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Innere Medizin (Heidelberg, Germany) Jul 2023Never before have so many people around the world been simultaneously affected by tuberculosis. Tuberculosis is the leading cause of death from a bacterial infectious... (Review)
Review
Never before have so many people around the world been simultaneously affected by tuberculosis. Tuberculosis is the leading cause of death from a bacterial infectious disease worldwide. The World Health Organization's ambitious goal from 2014 of achieving global elimination of tuberculosis does not seem realistic, but on current trends, tuberculosis could be eliminated in the European Union by 2040. Since the beginning of 2022, there have been more innovations for the treatment of tuberculosis than in no other comparable time period before. One month of rifapentine and isoniazid is effective in treating latent tuberculosis infection. However, rifapentine is licensed in the USA but not in the EU and must be imported for individual cases. The duration of the standard treatment for tuberculosis can be shortened to four months but this treatment regimen is also based on rifapentine, in addition to isoniazid, pyrazinamide, and moxifloxacin. The approval of rifapentine in Europe is a much-needed step towards shortening the treatment of tuberculosis. With new drugs an even shorter standard treatment of only 2 months is possible. The treatment of multidrug-resistant/rifampicin-resistant tuberculosis (MDR-/RR-TB) has been shortened to six months, the same length as the standard treatment available in Germany. The combination of bedaquiline, pretomanid, linezolid ± moxifloxacin, cured around 90% of affected patients were cured in studies with a treatment duration of six months. With 19 drugs in clinical trials, the treatment of tuberculosis is expected to continue to improve rapidly in the coming years.
Topics: Humans; Antitubercular Agents; Isoniazid; Moxifloxacin; Tuberculosis; Pyrazinamide; Tuberculosis, Multidrug-Resistant
PubMed: 37316702
DOI: 10.1007/s00108-023-01523-z -
The European Respiratory Journal Jul 2021Pyrazinamide is a potent sterilising agent that shortens the treatment duration needed to cure tuberculosis. It is synergistic with novel and existing drugs for...
Pyrazinamide is a potent sterilising agent that shortens the treatment duration needed to cure tuberculosis. It is synergistic with novel and existing drugs for tuberculosis. The dose of pyrazinamide that optimises efficacy while remaining safe is uncertain, as is its potential role in shortening treatment duration further.Pharmacokinetic data, sputum culture, and safety laboratory results were compiled from Tuberculosis Trials Consortium (TBTC) studies 27 and 28 and Pan-African Consortium for the Evaluation of Antituberculosis Antibiotics (PanACEA) multi-arm multi-stage tuberculosis (MAMS-TB), multi-centre phase 2 trials in which participants received rifampicin (range 10-35 mg·kg), pyrazinamide (range 20-30 mg·kg), plus two companion drugs. Pyrazinamide pharmacokinetic-pharmacodynamic (PK-PD) and pharmacokinetic-toxicity analyses were performed.In TBTC studies (n=77), higher pyrazinamide maximum concentration (C) was associated with shorter time to culture conversion (TTCC) and higher probability of 2-month culture conversion (p-value<0.001). Parametric survival analyses showed that relationships varied geographically, with steeper PK-PD relationships seen among non-African than African participants. In PanACEA MAMS-TB (n=363), TTCC decreased as pyrazinamide C increased and varied by rifampicin area under the curve (p-value<0.01). Modelling and simulation suggested that very high doses of pyrazinamide (>4500 mg) or increasing both pyrazinamide and rifampicin would be required to reach targets associated with treatment shortening. Combining all trials, liver toxicity was rare (3.9% with grade 3 or higher liver function tests (LFT)), and no relationship was seen between pyrazinamide C and LFT levels.Pyrazinamide's microbiological efficacy increases with increasing drug concentrations. Optimising pyrazinamide alone, though, is unlikely to be sufficient to allow tuberculosis treatment shortening; rather, rifampicin dose would need to be increased in parallel.
Topics: Antibiotics, Antitubercular; Antitubercular Agents; Humans; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis
PubMed: 33542052
DOI: 10.1183/13993003.02013-2020 -
American Family Physician Sep 2022Approximately 10 million people worldwide were infected with tuberculosis (TB) in 2019, resulting in 1.4 million deaths. In the United States that same year, there were...
