Line anti-TB Drugs Research Articles

Drug resistance pattern, prevalence and risk factors for resistance to second line anti-tuberculosis drugs in Balochistan, Pakistan

Background. Pakistan is high burden drug resistant tuberculosis (DR-TB) country. For devising a treatment regimen and optimizing empirical drug therapy, the local epidemiology and drug resistance patterns are needed to be considered. Objectives. To evaluate the drug resistance pattern, prevalence and risk factors for resistance to second line anti-tuberculosis drugs (SLD) among DR-TB patients in Balochistan, Pakistan. Design and setting. This cross-sectional study was carried out at the Fatimah Jinnah Chest and General Hospital in Quetta's programmatic management unit of the DR-TB (PMDT). Methods. This study included all DR-TB patients, regardless of their age, TB location, or medication resistance pattern. The sociodemographic, microbiological, and clinical data of the patients were gathered using a standard data collecting form. SPSS 20 was used to analyze the data. A statistically significant p-value was defined as less than 0.05. Results. A total of 354 patients were included in the final analysis. Among them majority were females (61.7%), belonged to the age group 19-30 years (36.7%), were previously treated for TB (95.8%) at public sector hospital (42.7%) and did not suffer from any other comorbidity(88.7%). The study participants were resistant to a median of three anti-TB drugs (range 1-8). The most common type of DR-TB was multi DR-TB (77.1%), followed by mono DR-TB (18.1%), extensive DR-TB(3.1%) and poly-DR (1.7%). A total of 147 (41.5%) patients were resistant to any second line anti-TB drug (SLD). Among SLD, the resistance was high for fluoroquinolones (38.4%), followed by ethionamide (4.8%) and injectable SLD(4.2%). Upon multivariate binary logistic regression analysis previous treatment of cat-II regimen had statistical significant association with resistance to any SLD (OR=5.273, 95%CI=1.098-25.316). Conclusion. It is concerning to see such a high level of SLD resistance, especially to fluoroquinolones. More stringent regulations are advised to regulate the non-prescription sale and indiscriminate use of fluoroquinolones, as well as testing for drug resistance in cat-I failures instead of placing patients on cat-II therapy.

A novel C-4-modified isotetrone acts as a potent bio-enhancer to augment the activities of anti-tuberculosis drugs against Mycobacterium tuberculosis

Mycobacterium tuberculosis is a deadly pathogen that claims millions of lives every year. Current research focuses on finding new anti-tuberculosis drugs that are safe and effective, with lesser side effects and toxicity. One important approach is to identify bio-enhancers that can improve the effectiveness of anti-tuberculosis drugs, resulting in reduced doses and shortened treatment times. The present study investigates the use of C-4 modified isotetrones as bio-enhancers. A series of studies suggest an isotetrone, labeled as C11, inhibits growth, improves MIC, MBC and enhances the killing of M. tuberculosis H37Rv strain when used in combination with the first line and injectable anti-TB drugs in a dose-dependent manner. The combination of C11 and rifampicin also reduces the generation of spontaneous mutants against rifampicin and reaches a mutation prevention concentration (MPC) with moderate rifampicin concentrations. The identified compounds are effective against the MDR strain of M. tuberculosis and non-cytotoxic in HepG2 cells. We find that C11 induces the generation of reactive oxygen species (ROS) inside macrophages and within bacteria, resulting in better efficacy.

Combination treatment of WHO standard drugs and Artemisia Afra for pulmonary tuberculosis - a Pilot study of 25 multi resistant patients

Introduction: Tuberculosis is one of the leading infectious causes of death worldwide. The WHO estimates that 1.7 billion people close to one quarter of the humanity are infected with Mycobacterium Tuberculosis the bacteria that causes TB. Last year, 10.6 million fell ill from TB and 1.6 million died.1 Moreover, multi resistance to the current anti-tuberculosis drugs is growing thus causing a serious challenge in controlling the spread of the disease worldwide. Fortunately, as we demonstrated on previous studies that Artemisia Afra infusions given with the WHO approved drugs can shorten treatment duration and resistance from 9 months to 52 days maximum2 and out of the 102 patients 95 were cured in 30 days and 7 in 52 days. Most recently we also demonstrated that 25 patients of regular tuberculosis completely recovered after 30 days or less by combining Artemisia Afra infusions whereby the other 25 patients who took the WHO treatment ALONE either abandoned their treatment and if they continued it, they were still sick on day 30.3 The objective of this pilot study is to demonstrate that 25 patients with multi resistant tuberculosis when given Artemisia Afra infusions combined with second line anti tb drugs were able to recover in 35 days maximum instead of 90 days or more. Methods: This case study involved 25 patients who were all multi resistant or recidivist to the tuberculosis and have failed the first line treatment. Moreover, they were confirmed by a GeneXpert test to be resistant to Rifampicin and or Isoniazid. All patients were hospitalized at Ijenda Hospital in Bujumbura rural Province, Burundi between February, and April 2024. They were given the second line treatment at the regular dose + Artemisia Afra infusion at 330 ml three times a day. The patients were also fed with a protein rich meal and nurses made sure that medications were taken regularly according to DOT [Directly Observed Technique]. Results: All the 25 patients recovered in 35 days maximum (see details in the Tables below). Conclusion: The combination therapy [Artemisia Afra infusions+ WHO protocol] has a lot of potential in curing tuberculosis but more studies on a larger cohort [300 patients] will be carried out and there will also be a third leg with multi resistant cases that failed first line treatment with many months of sickness.

