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Carbapenemase inhibitor

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https://www.readbyqxmd.com/read/28652234/meropenem-vaborbactam-tested-against-contemporary-gram-negative-isolates-collected-worldwide-during-2014-including-carbapenem-resistant-kpc-producing-multidrug-resistant-and-extensively-drug-resistant-enterobacteriaceae
#1
Mariana Castanheira, Michael D Huband, Rodrigo E Mendes, Robert K Flamm
We evaluated the activity of meropenem-vaborbactam against contemporary non-fastidious gram-negative clinical isolates, including resistant phenotypes and carbapenemase genotypes of Enterobacteriaceae Meropenem-vaborbactam (inhibitor at 8 μg/ml) and comparators were susceptibility tested using reference broth microdilution methods against 14,304 gram-negative clinical isolates collected worldwide during 2014. Carbapenemase encoding genes were screened by PCR/sequencing. Meropenem-vaborbactam (MIC50/90, ≤0...
June 26, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28562752/phenotypic-methods-for-screening-carbapenem-resistant-enterobacteriaceae-and-assessment-of-their-antimicrobial-susceptibility-profile
#2
Danielly da Costa Silva, Roberta Filipini Rampelotto, Vinícius Victor Lorenzoni, Silvana Oliveira Dos Santos, Juliana Damer, Manfredo Hörner, Rosmari Hörner
INTRODUCTION: In this study, we used phenotypic methods to screen carbapenem-resistant Enterobacteriaceae (CREs) and evaluated their antimicrobial sensitivity profile. METHODS: One hundred and seventy-eight CREs were isolated at a university hospital in south Brazil in a one-year period. Samples were assessed using disk diffusion tests with inhibitors of β-lactamases such as phenylboronic acid (AFB), cloxacillin (CLOXA), and ethylenediaminetetraacetic acid (EDTA)...
March 2017: Revista da Sociedade Brasileira de Medicina Tropical
https://www.readbyqxmd.com/read/28559248/structural-insights-into-tmb-1-and-the-role-of-residue-119-and-228-in-substrate-and-inhibitor-binding
#3
Susann Skagseth, Tony Christopeit, Sundus Akhter, Annette Bayer, Ørjan Samuelsen, Hanna-Kirsti S Leiros
Metallo-β-lactamases (MBLs) threatens the effectiveness of β-lactam antibiotics including carbapenems, and is a concern for the global public health. β-lactam/β-lactamase inhibitor combinations active against class A and class D carbapenemases are used, but currently no clinically useful MBL inhibitor is available. Tripoli metallo-β-lactamase-1 (TMB-1) and -2 (TMB-2) are MBL subclass B1a, where TMB-2 is a S228P variant of TMB-1.The role of S228P was studied by comparison TMB-1 and TMB-2, and E119 was investigated through construction site-directed mutants of TMB-1 E119Q/S/A...
May 30, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28550370/molecular-epidemiology-of-escherichia-coli-sequence-type-131-and-its-h30-h30-rx-subclones-recovered-from-extra-intestinal-infections-first-report-of-oxa-48-producing-st131-clone-from-iran
#4
Z Hojabri, M Mirmohammadkhani, F Kamali, K Ghassemi, S Taghavipour, O Pajand
Multidrug-resistant (MDR) O25b-ST131 clone of Escherichia coli is well established as a significant cause of extra-intestinal infections worldwide. However, there have been no studies about the prevalence of ST131 and its H30/H30Rx subclones from Iran. The prevalence of ST131 was 29.8% among phylogroups B2, D, and F of E.coli isolates recovered from extra-intestinal infections. Fifty-seven (90.4%) and six (9.6%) of isolates belonged to serogroups O25b and O16 respectively, and exhibited high rates of MDR (98...
