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Carbapenemase inhibitor

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https://www.readbyqxmd.com/read/29020404/colistin-vs-ceftazidime-avibactam-in-the-treatment-of-infections-due-to-carbapenem-resistant-enterobacteriaceae
#1
David van Duin, Judith J Lok, Michelle Earley, Eric Cober, Sandra S Richter, Federico Perez, Robert A Salata, Robert C Kalayjian, Richard R Watkins, Yohei Doi, Keith S Kaye, Vance G Fowler, David L Paterson, Robert A Bonomo, Scott Evans
Background: The efficacy of ceftazidime-avibactam - a cephalosporin-β-lactamase inhibitor combination with in vitro activity against Klebsiella pneumoniae carbapenemase (KPC)-producing carbapenem-resistant Enterobacteriaceae (CRE) - as compared to colistin remains unknown. Methods: Patients initially treated with either ceftazidime-avibactam or colistin for CRE infections were selected from the Consortium on resistance against carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE), a prospective, multicenter, observational study...
September 4, 2017: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
https://www.readbyqxmd.com/read/28978681/high-stringency-evaluation-of-the-automated-bd-phoenix%C3%A2-cpo-detect-and-rapidec%C3%A2-carba-np-tests-for-detection-and-classification-of-carbapenemases
#2
Gina Thomson, David Turner, William Brasso, Susan Kircher, Thierry Guillet, Kenneth Thomson
There is an urgent need for rapid, accurate detection and classification of carbapenemases. The current study evaluated the automated BD Phoenix™ CPO Detect and the manual bioMérieux RAPIDEC® CARBA NP for meeting these needs. Both tests were challenged with 294 Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii chosen to provide extreme diagnostic difficulty. Carbapenemases such as KPC, NMC-A, IMI, SME, NDM, SPM, IMP, VIM, OXA-23, 40, 48, 58, 72, 181, and 232 were produced by 243 isolates and 51 carbapenemase-negative isolates included porin mutants and producers of ESBLs, AmpCs, K1, and broad spectrum β-lactamases...
October 4, 2017: Journal of Clinical Microbiology
https://www.readbyqxmd.com/read/28942664/-clinical-aspects-of-severe-infections-caused-by-antibiotic-resistant-gram-negative-bacteria-the-empire-strikes-back
#3
János Sinkó
In our days, growing incidence of antibiotic resistant bacteria has become an eminent public health problem. For survival Gram-negative species possess several different tools to withstand antibiotics: they produce degrading and modifying enzymes, decrease their permeability or expel drug molecules. An increasing proportion of severe nosocomial infections are caused by strains resistant to several antimicrobials (multiresistant, extensively resistant or panresistant species). Development of new antibiotic compounds may serve as a possible solution to this problem...
October 2017: Orvosi Hetilap
https://www.readbyqxmd.com/read/28929963/-comparison-of-phenotypic-methods-and-polymerase-chain-reaction-for-the-detection-of-carbapenemase-production-in-clinical-klebsiella-pneumoniae-isolates
#4
Yamaç Tekintaş, Feriha Çilli, Bayrı Eraç, Melike Yaşar, Sabire Şöhret Aydemir, Mine Hoşgör Limoncu
Being a member of the Enterobacteriaceae family, Klebsiella pneumoniae is an opportunistic pathogen that inhabits normal human microbiota and causes predominantly hospital-acquired infections. The emergence of K.pneumoniae isolates which are resistant particularly to the carbapenem group of antibiotics has led to an increase in hospitalization period, mortality and morbidity. Although different rates of resistance are observed between countries, regions and even healthcare facilities, there has been a rapid increase in the prevalence of carbapenem-resistant strains in the last 10 years...
July 2017: Mikrobiyoloji Bülteni
https://www.readbyqxmd.com/read/28807908/activity-of-the-%C3%AE-lactamase-inhibitor-ln-1-255-against-carbapenem-hydrolyzing-class-d-%C3%AE-lactamases-from-acinetobacter-baumannii
#5
Juan Carlos Vázquez-Ucha, María Maneiro, Marta Martínez-Guitián, John Buynak, Christopher R Bethel, Robert A Bonomo, Germán Bou, Margarita Poza, Concepción González-Bello, Alejandro Beceiro
The number of infections caused by Gram-negative pathogens carrying carbapenemases is increasing, and the group of carbapenem-hydrolyzing class D β-lactamases (CHDLs) is especially problematic. Several clinically important CHDLs have been identified in A. baumannii, including OXA-23, OXA-24/40, OXA-58, OXA-143, OXA-235, and the chromosomally encoded OXA-51. The selection and dissemination of carbapenem-resistant A. baumannii strains constitutes a serious global threat. Carbapenems have been successfully utilized as last resort antibiotics for the treatment of multi-drug-resistant A...
