Treatment Of Drug-resistant Tuberculosis Research Articles

Readability of Patient-Facing Information of Antibiotics Used in the WHO Short 6-Month and 9-Month All Oral Treatment for Drug-Resistant Tuberculosis.

Readability of patient-facing information of oral antibiotics detailed in the WHO all oral short (6months, 9months) has not been described to date. The aim of this study was therefore to examine (i) how readable patient-facing TB antibiotic information is compared to readability reference standards and (ii) if there are differences in readability between high-incidence countries versus low-incidence countries. Ten antibiotics, including bedaquiline, clofazimine, ethambutol, ethionamide, isoniazid, levofloxacin, linezolid, moxifloxacin, pretomanid, pyrazinamide, were investigated. TB antibiotic information sources were examined, consisting of 85 Patient Information Leaflets (PILs) and 40 antibiotic web resouces. Of these 85 PILs, 72 were taken from the National Medicines Regulator from six countries (3TB high-incidence [Rwanda, Malaysia, South Africa] + 3TB low-incidence [UK, Ireland, Malta] countries). Readability data was grouped into three categories, including (i) high TB-incidence countries (n = 33 information sources), (ii) low TB-incidence countries (n = 39 information sources) and (iii) web information (n = 53). Readability was calculated using Readable software, to obtain four readability scores [(i) Flesch Reading Ease (FRE), (ii) Flesch-Kincaid Grade Level (FKGL), (iii) Gunning Fog Index and (iv) SMOG Index], as well as two text metrics [words/sentence, syllables/word]. Mean readability scores of patient-facing TB antibiotic information for FRE and FKGL, were 47.4 ± 12.6 (sd)(target ≥ 60) and 9.2 ± 2.0(target ≤ 8.0), respectively. There was no significant difference in readability between low incidence countries and web resources, but there was significantly poorer readability associated with PILs from high incidence countries versus low incidence countries (FRE; p = 0.0056: FKGL; p = 0.0095). Readability of TB antibiotic PILs is poor. Improving readability of PILs should be an important objective when preparing patient-facing written materials, thereby improving patient health/treatment literacy.

TREATMENT OUTCOME OF TUBERCULOSIS CASES AMONG PAEDIATRIC PATIENTS IN WESTERN RAJASTHAN

Objective: This study aimed to identify drug-resistant tuberculosis cases and treatment results. Because it is one of the few studies that have looked at the results of TB treatment among children in the nation, this one was noteworthy. Methods: Drug-resistant cases of paediatric TB were recruited from various districts of Western Rajasthan. Drug resistance in Mycobacterium tuberculosis was detected by line Probe Assay. The cases were followed up for treatment. Results: A total of 41 drug-resistant TB cases were evaluated. Out of 41, 21 were rifampicin mono-resistant, 8 were isoniazid mono-resistant, MDR and pre-XDR were 5 each, and XDR cases were 2. 19 cases were successfully cured and there was one death reported during treatment. Conclusion: Cure rate of paediatric TB is less than 50% in our region. Adherence to treatment and contact isolation are crucial to increase cure rate and decrease the incidence of drug-resistant TB.

Apramycin has high in vitro activity against Mycobacterium tuberculosis.

Introduction. Aminoglycoside antibiotics such as amikacin and kanamycin are important components in the treatment of Mycobacterium tuberculosis (Mtb) infection. However, more and more clinical strains are found to be aminoglycoside antibiotic-resistant. Apramycin is another kind of aminoglycoside antibiotic that is commonly used to treat infections in animals.Hypothesis. Apramycin may have in vitro activity against Mtb.Aim. This study aims to evaluate the efficacy of apramycin against Mtb in vitro and determine its epidemiological cut-off (ECOFF) value.Methodology. One hundred Mtb isolates, including 17 pansusceptible and 83 drug-resistant tuberculosis (DR-TB) strains, were analysed for apramycin resistance using the MIC assay.Results. Apramycin exhibited significant inhibitory activity against Mtb clinical isolates, with an MIC50 of 0.5 μg ml-1 and an MIC90 of 1 μg ml-1. We determined the tentative ECOFF value as 1 µg ml-1 for apramycin. The resistant rates of multidrug-resistant tuberculosis (MDR-TB), pre-extensively drug-resistant (pre-XDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) strains were 12.12 % (4/33), 20.69 % (6/29) and 66.67 % (14/21), respectively. The rrs gene A1401G is associated with apramycin resistance, as well as the cross-resistance between apramycin and other aminoglycosides.Conclusion. Apramycin shows high in vitro activity against the Mtb clinical isolates, especially the MDR-TB clinical isolates. This encouraging discovery calls for more research on the functions of apramycin in vivo and as a possible antibiotic for the treatment of drug-resistant TB.

