First-line Antituberculosis Drugs Research Articles

Discovery of novel reversible inhibitor of DprE1 based on benzomorpholine for the treatment of tuberculosis.

About a quarter of the world's population is infected with Mycobacterium tuberculosis, equivalent to about two billion people. With the emergence of multidrug-resistant tuberculosis, those existing anti-tuberculosis drugs no longer meet the demand for cure anymore; there is an urgent need for the development of new anti-tuberculosis drugs. Decaprenylphosphoryl-β-D-ribose 2´-epimerase (DprE1) has been proven to be a potential antimycobacterial target, and several inhibitors have entered clinical trial. Herein, we designed and synthesized a series of compounds based on the indole and benzomorpholine by using the strategy of scaffold hopping. The preferred compound B18 showed strong antimycobacterial activity in H37Rv and drug-resistant clinical isolates. In addition, compound B18 did not exhibit antimycobacterial efficacy against other species of strains. Subsequently, the target of B18 was identified as DprE1 by analyzing spontaneous compound-resistant mutation data, and a docking study was performed to illustrate the binding mode between B18 and DprE1. In general, compound B18 is compatible to current DprE1 inhibitors, even higher phosphodiesterase 6C selectivity and plasma protein binding rate, which represent a new type of effective reversible DprE1 inhibitor. IMPORTANCE Drug therapy remains the cornerstone of tuberculosis (TB) treatment, yet first-line anti-tuberculosis drugs are associated with significant adverse effects that can compromise patient outcomes. Moreover, prolonged and widespread use has led to an alarming rise in drug-resistant strains of Mycobacterium tuberculosis, including multidrug-resistant [MDR-tuberculosis (TB)] and extensively drug-resistant (XDR-TB) forms. Urgent action is needed to develop novel anti-tuberculosis agents capable of overcoming these challenges. We report that compound B18, a decaprenylphosphoryl-β-D-ribose 2´-epimerase inhibitor with a benzomorpholine backbone, exhibits potent activity against not only the non-pathogenic strain H37Ra, but also the pathogenic strain H37Rv and clinical MDR and XDR strains. Preliminary druggability studies indicate that B18 possesses high safety and acceptable pharmacokinetic properties, rendering it a promising candidate for further development as a novel anti-tuberculosis agent.

Features of the profile of drug resistance to first-line and second-line anti-tuberculosis drugs in patients with human immunodeficiency virus infection

BACKGROUND: Drug resistance to anti-tuberculosis drugs directly affects the disease course. However, a high percentage of multidrug resistance in patients with HIV infection not only worsens the disease course but also forces the development of new strategies for managing such patients.
 AIMS: To characterize drug resistance to anti-tuberculosis drugs in patients with HIV infection.
 MATERIALS AND METHODS: The study recruited patients with newly diagnosed tuberculosis by molecular genetic research methods and bacterial research methods in the Orenburg Regional Clinical Tuberculosis Dispensary.
 RESULTS: For 20182022, the proportion of people with HIV infection who are resistant to isoniazid by 14.6%, rifampicin by 28.85%, moxifloxacin by 717.39%, and amikacin by 104.25% has increased. The reduction in the choice of drugs and possibility of effective anti-tuberculosis therapy in people with HIV infection are also complicated by the detection of a multidrug-resistant culture in 20.34% of the examined patients and multidrug resistance in 39.6%. In over 5 years, the percentage of gene mutations of mycobacteria responsible for resistance to anti-tuberculosis drugs has increased.
 CONCLUSIONS: The results of this study indicate the need to search for new solutions and prevent resistance to existing anti-tuberculosis drugs and for the development of new drugs effective for use as first- and second-line drugs.