Interactive effect of oral anti-hyperglycaemic or anti-hypertensive drugs on the inhibitory and bactericidal activity of first line anti-TB drugs against M. tuberculosis.

Co-existence of life style disorders, like, Diabetes or Hypertension, increases risk of, treatment failure, deaths and developing drug-resistant TB. Concomitant administration of drugs to treat dual/multi-morbidities may alter their effectiveness, in additive/synergistic or adverse/antagonistic manner. We evaluated interactive effect of 7 anti-hyperglycaemic (HG) and 6 anti-hypertensive (HT) drugs on the inhibitory (MICs) and bactericidal (% killing of intracellular bacilli) activities of anti-TB drugs, Isoniazid (INH), Rifampicin (RFM), Ethambutol (EMB) and Streptomycin (STR) against M. tuberculosis. Five anti-HG drugs, namely, Acarbose, Acetohexamide, Glyburide, Repaglinide and Sitagliptin imparted either 'additive' or 'no effect' on the activities (inhibition or % killing) of all the four anti-TB drugs, as evident by their lower FICs (Fractional Inhibitory concentrations) and higher bacterial killing in combination. Metformin and Rosiglitazone, however, exerted adverse effect on the Ethambutol (FICs >2.0). All the six anti-HT drugs, namely, Atenolol, Hydrochlorothiazide, Ramipril, Valsartan, Nifedipine and Verapamil exerted either 'additive'/'synergistic' or 'no effect' on the activities of anti-TB drugs. These findings may help clinicians to select safe and helpful anti-HG or anti-HT drugs for TB patients, if, suffering with diabetes or hypertension like co-morbidities and receiving DOTs (a set regimen for the treatment of TB based on the WHO guidelines).

Anti-tuberculosis Drug-induced Hepatitis

Among the first line anti-TB drugs, INH, Rifampicin and Pyrazinamide are considered to be the most hepatotoxic drugs and cause drug induced hepatitis. Pyrazinamide causes both dose-dependent and idiosyncratic hepatitis whereas Isoniazid and Rifampicin induced hepatotoxicity are considered to be idiosyncratic. There are several risk factors for hepatotoxicity such as old age, malnutrition, genetic predisposition, HIV infection as well as chronic Hepatitis B and C infections. Anti-TB drug induced hepatitis usually occurs within 2 months after starting treatment. Patient may present with mild symptoms to severe acute hepatitis or even acute liver failure. Various guidelines have been published regarding the management of ATT and restarting anti TB drugs. This article reviews the incidence, risk factors, mechanism, diagnosis and management strategies of anti-TB drug induced hepatitis.
 BANGLADESH J CHILD HEALTH 2022; VOL 46 (1) : 23-27

Investigation of Efflux Pump Genes in Resistant Mycobacterium tuberculosis Complex Clinical Isolates Exposed to First Line Antituberculosis Drugs and Verapamil Combination