Beyond the diagnosis of drug-resistant Tuberculosis in Norway: patients’ experiences before, during and after treatment

BackgroundThis study aims to explore the varied experiences of patients with drug-resistant tuberculosis in Norway. The study emphasizes challenges and implications of being diagnosed with drug-resistant tuberculosis, including the impact on psychosocial health during the diagnosis, disease, treatment, isolation and recovery phases.Norway is a low endemic country of tuberculosis. Most patients are immigrants, and some of them have recently arrived in the country. Patients undergoing treatment for drug-resistant tuberculosis endure prolonged and demanding treatment that could affect their psychosocial health.MethodsThis qualitative study conducted 16 in-depth interviews with individuals aged 18 years and above who were diagnosed with drug-resistant tuberculosis. All participants completed the treatment between 2008 and 2020. Fourteen participants were immigrants, and eight of them had resided in Norway for less than four years before diagnosis. Data analysis followed the six-phase reflexive thematic analysis framework, focusing on identifying patterns in participants’ experiences, thoughts, expectations and attitudes.ResultsThe narratives of the participants highlighted the complexities of navigating the diagnosis of drug-resistant tuberculosis, treatment, side effects and life after treatment. Immigrants encountered additional challenges, including language barriers and adapting to new social environments. All participants reported experiencing physical health issues that additionally affected their mental health and social activity. Several participants had a delayed or prolonged diagnosis that complicated their disease trajectory. Participants with suspected or confirmed contagious pulmonary tuberculosis underwent hospital isolation for periods ranging from weeks to six months. The participants reported mental health issues, social isolation and stigma, however few were offered follow-up by a psychologist. Many participants had persistent problems at the time of the interviews. Three main themes emerged from the analysis: Delayed and prolonged diagnosis; Psychosocial impact of isolation during treatment; The life after tuberculosis.ConclusionThis study highlights the enduring impact of drug-resistant tuberculosis on patients and the significance of timely diagnosis, psychosocial support and post-treatment follow-up. The participants universally faced serious implications of the disease, including stigma and isolation. Participants who experienced delayed diagnosis, reflected on missed early intervention opportunities. We recommend further research in low endemic countries to evaluate the international and local recommendations on psychosocial support.

Results of Treatment of Patients with Multiple Drug Resistant Tuberculosis among Key Populations during the COVID-19 Pandemic in Dushanbe, Tajikistan

The objective: to identify changes in effectiveness of treatment of multiple drug resistant tuberculosis among key populations in Dushanbe, including the period of the COVID-19 pandemic.Subjects and Methods. Retrospective study of medical records of 431 MDR TB patients registered for treatment in Dushanbe was conducted (2017-2019 - Group 1 and 2020-2021 - Group 2 (the COVID-19 pandemic period)).Results. The duration of treatment was 15.4±6.9 months in Group 1, and 10.8±4.3 months in Group 2, which was due to the introduction of short-course regimens in that group. At the same time, in Group 2 there was an increase in effectiveness of MDR TB treatment to 85% versus 80% in Group 1, which was due to the use of new drugs and regimens containing them. In Group 1, a statistically significant association was found between MDR TB treatment failure and the following parameters: male gender (RR=2.3 (1.36-4.04), p=0.002), positive HIV status (RR=2.35 (1.37-4.05), p=0.011), hepatitis C infection (RR=3.0 (1.87-4.8), p <0.001), alcohol (RR=3.2 (1.96-5.2), p<0.001) and substances abuse (RR=3.99 (2.5-6.2), p<0.001), previous imprisonment (RR=2.6 (1.48-4.6), p<0.001), unemployment (RR=3.5 (1.8-6.7), p <0.001), and homelessness (RR=5.0 (3.9-6.5), p=0.0011). In Group 2, failure of MDR TB treatment was statistically significantly associated with hepatitis C (RR=3.3 (1.5-7.2), p=0.02), alcohol and drug abuse (RR= 4.4 ( 1.95-10.1). p =0.026), as well as (unlike Group 1) labor migration (RR=3.0 (1.45-6.2), p=0.0068), in-patient treatment (RR=3.8 (1.36-10.64), p=0.0056), while there was no association with HIV status.

