Second-line Antitubercular Drugs Research Articles

Recent Biochemical Advances in Antitubercular Drugs: Challenges and Future.

Tuberculosis (TB) is one of the leading causes of death world-wide after AIDS. It infects around one-third of global population and approximately two million people die annually from this disease because it is a very contagious disease spread by Mycobacterium tuberculosis. The increasing number of drug-resistant strains and the failure of conventional treatments against this strain are the challenges of the coming decades. New therapeutic techniques aim to confirm cure without deterioration, to reduce deaths, contagions and the formation of drug-resistant strains. A plethora of new diagnostic tests are available to diagnose the active tuberculosis, screen latent M. tuberculosis infection, and to identify drug-resistant strains of M. tuberculosis. When effective prevention strategies do not prevail, high rates of early case detection and successive cures to control TB emergence would not be possible. In this review, we discussed the structural features of M. tuberculosis, Multi drug resistance tuberculosis (MDR-TB), extremely drug-resistant tuberculosis (XDR-TB), the mechanism of M. tuberculosis infection, the mode of action of first and second-line antitubercular drugs, the mechanism of resistance to the existing drugs, compounds in preclinical and clinical trial and drugs presently available for the treatment of tuberculosis. Moreover, the new diagnostic techniques to detect M. Tuberculosis are also discussed in this review. </p>.

Pharmacokinetic-Pharmacodynamic (PK-PD) Analysis of Second-Line Anti-Tubercular Drugs in Indian Children with Multi-Drug Resistance.

To conduct a thorough pharmacokinetic (PK)- pharmacodynamic (PD) analysis of second-line anti-tubercular therapy (ATT) in children diagnosed with multi-drug resistant tuberculosis (MDR-TB). Twenty-seven children undergoing second-line ATT, including kanamycin (KM, n = 13), fluoroquinolones (FQs, n = 26), ethionamide (ETH, n = 20), para amino salicylic acid (PASA, n = 4), and cycloserine (CS, n = 15), were sampled at 0 (pre-dose), 1, 2, 3, and 4 h post-drug administration. Plasma drug levels were determined using a mass spectrometer and the collected dataset underwent non-compartmental PK analysis using PK solver ver2.0. PK/PD assessments involved individual drug simulation studies on 1000 subjects using Modviz Pop ver 1.0 in R-software. A total of 22 and 5 children were considered as responders and non-responders, respectively. Non-compartmental PK analysis revealed mean plasma drug levels of this study cohort attained the targeted maximum drug plasma concentration (Cmax). The ratio of Cmax /minimum inhibitory concentration (MIC) or the area under the curve (AUC)/MIC of the studied drugs had not shown a significant difference between responders and non-responders. Non-responders of ETH and ofloxacin had shown deviation from the derived dose-response profile for the simulated population. The management of MDR-TB with second-line ATT following national guidelines had cured the majority of the children (> 80%) who participated in the study. Inter-individual variability in few children from the targeted Cmax range suggests the need for future investigations on pharmacogenomic aspects of drug metabolism.

Marine-Fungi-Derived Gliotoxin Promotes Autophagy to Suppress Mycobacteria tuberculosis Infection in Macrophage.

The Mycobacterium tuberculosis (MTB) infection causes tuberculosis (TB) and has been a long-standing public-health threat. It is urgent that we discover novel antitubercular agents to manage the increased incidence of multidrug-resistant (MDR) or extensively drug-resistant (XDR) strains of MTB and tackle the adverse effects of the first- and second-line antitubercular drugs. We previously found that gliotoxin (1), 12, 13-dihydroxy-fumitremorgin C (2), and helvolic acid (3) from the cultures of a deep-sea-derived fungus, Aspergillus sp. SCSIO Ind09F01, showed direct anti-TB effects. As macrophages represent the first line of the host defense system against a mycobacteria infection, here we showed that the gliotoxin exerted potent anti-tuberculosis effects in human THP-1-derived macrophages and mouse-macrophage-leukemia cell line RAW 264.7, using CFU assay and laser confocal scanning microscope analysis. Mechanistically, gliotoxin apparently increased the ratio of LC3-II/LC3-I and Atg5 expression, but did not influence macrophage polarization, IL-1β, TNF-a, IL-10 production upon MTB infection, or ROS generation. Further study revealed that 3-MA could suppress gliotoxin-promoted autophagy and restore gliotoxin-inhibited MTB infection, indicating that gliotoxin-inhibited MTB infection can be treated through autophagy in macrophages. Therefore, we propose that marine fungi-derived gliotoxin holds the promise for the development of novel drugs for TB therapy.

