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Avibactam

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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
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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...
November 29, 2016: Diagnostic Microbiology and Infectious Disease
https://www.readbyqxmd.com/read/28057163/ceftazidime-avibactam-who-says-you-can-t-teach-an-old-drug-new-tricks
#8
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
#9
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
#10
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
#11
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
#12
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
https://www.readbyqxmd.com/read/27997706/exploring-the-potential-of-boronic-acids-as-inhibitors-of-oxa-24-40-%C3%AE-lactamase
#13
Josephine P Werner, Joshua M Mitchell, Magdalena A Taracila, Robert A Bonomo, Rachel A Powers
β-lactam antibiotics are crucial to the management of bacterial infections in the medical community. Due to overuse and misuse, clinically significant bacteria are now resistant to many commercially available antibiotics. The most widespread resistance mechanism to β-lactams is the expression of β-lactamase enzymes. To overcome β-lactamase mediated resistance, inhibitors were designed to inactivate these enzymes. However, current inhibitors (clavulanic acid, tazobactam, and sulbactam) for β-lactamases also contain the characteristic β-lactam ring, making them susceptible to resistance mechanisms employed by bacteria...
December 20, 2016: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/27988068/in-vivo-pharmacodynamics-of-piperacillin-tazobactam-implications-for-antimicrobial-efficacy-and-resistance-suppression-with-innovator-and-generic-products
#14
Carlos A Rodriguez, Maria Agudelo, Andres F Zuluaga, Omar Vesga
Recent studies have shown that the pharmacodynamic (PD) index driving the efficacy of β-lactam/β-lactamase inhibitor combinations such as ceftazidime/avibactam and ceftolozane/tazobactam is the percentage of time the free inhibitor concentration is above a threshold (fT>threshold). However, data with piperacillin/tazobactam (TZP) are scarce. Here we aimed to assess the relationship between fT>threshold and TZP antibacterial efficacy by a population pharmacokinetic study in mice and dose-effect experiments in a neutropenic murine thigh infection model with two isogenic strains of Escherichia coli differentially expressing TEM-1 β-lactamase...
November 23, 2016: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/27959289/newer-intravenous-antibiotics-in-the-intensive-care-unit-ceftaroline-ceftolozane-tazobactam-and-ceftazidime-avibactam
#15
Kathryn A Connor
No abstract text is available yet for this article.
October 2016: AACN Advanced Critical Care
https://www.readbyqxmd.com/read/27942218/ceftolozane-tazobactam-and-ceftazidime-avibactam-for-the-treatment-of-complicated-intra-abdominal-infections
#16
REVIEW
Kellie J Goodlet, David P Nicolau, Michael D Nailor
Complicated intra-abdominal infections (cIAI) represent a large proportion of all hospital admissions and are a major cause of morbidity and mortality in the intensive care unit. Rising rates of multidrug resistant organisms (MDRO), including extended-spectrum β-lactamase producing Enterobacteriaceae and carbapenem-nonsusceptible Pseudomonas spp., for which there are few remaining active antimicrobial agents, pose an increased challenge to clinicians. Patients with frequent exposures to the health care system or multiple recurrent IAIs are at increased risk for MDRO; however, treatment options have traditionally been limited, in some cases necessitating the utilization of last-line agents with unfavorable side-effect profiles...
2016: Therapeutics and Clinical Risk Management
https://www.readbyqxmd.com/read/27939093/susceptibility-to-cephalosporin-combinations-and-aztreonam-avibactam-among-third-generation-cephalosporin-resistant-enterobacteriaceae-recovered-on-hospital-admission
#17
Alexander Mischnik, Philipp Baumert, Axel Hamprecht, Anna Rohde, Silke Peter, Susanne Feihl, Johannes Knobloch, Hanna Gölz, Axel Kola, Birgit Obermann, Christiane Querbach, Matthias Willmann, Friedemann Gebhardt, Evelina Tacconelli, Petra Gastmeier, Harald Seifert, Winfried V Kern
As part of the multicentre Antibiotic Therapy Optimisation Study (ATHOS), minimum inhibitory concentrations (MICs) were determined for cephalosporins alone and in combination with the β-lactamase inhibitors tazobactam, clavulanic acid and avibactam against third-generation cephalosporin-resistant Escherichia coli, Klebsiella spp. and Enterobacter spp. isolates collected in German hospitals. MIC50/90 values were 0.25-4 mg/L for cefepime/tazobactam, 0.25-2 mg/L for ceftazidime/avibactam, 0.125-0.5 mg/L for ceftaroline/avibactam, 0...
November 28, 2016: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/27924470/emerging-issues-and-treatment-strategies-in-carbapenem-resistant-enterobacteriaceae-cre
#18
REVIEW
Dana R Bowers, Vanthida Huang
Carbapenems are the broadest spectrum antimicrobials utilized in the treatment of serious infections since the 1980s. Soon after their introduction, the discovery of carbapenem-resistant Enterobacteriaceae (CRE) was reported in the 1990s. Invasive CRE infections are associated with high mortality and limited treatment options making care for patients with these infections challenging for clinicians. Current practice has reverted back to the use of "older" antimicrobials, such as the polymyxins, tigecycline, and fosfomycin, to combat invasive CRE infections...
December 2016: Current Infectious Disease Reports
https://www.readbyqxmd.com/read/27912842/the-rapid-spread-of-carbapenem-resistant-enterobacteriaceae
#19
REVIEW
Robert F Potter, Alaric W D'Souza, Gautam Dantas
Carbapenems, our one-time silver bullet for multidrug resistant bacterial infections, are now threatened by widespread dissemination of carbapenem-resistant Enterobacteriaceae (CRE). Successful expansion of Enterobacteriaceae clonal groups and frequent horizontal gene transfer of carbapenemase expressing plasmids are causing increasing carbapenem resistance. Recent advances in genetic and phenotypic detection facilitate global surveillance of CRE diversity and prevalence. In particular, whole genome sequencing enabled efficient tracking, annotation, and study of genetic elements colocalized with carbapenemase genes on chromosomes and on plasmids...
November 2016: Drug Resistance Updates: Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy
https://www.readbyqxmd.com/read/27895902/effect-of-%C3%AE-lactamase-inhibitors-on-in-vitro-activity-of-%C3%AE-lactam-antibiotics-against-burkholderia-cepacia-complex-species
#20
Annelien Everaert, Tom Coenye
BACKGROUND: Bacteria belonging to the Burkholderia cepacia complex (Bcc) are an important cause of chronic respiratory tract infections in cystic fibrosis patients. Intrinsic resistance to a wide range of antimicrobial agents, including a variety of β-lactam antibiotics, is frequently observed in Bcc strains. Resistance to β-lactams is most commonly mediated by efflux pumps, alterations in penicillin-binding proteins or the expression of β-lactamases. β-lactamase inhibitors are able to restore the in vitro activity of β-lactam molecules against a variety of Gram-negative species, but the effect of these inhibitors on the activity of β-lactam treatment against Bcc species is still poorly investigated...
2016: Antimicrobial Resistance and Infection Control
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