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Antimicrobial Agents and Chemotherapy

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https://www.readbyqxmd.com/read/28807923/pbp4-mediates-%C3%AE-lactam-resistance-by-altered-function
#1
Som S Chatterjee, Liang Chen, Aubre Gilbert, Thaina M da Costa, Vinod Nair, Sandip K Datta, Barry N Kreiswirth, Henry F Chambers
Penicillin Binding Protein 4 (PBP4) can provide high-level β-lactam resistance in S. aureus A series of missense and promoter mutations associated with pbp4 were detected in strains that displayed high-level resistance. We hereby show that the missense mutations facilitate the β-lactam resistance mediated by PBP4 and the promoter mutations lead to the overexpression of pbp4 Our results also suggest a co-operative interplay between PBPs for β-lactam resistance.
August 14, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28807922/are-standard-doses-of-piperacillin-in-piperacillin-tazobactam-regimens-adequate-for-the-management-of-febrile-neutropenia-answers-from-population-pharmacokinetic-modelling-and-monte-carlo-simulations
#2
Fekade Bruck Sime, Uwe Hahn, Morgyn S Warner, Ing Soo Tiong, Michael S Roberts, Jeffrey Lipman, Sandra L Peake, Jason A Roberts
Changes in the pharmacokinetics of piperacillin in febrile neutropenic patients have been reported to result in sub-optimal exposures. This study aimed to develop a population pharmacokinetic model for piperacillin and perform dosing simulation to describe optimal dosing regimens for haematological malignancy patients with febrile neutropenia. Concentration-time data were obtained from previous prospective observational pharmacokinetic and interventional therapeutic drug monitoring studies. Non-parametric population pharmacokinetic analysis and Monte Carlo dosing simulations were performed with Pmetrics® package for R...
August 14, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28807921/candida-albicans-swi-snf-and-mediator-complexes-differentially-regulate-mrr1-induced-mdr1-expression-and-fluconazole-resistance
#3
Zhongle Liu, Lawrence C Myers
Long-term azole treatment of patients with chronic Candida albicans infections can lead to drug resistance. Gain-of-function (GOF) mutations in the transcription factor Mrr1 and the consequent transcriptional activation of MDR1, a drug efflux coding gene, is a common pathway by which this human fungal pathogen acquires fluconazole resistance. This work elucidates the previously unknown downstream transcription mechanisms utilized by hyperactive Mrr1. We've identified the Swi/Snf chromatin remodeling complex as a key co-activator for Mrr1, which is required to maintain basal and induced 'open' chromatin, and Mrr1 occupancy, at the MDR1 promoter...
August 14, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28807920/mediator-tail-module-is-required-for-tac1-activated-cdr1-expression-and-azole-resistance-in-candida-albicans
#4
Zhongle Liu, Lawrence C Myers
The human fungal pathogen Candida albicans develops drug resistance after long-term exposure to azole drugs in the treatment of chronic candidiasis. Gain-of-function (GOF) mutations in the transcription factor Tac1, and the consequent expression of its targets, drug efflux pumps Cdr1 and Cdr2, are a common mechanism by which C. albicans acquires fluconazole resistance. The mechanism by which GOF mutations hyperactivate Tac1 is currently unknown. Here, we define a transcriptional activation domain (TAD) at the C-terminus of Tac1...
August 14, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28807919/drug-susceptibility-and-replicative-capacity-of-multi-drug-resistant-recombinant-human-cytomegalovirus-harboring-mutations-in-ul56-and-ul54-genes
#5
Jocelyne Piret, Nathalie Goyette, Guy Boivin
Letermovir is an investigational antiviral agent with a novel mechanism of action involving the viral terminase (pUL56). We evaluated the impact of V236M mutation in UL56 gene alone and combined with E756K mutation in UL54 gene on drug susceptibility and viral replicative capacity of recombinant human cytomegalovirus. The double mutant exhibited at least borderline resistance to all antivirals tested (ganciclovir, foscarnet, cidofovir, brincidofovir and letermovir) and replicated less efficiently than the wild-type virus in vitro...
August 14, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28807918/relationships-of-vancomycin-pharmacokinetics-to-body-size-and-composition-by-computed-tomography-analysis-a-novel-pharmacomorphomic-approach
#6
Manjunath P Pai, Brian A Derstine, Matt Lichty, Brian E Ross, June Sullivan, Grace L Su, Stewart C Wang
Antibiotics such as vancomycin are empirically dosed on body weight, which may not be optimal across the expanding adult body size distribution. Our aim was to compare the relationships between morphomic parameters generated from computed tomography images to conventional body size metrics as predictors of vancomycin pharmacokinetics (PK). This single center retrospective study included 300 patients with 1622 vancomycin concentration (52% trough) measurements. Bayesian estimation was used to compute individual vancomycin volume of distribution of the central compartment (Vc) and clearance (CL)...