May 27, 2017: European Journal of Clinical Microbiology & Infectious Diseases
https://www.readbyqxmd.com/read/28333319/wck-4234-a-novel-diazabicyclooctane-potentiating-carbapenems-against-enterobacteriaceae-pseudomonas-and-acinetobacter-with-class-a-c-and-d-%C3%AE-lactamases
#5
Shazad Mushtaq, Anna Vickers, Neil Woodford, David M Livermore
Background: Several diazabicyclooctanes (DBOs) are under development as inhibitors of class A and C β-lactamases. Inhibition of OXA (class D) carbapenemases is variable, with those of Acinetobacter spp. remaining notably resistant. We describe a novel DBO, WCK 4234 (Wockhardt), with distinctive activity against OXA carbapenemases. Methods: MICs of imipenem and meropenem were determined by CLSI agar dilution with WCK 4234 added at 4 or 8 mg/L. Test organisms were clinical Enterobacteriaceae, Acinetobacter baumannii and Pseudomonas aeruginosa with carbapenemases or carbapenem resistance via porin loss plus AmpC or ESBL activity...
June 1, 2017: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/28320716/in-vitro-activity-of-imipenem-relebactam-against-gram-negative-eskape-pathogens-isolated-by-clinical-laboratories-in-the-united-states-in-2015-results-from-the-smart-global-surveillance-program
#6
Sibylle H Lob, Meredith A Hackel, Krystyna M Kazmierczak, Katherine Young, Mary R Motyl, James A Karlowsky, Daniel F Sahm
Relebactam (formerly MK-7655) is an inhibitor of class A and C β-lactamases, including Klebsiella pneumoniae carbapenemase (KPC), and is currently in clinical development in combination with imipenem-cilastatin. Using Clinical and Laboratory Standards Institute (CLSI)-defined broth microdilution methodology, we evaluated the in vitro activities of imipenem-relebactam, imipenem, and seven routinely tested parenteral antimicrobial agents against Gram-negative ESKAPE pathogens (including Klebsiella pneumoniae, n = 689; Acinetobacter baumannii, n = 72; Pseudomonas aeruginosa, n = 845; and Enterobacter spp...
June 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28291628/invitro-activity-of-imipenem-relebactam-against-gram-negative-bacilli-isolated-from-patients-with-lower-respiratory-tract-infections-in-the-united-states-in-2015-results-from-the-smart-global-surveillance-program
#7
Sibylle H Lob, Meredith A Hackel, Krystyna M Kazmierczak, Daryl J Hoban, Katherine Young, Mary R Motyl, James A Karlowsky, Daniel F Sahm
The β-lactamase inhibitor relebactam inactivates class A β-lactamases, including KPC-type carbapenemases, and class C β-lactamases. Relebactam combined with imipenem is in clinical development for several indications, including hospital-acquired and ventilator-associated pneumonia. Employing CLSI-defined broth microdilution methodology, we evaluated the activities of imipenem-relebactam (using imipenem MIC breakpoints) and comparators against non-Proteeae Enterobacteriaceae (n=853) and Pseudomonas aeruginosa (n=598) isolated from lower respiratory tract infection samples in 20 hospital laboratories in the United States participating in the 2015 SMART (Study for Monitoring Antimicrobial Resistance Trends) global surveillance program...
March 2, 2017: Diagnostic Microbiology and Infectious Disease
https://www.readbyqxmd.com/read/28264560/overcoming-an-extremely-drug-resistant-xdr-pathogen-avibactam-restores-susceptibility-to-ceftazidime-for-burkholderia-cepacia-complex-isolates-from-cystic-fibrosis-patients
#8
Krisztina M Papp-Wallace, Scott A Becka, Elise T Zeiser, Nozomi 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)...
July 14, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28160861/antibacterial-activity-of-epigallocatechin-3-gallate-egcg-and-its-synergism-with-%C3%AE-lactam-antibiotics-sensitizing-carbapenem-associated-multidrug-resistant-clinical-isolates-of-acinetobacter-baumannii
#9
Spencer Lee, Ghaida Saleh Al Razqan, Dong H Kwon
BACKGROUND: Infections caused by Acinetobacter baumannii were responsive to conventional antibiotic therapy. However, recently, carbapenem-associated multidrug resistant isolates have been reported worldwide and present a major therapeutic challenge. Epigallocatechin-3-Gallate (EGCG) extracted from green tea exhibits antibacterial activity. PURPOSE: We evaluated the antibacterial activity of EGCG and possible synergism with antibiotics in carbapenem-associated multidrug resistant A...
