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Carbapenemase inhibitor

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https://www.readbyqxmd.com/read/29649276/carbapenem-resistant-gram-negative-pathogens-in-a-german-university-medical-center-prevalence-clinical-implications-and-the-role-of-novel-%C3%AE-lactam-%C3%AE-lactamase-inhibitor-combinations
#1
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
https://www.readbyqxmd.com/read/29627985/strategic-approaches-to-overcome-resistance-against-gram-negative-pathogens-using-%C3%AE-lactamase-inhibitors-and-%C3%AE-lactam-enhancers-the-activity-of-three-novel-diazabicyclooctanes-wck-5153-zidebactam-wck-5107-and-wck-4234
#2
Krisztina M Papp-Wallace, Nhu Q Nguyen, Michael R Jacobs, Christopher R Bethel, Melissa D Barnes, Vijay Kumar, Saralee Bajaksouzian, Susan D Rudin, Philip N Rather, Satish Bhavsar, Tadiparthi Ravikumar, Prasad K Deshpande, Vijay Patil, Ravindra Yeole, Sachin S Bhagwat, Mahesh V Patel, Focco van den Akker, Robert A Bonomo
Limited treatment options exist to combat infections caused by multidrug-resistant (MDR) Gram negative bacteria possessing broad-spectrum β-lactamases. The design of novel β-lactamase inhibitors is of paramount importance. Here, three novel diazabicyclooctanes (DBOs), WCK 5153, zidebactam (WCK 5107), and WCK 4234 (compounds 1-3) were synthesized and biochemically characterized against clinically important bacteria. Compound 3 inhibited class A, C and D β-lactamases with unprecedented k2/K values against OXA carbapenemases...
April 7, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29610205/relebactam-is-a-potent-inhibitor-of-the-kpc-2-%C3%AE-lactamase-and-restores-the-susceptibility-of-imipenem-against-kpc-producing-enterobacteriaceae
#3
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
https://www.readbyqxmd.com/read/29531581/evaluation-of-combined-use-of-temocillin-disk-and-mastdisks-inhibitor-combination-set-against-polymerase-chain-reaction-for-detection-of-carbapenem-resistant-enterobacteriaceae
#4
Omnia A Shaker, Howayda E Gomaa, Shereen A ElMasry, Rania M Abdel Halim, Amany H Abdelrahman, Jackline S Kamal
AIM: To evaluate the diagnostic performance of MDI and temocillin disk (30 μg) for detection of carbapenem-resistant Enterobacteriaceae in comparison to real-time PCR. MATERIAL AND METHODS: Fifty specimens submitted to the Microbiology Laboratory of Ain Shams University Hospitals and showed resistance to carbapenem drugs through routine culture and susceptibility testing, were assessed by both temocillin disk (30 μg) and MDI set to detect carbapenem-resistant Enterobacteriaceae ...
February 15, 2018: Open Access Macedonian Journal of Medical Sciences
https://www.readbyqxmd.com/read/29530861/discovery-of-a-novel-metallo-%C3%A3-lactamase-inhibitor-which-can-potentiate-meropenem-activity-against-carbapenem-resistant-enterobacteriaceae
#5
Martin Everett, Nicolas Sprynski, Alicia Coelho, Jérôme Castandet, Maëlle Bayet, Juliette Bougnon, Clarisse Lozano, David T Davies, Simon Leiris, Magdalena Zalacain, Ian Morrissey, Sophie Magnet, Kirsty Holden, Peter Warn, Filomena De Luca, Jean-Denis Docquier, Marc Lemonnier
Infections caused by carbapenem-resistant Enterobacteriaceae (CRE) are increasingly prevalent and have become a major worldwide threat to human health. Carbapenem resistance is driven primarily by the acquisition of β-lactamase enzymes which are able to degrade carbapenem antibiotics (hence termed carbapenemases) and can result in high levels of resistance and treatment failure. Clinically relevant carbapenemases include both serine-β-lactamases (SBLs, e.g. KPC-2 and OXA-48) and metallo-β-lactamases (MBLs), such as NDM-1...
