ArticleAntimicrobial agents and chemotherapy2016
High Systemic Exposure of Pyrazinoic Acid Has Limited Antituberculosis Activity in Murine and Rabbit Models of Tuberculosis.
Article in Antimicrobial agents and chemotherapy, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
18 citing papers in PubMed, 23 citations in OpenAlex.
- Coadministration of Allopurinol To Increase Antimycobacterial Efficacy of Pyrazinamide as Evaluated in a Whole-Blood Bactericidal Activity Model.Antimicrobial agents and chemotherapy · 2017Trial
- The study of immunological markers in tuberculosis across animal models and its translation to human research.Lab animal · 2026Review
- TargetingMicrobiology (Reading, England) · 2024Review
- Pharmacokinetic Considerations for Optimizing Inhaled Spray-Dried Pyrazinoic Acid Formulations.Molecular pharmaceutics · 2023Article
- Cephem-Pyrazinoic Acid Conjugates: Circumventing Resistance in Mycobacterium tuberculosis.Chemistry (Weinheim an der Bergstrasse, Germany) · 2022Article
- Systematic measurement of combination-drug landscapes to predict in vivo treatment outcomes for tuberculosis.Cell systems · 2021Article
- Factors Affecting the Pharmacokinetics of Pyrazinamide and Its Metabolites in Patients Coinfected with HIV and Implications for Individualized Dosing.Antimicrobial agents and chemotherapy · 2021Article
- One Size Fits All? Not inFrontiers in cellular and infection microbiology · 2021Review
- Antitubercular Triazines: Optimization and Intrabacterial Metabolism.Cell chemical biology · 2020Article
- Vitamin in the Crosshairs: Targeting Pantothenate and Coenzyme A Biosynthesis for New Antituberculosis Agents.Frontiers in cellular and infection microbiology · 2020Review
- Pharmacological and Molecular Mechanisms Behind the Sterilizing Activity of Pyrazinamide.Trends in pharmacological sciences · 2019Review
- Why Wait? The Case for Treating Tuberculosis with Inhaled Drugs.Pharmaceutical research · 2019Review
- Impact of immunopathology on the antituberculous activity of pyrazinamide.The Journal of experimental medicine · 2018Article
- Article
- In Vivo-Selected Pyrazinoic Acid-Resistant Mycobacterium tuberculosis Strains Harbor Missense Mutations in the Aspartate Decarboxylase PanD and the Unfoldase ClpC1.ACS infectious diseases · 2017Article
- Missense Mutations in the Unfoldase ClpC1 of the Caseinolytic Protease Complex Are Associated with Pyrazinamide Resistance in Mycobacterium tuberculosis.Antimicrobial agents and chemotherapy · 2017Article
- Long-Chain Fatty Acyl Coenzyme A Ligase FadD2 Mediates Intrinsic Pyrazinamide Resistance in Mycobacterium tuberculosis.Antimicrobial agents and chemotherapy · 2017Article
- Pyrazinamide Resistance Is Caused by Two Distinct Mechanisms: Prevention of Coenzyme A Depletion and Loss of Virulence Factor Synthesis.ACS infectious diseases · 2016Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
Abstract
Pyrazinamide (PZA) is a prodrug requiring conversion to pyrazinoic acid (POA) by an amidase encoded by pncA for in vitro activity. Mutation of pncA is the most common cause of PZA resistance in clinical isolates. To determine whether the systemic delivery of POA or host-mediated conversion of PZA to POA could circumvent such resistance, we evaluated the efficacy of orally administered and host-derived POA in vivo Dose-ranging plasma and intrapulmonary POA pharmacokinetics and the efficacy of oral POA or PZA treatment against PZA-susceptible tuberculosis were determined in BALB/c and C3HeB/FeJ mice. The activity of host-derived POA was assessed in rabbits infected with a pncA-null mutant and treated with PZA. Median plasma POA values for the area under the concentration-time curve from 0 h to infinity (AUC0-∞) were 139 to 222 μg·h/ml and 178 to 287 μg·h/ml after doses of PZA and POA of 150 mg/kg of body weight, respectively, in mice. Epithelial lining fluid POA concentrations in infected mice were comparable after POA and PZA administration. In chronically infected BALB/c mice, PZA at 150 mg/kg reduced lung CFU counts by >2 log10 after 4 weeks. POA was effective only at 450 mg/kg, which reduced lung CFU counts by ∼0.7 log10 POA had no demonstrable bactericidal activity in C3HeB/FeJ mice, nor did PZA administered to rabbits infected with a PZA-resistant mutant. Oral POA administration and host-mediated conversion of PZA to POA producing plasma POA exposures comparable to PZA administration was significantly less effective than PZA. These results suggest that the intrabacillary delivery of POA and that producing higher POA concentrations at the site of infection will be more effective strategies for maximizing POA efficacy.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.