-
Clinical Microbiology and Infection :... Jan 2022Outcomes of treatment of tuberculosis patients with regimens including pretomanid have not yet been systematically reviewed. (Review)
Review
BACKGROUND
Outcomes of treatment of tuberculosis patients with regimens including pretomanid have not yet been systematically reviewed.
OBJECTIVES
To appraise existing evidence on efficacy and safety of pretomanid in tuberculosis.
DATA SOURCES
Pubmed, clinicaltrials.gov. and Cochrane library.
STUDY ELIGIBILITY CRITERIA
Quantitative studies presenting original data on clinical efficacy or safety of pretomanid.
PARTICIPANTS
Patients with tuberculosis.
INTERVENTIONS
Treatment with pretomanid or pretomanid-containing regimens in minimum one study group.
METHODS
Two authors independently extracted data and assessed risk of bias. Data on efficacy (early bactericidal activity, bactericidal activity, end-of-treatment outcomes and acquired resistance) and safety were summarized in tables. Mean differences in efficacy outcomes between regimens across studies were calculated.
RESULTS
Eight studies were included; four randomized controlled trials on 2-week early bactericidal activity in rifampicin-susceptible tuberculosis, three trials with randomized rifampicin-susceptible tuberculosis arms and a single rifampicin-resistant tuberculosis arm (two on 8-week bactericidal activity, one on end-of-treatment outcomes), one single-arm trial with end-of-treatment outcomes in highly resistant tuberculosis. Activity of pretomanid-moxifloxacin-pyrazinamide was superior to standard treatment on daily change in colony-forming units at days 0-2, 0-56 and 7-56 and time to culture conversion in rifampicin-susceptible tuberculosis (hazard ratio: 1.7; 95% CI 1.1-2.7), but not at end of treatment in one study. This study was stopped due to serious hepatotoxic adverse events, including three deaths, in 4% (95% CI 2-8) patients on pretomanid-moxifloxacin-pyrazinamide and none in controls. In patients with uncomplicated rifampicin-resistant tuberculosis on pretomanid-moxifloxacin-pyrazinamide treatment, 91% (95% CI 59-100) had favourable end-of-treatment outcomes. In patients with highly resistant tuberculosis, 90% (95% CI 83-95) on pretomanid-bedaquiline-linezolid had favourable outcomes six months after treatment, but linezolid-related toxicity was frequent. No acquired resistance to pretomanid was reported.
CONCLUSIONS
Evidence suggests an important role for pretomanid in rifampicin-resistant and highly resistant tuberculosis. Trials comparing pretomanid to existing core and companion drugs are needed to further define that role.
Topics: Antitubercular Agents; Humans; Linezolid; Moxifloxacin; Nitroimidazoles; Pyrazinamide; Randomized Controlled Trials as Topic; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant
PubMed: 34400340
DOI: 10.1016/j.cmi.2021.08.007 -
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 -
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 -
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 -
The Pan African Medical Journal 2022Purulent pericarditis is an infection of the pericardial space that produces pus that is found on gross examination of the pericardial sac or on the tissue microscopy....
Purulent pericarditis is an infection of the pericardial space that produces pus that is found on gross examination of the pericardial sac or on the tissue microscopy. In this case report, we will discuss a 31-year-old male who presented with a chief complaint of low-grade fevers, dry cough and difficulty breathing for about two weeks which preceded after removing of dental also two weeks prior. He was admitted and treated as COVID-19 in the isolation ward, he later developed cardiac tamponade and during pericardiocentesis thick pus was discharged. Pus culture and Gene Xpert tests were all negative. After his condition improved, the patient was transferred to the general ward with the pericardial window still discharging pus. Pericardiectomy was chosen as definitive management. The key takeaway in this report is that Empirical treatment with RHZE (rifampin, isoniazid, pyrazinamide, and ethambutol) in resource-limited settings is recommended due to difficulty in identifying the exact cause at a required moment.
Topics: Adult; COVID-19; Ethambutol; Humans; Isoniazid; Male; Mediastinitis; Pericarditis; Pericardium; Pyrazinamide; Rifampin; Sclerosis; Suppuration
PubMed: 36160276
DOI: 10.11604/pamj.2022.42.145.34018 -
The New England Journal of Medicine Mar 2022Two thirds of children with tuberculosis have nonsevere disease, which may be treatable with a shorter regimen than the current 6-month regimen. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Two thirds of children with tuberculosis have nonsevere disease, which may be treatable with a shorter regimen than the current 6-month regimen.
METHODS
We conducted an open-label, treatment-shortening, noninferiority trial involving children with nonsevere, symptomatic, presumably drug-susceptible, smear-negative tuberculosis in Uganda, Zambia, South Africa, and India. Children younger than 16 years of age were randomly assigned to 4 months (16 weeks) or 6 months (24 weeks) of standard first-line antituberculosis treatment with pediatric fixed-dose combinations as recommended by the World Health Organization. The primary efficacy outcome was unfavorable status (composite of treatment failure [extension, change, or restart of treatment or tuberculosis recurrence], loss to follow-up during treatment, or death) by 72 weeks, with the exclusion of participants who did not complete 4 months of treatment (modified intention-to-treat population). A noninferiority margin of 6 percentage points was used. The primary safety outcome was an adverse event of grade 3 or higher during treatment and up to 30 days after treatment.
