First-line Antituberculosis Drugs Research Articles

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...

Resistance Rates of Mycobacterium tuberculosis Complex Isolates to Primary Anti-tuberculosis Drugs: A 5-Year Retrospective Study

Background/Aim: Tuberculosis remains a major global health problem with a high morbidity and mortality rate, approximately a quarter of the population is infected with tuberculosis. Drug susceptibility testing is an essential tool for identifying and managing drug-resistant tuberculosis. This study was conducted to evaluate the drug susceptibility pattern of Mycobacterium tuberculosis complex strains isolated from a university hospital. Methods: A total of 10900 samples sent to the microbiology laboratory with the suspicion of tuberculosis clinically between January 2018 and January 2022 were analyzed retrospectively. The automated BACTEC MGIT 960 (Becton Dickinson, USA) was used for sample culture and susceptibility testing. The obtained data were statistically analyzed with the Statistical Package for Social Sciences (SPSS version 20). Results: Out of the 154 isolated positive samples, males and females constituted equal parts of the study population (50%). The majority of tuberculosis cases were in the age group 56–75 years (42.2%), Pulmonary TB was detected in (90.3%) of the patients, while extrapulmonary TB cases were observed in (9.7%). As a result of susceptibility studies on positive samples, isoniazid resistance was 5.2%; streptomycin resistance 1.3%; ethambutol resistance was detected at a rate of 0.6%, while no rifampicin resistant sample was found. Both streptomycin and isoniazid resistance were seen together in 1.3% of the samples. Conclusion: A similar resistance pattern of the first-line antituberculosis drugs was observed in other studies conducted in different provinces of Turkey. The absence of multi-drug resistant and extensively drug-resistant tuberculosis in our study indicates that the tuberculosis surveillance program implemented in our region was successful.

Pharmacogenetic variability of tuberculosis biomarkers in native and mestizo Peruvian populations.

In Peru, 29 292 people were diagnosed with tuberculosis in 2022. Although tuberculosis treatments are effective, 3.4%-13% are associated with significant adverse drug reactions, with drug-induced liver injury (DILI) considered the most predominant. Among the first-line antituberculosis drugs, isoniazid is the main drug responsible for the appearance of DILI. In liver, isoniazid (INH) is metabolized by N-acetyltransferase-2 (NAT2) and cytochrome P450 2E1 (CYP2E1). Limited information exists on genetic risk factors associated with the presence of DILI to antituberculosis drugs in Latin America, and even less is known about these factors in the native and mestizo Peruvian population. The aim of this study was to determine the prevalence of NAT2 and CYP2E1 genotypes in native and mestizo population. An analytical cross-sectional analysis was performed using genetic data from mestizo population in Lima and native participants from south of Peru. NAT2 metabolizer was determined as fast, intermediate and slow, and CYP2E1 genotypes were classified as c1/c1, c1/c2 and c2/c2, from molecular tests and bioinformatic analyses. Of the 472 participants, 36 and 6 NAT2 haplotypes were identified in the mestizo and native population, respectively. In mestizo population, the most frequent NAT2*5B and NAT2*7B haplotypes were associated with DILI risk; while in natives, NAT2*5G and NAT2*13A haplotypes were associated with decreased risk of DILI. For CYP2E1, c1/c1 and c1/c2 genotypes are the most frequent in natives and mestizos, respectively. The linkage disequilibrium of NAT2 single nucleotide polymorphisms (SNPs) was estimated, detecting a block between all SNPs natives. In addition, a block between rs1801280 and rs1799929 for NAT2 was detected in mestizos. Despite the limitations of a secondary study, it was possible to report associations between NAT2 and CYP2E alleles with Peruvian native and mestizo by prevalence ratios. The results of this study will help the development of new therapeutic strategies for a Tuberculosis efficient control between populations.

Trends in and Risk Factors for Drug Resistance in Mycobacterium tuberculosis in HIV-Infected Patients.