Tuberculosis (TB) is caused by Mycobacterium tuberculosis, still one of the most common life-threatening infectious diseases worldwide. Although drug resistance in M.tuberculosis is mainly due to spontaneous chromosomal mutations in genes encoding drug target or drug activating enzymes, the resistance cannot be explained only by these mutations. Low permeability of the cell wall, drug inactivating enzymes and especially efflux pumps (EPs) are other mechanisms of drug resistance in mycobacteria. Efflux pump inhibitors (EPIs) binding to M.tuberculosis EPs were shown to inhibit efflux of anti-TB drugs, to enhance M.tuberculosis killing, to reduce drug resistance and to produce synergistic effects with first line anti-TB drugs. In this study, we aimed to determine the minimum inhibitory concentration (MIC) of first-line anti-TB drugs in the presence of verapamil (VER) and the expression of 21 putative EP genes belonged to the ATP-binding cassette (ABC), major facilitator superfamily (MFS) and resistance-nodulation-division (RND) families which might have caused the resistance in nine M.tuberculosis complex clinical isolates resistant to all of the first line anti-TB drugs. MIC values of the isolates were determined in 96-well U-bottom plates by the resazurin microtiter test (REMA) method based on the color change principle. According to the determined MIC values of each isolate, freshly grown cultures in Middlebrook 7H9 broth were exposed to first-line anti-TB drugs and MIC of first-line anti-TB drugs in the presence of VER (½ MIC) at 37°C for 48 hours for RNA extraction. The non-drug exposed cultures were used as control. Total RNA was extracted using the RNeasy Mini Kit (Qiagen GmbH, Hilden, Germany) and then treated with DNase I (Thermo Fischer Scientific Inc., Waltham, MA). Complementary DNA (cDNA) from the extracted RNAs was synthesized with the "First strand cDNA synthesis kit" (Thermo Fischer Scientific Inc., Waltham, MA) using oligo primers. The expression levels of efflux pump genes by quantitative realtime polymerase chain reaction (qRt-PCR) were performed using the QuantiTect SYBR Green Rt-PCR Kit (Qiagen, Germany). The housekeeping sigma factor gene sigA (Rv2703) was used as internal control in qRt‑PCR assays. Relative quantification of the clinical isolates was determined by the 2-∆∆Ct method by comparing the expression levels of efflux genes in cultures exposed to primary anti-TB drugs and VER with those of non-drug exposed cultures. MIC values of nine isolates by REMA method was determined between 32-512 μg/mL, 1-128 μg/mL, 2-32 μg/mL, 4-16 μg/mL and 15.62-250 μg/mL for streptomycin (SM), isoniazid (INH), rifampicin (RIF), ethambutol (EMB) and VER, respectively. In the presence of ½ MIC VER, it was determined that the MIC of SM decreased 2-32 fold in eight isolates, the MIC of INH decreased by 2-8 fold in nine isolates, the MIC of RIF decreased by 2-16 fold in eight isolates, and the MIC of EMB decreased 2-4 fold in only five isolates. There was an increase in the expression of Rv1273c, Rv1456c, Rv1457 and Rv1819 efflux pump genes from the ABC family, Rv1634 and Rv0842 from the MFS family and Rv3823 efflux from the RND family in isolates exposed to ½ MIC of first-line anti-TB drugs stress. Rv1456c and Rv1819 were found to be associated with SM resistance, Rv1273c with EMB resistance, Rv1457, Rv0842 and Rv3823 with both RIF and EMB resistance, and Rv1634 with INH, RIF and EMB resistance. It was determined that there was a decrease in the expression levels of eight efflux pump genes from the ABC family (Rv1456c, Rv1457c, Rv1458c, Rv0194, Rv1272c, Rv1686c, Rv1687c, Rv1819c), six from MFS family (Rv0842, Rv0849, Rv1634, Rv2265, Rv2456c, Rv0876c) and two from RND family (Rv0507, Rv0676c) in isolates exposed to MIC of first-line anti-TB drugs in the presence of VER (½ MIC). Further studies with clinical isolates are needed to investigate the EPIs that can be used in alternative therapy and to determine the contribution of EPs to the development of resistance due to the increasing TB resistance.

DETECTION AND CHARACTERIZATION OF MUTATIONS IN GENES RELATED TO SECOND-LINE ANTI-TUBERCULOSIS DRUGS RESISTANCE IN MDR TB

Introduction: Drug-resistant tuberculosis is a major global health issue. Multidrug-resistant TB (MDRTB) and extensively drug-resistant TB (XDR-TB) are particularly concerning. Conventional phenotypic methods being cumbersome and time consuming, molecular assays for the detection of mutations that are associated with resistance to anti-TB drugs have emerged as an important tool for rapid diagnosis. Aims and Objectives: To determine and characterize mutations associated with resistance to second line anti-TB drugs in MDR TB. Methods: First line LPA Conrmed MDR TB and/ or mono rifampicin or mono isoniazid resistant cases were subjected to second line LPA (MTBDRsl ver 2.0 kit)) and banding patterns of resistant cases were obtained. These were then subjected to extended phenotypic DST (Gold Standard) using MGIT 960 for Moxioxacin – 1.0µg/ml, Kanamycin -2.5µg/ml, Capreomycin -2.5µg/ml. Results: The study analysed 1580 samples subjected to SL LPA and found that 37.65% were sensitive to both FQ and SLID. FQ resistance accounted for 60.56% and SLID resistance for 17.02%. Resistance to both seen in 15.15% samples. The most common mutation associated with FQ resistance was gyr A gene at codon D94G, for SLID resistance it was in rrs gene (A1401G) and eis gene (C-12T,G-10A). Conclusion: It was observed that there is a high prevalence (62.34%) of second-line anti-TB drug resistance and mutations in gyrA, gyrB (for FQ), rrs ( for SLID) and eis promoter regions (for low level kanamycin) were signicantly associated with secondline anti-TB drug resistance.

Multi-drug loaded eugenol-based nanoemulsions for enhanced anti-mycobacterial activity.