March 12, 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29514462/meropenem-vaborbactam-the-first-carbapenem-%C3%AE-lactamase-inhibitor-combination
#6
Jonathan C Cho, Monika T Zmarlicka, Kristy M Shaeer, Joe Pardo
OBJECTIVE: To review the pharmacology, spectrum of activity, pharmacokinetics, pharmacodynamics, safety, efficacy, administration, and considerations for clinical use of meropenem/vaborbactam (M/V). DATA SOURCES: A literature search using PubMed and clinicaltrials.gov (June 2013 to December 2017) was conducted using the search terms meropenem, vaborbactam, RPX7009, biapenem, RPX2003, and carbavance. References from relevant articles and conference abstracts were also reviewed...
March 1, 2018: Annals of Pharmacotherapy
https://www.readbyqxmd.com/read/29510189/in-vitro-activity-of-meropenem-vaborbactam-and-characterization-of-carbapenem-resistance-mechanisms-among-carbapenem-resistant-enterobacteriaceae-from-the-2015-meropenem-vaborbactam-surveillance-program
#7
Michael A Pfaller, Michael D Huband, Rodrigo E Mendes, Robert K Flamm, Mariana Castanheira
We evaluated meropenem-vaborbactam activity against 11,559 Enterobacteriaceae isolates, including 330 carbapenem-resistant phenotypes (CRE) and carbapenemase genotypes collected worldwide during 2015. Meropenem-vaborbactam (inhibitor at 8 mg/L) and comparators were susceptibility tested using reference broth microdilution methods. CRE isolates were screened for the presence of genes encoding carbapenemases and 292 (88.5%) of the CRE isolates carried these resistance genes. A total of 209 (63.3% of the CRE; 1...
March 3, 2018: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/29499316/ceftazidime-avibactam-susceptibility-by-three-different-susceptibility-testing-methods-in-carbapenemase-producing-gram-negative-bacteria-from-australia
#8
Norelle L Sherry, Sarah L Baines, Benjamin P Howden
Avibactam is a novel β-lactamase inhibitor active against classes A, C and some class D β-lactamases. In combination with ceftazidime, it may be useful for the treatment of infections due to carbapenemase-producing Gram negative (CPGN) bacteria from these classes; however, susceptibility data for some of the less-common carbapenemases are limited. To assess the in vitro activity of ceftazidime-avibactam (CZA), we tested a panel of fifty diverse CPGN collected from clinical isolates in Victoria, Australia, containing KPC, GES, SME, OXA-23 and OXA-48-like carbapenemases for CZA susceptibility using broth microdilution (BMD), E-tests and disc diffusion...
February 27, 2018: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/29444952/treatment-of-infections-caused-by-extended-spectrum-beta-lactamase-ampc-and-carbapenemase-producing-enterobacteriaceae
#9
REVIEW
Jesús Rodríguez-Baño, Belén Gutiérrez-Gutiérrez, Isabel Machuca, Alvaro Pascual
Therapy of invasive infections due to multidrug-resistant Enterobacteriaceae (MDR-E) is challenging, and some of the few active drugs are not available in many countries. For extended-spectrum β-lactamase and AmpC producers, carbapenems are the drugs of choice, but alternatives are needed because the rate of carbapenem resistance is rising. Potential active drugs include classic and newer β-lactam-β-lactamase inhibitor combinations, cephamycins, temocillin, aminoglycosides, tigecycline, fosfomycin, and, rarely, fluoroquinolones or trimethoprim-sulfamethoxazole...
April 2018: Clinical Microbiology Reviews
https://www.readbyqxmd.com/read/29442147/-urosepsis
#10
Mathias W Pletz, Sebastian Weis, Christina Forstner, Florian Wagenlehner
Urosepsis is defined as a severe disease due to organ failure caused by a urinary tract infection. An empirical antibiotic therapy should be instigated within the first hour after diagnosis. Urine cultures and blood cultures should be performed before antibiotic treatment. Further diagnostics should be carried out at an early stage to enable an interventional focus control in the case of urinary tract obstruction or abscess formation, if necessary. Gram-negative pathogens are most frequently isolated. Extended spectrum beta-lactamase (ESBL) forming bacteria as a cause of urosepsis are increasing...
