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Annals of Medicine Dec 2024The Directly Observed Treatment-Short Course (DOTS) Programme was implemented by WHO and includes a combination of four anti-tuberculosis (TB) drugs (isoniazid,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The Directly Observed Treatment-Short Course (DOTS) Programme was implemented by WHO and includes a combination of four anti-tuberculosis (TB) drugs (isoniazid, pyrazinamide, ethambutol and rifampicin) for a period of six months to eradicate the TB infection completely. Diabetes mellitus (DM) is recognized as one of a strong contributor of TB according to World Health Organization (WHO). The presence of diabetes mellitus type 2 (DM type 2) makes TB treatment complicated. Thus, the objective of the current meta-analysis was to identify and quantify the impact of type 2 DM on treatment outcomes of TB patients treated under the DOTS Programme.
METHODS
This meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Through a systematic review of relevant literature, we focused on studies investigating treatment outcomes including extended treatment duration and recurrence for individuals with both TB and DM undergoing DOTS therapy. The extracted information included study designs, sample sizes, patient characteristics and reported treatment results.
RESULTS
In 44 studies from different parts of the world, the pooled HR for the impact of DM on extended treatment duration and reoccurrence were HR 0.72, 95% CI 0.56-0.83, < .01 and HR 0.93, 95% CI 0.70-1.04, = .08, respectively. The pooled HR for impact of DM on composite TB treatment outcomes was calculated as 0.76 (95% CI 0.60-0.87), < .01 with an effect size of 41.18. The heterogeneity observed among the included studies was moderate ( = 55.79%).
CONCLUSIONS
A negative impact of DM was found on recurrence and extended treatment duration in TB patients treated with DOTS therapy. DM type 2 is responsible for the TB treatment prolongation and TB recurrence rates. By implementing effective management strategies and advancing research, the challenges can be mitigated, arising due to the complex interaction between DM and TB.
Topics: Humans; Tuberculosis; Diabetes Mellitus, Type 2; Comorbidity; Isoniazid; Ethambutol; Diabetes Mellitus
PubMed: 38346381
DOI: 10.1080/07853890.2024.2313683 -
BMJ Open Sep 2023To evaluate the efficacy of antituberculosis therapy on pregnancy outcomes in infertile women with genital tuberculosis.
OBJECTIVES
To evaluate the efficacy of antituberculosis therapy on pregnancy outcomes in infertile women with genital tuberculosis.
DESIGN
Systematic review.
DATA SOURCES
We searched in PubMed/MEDLINE, CENTRAL and EMBASE up to 15 January 2023. Additionally, we manually search the reference lists of included studies.
ELIGIBILITY CRITERIA
We included randomised controlled trials (RCT), non-RCTs (non-RCT) and cohort studies that evaluated the effects of antituberculosis treatment on pregnancy outcomes in infertile women with genital tuberculosis compared with not receiving antituberculosis treatment or receiving the treatment for a shorter period.
DATA EXTRACTION AND SYNTHESIS
Two independent reviewers extracted data. We used Cochrane Risk of Bias 1.0 and Risk Of Bias In Non-randomised Studies tools for risk of bias assessment and meta-analysis was not performed. We used Grading of Recommendations, Assessment, Development and Evaluations approach to assess the certainty of the evidence.
RESULTS
Two RCTs and one non-RCT were included. The antituberculosis regimens were based on isoniazid, rifampicin, pyrazinamide and ethambutol for 6-12 months. In women without structural damage, very low certainty of evidence from one RCT showed that the antituberculosis treatment may have little to no effect on pregnancy, full-term pregnancy, abortion or intrauterine death and ectopic pregnancy, but the evidence is very uncertain. In women with structural damage, very low certainty of evidence from one non-RCT showed that the antituberculosis treatment may reduce the pregnancy rate (297 fewer per 1000, 95% CI -416 to -101), but the evidence is very uncertain. In addition, very low certainty of evidence from one RCT compared a 9-month vs 6-month antituberculosis treatment regimen showed similar effects between the schemes, but the evidence is very uncertain. Two RCTs reported that no adverse events of antituberculosis treatment were noted or were similar in both groups.
CONCLUSION
The effect of antituberculosis treatment on pregnancy outcomes in infertile women with genital tuberculosis is very uncertain.
PROSPERO REGISTRATION NUMBER
CRD42022273145.
Topics: Female; Pregnancy; Humans; Pregnancy Outcome; Stillbirth; Infertility, Female; Antitubercular Agents; Tuberculosis; Genitalia
PubMed: 37758670
DOI: 10.1136/bmjopen-2022-070456 -
Clinical Microbiology and Infection :... Feb 2024Contacts of patients with multidrug-resistant tuberculosis (MDR-TB) are at risk of developing TB disease. Tuberculosis preventive treatment (TPT) is an intervention that... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Contacts of patients with multidrug-resistant tuberculosis (MDR-TB) are at risk of developing TB disease. Tuberculosis preventive treatment (TPT) is an intervention that can potentially reduce this risk.