Tuberculosis is one of the oldest bacterial infections known to mankind caused by Mycobacterium tuberculosis. The aim of this research is to optimize and formulate a multi-drug loaded eugenol based nanoemulsion system and to evaluate its ability as an antimycobacterial agent and its potential to be a low cost and effective drug delivery system. All the three eugenol based drug loaded nano-emulsion systems were optimized using response surface methodology (RSM)-central composite design (CCD) and were found stable at a ratio of 1 : 5 (oil : surfactant) when ultrasonicated for 8 minutes. The minimum inhibitory concentration (MIC) values against strains of Mycobacterium tuberculosis highly proved that these essential oil-based nano-emulsions showed more promising results and an even improved anti-mycobacterium activity on the addition of a combination of drugs. The absorbance of 1st line anti-tubercular drugs from release kinetics studies showed a controlled and sustained release in body fluids. Thus, we can conclude that this is a much more efficient and desirable method in treating infections caused by Mycobacterium tuberculosis and even its MDR/XDR strains. All these nano-emulsion systems were stable for more than 3 months.

A CASE OF DISSEMINATED MULTI-DRUG RESISTANT TUBERCULOSIS WITH BONY INVOLVEMENT

Drug resistant tuberculosis continues to be a public health problem, Early diagnosis and initiation of treatment play important role in management of MDR-TB. Here, we report a patient who is 27 year old female diagnose initially as a case of TB pleural effusion and was initiated on 1st line antiTB drugs, after initial response to therapy and completing intensive phase of treatment, in forth month of continuation phase patient presented with symptoms of fever, anorexia and weight loss. Further evaluation with CT scan thorax revealed bony involvement with osteolytic lesions involving multiple ribs and vertebral column leading to multiple paraspinal collections and cold abscess formation involving anterior chest wall, pus CBNAAT showed mycobacterium tuberculosis resistant to rifampicin which was conrm on culture. Patient was diagnosed as case of disseminated MDR-tuberculosis.

Design and Synthesis of Quinazolinone-Triazole Hybrids as Potent Anti-Tubercular Agents.

A straightforward and convenient methodology has been developed for the reaction of 2-aminobenzamide and carbonyls affording 2,3-dihydroquinazolin-4(1H)-ones using aqueous solution of [C12Py][FeCl3Br]. The developed methodology was applied for the synthesis of 25 quinazolinone-triazole hybrids followed by evaluation of their in vitro anti-tubercular (TB) activity. The results revealed that 8 quinazolinone-triazole hybrids displayed promising activity having MIC values of 0.78-12.5 μg/mL. The compound 3if with MIC 0.78 μg/mL was found to be the lead nominee among the series, better than Ethambutol, a first line anti-TB drug and comparable with Rifampicin. The active compounds with MIC values ≤ 6.25 μg/mL were subjected to in vitro cytotoxicity and found nontoxic. In drug-drug interaction, compounds 3ia and 3ii interacted synergistically with all the three anti-TB drugs, INH, RFM, and EMB. Other 3 compounds interacted either in synergistic or additive manners. Important information on the binding interaction of the target compounds with the active sites of 1DQY Antigen 85C from Mycobacterium tuberculosis and Enoyl acyl carrier protein reductase (InhA) enzymes was obtained from molecular docking studies. Screening of the drug-likeness properties and bioactivity score indicates that synthesized molecules could be projected as potential drug candidates. Based on the current study, quinazolinone-triazole hybrids framework can be useful in drug development for TB.

Determinants of stock-outs of first line anti-tuberculosis drugs: the case of public health facilities of Addis Ababa city administration health bureau, Addis Ababa, Ethiopia

BackgroundThe health sectors success has been determined by consistent and reasonably priced health commodities supply. Despite possible death from the disease, Tuberculosis (TB) can be prevented with early diagnosis and appropriate treatment for which enough, effective, and qualified medicines need to be available. However, studies revealed stock of anti-TB drugs in health facilities. Here we present the recent finding on determinants of stock out of Anti-TB drug at public health facilities of Addis Ababa.ObjectiveThis study aimed to identify determinants of stock outs of first line anti TB drugs at public health facilities under Addis Ababa City Administration Health Bureau.MethodMixed study design were employed. A total of 106 facilities were included in the sampling frame and data were collected from the study population such as drug store managers of health facilities providing TB treatment using semi structured questionnaire and through in-depth interview with Addis Ababa hubs of the Ethiopian Pharmaceuticals Supply Agency (EPSA), Addis Ababa City Administration Health Bureau and selected heads of pharmacy departments of health facilities from May 1–30, 2020 considering one year back retrospective data from March 20,2019 to March 20,2020. Structured record review of data from Logistics Management Information System (LMIS) tools having TB drugs was done using structured observation checklist. Data were entered, cleaned, and analyzed using SPSS Version 20. Both descriptive and multiple logistic regression analysis were performed.Result52(62.7%) of health facilities encountered stock out for at least one of these drugs during the past 1 year. Rifampicin 75 mg + Isoniazid 50 mg (RH 75/50 mg) were most stocked out first line anti-TB drug from 33(39.8%) of facilities with 17 mean stocks out days while Rifampicin 75 mg + Isoniazid 50 mg + Pyrazinamide 150 mg (RHZ 75/50/150 mg) were the least first line anti-TB drug stocked out from facilities with mean 5 days of stock out. Delayed supply of anti TB drug from EPSA, delivery of reduced quantity of anti TB drugs by EPSA and stocked out of anti TB Drugs at EPSA were significant determinate factors of stock out of first line anti-TB drug from facilities with 95%CI of 10.34(2.167–49.329), 11.452(2.183–60.079) and 5.646(1.240–25.707) respectively.ConclusionAbove median of health facilities encountered stock out of first line anti-TB drug in Addis Ababa. Delayed supply of anti TB drug from EPSA, delivery of reduced quantity of anti TB drugs by EPSA and stocked out of anti TB Drugs at EPSA were significant determinate factor of stocked out of first line anti-TB drug from facilities. EPSA and other responsible bodies shall work collaboratively to improve their service and ensure availability of adequate amount of Anti TB drug in health facilities.