Trends in and risk factors for drug resistance in Mycobacterium tuberculosis (M. tuberculosis) in human immunodeficiency virus (HIV)-infected patients with active tuberculosis were analyzed. The clinical data of M. tuberculosis and HIV-coinfected patients treated at the Shanghai Public Health Clinical Center between 2010 and 2022 were collected. The diagnosis of tuberculosis was confirmed by solid or liquid culture. The phenotypic drug susceptibility test was carried out via the proportional method, and the resistance to first-line and second-line drugs was analyzed. Logistic regression analysis was performed to identify associated risk factors for drug resistance in M. tuberculosis. Of the 304 patients with a M. tuberculosis-positive culture and first-line drug susceptibility test results, 114 (37.5%) were resistant to at least one first-line anti-tuberculosis drug. Of the 93 patients with first-line and second-line drug susceptibility test results, 40 (43%) were resistant to at least one anti-tuberculosis drug, and 20 (21.5%), 27 (29.0%), 19 (20.4%), 16 (17.2%), and 14 (15.1%) were resistant to rifampicin, streptomycin, ofloxacin, levofloxacin, and moxifloxacin, respectively; 17 patients (18.3%) had multidrug-resistant tuberculosis (MDR-TB). Between 2010 and 2021, the rate of resistance to streptomycin and rifampicin ranged from 14.3% to 40.0% and from 8.0% to 26.3%, respectively, showing an increasing trend year by year. From 2016 to 2021, the rate of resistance to quinolones fluctuated between 7.7% and 27.8%, exhibiting an overall upward trend. Logistic regression analysis showed that being aged <60 years old was a risk factor for streptomycin resistance, mono-drug resistance, and any-drug resistance (RR 4.139, p = 0.023; RR 7.734, p = 0.047; RR 3.733, p = 0.009). Retreatment tuberculosis was a risk factor for resistance to rifampicin, ofloxacin, of levofloxacin (RR 2.984, p = 0.047; RR 4.517, p = 0.038; RR 6.277, p = 0.014). The drug resistance rates of M. tuberculosis to rifampicin and to quinolones in HIV/AIDS patients were high and have been increasing year by year. Age and a history of previous anti-tuberculosis treatment were the main factors associated with the development of drug resistance in HIV/AIDS patients with tuberculosis.

Investigating the Impact of First-Line Anti-Tuberculosis Drugs Encapsulated in a Eugenol-Based Nanoemulsion on Human Serum Albumin.

Eugenol exhibits broad-spectrum antibacterial and anti-inflammatory properties. However, cytotoxicity at high concentrations limits the full utilization of eugenol-based drug complexes. Formulations of multidrug-loaded eugenol-based nanoemulsions have reduced cytotoxicity; however, it remains crucial to understand how these eugenol complexes interact with primary human carrier proteins to design and develop therapeutic alternatives. Consequently, this study primarily aims to investigate the impact on Human Serum Albumin (HSA) when it interacts with eugenol-based complexes loaded with first-line anti-tuberculosis drugs. This study used various spectroscopic such as UV-visible spectroscopy, Fluorescence spectroscopy, Fourier-transform infrared spectroscopy and computational methods such as molecular docking and 100 ns molecular simulation to understand the impact of eugenol-based first-line anti-tuberculosis drug-loaded nanoemulsions on HSA structure. The binding of the HSA protein and eugenol-based complexes was studied using UV-visible spectroscopic analysis. Minor changes in the fluorophores of the protein further confirmed binding upon interaction with the complexes. The Fourier-transform infrared spectra showed no significant changes in protein structure upon interaction with eugenol-based multidrug-loaded nanoemulsions, suggesting that this complex is safe for internal administration. Unlike eugenol or first-line anti-tuberculosis alone, molecular docking revealed the strength of the binding interactions between the complexes and the protein through hydrogen bonds. The docked complexes were subjected to a 100 ns molecular dynamics simulation, which strongly supported the conclusion that the structure and stability of the protein were not compromised by the interaction. From the results we could comprehend that the eugenol (EUG)-drug complex showed greater stability in HSA protein structure when compared to HSA interacting with isoniazid (INH), rifampicin (RIF), pyrazinamide (PYR), or ethambutol (ETH) alone or with EUG alone. Thus, inferring the potential of EUG-based drug-loaded formulations for a safer and efficient therapeutic use.

