberculosis and 50 age-sex-matched healthy controls. Initially, serum protein estimation and electrophoresis were performed in newly diagnosed patients and controls. All drugs were given as National Tuberculosis Elimination Programme (NTEP) guidelines and blood samples were collected at two-month, four-month, and six-month intervals, and different serum protein fractions were compared and analyzed. RESULTS: The total serum protein was significantly lower in the cases than in the controls; 6.12±0.61 vs. 7.02±0.56 g/dL (p˂0.0020, t-value=3.12). The mean serum albumin was also significantly lower in the cases compared to the controls; 1.65±0.69 vs. 3.87±0.47g/dL (p˂0.0001, t-value=10.98). The α1 globulin started to rise after four months of treatment and at six months level was 0.262±0.32 g/dL. The level of γ globulin continuously decreases after antituberculous treatment to 1.56±0.67 gm/dL at six months. CONCLUSION: The cause of the decrease in total protein and albumin may be due to malnutrition leading to low cellular immunity. Serum protein level and protein electrophoresis should be analyzed as routine tests in patients before, during, and after treatment. It helps us in identifying patients at risk of pulmonary tuberculosis as well prognosis of the disease. This study is a valuable guide in deciding the effective management of tuberculosis patients with drug treatment plans and appropriate dietary intake. Hence, it highlights the complex relationship that exists between poverty and disease.

Protein binding investigation of first-line and second-line antituberculosis drugs.

Data on protein binding are incomplete for first-line antituberculosis drugs, and lacking for second-line antituberculosis drugs that are used extensively for multi-drug-resistant tuberculosis (levofloxacin, linezolid and moxifloxacin). Thus, the main purposes of this study were to investigate: (i) the relationship between carrier protein concentration and drug binding; and (ii) the feasibility of predicting free drug concentration using in-vitro and in-vivo results. In-vitro experiments were performed on spiked plasma mimicking real-case samples (drug combinations from clinical practice). Median in-vivo protein binding was 1.5% for ethambutol, 9.7% for isoniazid, 0.7% for pyrazinamide and 88.2% for rifampicin; and median in-vitro protein binding was 26.2% for levofloxacin, 12.8% for linezolid and 46.3% for moxifloxacin. Albumin concentration (<30 g/L) had a moderate impact on moxifloxacin binding and a strong impact on levofloxacin, linezolid and rifampicin binding. Determination of the free drug concentration seems to be of little value for ethambutol, isoniazid, moxifloxacin and pyrazinamide; limited value for linezolid because of its low binding; and major value for rifampicin in hypoalbuminaemic patients with tuberculosis, and levofloxacin because total concentration was an inaccurate reflection of free concentration. The free concentration predicted by the mathematical model was suitable for levofloxacin and linezolid, whereas the real free concentration should be measured for rifampicin. Further investigations should be carried out to investigate the benefit of using free concentration for levofloxacin, linezolid and rifampicin, particularly in the critical period of active tuberculosis associated with hypoalbuminaemia.

[DRESS syndrome induced by anti-TB drugs]. / Síndrome de DRESS inducido por fármacos antituberculosos.

OBJETIVE: To describe the phenotype of DRESS syndrome induced by antituberculosis drugs. METHODS: Descriptive study, withdrawn from the review of the records of patients with DRESS syndrome, identified in the interconsultation of the Department of Research in Immunogenetics and Allergy, of the Insti-tuto Nacional de Enfermedades Respiratorias (INER) Ismael Cosío Villegas, among 2014 and 2020. Frequency analysis was performed. The associations between biomarkers and latency are calculated with the χ2 test and log-rank, and the evaluation of the change in the biomarkers with the Wilcoxon test. The value of p < 0.05 is considered statistically significant. For data analysis, the SPSS v.21 program was obtained. RESULTS: 15 patients were identified; represented by 0.02% of total cases treated in the Department for so-meimmuno-allergic condition (15/7052); the main symptomatology were: rash (100%), eosinophilia (93%), fe-ver (80%), adenomegaly (60%), kidney damage (40%), liver damage (33%), and latency of 21 days. Liver damage was associated with prolonged latency (p = 0.02). After treatment, the total levels of eosinophils (p < 0.001) and liver and kidney biomarkers (p < 0.04) decreased. DRESS syndrome induced by antituberculosis drugs is not associated with the number of drugs prescribed or with the pattern of resistance of Mycobacterium tuberculosis. CONCLUSIONS: DRESS syndrome induced by antituberculosis drugs is an atypical clinical reaction, similar to other types of DRESS syndrome that respond favorably to systemic corticosteroids.

