pyrazinamide

The rise of pyrazinamide (PZA)-resistant strains of Mycobacterium tuberculosis (MTB) poses a major challenge to conventional tuberculosis (TB) treatments. PZA, a cornerstone of TB therapy, must be activated by the mycobacterial enzyme pyrazinamidase (PZase) to convert its active form, pyrazinoic acid, which targets the ribosomal protein S1. Resistance, often associated with mutations in the RpsA protein, complicates treatment and highlights a critical gap in the understanding of structural dynamics and mechanisms of resistance, particularly in the context of the G97D mutation...

BACKGROUND: A multicountry randomized controlled trial has demonstrated that pan-susceptible pulmonary tuberculosis (TB) can be successfully treated with a 4-month regimen of daily isoniazid, rifapentine, moxifloxacin, and pyrazinamide (HPMZ). We piloted HPMZ in San Francisco (SF) using a modified version of the US Centers for Disease Control and Prevention HPMZ treatment guidelines. METHODS: In this retrospective cohort, patients consecutively referred to SF TB clinic were evaluated for HPMZ eligibility based on preestablished inclusion/exclusion criteria...

Due to its emerging resistance to first-line anti-TB medications, tuberculosis (TB) is one of the most contagious illness in the world. According to reports, the effectiveness of treating TB is severely impacted by drug resistance, notably resistance caused by mutations in the pncA gene-encoded pyrazinamidase (PZase) to the front-line drug pyrazinamide (PZA). The present study focused on investigating the resistance mechanism caused by the mutations D12N, T47A, and H137R to better understand the structural and molecular events responsible for the resistance acquired by the pncA gene of Mycobacterium tuberculosis (MTB) at the structural level...

OBJECTIVES: To develop physiologically based pharmacokinetic (PBPK) models for widely used anti-TB drugs, namely rifampicin, pyrazinamide, isoniazid, ethambutol and moxifloxacin lung pharmacokinetics (PK)-regarding both healthy and TB-infected tissue (cellular lesion and caseum)-in preclinical species and to extrapolate to humans. METHODS: Empirical models were used for the plasma PK of each species, which were connected to multicompartment permeability-limited lung models within a middle-out PBPK approach with an appropriate physiological parameterization that was scalable across species...

UNLABELLED: Treatment decisions for tuberculosis (TB) in the absence of full drug-susceptibility data can result in amplifying resistance and may compromise treatment outcomes. Genomics of Mycobacterium tuberculosis ( M.tb ) from clinical samples enables detection of drug resistance to multiple drugs. We performed whole-genome sequencing (WGS) for 600 clinical samples from patients with tuberculosis to identify the drug-resistance profile and mutation spectrum. We documented the reasons reported by clinicians for referral...

OBJECTIVES: Participation in an external (interlaboratory) quality control (QC) programme is an essential part of quality assurance as it provides laboratories with valuable insights into their analytical performance. We describe the 10 year results of an international QC programme for the measurement of anti-tuberculosis (TB) drugs. METHODS: Each year, two rounds were organized in which serum (or plasma) samples, spiked with known concentrations of anti-TB drugs, were provided to participating laboratories for analysis...

Tuberculosis (TB), a deadly infectious disease, is primarily caused by the bacterium Mycobacterium tuberculosis . The misuse of antibiotics has led to the development of drug resistance, prompting researchers to explore new technologies to combat multidrug-resistant Tuberculosis (MDR TB). Phospholipid-based nanotherapeutics, such as nanoemulsions, are gaining traction as they enhance drug solubility, stability, and bioavailability. Our study focuses on the interaction between Bovine Serum Albumin (BSA) and a drug-loaded nanoemulsion based on Eugenol...

INTRODUCTION: The lack of safe, effective, and simple short-course regimens (SCRs) for multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) treatment has significantly impeded TB control efforts in China. METHODS: This phase 4, randomized, open-label, controlled, non-inferiority trial aims to assess the efficacy and safety of a 9-month all-oral SCR containing bedaquiline (BDQ) versus an all-oral SCR without BDQ for adult MDR-TB patients (18-65 years) in China...

OBJECTIVE: Increasing reports of resistance to newer anti-tuberculosis drugs have prompted the search for other alternative drugs. Streptomycin could be used for the treatment of drug-resistant tuberculosis if susceptibility of Mycobacterium tuberculosis isolate to streptomycin could be accurately detected. We performed phenotypic and genotypic drug susceptibility testing (DST) of 118 M. tuberculosis isolates for streptomycin. MATERIALS AND METHODS: Fifty pansusceptible and 68 multidrug-resistant M...

Cases of active tuberculosis (TB) in the U.S. Military have fallen over the last century in large part due to improved screening and treatment options. The subset of multidrug-resistant TB (MDR-TB) is almost nonexistent within the U.S. Military. We present a case of MDR-TB in an active duty U.S. Military health care worker and discuss several considerations for treatment that may present challenges for U.S. Military medical practitioners. A 30-year-old active duty Soldier was referred to Army public health services after a bronchoscopy sample was positive for Mycobacterium tuberculosis complex...

BACKGROUND: Global tuberculosis (TB) drug resistance (DR) surveillance focuses on rifampicin. We examined the potential of public and surveillance Mycobacterium tuberculosis ( Mtb ) whole-genome sequencing (WGS) data, to generate expanded country-level resistance prevalence estimates (antibiograms) using in silico resistance prediction. METHODS: We curated and quality-controlled Mtb WGS data. We used a validated random forest model to predict phenotypic resistance to 12 drugs and bias-corrected for model performance, outbreak sampling and rifampicin resistance oversampling...