Improving Treatment Literacy of Antibiotic Use in Newly Defined WHO 6 Months and 9 Months All-oral Regimens for Drug-resistant Tuberculosis – Comparison of the Readability of Patient Information Leaflets from High Tuberculosis Burden Countries to 10 Antibiotics Used in the Treatment of Drug-resistant Tuberculosis

Improving Treatment Literacy of Antibiotic Use in Newly Defined WHO 6 Months and 9 Months All-oral Regimens for Drug-resistant Tuberculosis – Comparison of the Readability of Patient Information Leaflets from High Tuberculosis Burden Countries to 10 Antibiotics Used in the Treatment of Drug-resistant Tuberculosis

Savings from the introduction of BPaL and BPaLM regimens at the country level.

In 2022, the WHO recommended the 6-month regimens BPaL (bedaquiline + pretomanid + linezolid) and BPaLM (BPaL + moxifloxacin) as treatment options for most forms of drug-resistant TB. SLASH-TB estimates the cost-saving and cost-effectiveness for the healthcare system and patients when a country switches from current standard-of-care treatment regimens to BPaL/BPaLM. Country data from national TB programmes (NTP) are used to calculate the costs for all regimens and treatment outcomes. Where BPaL/BPaLM is not currently used, clinical trial outcomes data are used to estimate cost-effectiveness. DALYs are calculated using the Global Burden of Disease (GBD) database. We present the results of four countries that have used the tool and shared their data. When shorter and longer regimens are replaced with BPaL/BPaLM, the savings per patient treated in Pakistan, the Philippines, South Africa, and Ukraine are $746, $478, $757, and $2,636, respectively. An increased number of patients would be successfully treated with BPaL/BPaLM regimens, with 411, 1,025, 1,371 and 829 lives saved and 20,179, 27,443, 33,384 and 21,924 DALYs averted annually in the four countries, respectively. Through BPaL/BPaLM regimens, drug-resistant TB treatment has become more effective, shorter, less burdensome for patients, cheaper for both health systems and patients, and saves more lives.

A Transcriptomic Biomarker Predicting Linezolid-Associated Neuropathy During Treatment of Drug-Resistant Tuberculosis.

Neuropathic adverse events occur frequently in linezolid-containing regimens, some of which remain irreversible after drug discontinuation. We aimed to identify and validate a host RNA-based biomarker that can predict linezolid-associated neuropathy before multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) treatment initiation and to identify genes and pathways that are associated with linezolid-associated neuropathy. Adult patients initiating MDR/RR-TB treatment including linezolid were prospectively enrolled in 3 independent cohorts in Germany. Clinical data and whole blood RNA for transcriptomic analysis were collected. The primary outcome was linezolid-associated optic and/or peripheral neuropathy. A random forest algorithm was used for biomarker identification. The biomarker was validated in an additional fourth cohort of patients with MDR/RR-TB from Romania. A total of 52 patients from the 3 identification cohorts received linezolid treatment. Of those, 24 (46.2%) developed peripheral and/or optic neuropathies during linezolid treatment. The majority (59.3%) of the episodes were of moderate (grade 2) severity. In total, the expression of 1,479 genes differed significantly at baseline of treatment. Suprabasin (SBSN) was identified as a potential biomarker to predict linezolid-associated neuropathy. In the validation cohort, 10 of 42 (23.8%) patients developed grade ≥3 neuropathies. The area under the curve for the biomarker algorithm prediction of grade ≥3 neuropathies was 0.63 (poor; 95% confidence interval: 0.42 - 0.84). We identified and preliminarily validated a potential clinical biomarker to predict linezolid-associated neuropathies before the initiation of MDR/RR-TB therapy. Larger studies of the SBSN biomarker in more diverse populations are warranted.

