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The International Journal of... Jan 2020Low serum concentrations of first-line tuberculosis (TB) drugs have been widely reported. However, the impact of low serum concentrations on treatment outcome is less... (Meta-Analysis)
Meta-Analysis
Low serum concentrations of first-line tuberculosis (TB) drugs have been widely reported. However, the impact of low serum concentrations on treatment outcome is less well studied. A systematic search of MEDLINE/Pubmed and the Cochrane Central Register of Controlled Trials up to 31 March 2018 was conducted for articles describing drug concentrations of first-line TB drugs and treatment outcome in adult patients with drug-susceptible TB. The search identified 3073 unique publication abstracts, which were reviewed for suitability: 21 articles were acceptable for inclusion in the qualitative analysis comprising 13 prospective observational cohorts, 4 retrospective observational cohorts, 1 case-control study and 3 randomised controlled trials. Data for meta-analysis were available for 15 studies, 13 studies of rifampicin (RMP), 10 of isoniazid (INH), 8 of pyrazinamide (PZA) and 4 of ethambutol (EMB). This meta-analysis revealed that low PZA concentration appears to increase the risk of poor outcomes (8 studies, = 2727; RR 1.73, 95%CI 1.10-2.72), low RMP concentrations may slightly increase the risk of poor outcomes (13 studies, = 2753; RR 1.40, 95%CI 0.91-2.16), whereas low concentrations of INH (10 studies, = 2640; RR 1.32, 95%CI 0.66-2.63) and EMB (4 studies, = 551; RR 1.12, 95%CI 0.41-3.05) appear to make no difference to treatment outcome. There was no significant publication bias or between-study heterogeneity in any of the analyses. The potential clinical impact of low concentrations of PZA and RMP warrants further evaluation. Also, comprehensive assessments of the complex pharmacokinetic-pharmacodynamic relationships in the treatment of TB are urgently needed.
Topics: Adult; Antitubercular Agents; Case-Control Studies; Humans; Isoniazid; Observational Studies as Topic; Pharmaceutical Preparations; Pyrazinamide; Retrospective Studies; Treatment Outcome; Tuberculosis
PubMed: 32005307
DOI: 10.5588/ijtld.19.0025 -
Cureus Apr 2023Tuberculosis prevention treatment (TPT) is crucial to the eradication of tuberculosis (TB). Through a comprehensive review and meta-analysis, we compared the efficacy... (Review)
Review
Tuberculosis prevention treatment (TPT) is crucial to the eradication of tuberculosis (TB). Through a comprehensive review and meta-analysis, we compared the efficacy and safety of different TPT regimens. We searched PubMed, Google Scholar, and medrxiv.org with search terms Tuberculosis Preventive Treatment, TPT, efficacy, safety, and drug regimens for TPT and all RCT, irrespective of age, setting, or co-morbidities, comparing at least one TPT regimen to placebo, no therapy, or other TPT regimens were screened and those reporting either efficacy or safety or both were included. The meta-analysis data were synthesized with Review Manager and the risk ratio (RR) was calculated. Out of 4465 search items, 15 RCTs (randomized-controlled trials) were included. The TB infection rate was 82/6308 patients in the rifamycin plus isoniazid group (HR) as compared to 90/6049 in the isoniazid monotherapy (H) group (RR: 0.89 (95% CI: 0.66, 1.19; p=0.43). A total of 965/6478 vs 1065/6219 adverse drug reactions (ADRs) occurred in HR and H groups respectively (RR: 0.86 (95%CI: 0.80 0.93); P<0.0001). Efficacy analysis of the rifampicin plus pyrazinamide (RZ) vs H showed that the risk ratio of infection rate was not considerably varied (RR: 0.97 (95% CI: 0.47, 2.03); P=0.94). Safety analysis showed in 229/572 patients developed ADRs in rifampicin plus pyrazinamide as compared to 129/600 ADRs in the isoniazid group. (RR: 1.87 (95% CI: 1.44, 2.43)). Safety analysis of only rifamycin (R) vs H group showed 23/718 ADRs in R vs 57/718 ADRs in H group (RR: 0.40 (95% CI: 0.25 0.65); P=0.0002). Rifamycin plus isoniazid (3HP/R) has no edge over other regimens in terms of efficacy but this regimen was found significantly safer as compared to any other regimens used for TPT. Rifampicin plus pyrazinamide (RZ) was found equally efficacious but less safe as compared to other regimens.
