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Journal of Global Antimicrobial... Sep 2023The aim of the study was to update the classification of drugs used in multidrug-resistant tuberculosis (MDR-TB) regimens. Group A drugs (fluoroquinolones, bedaquiline... (Meta-Analysis)
Meta-Analysis Review
Evaluation of genetic mutations associated with phenotypic resistance to fluoroquinolones, bedaquiline, and linezolid in clinical Mycobacterium tuberculosis: A systematic review and meta-analysis.
OBJECTIVES
The aim of the study was to update the classification of drugs used in multidrug-resistant tuberculosis (MDR-TB) regimens. Group A drugs (fluoroquinolones, bedaquiline (BDQ), and linezolid (LZD)) are crucial drugs for the control of MDR-TB. Molecular drug resistance assays could facilitate the effective use of Group A drugs.
METHODS
We summarised the evidence implicating specific genetic mutations in resistance to Group A drugs. We searched PubMed, Embase, MEDLINE, and the Cochrane Library for studies published from the inception of each database until July 1, 2022. Using a random-effects model, we calculated the odds ratios and 95% confidence intervals as our measures of association.
RESULTS
A total of 5001 clinical isolates were included in 47 studies. Mutations in gyrA A90V, D94G, D94N, and D94Y were significantly associated with an increased risk of a levofloxacin (LFX)-resistant phenotype. In addition, mutations in gyrA G88C, A90V, D94G, D94H, D94N, and D94Y were significantly associated with an increased risk of a moxifloxacin (MFX)-resistant phenotype. In only one study, the majority of gene loci (n = 126, 90.65%) in BDQ-resistant isolates were observed to have unique mutations in atpE, Rv0678, mmpL5, pepQ, and Rv1979c. The most common mutations occurred at four sites in the rrl gene (g2061t, g2270c, g2270t, and g2814t) and at one site in rplC (C154R) in LZD-resistant isolates. Our meta-analysis demonstrated that there were no mutations associated with BDQ- or LZD-resistant phenotypes.
CONCLUSION
The mutations detected by rapid molecular assay were correlated with phenotypic resistance to LFX and MFX. The absence of mutation-phenotype associations for BDQ and LZD hindered the development of a rapid molecular assay.
Topics: Humans; Mycobacterium tuberculosis; Linezolid; Fluoroquinolones; Antitubercular Agents; Tuberculosis, Multidrug-Resistant; Levofloxacin; Phenotype
PubMed: 37172764
DOI: 10.1016/j.jgar.2023.05.001 -
PloS One 2016Multidrug-resistant tuberculosis (MDR-TB) represents a major obstacle towards successful TB control. Directly observed therapy (DOT) was recommended by WHO to improve... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Multidrug-resistant tuberculosis (MDR-TB) represents a major obstacle towards successful TB control. Directly observed therapy (DOT) was recommended by WHO to improve adherence and treatment outcomes of MDR-TB patients, however, the effectiveness of DOT on treatment outcomes of MDR-TB patients was mixed in previous studies. We conducted this systematic review and meta-analysis to assess the association between DOT and treatment outcomes and to examine the impact of different DOT providers and DOT locations on successful treatment outcomes in MDR-TB patients.
METHODS
We searched studies published in English between January 1970 and December 2015 in major electronic databases. Two reviewers independently screened articles and extracted information of DOT, treatment success rate and other characteristics of studies. Random effects model was used to calculate the pooled treatment success rate and 95% confidence interval (CI). Sub-group analyses were conducted to access factors associated with successful treatment outcomes.
RESULTS
A total of 31 articles 7,466 participants were included. Studies reporting full DOT (67.4%, 95% CI: 61.4-72.8%) had significantly higher pooled treatment success rates than those reporting self-administration therapy (46.9%, 95% CI: 41.4-52.4%). No statistically difference was found among DOT provided by healthcare providers (65.8%, 95% CI: 55.7-74.7%), family members (72.0%, 95% CI: 31.5-93.5%) and private DOT providers (69.5%, 95% CI: 57.0-79.7%); and neither did we find significantly difference on pooled treatment success rates between patients having health facility based DOT (70.5%, 95% CI: 61.5-78.1%) and home-based DOT (68.4%, 95% CI: 51.5-81.5%).
