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The Journal of Antimicrobial... Aug 2020Improved genetic understanding of Mycobacterium tuberculosis (MTB) resistance to novel and repurposed anti-tubercular agents can aid the development of rapid molecular...
Systematic review of mutations associated with resistance to the new and repurposed Mycobacterium tuberculosis drugs bedaquiline, clofazimine, linezolid, delamanid and pretomanid.
BACKGROUND
Improved genetic understanding of Mycobacterium tuberculosis (MTB) resistance to novel and repurposed anti-tubercular agents can aid the development of rapid molecular diagnostics.
METHODS
Adhering to PRISMA guidelines, in March 2018, we performed a systematic review of studies implicating mutations in resistance through sequencing and phenotyping before and/or after spontaneous resistance evolution, as well as allelic exchange experiments. We focused on the novel drugs bedaquiline, delamanid, pretomanid and the repurposed drugs clofazimine and linezolid. A database of 1373 diverse control MTB whole genomes, isolated from patients not exposed to these drugs, was used to further assess genotype-phenotype associations.
RESULTS
Of 2112 papers, 54 met the inclusion criteria. These studies characterized 277 mutations in the genes atpE, mmpR, pepQ, Rv1979c, fgd1, fbiABC and ddn and their association with resistance to one or more of the five drugs. The most frequent mutations for bedaquiline, clofazimine, linezolid, delamanid and pretomanid resistance were atpE A63P, mmpR frameshifts at nucleotides 192-198, rplC C154R, ddn W88* and ddn S11*, respectively. Frameshifts in the mmpR homopolymer region nucleotides 192-198 were identified in 52/1373 (4%) of the control isolates without prior exposure to bedaquiline or clofazimine. Of isolates resistant to one or more of the five drugs, 59/519 (11%) lacked a mutation explaining phenotypic resistance.
CONCLUSIONS
This systematic review supports the use of molecular methods for linezolid resistance detection. Resistance mechanisms involving non-essential genes show a diversity of mutations that will challenge molecular diagnosis of bedaquiline and nitroimidazole resistance. Combined phenotypic and genotypic surveillance is needed for these drugs in the short term.
Topics: Antitubercular Agents; Clofazimine; Diarylquinolines; Humans; Linezolid; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Pharmaceutical Preparations; Tuberculosis, Multidrug-Resistant
PubMed: 32361756
DOI: 10.1093/jac/dkaa136 -
Drugs Feb 2022Brivaracetam (BRV), cenobamate (CNB), eslicarbazepine acetate (ESL), lacosamide (LCM) and perampanel (PER) are antiseizure medications (ASMs) approved for adjunctive... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Brivaracetam (BRV), cenobamate (CNB), eslicarbazepine acetate (ESL), lacosamide (LCM) and perampanel (PER) are antiseizure medications (ASMs) approved for adjunctive treatment of focal-onset seizures. So far, no randomised controlled trial directly compared the efficacy and safety of these drugs.
OBJECTIVE
We estimated the comparative efficacy and safety of these ASMs for the treatment of focal-onset seizures in adults with epilepsy using a network meta-analysis (NMA).
METHODS
We systematically searched (June week 4, 2021) MEDLINE (accessed by PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL), and the US National Institutes of Health Clinical Trials Registry ( http://www.clinicaltrials.gov ). There were no date limitations or language restrictions. Randomised, double-blinded, controlled, parallel-group, add-on studies that compared oral BRV, CNB, ESL, LCM, and PER versus any comparator over maintenance periods of at least 12 weeks and included adult patients with focal seizures uncontrolled by concomitant ASMs were identified. The efficacy outcomes were the proportions of patients with ≥ 50% and 100% reduction in baseline seizure frequency during the maintenance period. The tolerability outcomes were the proportions of participants who experienced at least one treatment-emergent adverse event (TEAE) and experienced at least one TEAE leading to discontinuation. Effect sizes were estimated by network meta-analyses within a frequentist framework. The hierarchy of competing interventions was established using the surface under the cumulative ranking curve (SUCRA).