PubMed: 37252497
DOI: 10.7759/cureus.38182 -
The Journal of Pharmacy and Pharmacology Jun 2022To evaluate and update the evidence on the comparative efficacy and safety of antimicrobial drugs regimens for treating pulmonary drug-susceptible tuberculosis (DS-TB). (Meta-Analysis)
Meta-Analysis
OBJECTIVES
To evaluate and update the evidence on the comparative efficacy and safety of antimicrobial drugs regimens for treating pulmonary drug-susceptible tuberculosis (DS-TB).
METHODS
A systematic review was performed with searches in PubMed and Scopus (PROSPERO-CRD42019141463). We included randomised controlled trials comparing the effect of any antimicrobial regimen lasting at least 2 weeks. The outcomes of interest were culture conversion and incidence of adverse events. Bayesian network meta-analyses and surface under the cumulative ranking curve (SUCRA) analyses were performed. Results were reported as odds ratio with 95% credibility intervals.
KEY FINDINGS
Fifteen studies were included the meta-analysis (n = 7560 patients). No regimen was statistically more effective than the WHO standard approach (rifampicin, isoniazid, ethambutol, and pyrazinamide). The use of rifapentine 450 mg instead of rifampicin in the standard regimen demonstrated to be statistically safer than all other options for serious adverse events (e.g. hepatotoxicity, arthralgia) (OR ranging from 0.0 [Crl 0.00-0.04] to 0.0 [0.00-0.97]; SUCRA probabilities of 10%). Therapies containing rifapentine (Rp1500HEZ, Rp900HEZ) and moxifloxacin (RMEZ, RHMZ) are effective regarding culture conversion, but statistical uncertainty on their safety profile exists.
CONCLUSION
The WHO standard regimen remains an overall effective and safe alternative for DS-TB. For intensive phase treatments, drugs combinations with rifapentine and moxifloxacin seem to reduce treatment duration while maintaining efficacy.
Topics: Antitubercular Agents; Bayes Theorem; Drug Therapy, Combination; Humans; Moxifloxacin; Network Meta-Analysis; Rifampin; Tuberculosis, Pulmonary
PubMed: 35355071
DOI: 10.1093/jpp/rgac004 -
Journal of Chemotherapy (Florence,... Nov 2023Pyrazinamide (PZA) is an essential first-line tuberculosis drug for its unique mechanism of action active against multidrug-resistant-TB (MDR-TB). Thus, the aim of... (Meta-Analysis)
Meta-Analysis Review
Pyrazinamide (PZA) is an essential first-line tuberculosis drug for its unique mechanism of action active against multidrug-resistant-TB (MDR-TB). Thus, the aim of updated meta-analysis was to estimate the PZA weighted pooled resistance (WPR) rate in M. tuberculosis isolates based on publication date and WHO regions. We systematically searched the related reports in PubMed, Scopus, and Embase (from January 2015 to July 2022). Statistical analyses were performed using STATA software. The 115 final reports in the analysis investigated phenotypic PZA resistance data. The WPR of PZA was 57% (95% CI 48-65%) in MDR-TB cases. According to the WHO regions, the higher WPRs of PZA were reported in the Western Pacific (32%; 95% CI 18-46%), South East Asian region (37%; 95% CI 31-43%), and the Eastern Mediterranean (78%; 95% CI 54-95%) among any-TB patients, high risk of MDR-TB patients, and MDR-TB patients, respectively. A negligible increase in the rate of PZA resistance were showed in MDR-TB cases (55% to 58%). The rate of PZA resistance has been rising in recent years among MDR-TB cases, underlines the essential for both standard and novel drug regimens development.
Topics: Humans; Pyrazinamide; Mycobacterium tuberculosis; Antitubercular Agents; Tuberculosis, Multidrug-Resistant; Drug Resistance, Multiple, Bacterial; Amidohydrolases; Mutation; Microbial Sensitivity Tests; Tuberculosis
PubMed: 37211822
DOI: 10.1080/1120009X.2023.2214473 -
Open Forum Infectious Diseases Jun 2022Before August 2021, the only regimen recommended by the World Health Organization (WHO) to treat pediatric drug-susceptible tuberculous meningitis was a 12-month regimen...
BACKGROUND
Before August 2021, the only regimen recommended by the World Health Organization (WHO) to treat pediatric drug-susceptible tuberculous meningitis was a 12-month regimen consisting of isoniazid, rifampicin, ethambutol, and pyrazinamide (2HRZE/10HR). The comparative effectiveness of shorter regimens is unknown.
