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Avibactam

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https://www.readbyqxmd.com/read/28167547/bacteremia-due-to-carbapenem-resistant-enterobacteriaceae-cre-a-multicenter-clinical-and-molecular-epidemiologic-analysis-in-the-nation-s-epicenter-for-cre
#1
Michael J Satlin, Liang Chen, Gopi Patel, Angela Gomez-Simmonds, Gregory Weston, Angela C Kim, Susan K Seo, Marnie E Rosenthal, Steven J Sperber, Stephen G Jenkins, Camille L Hamula, Anne-Catrin Uhlemann, Michael H Levi, Bettina C Fries, Yi-Wei Tang, Stefan Juretschko, Albert D Rojtman, Tao Hong, Barun Mathema, Michael R Jacobs, Thomas J Walsh, Robert A Bonomo, Barry N Kreiswirth
Although the New York/New Jersey (NY/NJ) area is an epicenter for carbapenem-resistant Enterobacteriaceae (CRE), there are few multicenter studies of CRE from this region. We characterized patients with CRE bacteremia in 2013 at eight NY/NJ medical centers and determined the prevalence of carbapenem resistance among Enterobacteriaceae bloodstream isolates and CRE resistance mechanisms, genetic backgrounds, capsular types (cps), and antimicrobial susceptibilities. Of 121 patients with CRE bacteremia, 50% had cancer or transplantation...
February 6, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28167541/can-ceftazidime-avibactam-and-aztreonam-overcome-%C3%AE-lactam-resistance-conferred-by-metallo-%C3%AE-lactamases-in-enterobacteriaceae
#2
Steven Marshall, Andrea M Hujer, Laura J Rojas, Krisztina M Papp-Wallace, Romney M Humphries, Brad Spellberg, Kristine M Hujer, Emma K Marshall, Susan D Rudin, Federico Perez, Brigid M Wilson, Ronald B Wasserman, Linda Chikowski, David L Paterson, Alejandro J Vila, David van Duin, Barry N Kreiswirth, Henry F Chambers, Vance G Fowler, Michael R Jacobs, Mark E Pulse, William J Weiss, Robert A Bonomo
Based upon knowledge of the hydrolytic profile of major β-lactamases found in Gram negative bacteria, we tested the effectiveness of the combination of ceftazidime/avibactam (CAZ/AVI) with aztreonam (ATM) against carbapenem-resistant enteric bacteria possessing metallo-β-lactamases (MBLs). Disk-diffusion and agar based antimicrobial susceptibility testing were initially performed to determine the in vitro efficacy of a unique combination of CAZ/AVI and ATM against 21 representative Enterobacteriaceae isolates with a complex molecular background that included blaIMP, blaNDM, blaOXA-48, blaCTX-M, blaAmpC, and combinations thereof...
February 6, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28145085/prediction-of-in-vivo-and-in-vitro-infection-model-results-using-a-semimechanistic-model-of-avibactam-and-aztreonam-combination-against-multidrug-resistant-organisms
#3
Skb Sy, L Zhuang, H Xia, M-E Beaudoin, V J Schuck, H Derendorf
The combination of aztreonam-avibactam is active against multidrug-resistant Enterobacteriaceae that express metallo-β-lactamases. A complex synergistic interaction exists between aztreonam and avibactam bactericidal activities that have not been quantitatively explored. A two-state semimechanistic pharmacokinetic/pharmacodynamic (PK/PD) logistic growth model was developed to account for antimicrobial activities in the combination of bacteria-mediated degradation of aztreonam and the inhibition of aztreonam degradation by avibactam...
February 1, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28137941/pharmacodynamics-of-ceftazidime-avibactam-against-extracellular-and-intracellular-forms-of-pseudomonas-aeruginosa
#4
J M Buyck, C Luyckx, G G Muccioli, K M Krause, W W Nichols, P M Tulkens, F Van Bambeke
OBJECTIVES: When tested in broth, avibactam reverses ceftazidime resistance in many Pseudomonas aeruginosa that express ESBLs. We examined whether similar reversal is observed against intracellular forms of P. aeruginosa METHODS: Strains: reference strains; two engineered strains with basal non-inducible expression of AmpC and their isogenic mutants with stably derepressed AmpC; and clinical isolates with complete, partial or no resistance to reversion with avibactam. Pharmacodynamic model: 24 h concentration-response to ceftazidime [0...