Fluoroquinolone resistance mutations among Mycobacterium tuberculosis and their interconnection with treatment outcome.

Fluoroquinolone (FQ) antibiotics are among the most potent second-line antitubercular drugs these days. The aim of the study was to analyze the frequency and pattern of genetic mutation in preextensive (pre-XDR) and extensively drug-resistant Mycobacterium tuberculosis using second-line line probe assay (LPA) and to compare drug-resistant mutations with different treatment outcomes. Sputum, lymph node aspirate, and cold accesses from patients with rifampicin-resistant Tuberculosis (TB) were subjected to first-line and second-line LPA (Genotype MTBDRsl by Hain Life Science, Germany) to assess additional drug resistance to fluoroquinolones (levofloxacin and moxifloxacin). Final treatment outcomes as per the National TB Elimination Program were assessed and compared with the mutation profile. One hundred and fifty subjects were observed to have mutations associated with resistance to FQs and constituted the final study population. The most frequent mutation observed among GyrA drug resistance mutation was D94G (Gyr A MUT3C, 44/150, 66%) corresponding to high-level resistance to levofloxacin and moxifloxacin. The same mutation was associated with poor treatment outcome as died or treatment failure (odds ratio 2.50, relative risk 1.67, P = 0.043). The most common hetero-resistance mutation pattern observed in GyrA gene was wild type plus Asp94Gly mutation in 24.6% of isolates. GyrA MUT3C hybridization corresponding to single-point mutation of aspartic acid to glycine at codon 94 constitutes the most common mutation in GyrA gene locus in M. tuberculosis with significant association with treatment outcome as died compared to those with treatment outcome as cured.

Evidence for Implementation: Management of TB in HIV and Pregnancy.

Pregnant people living with HIV (PLWH) are at especially high risk for progression from latent tuberculosis infection (LTBI) to active tuberculosis (TB) disease. Among pregnant PLWH, concurrent TB increases the risk of complications such as preeclampsia, intrauterine fetal-growth restriction, low birth weight, preterm-delivery, perinatal transmission of HIV, and admission to the neonatal intensive care unit. The grave impact of superimposed TB disease on maternal morbidity and mortality among PLWH necessitates clear guidelines for concomitant therapy and an understanding of the pharmacokinetics (PK) and potential drug-drug interactions (DDIs) between antitubercular (anti-TB) agents and antiretroviral therapy (ART) in pregnancy. This review discusses the currently available evidence on the use of anti-TB agents in pregnant PLWH on ART. Pharmacokinetic and safety studies of anti-TB agents during pregnancy and postpartum are limited, and available data on second-line and newer anti-TB agents used in pregnancy suggest that several research gaps exist. DDIs between ART and anti-TB agents can decrease plasma concentration of ART, with the potential for perinatal transmission of HIV. Current recommendations for the treatment of LTBI, drug-susceptible TB, and multidrug-resistant TB (MDR-TB) are derived from observational studies and case reports in pregnant PLWH. While the use of isoniazid, rifamycins, and ethambutol in pregnancy and their DDIs with various ARTs are well-characterized, there is limited data on the use of pyrazinamide and several new and second-line antitubercular drugs in pregnant PLWH. Further research into treatment outcomes, PK, and safety data for anti-TB agent use during pregnancy and postpartum is urgently needed.