OBJECTIVES
To evaluate the effectiveness and safety of TPT for contacts of patients with MDR-TB.
DATA SOURCES
EMBASE, PubMed, Web of Science, and the Cochrane Library were searched for eligible studies on 24 July 2023, without start date restrictions.
STUDY ELIGIBILITY CRITERIA
We included studies that compared TPT with no treatment in contacts of patients with MDR-TB and reported outcomes of progression to TB disease.
PARTICIPANTS
Contacts of patients with MDR-TB.
INTERVENTIONS
TPT.
ASSESSMENT OF RISK OF BIAS
A modified version of the Newcastle-Ottawa Scale was used.
METHODS OF DATA SYNTHESIS
Random-effects meta-analysis was utilized to calculate the relative risk for disease progression to TB in contacts of patients with MDR-TB who received TPT compared to those who did not. Additionally, completion, adverse effect, and discontinued rates were assessed.
RESULTS
Involving 1105 individuals from 11 studies, the pooled relative risk for disease progression in contacts receiving TPT versus those without treatment was 0.34 (95% CI: 0.16-0.72). Subgroup analysis indicated a lower pooled relative risk for regimens based on the drug-resistance profile of the index patients with TB compared to uniform treatment regimens (0.22 [95% CI: 0.06-0.84] vs. 0.49 [95% CI: 0.17-1.35]), although not statistically significant. The pooled completed rate was 83.8%, adverse effect rate was 22.9%, and discontinued rate was 6.5%. After excluding the levofloxacin and pyrazinamide regimen study, the completed rate increased to 88.0%, and adverse effects and discontinued rates decreased to 8.0% and 4.0%, respectively.
DISCUSSION
TPT reduces TB disease progression risk in contacts of patients with MDR-TB. Tailored TPT regimens based on drug-resistance profiles may offer additional benefits. Furthermore, efforts to improve completed rates and manage adverse effects are essential for optimizing effectiveness and safety.
Topics: Humans; Antitubercular Agents; Tuberculosis, Multidrug-Resistant; Pyrazinamide; Levofloxacin; Drug-Related Side Effects and Adverse Reactions; Disease Progression
PubMed: 37741621
DOI: 10.1016/j.cmi.2023.09.015 -
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 -
International Journal of Antimicrobial... Sep 2023Pyrazinamide (PZA) is a first-line antituberculosis drug with potent sterilising activity. Variability in drug exposure may translate into suboptimal treatment... (Review)
Review
Pyrazinamide (PZA) is a first-line antituberculosis drug with potent sterilising activity. Variability in drug exposure may translate into suboptimal treatment responses. This systematic review, conducted according to PRISMA guidelines, aimed to evaluate the concentration-effect relationship. In vitro/in vivo studies had to contain information on the infection model, PZA dose and concentration, and microbiological outcome. Human studies had to present information on PZA dose, measures of drug exposure and maximum concentration, and microbiological response parameter or overall treatment outcome. A total of 34 studies were assessed, including in vitro (n = 2), in vivo (n = 3) and clinical studies (n = 29). Intracellular and extracellular models demonstrated a direct correlation between PZA dose of 15-50 mg/kg/day and reduction in bacterial count between 0.50-27.7 log CFU/mL. Consistent with this, higher PZA doses (>150 mg/kg) were associated with a greater reduction in bacterial burden in BALB/c mice models. Human pharmacokinetic studies displayed a linear positive correlation between PZA dose (i.e. 21.4-35.7 mg/kg/day) and drug exposure (AUC range 220.6-514.5 mg·h/L). Additionally, human studies confirmed a dose-effect relationship, with an increased 2-month sputum culture conversion rate at AUC/MIC targets of 8.4-11.3 with higher exposure/susceptibility ratios leading to greater efficacy. A 5-fold variability in AUC was observed at PZA dose of 25 mg/kg. A direct concentration-effect relationship and increased treatment efficacy with higher PZA exposure to susceptibility ratios was observed. Taking into account variability in drug exposure and treatment response, further studies on dose optimisation are justified.
Topics: Animals; Mice; Humans; Pyrazinamide; Mycobacterium tuberculosis; Tuberculosis; Antitubercular Agents; Mice, Inbred BALB C; Microbial Sensitivity Tests
PubMed: 37419292
DOI: 10.1016/j.ijantimicag.2023.106914 -
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 -
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 Infectious Diseases : An... May 2023Optimal doses of first-line drugs for treatment of drug-susceptible tuberculosis in children and young adolescents remain uncertain. We aimed to determine whether... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Optimal doses of first-line drugs for treatment of drug-susceptible tuberculosis in children and young adolescents remain uncertain. We aimed to determine whether children treated using World Health Organization-recommended or higher doses of first-line drugs achieve successful outcomes and sufficient pharmacokinetic (PK) exposures.
