First-line Antituberculosis Drugs Research Articles

Adverse Drug Events from First-Line Anti-tuberculosis Drugs in a Tertiary Medical Center

Adverse Drug Events from First-Line Anti-tuberculosis Drugs in a Tertiary Medical Center

Saliva-based point-of-care assay to measure the concentration of pyrazinamide using a mobile UV spectrophotometer.

Pyrazinamide, one of the first-line antituberculosis drugs, displays variability in drug exposure that is associated with treatment response. A simple, low-cost assay may be helpful to optimize treatment. This study aimed to develop and validate a point-of-care assay to quantify the concentration of pyrazinamide in saliva. All measurements were conducted using the nano-volume drop function on the mobile ultraviolet (UV) spectrophotometer (NP80, Implen, Germany). Assay development involved applying second derivative spectroscopy in combination with the Savitzky-Golay filter between wavelengths of 200-300 nm to increase spectral resolution. Assay validation included assessing selectivity, linearity, accuracy, precision, carry-over and matrix effects. Specificity was also analysed by evaluating the impact of co-administered medications on pyrazinamide results. Sample stability was measured at various temperatures up to 40°C. The calibration curve (7.5-200 mg/L) was linear (R2 = 0.9991). The overall accuracy (bias%) and precision (CV%) ranged from -0.66% to 5.15%, and 0.56% to 4.95%, respectively. Carry-over and matrix effects were both acceptable with a bias% of <±4% and CV% of <7.5%. Commonly co-administered medications displayed negligible interferences. Levofloxacin displayed analytical interference (bias% = -10.21%) at pyrazinamide concentrations < 25 mg/L, but this will have little clinical implications. Pyrazinamide was considered stable in saliva after 7 days in all storage conditions with a CV% of <6.5% and bias% of <±10.5% for both low- and high-quality control concentrations. A saliva-based assay for pyrazinamide has been successfully developed and validated using the mobile UV spectrophotometer.

Exploring gene mutations and multidrug resistance in Mycobacterium tuberculosis: a study from the Lung Hospital in Vietnam.

Drug-resistant tuberculosis not only diminishes treatment efficacy but also heightens the risk of transmission and mortality. Investigating Mycobacterium tuberculosis resistance to first-line antituberculosis drugs is essential to tackle a major global health challenge. Using Sanger sequencing, this study investigates gene mutations associated with multidrug resistance in drug-resistant M. tuberculosis strains. Among 30 samples, mutations were found in genes linked to first-line anti-tuberculosis drug resistance. Rifampicin resistance was observed in 46.67% of the samples, with the most frequent mutation in the rpoB gene at codon 450 (S450L) occurring in 23.33% of cases. Similarly, isoniazid resistance was found in 86.67% of samples, with 33.33% of cases indicating the katG gene mutation at codon 315 (S315T). Additionally, streptomycin resistance was present in 76.67% of samples, and 30% of these cases were mainly linked to the rpsL gene mutation at codon 43 (K43R). These findings illuminate the genetic mechanisms behind drug resistance in M. tuberculosis. By identifying specific genetic markers, this research enhances our ability to diagnose and treat drug-resistant Tuberculosis more accurately and efficiently.

Drug-induced liver injury associated with pretomanid, bedaquiline, and linezolid: Insights from FAERS database analysis.

The emergence of drug-resistant tuberculosis has necessitated novel treatments like the pretomanid, bedaquiline and linezolid (BPaL) regimen. This study investigated the association of drug-induced liver injury (DILI) with the BPaL regimen compared to first-line antituberculosis drugs (isoniazid, rifampin, pyrazinamide and ethambutol [HRZE]). A retrospective pharmacovigilance analysis was conducted using data from the US Food and Drug Administration Adverse Event Reporting System database from July 2019 to June 2023. Disproportionality analysis was employed to calculate the reporting odds ratio (ROR) of DILI for each component of the BPaL regimen. Onset time and mortality rates of DILI across different regimens were also compared. We identified 1242 cases of BPaL-related DILI. Most cases occurred in individuals under 65 years of age (63.8%), with more male patients affected than females (51.4% vs 39.5%). The association between antituberculosis drugs and DILI was stronger for the HRZE regimen (ROR = 7.99, 95% confidence interval [CI] 7.74-8.25) than the BPaL regimen (ROR = 4.75, 95% CI 4.55-4.97). The median onset time for DILI was significantly shorter with the BPaL regimen (8days, interquartile range [IQR] 3-28) compared to the HRZE regimen (20 days, IQR 6-48) (P < .001). Additionally, the BPaL regimen was associated with a higher risk of death due to DILI compared to the HRZE regimen (14.1% vs 10.4%, P = .003). Although the BPaL regimen had a lower overall risk of DILI compared to the HRZE regimen, it was significantly associated with DILI, indicating a need for careful monitoring during treatment.