Mutation detection and minimum inhibitory concentration determination against linezolid and clofazimine in confirmed XDR-TB clinical isolates

BackgroundThe emergence of multidrug-resistant tuberculosis (MDR-TB) has complicated the situation due to the decline in potency of second-line anti-tubercular drugs. This limits the treatment option for extensively drug-resistant tuberculosis (XDR-TB). The aim of this study was to determine and compare the minimum inhibitory concentration (MIC) by agar dilution and resazurin microtiter assay (REMA) along with the detection of mutations against linezolid and clofazimine in confirmed XDR-TB clinical isolates.ResultsA total of 169 isolates were found positive for Mycobacterium tuberculosis complex (MTBC). The MIC was determined by agar dilution and REMA methods. The isolates which showed non-susceptibility were further subjected to mutation detection by targeting rplC gene (linezolid) and Rv0678 gene (clofazimine). The MIC for linezolid ranged from 0.125 µg/ml to > 2 µg/ml and for clofazimine from 0.25 µg/ml to > 4 µg/ml. The MIC50 and MIC90 for linezolid were 0.5 µg/ml and 1 µg/ml respectively while for clofazimine both were 1 µg/ml. The essential and categorical agreement for linezolid was 97.63% and 95.26% and for clofazimine, both were 100%. The sequencing result of the rplC gene revealed a point mutation at position 460 bp, where thymine (T) was substituted for cytosine (C) while seven mutations were noted between 46 to 220 bp in Rv0678 gene.ConclusionREMA method has been found to be more suitable in comparison to the agar dilution method due to lesser turnaround time. Mutations in rplC and Rv0678 genes were reasons for drug resistance against linezolid and clofazimine respectively.

OTOTOXICITY IN MULTIDRUG-RESISTANT TUBERCULOSIS: A SCOPING REVIEW OF THE INDONESIAN STUDIES

A wide variation in ototoxicity or hearing loss due to injectable anti-tubercular drugs in patients with multidrug-resistant tuberculosis (MDR-TB) has been reported globally and in Indonesia. This scoping review assesses the ototoxicity of second-line injectable anti-tubercular drugs in Indonesian patients with MDR-TB. This review was conducted under the recommended PRISMA extension for scoping review (PRISMA-ScR). The Google Scholar and PubMed database were used to search the articles on MDR-TB in the Indonesian population. Seven studies were identified based on the inclusion criteria reporting kanamycin and capreomycin in the management of MDR-TB. Ototoxicity was observed in 39.3% (116/295) MDR-TB patients. Ototoxicity was observed in kanamycin, 38.7% (105/271 patients); capreomycin, 36,8% (7/19 patients); and kanamycin plus capreomycin, 80% (4/5 patients). Only one study reported risk factors ototoxicity in MDR-TB patients. Ototoxicity was significantly associated with older age and the length of kanamycin therapy correlates with hearing loss. This review identified a high prevalence of ototoxicity in Indonesian patients with MDR-TB treated with second-line injectable drugs. Efforts were urgently needed to develop guidelines for monitoring ototoxicity, improving pharmacist and clinician awareness, and educating patients or caregivers to report hearing loss symptoms as a sign of ototoxicity.&#x0D; &#x0D; Keywords: MDR-TB; Ototoxicity, Second-line injectable&#x0D; &#x0D;

Estimation of Success Rate of Treatment of XDR-TB admitted in a Nodal DRTB Centre

Background: Extensively drug-resistant TB is still a serious challenge in India, and before the introduction of new anti-tuberculosis drugs these patients were treated with a conventional regimen for XDR-TB according to the guidelines of RNTCP at that time for almost 24 to 36 months. Objective: To estimate the outcome of treatment of XDR-TB patients attended at our DRTB site and put under the conventional regimen during the period 2014-2017 according to protocol laid down by PMDT at that time i.e. 2014 to 2017.Methods: In this retrospective study, we selected 41 patients admitted with XDR-TB, in our DRTB site from April 2014 to March 2017. We studied their treatment outcomes (cured, treatment completed, treatment failure, death, and treatment after default) 30 to 36 months after treatment initiation according to PMDT (2014 -2017). Results: Among the 41 cases of XDR-TB that were included in the study 28 were male, 30 resided in rural areas and 28 had a BMI &lt; 18.5 kg/m2. 13 (32%) patients were successfully treated but 21 (50%) patients died during the treatment and treatment failure happened in 6 (15%) patients. Patients with low BMI (&lt; 18.5 kg/m2) had poor success rate (7%) and all the 21 patients who died during treatment, had low BMI. Conclusion: The present study finds that only one in every three XDR-TB cases are successfully treated with conventional second-line antitubercular drugs and this finding is the same as found in the NTEP report. Nearly half of the patients die. The patients with low BMI respond worst.

