Journal of Antimicrobial Chemotherapy最新文献

{"title":"The aphA1 kanamycin and neomycin resistance gene originated in Klebsiella michiganensis.","authors":"Robert A Moran, Ruth M Hall","doi":"10.1093/jac/dkaf372","DOIUrl":"https://doi.org/10.1093/jac/dkaf372","url":null,"abstract":"<p><strong>Background: </strong>The origins of several antibiotic resistance genes have been traced to intrinsic genes present in bacterial chromosomes. The aphA1 gene, which confers resistance to the aminoglycosides kanamycin and neomycin, is commonly found in diverse Gram-negative bacterial pathogens, and is associated with several different mobile genetic elements. However, its origin had not been identified.</p><p><strong>Objectives: </strong>To determine whether the aphA1-containing segments in novel compound and pseudo-compound transposons found in three historic plasmids, pIE545, R478 and Rts1, are found in the chromosome of a specific bacterial species.</p><p><strong>Methods: </strong>Passenger segments of transposons containing the aphA1 gene were compared to one another and to chromosomal sequences in GenBank using BLAST.</p><p><strong>Results: </strong>In pIE545, aphA1 is in a 5424 bp compound transposon, TnaphA1-pIE545, that is bounded by directly oriented copies of IS102. The 3.3 kb aphA1-containing passenger segment is >99% identical to a contiguous part of several Klebsiella michiganensis chromosomes. The 4.3 kb aphA1-containing segment of the IS26-bounded pseudo-compound transposon PTnaphA1-R478 in R478 is also >99% identical to a contiguous part of several K. michiganensis chromosomes that differ in the gene content surrounding aphA1. The 2.2 kb passenger segment of the IS26-bounded PTn2680 from Rts1 arose via a third independent acquisition from a K. michiganensis chromosome.</p><p><strong>Conclusions: </strong>The aphA1 gene has been captured and mobilized on at least three occasions from K. michiganensis chromosomes with related but distinct surrounding configurations.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Is ampicillin plus cephalosporins a therapeutic option for Ampicillin-Susceptible Enterococcus faecium?","authors":"Paula Bierge, Inmaculada Gómez-Sánchez, Cristina Garcia de la Mària, Miquel Sánchez-Osuna, Silvia Capilla, Antonio Casabella, Mateu Espasa, Carla Novais, Jose M Miró, Oscar Q Pich, Oriol Gasch","doi":"10.1093/jac/dkaf226","DOIUrl":"10.1093/jac/dkaf226","url":null,"abstract":"<p><strong>Objectives: </strong>Enterococcus faecium, a significant hospital associated pathogen, poses substantial treatment challenges. While combinations of ampicillin with cephalosporins are first-line therapies to treat Enterococcus faecalis high-mortality-rates infections, their efficacy against ampicillin-susceptible E. faecium (ASEfm) is less clear. This study evaluates the effectiveness of combining ampicillin with ceftriaxone or ceftaroline against ASEfm strains.</p><p><strong>Methods: </strong>Ten ASEfm bloodstream isolates from complicated infections were analyzed. Susceptibility to several antibiotics, including ceftriaxone, ceftaroline, and cefotaxime, was determined using standard methods. Time-kill assays were conducted to assess the synergistic and additive effects of ampicillin in combination with ceftriaxone or ceftaroline.</p><p><strong>Results: </strong>Time-kill studies revealed that ampicillin combined with ceftaroline demonstrated synergistic and/or additive effects in 7 out of 10 strains analyzed. In contrast, ampicillin combined with ceftriaxone showed less pronounced synergy, with only 3 out of 10 strains exhibiting synergistic and/or additive effects.</p><p><strong>Conclusions: </strong>Our findings indicate that ampicillin combined with ceftaroline, or ceftriaxone provides synergistic activity against some but not all ASEfm clinical isolates. The observed synergy suggests that these combinations could offer a potential therapeutic option for challenging ASEfm infections.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":"2622-2629"},"PeriodicalIF":3.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12494129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144835164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Global prevalence of nitrofurantoin-resistant uropathogenic Escherichia coli (UPEC) in humans: a systematic review and meta-analysis.","authors":"Christopher Larkin, Sabeel P Valappil, Navaneethan Palanisamy","doi":"10.1093/jac/dkaf305","DOIUrl":"10.1093/jac/dkaf305","url":null,"abstract":"<p><strong>Background: </strong>The global rise in antimicrobial resistance (AMR) is a significant health concern. Nitrofurantoin is used as a first-line antibiotic against many uropathogenic bacterial pathogens, including uropathogenic Escherichia coli (UPEC), and an analysis is required to assess the current global prevalence of nitrofurantoin-resistant UPEC.