The introduction of video-enabled directly observed therapy (video-DOT) for patients with drug-resistant TB disease in Eswatini amid the COVID-19 pandemic – a retrospective cohort study

BackgroundVideo-enabled directly observed therapy (video-DOT) has been proposed as an additional option for treatment provision besides in-person DOT for patients with drug-resistant TB (DRTB) disease. However, evidence and implementation experience mainly originate from well-resourced contexts. This study describes the operationalization of video-DOT in a low-resourced setting in Eswatini facing a high burden of HIV and TB amid the emergence of the COVID-19 pandemic.MethodsThis is a retrospectively established cohort of patients receiving DRTB treatment during the implementation of video-DOT in Shiselweni from May 2020 to March 2022. We described intervention uptake (vs. in-person DOT) and assessed unfavorable DRTB treatment outcome (death, loss to care) using Kaplan-Meier statistics and multivariable Cox-regression models. Video-related statistics were described with frequencies and medians. We calculated the fraction of expected doses observed (FEDO) under video-DOT and assessed associations with missed video uploads using multivariable Poisson regression analysis.ResultsOf 71 DRTB patients eligible for video-DOT, the median age was 39 (IQR 30–54) years, 31.0% (n = 22) were women, 67.1% (n = 47/70) were HIV-positive, and 42.3% (n = 30) were already receiving DRTB treatment when video-DOT became available. About half of the patients (n = 37; 52.1%) chose video-DOT, mostly during the time when COVID-19 appeared in Eswatini. Video-DOT initiations were lower in new DRTB patients (aHR 0.24, 95% CI 0.12–0.48) and those aged ≥ 60 years (aHR 0.27, 95% CI 0.08–0.89). Overall, 20,634 videos were uploaded with a median number of 553 (IQR 309–748) videos per patient and a median FEDO of 92% (IQR 84–97%). Patients aged ≥ 60 years were less likely to miss video uploads (aIRR 0.07, 95% CI 0.01–0.51). The cumulative Kaplan-Meier estimate of an unfavorable treatment outcome among all patients was 0.08 (95% CI 0.03–0.19), with no differences detected by DOT approach and other baseline factors in multivariable analysis.ConclusionsImplementing video-DOT for monitoring of DRTB care provision amid the intersection of the HIV and COVID-19 pandemics seemed feasible. Digital health technologies provide additional options for patients to choose their preferred way to support treatment taking, thus possibly increasing patient-centered health care while sustaining favorable treatment outcomes.

Cost and cost-effectiveness of BPaL regimen used in drug-resistant TB treatment in the Philippines.

In 2022, the WHO announced that the 6-month BPaL/M regimen should be used for drug-resistant TB (DR-TB). We estimate the patient and provider costs of BPaL compared to current standard-of-care treatment in the Philippines. Patients on BPaL under operational research, or 9-11-month standard short oral regimen (SSOR) and 18-21-month standard long oral regimen (SLOR) under programmatic conditions were interviewed using the WHO cross-sectional TB patient cost tool. Provider costs were assessed through a bottom-up and top-down costing analysis. Total patient costs per treatment episode were lowest with BPaL (USD518.0) and increased with use of SSOR (USD825.8) and SLOR (USD1,023.0). Total provider costs per successful treatment were lowest with BPaL (USD1,994.5) and increased with SSOR (USD3,121.5) and SLOR (USD10,032.4). Compared to SSOR, BPaL treatment was cost-effective at even the lowest willingness to pay threshold. As expected, SLOR was the costliest and least effective regimen. Costs incurred by patients on BPaL were 37% (95% CI 22-56) less than SSOR and 50% (95% CI 32-68) less than SLOR, while providers could save 36% (95% CI 21-56) to 80% (95% CI 64-93) per successful treatment, respectively. The study shows that treatment of DR-TB with BPaL was cost-saving for patients and cost-effective for the health system.