August 14, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28807917/bedaquiline-inhibits-the-atp-synthase-in-mycobacterium-abscessus-and-is-effective-in-infected-zebrafish
#7
Christian Dupont, Albertus Viljoen, Sangeeta Thomas, Françoise Roquet-Banères, Jean-Louis Herrmann, Kevin Pethe, Laurent Kremer
Pulmonary infections caused by Mycobacterium abscessus are emerging as a global threat, especially in cystic fibrosis patients. Further intensifying the concern of M. abscessus infection is the recent evidence of human-to-human transmission of the infection. M. abscessus is a naturally multidrug resistant, fast-growing pathogen for which pharmacological options are limited. Repurposing antitubercular drugs represents an attractive option for the development of chemotherapeutic alternatives against M. abscessus infections...
August 14, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28807916/inhibition-of-calcineurin-or-impdh-exerts-moderate-to-potent-antiviral-activity-against-norovirus-replication
#8
Wen Dang, Yuebang Yin, Yijin Wang, Wenshi Wang, Junhong Su, Dave Sprengers, Luc J W van der Laan, Krzysztof Felczak, Krzysztof W Pankiewicz, Kyeong-Ok Chang, Marion P G Koopmans, Herold J Metselaar, Maikel P Peppelenbosch, Qiuwei Pan
Norovirus is a major cause of acute gastroenteritis worldwide and has emerged as an important issue of chronic infection in transplantation patients. Since no approved antiviral is available, we evaluated the effects of different immunosuppressants and ribavirin on norovirus and explored their mechanism-of-actions by using a human norovirus (HuNV) replicon-harboring model and a surrogate murine norovirus (MNV) infectious model. Roles of corresponding drug targets were investigated by gain- or loss-of-function approaches...
August 14, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28807915/both-14-day-hybrid-and-bismuth-quadruple-therapies-cure-most-patients-with-helicobacter-pylori-infection-in-populations-with-moderate-antibiotic-resistance-a-randomized-controlled-trial
#9
Feng-Woei Tsay, Deng-Chyang Wu, Hsien-Chung Yu, Sung-Shuo Kao, Kung-Hung Lin, Jin-Shiung Cheng, Huay-Min Wang, Wen-Chi Chen, Wei-Chih Sun, Kuo-Wang Tsai, Ping-I Hsu
BACKGROUND & AIM: Hybrid therapy is a novel two-step treatment achieving a high eradication rate for H. pylori infection. Currently, whether this new therapy achieves a higher eradication rate than bismuth quadruple therapy remains an unanswered question. The aim of this prospective, randomized, comparive study was to investigate the efficacies of 14-day hybrid therapy and bismuth quadruple therapy in the treatment of H. pylori infection.METHODS: From July 2013 to June 2015, eligible H. pylori-infected subjects were randomly assigned to receive either 14-day bismuth quadruple therapy (pantoprazole, bismuth subcitrate, tetracycline, and metronidazole for 14 days) or 14-day hybrid therapy (a 7-day dual therapy with pantoprazole plus amoxicillin, followed by a 7-day quadraple therapy with pantoprazole plus amoxicillin, clarithromycin and metronidazole)...
August 14, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28807914/amplification-of-antimicrobial-resistance-in-gut-flora-of-patients-treated-with-ceftriaxone
#10
J Meletiadis, A Turlej-Rogacka, A Lerner, A Adler, E Taconelli, J W Mouton
Although antibacterial therapy has an impact on human intestinal flora and emergence of resistant bacteria, its role on amplification of antimicrobial resistance and the quantitative exposure-effect relationship is not clear. An observational prospective study was conducted to determine whether and how ceftriaxone exposure is related to amplification of resistance in non- ICU patients.Serial stool samples from 122 ESBL(+) hospitalized patients were analyzed with quantitative real-time PCR to quantify the resistant gene blaCTX-M Drug exposure was calculated for each patient using a population pharmacokinetic model...
August 14, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28807913/reducing-antibacterial-development-risk-for-gsk1322322-by-exploring-potential-human-dose-regimens-in-nonclinical-efficacy-studies-using-immunocompetent-rats
#11
Jennifer L Hoover, Christine M Singley, Philippa Elefante, Peter DeMarsh, Magdalena Zalacain, Stephen Rittenhouse
Directly testing proposed clinical dosing regimens in nonclinical studies can reduce risk during the development of novel antibacterial agents. Optimal dosing regimens can be identified in animal models by testing recreated human pharmacokinetic profiles. An example of this approach is presented using continuous intravenous infusions of GSK1322322 in immunocompetent rats to evaluate recreated Phase 1 human exposures in pneumonia models with Streptococcus pneumoniae and Haemophilus influenzae and an abscess model with Staphylococcus aureus GSK1322322 was administered via continuous intravenous infusion to recreate 1000 or 1500 mg oral doses every 12h in humans...