Protective Effect of Andropraphis Paniculata Aqueous Extract (EAAp) Against Isoniazid and Rifampicin-Induced Rat Liver Damage

Isoniazid (INH) and rifampicin (RIF) are first-line antituberculosis drugs (OAT) in tuberculosis treatment that are used for at least 6 months. The use of OAT has been associated with toxic reactions in the liver and causes hepatitis. This study aimed to determine the effect of an aqueous extract of Andrographis paniculata (EAAp) on liver damage induced by INH and RIF. Method: Male Sprague-Dawley rats weighing 250–300g were divided into 5 groups, each consisting of 6 mice. Animals were given isoniazid and rifampicin at 100 mg/kg, respectively, to induce liver damage, silymarin (25 mg/kg) for the positive control group, and Ap extract at doses of 200mg and 300 mg/kg for the test group. All treatments were given orally once daily for 28 days. Measurement of serum aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), bilirubin, and liver histopathology levels was carried out to determine the effect of EAAp on liver damage by INH and RIF. Results: Rats treated with INH+RIF were hepatotoxic, as evidenced by increased serum ALT, AST, and ALP activity, total bilirubin levels, and histopathological changes in the liver. Administration of Ap extract doses of 200 mg/kg and 300 mg/kg significantly decreased liver biochemical and histological changes caused by OAT. Conclusions: EAAp has a protective effect against hepatotoxic-induced INH and RIF in animal models.

Diclofenac sodium and Allopurinol induced Stevens Johnson Syndrome in pulmonary tuberculosis patients receiving intensive phase first-line antituberculosis drugs

One of the life-threatening multi-organ emergency conditions is Stevens-Johnson Syndrome (SJS). Although this is a rare disease and manifests as drug reactions, this condition can cause death.We present a case of a 63-year-old male with Diclofenac sodium and Allopurinol induced Stevens_Johnson Syndrome in pulmonary tuberculosis patients receiving intensive phase first-line antituberculosis drugs.The patient was undergoing outpatient TB treatment at the end of the first month. The patient comes to the emergency department of the hospital because of shortness of breath, fever, blistered skin, nasal and oral mucosa, cracks and wounds, visible pus, red eyes accompanied by erythematous rash all over the body after previously taking diclofenac sodium and allopurinol given by the doctor because felt joint pain all over body and uric acid increased. On physical examination of the lungs, crackles and wheezing were heard in both lung fields. The chest radiograph shows infiltrates in both lung fields. Laboratory results showed leukocytosis and the results of other blood laboratory tests were still within normal limits. Patient diagnosed Stevens-Johnson Syndrome based on clinical, laboratory, and radiology examination results. The patient was given treatments using nasal canule oxygen of 5 litres/minute, intravenous fluid dehydration D5% : NaCl 0.9%, ceftriaxone injection, gentamicin injection, dexamethasone injection, cetirizine ranitidine injection, compresses with 0.9% NaCl liquid, 2.5% hydrocortisone ointment. The patient was treated in the Intensive Care Unit for 8 days. The patient had no history of previous drug allergies. In this case, the likelihood of Diclofenac sodium and Allopurinol induced Stevens_Johnson Syndrome in pulmonary tuberculosis patients receiving intensive phase first-line antituberculosis drugs, needs to be a concerned, as well as the importance of evaluation and strict follow-up to prevent Stevens Johnson Syndrome disease.

Simultaneous detection and differentiation of Mycobacterium tuberculosis and nontuberculous mycobacteria coexisting in patients with pulmonary tuberculosis by single-tube multiplex PCR.

In clinical diagnostics, molecular methods are used to detect Mycobacterium tuberculosis bacilli (MTB) and to distinguish them from non-tuberculous mycobacteria (NTM). They are also used to make the right treatment decision for the patient as soon as possible. The aim of this study was to establish a rapid and novel multiplex PCR (mPCR) assay for the detection and differentiation of MTB and NTM in a single tube. 100 sputum samples positive for acid-fast bacilli (AFB) were included in this study. Mycobacterial culture, biochemical tests, and antibiotic susceptibility testing were performed on samples. After alkaline decontamination, total DNA was extracted from the samples. A primer pair targeting the rpoB gene, encoding the beta-subunit of RNA polymerase, was used to detect MTB and NTM, amplifying a 235-bp fragment of MTB and a 136-bp sequence of NTM. A pair of primers targeting a 190-bp fragment of the IS6110 region of MTB was also used to confirm the results. The sensitivity and specificity of the mPCR assay were evaluated using DNA extracted from standard strains. The amplified products were then analyzed by conventional agarose gel electrophoresis. Of 100 AFB smear-positive sputum samples, 92 MTB DNA, 7 NTM DNA, and one mixed-infection sample were identified in a single tube using mPCR assay. There was no correlation between the AFB degree of smear positivity and PCR results. Of seven NTM isolates, 6 (86%) were resistant to rifampin, isoniazid, and ethambutol, the three first-line anti-tuberculosis drugs. A single-tube mPCR assay based on the rpoB gene provides a rapid and reliable means of detecting and differentiating MTB and NTM in sputum specimens.