OBJETIVO: Describir el fenotipo del síndrome de DRESS inducido por fármacos antituberculosos. MÉTODOS: Estudio descriptivo efectuado a partir de la revisión de los expedientes de pacientes con síndrome de DRESS, identificados en la interconsulta del Departamento de Investigación en Inmunogénetica y Alergia, del Instituto Nacional de Enfermedades Respiratorias (INER) Ismael Cosío Villegas, entre 2014 y 2020. Se realizó análisis de frecuencias. Las asociaciones entre biomarcadores y latencia se calcularon con la prueba de χ2 y log-rank, y la evaluación del cambio en los biomarcadores con la prueba de Wilcoxon. Se consideró esta-dísticamente significativo el valor de p < 0.05. Para el análisis de los datos se utilizó el programa SPSS v.21. RESULTADOS: Se identificaron 15 pacientes, que representaron el 0.2% de los casos atendidos en el Departa-mento por algún padecimiento inmuno-alérgico (15/7052); las principales manifestaciones fueron: exantema (100%), eosinofilia (93%), fiebre (80%), adenomegalia (60%), daño renal (40%), daño hepático (33%) y latencia de 21 días. El daño hepático se asoció con latencia prolongada (p = 0.02). Posterior al tratamiento disminu-yeron las concentraciones totales de eosinófilos (p < 0.001) y biomarcadores hepáticos y renales (p < 0.04). El síndrome de DRESS inducido por fármacos antituberculosos no se asoció con la cantidad de fármacos prescritos ni con el patrón de resistencia de Mycobacterium tuberculosis. CONCLUSIONES: El síndrome de DRESS inducido por fármacos antituberculosos es una reacción clínica atípica, similar a otros tipos de síndrome de DRESS que responden favorablemente a corticosteroides sisté-micos.

Human Serum Albumin Nanoparticles: Synthesis, Optimization and Immobilization with Antituberculosis Drugs.

The aim of this study was to create nanoparticles of human serum albumin immobilized with anti-TB drugs (rifampicin, isoniazid) using the desolvation method. Central Composite Design (CCD) was applied to study the effect of albumin, urea, L-cysteine, rifampicin and isoniazid concentration on particle size, polydispersity and loading degree of the drugs. The optimized nanoparticles were spherical in shape with an average particle size of 216.7 ± 3.7 nm and polydispersity of 0.286 ± 4.9. The loading degree of rifampicin and isoniazid in the optimized nanoparticles were 44% and 27%, respectively. The obtained nanoparticles were examined by Fourier-transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC); the results showed the absence of drug-polymer interactions. The drug release from the polymer matrix was studied using dialysis membranes.

Is there a need to optimise pyrazinamide doses in patients with tuberculosis? A systematic review.

Pyrazinamide (PZA) is a first-line antituberculosis drug with potent sterilising activity. Variability in drug exposure may translate into suboptimal treatment responses. This systematic review, conducted according to PRISMA guidelines, aimed to evaluate the concentration-effect relationship. In vitro/in vivo studies had to contain information on the infection model, PZA dose and concentration, and microbiological outcome. Human studies had to present information on PZA dose, measures of drug exposure and maximum concentration, and microbiological response parameter or overall treatment outcome. A total of 34 studies were assessed, including in vitro (n = 2), in vivo (n = 3) and clinical studies (n = 29). Intracellular and extracellular models demonstrated a direct correlation between PZA dose of 15-50 mg/kg/day and reduction in bacterial count between 0.50-27.7 log10 CFU/mL. Consistent with this, higher PZA doses (>150 mg/kg) were associated with a greater reduction in bacterial burden in BALB/c mice models. Human pharmacokinetic studies displayed a linear positive correlation between PZA dose (i.e. 21.4-35.7 mg/kg/day) and drug exposure (AUC range 220.6-514.5 mg·h/L). Additionally, human studies confirmed a dose-effect relationship, with an increased 2-month sputum culture conversion rate at AUC/MIC targets of 8.4-11.3 with higher exposure/susceptibility ratios leading to greater efficacy. A 5-fold variability in AUC was observed at PZA dose of 25 mg/kg. A direct concentration-effect relationship and increased treatment efficacy with higher PZA exposure to susceptibility ratios was observed. Taking into account variability in drug exposure and treatment response, further studies on dose optimisation are justified.

Anaphylactic Shock After First-Line Treatment With Antituberculosis Drugs in a Patient With Lupus.