CONCLUSION
Providing DOT for a full course of treatment associated with a higher treatment success rate in MDR-TB patients.
Topics: Antitubercular Agents; Directly Observed Therapy; Humans; Treatment Outcome; Tuberculosis, Multidrug-Resistant
PubMed: 26930287
DOI: 10.1371/journal.pone.0150511 -
The Lancet. Microbe Feb 2024Clinical bedaquiline resistance predominantly involves mutations in mmpR5 (Rv0678). However, mmpR5 resistance-associated variants (RAVs) have a variable relationship... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Clinical bedaquiline resistance predominantly involves mutations in mmpR5 (Rv0678). However, mmpR5 resistance-associated variants (RAVs) have a variable relationship with phenotypic Mycobacterium tuberculosis resistance. We did a systematic review to assess the maximal sensitivity of sequencing bedaquiline resistance-associated genes and evaluate the association between RAVs and phenotypic resistance, using traditional and machine-based learning techniques.
METHODS
We screened public databases for articles published from database inception until Oct 31, 2022. Eligible studies performed sequencing of at least mmpR5 and atpE on clinically sourced M tuberculosis isolates and measured bedaquiline minimum inhibitory concentrations (MICs). A bias risk scoring tool was used to identify bias. Individual genetic mutations and corresponding MICs were aggregated, and odds ratios calculated to determine association of mutations with resistance. Machine-based learning methods were used to define test characteristics of parsimonious sets of diagnostic RAVs, and mmpR5 mutations were mapped to the protein structure to highlight mechanisms of resistance. This study was registered in the PROSPERO database (CRD42022346547).
FINDINGS
18 eligible studies were identified, comprising 975 M tuberculosis isolates containing at least one potential RAV (mutation in mmpR5, atpE, atpB, or pepQ), with 201 (20·6%) showing phenotypic bedaquiline resistance. 84 (29·5%) of 285 resistant isolates had no candidate gene mutation. Sensitivity and positive predictive value of taking an any mutation approach was 69% and 14%, respectively. 13 mutations, all in mmpR5, had a significant association with a resistant MIC (adjusted p<0·05). Gradient-boosted machine classifier models for predicting intermediate or resistant and resistant phenotypes both had receiver operator characteristic c statistic of 0·73 (95% CI 0·70-0·76). Frameshift mutations clustered in the α1 helix DNA-binding domain, and substitutions in the α2 and α3 helix hinge region and in the α4 helix-binding domain.
INTERPRETATION
Sequencing candidate genes is insufficiently sensitive to diagnose clinical bedaquiline resistance, but where identified, some mutations should be assumed to be associated with resistance. Genomic tools are most likely to be effective in combination with rapid phenotypic diagnostics. This study was limited by selective sampling in contributing studies and only considering single genetic loci as causative of resistance.
FUNDING
Francis Crick Institute and National Institute of Allergy and Infectious Diseases at the National Institutes of Health.
Topics: United States; Humans; Antitubercular Agents; Diarylquinolines; Tuberculosis; Mycobacterium tuberculosis; Genomics
PubMed: 38215766
DOI: 10.1016/S2666-5247(23)00317-8 -
BMC Infectious Diseases Nov 2014Tuberculosis (TB) during pregnancy may lead to severe consequences affecting both mother and child. Prenatal care could be a very good opportunity for TB care,... (Review)
Review
BACKGROUND
Tuberculosis (TB) during pregnancy may lead to severe consequences affecting both mother and child. Prenatal care could be a very good opportunity for TB care, especially for women who have limited access to health services. The aim of this review was to gather and evaluate studies on TB care for pregnant women.
METHODS
We used a combination of the terms "tuberculosis" and "pregnancy", limited to human, to search for published articles. Studies reflecting original data and focusing on TB care for pregnant women were included. All references retrieved were collected using the Reference Manager software (Version 11).
RESULTS
Thirty five studies were selected for review and their data showed that diagnosis was often delayed because TB symptoms during pregnancy were not typical. TB prophylaxis and anti-TB therapy appeared to be safe and effective for pregnant women and their babies when suitable follow up and early initiation were present, but the compliance rate to TB prophylaxis is still low due to lack of follow up and referral services. TB care practices in the reviewed studies were in line in principle with the WHO International Standards for Tuberculosis Care (ISTC).