Phylogenetic lineages of tuberculosis isolates and their association with patient demographics in Tanzania

BackgroundMycobacterium tuberculosis presents several lineages each with distinct characteristics of evolutionary status, transmissibility, drug resistance, host interaction, latency, and vaccine efficacy. Whole genome sequencing (WGS) has emerged as a new diagnostic tool to reliably inform the occurrence of phylogenetic lineages of Mycobacterium tuberculosis and examine their relationship with patient demographic characteristics and multidrug-resistance development.Methods191 Mycobacterium tuberculosis isolates obtained from a 2017/2018 Tanzanian drug resistance survey were sequenced on the Illumina Miseq platform at Supranational Tuberculosis Reference Laboratory in Uganda. Obtained fast-q files were imported into tools for resistance profiling and lineage inference (Kvarq v0.12.2, Mykrobe v0.8.1 and TBprofiler v3.0.5). Additionally for phylogenetic tree construction, RaxML-NG v1.0.3(25) was used to generate a maximum likelihood phylogeny with 800 bootstrap replicates. The resulting trees were plotted, annotated and visualized using ggtree v2.0.4ResultsMost [172(90.0%)] of the isolates were from newly treated Pulmonary TB patients. Coinfection with HIV was observed in 33(17.3%) TB patients. Of the 191 isolates, 22(11.5%) were resistant to one or more commonly used first line anti-TB drugs (FLD), 9(4.7%) isolates were MDR-TB while 3(1.6%) were resistant to all the drugs. Of the 24 isolates with any resistance conferring mutations, 13(54.2%) and 10(41.6%) had mutations in genes associated with resistance to INH and RIF respectively. The findings also show four major lineages i.e. Lineage 3[81 (42.4%)], followed by Lineage 4 [74 (38.7%)], the Lineage 1 [23 (12.0%)] and Lineages 2 [13 (6.8%)] circulaing in Tanzania.ConclusionThe findings in this study show that Lineage 3 is the most prevalent lineage in Tanzania whereas drug resistant mutations were more frequent among isolates that belonged to Lineage 4.

500 Mendelian Susceptibility to Mycobacterial Diseases (MSMD) with autosomal dominant Interferon Gama receptor one defect: A clinical diagnostic and treatment challenge for a 13 year old ethiopian girl

A 13 year old female patient had multiple hospital visits since age of 6months. The most striking diagnosis was repeated mycobacterial infections; which were diagnosed at times clinically and at other times with bacteriological confirmation. She had tuberculosis affecting lymph nodes, skin and soft tissue, bone and joints, lungs and epidural and para-spinal regions. She has been treated 4 times with first line, ones with second line anti-Tb drugs and now she still taking anti-TB. She has taken all childhood vaccines, including BCG.

High rate of successful treatment outcomes among childhood rifampicin/multidrug-resistant tuberculosis in Pakistan: a multicentre retrospective observational analysis