January 15, 2017: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/28128097/high-level-resistance-to-meropenem-in-clinical-isolates-of-pseudomonas-aeruginosa-in-the-absence-of-carbapenemases-role-of-active-efflux-and-porin-alterations
#10
Hussein Chalhoub, Yolanda Sáenz, Hector Rodriguez-Villalobos, Olivier Denis, Barbara C Kahl, Paul M Tulkens, Françoise Van Bambeke
High-level carbapenem resistance is worryingly increasing in clinical isolates and is often attributed to carbapenemase expression. This study aimed to determine the mechanisms leading to high-level meropenem resistance in six carbapenemase-negative Pseudomonas aeruginosa isolated from cystic fibrosis (CF) patients and seven carbapenemase-positive isolates from patients suffering from hospital-acquired pneumonia (HAP). MICs were determined in the absence or presence of l-arginine or glycine-glutamate as competitive substrates for OprD (OccD1) or OpdP (OccD3), respectively, or the efflux pump inhibitor Phe-Arg β-naphthylamide (PAβN)...
December 2016: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/28081233/differences-in-inflammatory-response-induced-by-two-representatives-of-clades-of-the-pandemic-st258-klebsiella-pneumoniae-clonal-lineage-producing-kpc-type-carbapenemases
#11
Giuseppe Castronovo, Ann Maria Clemente, Alberto Antonelli, Marco Maria D'Andrea, Michele Tanturli, Eloisa Perissi, Sara Paccosi, Astrid Parenti, Federico Cozzolino, Gian Maria Rossolini, Maria Gabriella Torcia
ST258-K. pneumoniae (ST258-KP) strains, the most widespread multidrug-resistant hospital-acquired pathogens, belong to at least two clades differing in a 215 Kb genomic region that includes the cluster of capsule genes. To investigate the effects of the different capsular phenotype on host-pathogen interactions, we studied representatives of ST258-KP clades, KKBO-1 and KK207-1, for their ability to activate monocytes and myeloid dendritic cells from human immune competent hosts. The two ST258-KP strains strongly induced the production of inflammatory cytokines...
2017: PloS One
https://www.readbyqxmd.com/read/28057163/ceftazidime-avibactam-who-says-you-can-t-teach-an-old-drug-new-tricks
#12
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/28031433/comparison-of-phenotypic-tests-and-an-immunochromatographic-assay-and-development-of-a-new-algorithm-for-detection-of-oxa-48-like-carbapenemases
#13
Florian Koroska, Stephan Göttig, Martin Kaase, Jörg Steinmann, Sören Gatermann, Julian Sommer, Thorsten Wille, Georg Plum, Axel Hamprecht
OXA-48 is the most prevalent carbapenemase in Enterobacteriaceae in Europe and the Middle East, but it is frequently missed because many isolates display low MICs for carbapenems. Furthermore, in contrast to metallo-β-lactamases or Klebsiella pneumoniae carbapenemases (KPC), no specific inhibitor is available for the phenotypic detection of OXA-48. Molecular detection of blaOXA-48 is the "gold standard" but is not available in many laboratories. A few phenotypic assays have been described but have not been independently evaluated...
March 2017: Journal of Clinical Microbiology
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
#14
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/27912842/the-rapid-spread-of-carbapenem-resistant-enterobacteriaceae
#15
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/27834322/a-structural-epidemiological-genetic-overview-of-klebsiella-pneumoniae-carbapenemases-kpcs
#16
REVIEW
C H Swathi, Rosy Chikala, K S Ratnakar, V Sritharan
Klebsiella pneumoniae carbapenemases (KPCs) are plasmid encoded carbapenem hydrolyzing enzymes which have the potential to spread widely through gene transfer. The instability of upstream region of blaKPC accelerates emergence of different isoforms. Routine antibiotic susceptibility testing failed to detect KPC producers and some commercial kits have been launched for early identification of KPC producers. Notable among the drugs under development against KPC are mostly derivatives of polymixin; ß-lactamase inhibitor NXL104 with combination of oxyimino cephalosporin as well as with ceftazidime; a novel tricyclic carbapenem, LK-157, potentially useful against class A and class C enzymes; BLI-489-a bicyclic penem derivative; PTK-0796, a tetracycline derivative and ACHN-490...
