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Drug Metabolism and Disposition: the... Aug 2021Pyrazinamide (PZA) is an important component of a standard combination therapy against tuberculosis. However, PZA is hepatotoxic, and the underlying mechanisms are... (Review)
Review
Pyrazinamide (PZA) is an important component of a standard combination therapy against tuberculosis. However, PZA is hepatotoxic, and the underlying mechanisms are poorly understood. Biotransformation of PZA in the liver was primarily suggested behind its hepatoxicity. This review summarizes the knowledge of the key enzymes involved in PZA metabolism and discusses their contributions to PZA hepatotoxicity. SIGNIFICANCE STATEMENT: This review outlines the current understanding of PZA metabolism and hepatotoxicity. This work also highlights the gaps in this field, which can be used to guide the future studies on PZA-induced liver injury.
Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Humans; Liver; Pyrazinamide; Tuberculosis
PubMed: 34074731
DOI: 10.1124/dmd.121.000389 -
Annals of Internal Medicine Aug 2017Treatment of latent tuberculosis infection (LTBI) is an important component of tuberculosis (TB) control, and this study updates a previous network meta-analysis of the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Treatment of latent tuberculosis infection (LTBI) is an important component of tuberculosis (TB) control, and this study updates a previous network meta-analysis of the best LTBI treatment options to inform public health action and programmatic management of LTBI.
PURPOSE
To evaluate the comparative efficacy and harms of LTBI treatment regimens aimed at preventing active TB among adults and children.
DATA SOURCES
PubMed, Embase, and Web of Science from indexing to 8 May 2017; clinical trial registries; and conference abstracts. No language restrictions were applied.
STUDY SELECTION
Randomized controlled trials that evaluated human LTBI treatments and recorded at least 1 of 2 prespecified end points (hepatotoxicity and prevention of active TB).
DATA EXTRACTION
2 investigators independently extracted data from eligible studies and assessed study quality according to a standard protocol.
DATA SYNTHESIS
The network meta-analysis of 8 new and 53 previously included studies showed that isoniazid regimens of 6 months (odds ratio [OR], 0.65 [95% credible interval {CrI}, 0.50 to 0.83]) or 12 to 72 months (OR, 0.50 [CrI, 0.41 to 0.62]), rifampicin-only regimens (OR, 0.41 [CrI, 0.19 to 0.85]), rifampicin-isoniazid regimens of 3 to 4 months (OR, 0.53 [CrI, 0.36 to 0.78]), rifampicin-isoniazid-pyrazinamide regimens (OR, 0.35 [CrI, 0.19 to 0.61]), and rifampicin-pyrazinamide regimens (OR, 0.53 [CrI, 0.33 to 0.84]) were efficacious compared with placebo. Evidence existed for efficacy of weekly rifapentine-isoniazid regimens compared with no treatment (OR, 0.36 [CrI, 0.18 to 0.73]). No conclusive evidence showed that HIV status altered treatment efficacy.
LIMITATION
Evidence was sparse for many comparisons and hepatotoxicity outcomes, and risk of bias was high or unknown for many studies.
CONCLUSION
Evidence exists for the efficacy and safety of 6-month isoniazid monotherapy, rifampicin monotherapy, and combination therapies with 3 to 4 months of isoniazid and rifampicin.
PRIMARY FUNDING SOURCE
U.K. National Institute for Health Research. (PROSPERO: CRD42016037871).
Topics: Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Child; Drug Combinations; Humans; Isoniazid; Latent Tuberculosis; Network Meta-Analysis; Pyrazinamide; Rifampin
PubMed: 28761946
DOI: 10.7326/M17-0609 -
Zhejiang Da Xue Xue Bao. Yi Xue Ban =... Dec 2022Tuberculosis (TB) is an ancient infectious disease. Before the availability of effective drug therapy, it had high morbidity and mortality. In the past 100 years, the... (Review)
Review
Tuberculosis (TB) is an ancient infectious disease. Before the availability of effective drug therapy, it had high morbidity and mortality. In the past 100 years, the discovery of revolutionary anti-TB drugs such as streptomycin, isoniazid, pyrazinamide, ethambutol and rifampicin, along with drug combination treatment, has greatly improved TB control globally. As anti-TB drugs were widely used, multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of emerged due to acquired genetic mutations, and this now presents a major problem for effective treatment. Genes associated with drug resistance have been identified, including mutations in isoniazid resistance, mutations in rifampin resistance, mutations in pyrazinamide resistance, and mutations in quinolone resistance. The major mechanisms of drug resistance include loss of enzyme activity in prodrug activation, drug target alteration, overexpression of drug target, and overexpression of the efflux pump. During the disease process, may reside in different microenvironments where it is expose to acidic pH, low oxygen, reactive oxygen species and anti-TB drugs, which can facilitate the development of non-replicating persisters and promote bacterial survival. The mechanisms of persister formation may include toxin-antitoxin (TA) modules, DNA protection and repair, protein degradation such as trans-translation, efflux, and altered metabolism. In recent years, the use of new anti-TB drugs, repurposed drugs, and their drug combinations has greatly improved treatment outcomes in patients with both drug-susceptible TB and MDR/XDR-TB. The importance of developing more effective drugs targeting persisters of is emphasized. In addition, host-directed therapeutics using both conventional drugs and herbal medicines for more effective TB treatment should also be explored. In this article, we review historical aspects of the research on anti-TB drugs and discuss the current understanding and treatments of drug resistant and persistent tuberculosis to inform future therapeutic development.
