Efficacy of Long-Acting Bedaquiline Regimens in a Mouse Model of Tuberculosis Preventive Therapy.

Rationale: Completion of preventive therapy is a major bottleneck in global tuberculosis control. Long-acting injectable drug formulations would shorten therapy administration and may thereby improve completion rates. Recently, a long-acting formulation of bedaquiline demonstrated antituberculosis activity for up to 12 weeks after injection in a validated mouse model of preventive therapy. Objectives: The objectives of this study were to 1) determine the total duration of activity after an injection of long-acting bedaquiline and 2) evaluate the activity of regimens comprised of long-acting bedaquiline plus short (2-4 wk) oral companion courses of bedaquiline, with or without rifapentine, using the validated mouse model of tuberculosis preventive therapy. Methods: After the establishment of a stable Mycobacterium tuberculosis lung infection in bacillus Calmette-Guérin (BCG)-immunized BALB/c mice, treatment was initiated with 1 of 12 randomly assigned regimens. In addition to positive and negative controls, six regimens included one or two injections of long-acting bedaquiline (alone or with oral bedaquiline with or without rifapentine), and four comparator regimens consisted of oral agents only. Lung bacterial burden was measured monthly for up to 28 weeks. Measurements and Main Results: One injection of long-acting bedaquiline at 160 mg/kg exerted antituberculosis activity for 12 weeks. Compared with the positive control (daily isoniazid-rifapentine for 4 wk), six regimens had equivalent bactericidal activity (including two all-oral comparator regimens), and two regimens had superior sterilizing activity: one injection with 2 weeks of oral bedaquiline and high-dose rifapentine; and two injections with 4 weeks of oral bedaquiline. Conclusions: Long-acting injectable bedaquiline has significant potential for shortening tuberculosis preventive therapy.

Ferroptosis: action and mechanism of chemical/drug-induced liver injury.

Drug-induced liver injury (DILI) is characterized by hepatocyte injury, cholestasis injury, and mixed injury. The liver transplantation is required for serious clinical outcomes such as acute liver failure. Current studies have found that many mechanisms were involved in DILI, such as mitochondrial oxidative stress, apoptosis, necroptosis, autophagy, ferroptosis, etc. Ferroptosis occurs when hepatocytes die from iron-dependent lipid peroxidation and plays a key role in DILI. After entry into the liver, where some drugs or chemicals are metabolized, they convert into hepatotoxic substances, consume reduced glutathione (GSH), and decrease the reductive capacity of GSH-dependent GPX4, leading to redox imbalance in hepatocytes and increase of reactive oxygen species (ROS) and lipid peroxidation level, leading to the undermining of hepatocytes; some drugs facilitated the autophagy of ferritin, orchestrating the increased ion level and ferroptosis. The purpose of this review is to summarize the role of ferroptosis in chemical- or drug-induced liver injury (chemical/DILI) and how natural products inhibit ferroptosis to prevent chemical/DILI.

Systematic review with network meta-analysis on the treatments for latent tuberculosis infection in children and adolescents.

BACKGROUND: We aimed to synthesize the evidence on the efficacy and safety of different treatment regimens for latent tuberculosis infection (LTBI) in children and adolescents. METHODS: A systematic review with network meta-analysis was performed (CRD142933). Searches were conducted in Pubmed and Scopus (Nov-2021). Randomized controlled trials comparing treatments for LTBI (patients up to 15 years), and reporting data on the incidence of the disease, death or adverse events were included. Networks using the Bayesian framework were built for each outcome of interest. Results were reported as odds ratio (OR) with 95% credibility intervals (CrI). Rank probabilities were calculated via the surface under the cumulative ranking analysis (SUCRA) (Addis-v.1.16.8). GRADE approach was used to rate evidence's certainty. RESULTS: Seven trials (n = 8696 patients) were included. Placebo was significantly associated with a higher incidence of tuberculosis compared to all active therapies. Combinations of isoniazid (15-25 mg/kg/week) plus rifapentine (300-900 mg/week), followed by isoniazid plus rifampicin (10 mg/kg/day) were ranked as best approaches with lower probabilities of disease incidence (10% and 19.5%, respectively in SUCRA) and death (20%). Higher doses of isoniazid monotherapy were significantly associated to more deaths (OR 18.28, 95% ICr [1.02, 48.60] of 4-6 mg/kg/day vs. 10 mg/kg/3x per week). CONCLUSIONS: Combined therapies of isoniazid plus rifapentine or rifampicin for short-term periods should be used as the first-line approach for treating LTBI in children and adolescents. The use of long-term isoniazid as monotherapy and at higher doses should be avoided for this population.