July 2016: Indian Journal of Medical Research
https://www.readbyqxmd.com/read/27758148/ceftazidime-avibactam-for-the-treatment-of-complicated-intra-abdominal-infections
#17
REVIEW
Sara A Buckman, Tamara Krekel, Anouk E Muller, John E Mazuski
The treatment of complicated intra-abdominal infections (cIAI) is increasingly challenging due to increased resistance of Gram-negative organisms. These multidrug resistant organisms lead to an increase in morbidity and mortality. This has led to renewed interest in use of older β-lactam antibiotics in combination with newer β-lactamase inhibitors. Ceftazidime-avibactam is one of the newest such combination antibiotics, which has been released for treatment of complicated intra-abdominal infections in combination with metronidazole...
December 2016: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/27703329/bulgecin-a-as-a-%C3%AE-lactam-enhancer-for-carbapenem-resistant-pseudomonas-aeruginosa-and-carbapenem-resistant-acinetobacter-baumannii-clinical-isolates-containing-various-resistance-mechanisms
#18
Marion J Skalweit, Mei Li
Genetic screening of Pseudomonas aeruginosa (PSDA) and Acinetobacter baumannii (ACB) reveals genes that confer increased susceptibility to β-lactams when disrupted, suggesting novel drug targets. One such target is lytic transglycosylase. Bulgecin A (BlgA) is a natural product of Pseudomonas mesoacidophila and a lytic transglycosolase inhibitor that works synergistically with β-lactams targeting PBP3 for Enterobacteriaceae. BlgA also weakly inhibits di-Zn(2+) metallo-β-lactamases like L1 of Stenotrophomonas maltophilia...
2016: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/27632226/structure-based-approach-for-identification-of-novel-phenylboronic-acids-as-serine-%C3%AE-lactamase-inhibitors
#19
Jacopo Sgrignani, Filomena De Luca, Hayarpi Torosyan, Jean-Denis Docquier, Da Duan, Beatrice Novati, Fabio Prati, Giorgio Colombo, Giovanni Grazioso
β-Lactamases are bacterial enzymes conferring resistance to β-lactam antibiotics in clinically-relevant pathogens, and represent relevant drug targets. Recently, the identification of new boronic acids (i.e. RPX7009) paved the way to the clinical application of these molecules as potential drugs. Here, we screened in silico a library of ~1400 boronic acids as potential AmpC β-lactamase inhibitors. Six of the most promising candidates were evaluated in biochemical assays leading to the identification of potent inhibitors of clinically-relevant β-lactamases like AmpC, KPC-2 and CTX-M-15...
October 2016: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/27623409/bisthiazolidines-a-substrate-mimicking-scaffold-as-an-inhibitor-of-the-ndm-1-carbapenemase
#20
Mariano M González, Magda Kosmopoulou, Maria F Mojica, Valerie Castillo, Philip Hinchliffe, Ilaria Pettinati, Jürgen Brem, Christopher J Schofield, Graciela Mahler, Robert A Bonomo, Leticia I Llarrull, James Spencer, Alejandro J Vila
Pathogenic Gram-negative bacteria resistant to almost all β-lactam antibiotics are a major public health threat. Zn(II)-dependent or metallo-β-lactamases (MBLs) produced by these bacteria inactivate most β-lactam antibiotics, including the carbapenems, which are "last line therapies" for life-threatening Gram-negative infections. NDM-1 is a carbapenemase belonging to the MBL family that is rapidly spreading worldwide. Regrettably, inhibitors of MBLs are not yet developed. Here we present the bisthiazolidine (BTZ) scaffold as a structure with some features of β-lactam substrates, which can be modified with metal-binding groups to target the MBL active site...
November 13, 2015: ACS Infectious Diseases
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