RESULTS
Sixteen trials (BRV: n = 3, CNB: n = 1, ESL: n = 4, LCM: n = 4, PER: n = 4) were included, overall enrolling 4507 patients randomised to add-on active treatments (BRV = 803, CNB = 221, ESL =9 90, LCM = 1104, and PER = 1389) and 2246 to add-on placebo. Cenobamate was associated with a higher rate of ≥ 50% seizure frequency reduction than BRV [odds ratio (OR) 2.02, 95% confidence interval (CI) 1.11-3.66], ESL (OR 1.93, 95% CI 1.07-3.48), LCM (OR 1.86, 95% CI 1.04-3.32), and PER (OR 2.07, 95% CI 1.16-3.70). There was a not statistically significant trend favouring CNB over ESL, LCM and PER for the seizure freedom outcome. Brivaracetam (OR 0.61, 95% CI 0.44-0.86) and LCM (OR 0.60, 95% CI 0.40-0.88) were associated with a lower proportion of participants experiencing TEAEs compared to ESL, and patients treated with PER were associated with a higher risk to experience at least one TEAE (OR 1.42, 95% CI 1.02-1.96) than BRV. According to SUCRA, CNB had the greatest likelihood of being the best option for the ≥ 50% and 100% seizure frequency reduction, and BRV and LCM had the highest probabilities of being the best-tolerated treatments.
CONCLUSIONS
Cenobamate ranked best for efficacy, and BRV and LCM were best tolerated over the other comparators. Although NMAs cannot replace direct comparisons, they may support physicians in clinical decision making.
Topics: Adult; Anticonvulsants; Carbamates; Chlorophenols; Dibenzazepines; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Lacosamide; Male; Middle Aged; Network Meta-Analysis; Nitriles; Pyridones; Pyrrolidinones; Randomized Controlled Trials as Topic; Seizures; Tetrazoles
PubMed: 35061214
DOI: 10.1007/s40265-021-01661-4 -
Nutrients Oct 2020The prevalence of type 2 diabetes is on the increase worldwide, and it represents about 90% of adults who are diagnosed with diabetes. Overweight and obesity, lifestyle,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The prevalence of type 2 diabetes is on the increase worldwide, and it represents about 90% of adults who are diagnosed with diabetes. Overweight and obesity, lifestyle, genetic predisposition and gut microbiota dysbiosis have been implicated as possible risk factors in the development of type 2 diabetes. In particular, low intake of dietary fibre and consumption of foods high in fat and sugar, which are common in western lifestyle, have been reported to contribute to the depletion of specific bacterial taxa. Therefore, it is possible that intake of high dietary fibre may alter the environment in the gut and provide the needed substrate for microbial bloom.
AIM
The current review is a systematic review and meta-analysis which evaluated the role of dietary fibre in modulating gut microbiota dysbiosis in patients with type 2 diabetes.
METHODS
This is a systematic review and meta-analysis of randomised controlled trials which relied on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework. Electronic searches were conducted using EBSCOHost with links to Health Sciences Research Databases, EMBASE and Google Scholar. The reference lists of articles were also searched for relevant studies. Searches were conducted from date of commencement of the database to 5 August 2020. The search strategy was based on the Population, Intervention, Comparator, Outcomes, Studies (PICOS) framework and involved the use of synonyms and medical subject headings (MesH). Search terms were combined with Boolean operators (OR/AND).
RESULTS
Nine studies which met the inclusion criteria were selected for the systematic review and meta-analysis, and four distinct areas were identified: the effect of dietary fibre on gut microbiota; the role of dietary fibre on short-chain fatty acids (SCFAs); glycaemic control; and adverse events. There was significant difference ( < 0.01) in the relative abundance of Bifidobacterium with a mean difference of 0.72 (95% CI, 0.56, 0.89) between the dietary fibre group compared with placebo. In relation to the meta-analysis for SCFAs, while there was significant difference ( = 0.02) between the dietary fibre group and placebo with a standardised mean difference of 0.5 (95% CI, 0.08, 0.91) regarding total SCFAs, the differences were not significant ( > 0.05) in relation to acetic acid, propionic acid and butyric acid. There was only significant improvement ( = 0.002) with respect to glycated haemoglobin with a mean difference of -0.18 (95% CI, -0.29, -0.06) between the dietary fibre group and placebo group. Differences between the two groups were not significant ( > 0.05) in relation to fasting blood glucose and homeostatic model assessment of insulin resistance (HOMA-IR). Furthermore, there were no significant differences between the two groups in subjects who reported adverse events. It is possible that the promotion of SCFA producers in greater diversity and abundance by dietary fibre in this review led to improvement in glycated haemoglobin, partly due to increased glucagon-like peptide-1 (GLP-1) production. In addition, Bifidobacterium lactis has been reported to increase glycogen synthesis, decrease expression of hepatic gluconeogenesis genes, improve translocation of glucose transport-4 and promote glucose uptake. It is also possible that the reduction in body weight of participants in the intervention group compared with control may have contributed to the observed improvement in glycated haemoglobin.