Approximately 10 million people worldwide were infected with tuberculosis (TB) in 2019, resulting in 1.4 million deaths. In the United States that same year, there were nearly 9,000 reported cases of TB disease and up to 13 million people were living with latent TB infection (LTBI), which is an asymptomatic, noncommunicable infection caused by Mycobacterium tuberculosis. Without treatment, LTBI will progress to active TB disease in approximately 5% to 10% of affected people. Individuals with symptoms of TB disease warrant testing. The U.S. Preventive Services Task Force recommends testing individuals at increased risk of LTBI with an interferon-gamma release assay or tuberculin skin testing. Because the incidence of LTBI in health care professionals is similar to that of the general population, periodic retesting is not recommended. After a positive test result, chest radiography should be performed and, in patients with suspected pulmonary TB disease, sputum collected for diagnosis. Both suspected and confirmed cases of LTBI and TB disease must be reported to local or state health departments. Preferred treatment regimens for LTBI include isoniazid in combination with rifapentine or rifampin, or rifampin alone for a duration of three and four months, respectively. Treatment of drug-susceptible TB disease includes an eight-week intensive phase with four drugs (isoniazid, rifampin, pyrazinamide, and ethambutol), followed by a continuation phase lasting 18 weeks or more, with two drugs based on susceptibility testing results. Consultation with a TB expert is necessary if there is suspicion or confirmation of drug-resistant TB.
Topics: Antitubercular Agents; Ethambutol; Humans; Isoniazid; Latent Tuberculosis; Pyrazinamide; Rifampin; Tuberculin; Tuberculosis; United States
PubMed: 36126013
DOI: No ID Found -
Medicina (Kaunas, Lithuania) Jan 2023: There is a lack of information regarding the effective duration of treatment necessary to prevent the development of acquired resistance when fluoroquinolones (FQ),...
: There is a lack of information regarding the effective duration of treatment necessary to prevent the development of acquired resistance when fluoroquinolones (FQ), and/or pyrazinamide (Z) resistance has occurred in patients with polydrug-resistant tuberculosis and isoniazid resistance. The management of these kinds of patients should be carried out in experienced centers according to drug susceptibility test results, clinical status of the patient and the extensity of the disease. : We evaluated treatment regimens, treatment outcomes, and drug adverse effects in seven patients with polydrug-resistant tuberculosis, including those with Z and/or FQ resistance in a retrospective analysis : Regarding the patients with polydrug-resistant tuberculosis in addition to isoniazid (H) resistance, three had Z, two had FQ, and the remaining two had both Z and FQ resistance. In the intensive phase of the treatment, the patients were given at least four drugs according to drug susceptibility tests, and at least three drugs in the continuation phase. The duration of treatment was 9-12 months. Two of the patients were foreign nationals, and could not be followed up with due to returning to their home countries. Regarding the remaining five patients, three of them were terminated as they completed treatment, and two as cured. No recurrence was observed in the first year of the treatment. The most common, and serious drug side effect was seen for amikacin. : In patients with polydrug-resistant TB, if Z and/or FQ resistance is detected in addition to H resistance, the treatment of these patients should be conducted on a case-by-case basis, taking into account the patient's resistance pattern, clinical condition, and disease prognosis. Close monitoring of the side effects will increase the success rate of the treatment.
Topics: Humans; Antitubercular Agents; Isoniazid; Retrospective Studies; Tuberculosis; Pyrazinamide; Fluoroquinolones; Tuberculosis, Multidrug-Resistant; Mycobacterium tuberculosis
PubMed: 36837448
DOI: 10.3390/medicina59020246 -
Drug Metabolism Reviews Aug 2023Tuberculosis (TB) remains a major global health burden. Antitubercular drugs (ATDs) such as isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA), and ethambutol are... (Review)
Review
Tuberculosis (TB) remains a major global health burden. Antitubercular drugs (ATDs) such as isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA), and ethambutol are used as first-line therapy in TB patients. Drug-induced liver injury is one of the common side effects that leads to the discontinuation of ATDs in TB patients. Therefore, this review discusses the molecular pathogenesis of ATDs induced liver injury. The biotransformation of INH, RIF, and PZA in the liver liberates several reactive intermediates, leading to peroxidation of the hepatocellular membrane and oxidative stress. INH + RIF administration decreased the expression of bile acid transporters such as the bile salt export pump and multidrug resistance-associated protein 2 and induced liver injury by sirtuin 1 and farnesoid X receptor pathway. INH inhibits the nuclear translocation of Nrf2 by interfering with its nuclear importer, karyopherin β1, thereby inducing apoptosis. INF + RIF treatments alter Bcl-2 and Bax homeostasis, mitochondrial membrane potential, and cytochrome c release, thereby triggering apoptosis. RIF administration enhances the expression of genes involved in fatty acid synthesis and hepatocyte fatty acid uptake (CD36). RIF induces the expression of peroxisome proliferator-activated receptor -γ and its downstream proteins and perilipin-2 by activating the pregnane X receptor in the liver to increase fatty infiltration into the liver. ATDs administration induces oxidative stress, inflammation, apoptosis, cholestasis, and lipid accumulation in the liver. However, ATDs toxic potentials are not elaborately studied at the molecular level in clinical samples. Therefore, future studies are warranted to explore ATDs induced liver injuries at the molecular level in clinical samples whenever possible.