CONCLUSIONS
Integration of TB care within prenatal care would improve TB diagnosis and treatment for pregnant women. To improve the quality of TB care, it is necessary to develop national level guidelines based on the ISTC with detailed guidelines for pregnant women.
Topics: Antitubercular Agents; Female; Humans; Pregnancy; Pregnancy Complications, Infectious; Prenatal Care; Prenatal Diagnosis; Tuberculosis
PubMed: 25407883
DOI: 10.1186/s12879-014-0617-x -
The Cochrane Database of Systematic... Jun 2013Currently the World Health Organization only recommend fluoroquinolones for people with presumed drug-sensitive tuberculosis (TB) who cannot take standard first-line... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Currently the World Health Organization only recommend fluoroquinolones for people with presumed drug-sensitive tuberculosis (TB) who cannot take standard first-line drugs. However, use of fluoroquinolones could shorten the length of treatment and improve other outcomes in these people. This review summarises the effects of fluoroquinolones in first-line regimens in people with presumed drug-sensitive TB.
OBJECTIVES
To assess fluoroquinolones as substitute or additional components in antituberculous drug regimens for drug-sensitive TB.
SEARCH METHODS
We searched the Cochrane Infectious Diseases Group Specialized Register; CENTRAL (The Cochrane Library 2013, Issue 1); MEDLINE; EMBASE; LILACS; Science Citation Index; Databases of Russian Publications; and metaRegister of Controlled Trials up to 6 March 2013.
SELECTION CRITERIA
Randomized controlled trials (RCTs) of antituberculous regimens based on rifampicin and pyrazinamide and containing fluoroquinolones in people with presumed drug-sensitive pulmonary TB.
DATA COLLECTION AND ANALYSIS
Two authors independently applied inclusion criteria, assessed the risk of bias in the trials, and extracted data. We used the risk ratio (RR) for dichotomous data and the fixed-effect model when it was appropriate to combine data and no heterogeneity was present. We assessed the quality of evidence using the GRADE approach.
MAIN RESULTS
We identified five RCTs (1330 participants) that met the inclusion criteria. None of the included trials examined regimens of less than six months duration. Fluoroquinolones added to standard regimensA single trial (174 participants) added levofloxacin to the standard first-line regimen. Relapse and treatment failure were not reported. For death, sputum conversion, and adverse events we are uncertain if there is an effect (one trial, 174 participants, very low quality evidence for all three outcomes). Fluoroquinolones substituted for ethambutol in standard regimens Three trials (723 participants) substituted ethambutol with moxifloxacin, gatifloxacin, and ofloxacin into the standard first-line regimen. For relapse, we are uncertain if there is an effect (one trial, 170 participants, very low quality evidence). No trials reported on treatment failure. For death, sputum culture conversion at eight weeks, or serious adverse events we do not know if there was an effect (three trials, 723 participants, very low quality evidence for all three outcomes). Fluoroquinolones substituted for isoniazid in standard regimens A single trial (433 participants) substituted moxifloxacin for isoniazid. Treatment failure and relapse were not reported. For death, sputum culture conversion, or serious adverse events the substitution may have little or no difference (one trial, 433 participants, low quality evidence for all three outcomes). Fluoroquinolines in four month regimensSix trials are currently in progress testing shorter regimens with fluoroquinolones.
AUTHORS' CONCLUSIONS
Ofloxacin, levofloxacin, moxifloxacin, and gatifloxacin have been tested in RCTs of standard first-line regimens based on rifampicin and pyrazinamide for treating drug-sensitive TB. There is insufficient evidence to be clear whether addition or substitution of fluoroquinolones for ethambutol or isoniazid in the first-line regimen reduces death or relapse, or increases culture conversion at eight weeks. Much larger trials with fluoroquinolones in short course regimens of four months are currently in progress.
Topics: Antitubercular Agents; Ciprofloxacin; Drug Substitution; Fluoroquinolones; Humans; Levofloxacin; Ofloxacin; Randomized Controlled Trials as Topic; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary
PubMed: 23744519
DOI: 10.1002/14651858.CD004795.pub4 -
Skin Research and Technology : Official... Mar 2024The purpose of this study is to investigate the effectiveness and safety of oral and injectable systemic treatments, such as methotrexate, azathioprine, cyclosporine,... (Review)
Review
AIMS AND OBJECTIVES
The purpose of this study is to investigate the effectiveness and safety of oral and injectable systemic treatments, such as methotrexate, azathioprine, cyclosporine, tofacitinib, baricitinib, corticosteroids, statins, zinc, apremilast, etc., for treating vitiligo lesions.