CONCLUSION
This systematic review and meta-analysis have demonstrated that dietary fibre can significantly improve ( < 0.05) the relative abundance of Bifidobacterium, total SCFAs and glycated haemoglobin. However, dietary fibre did not appear to have significant effect ( > 0.05) on fasting blood glucose, HOMA-IR, acetic acid, propionic acid, butyric acid and adverse events.
Topics: Adult; Diabetes Mellitus, Type 2; Dietary Fiber; Dysbiosis; Fatty Acids, Volatile; Female; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Glycated Hemoglobin; Glycemic Control; Humans; Male; Randomized Controlled Trials as Topic
PubMed: 33113929
DOI: 10.3390/nu12113239 -
Epileptic Disorders : International... Dec 2022We carried out a systematic review of published information on transfer of antiseizure medications (ASMs) into breastmilk, ASM serum concentrations in breastfed infants,...
We carried out a systematic review of published information on transfer of antiseizure medications (ASMs) into breastmilk, ASM serum concentrations in breastfed infants, and the wellbeing of infants breastfed by mothers on ASM treatment. Information was extracted from 85 relevant articles. No data on ASM levels in breastmilk or in breastfed infants was identified for cannabidiol, cenobamate, clobazam, eslicarbazepine-acetate, everolimus, felbamate, fenfluramine, retigabine, rufinamide, stiripentol, tiagabine, and vigabatrin. For ASMs, with available information on levels in breastfed infants, very low concentrations (in the order of 10% or less of maternal serum concentrations) were reported for carbamazepine, gabapentin, levetiracetam, oxcarbazepine, phenytoin, valproate, and clonazepam. Slightly higher levels (up to approximately 30% of maternal serum concentrations) have been observed with lamotrigine and topiramate, and in single case reports for brivaracetam, lacosamide, and perampanel. High infant levels (30% up to 100% of maternal serum concentrations) have been reported with ethosuximide, phenobarbital and zonisamide. Adverse infant effects during breastfeeding by mothers on ASMs appear to be rare regardless of the type of ASM, but systematic study is limited. Prospective long-term follow-up studies of developmental outcomes among children who have been breastfed by mothers taking ASMs are sparse and have mainly involved children whose mothers were taking carbamazepine, lamotrigine, levetiracetam, phenytoin or valproate as monotherapy while breastfeeding. Although these studies have not indicated poorer outcome among breastfed children compared with those who were not breastfed, further data on long-term outcomes are needed to draw firm conclusions. It is concluded that breastfeeding should in general be encouraged in women taking ASMs, given the well-established benefits of breastfeeding with regard to both short- and long-term infant health in the general population. Counselling needs to be individualized including information on the current knowledge regarding the woman's specific ASM treatment.
Topics: Breast Feeding; Cannabidiol; Carbamazepine; Child; Clobazam; Clonazepam; Epilepsy; Ethosuximide; Everolimus; Felbamate; Female; Fenfluramine; Gabapentin; Humans; Infant; Lacosamide; Lamotrigine; Levetiracetam; Oxcarbazepine; Phenobarbital; Phenytoin; Prospective Studies; Tiagabine; Topiramate; Valproic Acid; Vigabatrin; Zonisamide
PubMed: 36193017
DOI: 10.1684/epd.2022.1492 -
Diabetes Research and Clinical Practice Aug 2023The effect of fecal microbiota transplantation (FMT) on microbiota engraftment in patients with metabolic syndrome remains unclear. This systematic review employed a... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
The effect of fecal microbiota transplantation (FMT) on microbiota engraftment in patients with metabolic syndrome remains unclear. This systematic review employed a meta-analysis of RCTs for assessment on the role of FMT in treating obesity and metabolic syndrome, and its impact on clinically relevant parameters.
METHOD
Major databases and grey literatures were searched identifying RCTs comparing FMT of lean donors with placebo in obese/metabolic syndrome patients. Studies using any form of placebo were included. Variations in the parameters before and after treatment were calculated followed by meta-analyses.
RESULT
Ten studies met the inclusion criteria and a total of 334 patients were included for further analysis. Clinically significant parameters associated with obesity and metabolic syndrome were explored and FMT was identified significantly and negatively associated with most indices of abdominal adiposity including caloric intake, fasting glucose, HOMA-IR, systolic blood pressure, diastolic blood pressure, total cholesterol, HDL, LDL, triglycerides and CRP, Obesity parameters including fasting glucose and acetic acid were increased following FMT.
CONCLUSION
FMT is more advantageous for obese patients with elevated blood pressure, disordered glucose and insulin metabolism, and elevated blood lipids. The study of metabolic factors in obese patients will be our starting point in the future.