Interaction of eugenol-based anti-tuberculosis nanoemulsion with bovine serum albumin: A spectroscopic study including Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol

Tuberculosis (TB), a deadly infectious disease, is primarily caused by the bacterium Mycobacterium tuberculosis. The misuse of antibiotics has led to the development of drug resistance, prompting researchers to explore new technologies to combat multidrug-resistant Tuberculosis (MDR TB). Phospholipid-based nanotherapeutics, such as nanoemulsions, are gaining traction as they enhance drug solubility, stability, and bioavailability. Our study focuses on the interaction between Bovine Serum Albumin (BSA) and a drug-loaded nanoemulsion based on Eugenol. This nanoemulsion incorporates Eugenol, Clove, cinnamon oil, and first-line anti-tuberculosis drugs like Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol. The primary objective is to assess the biosafety profile of the nanoemulsion upon interaction with BSA. We employed Fluorescence, UV–visible, and Fourier Transform Infrared Spectroscopy (FTIR) to analyze this interaction.UV–visible spectroscopy detected changes in hydrophobicity due to structural alterations in BSA near the tryptophan residue, leading to the formation of ground-state complexes. Fluorescence spectroscopy demonstrated that the nanoemulsion effectively quenched fluorescence originating from tryptophan and tyrosine residues. Studies using synchronous and three-dimensional spectroscopy point to a potential modification of the aromatic environment of BSA by the nanoemulsion. Resonance light scattering spectra indicated the formation of large aggregates due to the interaction with the nanoemulsion. The second derivative FTIR spectra showed an increase in the magnitude of secondary structure bands, suggesting a conformational shift. This research has significant pharmacological implications for developing safer, more targeted drug delivery systems. The information obtained from the interaction of the nanoemulsion with the blood carrier protein is vital for the future development of superior carriers with minimal adverse effects on patients. It is crucial to remember that conformational changes brought on by drug-ligand complexes attaching to carrier proteins may have negative consequences. Therefore, this study enhances the in vitro evaluation of potential adverse effects of the nanoemulsion on serum proteins.

Model-Informed Precision Dosing of Isoniazid: Parametric Population Pharmacokinetics Model Repository.

Isoniazid (INH) is a crucial first-line anti tuberculosis (TB) drug used in adults and children. However, various factors can alter its pharmacokinetics (PK). This article aims to establish a population pharmacokinetic (popPK) models repository of INH to facilitate clinical use. A literature search was conducted until August 23, 2022, using PubMed, Embase, and Web of Science databases. We excluded published popPK studies that did not provide full model parameters or used a non-parametric method. Monte Carlo simulation works was based on RxODE. The popPK models repository was established using R. Non-compartment analysis was based on IQnca. Fourteen studies included in the repository, with eleven studies conducted in adults, three studies in children, one in pregnant women. Two-compartment with allometric scaling models were commonly used as structural models. NAT2 acetylator phenotype significantly affecting the apparent clearance (CL). Moreover, postmenstrual age (PMA) influenced the CL in pediatric patients. Monte Carlo simulation results showed that the geometric mean ratio (95% Confidence Interval, CI) of PK parameters in most studies were within the acceptable range (50.00-200.00%), pregnant patients showed a lower exposure. After a standard treatment strategy, there was a notable exposure reduction in the patients with the NAT2 RA or nonSA (IA/RA) phenotype, resulting in a 59.5% decrease in AUC0-24 and 83.2% decrease in Cmax (Infants), and a 49.3% reduction in AUC0-24 and 73.5% reduction in Cmax (Adults). Body weight and NAT2 acetylator phenotype are the most significant factors affecting the exposure of INH. PMA is a crucial factor in the pediatric population. Clinicians should consider these factors when implementing model-informed precision dosing of INH. The popPK model repository for INH will aid in optimizing treatment and enhancing patient outcomes.

Patterns of resistance to first-line anti-Tuberculosis drugs among patients in Abuja, Nigeria: 2009-2012

Patterns of resistance to first-line anti-Tuberculosis drugs among patients in Abuja, Nigeria: 2009-2012

Development and Validation of a UPLC-MS/MS Method for Therapeutic Drug Monitoring, Pharmacokinetic and Stability Studies of First-Line Antituberculosis Drugs in Urine.