METHOD
Databases including PubMed, Scopus, and Web of Science were meticulously searched for studies spanning from 2010 to August 2023, focusing on systemic oral and injectable therapies for vitiligo, using comprehensive keywords and search syntaxes tailored to each database. Key data extracted included study design, treatment efficacy, patient outcomes, patient satisfaction, and safety profiles.
RESULTS
In a total of 42 included studies, oral mini-pulse corticosteroid therapy (OMP) was the subject of six studies (14.2%). Minocycline was the focus of five studies (11.9%), while methotrexate, apremilast, and tofacitinib each were examined in four studies (9.5%). Antioxidants and Afamelanotide were the subjects of three studies each (7.1%). Cyclosporine, simvastatin, oral zinc, oral corticosteroids (excluding OMP) and injections, and baricitinib were each explored in two studies (4.8%). Azathioprine, mycophenolate mofetil, and Alefacept were the subjects of one study each (2.4%).
CONCLUSION
Systemic treatments for vitiligo have been successful in controlling lesions without notable side effects. OMP, Methotrexate, Azathioprine, Cyclosporine, Mycophenolate mofetil, Simvastatin, Apremilast, Minocycline, Afamelanotide, Tofacitinib, Baricitinib, Antioxidants, and oral/injectable corticosteroids are effective treatment methods. However, oral zinc and alefacept did not show effectiveness.
Topics: Humans; Methotrexate; Azathioprine; Vitiligo; Mycophenolic Acid; Minocycline; Alefacept; Cyclosporine; Adrenal Cortex Hormones; Hypopigmentation; Simvastatin; Zinc; Purines; Pyrazoles; Sulfonamides; Azetidines; Thalidomide
PubMed: 38454597
DOI: 10.1111/srt.13642 -
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 -
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 -
The European Respiratory Journal Dec 2012Linezolid is used off-label to treat multidrug-resistant tuberculosis (MDR-TB) in absence of systematic evidence. We performed a systematic review and meta-analysis on... (Meta-Analysis)
Meta-Analysis Review
Linezolid is used off-label to treat multidrug-resistant tuberculosis (MDR-TB) in absence of systematic evidence. We performed a systematic review and meta-analysis on efficacy, safety and tolerability of linezolid-containing regimes based on individual data analysis. 12 studies (11 countries from three continents) reporting complete information on safety, tolerability, efficacy of linezolid-containing regimes in treating MDR-TB cases were identified based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Meta-analysis was performed using the individual data of 121 patients with a definite treatment outcome (cure, completion, death or failure). Most MDR-TB cases achieved sputum smear (86 (92.5%) out of 93) and culture (100 (93.5%) out of 107) conversion after treatment with individualised regimens containing linezolid (median (inter-quartile range) times for smear and culture conversions were 43.5 (21-90) and 61 (29-119) days, respectively) and 99 (81.8%) out of 121 patients were successfully treated. No significant differences were detected in the subgroup efficacy analysis (daily linezolid dosage ≤ 600 mg versus >600 mg). Adverse events were observed in 63 (58.9%) out of 107 patients, of which 54 (68.4%) out of 79 were major adverse events that included anaemia (38.1%), peripheral neuropathy (47.1%), gastro-intestinal disorders (16.7%), optic neuritis (13.2%) and thrombocytopenia (11.8%). The proportion of adverse events was significantly higher when the linezolid daily dosage exceeded 600 mg. The study results suggest an excellent efficacy but also the necessity of caution in the prescription of linezolid.
Topics: Acetamides; Adolescent; Adult; Antitubercular Agents; Extensively Drug-Resistant Tuberculosis; Female; Humans; Linezolid; Male; Middle Aged; Oxazolidinones; Patient Safety; Sputum; Treatment Outcome; Tuberculosis, Multidrug-Resistant
PubMed: 22496332
DOI: 10.1183/09031936.00022912 -
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