METHODS
To inform a WHO guideline update, we undertook a systematic review and meta-analysis to evaluate outcomes from regimens of 6- to less than 12-months' duration that included, at a minimum, isoniazid, rifampicin, and pyrazinamide. We included studies that applied rigorous diagnostic criteria and reported outcomes for ≥10 children or adolescents. Using generalized linear mixed models, we estimated the random effects pooled proportions of patients with key outcomes.
RESULTS
Of 7 included studies, none compared regimens head-to-head. Three studies (724 patients) used a 6-month intensive regimen, which includes isoniazid and rifampicin at higher doses, pyrazinamide, and ethionamide instead of ethambutol (6HRZEto). Outcomes for this versus the 12-month regimen (282 patients, 3 studies) were, respectively, as follows: death, 5.5% (95% confidence interval [CI], 2.1%-13.4%) vs 23.9% (95% CI, 17.5%-31.7%); treatment success (survival with or without sequelae), 94.6% (95% CI, 73.9%-99.1%) vs 75.4% (95% CI, 68.7%-81.1%); and neurological sequelae among survivors, 66.0% (95% CI, 55.3%-75.3%) vs 36.3% (95% CI, 30.1%-43.0%). Relapse did not occur among 148 patients followed-up for 2 years after completing the 6-month intensive regimen.
CONCLUSIONS
Our findings are limited by the small number of studies and substantial potential for confounding. Nonetheless, the 6HRZEto regimen was associated with high treatment success and is now recommended by WHO as an alternative to the 12-month regimen.
PubMed: 35673608
DOI: 10.1093/ofid/ofac108 -
EClinicalMedicine Oct 2023Tuberculosis (TB) is the leading infectious cause of death globally. Several preventive measures are employed to prevent TB, yet there is a paucity of evidence on the...
BACKGROUND
Tuberculosis (TB) is the leading infectious cause of death globally. Several preventive measures are employed to prevent TB, yet there is a paucity of evidence on the effectiveness of these interventions. Therefore, this study aimed to identify the most effective interventions for reducing TB incidence.
METHODS
A systematic search was undertaken across five relevant databases including PubMed, SCOPUS, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from inception to February 22, 2023. Bayesian network meta-analysis (NMA) was conducted to compare the effectiveness of preventive interventions including preventive therapy, nutritional intervention, targeted screening, and vaccination in reducing TB incidence. Subgroup analysis was conducted to investigate the effectiveness of TB preventive treatments.
FINDINGS
Overall 82 articles were included in the NMA. Preventive therapy (OR = 0.44, 95% CrI 0.36-0.52), BCG vaccination (OR = 0.62, 95% CrI 0.39-0.98) and TB candidate vaccines (OR = 0.67, 95% CrI 0.46-0.98) were more effective than placebo or no intervention. When all active interventions were considered, preventive therapy ranked as the best intervention. Of the preventive treatments, isoniazid (OR = 0.46, 95% CrI 0.35-0.55), isoniazid plus rifampicin (OR = 0.56, 95% CrI 0.32-0.97), isoniazid plus rifapentine (OR = 0.49, 95% CrI 0.29-0.83), isoniazid plus ethambutol (OR = 0.39, 95% CrI 0.15-0.99), isoniazid plus streptomycin (OR = 0.12, 95% CrI 0.02-0.55), rifampicin (OR = 0.41, 95% CrI 0.18-0.92), and rifampicin plus pyrazinamide (OR = 0.51, 95% CrI 0.29-0.87) surpassed placebo/none.
INTERPRETATION
Our study suggested that when all available preventive interventions are considered, preventive therapy is likely the most effective intervention. Within TB preventive treatments, isoniazid plus streptomycin is likely ranked at the top. This comparative study provides important information for policymakers and stakeholders, enabling them to make informed decisions on preventive strategies, whilst considering local resources and capacity constraints.
FUNDING
Curtin University strategic scholarship and Australian National Health and Medical Research Council, through an Emerging Leadership Investigator grant.