Poly(malic acid) Nanoconjugates of Pyrazinoic Acid for Lung Delivery in the Treatment of Tuberculosis.

Tuberculosis (TB) remains a major global infection, and TB treatments could be improved by site-specific targeting with delivery systems that allow tissue and cell uptake. To increase the drug concentration at the target sites following lung delivery, polymeric nanoconjugates based on biodegradable poly(malic acid) were designed. Pyrazinoic acid (POA), the active moiety of pyrazinamide─a first-line antituberculosis drug─was covalently bound to poly(malic acid) using a hydrophobic linker at mole ratios of 25%, 50%, and 75%. Three linkers, hexanediol, octanediol, and decanediol, were considered. Independently of the linker or ratio, all the conjugates were able to self-assemble, forming nanoconjugates (NCs) in water with 130-190 nm in diameter. Pyrazinoic acid could be released in a controlled manner without any burst release effect. Its kinetics can be adjusted by modifying the grafting ratio and linker length. No cytotoxicity was observed on RAW 264.7 macrophages up to ∼14 μg/mL of POA. In addition, the nanoconjugates were efficiently taken up by these cells over 5 h. Thanks to their high loading capacity and modulable release profiles, these nanoconjugates hold great promise for more effective treatment of tuberculosis.

Incidence and risk factors of antituberculosis drug-induced liver injury in India: A systematic review and meta-analysis.

Antituberculosis drug-induced liver injury (ATDILI) is a significant problem of tuberculosis treatment. This systematic review and meta‑analysis aimed at evaluating the incidence and risk factors of ATDILI in adult patients with tuberculosis in India. Five electronic databases were searched comprehensively for studies on Indian adult patients with tuberculosis investigating the incidence and/or risk factors of ATDILI. The relevant data was pooled in a random or fixed-effect model to calculate the pooled incidence with a 95% confidence interval (CI), standardized mean difference (MD) or odds ratio (OR). Following the screening of 3221 records, 43 studies with 12,041 tuberculosis patients were finally included. Based on the random effect model, the pooled incidence of ATDILI was 12.6% (95% CI, 9.9-15.3%, p < 0.001, I2 = 95.1%). The pooled incidence was higher in patients with daily treatment regimen compared to the thrice weekly regimen (16.5% vs. 3.5%). The concurrent hepatitis B or C infection, alcohol consumption and underlying chronic liver disease were associated with high incidence of ATDILI. The pooled incidence of acute liver failure (ALF) among ATDILI patients was 6.78% (95% CI 3.9-9.5%). Female gender (OR 1.24), older age (MD 0.26), lean body mass index (OR 3.8), hypoalbuminemia (OR 3.09), N-acetyltransferase slow acetylator genotypes (OR 2.3) and glutathione S-transferases M null mutation (OR 1.6) were found to be associated with an increased risk of ATDILI. The pooled mortality rate of ATDILI patients was 1.72% (95% CI 0.4-3.0%) overall and 71.8% (95% CI 49.3-94.2%) in case of ALF. Overall, 12.6% patients of tuberculosis in India developed ATDILI when combination of first-line antituberculosis drugs was used. An average of 7% of ATDILI patients progressed to ALF which had a high mortality rate. Older age, female, poor nutritional status and some genetic polymorphisms were identified as significant risk factors.