Impact of the Anti-Tuberculosis Drug Rifampicin on the Feeding, Growth and Embryonic Developmental Profile of the Mosquitofish <i>Gambusia affinis</i>

Although the accumulation of pharmaceutical drugs in aquatic bodies has increased rapidly in recent years, the effect of rifampicin (RIF), a first-line anti-tuberculosis drug, on fish feeding, growth, and embryonic development is unknown. This investigation aimed to determine the impact of RIF on growth and embryonic developmental profile in the mosquitofish Gambusia affinis. Experimental groups included controls, which were kept in normal water for 21 days, whereas those in the second, third, and fourth groups were exposed to 50, 200, and 500 mg RIF/L water, respectively. The food intake rate and Specific Growth Rate (SGR) showed a concentration-dependent significant decrease in RIF-treated fish compared with controls, and a strong positive correlation was found between food consumption and SGR. A significant decrease in the number of embryos at an early stage of development and the total number of embryos in RIF-treated fish was associated with several congenital anomalies such as lack of vitellogenin accumulation, yolk sac regression, decreased pigmentation, aggregations of blood vessels, and curvature of the spinal cord compared with controls. Together, these results reveal for the first time that RIF treatment not only impacts feeding and growth, but also exerts potential teratogenic effect on embryonic developmental stages in the mosquitofish G. affinis.

Isoniazid acetylator phenotype and its clinical impact in patients treated with first-line antituberculosis drugs

Isoniazid acetylator phenotype and its clinical impact in patients treated with first-line antituberculosis drugs

Epidemiology-based wastewater monitoring for ecological risks of anti-tuberculosis drugs mixture effects

First-line anti-tuberculosis (TB) drugs are commonly used to treat TB worldwide, leading to more contaminated wastewater being widely discharged into aquatic environments. However, studies of mixture interactions of anti-TB drugs and their residues in aquatic environments are scarce. This study aimed to determine the toxic interactions of anti-TB drugs—isoniazid (INH), rifampicin (RMP), and ethambutol (EMB)—in binary and ternary mixtures on Daphnia magna and used the epidemiology of TB history to construct epidemiology-based wastewater monitoring for assessing the environmental release of residues and related ecological risks. The acute immobilization of median effect concentrations (EC50) was 25.6 mg L−1 for INH, 80.9 mg L−1 for RMP, and 188.8 mg L−1 for EMB, as toxic units (TUs) for assessing mixture toxicity. The ternary mixture exhibited the lowest TUs at 50 % effects with 1.12, followed by 1.28 for RMP + EMB, 1.54 for INH + RMP, and 1.93 for INH + EMB, indicating antagonistic interactions. Nevertheless, the combination index (CBI) was used to examine the mixture toxicity in response to immobilization, revealing that the ternary mixture of CBI ranged from 1.01 to 1.08, tending to have a nearly additive effect when suffering >50 % effect (at high concentration levels). The forecasted environmentally relevant concentrations of anti-TB drugs have been on downward trends with ng L−1 level from 2020 to 2030 in Kaohsiung, Taiwan. Although ecotoxicological risks from the wastewater treatment plant and receiving water in the field were slightly greater than the prediction from epidemiology-based wastewater monitoring, there were no risk concerns. Here, we achieved the establishment of evidence that anti-TB drug mixtures' interaction and epidemiological-based monitoring support a systematic approach, resolving the absence of the mixture toxicity information for anti-TB mixture risk assessment in aquatic environments.