Pattern of Mutations in Rifampicin Resistance (rpoB) Gene and Analysis of Rifampicin Indeterminate Result in Tuberculosis Detected by Xpert MTB/RIF Assay in Kalaburagi, India

Tuberculosis (TB) is a serious disease that has been observed since ancient times. In the mid-to late-20th century, the main clinical approach to this disease involved focusing on its diagnosis, prevention, and treatment. However, in the 21st century, the focus has shifted toward the diagnosis and treatment of drug-resistant TB. With the use of the Xpert MTB/RIF assay at the frontlines in India, interpreting indeterminate results to treatment with rifampicin, an antitubercular drug, can be challenging. This is further exacerbated by a lack of knowledge regarding mutation frequency in antitubercular drug-resistant genes in this region. Among antitubercular drugs, rifampicin is the most potent and effective drug for the treatment of tuberculosis; hence, understanding the pattern of rifampicin resistance (rpoB) gene mutations will provide insights into the genetic basis of this resistance, which may help in the prevention and treatment of TB. This retrospective observational study presents sociodemographic details, sample types, Mycobacterium tuberculosis load, types of probe mutations detected, and rifampicin indeterminate results from the Xpert MTB/RIF assay. Of the 314 samples analyzed, 258 showed rifampicin resistance as detected by MTB, with 56 samples of MTB-detected rifampicin indeterminate results. Type E probe mutation (58.9%) was the most common type, while the least frequent mutation was Type C probe (1.5%). No missing probe was observed in approximately 8.9% of samples. Among the 56 rifampicin indeterminate results, the maximum Cycle threshold value did not cross 34.5 in six samples.

The Burden of Drug-Resistant Tuberculosis among Kenya's Devolved Health Units and Associated Treatment Outcomes

Background: A devolution is a form of decentralisation or the transfer of authority and responsibility from central to lower levels of government for a range of public functions. The drafters of the 2010 Kenyan constitution chose to devolve functions to 47 newly created counties. In Kenya, health is a devolved function that county governments run. Tuberculosis is managed at the county level in coordination with the National Leprosy Tuberculosis and Lung Disease Program (NLTP) with a mission of End TB Strategy to achieve a 95% decline in deaths due to tuberculosis compared with the 2015 baseline and reach an equivalent 90% reduction in tuberculosis incidence rate. Methods: This was a retrospective cohort study that collected data from health facilities accredited by the NLTP for drug-resistant tuberculosis treatment. The study population included patients who tested positive for drug-resistant tuberculosis from 2014 to 2019. Data was sourced from NLTP Electronic Medical Records (TIBU-System). After abstraction, the data was entered into Excel and analysed through STATA software version 13. Results: Of the 2674 enrolled patients in total, there were more males affected with DRTB at 64 % compared to the female patients. The public facilities carried the immense burden of diagnosis and treatment of the patient, having a cumulative number of 83 %, while the prison sector had the lowest number. For the resistance pattern, the new, relapse, and failure of first-line drugs accounted for most drug-resistant cases at 80 %, with only 65 % of the total cases having been done a gene-expert test at the point of screening. Conclusion: With a devolved health unit in Kenya, there needs to be a more coordinated support system from the national government to the county health units in terms of surveillance of TB disease. Regional centralised laboratories for diagnosis and monitoring of TB would reduce the time it takes for samples to come to Nairobi for testing, which takes time before patents are initiated on treatment.

Treatment of MDR, Pre-XDR, XDR, and Rifampicin-Resistant Tuberculosis or in Case of Intolerance to at Least Rifampicin in Austria, Germany, and Switzerland.

Based on the assessment of new evidence, the World Health Organization (WHO) updated its guidelines for the treatment of drug-resistant tuberculosis (TB) in December 2022. The new recommendations and the latest study data made it necessary to update the existing guideline on the treatment of at least rifampicin-resistant TB (RR-TB) for the German-speaking countries, replacing the respective chapters of the treatment guidelines published in 2022. A shortened treatment of proven RR-TB and multidrug-resistant TB for at least 6 months using the fixed and non-modifiable drug combination of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) is now also recommended for Austria, Germany, and Switzerland under certain conditions considering the existing barriers for the implementation of the new treatment regimen. For the treatment of pre-extensively drug-resistant (pre-XDR-) TB, an individualized treatment for 18 months continues to be the primary recommendation. The non-modifiable drug combination of bedaquiline, pretomanid, and linezolid (BPaL) may be used alternatively in selected pre-XDR-TB cases, provided that all prerequisites are met. The necessary requirements for using BPaLM and BPaL are presented in detail in this amendment to the consensus-based TB treatment guideline for adult patients.