Topics: Humans; Pyrazinamide; Isoniazid; Antitubercular Agents; Tuberculosis, Multidrug-Resistant; Mycobacterium tuberculosis; Tuberculosis; Rifampin; Mutation; Drug Resistance, Multiple, Bacterial
PubMed: 36915970
DOI: 10.3724/zdxbyxb-2022-0454 -
PloS One 2022Mycobacterium tuberculosis strains with phenotypically susceptible rpoB mutations (rifampicin discordant) have emerged following implementation of rapid molecular drug...
INTRODUCTION
Mycobacterium tuberculosis strains with phenotypically susceptible rpoB mutations (rifampicin discordant) have emerged following implementation of rapid molecular drug resistance testing for tuberculosis. Whilst rifampicin resistance is known to be associated with resistance to other rifamycins (rifapentine and rifabutin) as well as isoniazid and pyrazinamide, rifampicin discordant strains have shown high rates of susceptibility to isoniazid and rifabutin. However, pyrazinamide susceptibly testing results have not been reported.
MATERIALS AND METHODS
We evaluated pyrazinamide resistance in 80 rifampicin discordant and 25 rifampicin and isoniazid susceptible isolates from KwaZulu-Natal in South Africa using Mycobacteria Growth Indicator Tube method and sequencing of the pncA. We also compared susceptibility of pyrazinamide with that of isoniazid.
RESULTS
Pyrazinamide resistance was found in 6/80 (7.5%) rifampicin discordant isolates. All pyrazinamide resistant isolates were also resistant to isoniazid and pyrazinamide resistance was found to be associated with isoniazid resistance. No pyrazinamide resistance was found among the isoniazid susceptible isolates.
CONCLUSION
Given the low prevalence of pyrazinamide resistance in rifampicin discordant TB, this anti-TB drug still has a significant role in the treatment of these patients. Performing pyrazinamide susceptibility testing remains a challenge, our findings show that isoniazid susceptible isolates are unlikely to be resistant to pyrazinamide among the discordant TB isolates.
Topics: Antitubercular Agents; Humans; Isoniazid; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Pyrazinamide; Rifabutin; Rifampin; South Africa; Tuberculosis; Tuberculosis, Multidrug-Resistant
PubMed: 36129921
DOI: 10.1371/journal.pone.0274688 -
Archives of Disease in Childhood Jan 2022To assess the pharmacokinetics and safety/tolerability of isoniazid, rifampicin and pyrazinamide in children and adolescents with tuberculous meningitis (TBM). (Observational Study)
Observational Study
OBJECTIVE
To assess the pharmacokinetics and safety/tolerability of isoniazid, rifampicin and pyrazinamide in children and adolescents with tuberculous meningitis (TBM).
DESIGN
Prospective observational pharmacokinetic study with an exploratory pharmacokinetic/pharmacodynamic analysis.
SETTING
Hasan Sadikin Hospital, Bandung, Indonesia.
PATIENTS
Individuals aged 0-18 years clinically diagnosed with TBM and receiving first-line anti-tuberculosis drug dosages according to revised WHO-recommended treatment guidelines.
INTERVENTIONS
Plasma and cerebrospinal fluid (CSF) concentrations of isoniazid, rifampicin and pyrazinamide were assessed on days 2 and 10 of treatment.
MAIN OUTCOME MEASURES
Plasma exposures during the daily dosing interval (AUC), peak plasma concentrations () and CSF concentrations.
RESULTS
Among 20 eligible patients, geometric mean AUC of isoniazid, rifampicin and pyrazinamide was 18.5, 66.9 and 315.5 hour∙mg/L on day 2; and 14.5, 71.8 and 328.4 hour∙mg/L on day 10, respectively. Large interindividual variabilities were observed in AUC and of all drugs. All patients had suboptimal rifampicin AUC for TBM treatment indication and very low rifampicin CSF concentrations. Four patients developed grade 2-3 drug-induced liver injury (DILI) within the first 4 weeks of treatment, in whom anti-tuberculosis drugs were temporarily stopped, and no DILI recurred after reintroduction of rifampicin and isoniazid. AUC of isoniazid, rifampicin and pyrazinamide along with of isoniazid and pyrazinamide on day 10 were higher in patients who developed DILI than those without DILI (p<0.05).