C-1 Substituted isoquinolines potentiate the antimycobacterial activity of rifampicin and ethambutol

IntroductionThe emergence of extensively drug-resistant strains ofMycobacterium tuberculosisthreatens decades of progress in the treatment of a disease which remains one of the leading infectious causes of death worldwide. The development of novel antimycobacterial compounds is therefore essential to reinforce the existing antitubercular drug discovery pipeline. There is also interest in new compounds which can synergize with existing antitubercular drugs and can be deployed as part of a combination therapy. This strategy could serve to delay the emergence of resistance to first-line anti-tuberculosis drugs and increase their efficacy against resistant strains of tuberculosis. Previous research has established that several C-1 substituted tetrahydroisoquinolines have antimycobacterial activity. Here we sought to expand our understanding of their antimycobacterial structure activity relationships and their potential to act as adjunct therapies alongside existing antitubercular drugs.MethodsThree chemical series were synthesised and assayed for their antimycobacterial potency, mammalian cell toxicity, inhibition of whole-cell efflux and synergism with isoniazid, rifampicin, and ethambutol.ResultsSeveral compounds were found to inhibit the growth of mycobacteria. Potent inhibitors of whole-cell efflux were also identified, as well as compounds which exhibited synergism with rifampicin and ethambutol.ConclusionsStructure-activity relationships were identified for antimycobacterial potency, improved selectivity, whole cell efflux inhibition and synergism. Potent whole-cell efflux inhibitors and synergistic compounds were identified, suggesting potential development as adjuncts to existing anti-tuberculosis chemotherapy.

Detection of katG, inhA and ahpC gene mutation in clinical isolates of isoniazid-resistant Mycobacterium tuberculosis in Makassar City, South Sulawesi, Indonesia

BackgroundTuberculosis (TB) is an airborne disease caused by Mycobacterium tuberculosis (M. tuberculosis). The world is currently facing challenges due to the spread of anti-tuberculosis drug-resistant of M. tuberculosis. Isoniazid-resistant (INH), is one of the first-line anti-tuberculosis agents that has a high resistance case. This study used Multiplex allele-specific Polymerase Chain Reaction (MAS-PCR) to detect the most common mutations associated with isoniazid resistance on inhA, katG, and ahpC gene. MethodsThis study used samples from clinical isolates of M. tuberculosis which had been tested for their antibiotic sensitivity of first-line anti-tuberculosis drugs. The DNA extraction process was carried out using the boiling method and then amplified with specific primers for inhA, katG, and ahpC genes using the MAS-PCR method. The results are then read on the electrophoretic gel with an interpretation of the mutation gene when the target gene DNA bands were absent according to the allele-specific fragments target. ResultsA total of 200 isolates were tested in this study consisting of isoniazid-resistant and susceptible with the largest distribution of Multi-Drug Resistant (MDR) isolates with a total of 146 isolates (73%). The most significant gene mutation was on the ahpC gene in 61 isolates (30,5%) and the combination mutation of the katG + ahpC gene in 52 isolates (26%) with sensitivity and specificity of the test reaching 87% and 42% for the detection of INH-resistant. ConclusionMutation on the ahpC gene has the highest percentage in this study. AhpC gene can be considered one of the essential genes to be tested for the cause of isoniazid-resistant. Using MAS-PCR for detecting gene mutation in isoniazid-resistant was simple and easy, it has the potential to be widely used as a rapid screening molecular test.

Clinical impact of plasma concentrations of first-line antituberculosis drugs.

The clinical significance of low antituberculosis (anti-TB) drug concentrations has not been fully elucidated. To investigate the clinical consequences of first-line drug concentrations in adult patients with drug-susceptible pulmonary TBin South Africa (SA). We conducted a pharmacokinetic study nested within the control arm of the Improving Treatment Success (IMPRESS) trial(NCT02114684) in Durban, SA. During the first 2 months of treatment, participants received weight-based dosing of first-line anti-TBdrugs (rifampicin, isoniazid, pyrazinamide and ethambutol), and had plasma drug concentrations measured at 2 and 6 hours after drugadministration during the 8th week of treatment. Intermediate (8 weeks), end-of-treatment (6 months) and follow-up TB outcomes wereassessed using World Health Organization criteria. We measured plasma drug concentrations on available samples in 43 participants. Peak drug concentrations were below thetherapeutic range in 39/43 (90.7%) for rifampicin, 32/43 (74.4%) for isoniazid, 27/42 (64.3%) for pyrazinamide and 5/41 (12.2%) forethambutol. At the end of the intensive phase of treatment (week 8), 20.9% (n=9/43) of participants remained culture positive. We did notfind a relationship between the concentrations of first-line drugs and treatment outcomes at week 8. All participants were cured at the endof treatment, and there were no relapses during the 12-month follow-up period. Treatment outcomes were favourable despite low drug concentrations as defined by current reference thresholds.