Tuberculosis (TB) remains one of the leading global causes of mortality. Several methods have been established to detect anti-TB agents in human plasma and serum. However, there is a notable absence of studies analyzing TB drugs in urine. Thus, our objective was to validate a method for quantifying first-line anti-TB agents: isoniazid (INH), pyrazinamide (PZA), ethambutol (ETH), and rifampicin (RIF), along with its metabolite 25-desacetylrifampicin, and degradation products: rifampicin quinone and 3-formyl-rifampicin in 10 µL of urine. Chromatographic separation was achieved using a Kinetex Polar C18 analytical column with gradient elution (5 mM ammonium acetate and acetonitrile with 0.1% formic acid). Mass spectrometry detection was carried out using a triple-quadrupole tandem mass spectrometer operating in positive ion mode. The lower limit of quantification (LLOQ) was 0.5 µg/mL for INH, PZA, ETH, and RIF, and 0.1 µg/mL for RIF's metabolites and degradation products. The method was validated following FDA guidance criteria and successfully applied to the analysis of the studied compounds in urine of TB patients. Additionally, we conducted a stability study of the anti-TB agents under various pH and temperature conditions to mimic the urine collection process in different settings (peripheral clinics or central laboratories).

Hypersensitivity reactions with first-line antituberculosis drugs and outcomes of rapid desensitizations

BackgroundData about drug hypersensitivity reactions with first-line antituberculosis drugs and their management is limited. Rapid drug desensitization seems to be an appropriate management. ObjectiveEvaluate the efficacy of the rapid desensitization protocols in patients who had a reaction phenotypically compatible with immediate-type drug hypersensitivity with first-line antituberculosis drugs and identify possible risk factors of breakthrough reactions during the protocols. MethodsThis is a retrospective study of active tuberculosis patients who had a reaction phenotypically compatible with immediate-type drug hypersensitivity with first-line antituberculosis drugs and underwent desensitization with the drugs used during the reaction. Characteristics of drug hypersensitivity and breakthrough reactions, and outcomes of rapid desensitizations were recorded. ResultsOne hundred and seventy-nine patients were included in the study. Most of the initial reactions (n = 132, 73.7%) occurred within the first week of treatment and were mild (n = 146, 81.6%). A total of 690 desensitizations were performed. Desensitizations were successfully completed without any breakthrough reaction in 103 (57.5%) patients and in 29 of 36 (80.6%) patients after a breakthrough reaction. The overall success of desensitizations were found to be 95% (132 of 139 patients). Most of the breakthrough reactions (84%) were mild. Sixteen patients had breakthrough reactions with multiple drugs. Although pyrazinamide was the most common culprit of breakthrough reactions and had the lowest desensitization success, it had the highest rate of a single breakthrough reaction (p < 0.001). Timing of the initial reaction and concomitant breakthrough reaction with ethambutol were found to have increased the risk for breakthrough reaction caused by rifampicin (p = 0.017 and p = 0.010 respectively). ConclusionThe rapid desensitization protocols used in this study provide a successful and effective management of the patients with a reaction phenotypically compatible with immediate-type drug hypersensitivity with first-line antituberculosis drugs.

Two Difficult Pandemics: Tuberculosis and COVID-19.

The coinfection of Mycobacterium tuberculosis and SARS-CoV-2 is called tuberculosis and COVID-19 coinfection (TB-COVID-19). We aimed to share the clinical, radiological, and laboratory findings and treatment processes of our patients with TB-COVID-19 coinfection in our tertiary reference hospital. Patients aged 18 years and over and hospitalized in the tuberculosis service between March 2020 and September 2022 were included. All coinfected patients whose COVID-19 polymerase chain reaction results were positive while receiving tuberculosis treatment or who were diagnosed with tuberculosis while receiving treatment for COVID-19 were included. The number of patients was 39; 61.6% of males; the mean age was 52 ± 17.1 years; 20% were foreign nationals; 92.5% were Asian; 69.5% had a bacteriological diagnosis; 84.6% had pulmonary tuberculosis; 10% had received antituberculosis treatment before; and 87.5% were sensitive to the first-line antituberculosis drugs. The most common comorbidities were diabetes and hypertension. 87.5% of the patients were diagnosed with tuberculosis and were superinfected with COVID-19 while receiving tuberculosis treatment. 49.5% of patients had received at least one dose of COVID-19 vaccine. The most common presenting symptom was cough and sputum; the prominent laboratory parameter was C-reactive protein increase, and thorax computed tomography finding was consolidation, tree-in-bud, and cavitation. While 45.9% of the patients were still under treatment, 1 (2.5%) patient also resulted in mortality. In this study, attention was drawn to two infectious diseases seen with respiratory tract symptoms. The mortality rate was found to be low. Neither disease was found to be a factor aggravating the course of each other.