August 14, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28782704/geographical-variation-in-therapy-for-bloodstream-infections-due-to-multidrug-resistant-enterobacteriaceae-a-post-hoc-analysis-of-the-increment-study
#6
Patrick N A Harris, M Diletta Pezzani, Belén Gutiérrez-Gutiérrez, Pierluigi Viale, Po-Ren Hsueh, Patricia Ruiz-Garbajosa, Mario Venditti, Mario Tumbarello, Carolina Navarro-Francisco, Esther Calbo, Murat Akova, Helen Giamarellou, Antonio Oliver, Benito Almirante, Oriol Gasch, Luis Martínez-Martínez, Mitchell J Schwaber, George Daikos, Johann Pitout, Carmen Peña, Alicia Hernández-Torres, Yohei Doi, Federico Pérez, Felipe Francisco Tuon, Evelina Tacconelli, Yehuda Carmeli, Robert A Bonomo, Álvaro Pascual, David L Paterson, Jesús Rodríguez-Baño
We aimed to describe regional differences in therapy for bloodstream infection (BSI) caused by extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-E) or carbapenemase-producing Enterobacteriaceae (CPE). 1,482 patients in 12 countries were included from an observational study of BSI caused by ESBL-E or CPE. Multivariate logistic regression was used to calculate adjusted odds ratios (aORs) for the influence of country of recruitment on empirical use of β-lactam/β-lactamase inhibitors (BLBLI) or carbapenems, targeted use of BLBLI for ESBL-E and use of targeted combination therapy for CPE...
August 3, 2017: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/28777084/the-role-of-conserved-surface-hydrophobic-residues-in-the-carbapenemase-activity-of-the-class-d-%C3%AE-lactamases
#7
Marta Toth, Clyde A Smith, Nuno T Antunes, Nichole K Stewart, Lauren Maltz, Sergei B Vakulenko
Carbapenem-hydrolyzing class D β-lactamases (CHDLs) produce resistance to the last-resort carbapenem antibiotics and render these drugs ineffective for the treatment of life-threatening infections. Here, it is shown that among the clinically important CHDLs, OXA-143 produces the highest levels of resistance to carbapenems and has the highest catalytic efficiency against these substrates. Structural data demonstrate that acylated carbapenems entirely fill the active site of CHDLs, leaving no space for water molecules, including the deacylating water...
August 1, 2017: Acta Crystallographica. Section D, Structural Biology
https://www.readbyqxmd.com/read/28767588/successful-ceftazidime-avibactam-treatment-of-mdr-kpc-positive-klebsiella-pneumoniae-infection-in-a-patient-with-traumatic-brain-injury-a-case-report
#8
Agnese Gugliandolo, Carla Caio, Maria Lina Mezzatesta, Carmela Rifici, Placido Bramanti, Stefania Stefani, Emanuela Mazzon
RATIONALE: Carbapenem-resistant Enterobacteriaceae infections are a serious health care problem, because of the high mortality. Carbapenem resistance is mainly caused by carbapenemases production, including Klebsiella pneumoniae carbapenemase (KPC). Ceftazidime-avibactam is a new cephalosporin/β-lactamase inhibitor combination for the treatment of complicated urinary, intra-abdominal infections, and nosocomial pneumonia caused by gram negative, or other serious gram-negative infections...
August 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/28743813/curative-treatment-of-severe-gram-negative-bacterial-infections-by-a-new-class-of-antibiotics-targeting-lpxc
#9
Nadine Lemaître, Xiaofei Liang, Javaria Najeeb, Chul-Jin Lee, Marie Titecat, Emmanuelle Leteurtre, Michel Simonet, Eric J Toone, Pei Zhou, Florent Sebbane
The infectious diseases caused by multidrug-resistant bacteria pose serious threats to humankind. It has been suggested that an antibiotic targeting LpxC of the lipid A biosynthetic pathway in Gram-negative bacteria is a promising strategy for curing Gram-negative bacterial infections. However, experimental proof of this concept is lacking. Here, we describe our discovery and characterization of a biphenylacetylene-based inhibitor of LpxC, an essential enzyme in the biosynthesis of the lipid A component of the outer membrane of Gram-negative bacteria...
July 25, 2017: MBio
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
#10
Mariana Castanheira, Michael D Huband, Rodrigo E Mendes, Robert K Flamm
We evaluated the activity of meropenem-vaborbactam against contemporary nonfastidious Gram-negative clinical isolates, including Enterobacteriaceae isolates with resistance phenotypes and carbapenemase genotypes. Meropenem-vaborbactam (inhibitor at 8 μg/ml) and comparators were susceptibility tested by reference broth microdilution methods against 14,304 Gram-negative clinical isolates collected worldwide during 2014. Carbapenemase-encoding genes were screened by PCR and sequencing. Meropenem-vaborbactam (MIC50/90, ≤0...
September 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
#11
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-residues-119-and-228-in-substrate-and-inhibitor-binding
#12
Susann Skagseth, Tony Christopeit, Sundus Akhter, Annette Bayer, Ørjan Samuelsen, Hanna-Kirsti S Leiros
Metallo-β-lactamases (MBLs) threaten the effectiveness of β-lactam antibiotics, including carbapenems, and are a concern for global public health. β-Lactam/β-lactamase inhibitor combinations active against class A and class D carbapenemases are used, but no clinically useful MBL inhibitor is currently available. Tripoli metallo-β-lactamase-1 (TMB-1) and TMB-2 are members of MBL subclass B1a, where TMB-2 is an S228P variant of TMB-1. The role of S228P was studied by comparisons of TMB-1 and TMB-2, and E119 was investigated through the construction of site-directed mutants of TMB-1, E119Q, E119S, and E119A (E119Q/S/A)...
August 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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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