A complex case study: coexistence of multi-drug-resistant pulmonary tuberculosis, HBV-related liver failure, and disseminated cryptococcal infection in an AIDS patient

BackgroundHepatitis B virus (HBV) infection can cause liver failure, while individuals with Acquired Immunodeficiency Virus Disease (AIDS) are highly susceptible to various opportunistic infections, which can occur concurrently. The treatment process is further complicated by the potential occurrence of immune reconstitution inflammatory syndrome (IRIS), which presents significant challenges and contributes to elevated mortality rates.Case presentationThe 50-year-old male with a history of chronic hepatitis B and untreated human immunodeficiency virus (HIV) infection presented to the hospital with a mild cough and expectoration, revealing multi-drug resistant pulmonary tuberculosis (MDR-PTB), which was confirmed by XpertMTB/RIF PCR testing and tuberculosis culture of bronchoalveolar lavage fluid (BALF). The patient was treated with a regimen consisting of linezolid, moxifloxacin, cycloserine, pyrazinamide, and ethambutol for tuberculosis, as well as a combination of bictegravir/tenofovir alafenamide/emtricitabine (BIC/TAF/FTC) for HBV and HIV viral suppression. After three months of treatment, the patient discontinued all medications, leading to hepatitis B virus reactivation and subsequent liver failure. During the subsequent treatment for AIDS, HBV, and drug-resistant tuberculosis, the patient developed disseminated cryptococcal disease. The patient’s condition worsened during treatment with liposomal amphotericin B and fluconazole, which was ultimately attributed to IRIS. Fortunately, the patient achieved successful recovery after appropriate management.ConclusionEnhancing medical compliance is crucial for AIDS patients, particularly those co-infected with HBV, to prevent HBV reactivation and subsequent liver failure. Furthermore, conducting a comprehensive assessment of potential infections in patients before resuming antiviral therapy is essential to prevent the occurrence of IRIS. Early intervention plays a pivotal role in improving survival rates.

Quantification of isoniazid in tablets for tuberculosis treatment by thin layer chromatography with smartphone image capture and ImageJ analysis

Isoniazid (INH) oral dosage tablets are an antibacterial medication commonly used to treat tuberculosis (TB). While this medication can be highly effective in managing and curing TB, manufacturing of poor-quality INH products can lead to the proliferation of drug resistant TB strains – particularly in low- and middle-income countries (LMICs). It is therefore imperative that reliable methods of quality screening of INH tablets are available for areas that have limited access to traditional testing resources. In this study, a thin layer chromatography (TLC) procedure for INH identification is validated in conjunction with smartphone image capture and open-source image analysis software to provide an alternative quantitative quality screening method for INH tablets, primarily intended for applications in LMICs. The method assessed two individual tablet formulations: 100 mg and 300 mg INH, each from different manufacturers. The modified TLC procedure used for the study was based on a validated high-performance thin layer chromatography method for the determination of rifampicin, INH, and pyrazinamide in a fixed dosage tablet. Quantitation was performed by visualizing and photographing TLC plates using a UV lamp, 3D-printed light box, and Apple iPhone SE 2nd Generation (2020) and Google Pixel 4a (5G) smartphones, and images were then analyzed using ImageJ Fiji software. The processed images’ pixel data were used to create a calibration curve from the INH standard spots to determine the concentration of an INH sample spot. Linearity, range, accuracy, repeatability and intermediate precision, specificity, and robustness were evaluated. The method was linear in the range of 0.150–0.450 mg mL−1, with coefficients of determination ≥0.98. The overall accuracy of the method was 99.2 % with an RSD of 2.4 % for image sets captured using the Apple iPhone, and 99.7 % with an RSD of 3.3 % for image sets captured using the Google Pixel. The pooled standard deviations for repeatability and intermediate precision were 2.27 % and 3.25 %, respectively, for the iPhone and 2.62 % and 3.74 %, respectively, for the Pixel. The method demonstrated sufficient specificity and robustness. The results of this method validation suggest that this procedure may provide a feasible alternative to traditional testing as a low-cost means of quality screening in LMICs.