January 30, 2017: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/28134677/are-there-any-reasons-to-change-our-behavior-in-necrotizing-fasciitis-with-the-advent-of-new-antibiotics
#5
Francesco Menichetti, Simone Giuliano, Simona Fortunato
PURPOSE OF REVIEW: The treatment of necrotizing fasciitis requires a multifaceted approach, consisting of surgical source control with immediate surgical debridement along with life support, clinical monitoring, and antimicrobial therapy. Many drugs are now available for the treatment of this life-threatening infectious disease, and the purpose of this review is to provide the reader with an updated overview of the newest therapeutic options. RECENT FINDINGS: Because most necrotizing soft tissue infections are polymicrobial, broad-spectrum coverage is advisable...
January 27, 2017: Current Opinion in Infectious Diseases
https://www.readbyqxmd.com/read/28115350/antimicrobial-activities-of-ceftazidime-avibactam-and-comparator-agents-against-clinical-bacteria-isolated-from-patients-with-cancer
#6
Ray Hachem, Ruth Reitzel, Kenneth Rolston, Anne-Marie Chaftari, Issam Raad
A total of 521 unique clinical isolates from cancer patients, primarily (>90 %) with bloodstream infections were tested for susceptibility to ceftazidime/avibactam and comparators using broth microdilution methods. Ceftazidime/avibactam inhibited 97.8 % of all Enterobacteriaceae (N=321) at the susceptibility breakpoint of ≤8/4 μg/ml (there were 7 non-susceptible strains). It was also active against Pseudomonas aeruginosa (91.7 % isolates susceptible, N=121) including many isolates not susceptible to meropenem, cefepime, ceftazidime, piperacillin/tazobactam and other comparators...
January 23, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28115348/cyclic-boronates-inhibit-all-classes-of-%C3%AE-lactamase
#7
Samuel T Cahill, Ricky Cain, David Y Wang, Christopher T Lohans, David W Wareham, Henry P Oswin, Jabril Mohammed, James Spencer, Colin W G Fishwick, Michael A McDonough, Christopher J Schofield, Jürgen Brem
β-Lactamase-mediated resistance is a growing threat to the continued use of β-lactam antibiotics. The use of the β-lactam-based serine-β-lactamase (SBL) inhibitors clavulanic acid, sulbactam, tazobactam, and, more recently, the non-β-lactam inhibitor avibactam has extended the utility of β-lactams against bacterial infections demonstrating resistance via these enzymes. These molecules are, however, ineffective against the metallo-β-lactamases (MBLs), which catalyse their hydrolysis. To date, there are no clinically available metallo-β-lactamase inhibitors...
January 23, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28109883/probing-transport-of-charged-%C3%AE-lactamase-inhibitors-through-ompc-a-membrane-channel-from-e-%C3%A2-coli
#8
Ishan Ghai, Mathias Winterhalter, Richard Wagner
One of the major causes of antibiotic resistance in the Gram-negative bacteria is the low permeability across the outer membrane. Currently a main bottleneck in the development of effective antibiotics is the lack of a general method to quantify permeation which would allow screening for optimal scaffolds. Here, we present a permeation assay based on conventional electrophysiology. The method mainly involves application of concentration gradients of charged molecules with different electrophoretic mobilities through a membrane channel...
January 18, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28096155/inhibition-of-the-%C3%AE-lactamase-blamab-by-avibactam-improves-the-in-vitro-and-in-vivo-efficacy-of-imipenem-against-mycobacterium-abscessus
#9
Anne-Laure Lefebvre, Vincent Le Moigne, Audrey Bernut, Carole Veckerlé, Fabrice Compain, Jean-Louis Herrmann, Laurent Kremer, Michel Arthur, Jean-Luc Mainardi
Mycobacterium abscessus pulmonary infections are treated with a macrolide (clarithromycin or azithromycin), an aminoglycoside (amikacin), and a β-lactam (cefoxitin or imipenem). The triple combination is used without any β-lactamase inhibitor despite production of the broad spectrum β-lactamase BlaMab We determine whether inhibition of BlaMab by avibactam improves the activity of imipenem against M. abscessus. Bactericidal activity of drug combinations was assayed in broth and in human macrophages. The in vivo efficacy of the drugs was tested by monitoring the survival of infected zebrafish embryos...
January 17, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28088768/in-vitro-activity-of-ceftazidime-avibactam-against-urinary-isolates-from-patients-in-a-phase-3-clinical-trial-programme-for-the-treatment-of-complicated-urinary-tract-infections
#10
Gregory G Stone, Patricia A Bradford, Katrina Yates, Paul Newell
OBJECTIVES: To evaluate the in vitro activity of ceftazidime/avibactam relative to comparator agents against Gram-negative isolates from a Phase 3 clinical trial programme for complicated urinary tract infections (RECAPTURE). METHODS: The in vitro activity of ceftazidime/avibactam was evaluated against 840 Gram-negative pathogens isolated at baseline from 1033 randomized patients in two pivotal Phase 3 clinical trials for the treatment of complicated urinary tract infections...