</p><p><strong>Methods: </strong>Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a literature search using PubMed and Google Scholar was performed to find studies reporting nitrofurantoin-resistant UPEC in humans. Studies were included/excluded based on predefined criteria and focused only on isolates collected from the urinary tract. The quality of the studies was assessed using the Joanna Briggs Institute's (JBI's) Checklist for Prevalence Studies. Statistical analysis was performed using Metafor and Meta (R packages) to estimate the pooled prevalence, assess publication bias and perform heterogeneity analysis.</p><p><strong>Results: </strong>Sixty-three studies comprising 774 499 UPEC isolates collected between 1996 and 2024 were analysed and demonstrated a global pooled prevalence of nitrofurantoin-resistant UPEC isolates to be 6.9% (95% CI: 4.8%-9.7%). Continent-wise subgroup analysis showed Europe to have the lowest prevalence, while Asia has the highest prevalence. Decade-wise subgroup analysis showed the global prevalence increased from 2.8% (1996-04) to 8.2% (2005-14) and then decreased to 7.6% in the last decade (2015-24). Substantial heterogeneity was seen among the studies examined, as well as statistically significant publication bias.</p><p><strong>Conclusions: </strong>The findings show considerable global prevalence of nitrofurantoin-resistant UPEC isolates, with the prevalence being higher in low- and middle-income countries (LMICs). Sufficient education should be provided where possible, and antimicrobial stewardship should be intensified to slow the rate of AMR increase worldwide.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":"2609-2621"},"PeriodicalIF":3.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12494140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144955190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oritavancin in a patient with recurrent endocarditis by Enterococcus faecalis: a new therapeutic option?","authors":"Giulia Turicchi, Marco Bongiovanni","doi":"10.1093/jac/dkaf215","DOIUrl":"10.1093/jac/dkaf215","url":null,"abstract":"","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":"2873-2874"},"PeriodicalIF":3.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative outcomes of polymyxins in neurocritical care patients with carbapenem-resistant Gram-negative bacterial pneumonia: a retrospective cohort study.","authors":"Qian Zeng, Huawei Huang, Jiaqi Lu, Lei Wu, Shaolan Zhang, Jingwei Zhao, Guangqiang Chen, Guangzhi Shi","doi":"10.1093/jac/dkaf295","DOIUrl":"10.1093/jac/dkaf295","url":null,"abstract":"<p><strong>Objectives: </strong>The spread of carbapenem-resistant Gram-negative bacteria (CR-GNB) related to nosocomial infections is an important public health challenge, and polymyxins have become the last line of defence against CR-GNB. In this study, we aimed to compare the efficacy and safety of different polymyxins.</p><p><strong>Methods: </strong>This retrospective cohort study included neurocritical care patients with CR-GNB pneumonia. The efficacy and safety were compared in original and inverse probability of treatment weighting cohorts. A subgroup analysis was further conducted to explore the impact of augmented renal clearance status at baseline on treatment efficacy.</p><p><strong>Results: </strong>Of the 331 patients included, 90 received colistin sulphate, 187 received polymyxin B, and 54 received colistin methanesulfonate sodium. Compared with colistin sulphate, colistin methanesulfonate sodium significantly reduced the clinical failure rate on Day 7 (20.8% versus 37.2%, P = 0.034) and 28-day mortality rate (6.2% versus 16.9%, P = 0.013) and improved the microbiological eradication rate on Day 28 (94.8% versus 84.2%, P = 0.013). The colistin methanesulfonate sodium group also had a lower mortality rate (6.2% versus 15.7%, P = 0.005) and clinical failure rate on Day 28 (17.1% versus 27.4%, P = 0.020) than the polymyxin B group. However, colistin methanesulfonate sodium was more nephrotoxic than colistin sulphate and polymyxin B (P = 0.001 and P = 0.004, respectively). Subgroup analysis revealed no statistical difference in clinical failure rate and mortality risk between the three groups.</p><p><strong>Conclusions: </strong>For CR-GNB pneumonia in neurocritical care patients, intravenous colistin methanesulfonate sodium may provide a useful treatment option, but vigilance is warranted for nephrotoxicity.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":"2759-2772"},"PeriodicalIF":3.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144835184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Outcomes of ceftriaxone 2 g versus 1 g daily in hospitalized patients with pneumonia: a nationwide retrospective cohort study-right to reply-authors' response.","authors":"Jumpei Taniguchi, Shotaro Aso, Hideo Yasunaga","doi":"10.1093/jac/dkaf327","DOIUrl":"10.1093/jac/dkaf327","url":null,"abstract":"","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":"2885-2886"},"PeriodicalIF":3.