PubMed: 37731939
DOI: 10.1016/j.eclinm.2023.102209 -
The Journal of Infectious Diseases May 2024For simultaneous prediction of phenotypic drug susceptibility test (pDST) for multiple antituberculosis drugs, the whole genome sequencing (WGS) data can be analyzed... (Meta-Analysis)
Meta-Analysis
BACKGROUND
For simultaneous prediction of phenotypic drug susceptibility test (pDST) for multiple antituberculosis drugs, the whole genome sequencing (WGS) data can be analyzed using either a catalog-based approach, wherein 1 causative mutation suggests resistance, (eg, World Health Organization catalog) or noncatalog-based approach using complicated algorithm (eg, TB-profiler, machine learning). The aim was to estimate the predictive ability of WGS-based tests with pDST as the reference, and to compare the 2 approaches.
METHODS
Following a systematic literature search, the diagnostic test accuracies for 14 drugs were pooled using a random-effect bivariate model.
RESULTS
Of 779 articles, 44 with 16 821 specimens for meta-analysis and 13 not for meta-analysis were included. The areas under summary receiver operating characteristic curve suggested test accuracy was excellent (0.97-1.00) for 2 drugs (isoniazid 0.975, rifampicin 0.975), very good (0.93-0.97) for 8 drugs (pyrazinamide 0.946, streptomycin 0.952, amikacin 0.968, kanamycin 0.963, capreomycin 0.965, para-aminosalicylic acid 0.959, levofloxacin 0.960, ofloxacin 0.958), and good (0.75-0.93) for 4 drugs (ethambutol 0.926, moxifloxacin 0.896, ethionamide 0.878, prothionamide 0.908). The noncatalog-based and catalog-based approaches had similar ability for all drugs.
CONCLUSIONS
WGS accurately identifies isoniazid and rifampicin resistance. For most drugs, positive WGS results reliably predict pDST positive. The 2 approaches had similar ability.
CLINICAL TRIALS REGISTRATION
UMIN-ID UMIN000049276.
Topics: Antitubercular Agents; Whole Genome Sequencing; Mycobacterium tuberculosis; Humans; Microbial Sensitivity Tests; Phenotype; Tuberculosis, Multidrug-Resistant; Drug Resistance, Bacterial; Rifampin; Isoniazid
PubMed: 37946558
DOI: 10.1093/infdis/jiad480 -
Annals of Palliative Medicine Jun 2021Isoniazid (INH), rifampicin (RMP), pyrazinamide (PZA), and ethambutol (EMB) are the four most common drugs for the first-line treatment of tuberculosis (TB). Although... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Isoniazid (INH), rifampicin (RMP), pyrazinamide (PZA), and ethambutol (EMB) are the four most common drugs for the first-line treatment of tuberculosis (TB). Although chemotherapy drugs are widely used in the treatment of TB, and achieved good results, but the side effects, especially anti-tuberculosis drug-induced liver injury (ATDILI), cannot be overlooked. Many researchers have made efforts to uncover the association of cytochrome P450 (CYP) enzyme genetic polymorphisms with ATDILI. In this study, we systematically reviewed and meta-analyzed the relationship between CYP polymorphism and susceptibility to ATDILI.
METHODS
We carried out literature searches of PubMed, Ovid, the Cochrane Library, Web of Science and Chinese National Knowledge Infrastructure (CNKI). Medical Subject Headings (MeSH) terms including "cytochrome P450 enzyme", "drug-induced liver injury", "polymorphism", "tuberculosis", and "hepatotoxicity" were used as keywords for our searches.
RESULTS
The pooled odds ratio (OR) of all studies for CYP2E1 to the risk of ATDILI was 1.18 [95% confidence interval (CI): 0.82-1.71]. The articles in this meta-analysis were observed to be mildly heterogeneous. Further subgroup analysis revealed that the patients who receiving a four-drug protocol (INH + RIF + PZA + EMB) or three-drug protocol (INH + RIF + PZA) regimens showed a higher risk of ATDILI than those who receiving INH alone. However, subgroup analyses according to participants' ethnic origin, study type, and the definition of ATDILI produced no statistically significant results. Associations between other genes in the CYP family and ATDILI were indistinct and equivocal.
DISCUSSION
Our meta-analysis has uncovered an association between CYP2E1 RsaI/PstI polymorphisms and ATDILI, especially among patients who receive a four-drug (INH + RIF + PZA + EMB) or three-drug (INH + RIF + PZA) anti-TB treatment regimen.
Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme System; Humans; Polymorphism, Genetic; Tuberculosis
PubMed: 34154362
DOI: 10.21037/apm-21-1224 -
Clinical Pharmacokinetics Mar 2023Understanding the pharmacokinetics (PK) of antimicrobial drugs in pregnant women is crucial to provide effective and safe treatment. This study is part of a series that...