January 14, 2017: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/28077672/potentiation-of-ceftazidime-by-avibactam-against-%C3%AE-lactam-resistant-pseudomonas-aeruginosa-in-an-in-vitro-infection-model
#11
Sherwin K B Sy, Luning Zhuang, Marie-Eve Beaudoin, Philipp Kircher, Maria A M Tabosa, Noely C T Cavalcanti, Christian Grunwitz, Sebastian Pieper, Virna J Schuck, Wright W Nichols, Hartmut Derendorf
OBJECTIVES: This study evaluated the in vitro pharmacodynamics of combinations of ceftazidime and the non-β-lactam β-lactamase inhibitor, avibactam, against ceftazidime-, piperacillin/tazobactam- and meropenem-multiresistant Pseudomonas aeruginosa by a quantitative time-kill method. METHODS: MICs of ceftazidime plus 0-16 mg/L avibactam were determined against eight isolates of P. aeruginosa Single-compartment, 24 h time-kill kinetics were investigated for three isolates at 0-16 mg/L avibactam with ceftazidime at 0...
January 10, 2017: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/28069652/antimicrobial-susceptibility-of-pseudomonas-aeruginosa-results-from-four-years-2012-2015-of-the-international-network-for-optimal-resistance-monitoring-inform-program-in-the-united-states
#12
Helio S Sader, Michael D Huband, Mariana Castanheira, Robert K Flamm
Pseudomonas aeruginosa represents a major cause of health-care associated infections, and inappropriate initial antimicrobial therapy is associated with increased morbidity and mortality. The International Network for Optimal Resistance Monitoring (INFORM) program monitors the in vitro activity of ceftazidime-avibactam and many comparators agents. We evaluated the antimicrobial susceptibility of 7,452 P. aeruginosa isolates collected from 79 USA medical centers in 2012-2015. The isolates were collected and tested consecutively for susceptibility by broth microdilution method...
January 9, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28069651/inhibition-by-avibactam-and-clavulanate-of-the-%C3%AE-lactamases-kpc-2-and-ctx-m-15-harboring-the-substitution-n132g-in-the-conserved-motif-sdn
#13
Clément Ourghanlian, Daria Soroka, Michel Arthur
The substitution N(132)G in the motif SDN of class A β-lactamases from rapidly-growing mycobacteria was previously shown to impair their inhibition by avibactam but to improve the stability of acyl-enzymes formed with clavulanate. The same substitution was introduced in KPC-2 and CTX-M-15 to assess its impact on β-lactamases from Enterobacteriaceae and evaluate whether it could lead to resistance to the ceftazidime-avibactam combination. Kinetic parameters for the inhibition of the β-lactamases by avibactam and clavulanate were determined by spectrophotometry using nitrocefin as the substrate...
January 9, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28069649/antimicrobial-activity-of-ceftazidime-avibactam-when-tested-against-gram-negative-bacteria-isolated-from-patients-hospitalized-with-pneumonia-in-united-states-medical-centers-2011-2015
#14
Helio S Sader, Mariana Castanheira, Robert K Flamm
Bacterial isolates were collected from patients hospitalized with pneumonia (PHP), including ventilator-associated (VAP), from 76 USA medical centers in 2011-2015. The Gram-negative organisms (n=11,185; including 1,097 from VAP) were tested for susceptibility against ceftazidime-avibactam and comparators by broth microdilution method. β-lactamase-encoding genes were screened using a microarray based assay on selected isolates. Pseudomonas aeruginosa and Klebsiella spp. were the most common Gram-negatives isolated from PHP and VAP...
January 9, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28069328/antimicrobial-activity-of-ceftazidime-avibactam-and-comparator-agents-when-tested-against-bacterial-isolates-causing-infection-in-cancer-patients-2013-2014
#15
Helio S Sader, Mariana Castanheira, Ronald N Jones, Robert K Flamm
We evaluated the antimicrobial susceptibility of 623 Gram-negative organisms causing infection in patients with cancer in 52 United States hospitals (2013-2014) as part of the International Network for Optimal Resistance Monitoring (INFORM) program. Isolates were tested for susceptibility by broth microdilution method. β-lactamase encoding genes were evaluated for all Escherichia coli and Klebsiella spp. with an extended-spectrum β-lactamase (ESBL) phenotype by microarray-based assay. ESBL-phenotype was observed among 17...