Performances of bioinformatics tools for the analysis of sequencing data of Mycobacterium tuberculosis complex strains

Whole-genome sequencing of Mycobacterium tuberculosis complex (MTBC) strains is a rapidly growing tool to obtain results regarding the resistance and phylogeny of the strains. We evaluated the performances of two bioinformatics tools for the analysis of whole-genome sequences of MTBC strains.Two hundred and twenty-seven MTBC strains were isolated and whole-genome sequenced at the laboratory of Avicenne Hospital between 2015 and 2021. We investigated the resistance and susceptibility status of strains using two online tools, Mykrobe and PhyResSE. We compared the genotypic and phenotypic resistance results obtained by drug susceptibility testing.Unlike with the Mykrobe tool, sequencing quality data were obtained using PhyResSE: average coverage of 98% and average depth of 119X. We found a similar concordance between phenotypic and genotypic results when determining susceptibility to first-line anti-tuberculosis drugs (95%) with both tools. The sensitivity and specificity of each tool compared to the phenotypic method were respectively 72% [52–87] and 98% [96–99] for Mykrobe and 76% [57–90] and 97% [94–99] for PhyResSE.Mykrobe and PhyResSE were easy to use and efficient. These platforms are accessible to people not trained in bioinformatics and constitute a complementary approach to phenotypic methods for the study of MTBC strains.

Evaluation of two colorimetric microplate microtiter tests for susceptibility testing of clinical isolates of Mycobacterium tuberculosis to first-line antituberculosis drugs.

Drug-resistance tuberculosis (TB) is one of the most important global public health problems. Accurate and rapid drug-susceptibility testing is critical for the effective treatment of TB patients. Various colorimetric methods are used for anti-TB drug-susceptibility testing (DST) and minimum inhibitory concentration (MIC) determination. This study was conducted to evaluate the resazurin microtiter assay (REMA) and malachite green decolorization assay (MGDA). A total of 65 Mycobacterium tuberculosis strains isolated from patients with suspected TB using REMA and malachite green microtiter assay methods were tested against streptomycin (SM), isoniazid (INH), rifampicin (RIF), and ethambutol (ETB). The Mycobacterial Growth Indicator Tube 960 DST method was accepted as the gold standard in the evaluation of test results. The sensitivity of REMA and MGDA tests was found to be 87.5% and 62.5% for INH, respectively. RIF and SM sensitivity for both tests was 100%. While ETB sensitivity was 81.8 for the REMA test, this rate was 60% for the MGDA test. Specificity of both tests varied between 92.5% and 98.2% according to the drug types. REMA and MGDA are a simple, rapid, and low cost. They can be used as an alternative test for drug-susceptibility testing and MIC determination. Extensive studies and standardization are needed for the routine use of both tests.

Patient-reported usability and satisfaction with electronic medication event reminder and monitor device for tuberculosis: a multicentre, randomised controlled trial