August 14, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28807912/safety-and-efficacy-of-mhaa4549a-a-broadly-neutralizing-monoclonal-antibody-in-a-human-influenza-a-challenge-model-a-phase-2-randomized-trial
#12
Jacqueline M McBride, Jeremy J Lim, Tracy Burgess, Rong Deng, Michael A Derby, Mauricio Maia, Priscilla Horn, Omer Siddiqui, Daniel Sheinson, Haiyin Chen-Harris, Elizabeth M Newton, Dimitri Fillos, Denise Nazzal, Carrie M Rosenberger, Maikke B Ohlson, Rob Lambkin-Williams, Hosnieh Fathi, Jeffrey M Harris, Jorge A Tavel
BACKGROUND: MHAA4549A, a human monoclonal antibody targeting the hemagglutinin stalk region of influenza A virus (IAV), is being developed as a therapeutic for patients hospitalized with severe IAV infection. Safety and efficacy of MHAA4549A were assessed in a randomized, double-blind, placebo-controlled, dose-ranging study in a human IAV-challenge model. METHODS: One hundred healthy volunteers were inoculated with A/Wisconsin/67/2005 (H3N2) IAV and, 24-36 hours later, administered a single intravenous dose of either placebo, MHAA4549A (400, 1200, or 3600 mg) or a standard oral dose of oseltamivir...
August 14, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28807911/systematic-review-and-meta-analyses-of-the-effect-of-chemotherapy-on-pulmonary-mycobacterium-abscessus-outcomes-and-disease-recurrence
#13
Jotam G Pasipanodya, Deborah Ogbonna, Beatriz E Ferro, Gesham Magombedze, Shashikant Srivastava, Devyani Deshpande, Tawanda Gumbo
Background. In pharmacokinetic/pharmacodynamics models of pulmonary Mycobacterium abscessus complex, the recommended macrolide-containing combination therapy has poor kill rates. However, clinical outcomes are unknown.Methods We searched the literature for studies published between 1990-2017 that reported microbial outcomes in patients treated for pulmonary M. abscessus disease. Good outcome was defined as sustained sputum culture conversion (SSCC) without relapse. Random effects models were used to pool studies and estimate proportions of patients with good outcomes...
August 14, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28807910/24-hour-pharmacokinetic-relationships-for-vancomycin-and-novel-urinary-biomarkers-of-acute-kidney-injury
#14
J Nicholas O'Donnell, Nathaniel J Rhodes, Thomas P Lodise, Walter C Prozialeck, Cristina M Miglis, Medha Joshi, Natarajan Venkatesan, Gwendolyn Pais, Cameron Cluff, Peter C Lamar, Seema Briyal, John Z Day, Anil Gulati, Marc H Scheetz
Introduction: Vancomycin has been associated with acute kidney injury in preclinical and clinical settings, however the precise exposure profiles associated with vancomycin induced acute kidney injury has not been defined. We sought to determine pharmacokinetic/pharmacodynamics indices associated with the development of acute kidney injury using sensitive urinary biomarkers.Methods: Male Sprague-Dawley rats received clinical grade vancomycin or normal saline as an intraperitoneal injection. Total daily doses between 0 and 400 mg/kg/day were administered as single or 2 divided doses over a 24-hour period...
August 14, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28807909/development-and-use-of-personalized-bacteriophage-based-therapeutic-cocktails-to-treat-a-patient-with-a-disseminated-resistant-acinetobacter-baumannii-infection
#15
Robert T Schooley, Biswajit Biswas, Jason J Gill, Adriana Hernandez-Morales, Jacob Lancaster, Lauren Lessor, Jeremy J Barr, Sharon L Reed, Forest Rohwer, Sean Benler, Anca M Segall, Randy Taplitz, Davey M Smith, Kim Kerr, Monika Kumaraswamy, Victor Nizet, Leo Lin, Melanie D McCauley, Steffanie A Strathdee, Constance A Benson, Robert K Pope, Brian M Leroux, Andrew C Picel, Alfred J Mateczun, Katherine E Cilwa, James M Regeimbal, Luis A Estrella, David M Wolfe, Matthew S Henry, Javier Quinones, Scott Salka, Kimberly A Bishop-Lilly, Ry Young, Theron Hamilton
Widespread antibiotic use in clinical medicine and the livestock industry has contributed to the global spread of multidrug-resistant (MDR) bacterial pathogens, including Acinetobacter baumannii We report on a method used to produce a personalized bacteriophage-based therapeutic treatment for a 68-year old diabetic patient with necrotizing pancreatitis complicated by a MDR A. baumannii infection. Despite multiple antibiotic courses and efforts at percutaneous drainage of a pancreatic pseudocyst, the patient deteriorated over a four-month period...