INTRODUCTION
Understanding the pharmacokinetics (PK) of antimicrobial drugs in pregnant women is crucial to provide effective and safe treatment. This study is part of a series that systematically reviews literature on the PK and analyzes if, based on the changed PK, evidence-based dosing regimens have been developed for adequate target attainment in pregnant women. This part focusses on antimicrobials other than penicillins and cephalosporins.
METHODS
A literature search was conducted in PubMed according to the PRISMA guidelines. Search strategy, study selection, and data extraction were independently performed by two investigators. Studies were labeled as relevant when information on the PK of antimicrobial drugs in pregnant women was available. Extracted parameters included bioavailability for oral drugs, volume of distribution (Vd) and clearance (CL), trough and peak drug concentrations, time of maximum concentration, area under the curve and half-life, probability of target attainment, and minimal inhibitory concentration (MIC). In addition, if developed, evidence-based dosing regimens were also extracted.
RESULTS
Of the 62 antimicrobials included in the search strategy, concentrations or PK data during pregnancy of 18 drugs were reported. Twenty-nine studies were included, of which three discussed aminoglycosides, one carbapenem, six quinolones, four glycopeptides, two rifamycines, one sulfonamide, five tuberculostatic drugs, and six others. Eleven out of 29 studies included information on both Vd and CL. For linezolid, gentamicin, tobramycin, and moxifloxacin, altered PK throughout pregnancy, especially in second and third trimester, has been reported. However, no target attainment was studied and no evidence-based dosing developed. On the other hand, the ability to reach adequate targets was assessed for vancomycin, clindamycin, rifampicin, rifapentine, ethambutol, pyrazinamide, and isoniazid. For the first six mentioned drugs, no dosage adaptations during pregnancy seem to be needed. Studies on isoniazid provide contradictory results.
CONCLUSION
This systematic literature review shows that a very limited number of studies have been performed on the PK of antimicrobials drugs-other than cephalosporins and penicillins-in pregnant women.
Topics: Female; Humans; Pregnancy; Cephalosporins; Penicillins; Isoniazid; Anti-Bacterial Agents; Clindamycin
PubMed: 36940039
DOI: 10.1007/s40262-023-01226-6 -
Clinical Pharmacology : Advances and... 2021Tuberculosis remains the major public health problem besides tremendous efforts to combat it. Most tuberculosis patients are treated with a standard dose of first-line...
BACKGROUND
Tuberculosis remains the major public health problem besides tremendous efforts to combat it. Most tuberculosis patients are treated with a standard dose of first-line anti-TB drugs. The cure rate, however, varies from patient to patient. Various factors have been related to anti-TB treatment failure. In recent years, studies associating lower plasma concentrations of anti-TB drugs with poor treatment outcomes are emerging although the results are inconclusive.
OBJECTIVE
Investigate the impact of first-line anti-tubercular drugs pharmacokinetics on treatment outcome.
METHODS
A systematic search of Pubmed, EMBASE, Web of Science, and the Cochrane Library for articles published in the English language between January 2010 to June 2020 was conducted to identify eligible studies describing associations of first-line anti-tubercular drug pharmacokinetics with treatment outcomes. The primary outcomes considered were pharmacokinetics parameter results and its association with treatment outcome.
RESULTS
The search identified 1754 articles of which twelve articles; ten prospective observational studies and two controlled clinical trials fulfilled the eligibility criteria. The majority of the studies showed target concentrations for the first-line anti-tubercular drugs below the current standard range. Among the twelve studies, eleven studies assessed rifampicin pharmacokinetics of which eight reported association of drug concentration and treatment outcomes. Similarly, four out of eight and three out of seven reported drug concentration and treatment outcome association for isoniazid and pyrazinamide, respectively. Despite the low plasma concentration, a favorable treatment outcome was achieved for the bulk of the patients. Irrespective of the inconsistency, an increase in exposure to rifampicin improved the outcome, and lower rifampicin, isoniazid, and pyrazinamide concentration are associated with poor outcome. No data are available for ethambutol associating its pharmacokinetics with treatment outcomes.
CONCLUSION
The pharmacokinetics of first-line antitubercular drugs can influence treatment outcomes. Further controlled clinical studies are, however, required to establish these relationships.
PubMed: 33469389
DOI: 10.2147/CPAA.S289714