March 2017: Diagnostic Microbiology and Infectious Disease
https://www.readbyqxmd.com/read/28057163/ceftazidime-avibactam-who-says-you-can-t-teach-an-old-drug-new-tricks
#16
Katie E Barber, Jessica K Ortwine, Ronda L Akins
PURPOSE: Gram-negative resistance continues to rise with treatment options becoming more limited. Ceftazidime/avibactam was recently approved in the United States and Europe, which combines an established third-generation cephalosporin with a new, unique, non-β-lactam β-lactamase inhibitor. This review conducts a thorough examination of structure, pharmacology, spectrum of activity, pharmacokinetics/pharmacodynamics, in vitro and clinical efficacy and safety/tolerability of ceftazidime/avibactam, as well as detailed future directions for the agent...
October 2016: Journal of Pharmacy & Pharmaceutical Sciences: a Publication of the Canadian Society for Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28039278/inhibition-of-%C3%AE-lactamases-of-mycobacteria-by-avibactam-and-clavulanate
#17
Daria Soroka, Clément Ourghanlian, Fabrice Compain, Marion Fichini, Vincent Dubée, Jean-Luc Mainardi, Jean-Emmanuel Hugonnet, Michel Arthur
OBJECTIVES: Mycobacterium tuberculosis and Mycobacterium abscessus produce broad-spectrum class A β-lactamases, BlaC and BlaMab, which are inhibited by clavulanate and avibactam, respectively. BlaC differs from BlaMab at Ambler position 132 in the conserved motif SDN (SDG versus SDN, respectively). Here, we investigated whether this polymorphism could account for the inhibition specificity of β-lactamases from slowly and rapidly growing mycobacteria. METHODS: Enzyme kinetics were determined to assess the impact of the substitutions G(132)N in BlaC and N(132)G in BlaMab on β-lactamase inhibition by clavulanate and avibactam...
December 30, 2016: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/28039276/the-pharmacodynamics-of-avibactam-in-combination-with-ceftaroline-or-ceftazidime-against-%C3%AE-lactamase-producing-enterobacteriaceae-studied-in-an-in-vitro-model-of-infection
#18
Alasdair MacGowan, Sharon Tomaselli, Alan Noel, Karen Bowker
OBJECTIVES: Pharmacodynamics of β-lactamase inhibitors are an area of intense interest as new β-lactam/β-lactamase inhibitor combinations enter clinical development and clinical practice. Avibactam, a non-β-lactam β-lactamase inhibitor, has been combined with ceftaroline or ceftazidime but these two combinations have not been directly compared. METHODS: Using an in vitro pharmacokinetic model we simulated human drug concentration-time courses associated with ceftaroline 600 mg every 8 h and ceftazidime 2000 mg every 8 h...
December 30, 2016: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/28031201/emergence-of-ceftazidime-avibactam-resistance-due-to-plasmid-borne-blakpc-3-mutations-during-treatment-of-carbapenem-resistant-klebsiella-pneumoniae-infections
#19
Ryan K Shields, Liang Chen, Shaoji Cheng, Kalyan D Chavda, Ellen G Press, Avin Snyder, Ruchi Pandey, Yohei Doi, Barry N Kreiswirth, M Hong Nguyen, Cornelius J Clancy
Ceftazidime-avibactam is a novel β-lactam/β-lactamase inhibitor with activity against carbapenem-resistant Enterobacteriaceae (CRE) that produce Klebsiella pneumoniae carbapenemase (KPC). We report the first cases of ceftazidime-avibactam resistance to develop during treatment of CRE infections, and identify resistance mechanisms. Ceftazidime-avibactam resistant K. pneumoniae emerged in three patients after ceftazidime-avibactam treatment for 10-19 days. Whole genome sequencing (WGS) of longitudinal ceftazidime-avibactam susceptible and resistant K...
December 28, 2016: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28031200/low-frequency-of-ceftazidime-avibactam-resistance-among-enterobacteriaceae-isolates-carrying-blakpc-collected-in-hospitals-from-the-united-states-from-2012-to-2015
#20
Mariana Castanheira, Rodrigo E Mendes, Helio S Sader
KPC-producing Enterobacteriaceae isolates have been increasingly reported worldwide and therapeutic options to treat infections caused by these organisms are limited. We evaluated the activity of ceftazidime-avibactam and comparators against 456 Enterobacteriaceae isolates carrying blaKPC collected from 79 United States hospitals during 2012-2015. Overall, ceftazidime-avibactam (MIC50/90, 0.5/2 μg/mL; 99.3% susceptible) and tigecycline (MIC50/90, 0.5/1 μg/mL; 98.9% at ≤2 μg/mL) were the most active agents...
December 28, 2016: Antimicrobial Agents and Chemotherapy
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