Profile of gene mutations responsible for M.Tuberculosis resistance to antituberculosis drugs

The implementation of rapid diagnostic tests and drug susceptibility testing requires a complex approach to these methods. The pattern of gene mutations responsible for resistance to first-line antituberculosis drugs was studied in patients with resistant tuberculosis undergoing treatment in the inpatient department of the Phthisiopneumology Institute. The obtained results were compared with similar data from previous studies. It was determined that in the last 5 years the resistance to RIF is predominantly determined by the rpoB S531L mutation (82.9%), for the resistance to INH the katG S315T1 mutation (94.6%) is responsible.

Drug-resistant pulmonary tuberculosis at Maradi Regional Hospital Center, Niger (2014-2018)

To describe the clinical, therapeutic and evolutionary profile of patients followed for rifampicin-resistant pulmonary tuberculosis (RR-TB) at the Regional Hospital Centre (RHC) of Maradi (Niger) from 2014 to 2018. We conducted a retrospective and descriptive study based on the records of patients followed for Multidrug-resistant tuberculosis (MDR-TB) between January 1, 2014 and June 30, 2018 at the resistant tuberculosis management unit in Maradi (Niger). This unit is located within the RHC of Maradi and has a capacity of 20 beds in 4 wards. It receives patients with tuberculosis resistant to first-line anti-tuberculosis drugs. In this study, patients diagnosed with RR-TB by genotypic (GeneXpert MTB/RIF) or phenotypic (culture) testing were included. We excluded from this study: patients previously treated for more than 1 month with second-line anti-TB drugs; patients with resistance to second-line injectables (SLI) and/or fluoroquinolones (FQ); patients with an electrocardiogram QTc greater than 500 ms (the corrected QT (QTc) estimates the QT interval at a rate of 60 beats per second); cases of atypical mycobacteriosis detected by phenotypic testing.Patients were previously on 2RHZE/4RH prior to the discovery of resistance. The treatment protocol for resistant TB was as follows: 4KmMfxPtoCfzHZE/5MfxCfzZE (The second-line injectable was replaced by Lzd in case of initial or treatment-emergent deafness). HIV co-infected patients received, in addition to anti-tuberculosis drugs, antiretrovirals and cotrimoxazole in preventive doses. A total of 80 patients were included in the present study (70 males and 10 females, mean age 34.4 years with extremes ranging from 18 to 71 years). Patients aged 18-35 years accounted for more than half. Patients with primary treatment failure were the most frequent type (36%) followed by patients with retreatment failure (24%) and patients with retreatment relapse (17%). It should be noted that 77 patients (96%) were previously treated for TB and only 3 patients (4%) were new cases. The majority of patients (70%) had a Body mass index of less than 18 kg/m2. 7.5% of patients were HIV positive, one was diabetic, 52% of the patients had grade 2 radiological lesions. Grade 1 deafness was noted at the beginning of treatment in 3%. A third of patients (36%) were primary treatment failures. The treatment protocol was as follows: 4KmMfxPtoCfzHZE/5MfxCfzZE. Only 1 patient had a positive culture at the end of the 4th month of treatment. Most of the patients had experienced adverse events, mainly digestive, with vomiting being the most common. The therapeutic success rate was 88%. We noted 10% of deaths, 1% of therapeutic failure and 1% of lost to follow-up.Six months after treatment, 48 patients (60%) were smear negative and 43 (54%) were culture negative. In 32 patients (40%), the smear was not performed and culture was not performed in 37. The short treatment regime gives satisfactory results in the absence of resistance to fluoroquinolones, with rare adverse effects. In Niger, further efforts should be made to minimize the delay in diagnosis which is responsible for most deaths during treatment. A centre could usefully be designated to organize "TB consiliums" allowing any practitioner to submit difficult cases of MDR-TB.