OBJECTIVE: We conducted a descriptive analysis of multi-drug resistant tuberculosis (MDR-TB) in Vietnam's two largest cities, Hanoi and Ho Chi Minh city. METHODS: All patients with rifampicin resistant tuberculosis were recruited from Hanoi and surrounding provinces between 2020 and 2022. Additional patients were recruited from Ho Chi Minh city over the same time period. Demographic data were recorded from all patients, and samples collected, cultured, whole genome sequenced and analysed for drug resistance mutations...

OBJECTIVE: Anti-tuberculosis drugs Rifampicin and Pyrazinamide combination in pregnancy can cause morphological, visceral and skeletal damage. Several studies showed that propolis improves pregnancy outcomes. This study aims to determine the fetal protective effect of propolis in BALB/c mice given the anti-tuberculosis drug combination Rifampicin and Pyrazinamide. METHODS: A total of 21 pregnant mice were randomly divided into three groups: the normal group (N) was given distilled water as a vehicle, the positive control group (RP) were given rifampicin 15 mg/kg BW, pyrazinamide 35 mg/kg BW and the treatment group (IP) were given rifampicin 15 mg/kg BB, pyrazinamide 35 mg/kg BW and propolis 400 mg/kg BW...

BACKGROUND: Pyrazinamide is one of four first-line antibiotics used to treat tuberculosis; however, antibiotic susceptibility testing for pyrazinamide is challenging. Resistance to pyrazinamide is primarily driven by genetic variation in pncA , encoding an enzyme that converts pyrazinamide into its active form. METHODS: We curated a dataset of 664 non-redundant, missense amino acid mutations in PncA with associated high-confidence phenotypes from published studies and then trained three different machine-learning models to predict pyrazinamide resistance...

BACKGROUND: Paravertebral abscess represents a prevalent manifestation of thoracic tuberculosis, often necessitating surgical intervention. In this study, we introduced a novel approach by employing bilateral endoscopic debridement to address large Paravertebral abscesses associated with thoracic tuberculosis, a method not previously proposed in the literature. The clinical efficacy was examined through a comprehensive 4-year follow-up. METHODS: We conducted a retrospective analysis on patients diagnosed with thoracic tuberculosis and paravertebral abscess (TB-PA) who underwent bilateral endoscopic debridement combined with local antituberculosis drugs (BED+LAD) between February 2015 and February 2019...

BACKGROUND: Resistance to anti-tuberculous drugs is a major challenge in the treatment of tuberculosis (TB). We aimed to evaluate the clinical availability of nanopore-based targeted next-generation sequencing (NanoTNGS) for the diagnosis of drug-resistant tuberculosis (DR-TB). METHODS: This study enrolled 253 patients with suspected DR-TB from six hospitals. The diagnostic efficacy of NanoTNGS for detecting Mycobacterium tuberculosis and its susceptibility or resistance to first- and second-line anti-tuberculosis drugs was assessed by comparing conventional phenotypic drug susceptibility testing (pDST) and Xpert MTB/RIF assays...

BACKGROUND: A 32-year-old male patient was diagnosed with a 30% left pneumothorax on November 5, 2020, during which chest imaging indicated abnormalities. Despite this, pulmonary tuberculosis (TB) was not diagnosed or treated at that time due to a negative result in the MGIT960 culture. The patient experienced symptoms of cough and expectoration on April 24, 2022. Upon repeating the chest imaging, the condition had worsened, confirming the presence of pulmonary TB, leading to the patient's hospitalization...

Mycobacterium avium complex (MAC) infections can present as a variety of severe diseases. While it has a predilection for immunocompromised patients such as those with Human immunodeficiency virus (HIV), it can also affect immunocompetent patients as well. One of the rare yet severe diseases that MAC infections can present is MAC peritonitis. Often hard to distinguish from other causes of peritonitis, high clinical suspicion should be maintained for those who are susceptible. Here we present an 85-year-old female with a past medical history of end-stage renal disease on peritoneal dialysis who presented with nausea and vomiting...

Mortality from tuberculous meningitis (TBM) remains around 30%, with most deaths occurring within 2 months of starting treatment. Mortality from drug-resistant strains is higher still, making early detection of drug resistance (DR) essential. Targeted next-generation sequencing (tNGS) produces high read depths, allowing the detection of DR-associated alleles with low frequencies. We applied Deeplex Myc-TB-a tNGS assay-to cerebrospinal fluid (CSF) samples from 72 adults with microbiologically confirmed TBM and compared its genomic drug susceptibility predictions to a composite reference standard of phenotypic susceptibility testing (pDST) and whole genome sequencing, as well as to clinical outcomes...

Both latent and multidrug-resistant tuberculosis (TB) have been causing significant concern worldwide. A novel drug, pretomanid (PA-824), has shown a potent bactericidal effect against both active and latent forms of Mycobacterium tuberculosis (MTb) and a synergistic effect when combined with pyrazinamide and moxifloxacin. This study aimed to develop triple combination spray dried inhalable formulations composed of antitubercular drugs, pretomanid, moxifloxacin, and pyrazinamide (1:2:8 w/w/w), alone (PaMP) and in combination with an aerosolization enhancer, L-leucine (20 % w/w, PaMPL)...