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https://www.readbyqxmd.com/read/28314920/-new-antibiotics-standstill-or-progress
#1
J Rademacher, T Welte
The development of resistance to antibiotics has been ignored for a long time. But nowadays, increasing resistance is an important topic. For a decade no new antibiotics had been developed and it is not possible to quickly close this gap of new resistance and no new drugs. This work presents six new antibiotics (ceftaroline, ceftobiprole, solithromycin, tedizolid, ceftolozane/tazobactam, ceftazidime/avibactam). In part, only expert opinions are given due to lack of study results.The two 5th generation cephalosporins ceftaroline and ceftobiprole have beside their equivalent efficacy to ceftriaxone (ceftaroline) and cefipim (ceftobiprole) high activity against MRSA...
March 17, 2017: Medizinische Klinik, Intensivmedizin und Notfallmedizin
https://www.readbyqxmd.com/read/28264560/overcoming-an-extreme-drug-resistant-xdr-pathogen-avibactam-restores-susceptibility-to-ceftazidime-for-burkholderia-cepacia-complex-isolates-from-cystic-fibrosis-patients
#2
Krisztina M Papp-Wallace, Scott A Becka, Elise T Zeiser, Nozumi Ohuchi, Maria F Mojica, Julian A Gatta, Monica Falleni, Delfina Tosi, Elisa Borghi, Marisa L Winkler, Brigid M Wilson, John J LiPuma, Michiyoshi Nukaga, Robert A Bonomo
Burkholderia multivorans is a significant health threat to persons with cystic fibrosis (CF). Infections are difficult to treat as this pathogen is inherently resistant to multiple antibiotics. Susceptibility testing of isolates obtained from CF respiratory cultures revealed that single agents selected from different antibiotic classes were unable to inhibit growth. However, all isolates were found to be susceptible to ceftazidime when combined with the novel non-β-lactam β-lactamase inhibitor, avibactam (all minimum inhibitor concentrations (MICs) were ≤ 8 mg/L of ceftazidime and 4 mg/L of avibactam)...
March 6, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28242667/in-vitro-selection-of-meropenem-resistance-among-ceftazidime-avibactam-resistant-meropenem-susceptible-klebsiella-pneumoniae-isolates-with-variant-kpc-3-carbapenemases
#3
Ryan K Shields, M Hong Nguyen, Ellen G Press, Liang Chen, Barry N Kreiswirth, Cornelius J Clancy
Ceftazidime-avibactam resistance is mediated by blaKPC-3 mutations, which restore carbapenem susceptibility. We subjected blaKPC-3 mutant (n=5) and wild-type (n=2) K. pneumoniae isolates to serial meropenem passage. Meropenem MICs against all isolates increased. Ompk36 porin mutations evolved in 5 isolates, including those with wild-type blaKPC-3 In different passage lineages, blaKPC-3 mutations reverted to wild-type, were replaced by new mutations, or were retained. Carbapenem treatment of ceftazidime-avibactam resistant K...
February 27, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28242258/impact-of-defined-cell-envelope-mutations-in-escherichia-coli-on-the-in-vitro-antibacterial-activity-of-avibactam-%C3%AE-lactam-combinations
#4
Sarah M McLeod, Sara A Patey, Michael D Huband, Wright W Nichols
Avibactam is a novel non-β-lactam β-lactamase inhibitor being developed in combination with ceftazidime, ceftaroline and aztreonam for the treatment of infections caused by Gram-negative bacteria. Avibactam protects the antibacterial activity of these antibiotics by inhibiting Ambler classes A and C and some class D β-lactamases. The Gram-negative cell envelope presents a complex barrier to hydrophilic solutes and contains multiple molecular determinants of antibiotic susceptibility and resistance. To investigate the role of some of these determinants in the activity of avibactam and its partner antibiotics in Escherichia coli, an isogenic panel with deletions in specific components of the cell envelope was constructed in an E...
February 24, 2017: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/28223379/mutations-in-blakpc-3-that-confer-ceftazidime-avibactam-resistance-encode-novel-kpc-3-variants-that-function-as-extended-spectrum-%C3%AE-lactamases
#5
Ghady Haidar, Cornelius J Clancy, Ryan K Shields, Binghua Hao, Shaoji Cheng, M Hong Nguyen
We identified four blaKPC-3 mutations in ceftazidime-avibactam resistant clinical Klebsiella pneumoniae isolates, corresponding to D179Y, T243M, D179Y/T243M, and EL165 KPC-3 variants. Using site-directed mutagenesis and transforming vectors into Escherichia coli, we conclusively demonstrated that mutant blaKPC-3 encoded enzymes that functioned as extended-spectrum β-lactamases; mutations directly conferred higher MICs of ceftazidime-avibactam MICs, and decreased MICs of carbapenems and other β-lactams. Impact was strongest for the D179Y mutant, highlighting the importance of the KPC Ω-loop...
February 21, 2017: Antimicrobial Agents and Chemotherapy
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
#6
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
#7
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/28137941/pharmacodynamics-of-ceftazidime-avibactam-against-extracellular-and-intracellular-forms-of-pseudomonas-aeruginosa
#8
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
#9
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...
April 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
#10
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/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
#11
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
#12
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/pseudomonas-aeruginosa-antimicrobial-susceptibility-results-from-four-years-2012-to-2015-of-the-international-network-for-optimal-resistance-monitoring-program-in-the-united-states
#13
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 comparator agents. We evaluated the antimicrobial susceptibility of 7,452 P. aeruginosa isolates collected from 79 U.S. medical centers in 2012 to 2015. The isolates were collected and tested consecutively for susceptibility by broth microdilution method...
March 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-n-132-g-in-the-conserved-sdn-motif
#14
Clément Ourghanlian, Daria Soroka, Michel Arthur
The substitution N(132)G in the SDN motif 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 may 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...
March 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
#15
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
#16
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
#17
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/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 to 19 days. Whole-genome sequencing (WGS) of longitudinal ceftazidime-avibactam-susceptible and -resistant K...
March 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28031200/low-frequency-of-ceftazidime-avibactam-resistance-among-enterobacteriaceae-isolates-carrying-blakpc-collected-in-u-s-hospitals-from-2012-to-2015
#20
Mariana Castanheira, Rodrigo E Mendes, Helio S Sader
Klebsiella pneumoniae carbapenemase (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 U.S. hospitals during 2012 to 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% susceptible at ≤2 μg/ml) were the most active agents...
March 2017: Antimicrobial Agents and Chemotherapy
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