Drug-resistant Tuberculosis in Pediatric

Introduction: Drug-resistant tuberculosis (DR TB) is a condition where Mycobacterium tuberculosis is resistant to isoniazid, rifampicin or resistant to isoniazid and rifampin as well as other first-line anti-tuberculosis drugs (OAT). Tuberculosis (TB) is a contagious infectious disease, caused by Mycobacterium tuberculosis germs where the source of transmission is through droplets containing TB germs. Case Report: A 10 years 7 months girl, came to the MDR Polyclinic at the Haji Adam Malik Medan Central General Hospital (RSUP HAM Medan) on March 21 2023 bringing the results of the TB Molecular Rapid Test (TCM-TB) examination from the Teladan Barat Health Center with Rifampicin results were resistant and on March 24 2023 the patient was hospitalized. Currently, the patient is complaining of a cough that has been experiencing for ± 3 weeks. Cough with the impression of a dry cough and is continuous so that it interferes with daily activities. The cough does not improve even though the patient has taken cough medicine. There is no fever, there is also no history of previous fever. According to the anamnesis from the patient's parents, there has been a weight loss in the last 2 months, around ± 4 kg. There is no family history of long-term cough, but according to parents, there is a neighbor of the patient who suffers from pulmonary TB and is undergoing treatment. Discussion: After the diagnosis of drug-resistant tuberculosis is confirmed, an evaluation is carried out whether the patient meets the criteria for drug-resistant TB treatment guided by short-term or long-term oral drug-resistant tuberculosis. Patients who meet the evaluation criteria for treatment can immediately be given short-term oral drug-resistant tuberculosis therapy. If the patient does not meet the criteria for short-term treatment, long-term drug-resistant tuberculosis treatment is given. Routine evaluations are carried out during treatment and when the results of drug sensitivity tests are available, treatment is adjusted according to the examination results. Conclusion: A case of drug-resistant tuberculosis in a girl aged 10 years 7 months has been reported which was diagnosed based on anamnesis, physical examination, and supporting examinations, there was also a history of close contact with TB sufferers, and the results of TCM examination of sputum fluid showed rifampicin resistant MTB growth. Patients are treated as drug-resistant TB cases with a short-term regimen with regular monitoring of treatment response and side effects.

Multi-drug-resistant tuberculosis and its associated factors among pulmonary tuberculosis patients linked to first-line anti-tuberculosis drugs in north-west Ethiopia

Introduction. Multi-drug-resistant tuberculosis (MDR-TB) is an emerging global challenge. Ethiopia is one of the 20 top countries with the highest estimated numbers of incidents of MDR-TB. Recently, the World Health Organization warned that drug-resistant TB is escalating and called for concerted action to reduce the spread of drug resistance. Hypothesis. The current study investigated MDR-TB in patients receiving first-line anti-TB drug treatment and associated factors. Aim. The study aimed to determine the prevalence of MDR-TB and its associated factors among smear-positive pulmonary TB patients receiving first-line anti-TB drug treatment. Methodology. An institution-based cross-sectional study was employed. All data were collected from laboratory result log books and information via a questionnaire. Samples from 205 smear-positive pulmonary TB patients were selected among first-line drug treatment by a systematic sampling method. Specimens were transported to Felege Hiwot referral hospital laboratory for GeneXpert testing. Factors associated with an outcome variable in binary multi-variable logistic regression analysis at P&lt;0.05 were considered statistically significant variables. An ethical approval letter was taken to the respective health facility and written consent was obtained from each participant. Results. The overall prevalence of MDR-TB was 9.3 % (95 % CI, 5.4 13.7 %). Sign and symptom experience of anti-TB drug side effects [adjusted odds ratio (AOR)=0.18, 95 % CI=0.03–0.99, P=0.049] and co-morbidity (AOR=0.03, 95 % CI=0.01–0.55, P=0.02) were statistically associated with the development of MDR-TB infection Conclusion. The prevalence of MDR-TB was high (9.3 %) and contributed highly to new cases (8.3 %). Factors associated with MDR-TB were previous treatment, co-morbidity and laboratory diagnosis method prior to TB treatment. Therefore, this finding aims to maximize early detection and treatment, strengthening TB infection control, and proper implementation of directly observed therapy short course recommendations to reduce the burden of MDR-TB.

