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Ka Lip Chew, Michelle K L Tay, Bernadette Cheng, Raymond T P Lin, Sophie Octavia, Jeanette W P Teo
Newly approved Food and Drug Administration (FDA) β-lactam-β-lactamase inhibitor (βL-βLI) inhibitor combinations such as ceftazidime-avibactam and meropenem-vaborbactam are potent inhibitors of class A carbapenemase (typified by KPC [ Klebsiella pneumoniae carbapenemase]-like) (1, 2) but are ineffective against carbapenemase-producing Enterobacteriaceae (CPE) producing class B metallo-β-lactamases (MβLs) such as New Delhi metallo-β-lactamase (NDM) (1-4).….
May 14, 2018: Antimicrobial Agents and Chemotherapy
James A Karlowsky, Krystyna M Kazmierczak, Samuel K Bouchillon, Boudewijn L M de Jonge, Gregory G Stone, Daniel F Sahm
The in vitro activities of ceftazidime-avibactam and comparators were determined for 9,149 isolates of Enterobacteriaceae and 2,038 isolates of Pseudomonas aeruginosa collected by 42 medical centers in nine countries in the Asia-Pacific region from 2012 to 2015 as part of the International Network For Optimal Resistance Monitoring (INFORM) global surveillance program. Antimicrobial susceptibility testing was conducted by CLSI broth microdilution and isolate subset analysis performed based on resistant phenotypes and β-lactamase content...
May 14, 2018: Antimicrobial Agents and Chemotherapy
Patricia A Bradford, Michael D Huband, Gregory G Stone
Selection of the avibactam concentration to combine with ceftazidime in susceptibility testing was determined using Gram-negative isolates with characterized β-lactamases predefined as "susceptible" or "resistant" based on the known inhibition spectrum of avibactam. MIC values were determined by broth microdilution of ceftazidime with fixed concentrations and ratios of avibactam. A constant concentration of 4 μg/mL of avibactam was selected for susceptibility testing with ceftazidime because of its ability to correctly categorize susceptible and resistant isolates while minimizing categorical errors...
May 7, 2018: Antimicrobial Agents and Chemotherapy
Dhruvitkumar S Sutaria, Bartolome Moya, Kari B Green, Tae Hwan Kim, Xun Tao, Yuanyuan Jiao, Arnold Louie, George L Drusano, Jürgen B Bulitta
Penicillin-binding proteins (PBPs) are the high affinity target sites of all β-lactam antibiotics in bacteria. It is well known that each β-lactam covalently binds to and thereby inactivates different PBPs with varying affinity. Despite β-lactams serving as cornerstone of our therapeutic armamentarium against Klebsiella pneumoniae , PBP binding data are missing for this pathogen. We aimed to generate the first PBP binding data on 13 chemically diverse and clinically relevant β-lactams and β-lactamase inhibitors in K...
April 30, 2018: Antimicrobial Agents and Chemotherapy
Ignacio Lizana, Eduardo J Delgado
The inhibition mechanism of CTX-M-15 class A serine hydrolase by the inhibitor avibactam is addressed by a combined molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) approach postulating that the residue Ser70 is the sole reacting residue, that is, itself may play the role of the acid-base species required for the enzyme inhibition. Other residues located in the active site have key participation in the positioning of the inhibitor in the right conformation to favor the attack of Ser70, in addition to the stabilization of the transition state by electrostatic interactions with avibactam...
April 29, 2018: Journal of Computational Chemistry
Abdullah Algwizani, Mohammad Alzunitan, Ahmad Alharbi, Abdulrahman Alsaedy, Sameera Aljohani, Bassam Alalwan, Jawaher Gramish, Adel Alothman
INTRODUCTION: Carbapenem-resistant organisms have become major healthcare-associated pathogens and are responsible for significant morbidity and mortality worldwide. CASES AND MANAGEMENTS: This case-series describes our experience with ceftazidime-avibactam in the treatment of six cases with carbapenem-resistant organisms in King Abdulaziz Medical City in Riyadh, Saudi Arabia. After trying various combinations of antibiotic therapies without improvement, cases were treated with ceftazidime-avibactam...
April 26, 2018: Journal of Infection and Public Health
Danna R Gifford, Victoria Furió, Andrei Papkou, Tom Vogwill, Antonio Oliver, R Craig MacLean
There is an urgent need to develop novel approaches for predicting and preventing the evolution of antibiotic resistance. Here, we show that the ability to evolve de novo resistance to a clinically important β-lactam antibiotic, ceftazidime, varies drastically across the genus Pseudomonas. This variation arises because strains possessing the ampR global transcriptional regulator evolve resistance at a high rate. This does not arise because of mutations in ampR. Instead, this regulator potentiates evolution by allowing mutations in conserved peptidoglycan biosynthesis genes to induce high levels of β-lactamase expression...