Evaluating the efficacy of whole genome sequencing in predicting susceptibility profiles for first-line antituberculosis drugs

ObjectivesThis study aimed to examine the efficacy of whole genome sequencing (WGS) in accurately predicting susceptibility profiles, potentially eliminating the need for conventional phenotypic drug susceptibility testing (pDST) for first-line antituberculosis drugs in routine tuberculosis diagnosis. MethodsOver the period of 2017 to 2020, 1114 Mycobacterium tuberculosis complex isolates were collected with drug susceptibility testing conducted using the MGIT960 system and WGS performed for predicting drug resistance profiles. In addition, we implemented a new algorithm with an updated WGS workflow, omitting pan-susceptible strains from pDST. ResultsResults showed that out of 1075 analysed isolates, WGS-based genotypic sensitivity predictions for isoniazid, rifampicin, ethambutol, and pyrazinamide were 100% (95% CI, 99.6–100%), 100% (95% CI, 99.62–100%), 99.8% (95% CI, 99.26–99.94%), and 100% (95% CI, 99.63–100%), respectively. In contrast, the WGS-based genotypic resistance prediction, was 98.85% (95% CI, 93.77–99.79%) for isoniazid, 94.74% (95% CI, 82.71–98.54%) for rifampicin, 86.96% (95% CI, 67.87–95.46%) for ethambutol, and 75.7% (95% CI, 59.9–86.63%) for pyrazinamide. Moreover, WGS enabled the implementation of a new testing algorithm that made it unnecessary to perform pDST in 954 of all 1075 samples (88.7%) and in 890 of 901 pan-susceptible samples (98.8%). DiscussionIntegrating WGS into tuberculosis management offers significant potential to replace phenotypic drug susceptibility testing, especially for problematic drugs like pyrazinamide and ethambutol, potentially improving treatment outcomes.

A Case Report : Tuberculosis Drug Induced Liver Injury: A Case Report

Tuberculosis is one of world health problem, especially in developing countries. Treatment regimen with multiple first-line anti-tuberculosis drugs (ATD) such as Isoniazid, Rifampicin, Pyrazinamide, Ethambutol, And Streptomycin remains the most effective for treatment of tuberculosis. Adverse drug reactions (ADRs) to antituberculosis drugs may range from mild gastrointestinal disturbances to serious hepatotoxicity, peripheral neuropathy, and cutaneous adverse effects. We report a 65 year old male patient with a complaint of yellowish discoloration of sclera, nausea and vomitting after three days of initiation of ATD theraphy. The patient has been diagnosed with Tuberculosis relaps and has been taking ATD since June 2024. Patient noted epigastric pain. Laboratory examination found an increase in bilirubin level and imbalance electrolyte. The treatment is in the form of discontinuation of ATD, supportive therapy and followed by hepatoprotective supplements. ATD should be discontinued in patients with hepatotoxicity and fixed drug eruption until liver function and clinical symptoms improve. Initiation of ATD administration is carried out by administering one by one regimen. The patient is currently experiencing antituberculosis drug-induced hepatotoxicity, which is managed by providing supportive care and different AT regimen was prescribed.

Drug resistance in drug-resistant tuberculosis patients with and without diabetes mellitus: a comparative analysis

BackgroundThis dual burden of tuberculosis (TB) and diabetes mellitus (DM) has become a global public health concern. This study aims to compare drug resistance in drug-resistant tuberculosis (DR-TB) patients with and without DM and analyse the risk factors of multidrug-resistant tuberculosis (MDR-TB).MethodsA total of 893 DR-TB patients were admitted to Wenzhou Central Hospital between January 2018 and December 2022. After excluding 178 cases with incomplete clinical and laboratory data, 715 patients were included in the study. These patients were then categorized into two groups based on the presence of type 2 DM: the DM group (160 cases) and the non-DM group (555 cases). Demographic information, baseline clinical characteristics, laboratory and imaging test results, clinical diagnoses, and other relevant data were collected for analysis. Statistical analysis was conducted on demographic information, clinical parameters, drug resistance spectrum, and risk factors for multidrug resistance.ResultsIn both the DM and non-DM groups, the order of resistance to first-line anti-tuberculosis drugs is isoniazid, streptomycin, rifampicin, and ethambutol. There is no significant difference in the proportion of mono-resistant tuberculosis, polydrug-resistant tuberculosis, and multidrug-resistant tuberculosis between the two groups (P > 0.05). The prevalence of MDR-TB in both groups shows a downward trend between 2018 and 2022, but the trend is not statistically significant (P > 0.05). Among patients without DM, residence in rural areas, retreatment of tuberculosis, pulmonary cavity, and uric acid ≥ 346 µmol/L are identified as independent risk factors for MDR-TB. Among patients with DM, residence in rural areas, retreatment of tuberculosis, pulmonary cavity, and HbA1c ≥ 9.8% were identified as independent risk factors for MDR-TB.ConclusionIsoniazid is the most resistant drug among DR-TB patients with and without DM. There is no statistically significant difference in drug resistance patterns between the two groups. Some progress has been made in the prevention and control of DR-TB in this area, but the effect is not very significant. There are differences in the risk factors of MDR-TB between patients with and without DM.