Topics: Humans; Antitubercular Agents; Chemical and Drug Induced Liver Injury, Chronic; Isoniazid; Pyrazinamide; Rifampin; Chemical and Drug Induced Liver Injury
PubMed: 37218081
DOI: 10.1080/03602532.2023.2215478 -
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 -
The Journal of Antibiotics Sep 2019Pyrazinamide is an anti-tubercular agent, used as a part of a three-drug regime (any three of the following: rifampicin, isoniazid, pyrazinamide, streptomycin or...
Pyrazinamide is an anti-tubercular agent, used as a part of a three-drug regime (any three of the following: rifampicin, isoniazid, pyrazinamide, streptomycin or ethambutol) for the initial phase of treatment. One of the effects pyrazinamide has on mammalian cells is to regulate NAD/NADH levels. We have recently found that changes in NAD/NADH are associated with regulation of expression levels of SUR2A, a cardioprotective protein serving as a regulatory subunit of cardiac ATP-sensitive K (K) channels. Here, we have tested whether pyrazinamide regulate expression of SUR2A/K channel subunits and resistance to metabolic stress in embryonic heart-derived H9c2 cells. We have found that 24-h-long treatment with pyrazinamide (3 mcg/ml) increased mRNA levels of SUR2A, SUR2B and Kir6.1 without affecting mRNA levels of other K channel subunits. This treatment with pyrazinamide (3 mcg/ml) protected H9c2 cells against stress induced by 10 mM 2,4-dinitrophenol (DNP). The survival rate of DNP-treated cells was 45.6 ± 2.3% (n = 5) if not treated with pyrazinamide and 90.8 ± 2.3% (n = 5; P < 0.001) if treated with pyrazinamide. We conclude that pyrazinamide increases resistance to metabolic stress in heart H9c2 cells probably by increasing SUR2A and SUR2B expression. Our results of this study indicate that pyrazinamide should be seriously considered as a drug of choice for patients with tuberculosis and ischaemic heart disease.
Topics: Animals; Antitubercular Agents; Cardiotonic Agents; Cell Line; KATP Channels; Pyrazinamide; Rats; Stress, Physiological; Sulfonylurea Receptors
PubMed: 31243346
DOI: 10.1038/s41429-019-0202-z -
Journal of Microbiology, Immunology,... Dec 2023Pyrazinamide (PZA) and fluoroquinolone (FQ), particularly moxifloxacin (MXF), are essential drugs in the World Health Organization (WHO) recommended short-course regimen...
BACKGROUND
Pyrazinamide (PZA) and fluoroquinolone (FQ), particularly moxifloxacin (MXF), are essential drugs in the World Health Organization (WHO) recommended short-course regimen to treat drug-susceptible tuberculosis (TB).
METHODS
To understand the extent of PZA and MXF susceptibility in general TB cases in Taiwan, we conducted retrospective analyses of 385 conservative Mycobacterium tuberculosis complex (MTBC) isolates identified from 4 TB laboratories in different regions of Taiwan. The case information was obtained from the TB registry. Genotypic drug susceptibility testing (DST) was performed by sequencing drug-resistance associated genes, PZA (pncA) and FQ (gyrA, and gyrB). Phenotypic DST was determined using the Bactec MGIT 960 system or the agar proportion method. Genotyping was carried out using spacer oligonucleotide typing.