Evaluating the biomolecular interaction between delamanid/formulations and human serum albumin by fluorescence, CD spectroscopy and SPR: Effects on protein conformation, kinetic and thermodynamic parameters

Delamanid is an anti-tuberculosis drug used for the treatment of drug-resistant tuberculosis. Since delamanid has a high protein bound potential, even patients with low albumin levels should experience high and rapid delamanid clearance. However, the interaction between delamanid and albumin should be better controlled to optimize drug efficacy. This study was designed to evaluate the binding characteristics of delamanid to human serum albumin (HSA) using various methods: fluorescence spectroscopy, circular dichroism (CD), surface plasmon resonance (SPR), and molecular docking simulation. The fluorescence emission band without any shift indicated the interaction was not affected by the polarity of the fluorophore microenvironment. The reduction of fluorescence intensity at 344 nm was proportional to the increment of delamanid concentration as a fluorescence quencher. UV-absorbance measurement at the maximum wavelength (λmax, 280 nm) was evaluated using inner filter effect correction. The HSA conformation change was explained by the intermolecular energy transfer between delamanid and HSA during complex formation. The study, which was conducted at temperatures of 298 K, 303 K, and 310 K, revealed a static quenching mechanism that correlated with a decreased of bimolecular quenching rate constant (kq) and binding constant (Ka) at increased temperatures. The Ka was 1.75–3.16 × 104 M−1 with a specific binding site with stoichiometry 1:1. The negative enthalpy change, negative entropy change, and negative Gibbs free energy change demonstrated an exothermic-spontaneous reaction while van der Waals forces and hydrogen bonds played a vital role in the binding. The molecular displacement approach and molecular docking confirmed that the binding occurred mainly in subdomain IIA, which is a hydrophobic pocket of HSA, with a theoretical binding free energy of −9.33 kcal/mol. SPR exhibited a real time negative sensorgram that resulted from deviation of the reflex angle due to ligand delamanid-HSA complex forming. The binding occurred spontaneously after delamanid was presented to the HSA surface. The SPR mathematical fitting model revealed that the association rate constant (kon) was 2.62 × 108 s−1M−1 and the dissociation rate constant (koff) was 5.65 × 10−3 s−1. The complexes were performed with an association constant (KA) of 4.64 × 1010 M−1 and the dissociation constant (KD) of 2.15 × 10−11 M. The binding constant indicated high binding affinity and high stability of the complex in an equilibrium. Modified CD spectra revealed that conformation of the HSA structure was altered by the presence of delamanid during preparation of the proliposomes that led to the reduction of secondary structure stabilization. This was indicated by the percentage decrease of α-helix. These findings are beneficial to understanding delamanid-HSA binding characteristics as well as the drug administration regimen.

Prevalence and genetic basis of Mycobacterium tuberculosis resistance to pretomanid in China

BackgroundPretomanid is a key component of new regimens for the treatment of drug-resistant tuberculosis (TB) which are being rolled out globally. However, there is limited information on the prevalence of pre-existing resistance to the drug.MethodsTo investigate pretomanid resistance rates in China and its underlying genetic basis, as well as to generate additional minimum inhibitory concentration (MIC) data for epidemiological cutoff (ECOFF)/breakpoint setting, we performed MIC determinations in the Mycobacterial Growth Indicator Tube™ (MGIT) system, followed by WGS analysis, on 475 Mycobacterium tuberculosis (MTB) isolated from Chinese TB patients between 2013 and 2020.ResultsWe observed a pretomanid MIC distribution with a 99% ECOFF equal to 0.5 mg/L. Of the 15 isolates with MIC values > 0.5 mg/L, one (MIC = 1 mg/L) was identified as MTB lineage 1 (L1), a genotype previously reported to be intrinsically less susceptible to pretomanid, two were borderline resistant (MIC = 2–4 mg/L) and the remaining 12 isolates were highly resistant (MIC ≥ 16 mg/L) to the drug. Five resistant isolates did not harbor mutations in the known pretomanid resistant genes.ConclusionsOur results further support a breakpoint of 0.5 mg/L for a non-L1 MTB population, which is characteristic of China. Further, our data point to an unexpected high (14/475, 3%) pre-existing pretomanid resistance rate in the country, as well as to the existence of yet-to-be-discovered pretomanid resistance genes.