Assessment of resistance to second line anti-tubercular drugs by line probe assay at a tertiary care hospital

Context: Emergence and spread of extensively drug resistance (XDR) tuberculosis (TB) is a challenge in resource-limited settings. Although India accounts for one-fourth burden of multi-drug resistant cases of TB, the prevalence of XDR TB varies widely. Timely detection of resistance to anti-tubercular drugs is important for optimal case management. Aims: Characterization of resistance mutations to second-line anti-tubercular therapy (ATT) using line probe assay (LPA). Materials and Methods: In this cross-sectional, conducted at a Tertiary Care Teaching Hospital in Western Maharashtra, we assessed resistance to second-line antitubercular drugs in 100 consecutive sputum specimens from patients failing first-line ATT as per national guidelines by LPA. Results: Of the 100 specimens studied, a total of 94 assay results were valid. Of these, no resistance was seen in 52 specimens. Resistance to fluoroquinolones (FLQ) was detected in 30% of specimen with a predominance of gyrA gene mutations. A total of 12% isolates were resistant to aminoglycosides with mutations observed in rrs gene. Conclusions: The study demonstrates the utility of LPA as a tool to support the diagnosis of drug-resistant TB in clinical setting.

In vitro and in vivo evaluation of genotoxicity of second-line antitubercular drug loaded nanoparticles

In vitro and in vivo evaluation of genotoxicity of second-line antitubercular drug loaded nanoparticles

Assessment of drug-drug interactions and its associated factors in patients receiving second-line antitubercular drugs (MDR TB/XDR TB) in a tertiary care hospital in eastern India

This was a prospective, observational study conducted to assess prevalence of different spectrum of DDIs in MR/XDR TB patients by analyzing 42 prescriptions. DDIs were analysed by softwares like Lexicomp, Micromedex, and Drugs.com, Medscape.com. Only interactions of major/moderate severity were included in the potential DDIs analysis. Quantitative assessments were compared using one way ANOVA. Qualitative assessment of software was done manually by mere observation. Patients received 12.52 (±4.04) drugs during their total treatment period. Among 467 interactions observed, 34.04% were major, 50.10% moderate. All the patients had at least one potential DDI and 92.85% were exposed to at least one major potential DDI. Among the 'risk rating avoid combinations' (X) were 7.28%, 'modify regimen' (D) were 15.04%. Most DDIs were of moderate severity (50.10%) and the possible mechanism of DDI found was of pharmacodynamic in nature (49.76%). This study assists in understanding the utility of computer software-based programs to assess potential DDIs and the factors associated with them.

A piperidinol-containing molecule is active against Mycobacterium tuberculosis by inhibiting the mycolic acid flippase activity of MmpL3

