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Avibactam

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https://www.readbyqxmd.com/read/28685153/emergence-of-ceftazidime-avibactam-resistance-and-restoration-of-carbapenem-susceptibility-in-klebsiella-pneumoniae-carbapenemase-producing-k-pneumoniae-a-case-report-and-review-of-literature
#1
Ryan K Shields, M Hong Nguyen, Ellen G Press, Liang Chen, Barry N Kreiswirth, Cornelius J Clancy
We used meropenem to successfully treat a patient with bacteremia due to ceftazidime-avibactam-resistant, meropenem- susceptible Klebsiella pneumoniae that carried mutant blaKPC-3. Meropenem was bactericidal against ceftazidime-avibactam- resistant K pneumoniae isolates in vitro. Nevertheless, the role of carbapenems in treating such infections remains uncertain, because meropenem resistance is selected readily during passage experiments.
2017: Open Forum Infectious Diseases
https://www.readbyqxmd.com/read/28678295/-13-c-carbamylation-as-a-mechanistic-probe-for-the-inhibition-of-class-d-%C3%AE-lactamases-by-avibactam-and-halide-ions
#2
Christopher T Lohans, David Y Wang, Christian Jorgensen, Samuel T Cahill, Ian J Clifton, Michael A McDonough, Henry P Oswin, James Spencer, Carmen Domene, Timothy D W Claridge, Jürgen Brem, Christopher J Schofield
The class D (OXA) serine β-lactamases are a major cause of resistance to β-lactam antibiotics. The class D enzymes are unique amongst β-lactamases because they have a carbamylated lysine that acts as a general acid/base in catalysis. Previous crystallographic studies led to the proposal that β-lactamase inhibitor avibactam targets OXA enzymes in part by promoting decarbamylation. Similarly, halide ions are proposed to inhibit OXA enzymes via decarbamylation. NMR analyses, in which the carbamylated lysines of OXA-10, -23 and -48 were (13)C-labelled, indicate that reaction with avibactam does not ablate lysine carbamylation in solution...
July 19, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28674059/in-vivo-emergence-of-resistance-to-novel-cephalosporin-%C3%AE-lactamase-inhibitor-combinations-through-the-duplication-of-the-amino-acid-d149-from-oxa-2-%C3%AE-lactamase-oxa-539-in-st235-pseudomonas-aeruginosa
#3
Pablo A Fraile-Ribot, Xavier Mulet, Gabriel Cabot, Ester Del Barrio-Tofiño, Carlos Juan, José L Pérez, Antonio Oliver
Resistance development to novel cephalosporin-β-lactamase inhibitor combinations during ceftazidime treatment of a surgical infection by Pseudomonas aeruginosa was investigated. Both, initial (97C2) and final (98G1) isolates, belonged to the high-risk clone ST235 and were resistant to carbapenems (oprD-), fluoroquinolones (GyrA-T83I, ParC-S87L) and aminoglycosides (aacA7/aacA8/aadA6). 98G1 additionally showed resistance to ceftazidime, ceftazidime-avibactam and ceftolozane-tazobactam. Sequencing identified blaOXA-2 in 97C2, but 98G1 contained a 3-bp insertion leading to the duplication of the key residue D149 (designated OXA-539)...
July 3, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28637339/emergence-of-ceftazidime-avibactam-non-susceptibility-in-an-mdr-klebsiella-pneumoniae-isolate
#4
Anna Both, Henning Büttner, Jiabin Huang, Markus Perbandt, Cristina Belmar Campos, Martin Christner, Florian P Maurer, Stefan Kluge, Christina König, Martin Aepfelbacher, Dominic Wichmann, Holger Rohde
Background: Avibactam is a novel broad-range β-lactamase inhibitor active against Ambler class A (including ESBL and KPC) and some Ambler class C and D (e.g. OXA-48) enzymes. We here report on the emergence of ceftazidime/avibactam resistance in clinical, multiresistant, OXA-48 and CTX-M-14-producing Klebsiella pneumoniae isolate DT12 during ceftazidime/avibactam treatment. Methods and results: Comparative whole-genome sequence analysis identified two SNPs in the CTX-M-14-encoding gene leading to two amino acid changes (P170S and T264I)...
June 16, 2017: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/28630202/identifying-spectra-of-activity-and-therapeutic-niches-for-ceftazidime-avibactam-and-imipenem-relebactam-against-carbapenem-resistant-enterobacteriaceae
#5
Ghady Haidar, Cornelius J Clancy, Liang Chen, Palash Samanta, Ryan K Shields, Barry N Kreiswirth, M Hong Nguyen
We determined imipenem, imipenem-relebactam, ceftazidime and ceftazidime-avibactam minimum inhibitory concentrations (MICs) against 100 CRE isolates that underwent whole genome sequencing. KPCs were the most common carbapenemases. Forty-six isolates carried ESBLs. With the addition of relebactam, imipenem susceptibility increased from 8% to 88%. With the addition of avibactam, ceftazidime susceptibility increased from 0% to 85%. Neither imipenem-relebactam nor ceftazidime-avibactam was active against MBL-producers...