The success of a tuberculosis digital adherence technology relies on patients' satisfaction with and the usability of the technology. This study aimed to evaluate treatment satisfaction and usability of a digital medication event reminder and monitor (MERM) device for patients with tuberculosis to address the prespecified secondary endpoint of the SELFTB trial. In this multicenter, randomised controlled trial, adults (≥18 years) with new or previously treated, bacteriologically-confirmed, drug-sensitive pulmonary tuberculosis who were eligible to start anti-tuberculosis therapy were recruited from 10 healthcare facilities in Ethiopia. With a computer-generated random number sequence, participants were randomly assigned 1:1 to receive a 15-day tuberculosis medication supply dispensed with an evriMED500® MERM device to self-administer and return every 15 days or the standard in-person DOT. Both arms were followed throughout the standard two-month intensive treatment phase. Treatment was based on the WHO-recommended two-month fixed-dose-combination of first-line anti-tuberculosis drug delivered as a single daily dose (2RHZE). Treatment Satisfaction Questionnaire for Medication version 4 (TSQM 1.4©) was used to measure and compare treatment satisfaction between arms. Adapted System Usability Scale (SUS) was used to assess the usability of the device, with emphasis on ease of use, challenges, benefits, motivation, popularity, and recommendation. The findings were correlated with adherence and clinical endpoints including sputum smear conversion and IsoScreen urine isoniazid test results. This trial is registered with ClinicalTrials.gov, NCT04216420. Between June 2, 2020, and June 15, 2021, 337 patients were screened for eligibility, of whom 109 participants enrolled and completed the satisfaction [control (n=57) and intervention (n=52) arms] and usability [intervention arm (n=52)] questionnaires. TSQM 1.4© geometric mean scores were: Effectiveness 73.25 [geometric standard deviation (GSD) 1.28], Side Effects 100, Convenience 63.31 (GSD 1.45), and Global Satisfaction 77.29 (GSD 1.25). TSQM score was significantly higher in the intervention vs the control: Effectiveness [85.78 vs 63.43, 95% CI 1.35 (1.26-1.45), p<0.001], Convenience [85.41 vs 48.18, 95% CI 1.77 (1.63-1.93), p<0.001], and Global Satisfaction [90.19 vs 67.11, 95% CI 1.34 (1.26-1.43), p<0.001]. There were significant associations between Global Satisfaction and medication adherence (p=0.017). Average SUS score was 97.45%, which was close to the best imaginable SUS value of 100%. Likelihood to Recommend (LTR) value was ≥9, on a scale of 0-10, for 90.4% of MERM users, yielding higher net promoters. There was no significant association between usability and medication adherence (p=0.691). Our findings suggested that treatment satisfaction scores were superior in the intervention vs control arms and across the domains of Effectiveness, Convenience, and Global Satisfaction. There was excellent usability of the MERM device and a significantly higher number of users likely to promote the device. High tuberculosis burden countries may transform patient-centered care through ongoing evaluation and scale-up of digital health innovations. U.S. National Institute of Health (NIH) Fogarty International Center and National Institute of Allergy and Infectious Diseases (D43 TW009127) and the Emory Center for AIDS Research (P30 AI050409).

First and Second-Line Anti-Tuberculosis Drug-Resistance Patterns in Pulmonary Tuberculosis Patients in Zambia.

Drug-resistant tuberculosis has continued to be a serious global health threat defined by complexity as well as higher morbidity and mortality wherever it occurs, Zambia included. However, the paucity of information on drug-susceptibility patterns of both first-line and second-line anti-tuberculosis (anti-TB) drugs, including the new and repurposed drugs used in the management of drug-resistant tuberculosis in Zambia, was the major thrust for conducting this study. A total of 132 bacteriologically confirmed TB isolates were collected from patients with pulmonary TB during the period from April 2020 to December 2021 in Southern and Eastern Provinces of Zambia. Drug-resistance profiles were determined according to four first-line and five second-line anti-TB drugs. Standard mycobacteriological methods were used to isolate and determine phenotypic drug susceptibility. Data on the participants' social-demographic characteristics were obtained using a pre-test checklist. Overall, the prevalence of resistance to one or more anti-TB drugs was 23.5% (31/132, 95% CI: 16.5-31.6%). A total of 9.8% (13/132, 95% CI: 5.3-16.2%) of the patients had multidrug-resistant TB and 1.2% were new cases, while 25.5% had a history of being previously treated for TB. Among those with mono-resistant TB strains, isoniazid (INH) resistance was the highest at 9.8% (13/132, 95% CI: 5.3-16.2%). Two (2/31) (6.5%) XDR-TB and one (1/31) (3.2%) pre-XDR-TB cases were identified among the MDR-TB patients. Previously treated patients were 40 times more likely (OR; 40.3, 95% CI: 11.1-146.5%) to have drug-resistant TB than those who had no history of being treated for TB. This study has established a high rate of multidrug-resistant TB and has further identified both pre-XDR- and XDR-TB. There is a need to intensify surveillance of MDR- and XDR-TB to inform future guidelines for effective treatment and monitoring.