Perianal ulcerative tuberculosis: A case report.

Perianal tuberculosis (TB) is an extremely rare form of mycobacterial infection, in which the anal mucocutaneous junction becomes infected by autoinoculation from an active draining gastrointestinal tract infection. The case of a 73-year-old immunocompetent male patient, who came in with a refractory perianal ulcer is presented. The patient had no history of TB and his lab tests for TB were all negative. A chest X-ray showed streak and nodular opacities in both upper lungs. The ulcer was biopsied twice and a diagnosis of TB was finally rendered by histological examination with confirmatory Polymerase chain reaction (PCR). The lesion was finally cured by intensive anti-TB treatment. Perianal TB needs to be excluded in patients with a refractory perianal ulcer, including immunocompetent cases without TB history. Biopsies and microbiological tests should be performed for any suspicious lesion and repeated if there is high clinical concern. Consideration of differential diagnoses, especially inflammatory bowel disease, is essential. Early and sufficient antitubercular treatment should be initiated to minimize morbidity.

High Rates of Recurrent Tuberculosis Disease: A Population-level Cohort Study.

BACKGROUND: Retreatment tuberculosis (TB) disease is common in high-prevalence settings. The risk of repeated episodes of recurrent TB is unknown. We calculated the rate of recurrent TB per subsequent episode by matching individual treatment episodes over a period of 13 years. METHODS: All recorded TB episodes in Cape Town between 2003 and 2016 were matched by probabilistic linkage of personal identifiers. Among individuals with a first episode notified in Cape Town and who completed their prior treatment successfully we estimated the recurrence rate stratified by subsequent episode and HIV status. We adjusted person-time to background mortality by age, sex, and HIV status. RESULTS: A total of 292 915 TB episodes among 263 848 individuals were included. The rate of recurrent TB was 16.4 per 1000 person-years (95% CI, 16.2-16.6), and increased per subsequent episode (8.4-fold increase, from 14.6 to 122.7 per 1000 from episode 2 to 6, respectively). These increases were similar stratified by HIV status. Rates among HIV positives were higher than among HIV negatives for episodes 2 and 3 (2- and 1.5-fold higher, respectively), and the same thereafter. CONCLUSIONS: TB recurrence rates were high and increased per subsequent episode, independent of HIV status. This suggests that HIV infection is insufficient to explain the high burden of recurrence; it is more likely due to a high annual risk of infection combined with an increased risk of infection or progression to disease associated with a previous TB episode. The very high recurrence rates would justify increased TB surveillance of patients with >1 episode.

Increased diversity, fungal burden, and virulence of oral Candida spp. in patients undergoing anti-tuberculosis treatment.

Some studies have demonstrated a high prevalence of Candida species in patients with tuberculosis (TB). This is most likely due to long-term antimicrobial therapy. To date, no longitudinal studies addressed the effects of anti-TB treatment on the fungal burden and virulence of Candida spp. This study investigated the prevalence and virulence of Candida spp. in the oral cavity of 30 TB patients at different stages of treatment through a cohort study. These results were compared with those of 60 systemically healthy individuals in a cross-sectional study. Oral rinse samples from TB patients were collected before 45 and after 120 days of treatment. In the control group, the biological samples were collected only once. Candida spp. were identified by restriction fragment length polymorphism (RFLP) assays, and the following virulence factors were studied: phospholipase C and proteinase production, as well as Candida spp. biofilm and hyphae formation. The clinical diagnosis of TB and its treatment time were associated with the greater fungal burden (p < 0.0001), presence of non-albicans Candida (NAC) species (p = 0.0003), and increased virulence factors when compared with the Candida spp. isolated from systemically healthy individuals. The results showed that anti-TB treatment time was responsible for the increased fungal burden and isolation of NAC in TB patients (p = 0.0233). The increased prevalence, quantification, and virulence of Candida spp. isolated from the oral cavity of TB patients highlight the greater risk of oral lesions and cases of systemic dissemination in these patients.

Effect of serum isoniazid level on treatment outcomes among tuberculosis patients with slow response - A retrospective cohort study.