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145015449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systematic reviews and the Journal of Antimicrobial Chemotherapy; past, present and future. A systematic reappraisal.","authors":"James C Hurley","doi":"10.1093/jac/dkaf282","DOIUrl":"10.1093/jac/dkaf282","url":null,"abstract":"<p><p>Since 2003, >200 systematic reviews (SRs) have been published in the Journal of Antimicrobial Chemotherapy (JAC). Many have been widely cited. Guidelines for proper execution were outlined in 2005. Since then, new threats, challenges and methods have emerged. Data provenance is an emerging threat. There are several assumptions and limitations of both SR methods and the primary studies they include. The pivotal impact of these assumptions is illustrated using 13 SRs of pneumonia prevention in ICU patients on inferences towards the aspirational goal of 'Pneumonia zero' as a case study. Depending on these assumptions, the SRs of antimicrobial-based interventions pivot between two not incompatible inferences of pneumonia prevention for individual ICU patients versus harm for ICU populations. The case study highlights how newer methods for data visualization enhance reader insight into the underlying data beyond the summary effect size. To remain relevant to evidence-based medicine, SRs will need to adapt to emerging challenges and to recognize and validate the key underlying assumptions. This is especially so for antimicrobial-based infection prevention interventions given their potential for spillover effects.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":"2587-2596"},"PeriodicalIF":3.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12494136/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144955264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interlaboratory comparison of a dried blood spot assay for antiretroviral adherence: implications for clinical application.","authors":"Nathan Engel, Craig Sykes, Amanda P Schauer, Angela D M Kashuba, Peter L Anderson, Lane R Bushman, Mackenzie L Cottrell","doi":"10.1093/jac/dkaf279","DOIUrl":"10.1093/jac/dkaf279","url":null,"abstract":"<p><strong>Background and objectives: </strong>The active metabolites of HIV pre-exposure prophylaxis (PrEP)-tenofovir-diphosphate and emtricitabine-triphosphate-can be measured in dried blood spots (DBSs) to monitor patient adherence. To this end, multiple HPLC-MS/MS assays have been developed. To inform DBS clinical application by characterizing (i) bias between two HPLC-MS/MS approaches (direct versus indirect measurement) to quantify tenofovir-diphosphate/emtricitabine-triphosphate in DBS; and (ii) room temperature (RT) storage stability.</p><p><strong>Methods: </strong>Thirty-eight DBS cards from adults taking emtricitabine/tenofovir disoproxil fumarate or emtricitabine/tenofovir alafenamide for PrEP were analysed by UNC Clinical Pharmacology and Analytical Chemistry Core (CPAC) and Colorado Antiviral Pharmacology Laboratory (CAVP) using published methods. Samples were selected from larger clinical trial datasets to represent a wide range of clinically relevant concentrations. CPAC extracts one 3 mm DBS punch using a directly measured metabolite method, whereas CAVP extracts either one 3 mm (emtricitabine/tenofovir disoproxil fumarate) or two 7 mm (emtricitabine/tenofovir alafenamide) DBS punches using an indirect method. Concentrations were converted to fmol/mm². Bias was assessed by CPAC:CAVP concentration ratios and linear regression. Percent change versus time at RT was fit to a nonlinear regression model.</p><p><strong>Results: </strong>CPAC tenofovir-diphosphate was higher [median (IQR) ratio = 1.60 (1.38-1.75)] correlating strongly with CAVP (r2 = 0.97). CPAC emtricitabine-triphosphate was similar [median (IQR) = 1.08 (1.05-1.20)] and correlated (r2 = 0.90) only for CAVP's 3 mm assay. Tenofovir-diphosphate/emtricitabine-triphosphate RT decay fit a three-parameter exponential decay model (r2 = 0.87).</p><p><strong>Conclusions: </strong>A 1.6-fold bias adjustment is needed for tenofovir-diphosphate concentrations between assays. When punch size is matched, emtricitabine-triphosphate adjustment is unnecessary, otherwise variability confounds comparison. Bias and stability adjustments aid clinical interpretation for real-world application of this adherence monitoring technique.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":"2727-2731"},"PeriodicalIF":3.