Hepatoprotective Pyrazinamide–Baicalein Cocrystal with a Rare Ratio of 7:3

Exploring solid forms with low toxicity and high safety is a universal theme in drug research. This study developed a new cocrystal to optimize the severe hepatotoxicity of the first-line antituberculosis drug pyrazinamide (PZA). Baicalein (BCL) was chosen as the cocrystal former for its powerful hepatoprotective effect. The PZA–BCL cocrystal was structurally characterized by single-crystal X-ray diffraction (SCXRD), powder XRD (PXRD), differential scanning calorimetry–thermogravimetry (DSC-TG), and infrared (IR) spectroscopy. Meanwhile, the in vitro dissolution and in vivo pharmacokinetics and hepatotoxicity of the cocrystal were evaluated systematically. The results highlight that the BCL obtained tremendous improvements in water solubility, bioavailability, and hepatoprotective effect after cocrystal formation, hence almost removing the toxicity of PZA finally. Furthermore, it is worth noting that the molar ratio of 7:3 was first observed in the cocrystal, which is rare relative to the widely reported simple integer ratio of pharmaceutical cocrystals. The present research provides an interesting case for applying cocrystal technology in the field of drug safety.

Adverse drug reactions to first-line antituberculosis drugs at four DOTS centers in Goa, India

BACKGROUND: Major adverse drug reactions (ADRs) can cause significant morbidity and can compromise the treatment regimen. This can result in substantial additional cost due to added outpatient visits to the health facility or laboratory investigations or hospitalization in serious instances. Treatment is often prolonged with additional challenge of compliance. Hence, there is a need to monitor and manage these ADRs timely for better patient care and outcome. This study was carried out with the objective of studying the pattern of ADRs due to first-line antitubercular drugs and to carry out the causality and severity assessment of the reported ADRs.METHODOLOGY: A prospective observational study was conducted at four DOTS centers. All tuberculosis (TB) patients registered and receiving treatment under DOTS were enrolled for the study and were followed up at regular intervals till the end of their treatment. Patients' demographic, personal, disease, investigation, and ADRs details were entered in a predesigned patient recording form. Causality assessment of all ADRs were done using Naranjo algorithm. Severity assessment was done using modified Hartwig and Siegel scale. The study was approved by the institutional ethics committee of the institute. Statistical analysis was conducted using IBM SPSS Statistics for Windows.RESULTS: Of 186 patients, 23 patients (12.26%) developed one or more ADRs. The average number of ADRs per person was 1.43. Majority of the ADRs were reported in the 20–40 years of age group and ADRs were more likely to be among females compared to males. There was no association between type of TB, site of TB, regimen of anti-TB drugs, treatment outcomes, and ADRs. Around 84.85% and 15.15% of ADRs were classified as of mild and moderate severity, respectively, as per modified Hartwig and Siegel scale, while, as per Naranjo algorithm, 72.73% of the ADRs were classified as probable and 27.27% of ADRs as possible. No ADRs were classified as definite.CONCLUSION: Thorough understanding of the various ADRs and their management will help in the effective treatment of TB as well as designing effective counseling methods, which will help in adherence to treatment and also to have better compliance.

Systematic-review-of-population-pharmacokinetic-models-of-isoniazid-in-children-and-adults-with-tuberculosis

Introduction: Isoniazid (INH) is one of the first-line anti-tuberculosis (anti-TB) drugs that have both bactericidal and bacteriostatic properties depending on the rate of mycobacterial growth. Several population pharmacokinetic (PPK) models of INH were established. This systemic review aims to summarise published PPK parameters of INH in the models and to identify covariates influencing the INH pharmacokinetic parameters of models. Method: A search of publications for PPK analyses of INH in volunteers or TB patients from 2011 to 2021 was conducted in PubMed and Scopus databases. Reviews, methodology articles, non-compartmental analysis, in vitro, and animal studies were excluded. Result: Twelve studies were included in this review. Most of the included studies described the pharmacokinetics of INH as two-compartmental with first-order absorption and elimination in most of the included studies. Eleven studies reported N-acetyltransferase 2 (NAT2) genotype polymorphism as the most common significant covariate affecting the pharmacokinetic parameters of INH. Other common significant covariates reported include body weight (n = 2) and body mass index (BMI) (n = 1). Conclusion: The variability of population clearance parameters of INH was explained mainly by the NAT2 genotype polymorphism. This indicates that to optimise and rationalise the dosing regimen of INH, a patient’s NAT2 genotype should be considered. At the same time, body weight and BMI values should be considered when making dosing adjustments for INH to achieve the therapeutic range.