June 19, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28630192/in-vitro-activity-of-aztreonam-avibactam-against-enterobacteriaceae-and-pseudomonas-aeruginosa-isolated-by-clinical-laboratories-in-40-countries-from-2012-to-2015
#6
James A Karlowsky, Krystyna M Kazmierczak, Boudewijn L M de Jonge, Meredith A Hackel, Daniel F Sahm, Patricia A Bradford
The combination of the monobactam, aztreonam, and the non-β-lactam β-lactamase inhibitor, avibactam, is currently in clinical development for the treatment of serious infections caused by metallo-β-lactamase (MBL)-producing Enterobacteriaceae, a difficult to treat subtype of carbapenem-resistant Enterobacteriaceae for which therapeutic options are currently very limited. The present study tested clinically significant isolates of Enterobacteriaceae (n=51,352) and Pseudomonas aeruginosa (n=11,842) collected from hospitalized patients in 208 medical center laboratories from 40 countries from 2012 to 2015 for in vitro susceptibility to aztreonam-avibactam, aztreonam, and comparator antimicrobial agents using standard broth microdilution methodology...
June 19, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28630191/ceftazidime-avibactam-and-aztreonam-an-interesting-strategy-to-overcome-%C3%AE-lactam-resistance-conferred-by-metallo-%C3%AE-lactamases-in-enterobacteriaceae-and-pseudomonas-aeruginosa
#7
Benjamin Davido, Lesly Fellous, Christine Lawrence, Virginie Maxime, Martin Rottman, Aurélien Dinh
We have read with great interest Marshal S. et al. regarding the efficacy of the ceftazidime-avibactam (CAZ-AVI) and aztreonam (ATM) combination on metallo- β -lactamases producing Enterobacteriaceae (1).….
June 19, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28610832/comparison-of-antimicrobial-activity-between-ceftolozane-tazobactam-and-ceftazidime-avibactam-against-multidrug-resistant-isolates-of-escherichia-coli-klebsiella-pneumoniae-and-pseudomonas-aeruginosa
#8
Adnan Alatoom, Hashim Elsayed, Karen Lawlor, Laila AbdelWareth, Rania El-Lababidi, Lysettee Cardona, Mohammad Mooty, Maria-Fernanda Bonilla, Ahmad Nusair, Imran Mirza
OBJECTIVE: This study compared the activity of ceftolozane-tazobactam and ceftazidime-avibactam against 120 bacterial strains, including extended-spectrum beta-lactamase (ESBL) producers, carbapenem-resistant Enterobacteriaceae (CRE), and Pseudomonas aeruginosa, isolated from patients admitted to Cleveland Clinic Abu Dhabi, United Arab Emirates. METHODS: In vitro susceptibility was tested using the Etest strip minimum inhibitory concentration (MIC) method, and PCR was used to characterize the carbapenemase enzymes produced by CRE strains...
June 10, 2017: International Journal of Infectious Diseases: IJID
https://www.readbyqxmd.com/read/28602518/synergistic-activity-of-ceftazidime-avibactam-and-aztreonam-against-serine-and-metallo-%C3%AE-lactamase-producing-gram-negative-pathogens
#9
Eric Wenzler, Matthew F Deraedt, Amanda T Harrington, Larry H Danizger
This study assessed the in vitro synergy between ceftazidime, aztreonam, and ceftazidime-avibactam against serine and metallo-β-lactamase (MBL)-producing pathogens via the Etest MIC:MIC ratio and Agar-Etest synergy methods. The combination of aztreonam and ceftazidime-avibactam was synergistic against all Enterobacteriaceae. None of the tested combinations were consistently synergistic against IMP-producing P. aeruginosa.
May 18, 2017: Diagnostic Microbiology and Infectious Disease
https://www.readbyqxmd.com/read/28594170/pharmaceutical-approaches-to-target-antibiotic-resistance-mechanisms
#10
Domenico Schillaci, Virginia Spanò, Barbara Parrino, Anna Carbone, Alessandra Montalbano, Paola Barraja, Patrizia Diana, Girolamo Cirrincione, Stella Cascioferro
There is urgent need for new therapeutic strategies to fight the global threat of antibiotic resistance. The focus of this Perspective is on chemical agents that target the most common mechanisms of antibiotic resistance such as enzymatic inactivation of antibiotics, changes in cell permeability, and induction/activation of efflux pumps. Here we assess the current landscape and challenges in the treatment of antibiotic resistance mechanisms at both bacterial cell and community levels. We also discuss the potential clinical application of chemical inhibitors of antibiotic resistance mechanisms as add-on treatments for serious drug-resistant infections...