BackgroundThere was a complete lack of information about the treatment outcomes of rifampicin/multidrug resistant (RR/MDR) childhood TB patients (age ≤ 14 years) from Pakistan, an MDR-TB 5th high burden country. Therefore, this study evaluated the socio-demographic characteristics, drug resistance pattern, treatment outcomes and factors associated with unsuccessful outcomes among childhood RR/MDR-TB patients in Pakistan.MethodsThis was a multicentre retrospective record review of all microbiologically confirmed childhood RR/MDR-TB patients (age ≤ 14 years) enrolled for treatment at seven units of programmatic management of drug-resistant TB (PMDT) in Pakistan. The baseline and follow-up information of enrolled participants from treatment initiation until the end of treatment were retrieved from electronic nominal recording and reporting system. World Health Organization (WHO) defined criterion was used for deciding treatment outcomes. The outcomes of “cured” and “treatment completed” were collectively grouped as successful, whereas “death”, “treatment failure” and “lost to follow-up” were grouped together as unsuccessful outcomes. Multivariable binary logistic regression analysis was used to find factors associated with unsuccessful outcomes. A p-value < 0.05 reflected statistically significant findings.ResultsA total of 213 children RR/MDR-TB (84 RR and 129 MDR-TB) were included in the study. Majority of them were females (74%), belonged to the age group 10–14 years (82.2%) and suffered from pulmonary TB (85.9%). A notable proportion (37.1%) of patients had no history of previous TB treatment. Patients were resistant to a median of two drugs (interquartile range: 1–4) and 23% were resistant to any second line anti-TB drug. A total of 174 (81.7%) patients achieved successful treatment outcomes with 144 (67.6%) patients being cured and 30 (14.1%) declared treatment completed. Among the 39 (18.3%) patients with unsuccessful outcomes, 35 (16.4%) died and 4 (1.9%) experienced treatment failure. In multivariable analysis, the use of ethambutol had statistically significant negative association with unsuccessful outcomes (odds ratio = 0.36, p-value = 0.02).ConclusionsIn this study, the WHO target of successful treatment outcomes (≥ 75%) among childhood RR/MDR-TB patients was achieved. The notable proportion of patients with no history of previous TB treatment (37.1%) and the disproportionately high number of female patients (74%) respectively stress for infection control measures and provision of early and high quality care for female drug susceptible TB patients.

Common Adverse drug reactions to First line drugs in Tuberculosis care and the role of m-Health in patient self-reporting and pharmacovigilance in Nigeria: A Narrative review

The treatment of tuberculosis requires the use of First line drugs that often cause adverse drug reactions (ADR) in some patients and this is capable of affecting adherence to the treatment. Many patients do not report these ADRs even though technologies are available at their disposal. The objectives of this review are to assess the common adverse drug reactions reported during the care of patients on First line anti-TB drugs and the use of m-health in self-reporting the ADRs by patients receiving anti-TB care. A literature search was conducted using key words on PUBMED and GOOGLE SCHOLAR. The commonest ADRs many patients presented with were gastrointestinal symptoms and symptoms of drug induced hepatotoxicity. The use of m-Health as an intervention for reporting ADRs is poor in sub-Saharan Africa, however in spite of some challenges, it is seen as a veritable opportunity for patient reporting of ADRs and the improvement of outcomes of Directly Observed Therapy Short course, (DOTS) for tuberculosis management.

Level of Mycobacteria in Pre-Treatment Sputum and Susceptibility of M. tuberculosis Strains Isolated from Patients with non-Multidrug-Resistant Pulmonary Tuberculosis AFB (+) and Factors Influencing MGIT Results after the First 8 Weeks of Anti-Tuberculosi