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12494132/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144835163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Studying intrapulmonary pharmacokinetics for tuberculosis treatment: a systematic review of methodology.","authors":"Isabella van der Feltz, Haini Wen, Rob E Aarnoutse, Cecile Magis-Escurra, Elin M Svensson, Lindsey H M Te Brake","doi":"10.1093/jac/dkaf274","DOIUrl":"10.1093/jac/dkaf274","url":null,"abstract":"<p><strong>Objectives: </strong>Drug concentrations at the site of disease in pulmonary tuberculosis (TB) remain limitedly available, while adequate exposures of anti-TB drugs in the lungs are required for sterilization of lesions. Intrapulmonary concentration data could benefit TB treatment optimization. We conducted a systematic review to identify methods that can be used for sampling, quantifying, describing and predicting intrapulmonary pharmacokinetics of anti-TB drugs in humans.</p><p><strong>Methods: </strong>Two systematic search strategies were conducted in databases Embase and PubMed, last searched on 18 July 2024. In total, 253 studies were identified, and their applied methods were classified into three different categories: (i) sampling techniques, (ii) quantitative analysis and (iii) modelling methods. All types of pulmonary diseases were included in the search.</p><p><strong>Results: </strong>Sputum sampling was reported as sampling method in nine studies, tissue biopsy in 51, bronchoalveolar lavage in 115, bronchoscopic microsampling in eight, bronchoabsorption in one and microdialysis in 12 studies. LC-MS/MS, the gold standard for drug quantification in biological samples, was used in 67 studies. Other quantification methods included positron emission tomography, reported in 12 studies and matrix-assisted laser desorption ionization mass spectrometry on lung tissue in three studies. For prediction and description of (pre)clinical intrapulmonary concentration data, population pharmacokinetic modelling was reported in 32 studies and physiologically based pharmacokinetic modelling in 35 studies.</p><p><strong>Conclusions: </strong>Many of the identified methods are associated with considerable limitations including invasiveness, complexity, cost and lack of standardization. Most importantly, the method of choice must provide adequate representation of site of disease pharmacokinetics. Determining the best approach for studying intrapulmonary pharmacokinetics involves careful consideration of all these factors.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":"2597-2608"},"PeriodicalIF":3.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12494137/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144846595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical impact of the BCID2 and rapid AST VITEK® REVEALTM on antibiotic optimisation in critically ill patients with Gram-negative bloodstream infections: a quasi-experimental pre/post interventional study.","authors":"Louis Oudiane, Massinissa Benyahia, Florian Salipante, Adeline Dubois, Laurent Muller, Jean-Philippe Lavigne, Alix Pantel, Claire Roger","doi":"10.1093/jac/dkaf271","DOIUrl":"10.1093/jac/dkaf271","url":null,"abstract":"<p><strong>Background: </strong>Rapid diagnostic tools (RDT), together with rapid antimicrobial susceptibility testing (rAST), have emerged as means to shorten the time to pathogen identification and AST for bloodstream infections (BSI). Whether these techniques significantly impact antimicrobial therapy in critically ill patients with BSI remains to be determined.</p><p><strong>Methods: </strong>A single-center quasi-experimental study comparing antibiotic optimisation before and after the implementation of innovative RDT, BIOFIRE® Blood Culture Identification 2 (BCID2) Panel and VITEK® REVEALTM (bioMérieux), was conducted. All adult patients admitted to the intensive care unit (ICU) with a first episode of Gram-Negative Bacilli BSI were included in the study. The primary outcome was the proportion of patients receiving optimized antibiotic therapy within 24 h of blood culture incubation.</p><p><strong>Results: </strong>A total of 100 patients, 50 in each study period, were included. The proportion of patients receiving optimized antibiotic therapy within 24 h of blood culture incubation was not significantly different in the post-interventional (28%) compared with the pre-interventional group (20%) (P = 0.3). When considering antibiotic therapy optimisation within 24 h of positive blood culture, the proportion of patients with optimized antibiotic therapy was significantly higher in the post-intervention group (46% versus 26%, P = 0.037). The time to optimisation in the RDT group was shorter than in the conventional group, 27 h versus 46 h, respectively (P < 0.001).</p><p><strong>Conclusions: </strong>The real-world implementation of RDT significantly shortened time to results but did not improve antibiotic therapy optimisation within 24 h of blood culture incubation. An antimicrobial stewardship programme could help enhance the clinical impact of RDT.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":"2665-2675"},"PeriodicalIF":3.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144775431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}