CONCLUSION
Higher rifampicin doses are strongly warranted in treatment of children and adolescents with TBM. The association between higher plasma concentrations of isoniazid, rifampicin and pyrazinamide and the development of DILI needs confirmatory studies.
Topics: Adolescent; Antitubercular Agents; Area Under Curve; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Female; Humans; Indonesia; Infant; Infant, Newborn; Isoniazid; Male; Prospective Studies; Pyrazinamide; Rifampin; Tuberculosis, Meningeal
PubMed: 34183327
DOI: 10.1136/archdischild-2020-321426 -
Clinical Infectious Diseases : An... Aug 2022In 2010, the World Health Organization (WHO) revised dosing guidelines for treatment of childhood tuberculosis. Our aim was to investigate first-line antituberculosis...
Optimizing Dosing and Fixed-Dose Combinations of Rifampicin, Isoniazid, and Pyrazinamide in Pediatric Patients With Tuberculosis: A Prospective Population Pharmacokinetic Study.
BACKGROUND
In 2010, the World Health Organization (WHO) revised dosing guidelines for treatment of childhood tuberculosis. Our aim was to investigate first-line antituberculosis drug exposures under these guidelines, explore dose optimization using the current dispersible fixed-dose combination (FDC) tablet of rifampicin/isoniazid/pyrazinamide; 75/50/150 mg, and suggest a new FDC with revised weight bands.
METHODS
Children with drug-susceptible tuberculosis in Malawi and South Africa underwent pharmacokinetic sampling while receiving first-line tuberculosis drugs as single formulations according the 2010 WHO recommended doses. Nonlinear mixed-effects modeling and simulation was used to design the optimal FDC and weight-band dosing strategy for achieving the pharmacokinetic targets based on literature-derived adult AUC0-24h for rifampicin (38.7-72.9), isoniazid (11.6-26.3), and pyrazinamide (233-429 mg ∙ h/L).
RESULTS
In total, 180 children (42% female; 13.9% living with human immunodeficiency virus [HIV]; median [range] age 1.9 [0.22-12] years; weight 10.7 [3.20-28.8] kg) were administered 1, 2, 3, or 4 FDC tablets (rifampicin/isoniazid/pyrazinamide 75/50/150 mg) daily for 4-8, 8-12, 12-16, and 16-25 kg weight bands, respectively. Rifampicin exposure (for weight and age) was up to 50% lower than in adults. Increasing the tablet number resulted in adequate rifampicin but relatively high isoniazid and pyrazinamide exposures. Administering 1, 2, 3, or 4 optimized FDC tablets (rifampicin/isoniazid/pyrazinamide 120/35/130 mg) to children < 6, 6-13, 13-20. and 20-25 kg, and 0.5 tablet in < 3-month-olds with immature metabolism, improved exposures to all 3 drugs.
CONCLUSIONS
Current pediatric FDC doses resulted in low rifampicin exposures. Optimal dosing of all drugs cannot be achieved with the current FDCs. We propose a new FDC formulation and revised weight bands.
Topics: Adult; Antitubercular Agents; Child; Drug Combinations; Ethambutol; Female; Humans; Infant; Isoniazid; Male; Prospective Studies; Pyrazinamide; Rifampin; Tablets; Tuberculosis
PubMed: 34665866
DOI: 10.1093/cid/ciab908 -
Microbiology and Molecular Biology... May 2020Pyrazinamide (PZA) is a cornerstone antimicrobial drug used exclusively for the treatment of tuberculosis (TB). Due to its ability to shorten drug therapy by 3 months... (Review)
Review
Pyrazinamide (PZA) is a cornerstone antimicrobial drug used exclusively for the treatment of tuberculosis (TB). Due to its ability to shorten drug therapy by 3 months and reduce disease relapse rates, PZA is considered an irreplaceable component of standard first-line short-course therapy for drug-susceptible TB and second-line treatment regimens for multidrug-resistant TB. Despite over 60 years of research on PZA and its crucial role in current and future TB treatment regimens, the mode of action of this unique drug remains unclear. Defining the mode of action for PZA will open new avenues for rational design of novel therapeutic approaches for the treatment of TB. In this review, we discuss the four prevailing models for PZA action, recent developments in modulation of PZA susceptibility and resistance, and outlooks for future research and drug development.
Topics: Animals; Antitubercular Agents; Clinical Trials as Topic; Drug Development; Drug Resistance, Multiple, Bacterial; Humans; Mice; Mutation; Mycobacterium tuberculosis; Pyrazinamide; Tuberculosis, Multidrug-Resistant
PubMed: 32132245
DOI: 10.1128/MMBR.00070-19 -
Antimicrobial Agents and Chemotherapy Apr 2022A recent landmark trial showed a 4-month regimen of rifapentine, pyrazinamide, moxifloxacin, and isoniazid (PZMH) to be noninferior to the 6-month standard of care....