Topics: Humans; Fecal Microbiota Transplantation; Metabolic Syndrome; Obesity; Glucose; Lipids
PubMed: 37356723
DOI: 10.1016/j.diabres.2023.110803 -
European Respiratory Review : An... Dec 2023Methicillin-resistant (MRSA) is responsible for an array of problematic community- and healthcare-acquired infections, including pneumonia, and is frequently associated... (Review)
Review
Methicillin-resistant (MRSA) is responsible for an array of problematic community- and healthcare-acquired infections, including pneumonia, and is frequently associated with severe disease and high mortality rates. Standard recommended treatments for empiric and targeted coverage of suspected MRSA in patients with community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP), including ventilator-associated pneumonia (VAP), are vancomycin and linezolid. However, adverse events such as acute kidney injury and infection have been associated with these antibiotics. Ceftaroline fosamil is a β-lactam/extended-spectrum cephalosporin approved for the treatment of adults and children with CAP and complicated skin and soft tissue infections. Ceftaroline has activity against a range of common Gram-positive bacteria and is distinct among the β-lactams in retaining activity against MRSA. Due to the design of the pivotal randomised controlled trials of ceftaroline fosamil, outcomes in patients with MRSA CAP were not evaluated. However, various reports of real-world outcomes with ceftaroline fosamil for pneumonia caused by MRSA, including CAP and HAP/VAP, been published since its approval. A systematic literature review and qualitative analysis of relevant publications was undertaken to collate and summarise relevant published data on the efficacy and safety of ceftaroline fosamil in patients with MRSA pneumonia. While relatively few real-world outcomes studies are available, the available data suggest that ceftaroline fosamil is a possible alternative to linezolid and vancomycin for MRSA pneumonia. Specific scenarios in which ceftaroline fosamil might be considered include bacteraemia and complicating factors such as empyema.
Topics: Adult; Child; Humans; Methicillin-Resistant Staphylococcus aureus; Linezolid; Vancomycin; Cephalosporins; Anti-Bacterial Agents; Community-Acquired Infections; Pneumonia, Ventilator-Associated; Ceftaroline
PubMed: 37852658
DOI: 10.1183/16000617.0117-2023 -
World Journal of Pediatrics : WJP Feb 2023We aimed to evaluate the tolerability and efficacy of linezolid in children for treating suspected and diagnosed Gram-positive bacterial infections. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
We aimed to evaluate the tolerability and efficacy of linezolid in children for treating suspected and diagnosed Gram-positive bacterial infections.
METHODS
A systematic literature search was conducted up to April 23, 2021, using linezolid and its synonyms as search terms. Two reviewers independently identified and extracted relevant randomized controlled trials and prospective cohort studies. The extracted studies were included in a single-rate meta-analysis of adverse events and clinical outcomes using random-effects models.
RESULTS
A total of 1082 articles were identified, and nine studies involving 758 children were included in the meta-analysis. The overall proportion of adverse events was 8.91% [95% confidence interval (CI) = 1.64%-36.52%], with diarrhea (2.24%), vomiting (2.05%), and rash (1.72%) being the most common. The incidences of thrombocytopenia and anemia were 0.68% and 0.16%, respectively. Some specific adverse events, including rash and gastrointestinal events, were more frequent in the oral administration subgroup. In terms of efficacy, the overall proportion of clinical improvement was 88.80% (95% CI = 81.31%-93.52%). Children with a history of specific bacteriological diagnosis or concomitant antibiotic therapy had a 1.13-fold higher clinical improvement than children without such histories. The proportion of microbial eradication was 92.68% (95% CI = 84.66%-96.68%). The proportion of all-cause mortality was 0.16% (95% CI = 0.00%-7.75%).
CONCLUSIONS
Linezolid was well-tolerated in pediatric patients and was associated with a low frequency of adverse events, such as anemia, thrombocytopenia, and neutropenia. Moreover, linezolid was effective in children with diagnosed and suspected Gram-positive infections.
Topics: Child; Humans; Linezolid; Prospective Studies; Anti-Bacterial Agents; Treatment Outcome; Diarrhea
PubMed: 36562929
DOI: 10.1007/s12519-022-00650-1 -
Investigative Ophthalmology & Visual... Aug 2021Diabetic retinopathy (DR), a common microvascular complication of diabetes, is the leading cause of acquired blindness in the working-age population. Individuals with...
PURPOSE
Diabetic retinopathy (DR), a common microvascular complication of diabetes, is the leading cause of acquired blindness in the working-age population. Individuals with diabetes still develop DR despite appropriate glycemic and blood pressure control, highlighting the pressing need to identify useful biomarkers for risk stratification. The purpose of this review is to systematically summarize potential metabolic biomarkers and pathways of DR, which could facilitate developing an understanding of the disease mechanisms, as well as new therapeutic measures.