Drug Targets, Current and Future Therapeutics for the Treatment of Multi Drug Resistant Tuberculosis with their Clinical Applications: A Critical Review

Abstract: Multi drug-resistant or extensive drug resistance Mycobacterium tuberculosis poses numerous challenges for health care workers and for public health authorities. Treating multidrug resistant or extensive drug resistance tuberculosis continues to be a difficult task, as a longer regimen is associated with a higher number of adverse drug events and economic burden and has a significant negative effect on health care resources. Many trials and observational studies were conducted. Few studies are underway to develop the universal regimen and improve the outcomes related to multi or extensive drug resistance tuberculosis with a shorter regimen duration. The current review will discuss which drug inhibits what target, their synthesis, genetic aspects, repurposed drugs, novel drugs, and extensive trials for the treatment of multi or extensive drug resistance tuberculosis.

Bedaquiline-pretomanid-moxifloxacin-pyrazinamide for drug-sensitive and drug-resistant pulmonary tuberculosis treatment: a phase 2c, open-label, multicentre, partially randomised controlled trial

Bedaquiline-pretomanid-moxifloxacin-pyrazinamide for drug-sensitive and drug-resistant pulmonary tuberculosis treatment: a phase 2c, open-label, multicentre, partially randomised controlled trial

Epidemiology and outcomes of drug-resistant tuberculosis cases notified in a low-resource district in Kerala, India 2017–2021 – A 5-year retrospective analysis

Objectives: Kasaragod district reports the highest drug-resistant tuberculosis (DR-TB) case notification rates in Kerala. We conducted a cross-sectional study in Kasaragod to describe the DR-TB cases notified from January 2017 to December 2021 and to identify the factors associated with unfavorable treatment outcomes in DR-TB patients. Materials and Methods: We analyzed the programmatic data from the “Nikshay portal” (a web-based patient management information system for [TB] under the National TB Elimination Program), DR-TB treatment cards, and treatment registers available with the district TB center for all the DR-TB patients notified during the study period. We described the DR-TB cases by year, local self-government area (the local administrative setup), age, gender, income level, and treatment outcomes. We compared sociodemographic, anthropometric, and clinical factors among the DR-TB patients with favorable (cured and treatment completed) and unfavorable (died, lost to follow-up, and treatment failure) treatment outcomes. Results: From January 2017 to December 2021, 128 DR-TB cases were notified from Kasaragod. Annual notification rates varied from 1.4 to 3.4/100,000 population with the highest notification in 2019. The proportion of new TB cases notified tested for drug sensitivity rose from 22% in 2017 to 86% in 2021. Seven of 41 local self-government areas had not notified DR-TB cases during 2017–2021. The notification was higher in inter-state border areas and the coastal belt of the district. The notification of DR-TB cases was highest among the 45–59 age group (17/100,000), followed by the 60 above group (11/100,000). Males and those living below the poverty line had higher notification rates. Among the outcomes evaluated 118 DR-TB patients, 89 (75.4%) had favorable outcomes, whereas the remaining 24.6% had unfavorable outcomes (death 18 [15.3%], loss to follow-up 7 [6%], and treatment failure 4 [3.4%]). Age more than 45 years adjusted odds ratio (aOR) 3.1 (95% confidence interval [CI] 1.1–8.8), income category below the poverty line aOR 6 (95% CI 1.2–28.6), admitted at least twice during treatment aOR 9.2 (95% CI 2.8–30.3), and body mass index at diagnosis <18.5 kg/m2 aOR 3 (95% CI 1.1–10.3) were found to be significantly associated with unfavorable treatment outcomes. Conclusion: DR-TB notifications have increased in the Kasaragod district from 2017 to 2021, with a high burden among males aged 45 years and above. The favorable treatment outcome is better than the national and state average. Regular monitoring and follow-up of multidrug-resistant patients with low incomes, above 45 years, and underweight may improve the final treatment outcomes.