Mycobacterium tuberculosis, the causative agent of tuberculosis, remains a major human pathogen, and current treatment options to combat this disease are under threat because of the emergence of multidrug-resistant and extensively drug-resistant tuberculosis. High-throughput whole-cell screening of an extensive compound library has recently identified a piperidinol-containing molecule, PIPD1, as a potent lead compound against M. tuberculosis Herein, we show that PIPD1 and related analogs exert in vitro bactericidal activity against the M. tuberculosis strain mc26230 and also against a panel of multidrug-resistant and extensively drug-resistant clinical isolates of M. tuberculosis, suggesting that PIPD1's mode of action differs from those of most first- and second-line anti-tubercular drugs. Selection and DNA sequencing of PIPD1-resistant mycobacterial mutants revealed the presence of single-nucleotide polymorphisms in mmpL3, encoding an inner membrane-associated mycolic acid flippase in M. tuberculosis Results from functional assays with spheroplasts derived from a M. smegmatis strain lacking the endogenous mmpL3 gene but harboring the M. tuberculosis mmpL3 homolog indicated that PIPD1 inhibits the MmpL3-driven translocation of trehalose monomycolate across the inner membrane without altering the proton motive force. Using a predictive structural model of MmpL3 from M. tuberculosis, docking studies revealed a PIPD1-binding cavity recently found to accommodate different inhibitors in M. smegmatis MmpL3. In conclusion, our findings have uncovered bactericidal activity of a new chemical scaffold. Its anti-tubercular activity is mediated by direct inhibition of the flippase activity of MmpL3 rather than by inhibition of the inner membrane proton motive force, significantly advancing our understanding of MmpL3-targeted inhibition in mycobacteria.

Hepatitis C virus infection: a challenge in the complex management of two cases of multidrug-resistant tuberculosis

BackgroundMultidrug-resistant tuberculosis (MDR-TB) requires lengthy use of second-line drugs, burdened by many side effects. Hepatitis C virus (HCV) chronic infection increases risk of drug-induced liver injury (DILI) in these patients. Data on MDR-TB patients with concurrent HCV chronic infection treated at the same time with second-line antitubercular drugs and new direct-acting antivirals (DAAs) are lacking. We evaluate if treating at the same time HCV infection and pulmonary MDR-TB is feasible and effective.Cases presentationIn this study, we described two cases of patients with pulmonary MDR-TB and concurrent HCV chronic infection cured with DAAs at a Tertiary Infectious Diseases Hospital in Italy. During antitubercular treatment, both patients experienced a DILI before treating HCV infection.After DAAs liver enzymes normalized and HCV RNA was undetectable. Then antitubercular regimen was started according to the institutional protocol, drawn up following WHO MDR-TB guidelines. It was completed without further liver side effects and patients were declared cured from both HCV infection and MDR-TB.ConclusionsWe suggest to consider treatment of chronic hepatitis C with DAAs as a useful intervention for reintroduction of second-line antitubercular agents in those patients who developed DILI, reducing the risk of treatment interruption when re-exposed to these drugs.

Nephrotoxicity and ototoxic symptoms of injectable second-line anti-tubercular drugs among patients treated for MDR-TB in Ethiopia: a retrospective cohort study

BackgroundNephrotoxicity and ototoxicity are clinically significant dose-related adverse effects associated with second-line anti-tubercular injectables drugs (aminoglycosides and capreomycin) used during intensive phase of treatment of multi-drug resistant tuberculosis (MDR-TB) patients. Data are scarce on injectable-induced nephrotoxicity and ototoxicity in Ethiopian MDR-TB patients. The aim of this study was to assess the prevalence, management of nephrotoxicity and ototoxic symptoms and treatment outcomes of patients treated for MDR-TB with injectable-based regimens.MethodThis was retrospective cohort study based on review of medical records of about 900 patients on MDR-TB treatment from January 2010 to December 2015 at two large TB referral hospitals in Addis Ababa, Ethiopia. Nephrotoxicity in study participants was screened using baseline and monthly measurement of serum creatinine and clinical diagnosis and patient reports.ResultsOverall, 473 (54.2%) of participants were male. Children accounted for 47 (5.5%) of cases and the mean age of participants was 32 ± 12.6 years with range of 2–75 years. The majority (n = 788, 84.6%) of participants had past history of TB. The most commonly used injectable anti-TB drug was capreomycin (n = 789, 84.7%), while kanamycin and amikacin were also used. There was a statistically significant increment (p<0.05) in the mean serum creatinine values from baseline throughout intensive phase of treatment with a 10–18% prevalence of nephrotoxicity. Based on clinical criteria, nephrotoxicity was detected in 62 (6.7%) and ototoxic symptoms were detected in 42 (4.8%) participants. Nephrotoxicity and ototoxic symptoms were clinically managed by modification of treatment regimens including dose and frequency of drug administration.ConclusionNephrotoxicity and ototoxic symptoms were significant problems among patients on follow-up for MDR-TB treatment. Based on laboratory criteria (serum creatinine), nephrotoxicity remained significant adverse events throughout intensive phase of treatment, indicating close monitoring of patients for successful outcome is mandatory until countries adopt the recent injectable-free WHO guideline and under specific conditions.