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.

Evaluation of therapeutic effectiveness of antituberculosis injection based on conversion time in drug-resistant tuberculosis

Drug-resistant tuberculosis is a condition in which Mycobacterium tuberculosis is resistant to first-line anti-tuberculosis drugs, namely isoniazid and rifampicin, which are the two most effective anti-tuberculosis agents. Conversion time is a parameter to assess whether the therapeutic effect of injection has been achieved by carrying out two acid-resistant bacilli (ARB) sputum examinations within a maximum period of 2 consecutive months. Kanamycin and capreomycin are injectable drugs that are used in the intensive phase. This cross-sectional study aimed to evaluate the therapeutic effect of injection using ARB sputum conversion time and to analyze other factors related to ARB sputum conversion time. The study used retrospective data from patients’ medical records, collected with purposive sampling technique. The results of the study showed that from 101 patients who met the inclusion criteria 57.4% used kanamycin and 42.6% received capreomycin. The therapeutic effect was achieved in 87.1%. There was no significant correlation between the type of injection therapy and therapeutic effectiveness (p-value = 0.983). In conclusion, therapy using injections for drug-resistant tuberculosis is effective but still requires close monitoring due to the high adverse drug reaction (ADR).

Clinical risk factors for moderate and severe antituberculosis drug-induced liver injury.

To analyze the clinical and laboratory characteristics and to identify predictors of moderate to severe anti-tuberculosis drug-induced liver injury (ATB-DILI) in patients with tuberculosis. This prospective study enrolled Tuberculosis (TB) patients treated with first-line anti-tuberculosis drugs at the Affiliated Hospital of Zunyi Medical University between May 2022 and June 2023. The occurrence of ATB-DILI was monitored, and demographic and clinical data were gathered. We analyzed risk factors for the development of moderate to severe ATB-DILI. ATB-DILI was detected in 120 (10.7%) of the patients, with moderate to severe ATB-DILI occurring in 23 (2.0%) of the 1,124 patients treated with anti-tuberculosis treatment. Multivariate cox regression analysis identified malnutrition (HR = 4.564, 95% CI: 1.029-20.251, p = 0.046) and hemoglobin levels <120g/L (HR = 2.825, 95% CI: 1.268-11.540, p = 0.017) as independent risk factors for moderate to severe ATB-DILI. The incidence of moderate to severe ATB-DILI was found to be 2.0%. Malnutrition and hemoglobin levels below 120g/L emerged as significant independent risk factors for the occurrence of moderate to severe ATB-DILI in this patient population.

Natural deep eutectic solvent for the simultaneous derivatization and microextraction of isoniazid from human plasma

