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Avibactam

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https://www.readbyqxmd.com/read/28338347/ceftazidime-avibactam-novel-antimicrobial-combination-for-the-treatment-of-complicated-urinary-tract-infections
#1
Jakhongir F Alidjanov, Moritz Fritzenwanker, Ivan Hoffman, Florian M Wagenlehner
Ceftazidime-avibactam is a combination of a third-generation cephalosporin and a novel non-beta-lactam beta-lactamase inhibitor. This combination was recently recommended for the treatment of complicated urinary tract infections, including acute pyelonephritis, in adults with limited or no alternative treatment options. The current review is aimed to determine activity, efficacy and safety of ceftazidime-avibactam in the treatment of patients with complicated urinary tract infections.
March 24, 2017: Future Microbiology
https://www.readbyqxmd.com/read/28333323/high-ceftazidime-hydrolysis-activity-and-porin-ompk35-deficiency-contribute-to-the-decreased-susceptibility-to-ceftazidime-avibactam-in-kpc-producing-klebsiella-pneumoniae
#2
Zhen Shen, Baixing Ding, Meiping Ye, Peng Wang, Yingmin Bi, Shi Wu, Xiaogang Xu, Qinglan Guo, Minggui Wang
Objectives: To investigate mechanisms for the decreased susceptibility to ceftazidime/avibactam in KPC-producing Klebsiella pneumoniae (KPC-KP). Methods: A total of 24 isolates, 8 each with ceftazidime/avibactam MICs of 4-8, 1-2 and ≤0.5 mg/L, were randomly selected from 214 clinical isolates of KPC-KP, and the β-lactamase hydrolysis activity and porin expression profiles were determined. Plasmid profile and relative expression and copy number of the bla KPC gene were also analysed...
March 15, 2017: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/28326811/combinations-of-avibactam-and-carbapenems-exhibit-enhanced-potencies-against-drug-resistant-mycobacterium-abscessus
#3
Amit Kaushik, Chhavi Gupta, Stefanie Fisher, Elizabeth Story-Roller, Christos Galanis, Nicole Parrish, Gyanu Lamichhane
AIM: The objective of this study was to assess if avibactam, a new β-lactamase inhibitor, can restore the potency of carbapenems, a sub-class of β-lactams, against Mycobacterium abscessus clinical isolates. MATERIALS & METHODS: Twenty-eight M. abscessus clinical isolates that are resistant to multiple drugs currently used to treat its infection were included. MIC of carbapenems alone and in combination with avibactam against these strains were determined. RESULTS: Tebipenem, an oral carbapenem, and ertapenem and panipenem exhibited the greatest shift in MIC when supplemented with avibactam...
February 16, 2017: Future Microbiology
https://www.readbyqxmd.com/read/28314920/-new-antibiotics-standstill-or-progress
#4
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/28303449/novel-beta-lactamase-inhibitors-unlocking-their-potential-in-therapy
#5
Darren Wong, David van Duin
Carbapenem-resistant Enterobacteriaceae are amongst the most feared pathogens due to severely limited treatment options. In response to this threat, three novel β-lactamase inhibitors have been developed in an attempt to reinvigorate and sustain our current antimicrobial therapies. Avibactam, vaborbactam, and relebactam are inhibitor agents with high affinity to Ambler class A and C β-lactamases and favorable outcomes in current clinical trials. However, although they do possess key similarities, these agents have unique differences which may have important clinical implications...
March 16, 2017: Drugs
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
#6
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
#7
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
#8
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/28240914/general-method-to-determine-the-flux-of-charged-molecules-through-nanopores-applied-to-%C3%AE-lactamase-inhibitors-and-ompf
#9
Ishan Ghai, Alessandro Pira, Mariano Andrea Scorciapino, Igor Bodrenko, Lorraine Benier, Matteo Ceccarelli, Mathias Winterhalter, Richard Wagner
A major challenge in the discovery of the new antibiotics against Gram-negative bacteria is to achieve sufficiently fast permeation in order to avoid high doses causing toxic side effects. So far, suitable assays for quantifying the uptake of charged antibiotics into bacteria are lacking. We apply an electrophysiological zero-current assay using concentration gradients of β-lactamase inhibitors combined with single-channel conductance to quantify their flux rates through OmpF. Molecular dynamic simulations provide in addition details on the interactions between the nanopore wall and the charged solutes...
March 6, 2017: Journal of Physical Chemistry Letters
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
#10
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
#11
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
#12
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 efficacy 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...
April 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
#13
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...
March 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28137941/pharmacodynamics-of-ceftazidime-avibactam-against-extracellular-and-intracellular-forms-of-pseudomonas-aeruginosa
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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