ADME, Synthesis and Antimycobacterial Activity of 1,2,4-Triazol-3-thiol Linked Phenylacetamide Derivatives

Background:: Tuberculosis (TB) is caused by Mycobacterium tuberculosis and is one of the most contagious and fatal human pathogens which necessitates the development of modified existing drugs or derivatives with action against novel targets. Aims and Objectives:: In the present work, we have explored a few, 2-(5-(substituted)-4H-1,2,4-triazole-2-ylthio)-N-(substituted) phenyl acetamide (5A-5E) derivatives as anti-TB. Materials and Methods:: On the basis of SAR were synthesized and screened against Mycobacterium tuberculosis H37Rv using MABA assay. Their ADME properties were also checked. Results:: ADME analysis showed results comparable with standard drug (rifampicin). Derivative 5D turned out to be the most active amongst all the derivatives with MIC of 0.8μg/ml, comparable to standard drugs like rifampicin(0.8μg/ml) and streptomycin(0.8μg/ml). Conclusion:: All five compounds have shown excellent inhibitory activity (1.6μg/ml) against the Mycobacterium tuberculosis H37Rv strain. Compound 5D shows a promising activity (0.8μg/ml) as compared to standard drugs and also it has shown the highest docking score. Literature search has revealed the presence of 1,2,4-triazole derivatives linked to aromatic link and possessing amide linkage and the presence of Sulphur atom in the most active derivatives, which supports our designed compounds. Based on these findings, further derivatives would be synthesized and explored for their role in tuberculosis.

First-Line Antituberculosis Drug Concentrations in Infants With HIV and a History of Recent Admission With Severe Pneumonia.

Optimal antituberculosis therapy is essential for favorable clinical outcomes. Peak plasma concentrations of first-line antituberculosis drugs in infants with living HIV receiving WHO-recommended dosing were low compared with reference values for adults, supporting studies on increased doses of first-line TB drugs in infants.

Acute generalized exanthematous pustulosis induced by isoniazid and pyrazinamide in a child

An 8-year-old female with cervical lymph node tuberculosis, received rifampicin, isoniazid, pyrazinamide, and ethambutol. Two weeks later, she developed a fever and a generalized erythematous rash covered with pustules. Acute generalized exanthematous pustulosis diagnosis was confirmed by a skin biopsy. Antitubercular therapy was discontinued. Drug causality was found using oral provocation tests and patch tests. Cutaneous adverse drug reactions to first-line antituberculosis drugs are common. However, acute generalized exanthematous pustulosis is rare. It is a severe form of cutaneous drug reaction, primarily associated with beta-lactam antibiotics, and clinically characterized by non-follicular pustules on erythematous skin.

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

Data about antituberculosis drugs binding are incomplete for first-line drugs and lacking for second-line drugs that are used extensively for multi-drug resistant tuberculosis (levofloxacin, linezolid and moxifloxacin). Thus, the main purposes of this study were first to investigate thoroughly the relation between the carrier-proteins level and the drug binding and second to investigate the feasibility of predicting the free drug concentrations by the means of in vitro and in vivo results. In vitro experiments mimicked real-case samples by spiking drugs combinations from the clinical practice. We measured a median in vivo protein binding of 1.5% for ethambutol, 9.7% for isoniazid, 0.7% for pyrazinamide and 88.2% for rifampicin; and a median in vitro protein binding of 26.2% for levofloxacin, 12.8% for linezolid and 46.3% for moxifloxacin. The albumin concentration had a moderate impact on the moxifloxacin binding and a strong impact on the levofloxacin, linezolid and rifampicin binding (below values of 30 g/L). The determination of the free drug concentration seems to have few interests for ethambutol, isoniazid, moxifloxacin and pyrazinamide, a limited interest for linezolid because of its low binding and a major interest for rifampicin in hypoalbuminemia TB patients and for levofloxacin because their total concentration was an inaccurate reflection of the free concentration. The free concentration predicted by mathematical model was suitable for levofloxacin and linezolid, unlike for rifampicin, where the real free concentration should be measured. Further investigations should be carried out to investigate the benefit of the free concentration for levofloxacin, linezolid and rifampicin mainly in the critical period of active tuberculosis associated to hypoalbuminemia.