RESULTS
From July 2016 through July 2018, a total of 1204 children underwent randomization (602 in each group). The median age of the participants was 3.5 years (range, 2 months to 15 years), 52% were male, 11% had human immunodeficiency virus infection, and 14% had bacteriologically confirmed tuberculosis. Retention by 72 weeks was 95%, and adherence to the assigned treatment was 94%. A total of 16 participants (3%) in the 4-month group had a primary-outcome event, as compared with 18 (3%) in the 6-month group (adjusted difference, -0.4 percentage points; 95% confidence interval, -2.2 to 1.5). The noninferiority of 4 months of treatment was consistent across the intention-to-treat, per-protocol, and key secondary analyses, including when the analysis was restricted to the 958 participants (80%) independently adjudicated to have tuberculosis at baseline. A total of 95 participants (8%) had an adverse event of grade 3 or higher, including 15 adverse drug reactions (11 hepatic events, all but 2 of which occurred within the first 8 weeks, when the treatments were the same in the two groups).
CONCLUSIONS
Four months of antituberculosis treatment was noninferior to 6 months of treatment in children with drug-susceptible, nonsevere, smear-negative tuberculosis. (Funded by the U.K. Medical Research Council and others; SHINE ISRCTN number, ISRCTN63579542.).
Topics: Adolescent; Africa; Antitubercular Agents; Child; Child, Preschool; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; India; Infant; Intention to Treat Analysis; Isoniazid; Male; Patient Acuity; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis
PubMed: 35263517
DOI: 10.1056/NEJMoa2104535 -
Clinical Microbiology and Infection :... May 2022Phenotypic drug susceptibility testing for prediction of tuberculosis (TB) drug resistance is slow and unreliable, limiting individualized therapy and monitoring of...
OBJECTIVES
Phenotypic drug susceptibility testing for prediction of tuberculosis (TB) drug resistance is slow and unreliable, limiting individualized therapy and monitoring of national TB data. Our study evaluated whole-genome sequencing (WGS) for its predictive accuracy, use in TB drug-resistance surveillance and ability to quantify the effects of resistance-associated mutations on MICs of anti-TB drugs.
METHODS
We used WGS to measure the susceptibility of 4880 isolates to ten anti-TB drugs; for pyrazinamide, we used BACTEC MGIT 960. We determined the accuracy of WGS by comparing the prevalence of drug resistance, measured by WGS, with the true prevalence, determined by phenotypic susceptibility testing. We used the Student-Newman-Keuls test to confirm MIC differences of mutations.
RESULTS
Resistance to isoniazid, rifampin and ethambutol was highly accurately predicted with at least 92.92% (95% confidence interval [CI], 88.19-97.65) sensitivity, resistance to pyrazinamide with 50.52% (95% CI, 40.57-60.47) sensitivity, and resistance to six second-line drugs with 85.05% (95% CI, 80.27-89.83) to 96.01% (95% CI, 93.89-98.13) sensitivity. The rpoB S450L, katG S315T and gyrA D94G mutations always confer high-level resistance, while rpoB L430P, rpoB L452P, fabG1 C-15T and embB G406S often confer low-level resistance or sub-epidemiological cutoff (ECOFF) MIC elevation.
CONCLUSION
WGS can predict phenotypic susceptibility with high accuracy and could be a valuable tool for drug-resistance surveillance and allow the detection of drug-resistance level; It can be an important approach in TB drug-resistance surveillance and for determining therapeutic schemes.
Topics: Antitubercular Agents; Drug Resistance; Drug Resistance, Multiple, Bacterial; Humans; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Pyrazinamide; Tuberculosis; Tuberculosis, Multidrug-Resistant
PubMed: 34600118
DOI: 10.1016/j.cmi.2021.09.014 -
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 -
GMS Infectious Diseases 2018Urogenital tuberculosis (UGTB) should in general be treated as pulmonary TB with a four-drug regimen of Isoniazid, Rifampicin, Ethambutol and Pyrazinamide for a total of... (Review)
Review
Urogenital tuberculosis (UGTB) should in general be treated as pulmonary TB with a four-drug regimen of Isoniazid, Rifampicin, Ethambutol and Pyrazinamide for a total of 6 months, Ethambutol and Pyrazinamide only the first two months. Some patients may need longer treatment (cavitary disease, kidney abscess/malfunction, HIV co-infection). Treatment of multi-drug resistant tuberculosis (MDR-TB) requires use of long-term intravenous treatment with aminoglycosides and other drugs with considerable toxicity for 18-24 months. Complications such as urinary tract obstruction may occur and should be treated with corticosteroids or surgery.
PubMed: 30671335
DOI: 10.3205/id000039 -
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