Pharmacokinetics of Second-Line Anti-Tubercular Drugs.

Multidrug-resistant tuberculosis (MDR TB) has become a major global health concern and is also an issue in children. Children with MDR TB need longer duration of treatment with multiple drugs. The MDR TB treatment regimen usually comprises of a fluoroquinolone, an aminoglycoside, ethionamide, cycloserine, pyrazinamide and ethambutol. In the absence of pediatric friendly tablets/formulations, in most cases the adult tablets are either crushed or broken. This is likely to lead to inaccurate dosing. Very limited information is available on the pharmacokinetics of second-line anti-TB drugs in children with MDR TB, except for few studies from South Africa and one from India. Drugs such as linezolid, clofazimine are also being considered for the treatment of MDR TB in children. However, their pharmacokinetics is not known in the pediatric population. It is important to generate pharmacokinetic studies of drugs used to treat MDR TB in children in different settings, which would provide useful information on the adequacy of drug doses.

Methionine Antagonizes para-Aminosalicylic Acid Activity via Affecting Folate Precursor Biosynthesis in Mycobacterium tuberculosis.

para-Aminosalicylic acid (PAS) is a second-line anti-tubercular drug that is used for the treatment of drug-resistant tuberculosis (TB). PAS efficacy in the treatment of TB is limited by its lower potency against Mycobacterium tuberculosis relative to many other drugs in the TB treatment arsenal. It is known that intrinsic metabolites, such as, para-aminobenzoic acid (PABA) and methionine, antagonize PAS and structurally related anti-folate drugs. While the basis for PABA-mediated antagonism of anti-folates is understood, the mechanism for methionine-based antagonism remains undefined. In the present study, we used both targeted and untargeted approaches to identify factors associated with methionine-mediated antagonism of PAS activity. We found that synthesis of folate precursors as well as a putative amino acid transporter, designated MetM, play crucial roles in this process. Disruption of metM by transposon insertion resulted in a ≥30-fold decrease in uptake of methionine in M. bovis BCG, indicating that metM is the major facilitator of methionine transport. We also discovered that intracellular biotin confers intrinsic PAS resistance in a methionine-independent manner. Collectively, our results demonstrate that methionine-mediated antagonism of anti-folate drugs occurs through sustained production of folate precursors.

Follow up of Drug-Resistant Pulmonary Tuberculosis Patients in a DRTB Center in First Fifteen Months of Treatmen

Background and Objective: Multidrug-resistant tuberculosis (MDR-TB) is defined as resistant to both INH and Rifampicin with or without resistance to other first-line antitubercular drugs. The aim of the study was to assess the sputum culture conversion rate during first 12 months of treatment in drug-resistant TB patients, to assess the impact of comorbid illnesses and other factors on culture conversion by following up the patients up to 15 months after initiation of treatment. Materials and Methods: This was a prospective study comprising of 142 diagnosed patients of drug-resistant TB admitted in this center from April 2014 to March 2015 for treatment initiation, excluding extrapulmonary TB and already diagnosed extensively drug-resistant tuberculosis (XDR-TB). After pretreatment evaluation, standard second-line antitubercular drug (CAT-IV) was started. Patients were followed up in first 15 months of treatment. Results of sputum culture for mycobacteria at 3rd, 4th, 5th, 6th, 7th, 9th and 12th months after treatment initiation were analyzed. Results: Sputum culture for mycobacteria was converted negative within one year in 95 cases (67%); whereas 18 patients died during follow up, 27 defaulted and 2 patients switched over to CAT-V after development of extended drug-resistance during follow up. Conclusion: Though drug-resistant tuberculosis (DRTB) is one of the biggest challenges to public health program in India, treatment with standardized second-line drugs under RNTCP have a favorable outcome as indicated by sputum culture conversion of as many as 67% of patients within one year in this study.