Vietnam is among 30 high TB ​​burden countries even though the Vietnam National TB Program has made great efforts to detect and treat tuberculosis. Objectives: Assessment of Mycobacterial level in sputum before treatment, and susceptibility to the first line anti-TB drugs of M. tuberculosis strains isolated from TB patients with AFB (+) and non-multidrug-resistant. Moreover, factors influencing MGIT outcome after the first 8 weeks of first-line anti-TB drugs therapy in patients with pulmonary tuberculosis was also analysed. Methodology: An observational, analytical study was performed in 128 patients with non-multidrug-resistant pulmonary tuberculosis AFB (+) for evaluating the level of Mycobacteria in sputum before treatment by smear microscopy method; the susceptibility of M. tuberculosis isolated from sputum of the patient was analysed by Lowenstein - Jensen method. Factors affecting positive MGIT results after 2 months of treatment were determined by multivariate logistics regression. Results: The patients had AFB 3+ were 28% in new cases and 24,5% retreatment patients. The rate of M. tuberculosis strains was susceptible to the first line anti-TB drugs in new cases was higher than retreatment patients. The percentage of any anti-TB drug resistance in retreatment tuberculosis was 59,6%, higher than that of new case TB (23,6%). There was high rate of M. tuberculosis strains resistant to Streptomycin and Isoniazid (12,5% and 16,8% for new cases; 42,3% and 36,5% for retreatment cases, respectively). Large radiographic chest lesions and high AFB levels in pre-treatment sputum were factors associated with a positive MGIT result after the first 8 weeks of treatment. Conclusion: Most of TB patients had high level of Mycobacteria in sputum samples collected before treatment. The percentage of M. tuberculosis strains isolated from sputum of pulmonary non MDR-TB patients had any anti-TB drug resistance were high. High Mycobacteria level in pre-treatment sputum and radiographic chest lesions related to positive MGIT result after the first 8 weeks of treatment.&#x0D; Keywords&#x0D; Pulmonary tuberculosis, first-line anti-TB drugs, anti-TB drug resistance, susceptibility, M. tuberculosis.&#x0D; References&#x0D; [1] World Health Organization, Global Tuberculosis Report 2020. Tuberculosis profiles: Viet Nam (2020) Available: https://worldhealthorg.shinyapps.io/tb_profiles/?_inputs_&amp;entity_type=%22country%22&amp;lan=%22EN%22&amp;iso2=%22VN%22 (accessed 10 April 2020).[2] L.T. Luyen, N.V. Hung, Methods for Diagnosis in Tuberculosis, in Le Thi Luyen (Ed), Tuberculosis - Textbook for General Medical Students. Vietnam National University Press, Hanoi, 2020, pp: 47-69 (in Vietnamese).[3] Ministry of Health - National Tuberculosis Programme Guideline for Standard Operating Procedures of Microbiology Laboratory Methods for Mycobacteria. Vietnam National Tuberculosis Programme, Hanoi (2013) (in Vietnamese).[4] Ministry of Health (2018) Guideline for Management, Diagnosis and Treatment for Tuberculosis. (in Vietnamese) Available: https://kcb.vn/vanban/quyet-dinh-so-3216-qd-byt-ngay-23-5-2018-ve-viec-ban-hanh-huong-dan-chan-doan-dieu-tri-va-du-phong-benh-lao (Accessed 12 January 2019)[5] A.P. Ralph, M. Ardian, A. Wiguna et al. A simple, valid, numerical score for grading chest x-ray severity in adult smear-positive pulmonary tuberculosis. Thorax 2010 Oct;65(10):863-869. https://doi.org/10.1136/thx.2010.136242[6] C.T. Minh, L.T. Luyen, N.T.L. Huong et al. Plasma concentration of anti-tubeculosis drugs in pulmonary tuberculosis patients, who treatment in National Tuberculosis and Lung Diseases Hospital 2008 Journal of Practical Medicine 651(2009) 50-53 (in Vietnamese).[7] N.V. Nhung, N.B. Hoa, D.N. Sy, C.M. Hennig, A.S. Dean (2015) The fourth national anti-tuberculosis drug resistance survey in Viet Nam. Int J Tuberc Lung Dis. Jun 2015 19(6) 670-675. https://doi.org/10.5588/ijtld.14.0785[8] N.T. Hang, S. Maeda, L.T. Lien, et al. Primary drug-resistant tuberculosis in Hanoi, Viet Nam: present status and risk factors. PloS one 8(8) (2013) e71867. https://doi.org/10.1371/journal.pone.0071867[9] R. Hafner, J.A. Cohn, D.J. Wright, et al. Early bactericidal activity of isoniazid in pulmonary tuberculosis. Optimization of methodology. The DATRI 008 Study Group. Am J Respir Crit Care Med 156 (1997) 918–923. https://doi.org/10.1164/ajrccm.156.3.9612016[10] A. Jindani, V.R. Aber, E.A. Edwards, D.A. Mitchison. The early bactericidal activity of drugs in patients with pulmonary tuberculosis. Am J Respir Crit Care Med. 121(1980)(6) 939-949. Available: https://www.atsjournals.org/doi/10.1164/arrd.1980.121.6.939 (Accessed 12 January 2019).[11] H.L. Rieder. Intervention for Tuberculosis Control and Elimination. International Union of Tuberculosis and Lung Diseases, Paris, France, 2002.

Targeting Xenobiotic Nuclear Receptors PXR and CAR to Prevent Cobicistat Hepatotoxicity.

Liver-related diseases including drug-induced liver injury are becoming increasingly prominent in AIDS patients. Cobicistat (COBI) is the backbone of multiple regimens for antiretroviral therapy. The current work investigated the mechanisms of adverse drug-drug interactions associated with COBI that lead to liver damage. For individuals co-infected with HIV and tuberculosis (TB), the World Health Organization recommends the initiation of TB treatment followed by antiretroviral therapy. Rifampicin (RIF), a first line anti-TB drug, is a human specific activator of pregnane X receptor (PXR). Using PXR-humanized mice, we found that RIF-mediated PXR activation potentiates COBI hepatotoxicity. In contrast, rifabutin, a PXR-neutral analog of RIF, has no impact on COBI hepatotoxicity. Because of the crosstalk between PXR and the constitutive androstane receptor (CAR), the role of CAR in COBI hepatotoxicity was also investigated. Similar to PXR, ligand-dependent activation of CAR also potentiates COBI hepatotoxicity. Our further studies illustrated that PXR and CAR modulate COBI hepatotoxicity through the CYP3A4-dependent pathways. In summary, the current work determined PXR and CAR as key modulators of COBI hepatotoxicity. Given the fact that many prescription drugs and herbal supplements can activate PXR and CAR, these two receptors should be considered as targets to prevent COBI hepatotoxicity in the clinic.