Tuberculosis (TB) is still a major public health concern in Morocco. Although first-line antituberculosis drugs (ATD) are generally considered safe and effective, serious adverse events can occur. In this case report, we describe a female with pulmonary TB who experienced anaphylaxis induced by rifampicin (RFP) and pyrazinamide (PZA) during ATD therapy. Anaphylactic reactions to first-line ATD can occur and may lead to treatment discontinuation and challenges in finding effective alternative treatment options. Healthcare professionals should be aware of the potential of anaphylaxis with the use of these drugs, especially in patients with a history of lupus. Further research is needed to better understand the mechanisms underlying anaphylaxis and develop effective preventive and management strategies. A young female patient with a history of lupus and splenectomy presented with respiratory symptoms and deterioration of general condition. She was diagnosed with pulmonary tuberculosis and received first-line ATD, which caused complications including liver dysfunction and anaphylactic shock. Despite these challenges, the anaphylactic shock was successfully managed; she was put on a combination of levofloxacin, kanamycin, and ethambutol (ETB), as well as a desensitization protocol for isoniazid (INH); the patient was cured.

Analysis of serum microRNA-122 in a randomized controlled trial of N-acetylcysteine for treatment of antituberculosis drug-induced liver injury.

AIM: Serum microRNA-122 (miR-122) is a novel biomarker for drug-induced liver injury, with good sensitivity in the early diagnosis of paracetamol-induced liver injury. We describe miR-122 concentrations in participants with antituberculosis drug-induced liver injury (AT-DILI). We explored the relationship between miR-122 and alanine aminotransferase (ALT) concentrations and the effect of N-acetylcysteine (NAC) on miR-122 concentrations. METHODS: We included participants from a randomized placebo-controlled trial of intravenous NAC in AT-DILI. ALT and miR-122 concentrations were quantified before and after infusion of NAC/placebo. We assessed correlations between ALT and miR-122 concentrations and described changes in ALT and miR-122 concentrations between sampling occasions. RESULTS: We included 45 participants; mean age (± standard deviation) 38 (±10) years, 58% female and 91% HIV positive. The median (interquartile range) time between pre- and post-infusion biomarker specimens was 68 h (47-77 h). The median pre-infusion ALT and miR-122 concentrations were 420 U/L (238-580) and 0.58 pM (0.18-1.47), respectively. Pre-infusion ALT and miR-122 concentrations were correlated (Spearman's ρ = .54, P = .0001). Median fold-changes in ALT and miR-122 concentrations between sampling were 0.56 (0.43-0.69) and 0.75 (0.23-1.53), respectively, and were similar in the NAC and placebo groups (P = .40 and P = .68 respectively). CONCLUSIONS: miR-122 concentrations in our participants with AT-DILI were considerably higher than previously reported in healthy volunteers and in patients on antituberculosis therapy without liver injury. We did not detect an effect of NAC on miR-122 concentrations. Further research is needed to determine the utility of miR-122 in the diagnosis and management of AT-DILI.

Naringenin protects hepato-renal tissues against antituberculosis drugs induced toxic manifestations by modulating interleukin-6, insulin like growth factor-1, biochemical and ultra-structural integrity.

BACKGROUND: The antituberculosis drugs (ATDs), isoniazid, rifampicin, pyrazinamide and ethambutol prompt extreme hepatic and renal damage during treatment of tuberculosis. The present study aimed to investigate protective potential of naringenin against ATDs induced hepato-renal injury. METHODS: Rats were administered with ATDs (pyrazinamide; 210, ethambutol; 170, isoniazid; 85, rifampicin; 65 mg/kg b.wt) orally for 8 weeks (3 days/week) followed by naringenin at three different doses (10, 20 and 40 mg/kg b.wt) conjointly for 8 weeks (3 days/week alternately to ATDs administration) and silymarin (50 mg/kg b.wt) as positive control. RESULTS: Exposure to ATDs caused significant increase in interleukin-6 (IL-6), triglycerides, cholesterol, bilirubin whereas depletion in insulin like growth factor-1 (IGF-1), albumin and glucose in serum. Endogenous antioxidant enzymes glutathione reductase (GR), glutathione peroxidase (GPx) and glucose-6-phosphate-dehydrogenase (G-6-PDH) were diminished in liver and kidney tissues with parallel increase in triglycerides, cholesterol, microsomal LPO and aniline hydroxylase (CYP2E1 enzyme). Ultra-structural observations of liver and kidney showed marked deviation in plasma membranes of various cellular and sub-cellular organelles after 8 weeks of exposure to ATDs. CONCLUSIONS: Conjoint treatment of naringenin counteracted ATDs induced toxic manifestations by regulating IL-6, IGF-1, CYP2E1, biochemical and ultra-structural integrity in a dose dependent manner. Naringenin has excellent potential to protect ATDs induced hepato-renal injury by altering oxidative stress, modulation of antioxidant enzymes, serum cytokines and ultra-structural changes.