METHODS
Titles, abstracts, and full-text articles were screened. We searched PubMed, EMBASE, CENTRAL, and trial registries from 2010 to 2021. We included studies in children aged <18 years being treated for drug-susceptible tuberculosis with rifampicin (RIF), pyrazinamide, isoniazid, and ethambutol. Outcomes were treatment success rates and drug exposures. The protocol for the systematic review was preregistered in PROSPERO (no. CRD42021274222).
RESULTS
Of 304 studies identified, 46 were eligible for full-text review, and 12 and 18 articles were included for the efficacy and PK analyses, respectively. Of 1830 children included in the efficacy analysis, 82% had favorable outcomes (range, 25%-95%). At World Health Organization-recommended doses, exposures to RIF, pyrazinamide, and ethambutol were lower in children than in adults. Children ≤6 years old have 35% lower areas under the concentration-time curve (AUCs) than older children (mean of 14.4 [95% CI 9.9-18.8] vs 22.0 [13.8-30.1] μg·h/mL) and children with human immunodeficiency virus (HIV) had 35% lower RIF AUCs than HIV-negative children (17.3 [11.4-23.2] vs 26.5 [21.3-31.7] μg·h/mL). Heterogeneity and small sample sizes were major limitations.
CONCLUSIONS
There is large variability in outcomes, with an average of 82% favorable outcomes. Drug exposures are lower in children than in adults. Younger children and/or those with HIV are underexposed to RIF. Standardization of PK pediatric studies and individual patient data analysis with safety assessment are needed to inform optimal dosing.
Topics: Adult; Adolescent; Child; Humans; Antitubercular Agents; Pyrazinamide; Ethambutol; Tuberculosis; Rifampin; Isoniazid; HIV; HIV Infections
PubMed: 36609692
DOI: 10.1093/cid/ciac973 -
The European Respiratory Journal Mar 2023Suboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Suboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level.
METHODS
We systematically searched MEDLINE, Embase and Web of Science (1990-2021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration-time curve from 0 to 24 h post-dose (AUC) and peak plasma concentration ( ) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC and were assessed with linear mixed-effects models.
RESULTS
Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC were summarised for isoniazid (18.7 (95% CI 15.5-22.6) h·mg·L), rifampicin (34.4 (95% CI 29.4-40.3) h·mg·L), pyrazinamide (375.0 (95% CI 339.9-413.7) h·mg·L) and ethambutol (8.0 (95% CI 6.4-10.0) h·mg·L). Our multivariate models indicated that younger age (especially <2 years) and HIV-positive status were associated with lower AUC for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC for isoniazid and pyrazinamide. -acetyltransferase 2 rapid acetylators had lower isoniazid AUC and slow acetylators had higher isoniazid AUC than intermediate acetylators. Determinants of were generally similar to those for AUC.
CONCLUSIONS
This study provides the most comprehensive estimates of plasma exposures to first-line anti-TB drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring.
Topics: Child; Adolescent; Humans; Child, Preschool; Antitubercular Agents; Isoniazid; Pyrazinamide; Ethambutol; Rifampin
PubMed: 36328357
DOI: 10.1183/13993003.01596-2022 -
Journal of Clinical Medicine Oct 2022(1) Background: Intravesical instillation of therapeutic Bacillus Calmette-Guerin (BCG) is the standard of treatment for non-muscular invasive bladder cancer. Although...
(1) Background: Intravesical instillation of therapeutic Bacillus Calmette-Guerin (BCG) is the standard of treatment for non-muscular invasive bladder cancer. Although the exact immunomodulatory effects of BCG therapy in non-muscular invasive bladder cancer (NMIBC) are still unclear, it has been considered a safe and effective treatment with the largest to-date report of complications citing minimal side effects, none of which included arterial involvement; (2) Methods: A systematic literature review was performed using PubMed, Cochrane, Medline, and Google Scholar from database inception to March 2021. Only eligible studies reporting aneurysm formation in adult patients with a history of BCG immunotherapy and no previous vascular pathology were included; (3) Results: A systematic literature review was conducted, highlighting 17 reports suggestive of BCG-induced mycotic aneurysm development. We added a case of a 78-year-old male, 30 months after last BCG-instillation, with a mycotic abdominal aneurysm yielding with pyrazinamide resistance culture.; (4) Conclusions: Concluding results suggest a higher incidence of vascular complications from BCG intravesical therapy in the treatment of non-muscular invasive bladder cancer than previously reported. Recommendations are made to emphasize further research of this immunotherapy complication to facilitate the creation of guidelines for diagnosis and management of these patients.
PubMed: 36294547
DOI: 10.3390/jcm11206226