BACKGROUND: In this study, we investigate the effects of low serum TB drug level on treatment outcome among TB patients with slow response in South Korea, where the prevalence of rapid acetylator is relatively high. METHODS: Among the pulmonary TB patients whose treatment outcomes were reported between 2014 and 2018 at Incheon St. Mary hospital, those who underwent TDM because of delayed culture conversion or reversion were included. Primary outcome was microbiological failure defined as (1) positive sputum culture after 120 days of treatment, or (2) culture-confirmed relapse within one year after treatment completion. Patients with culture conversion within 120 days and no relapse were classified as the final conversion group. Clinical characteristics and serum drug concentration at 2 h after administration (C2hr) were compared between those two groups. RESULTS: A total of 55 pulmonary TB patients were included. Prevalence of subtherapeutic range of C2hr for isoniazid and rifampin was 78.2% and 21.8%, respectively. With one year of follow-up, 21 cases were classified as the microbiological failure group, and 34 cases as the final conversion group. In a multivariable logistic regression model for predicting microbiological failure, C2hr of isoniazid was the most significant predictor after adjusting for the effects of age and sex (adjusted odds ratio, 0.29; p = 0.009). In a tree-based classification model, C2hr of isoniazid with cutoff level 2.5 µg/ml was the most important variable for predicting microbiological failure. CONCLUSIONS: Low serum isoniazid level was related to poor treatment outcomes among the TB patients with slow response.

Erythema induratum of Bazin in a 10-year-old boy.

Erythema induratum of Bazin (EIB) is a form of tuberculid resulting from hypersensitivity to tuberculosis antigen. EIB occurs most commonly in middle-aged women and is not typically seen in children. Here, we present a rare case of EIB, presenting as a chronic nodular panniculitis, in a 10-year-old Korean boy.

Synthesis, Characterization and Biological Evaluation of New 3,5-Disubstituted-Pyrazoline Derivatives as Potential Anti-Mycobacterium tuberculosis H37Ra Compounds.

A total of fourteen pyrazoline derivatives were synthesized through cyclo-condensation reactions by chalcone derivatives with different types of semicarbazide. These compounds were characterized by IR, 1D-NMR (1H, 13C and Distortionless Enhancement by Polarization Transfer - DEPT-135) and 2D-NMR (COSY, HSQC and HMBC) as well as mass spectroscopy analysis (HRMS). The synthesized compounds were tested for their antituberculosis activity against Mycobacterium tuberculosis H37Ra in vitro. Based on this activity, compound 4a showed the most potent inhibitory activity, with a minimum inhibitory concentration (MIC) value of 17 µM. In addition, six other synthesized compounds, 5a and 5c-5g, exhibited moderate activity, with MIC ranges between 60 µM to 140 µM. Compound 4a showed good bactericidal activity with a minimum bactericidal concentration (MBC) value of 34 µM against Mycobacterium tuberculosis H37Ra. Molecular docking studies for compound 4a on alpha-sterol demethylase was done to understand and explore ligand-receptor interactions, and to hypothesize potential refinements for the compound.

Culture Conversion at 6 Months in Patients Receiving Delamanid-containing Regimens for the Treatment of Multidrug-resistant Tuberculosis.

Delamanid should be effective against highly resistant strains of Mycobacteriumtuberculosis, but uptake has been slow globally. In the endTB (expand new drug markets for TB) Observational Study, which enrolled a large, heterogeneous cohorts of patients receiving delamanid as part of a multidrug regimen, 80% of participants experienced sputum culture conversion within 6 months. Clinical Trials Registration. NCT02754765.

New pyrazolyl-dibenzo[b,e][1,4]diazepinones: room temperature one-pot synthesis and biological evaluation.

Several new (5-aryloxy-pyrazolyl)- and (5-aryl/olefin-sulfanyl-pyrazolyl)-dibenzo[b,e] [1,4] diazepinone scaffolds have been synthesized, by assembling 5-substituted 3-methyl-1-phenyl-pyrazole-4-carbaldehydes of varied nature with different cyclic diketones and aromatic diamines successfully in the presence of indium chloride in acetonitrile, at room temperature. Desired products are excellent in the purity and isolated without chromatography. All new structures are confirmed, on the basis of single-crystal X-ray diffraction data of representative 29e. Compounds reported in the present work revealed good antioxidant, antimicrobial and antiproliferative activities with promising FRAP (ferric reducing antioxidant power), bacterial resistance and human solid tumor cell growth inhibitory values, respectively. Compounds 25c and 29e, overall, registered good to moderate activity against A549 (lung), HeLa (cervix), SW1573 (lung) T-47D (breast) and WiDr (colon) cell lines, with GI50 values in the 2.6-5.1 µM and 1.8-7.5 µM ranges, respectively. Molecular docking was carried out to elucidate the binding modes of the compounds (25c, 29e) to topoisomerase I and II.

Identification of novel selective Mtb-DHFR inhibitors as antitubercular agents through structure-based computational techniques.