April 23, 2018: Nature Ecology & Evolution
Gregory G Stone, Paul Newell, Patricia A Bradford
Increasing prevalence of multidrug-resistant Gram-negative pathogens has generated a requirement for new treatment options. Avibactam, a novel non-β-lactam β-lactamase inhibitor, restores activity of ceftazidime against Ambler class A, C and some class D β-lactamase-producing strains of Enterobacteriaceae and Pseudomonas aeruginosa In vitro activity of ceftazidime-avibactam versus comparators was evaluated against 1,440 clinical isolates obtained in a phase 3 clinical trial in patients with complicated intra-abdominal infections (cIAI; NCT01499290)...
April 23, 2018: Antimicrobial Agents and Chemotherapy
Matt Shirley
Ceftazidime-avibactam (Zavicefta® ) is an intravenously administered combination of the third-generation cephalosporin ceftazidime and the novel, non-β-lactam β-lactamase inhibitor avibactam. In the EU, ceftazidime-avibactam is approved for the treatment of adults with complicated urinary tract infections (cUTIs) [including pyelonephritis], complicated intra-abdominal infections (cIAIs), hospital-acquired pneumonia (HAP) [including ventilator-associated pneumonia (VAP)], and other infections caused by aerobic Gram-negative organisms in patients with limited treatment options...
April 18, 2018: Drugs
Neta Sternbach, Yaara Leibovici Weissman, Tomer Avni, Dafna Yahav
Background: Ceftazidime/avibactam is approved for complicated intra-abdominal and urinary tract infections (UTIs) based on results from randomized controlled trials (RCTs). Data regarding its effectiveness in treating hospital-acquired infections or resistant pathogens have not been systematically compiled. Methods: A systematic review and meta-analysis including RCTs evaluating ceftazidime/avibactam versus comparator for the treatment of any infection. Primary outcome was 30 day all-cause mortality...
April 6, 2018: Journal of Antimicrobial Chemotherapy
Juri Katchanov, Lucia Asar, Eva-Maria Klupp, Anna Both, Camilla Rothe, Christina König, Holger Rohde, Stefan Kluge, Florian P Maurer
OBJECTIVES: To determine the spectrum of infections with multidrug-resistant Gram-negative bacteria (MDR-GNB) and the clinical impact of the newly available betalactam/betalactamase inhibitor combinations ceftolozane/tazobactam and ceftazidime/avibactam in a German academic tertiary care center. METHODS: Retrospective analysis. RESULTS: Between September 1, 2015 and August 31, 2016, 119 individual patients (0.22% of all hospital admissions) were colonized or infected with carbapenem-resistant MDR-GNB...
2018: PloS One
Raúl Recio, Jennifer Villa, Esther Viedma, María Ángeles Orellana, Jaime Lora-Tamayo, Fernando Chaves
Predictors of mortality and the impact of multidrug resistance and virulence on patients with Pseudomonas aeruginosa (PA) bacteraemia were evaluated. Patients with PA bacteraemia in a 12-month period were retrospectively analysed. Carbapenemase production, molecular typing and identification of virulence factor ExoU were carried out. The activity of ceftolozane-tazobactam and ceftazidime-avibactam was also investigated. The primary endpoint was 30-day crude mortality. Of 64 patients with bacteraemia, 24 (37...
April 2, 2018: International Journal of Antimicrobial Agents
Wright W Nichols, Paul Newell, Ian Critchley, Todd Riccobene, Shampa Das
Avibactam is a novel non-β-lactam β-lactamase inhibitor that has been approved in the USA and Europe for use in combination with ceftazidime. Combinations of avibactam with aztreonam or ceftaroline fosamil have also been clinically evaluated. Until recently, there has been very little precedence of which pharmacokinetic/pharmacodynamic (PK/PD) indices and magnitudes are appropriate to use for β-lactamase inhibitors in population PK modeling for analyzing potential doses and susceptibility breakpoints. For avibactam, several preclinical studies using different in vitro and in vivo models have been conducted to identify the PK/PD index of avibactam and the magnitude of exposure necessary for effect in combination with ceftazidime, aztreonam, or ceftaroline fosamil...
April 2, 2018: Antimicrobial Agents and Chemotherapy
Krisztina M Papp-Wallace, Melissa D Barnes, Jim Alsop, Magdalena A Taracila, Christopher R Bethel, Scott A Becka, David van Duin, Barry N Kreiswirth, Keith S Kaye, Robert A Bonomo
The imipenem-relebactam combination is in development as a potential treatment regimen for infections caused by Enterobacteriaceae possessing complex β-lactamase backgrounds. Relebactam is a β-lactamase inhibitor that possesses the diazabicyclooctane core similar to avibactam, however relebactam's R1 side chain also includes a piperidine ring compared to the carboxyamide of avibactam. Here, we investigated the inactivation of Klebsiella pneumoniae carbapenemase (KPC-2), the most widespread class A carbapenemase, by relebactam and performed susceptibility testing with imipenem-relebactam using KPC-producing clinical isolates of Enterobacteriaceae...