Anti-Tuberculosis Therapy in The Drug Resistant Tuberculosis Patients of Kashmir Valley

Drug-resistant tuberculosis (DR-TB) strains are a significant threat to global TB control. Due to a lack of resources and inadequate healthcare infrastructure, it is difficult to identify and monitor drug resistance situations in low and middle-income nations. The study aimed to evaluate the anti-tuberculosis therapy regimen in drug-resistant tuberculosis patients of the mountainous valley of Kashmir. The current study was carried out at Government Medical College, Department of Pulmonary Medicine, Chest Diseases Hospital (CDH), Srinagar, Kashmir. A total of 1100 suspected tuberculosis subjects were included in the study, and out of 1100 TB subjects, 195 were documented medication resistance cases. Of the total 1100 Line Probe Assay (LPA) tests done, 69 (6.2%) such samples in the Tuberculosis band were absent. Of the real samples tested by LPA, Tuberculosis band (TUB) was present in 1031 samples (93.7%), of which 24 (2.3%) were multidrugresistant (MDR), 121 (11.7%) were rifampicin mono-resistant, 42 (4.0%) were isoniazid mono-resistant, 8 (0.77%) were extensively drugresistant (XDR), and 836 (81%) samples were pan-sensitive. Smoking remained an independent risk factor for poor treatment outcomes in the multivariate analysis (p-value = 0.014, OR = 4.356, 95% CI [1.425�12.45]). This study found a low incidence of Drug-Resistant Tuberculosis (DR-TB). Most of the cases were resistant to first-line anti-tuberculosis drugs. Special attention should be paid to high-risk DR-TB patients to improve treatment results even further. Further studies are recommended with a large sample size.

Evaluation Study of xMAP TIER Assay on a Microsphere-Based Platform for Detecting First-Line Anti-Tuberculosis Drug Resistance

Early diagnosis of drug susceptibility for tuberculosis (TB) patients could guide the timely initiation of effective treatment. We evaluated a novel multiplex xMAP TIER (Tuberculosis-Isoniazid-Ethambutol-Rifampicin) assay based on the Luminex xMAP system to detect first-line anti-tuberculous drug resistance. Deoxyribonucleic acid samples from 353 Mycobacterium tuberculosis clinical isolates were amplified by multiplex polymerase chain reaction, followed by hybridization and analysis through the xMAP system. Compared with the broth microdilution method, the sensitivity and specificity of the xMAP TIER assay for detecting resistance was 94.9% (95%CI, 90.0-99.8%) and 98.9% (95%CI, 97.7-100.0%) for rifampicin; 89.1% (95%CI, 83.9-94.3%) and 100.0% (95%CI, 100.0-100.0%) for isoniazid; 82.1% (95% CI, 68.0-96.3%) and 99.7% (95% CI, 99.0-100.0%) for ethambutol. With DNA sequencing as the reference standard, the sensitivity and specificity of xMAP TIER for detecting resistance were 95.0% (95% CI, 90.2-99.8%) and 99.6% (95% CI, 98.9-100.0%) for rifampicin; 96.9% (95% CI, 93.8-99.9%) and 100.0% (95% CI, 100.0-100.0%) for isoniazid; 86.1% (95% CI, 74.8-97.4%) and 100.0% (95% CI, 100.0-100.0%) for ethambutol. The results achieved showed that the xMAP TIER assay had good performance for detecting first-line anti-tuberculosis drug resistance, and it has the potential to diagnose drug-resistant tuberculosis more accurately due to the addition of more optimal design primers and probes on open architecture xMAP system.