Inhibition of dihydrofolate reductase from Mycobacterium tuberculosis-dihydrofolate reductase (Mtb-DHFR) has emerged as a promising approach for the treatment of tuberculosis. To identify novel Mtb-DHFR inhibitors, structure-based virtual screening (SBVS) of the Molecular Diversity Preservation International (MolMall) database was performed using Glide against the Mtb-DHFR and h-DHFR enzymes. On the basis of SBVS, receptor fit, drug-like filters, and ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis, 16 hits were selected and tested for their antitubercular activity against the H37 RV strain of M. tuberculosis. Five compounds showed promising activity with compounds 11436 and 15275 as the most potent hits with IC50 values of 0.65 and 12.51 µM, respectively, against the H37 RV strain of M. tuberculosis. The two compounds were further tested in the Mtb-DHFR and h-DHFR enzymatic assay for selectivity and were found to be three- to eight-fold selective towards Mtb-DHFR over h-DHFR with minimum inhibitory concentration values of 5.50, 73.89 µM and 42.00, 263.00 µM, respectively. In silico simulation studies also supported the stability of the protein-ligand complex formation. The present study demonstrates the successful utilization of in silico SBVS tools for the identification of novel and potential Mtb-DHFR inhibitors and compound 11436 ((2,4-dihydroxyphenyl)(3,4,5-trihydroxyphenyl)methanone) as a potential lead for the development of novel Mtb-DHFR inhibitors.

In Vitro Antimycobacterial Activity and Physicochemical Characterization of Diaryl Ether Triclosan Analogues as Potential InhA Reductase Inhibitors.

Two sets of diphenyl ether derivatives incorporating five-membered 1,3,4-oxadiazoles, and their open-chain aryl hydrazone analogs were synthesized in good yields. Most of the synthesized compounds showed promising in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv. Three diphenyl ether derivatives, namely hydrazide 3, oxadiazole 4 and naphthylarylidene 8g exhibited pronounced activity with minimum inhibitory concentrations (MICs) of 0.61, 0.86 and 0.99 µg/mL, respectively compared to triclosan (10 µg/mL) and isoniazid (INH) (0.2 µg/mL). Compounds 3, 4, and 8g showed the InhA reductase enzyme inhibition with higher IC50 values (3.28-4.23 µM) in comparison to triclosan (1.10 µM). Correlation between calculated physicochemical parameters and biological activity has been discussed which justifies a strong correlation with respect to the inhibition of InhA reductase enzyme. Molecular modeling and drug-likeness studies showed good agreement with the obtained biological evaluation. The structural and experimental information concerning these three InhA inhibitors will likely contribute to the lead optimization of new antibiotics for M. tuberculosis.

Cinnamic Derivatives as Antitubercular Agents: Characterization by Quantitative Structure-Activity Relationship Studies.

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains one of the top ten causes of death worldwide and the main cause of mortality from a single infectious agent. The upsurge of multi- and extensively-drug resistant tuberculosis cases calls for an urgent need to develop new and more effective antitubercular drugs. As the cinnamoyl scaffold is a privileged and important pharmacophore in medicinal chemistry, some studies were conducted to find novel cinnamic acid derivatives (CAD) potentially active against tuberculosis. In this context, we have engaged in the setting up of a quantitative structure-activity relationships (QSAR) strategy to: (i) derive through multiple linear regression analysis a statistically significant model to describe the antitubercular activity of CAD towards wild-type Mtb; and (ii) identify the most relevant properties with an impact on the antitubercular behavior of those derivatives. The best-found model involved only geometrical and electronic CAD related properties and was successfully challenged through strict internal and external validation procedures. The physicochemical information encoded by the identified descriptors can be used to propose specific structural modifications to design better CAD antitubercular compounds.

Discovery and evaluation of novel nitrodihydroimidazooxazoles as promising anti-tuberculosis agents.

New analogues of antitubercular drug Delamanid were prepared, seeking drug candidates with enhanced aqueous solubility and high efficacy. The strategy involved replacement of phenoxy linker proximal to the 2-nitroimidazooxazole of Delamanid by piperidine fused 5 or 6-membered ring heterocycles (ring A). The new compounds were all more hydrophilic than Delamanid, and several class of analogues showed remarkable activities against M. bovis. And among these series, the tetrahydro-naphthyridine-linked nitroimidazoles displayed excellent antimycobacterial activity against both replicating (MABA) and nonreplicating (LORA) M. tb H37Rv and low cytotoxicity. Compared to Delamanid, these new compounds (6, 7, 45) demonstrated dramatically improved physicochemical properties and are suitable for further in vitro and in vivo evaluation.