August 14, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28807908/activity-of-the-%C3%AE-lactamase-inhibitor-ln-1-255-against-carbapenem-hydrolyzing-class-d-%C3%AE-lactamases-from-acinetobacter-baumannii
#16
Juan Carlos Vázquez-Ucha, María Maneiro, Marta Martínez-Guitián, John Buynak, Christopher R Bethel, Robert A Bonomo, Germán Bou, Margarita Poza, Concepción González-Bello, Alejandro Beceiro
The number of infections caused by Gram-negative pathogens carrying carbapenemases is increasing, and the group of carbapenem-hydrolyzing class D β-lactamases (CHDLs) is especially problematic. Several clinically important CHDLs have been identified in A. baumannii, including OXA-23, OXA-24/40, OXA-58, OXA-143, OXA-235, and the chromosomally encoded OXA-51. The selection and dissemination of carbapenem-resistant A. baumannii strains constitutes a serious global threat. Carbapenems have been successfully utilized as last resort antibiotics for the treatment of multi-drug-resistant A...
August 14, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28807907/an-original-chemical-series-of-pyrimidine-biosynthesis-inhibitors-that-boost-the-antiviral-interferon-response
#17
Marianne Lucas-Hourani, Daniel Dauzonne, Hélène Munier-Lehmann, Samira Khiar, Sébastien Nisole, Julien Dairou, Olivier Helynck, Philippe V Afonso, Frédéric Tangy, Pierre-Olivier Vidalain
De novo pyrimidine biosynthesis is a key metabolic pathway involved in multiple biosynthetic processes. Here, we identified an original series of 3-(1H-indol-3-yl)-2,3-dihydro-4H-furo[3,2-c]chromen-4-one derivatives as a new class of pyrimidine biosynthesis inhibitors formed by two edge-fused polycyclic moieties. We show that identified compounds exhibit a broad-spectrum antiviral activity as well as immunostimulatory properties, in line with recent reports linking de novo pyrimidine biosynthesis with innate defense mechanisms against viruses...
August 14, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28807906/impact-of-type-iii-secretion-effectors-and-of-phenoxyacetamide-inhibitors-of-type-iii-secretion-on-abscess-formation-in-a-mouse-model-of-pseudomonas-aeruginosa-infection
#18
Bryan J Berube, Katherine Murphy, Matthew C Torhan, Nicholas O Bowlin, John D Williams, Terry L Bowlin, Donald T Moir, Alan R Hauser
Pseudomonas aeruginosa is a leading cause of intra-abdominal infections, wound infections, and community-acquired folliculitis, each of which may involve macro- or micro-abscess formation. The rising incidence of multi-drug resistance among P. aeruginosa isolates has increased both the economic burden and the morbidity and mortality associated with P. aeruginosa disease and necessitates a search for novel therapeutics. Previous work from our group detailed novel phenoxyacetamide inhibitors that block type III secretion and injection into host cells in vitro In this study, we used a murine abscess model of P...
August 14, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28807905/pulmonary-pharmacokinetics-of-colistin-following-administration-of-dry-powder-aerosols-in-rats
#19
Yu-Wei Lin, Qi Tony Zhou, Yang Hu, Nikolas J Onufrak, Siping Sun, Jiping Wang, Alan Forrest, Hak-Kim Chan, Jian Li
Colistin has been administered via nebulization for the treatment of respiratory tract infections. Recently, dry powder inhalation (DPI) has attracted increasing attention. The current study aimed to investigate the pharmacokinetics (PK) of colistin in epithelial lining fluid (ELF) and plasma following DPI and intravenous (IV) administration in healthy Sprague-Dawley rats. Rats were given colistin as DPI intratracheally (0.66 and 1.32 mg base/kg) or IV injection (0.66 mg base/kg). Histopathological examination of lung tissue was performed at 24 h...
August 14, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28807904/no-clinically-relevant-drug-drug-interactions-between-methadone-or-buprenorphine-naloxone-and-anti-viral-combination-glecaprevir-and-pibrentasvir
#20
Matthew Kosloski, Weihan Zhao, Armen Asatryan, Jens Kort, Pierre Geoffroy, Wei Liu
The combination of glecaprevir (formerly ABT-493), a nonstructural (NS) protein 3/4A protease inhibitor, and pibrentasvir (formerly ABT-530), a NS5A protein inhibitor, is being developed as treatment for HCV genotype 1-6 infection. The pharmacokinetics, pharmacodynamics, safety, and tolerability of methadone or buprenorphine/naloxone when coadministered with the glecaprevir and pibrentasvir combination in HCV-negative subjects on stable opioid maintenance therapy were investigated in a Phase 1, single-center, two-arm, multiple-dose, open-label sequential study...
August 14, 2017: Antimicrobial Agents and Chemotherapy
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