June 20, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28590820/activity-of-ceftazidime-avibactam-against-clinical-isolates-of-klebsiella-pneumoniae-including-kpc-carrying-isolates-endemic-to-new-york-city
#11
Nyla Manning, Gregory Balabanian, Michael Rose, David Landman, John Quale
In this report, we examined the (1) activity of ceftazidime-avibactam against clinical isolates Klebsiella pneumoniae, including those harboring blaKPC, (2) potential mechanisms leading to reduced susceptibility, and (3) activity of ceftazidime-avibactam when combined with other agents. Of 802 carbapenem-resistant isolates of K. pneumoniae gathered from New York City from 1999 to 2014, all were susceptible to ceftazidime-avibactam. Minimum inhibitory concentrations (MICs) were higher in isolates with K. pneumoniae, with the carbapenemase (KPC)-3 (compared to KPC-2), and those with a frameshift mutation in ompK35...
June 7, 2017: Microbial Drug Resistance: MDR: Mechanisms, Epidemiology, and Disease
https://www.readbyqxmd.com/read/28559260/an-unusual-e-coli-pbp3-insertion-sequence-identified-from-a-collection-of-carbapenem-resistant-enterobacteriaceae-cre-tested-in-vitro-with-ceftazidime-ceftaroline-or-aztreonam-avibactam-combinations
#12
Yunliang Zhang, Ankita Kashikar, C Adam Brown, Gerald Denys, Karen Bush
Carbapenemase-producing Enterobacteriaceae isolates (n=110) from healthcare centers in central Indiana (2010-2013) were tested for susceptibility to combinations of avibactam (4 μg/ml) with ceftazidime, ceftaroline or aztreonam. MIC50/MIC90 values were 1/2 μg/ml (ceftazidime-avibactam), 0.5/2 μg/ml (ceftaroline-avibactam) and 0.25/0.5 μg/ml (aztreonam-avibactam.) A β-lactam MIC of 8 μg/ml was reported for the three combinations against one Escherichia coli isolate with an unusual TIPY insertion following Tyr344 in penicillin-binding protein 3 (PBP3) as the result of gene duplication...
May 30, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28559250/ceftazidime-avibactam-is-superior-to-other-treatment-regimens-against-carbapenem-resistant-klebsiella-pneumoniae-bacteremia
#13
Ryan K Shields, M Hong Nguyen, Liang Chen, Ellen G Press, Brian A Potoski, Rachel V Marini, Yohei Doi, Barry N Kreiswirth, Cornelius J Clancy
There are no data comparing outcomes of patients treated with ceftazidime-avibactam vs. comparators for carbapenem-resistant Enterobacteriaceae infections. At our center, ceftazidime-avibactam treatment of carbapenem-resistant Klebsiella pneumoniae bacteremia was associated with higher rates of clinical success (P=0.006) and survival (P=0.01) than other regimens. Across treatment groups, there were no differences in underlying diseases, severity of illness, source of bacteremia, or strain characteristics (97% were KPC-producing)...
May 30, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28505331/antimicrobial-susceptibility-of-clinical-isolates-of-neisseria-gonorrhoeae-to-alternative-antimicrobials-with-therapeutic-potential
#14
P R S Lagacé-Wiens, H J Adam, N M Laing, M R Baxter, I Martin, M R Mulvey, J A Karlowsky, D J Hoban, G G Zhanel
Background: The prevalence of MDR Neisseria gonorrhoeae is increasing globally and represents a public health emergency. Development and approval of new anti-gonococcal agents may take years. As a concurrent approach to developing new antimicrobials, the laboratory and clinical evaluation of currently licensed antimicrobials not widely used for the treatment of gonorrhoea may provide new options for the treatment of gonococcal infections. Objectives: To determine the in vitro activity of nine alternative, currently licensed and late-development antimicrobials with the potential to treat gonococcal infections against 112 clinical isolates of N...