BackgroundPersonalized medicine is a rapidly revolving field that offers new opportunities for tailoring disease treatment to individual patients. The main idea behind this approach is to carefully select safe and effective medications and treatment plant based on each patient's unique pharmacokinetic profile. Isoniazid is a first-line anti-tuberculosis drug that has interindividual variability in its metabolic processing, leading to significant differences in plasma concentrations among patients receiving equivalent doses. This variability necessitates the creation of individualized treatment regimens as part of personalized medicine to achieve more effective therapy. ResultsIn this work, a deep eutectic solvent-based liquid-liquid microextraction approach for the separation and determination of isoniazid in human plasma by high-performance liquid chromatography with UV–Vis detection was developed for the first time. A new natural deep eutectic solvent based on thymol as a hydrogen bond donor and 4-methoxybenzaldehyde as a hydrogen bond acceptor was proposed as the extraction solvent. The developed microextraction procedure assumed two simultaneous processes during the mixing of the sample and extraction solvent: the derivatization of the polar analyte in the presence of 4-methoxybenzaldehyde (component of the natural deep eutectic solvent) with the formation of a hydrophobic Schiff base (1); mass transfer of the Schiff base from the sample phase to the extraction solvent phase (2). Under optimal conditions, the limits of detection and quantification were 20 and 60 μg L−1, respectively. The RSD value was <10 %, the extraction recovery was 95 %. SignificanceIn this work, the possibility of isoniazid derivatization in the natural deep eutectic solvent phase with the formation of the Schiff base was presented for the first time. The approach provided the separation and preconcentration of polar isoniazid without the use of expensive derivatization agents and solid-phase extraction cartridges. The formation of the Schiff base was confirmed by mass spectrometry.

The Role of Pharmacogenomics Studies for Precision Medicine Among Ethiopian Patients and Their Clinical Implications: A Scoping Review.

Pharmacogenomics research is currently revolutionizing treatment optimization by discovering molecular markers. Medicines are the cornerstone of treatment for both acute and chronic diseases. Pharmacogenomics associated treatment response varies from 20% to 95%, resulting in from lack of efficacy to serious toxicity. Pharmacogenomics has emerged as a useful tool for therapy optimization and plays a bigger role in clinical care going forward. However, in Africa, in particular in Ethiopia, such studies are scanty and not generalizing. Therefore, the objective of this review was to outline such studies, generating comprehensive evidence and identify studied variants' association with treatment responses in Ethiopian patients. The Joanna Briggs Institute's updated 2020 methodological guidelines for conducting and guidance for scoping reviews were used. We meticulously adhered to the systemic review reporting items checklist and scoping review meta-analyses extension. Two hundred twenty-nine possibly relevant studies were searched. These include: 64, 54, 21, 48 and 42 from PubMed, Scopus, Google Scholar, EMBASE, and manual search, respectively. Seventy-seven duplicate studies were removed. Thirty-nine papers were rejected with justification, whereas 58 studies were qualified for full-text screening. Finally 19 studies were examined. The primary pharmacogene that was found to have a significant influence on the pharmacokinetics of efavirenz was CYP2B6. Drug-induced liver injury has frequently identified toxicity among studied medications. Pharmacogenomics studies in Ethiopian populations are less abundant. The studies conducted focused on infectious diseases, specifically on HAART commonly efavirenz and backbone first-line anti-tuberculosis drugs. There is a high need for further pharmacogenomics research to verify the discrepancies among the studies and for guiding precision medicine. Systematic review and meta-analysis are also recommended for pooled effects of different parameters in pharmacogenomics studies.

First-Line Antituberculosis Drug Challenge Reactions in Drug Reaction With Eosinophilia and Systemic Symptoms Syndrome in an HIV Endemic Setting

BackgroundIn 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. ObjectiveWe aimed to describe characteristics of FLTD-associated DRESS patients, their treatment-limiting SADC reactions and related outcomes. MethodsPatients 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. ResultsSADC 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. ConclusionsSADC 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.

Drug susceptibility testing and line probe assay of first-line anti-tuberculosis drugs among presumptive tuberculosis patients attending a secondary care hospital in Bhubaneswar.

Pyrazinamide (PZA) is important for identification in multi-drug-resistant tuberculosis patients before starting therapy. PZA drug susceptibility testing (DST) is essential for the management of drug-resistant and susceptible TB patients. The degree of drug resistance among TB patients and discrepancy between DST results of the phenotype and genotype were assessed. Socio-demographic and clinical profiles of TB patients recruited in the study were documented. Sputum samples were processed for diagnosis using TrueNat Xpert MTB, TrueNat Xpert MTB Plus, and MGIT culture. Rifampicin (RIF) line probe assay (LPA) showed the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 100%, whereas isoniazid (INH) LPA testing showed a sensitivity of 85.7%, a specificity and PPV of 100%, and NPV of 94.8%. The gene mutation for RIF resistance was between the codon, 530-533 of rpoB gene, and that for INH resistance was at the codon, 315 of katG gene. Our findings demonstrated high prevalence of mono- and poly-drug resistance as well as pyrazinamide resistance.