A recent landmark trial showed a 4-month regimen of rifapentine, pyrazinamide, moxifloxacin, and isoniazid (PZMH) to be noninferior to the 6-month standard of care. Here, two murine models of tuberculosis were used to test whether novel regimens replacing rifapentine and isoniazid with bedaquiline and another drug would maintain or increase the sterilizing activity of the regimen. In BALB/c mice, replacing rifapentine in the PZM backbone with bedaquiline (i.e., BZM) significantly reduced both lung CFU counts after 1 month and the proportion of mice relapsing within 3 months after completing 1.5 months of treatment. The addition of rifabutin to BZM (BZMRb) further increased the sterilizing activity. In the C3HeB/FeJ mouse model characterized by caseating lung lesions, treatment with BZMRb resulted in significantly fewer relapses than PZMH after 2 months of treatment. A regimen combining the new DprE1 inhibitor OPC-167832 and delamanid (BZOD) also had superior bactericidal and sterilizing activity compared to PZM in BALB/c mice and was similar in efficacy to PZMH in C3HeB/FeJ mice. Thus, BZM represents a promising backbone for treatment-shortening regimens. Given the prohibitive drug-drug interactions between bedaquiline and rifampin or rifapentine, the BZMRb regimen represents the best opportunity to combine, in one regimen, the treatment-shortening potential of the rifamycin class with that of BZM and deserves high priority for evaluation in clinical trials. Other 4-drug BZM-based regimens and BZOD represent promising opportunities for extending the spectrum of treatment-shortening regimens to rifamycin- and fluoroquinolone-resistant tuberculosis.
Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Diarylquinolines; Disease Models, Animal; Drug Administration Schedule; Drug Therapy, Combination; Isoniazid; Mice; Mice, Inbred BALB C; Moxifloxacin; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Pyrazinamide; Rifabutin; Tuberculosis
PubMed: 35315690
DOI: 10.1128/aac.02398-21 -
Microbiology Spectrum Aug 2014Pyrazinamide (PZA) is a unique antituberculosis (anti-TB) drug that plays a key role in shortening TB therapy. PZA kills nonreplicating persisters that other TB drugs... (Review)
Review
Pyrazinamide (PZA) is a unique antituberculosis (anti-TB) drug that plays a key role in shortening TB therapy. PZA kills nonreplicating persisters that other TB drugs fail to kill, which makes it an essential drug for inclusion in any drug combinations for treating drug-susceptible and drug-resistant TB such as multidrug-resistant TB. PZA acts differently from common antibiotics by inhibiting multiple targets such as energy production, trans-translation, and perhaps pantothenate/coenzyme A required for persister survival. Resistance to PZA is mostly caused by mutations in the pncA gene encoding pyrazinamidase, which is involved in conversion of the prodrug PZA to the active form pyrazinoic acid. Mutations in the drug target ribosomal protein S1 (RpsA) are also found in some PZA-resistant strains. The recent finding that panD mutations are found in some PZA-resistant strains without pncA or rpsA mutations may suggest a third PZA resistance gene and a potential new target of PZA. Current phenotype-based PZA susceptibility testing is not reliable due to false resistance; sequencing of the pncA gene represents a more rapid, cost-effective, and reliable molecular test for PZA susceptibility testing and should be used for guiding improved treatment of multidrug-resistant and extensively multidrug-resistant TB. Finally, the story of PZA has important implications for not only TB therapy but also chemotherapy in general. PZA serves as a model prototype persister drug and hopefully a "tipping point" that inspires new efforts at developing a new type of antibiotic or drug that targets nonreplicating persisters for improved treatment of not only TB but also other persistent bacterial infections.
Topics: Amidohydrolases; Antitubercular Agents; Drug Resistance, Bacterial; Genotyping Techniques; Microbial Sensitivity Tests; Mutation, Missense; Pyrazinamide; Ribosomal Proteins
PubMed: 26104205
DOI: 10.1128/microbiolspec.MGM2-0023-2013 -
Current HIV/AIDS Reports Dec 2022Pregnant people living with HIV (PLWH) are at especially high risk for progression from latent tuberculosis infection (LTBI) to active tuberculosis (TB) disease. Among... (Review)
Review
PURPOSE OF REVIEW
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.
RECENT FINDINGS
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.
Topics: Pregnancy; Female; Infant, Newborn; Humans; Infectious Disease Transmission, Vertical; HIV Infections; Antitubercular Agents; Tuberculosis, Multidrug-Resistant; Pyrazinamide
PubMed: 36308580
DOI: 10.1007/s11904-022-00641-x