Burden of Drug resistant Tuberculosis in newly diagnosed Tuber-culosis patients of Khyber Pakhtunkhwa, Pakistan

Abstract Objective: To explore the burden of drug resistant tuberculosis in Khyber Pakhtunkhwa, Pakistan. Methods: A total of 8220 referred suspected TB patient samples were collected from 1st March 2016 to 28th February 2017 from TB laboratories across all districts of Khyber Pakhtunkhwa province and processed for the detection of drug resistant tuberculosis (DR-TB). Drug Susceptibility testing (DST) on all Mycobacterium tuberculosis complex (MTC) strains was performed at Provincial TB Reference Laboratory, Peshawar. Results: Among the 8220 suspected TB samples, 1351 samples were declared positive on culture. The DST results showed that 525 samples were resistant to at least one of the first and second line anti-TB drugs. Importantly, among these 525 TB resistance cases, XDR-TB were 0.4% (n=5), MDR-TB were 4.6% (n=62), polyresistant were 18% (n=243), monoresistant was 16% (n=215) and 61% (n=826) were reported as pan-sensitive. Gender wise ratio are slightly increased in female (n= 4230; 51.5%) as compared to male (n=3990; 48.5%), while the age group 15-24 were the main target of TB disease (n=1978; 24%). Conclusion: Our data suggests that DR-TB cases especially MDR-TB and XDR-TB in newly diagnosed TB patients are alarmingly increased in Khyber Pakhtunkhwa region. Furthermore, the timely detection of drug resistance is important to optimize treatment and management of MDR-TB as well as XDR-TB. Key words: Tuberculosis; MDR-TB; XDR-TB; Continuous....

Community-Based Active Case Finding to Increase Tuberculosis Case Detection and Treatment Success Rate in High Tuberculosis Burden Areas of Arsi Zone, Oromia

<i>Background</i>: More than 9 million new cases of tuberculosis (TB) occur per year and about two million people die of TB. The probable cause of death is delay in diagnosis, low case detection rate and treatment success rate. Due to the low potential of tuberculosis (TB) microscopic examination and the need to increase rate of new TB case identification is also increased. <i>Objective</i>: To determine magnitude of active tuberculosis cases, evaluate the performance of LED-FM and X-pert MTB/RIF assay and characterize treatment outcome <i>Methods</i>: The door-to-door survey for TB in high TB burden areas of Arsi zone was performed. The participants were screened based on typical TB symptoms. The sputum samples were collected and transported to the laboratories. Culture, LED-FM and X-pert MTB/RIF assay were performed to confirm tuberculosis infection. Result was communicated through cell phone or short message system (SMS) for issuing of positive results. The health extension worker would contact diagnosed patients referred to their local health center for care. Finally, the performance of diagnostic tests, case detection rate and treatment success were determined. <i>Result</i>: In this study 344 pulmonary TB suspected study participants were involved from the three study sites. Based on the LED microscope results the general prevalence of pulmonary TB among the current study participants was 2.3%. On the other hand Gene X-pert MTB/RIF assay could show that 9 (2.6%) of the study participants became positive for pulmonary TB cases. There was 1 (0.3%) discordant result between the two assay methods. LED microscope missed one TB suspected case which was detected by Gen X-pert MTB/RIF assay and then confirmed by LJ culture media and become positive for pulmonary TB. Hence, the overall prevalence of pulmonary TB in our current study became 2.6% with 95% CI (1.2-4.5) using LJ culture media as tiebreaker. Of 344 study participants in this study, 9 (2.6%) were positive for pulmonary TB and given first line anti-TB drugs. Of the nine pulmonary TB test positive study participants who had prescribed with first line anti-TB drugs in which 2 (22.2%) were known to be cured as well as 7 (77.8%) had completed the treatment regimen prescribed for them.

Biochemical evaluation and molecular docking studies on encapsulated astaxanthin for the growth inhibition of Mycobacterium tuberculosis

Astaxanthin,, a tetraterpenoid compound was formulated as liposomes and screened for anti-tubercular activity against different strains of Mycobacterium tuberculosis: MTB, MDR-TB and H37Rv isolated from the patient sputum samples. Minimum inhibitory concentration (MIC) was determined by proportion-based method. The molecular docking analysis of astaxanthin with various mycobacterial drug target proteins were performed using in silico tools. Encapsulated astaxanthin showed better inhibition of M. tuberculosis with MIC value of 500μg/mL against all the selected strains. The docking analysis provided the interacting amino acid residues of selected mycobacterial enzymes and mode of ligand-protein interaction. Based on the present study, it was concluded that encapsulated astaxanthin could be a better cost effective natural compound for the treatment of tuberculosis among the patients which will combat side effects in comparison with the first line AntiTB drugs like rifampicin and isoniazid.