Increased Doses Lead to Higher Drug Exposures of Levofloxacin for Treatment of Tuberculosis.

Patients with multidrug-resistant tuberculosis in Peru and South Africa were randomized to a weight-banded nominal dose of 11, 14, 17, or 20 mg/kg/day levofloxacin (minimum, 750 mg) in combination with other second-line agents. A total of 101 patients were included in noncompartmental pharmacokinetic analyses. Respective median areas under the concentration-time curve from 0 to 24 h (AUC0-24) were 109.49, 97.86, 145.33, and 207.04 µg · h/ml. Median maximum plasma concentration (Cmax) were 11.90, 12.02, 14.86, and 19.17 µg/ml, respectively. Higher levofloxacin doses, up to 1,500 mg daily, resulted in higher exposures. (This study has been registered at ClinicalTrials.gov under identifier NCT01918397.).

Synthesis, evaluation and CoMFA/CoMSIA study of nitrofuranyl methyl N-heterocycles as novel antitubercular agents.

A series of novel nitrofuranyl methyl N-heterocycles based on the structure of IIIM-MCD-211 were designed and synthesized. Compounds 6d, 8b and 12a show excellent activity against MTB H37Rv strain (MIC: 0.031-0.062 µg/mL) roughly comparable to INH and IIIM-MCD-211. In addition, a three-dimensional quantitative structure-activity relationship (3D-QSAR) study was performed on the above mentioned chemical series employing comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) techniques. The developed CoMFA and CoMSIA models display high external predictability (r2pred of 0.954 and 0.935, respectively) and good statistical robustness. More importantly, the newly designed compounds 16a and 16b (MIC: <0.016 µg/mL) based on the two models, as expected, were found to be more active than 12a and IIIM-MCD-21. Design and synthesis of more potent nitrofuranyl methyl N-heterocycles as anti-TB agents are currently in progress.

Therapeutic drug monitoring of antitubercular agents for disseminated Mycobacterium tuberculosis during intermittent haemodialysis and continuous venovenous haemofiltration.

WHAT IS KNOWN AND OBJECTIVE: There is a lack of data regarding therapeutic drug monitoring (TDM) of antitubercular agents in the setting of continuous venovenous haemofiltration (CVVH). We describe TDM results of numerous antitubercular agents in a critically ill patient during CVVH and haemodialysis. CASE SUMMARY: A 49-year-old man was initiated on treatment for disseminated Mycobacterium tuberculosis. During hospital admission, the patient developed critical illness and required renal replacement therapy. TDM results and pharmacokinetic calculations showed adequate serum concentrations of rifampin, ethambutol and amikacin during CVVH and of rifampin, pyrazinamide, ethambutol and levofloxacin during intermittent haemodialysis. WHAT IS NEW AND CONCLUSION: The presence of critical illness and renal replacement therapy can induce pharmacokinetic changes that may warrant vigilant TDM to ensure optimal therapy. To our knowledge, this is the first report to describe TDM for several antitubercular agents during CVVH in a critically patient with disseminated M. tuberculosis.

Interstitial Lung Diseases Misdiagnosed as Tuberculosis.

OBJECTIVE: To determine the frequency of misdiagnosis of tuberculosis in interstitial lung disease cases. METHODS: This is a prospective study including patients registered in the interstitial lung disease clinic, Jinnah Postgraduate Medical Center, Karachi, during May-June 2017. Diagnosis of tuberculosis was only confirmed if there was any bacteriological evidence of tuberculosis at the time of diagnosis or if there was improvement in symptoms after treatment in patients diagnosed as having tuberculosis on clinical grounds. RESULTS: Seventy-three patients were included in the study, out of which 53 (72.60%) were females and 20 (27.39%) were males. Tuberculosis was treated before presentation in 28 (38.35%) of interstitial lung disease patients. Except for two silicosis patients who had smear positive tuberculosis, rest of the patients were misdiagnosed as having tuberculosis. CONCLUSION: Interstitial lung diseases are the disorders that are frequently unrecognized and misdiagnosed. More commonly the confusion is with tuberculosis. Thorough knowledge about interstitial lung diseases should be provided to the primary care physicians, especially in countries with high tuberculosis burden, so that to limit maltreatment with anti-tuberculous drugs when they are not needed and early referral to interstitial lung disease clinic.

Six-Month Response to Delamanid Treatment in MDR TB Patients.

Delamanid, recently available for the treatment of multidrug-resistant tuberculosis (MDR TB), has had limited use outside clinical trials. We present the early treatment results for 53 patients from 7 countries who received a delamanid-containing treatment for MDR TB. Results show good tolerability and treatment response at 6 months.