Hepatotoxicity of first-line anti-tuberculosis drugs

Hepatotoxicity of first-line anti-tuberculosis drugs

Effects of compound Anoectochilus roxburghii (Wall.) Lindl. oral liquid on relative metabolic enzymes and various biochemical indices in Wistar rats with isoniazid-induced liver injury

Isoniazid (INH) is the first-line anti-tuberculosis drug in clinical practice, and its main adverse effect is drug-induced liver injury (DILI). This study aimed to investigate the hepatoprotective effect of Compound Anoectochilus roxburghii (Wall.) Lindl. Oral Liquid (CAROL) and to provide a new strategy for the search of potential drugs against INH-induced liver injury in Wistar rats. Animal experiment was based on INH (100 mg/kg) induced liver injury to explore the intervention effects of CAROL at doses of 1.35, 2.70, and 5.40 mL/kg. LC-QTOF-MS/MS was used to identify hepatoprotective components in CAROL and its’ exposed components in rat serum. The hepatoprotective effect of CAROL was evaluated by pathological observation of rat liver tissue and changes in levels of biochemical indices and cytokines in serum or liver tissue. Of the 58 hepatoprotective components identified, 15 were detected in the serum of rats with liver-injured treated by high-dose CAROL. Results of animal experiments showed that the levels of various biochemical indexes and cytokines were significantly reversed with CAROL intervention. In particular, the expression level of cytokeratin-18 and high-mobility group box 1, as specific and sensitive indicators of DILI, was significantly reduced in the serum of rats with CAROL intervention compared with the INH model group. The same reversal was observed in the levels of TBIL, ALP, ALT, and AST in serum, as well as in the levels of TNF-α, IL-6, SOD, and MDA in liver tissue. For INH-metabolizing enzymes, an evident expression inhibition was observed in N-acetyltransferase 2 and glutathione S-transferases with CAROL intervention, which may be the key to controlling INH hepatotoxicity. CAROL has a favorable hepatoprotective effect on INH-induced liver injury. This study takes the first step in studying the hepatoprotective mechanism of CAROL against INH hepatotoxicity and provides reference for wider clinical applications.

Development and Validation of a Simple High-Pressure Liquid Chromatography-Ultraviolet Detection Method for Simultaneous Quantitation of First-Line Anti-Tuberculosis Drugs in Formulations of Fixed-Dose Combination.

The current treatment protocol for drug-sensitive tuberculosis involves all four first-line anti-tuberculosis drugs: rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride in a single tablet, known as fixed-dose combination tablets. However, the analytical methods are scanty to test all these drugs simultaneously in a single run without any pre-sample process or using a simple method suitable for resource-limited settings. In this method, 50mM potassium phosphate buffer containing 0.2% triethylamine (without pH adjustment) added with acetonitrile (98:2, v/v) was served as mobile phase A, while mobile phase B was 100% acetonitrile. All four drugs were separated within 10.3min using a gradient mobile phase program in a C18 column (150mm × 4.6mm; 5μm) and detected at two ultraviolet wavelengths (238nm for rifampicin, isoniazid and pyrazinamide, and 210nm for ethambutol hydrochloride). The method was selective, sensitive and linear with a correlation coefficient >0.999 with the acceptable precision and accuracy (<2% relative standard deviation) for all four drugs. In conclusion, the method is simple and it does not require any pH adjustment of the buffer/mobile phase, and within 11min, the separation of all four drugs can be achieved. Overall, the method is suitable for quality testing of fixed-dose combination tablets in limited-resource settings.

Determinants of multidrug-resistant tuberculosis among adults undergoing treatment for tuberculosis in Tigray Region, Ethiopia: a case–control study

BackgroundMultidrug-resistant tuberculosis is a type of tuberculosis that is resistant to at least the first-line antituberculosis drugs namely, rifampicin and isoniazid. However, most of these studies were limited only to...