RESULTS
In this study, 4.7% (18/385) cases' isolates harbored pncA mutations and 7.0% (27/385) cases' isolates harbored gyrA or gyrB mutation. Notably, pncA mutation was associated with Beijing family genotypes (P = 0.028), East African-Indian (EAI) genotypes (P = 0.047) and MDR-TB (P < 0.001). Whereas, gyrA or gyrB mutation was associated with EAI genotypes (P = 0.020) and MDR-TB (P = 0.006). In addition, a statistically significant difference was found between the favorable outcomes using active and inactive PZA (P = 0.009) in 38 case isolates with any pncA, gyrA, or gyrB mutation.
CONCLUSION
We concluded that routine PZA and FQ susceptibility tests are recommended for guiding the treatment of TB.
Topics: Humans; Pyrazinamide; Antitubercular Agents; Mycobacterium tuberculosis; Fluoroquinolones; Microbial Sensitivity Tests; Taiwan; Retrospective Studies; Drug Resistance, Multiple, Bacterial; Amidohydrolases; Tuberculosis; Tuberculosis, Multidrug-Resistant; Mutation; Moxifloxacin
PubMed: 37690869
DOI: 10.1016/j.jmii.2023.08.013 -
The Indian Journal of Tuberculosis Oct 2023Drug-induced thrombocytopenia is a known adverse event of several drugs. Antitubercular therapy (ATT) is rarely reported but important cause of thrombocytopenia. The... (Review)
Review
INTRODUCTION
Drug-induced thrombocytopenia is a known adverse event of several drugs. Antitubercular therapy (ATT) is rarely reported but important cause of thrombocytopenia. The present review aimed to understand the profile of thrombocytopenia caused by first-line ATT i.e. isoniazid, rifampicin, pyrazinamide, and ethambutol.
MATERIALS AND METHODS
We screened case reports, case series, and letter-to-editor from databases, like Pubmed/MEDLINE, Ovid, and EMBASE from 1970 to 2021. The PRISMA guidelines were followed in the present systematic review.
RESULTS
Categorical data were expressed as n (%) and quantitative data were expressed as median (IQR). After applying the inclusion/exclusion criteria, 17 case reports and 7 letters to the editor were selected for the present review. Rifampicin was most frequently associated with thrombocytopenia (65%). A median (IQR) drop to 20,000 (49,500) platelets/mm3 was observed. Anti-rifampicin associated antibodies and anti-dsDNA positivity were found in six studies. Except for two, all patients responded to symptomatic treatment.
DISCUSSION
ATT-induced thrombocytopenia can be life-threatening and require hospitalization. Clinicians should be aware of the association of ATT with thrombocytopenia and should take appropriate measures for patient management.
CONCLUSION
This review provides clinicians a comprehensive picture of adverse effects and their management in ATT induced thrombocytopenia.
Topics: Humans; Rifampin; Antitubercular Agents; Pyrazinamide; Isoniazid; Thrombocytopenia
PubMed: 37968056
DOI: 10.1016/j.ijtb.2023.04.029 -
The International Journal of... Jan 2017Resistance to anti-tuberculosis drugs threatens to undermine effective control of tuberculosis (TB). In areas with weak TB control and misuse of anti-tuberculosis drugs,... (Review)
Review
BACKGROUND
Resistance to anti-tuberculosis drugs threatens to undermine effective control of tuberculosis (TB). In areas with weak TB control and misuse of anti-tuberculosis drugs, hotspots of multidrug-resistant TB (MDR-TB) have appeared. The aim of this review is to determine the prevalence rate of any anti-tuberculosis drug resistance, monoresistance and MDR-TB in Ethiopia.
METHODS
A systematic review of the literature on any resistance, monoresistance and MDR-TB was conducted.
RESULTS
Of the total 468 articles found using electronic search, 14 met the eligibility criteria and were included in the review. The prevalence rate of any drug resistance, polyresistance and MDR-TB was respectively 6.7-72.9%, 0-54% and 0-46%. A higher rate of streptomycin monoresistance (1.5-20.4%) was observed.
CONCLUSION
The prevalence and distribution of drug-resistant TB remains a serious public health problem in Ethiopia. Rapid, advanced diagnostic tools should be introduced, along with strong treatment and follow-up strategies.
Topics: Antitubercular Agents; Drug Resistance, Multiple, Bacterial; Ethambutol; Ethiopia; Humans; Isoniazid; Prevalence; Public Health; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis, Multidrug-Resistant
PubMed: 28157460
DOI: 10.5588/ijtld.16.0286