Fragment Screening against the EthR-DNA Interaction by Native Mass Spectrometry.

Native nanoelectrospray ionization mass spectrometry is an underutilized technique for fragment screening. In this study, the first demonstration is provided of the use of native mass spectrometry for screening fragments against a protein-DNA interaction. EthR is a transcriptional repressor of EthA expression in Mycobacterium tuberculosis (Mtb) that reduces the efficacy of ethionamide, a second-line antitubercular drug used to combat multidrug-resistant Mtb strains. A small-scale fragment screening campaign was conducted against the EthR-DNA interaction using native mass spectrometry, and the results were compared with those from differential scanning fluorimetry, a commonly used primary screening technique. Hits were validated by surface plasmon resonance and X-ray crystallography. The screening campaign identified two new fragments that disrupt the EthR-DNA interaction in vitro (IC50 =460-610 μm) and bind to the hydrophobic channel of the EthR dimer.

Adverse drug reactions and treatment outcome analysis of DOTS-plus therapy of MDR-TB patients at district tuberculosis centre: A four year retrospective study.

Background:Treatment of multidrug-resistant tuberculosis (MDR-TB) requires the use of expensive and toxic second-line anti-tubercular drugs which are given for a longer duration. Adverse drug reactions (ADRs) of second-line antitubercular drugs affect compliance and thereby treatment outcome. We set out to analyze ADRs and treatment outcome of MDR-TB patients receiving directly observed treatments plus therapy.Materials and Methods:A retrospective study of registered MDR-TB cases at district tuberculosis center during 2010–2014 was performed. Data regarding sociodemographic profile, diagnosis, and treatment as well as ADRs were recorded and evaluated. ADRs were evaluated for causality, severity assessment, management aspects, and impact on treatment outcome.Results:In total 147 ADRs were reported among 72 cases. Most commonly observed ADRs were gastrointestinal (24.5%) followed by self reported weakness (21.23%), psychological (14.38%), joint pain (14.38%), and respiratory symptoms. Discontinuation of the drugs due to ADRs was required in 36 (24.48%) events. ADRs were significantly associated with nontreatment adherence and defaulter outcome. Cure rate was higher in MDR-TB cases with ADRs (59.72%) than MDR-TB cases without ADRs (30.18%).Conclusion:Attention needs to be paid for timely recognition and treatment of ADR with minimum modification of treatment regimen. Equal attention should be paid to MDR-TB without ADR cases to raise over all cure rate.

Study of factors influencing response and outcome of Cat-IV regimen in MDRTB patients

BackgroundCAT IV regimen or the standardized drug regimen (SDR) under the Revised National Control Program (RNTCP) uses six second-line anti-tubercular drugs in the initial intensive phase (IP). These drugs have many side effects and toxicity; they are less efficacious and have poor acceptability. The present study was conducted to evaluate the efficacy and outcome of Cat-IV regimen and the factors which influence the treatment outcome in MDR TB patients. MethodsIt was a prospective observational study, which was done in the CAT II treatment failure, LPA proven MDR TB patients, above the age of 18 years, who were referred to DOTS Plus center for treatment. The study was approved by the hospital ethics committee and patient consent was obtained before inclusion. ResultsWe observed culture conversion in 63.04% and ADR in 96.5%, default in 15.65%, and death in11.3% cases. The factors which influenced outcome included low body weight, long duration of illness cavitatory disease and indulgence in both tobacco & alcohol. The radiological favorable response strongly and significantly correlated with the bacteriological and clinical response during the IP. ConclusionWe suggest that the efficacy can be further augmented by reducing default and controlling deaths which accounts for substantial numbers and occur mostly during IP.