Influence of sex on the exposure to isoniazid in patients with pulmonary tuberculosis

ABSTRACT Isoniazid is a key component of tuberculosis treatment. Adequate exposure is a determinant for therapeutic success; however, considerable inter- and intraindividual variations in drug plasma levels can lead to unfavorable outcomes. While some predictors of isoniazid levels are well-known, others, such as sex, yield controversial results, requiring further investigation to optimize exposure. This study investigates whether the sex of patients influences the dose administered and the concentrations of isoniazid in plasma. Levels of isoniazid were associated with the N-acetyltransferase 2 phenotypes. A total of 76 male and 58 female patients were included. Isoniazid was measured by high-performance liquid chromatography, and N-acetyltransferase 2 phenotypes were assessed using molecular techniques. The results show that the dose administered, expressed in mg/kg, was higher in females, but the plasma levels were similar between both sexes. Among patients, 46.2%, 38.8%, and 15% were slow, intermediate, and fast acetylators, respectively. As expected, isoniazid levels were associated with the acetylation phenotypes, with higher concentrations in the slow acetylators. Thus, sex-related difference in isoniazid levels is due to the body weight of patients, and the optimized dose regimen based on patient weight and acetylator phenotypes can improve the treatment outcomes.

THP-1 cell line model for tuberculosis: A platform for in vitro macrophage manipulation.

Macrophages are large mononuclear phagocytic cells that play a vital role in the immune response. They are present in all body tissues with extremely heterogeneous and plastic phenotypes that adapt to the organs and tissues in which they live and respond in the first-line against invading microorganisms. Tuberculosis (TB) is caused by the pathogenic bacteria Mycobacterium tuberculosis (Mtb), which is among the top 10 global infectious agents and the leading cause of mortality, ranking above human immunodeficiency virus (HIV), as a single infectious agent. Macrophages, upon Mtb infection, not only phagocytose the bacteria and present the antigens to T-cells, but also react rapidly by developing antimycobacterial immune response depending highly on the production of cytokines. However, Mtb is also capable of intracellular survival in instances of sub-optimal activation of macrophages. Hence, several systems have been established to evaluate the Mtb-macrophage interaction, where the THP-1 monocytes have been developed as an attractive model for in vitro polarized monocyte-derived macrophages. This model is extensively used for Mtb as well as other intracellular bacterial studies. Herein, we have summarized the updated implications of the THP-1 model for TB-related studies and discussed the pros and cons compared to other cell models of TB.

Pharmacokinetics of isoniazid and rifapentine in young pediatric patients with latent tuberculosis infection.

OBJECTIVES: This study investigated the steady-state pharmacokinetic profiles of 3-month weekly rifapentine plus isoniazid (3HP) in children with latent tuberculosisinfection (LTBI). We also assessed other factors, including tablet integrity, food, and pharmacogenetics. METHODS: During the 3HP treatment, blood and urine samples were collected in week 4. Isoniazid and rifapentine levels were measured using a high-performance liquid chromatography technique. The genetic variation of arylamine N-acetyltransferase 2 (NAT2) and arylacetamide deacetylase (AADAC) were assessed by the MassARRAY®. Safety and clinical outcomes at week 48 were monitored. RESULTS: A total of 12 children with LTBI (age 3.8 [range 2.1-4.9 years old]) completed the treatment (isoniazid and rifapentine dose 25.0 [range 21.7-26.8] and 25.7 [range 20.7-32.1] mg/kg, respectively). No serious adverse events or active TB occurred. Tablet integrity was associated with decreased area under the concentration-time curve (91 vs 73 mg.h/l, P= 0.026) and increased apparent oral clearance of isoniazid (0.27 vs 0.32 l/h/kg, P= 0.019) and decreased rifapentine's renal clearance (CLR, 0.005 vs 0.003 l/h, P= 0.014). Food was associated with increased CLR of isoniazid (3.45 vs 8.95 l/h, P= 0.006) but not rifapentine. Variability in NAT2 and AADAC did not affect the pharmacokinetics of both drugs. CONCLUSION: There is high variability in the pharmacokinetic profiles of isoniazid and rifapentine in young children with LTBI. The variability was partly influenced by tablet integrity and food, but not pharmacogenetics. Further study in a larger cohort is warranted to display the relationship of these factors to treatment outcomes.