April 2, 2018: Antimicrobial Agents and Chemotherapy
Mark G Wise, Mark A Estabrook, Daniel F Sahm, Gregory G Stone, Krystyna M Kazmierczak
A set of 908 clinically derived colistin-resistant Enterobacteriaeae isolates collected worldwide in 2014-2016 were screened for the presence of the plasmid-borne mcr-1, mcr-2, mcr-3, mcr-4 and mcr-5 genes. In total 3.2% (29/908) of the collection were positive for mcr, including 27 Escherichia coli, 1 Klebsiella pneumoniae and 1 Enterobacter cloacae. Twenty-four isolates possessed genes from the mcr-1 family, including the original mcr-1 (n = 22), as well as mcr-1.2 (n = 1) and mcr-1.5 (n = 1), which each differ from mcr-1 by encoding single amino acid variations...
2018: PloS One
L M Koeth, E Matuschek, G Kahlmeter, G Stone
Ceftazidime-avibactam disk studies were performed for disk mass selection and for establishing EUCAST quality control ranges and zone diameter breakpoints. The disk mass study included disk diffusion testing with ceftazidime-avibactam 10-4 and 10-6 μg disks and broth microdilution MIC testing for challenge set of 94 Enterobacteriaceae and 45 Pseudomonas aeruginosa. EUCAST SOP 9.0-based QC and MIC-disk correlations studies were followed for development of ceftazidime-avibactam 10-4 μg ranges for Escherichia coli ATCC 25922, P...
March 30, 2018: European Journal of Clinical Microbiology & Infectious Diseases
Zainab Edoo, Laura Iannazzo, Fabrice Compain, Inès Li de la Sierra Gallay, Herman van Tilbeurgh, Matthieu Fonvielle, Flavie Bouchet, Eva Le Run, Jean-Luc Mainardi, Michel Arthur, Mélanie Ethève-Quelquejeu, Jean-Emmanuel Hugonnet
There is a renewed interest for β-lactams for treating infections due to Mycobacterium tuberculosis and M. abscessus since their β-lactamases are inhibited by classical (clavulanate) or new generation (avibactam) inhibitors, respectively. Here, we report access to an azido derivative of the diazabicyclooctane (DBO) scaffold of avibactam for functionalization by the Huisgen-Sharpless cycloaddition reaction. The amoxicillin-DBO combinations were active indicating that the triazole ring is compatible with drug penetration (minimal inhibitory concentration of 16 µg/ml for both species)...
March 30, 2018: Chemistry: a European Journal
Pranita D Tamma, Yunfan Fan, Yehudit Bergman, Anna C Sick-Samuels, Alice J Hsu, Winston Timp, Patricia J Simner, Bonnie C Prokesch, David E Greenberg
We report our clinical experience treating a 2-month-old infant with congenital diaphragmatic hernia who experienced prolonged bacteremia with Burkholderia cepacia complex (Bcc) despite conventional antibiotic therapy and appropriate source control measures. The infection resolved after initiation of ceftazidime-avibactam. Whole-genome sequencing revealed that the isolate most closely resembled B. contaminans and identified the mechanism of resistance that likely contributed to clinical cure with this agent...
April 2018: Antimicrobial Agents and Chemotherapy
Hélène Bouxom, Damien Fournier, Kevin Bouiller, Didier Hocquet, Xavier Bertrand
We evaluated the activity of 18 non-carbapenem antibiotics on 100 ESBL-producing Escherichia coli (ESBL-Ec) and 50 ESBL-producing Klebsiella pneumoniae (ESBL-Kp) isolated from urinary tract infections and bacteremia in 2016. MICs were determined using reference methods and susceptibility profiles were defined according to the EUCAST 2017 recommendations. All the ESBL-Ec isolates were susceptible to ceftazidime-avibactam and a great majority of them were susceptible to fosfomycin (98%), piperacillin-tazobactam (97%), amikacin (97%) and nitrofurantoin (96%)...
March 23, 2018: International Journal of Antimicrobial Agents
Paolo Gaibani, Caterina Campoli, Russell E Lewis, Silvia Lidia Volpe, Erika Scaltriti, Maddalena Giannella, Stefano Pongolini, Andrea Berlingeri, Francesco Cristini, Michele Bartoletti, Sara Tedeschi, Simone Ambretti
Objectives: KPC-producing Klebsiella pneumoniae (KPC-Kp) represent a serious problem worldwide. Herein, we describe the evolution of ceftazidime/avibactam resistance by sequencing longitudinal clinical isolates from a patient with KPC-Kp bloodstream infection undergoing ceftazidime/avibactam treatment. Methods: WGS was performed on one ceftazidime/avibactam-susceptible KPC-Kp (BOT-CA-S) and two phenotypically different ceftazidime/avibactam-resistant KPC-Kp with low (BOT-CA-R) and high (BOT-EMO) carbapenem MICs...
March 16, 2018: Journal of Antimicrobial Chemotherapy
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