METHODS
We searched PubMed and Web of Science for relevant metabolomics studies on humans published before September 30, 2020. Information regarding authors, title, publication date, study subjects, analytical platforms, methods of statistical analysis, biological samples, directions of change of potential metabolic biomarkers, and predictive values of metabolic biomarker panels was extracted, and the quality of the studies was assessed. Pathway analysis, including enrichment analysis and topology analysis, was derived from integrating differential metabolites using MetaboAnalyst 3.0, based on the Kyoto Encyclopedia of Genes and Genomes and Human Metabolome Database.
RESULTS
We found nine studies focused on the identification of potential biomarkers. Repeatedly identified metabolites including l-glutamine, l-lactic acid, pyruvic acid, acetic acid, l-glutamic acid, d-glucose, l-alanine, l-threonine, citrulline, l-lysine, and succinic acid were found to be potential biomarkers of DR. It was observed that l-glutamine and citrulline changed in all biological samples. Dysregulation of metabolic pathways involved amino acid and energy metabolism.
CONCLUSIONS
This review summarizes potential biomarkers and metabolic pathways, providing insights into new pathogenic pathways for this microvascular complication of diabetes.
Topics: Biomarkers; Diabetic Retinopathy; Humans; Metabolic Networks and Pathways; Metabolome; Metabolomics
PubMed: 34347011
DOI: 10.1167/iovs.62.10.4 -
Epilepsy & Behavior : E&B Jun 2022New-onset movement disorders have been frequently reported in association with the use of antiseizure medications (ASMs). The frequency of specific motor manifestations... (Review)
Review
New-onset movement disorders have been frequently reported in association with the use of antiseizure medications (ASMs). The frequency of specific motor manifestations and the spectrum of their semiology for various ASMs have not been well characterized. We carried out a systematic review of literature and conducted a search on CINAHL, Cochrane Library, EMBASE, MEDLINE, PsycINFO, and Scopus from inception to April 2021. We compiled the data for all currently available ASMs using the conventional terminology of movement disorders. Among 5123 manuscripts identified by the search, 437 met the inclusion criteria. The largest number of reports of abnormal movements were in association with phenobarbital, valproic acid, lacosamide, and perampanel, and predominantly included tremor and ataxia. The majority of attempted interventions for all agents were discontinuation of the offending drug or dose reduction which led to the resolution of symptoms in most patients. Familiarity with the movement disorder phenomenology previously encountered in relation with specific ASMs facilitates early recognition of adverse effects and timely institution of targeted interventions.
Topics: Anticonvulsants; Humans; Lacosamide; Movement Disorders; Phenobarbital; Valproic Acid
PubMed: 35483204
DOI: 10.1016/j.yebeh.2022.108693 -
Cancers May 2022Cervical dysplasia is a common precancerous lesion affecting 1% to 2% of women worldwide. Significant progress in the diagnosis and treatment of cervical dysplasia have... (Review)
Review
Cervical dysplasia is a common precancerous lesion affecting 1% to 2% of women worldwide. Significant progress in the diagnosis and treatment of cervical dysplasia have been made in the last decade. We performed a systematic literature search of the databases PubMed and Cochrane Central Register of Controlled Trials to identify controlled clinical trials reporting on the efficacy and safety of diagnostic and therapeutic interventions for cervical dysplasia. Data were analyzed according to PRISMA guidelines. In total, 33 studies reporting on 5935 women were identified. We recommend intravenous or intracervical lidocaine for pain reduction during colposcopically-directed cervical biopsies but not topical lidocaine, music, or video colposcopy. Monsel’s solution might be used to control bleeding after cervical biopsies. The acetic acid test should be scored 1 min after the application of acetic acid and should be followed by Lugol’s iodine test for an optimal yield of LSIL/HSIL. LEEP/LLETZ remains the standard and techniques such as SWETZ, C-LETZ, and TCBEE are not superior. LEEP/LLETZ should be performed under local anesthesia and with direct colposcopic vision. Cryotherapy and thermoablation might be used in women with LSIL, especially in women with HIV infection, but LEEP/LLETZ remains the standard for HSIL. Topical imiquimod remains an experimental procedure. In conclusion, significant progress has been made in the last decade regarding both diagnostic interventions as well as therapeutic interventions for women with cervical dysplasia. Based on >30 controlled clinical trials, we were able to formulate specific and evidence-based recommendations.
PubMed: 35681649
DOI: 10.3390/cancers14112670