May 12, 2017: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/28483952/multicenter-study-of-outcomes-with-ceftazidime-avibactam-in-patients-with-carbapenem-resistant-enterobacteriaceae-infections
#15
Madeline King, Emily Heil, Safia Kuriakose, Tiffany Bias, Vanthida Huang, Claudine El-Beyrouty, Dorothy McCoy, Jon Hiles, Lynette Richards, Julianne Gardner, Nicole Harrington, Kenneth Biason, Jason C Gallagher
Ceftazidime-avibactam is a novel cephalosporin-beta-lactamase inhibitor combination that is active against many carbapenem-resistant Enterobacteriaceae (CRE). We describe a retrospective chart review for 60 patients who received ceftazidime-avibactam for a CRE infection. In-hospital mortality was 32%, 53% of patients had microbiological cure, and 65% had clinical success. In this severely ill population with CRE infections, ceftazidime-avibactam was an appropriate option.
July 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28461318/impaired-inhibition-by-avibactam-and-resistance-to-the-ceftazidime-avibactam-combination-due-to-the-d-179-y-substitution-in-the-kpc-2-%C3%AE-lactamase
#16
Fabrice Compain, Michel Arthur
The ceftazidime-avibactam antibiotic combination was recently shown to be at risk for the emergence of resistance under treatment. To gain insight into the underlying mechanism, we have analyzed the catalytic properties of a Klebsiella pneumoniae carbapenemase type 2 (KPC-2) β-lactamase harboring the D(179)Y substitution. We show that impaired inhibition by avibactam combined with significant residual activity for ceftazidime hydrolysis accounts for the resistance. In contrast, the D(179)Y substitution abolished the hydrolysis of aztreonam and imipenem, indicating that these drugs might provide therapeutic alternatives...
July 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28439137/compatibility-of-ceftazidime-avibactam-ceftolozane-tazobactam-and-piperacillin-tazobactam-with-vancomycin-in-dextrose-5-in-water
#17
Kevin Meyer, Maressa Santarossa, Larry H Danziger, Eric Wenzler
Objectives: The compatibility of vancomycin with existing and novel β-lactam/β-lactamase inhibitors at clinically relevant concentrations in 5% dextrose in water has not been fully explored to date. Methods: Vancomycin concentrations tested ranged from 5 to 20 mg/mL. Ceftazidime-avibactam was tested at 8, 20, and 40 mg/mL, ceftolozane-tazobactam at 15 mg/mL, and piperacillin-tazobactam at 28 mg/mL. Compatibility of drug admixtures were tested via both simulated and actual y-site infusion. For the simulated y-site compatibility assessment, 1:1 mixtures of each respective drug were analyzed over 24 hours...
March 2017: Hospital Pharmacy
https://www.readbyqxmd.com/read/28416558/in-vitro-discordance-with-in-vivo-activity-humanized-exposures-of-ceftazidime-avibactam-aztreonam-and-tigecycline-alone-and-in-combination-against-new-delhi-metallo-%C3%AE-lactamase-producing-klebsiella-pneumoniae-in-a-murine-lung-infection-model
#18
M L Monogue, L M Abbo, R Rosa, J F Camargo, O Martinez, R A Bonomo, D P Nicolau
The management of infections with New Delhi metallo-beta-lactamase-1 (NDM)-producing bacteria remains clinically challenging given the multidrug resistant (MDR) phenotype associated with these bacteria. Despite resistance in vitro, ceftazidime-avibactam previously demonstrated in vivo activity against NDM-positive Enterobacteriaceae Herein, we observed in vitro synergy with ceftazidime-avibactam and aztreonam against an MDR Klebsiella pneumoniae harboring NDM. In vivo, humanized doses of ceftazidime-avibactam monotherapy resulted in >2 log10 CFU bacterial reduction; therefore, no in vivo synergy was observed...
July 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28416553/pharmacokinetics-and-dialytic-clearance-of-ceftazidime-avibactam-in-a-critically-ill-patient-on-continuous-venovenous-hemofiltration
#19
Eric Wenzler, Kristen L Bunnell, Susan C Bleasdale, Scott Benken, Larry H Danziger, Keith A Rodvold
Ceftazidime-avibactam administered at 1.25 g every 8 h was used to treat multidrug-resistant Pseudomonas aeruginosa bacteremia in a critically ill patient on continuous venovenous hemofiltration (CVVH). Prefiltration plasma drug concentrations of ceftazidime and avibactam were measured at 0, 1, 2, 4, 6, and 8 h along with postfiltration and ultrafiltrate concentrations at h 2 and h 6. Plasma pharmacokinetic parameters of ceftazidime and avibactam, respectively, were as follows: maximum plasma concentration (Cmax), 61...
July 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28396547/resistance-to-ceftazidime-avibactam-in-klebsiella-pneumoniae-due-to-porin-mutations-and-the-increased-expression-of-kpc-3
#20
LETTER
Romney M Humphries, Peera Hemarajata
No abstract text is available yet for this article.
June 2017: Antimicrobial Agents and Chemotherapy
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