March 2018: Medizinische Klinik, Intensivmedizin und Notfallmedizin
https://www.readbyqxmd.com/read/29432937/detection-of-vim-2-imp-1-and-ndm-1-producing-multidrug-resistant-pseudomonas-aeruginosa-in-malaysia
#11
Siew Mun Liew, Ganeswrei Rajasekaram, Savithri D Puthucheary, Kek Heng Chua
OBJECTIVES: The increasing incidence of carbapenem-resistant Pseudomonas aeruginosa along with the discovery of novel metallo-β-lactamases (MBLs) is of concern. In this study, the isolation of Malaysian MBL-producing P. aeruginosa clinical strains was investigated. METHODS: Fifty-three P. aeruginosa clinical strains were isolated from different patients in Sultanah Aminah Hospital, Johor Bahru, Malaysia in 2015. Antimicrobial susceptibility test was conducted. Minimum inhibitory concentrations (MICs) of imipenem and meropenem were determined by Etest...
February 9, 2018: Journal of Global Antimicrobial Resistance
https://www.readbyqxmd.com/read/29427523/meropenem-and-vaborbactam-stepping-up-the-battle-against-carbapenem-resistant-enterobacteriaceae
#12
Sarah Christina Jane Jorgensen, Michael Joseph Rybak
Vaborbactam (VAB; formerly RPX7009) is a novel beta-lactamase inhibitor based on a cyclic boronic acid pharmacophore with potent inhibitory activity against Ambler class A and C beta-lactamases. It has been co-formulated with meropenem to restore its activity against Klebsiella pneumoniae carbapenemases (KPC). VAB does not inhibit class B or D carbapenemases, nor does it improve the activity of meropenem against multidrug-resistant non-fermenting Gram-negative bacilli, notably Acinetobacter spp. and Pseudomonas aeruginosa...
February 10, 2018: Pharmacotherapy
https://www.readbyqxmd.com/read/29422890/embelin-restores-carbapenem-efficacy-against-ndm-1-positive-pathogens
#13
Nian-Zhi Ning, Xiong Liu, Fanghong Chen, Peng Zhou, Lihong Hu, Jian Huang, Zhan Li, Jie Huang, Tao Li, Hui Wang
The emergence and spread of carbapenemase in Gram-negative pathogens poses an enormous threat to global public health. New Delhi metallo-β-lactamase-1 (NDM-1) inactivates nearly every class of β-lactam antibiotics, including carbapenem; however, there is no clinically useful NDM-1 inhibitor. Embelin, an important ingredient in traditional herbal medicine, has anti-tumor effects. The current study is the first to discover and examine the inhibitory activity of embelin against β-lactamase NDM-1. The IC50 of embelin was 2...
2018: Frontiers in Microbiology
https://www.readbyqxmd.com/read/29373087/an-outbreak-of-ndm-1-producing-klebsiella-pneumoniae-associated-with-ompk35-and-ompk36-porin-loss-in-tunisia
#14
Zaineb Hamzaoui, Alain Ocampo-Sosa, Elaa Maamar, Marta Fernandez Martinez, Sana Ferjani, Samia Hammami, Sarra Harbaoui, Nathalie Genel, Guillaume Arlet, Mabrouka Saidani, Amine Slim, Ilhem Boutiba-Ben Boubaker, Luis Martinez-Martinez
OBJECTIVES: To describe clinical and molecular characteristics of an outbreak due to metallo-β-lactamases (MBLs) producing Klebsiella pneumoniae collected at Charles Nicolle Hospital of Tunis and to analyze the impact of outer membrane porin (OMP) loss on carbapenem resistance levels. METHODS: Between 2010 and 2015, 178 carbapenem-resistant Enterobacteriaceae were isolated. Screening for MBL production was performed using combined disk diffusion method, with imipenem and ethylene diamine tetraacetic acid (EDTA) as inhibitors...
January 26, 2018: Microbial Drug Resistance: MDR: Mechanisms, Epidemiology, and Disease
https://www.readbyqxmd.com/read/29358299/shaping-substrate-selectivity-in-a-broad-spectrum-metallo-%C3%AE-lactamase
#15
Lisandro J González, Cintia Stival V, Juan L Puzzolo, Diego M Moreno, Alejandro J Vila
Metallo-β-lactamases (MBLs) are the major group of carbapenemases produced by bacterial pathogens. The design of MBL inhibitors has been limited, among other issues, by the incomplete knowledge about how these enzymes modulate substrate recognition. While most MBLs are broad-spectrum enzymes, B2 MBLs are exclusive carbapenemases. This narrower substrate profile has been attributed to a sequence insertion present in B2 enzymes that limits the accessibility to the active site. In this work, we evaluate the role of sequence insertions naturally occurring in the B2 enzyme Sfh-I and in the broad-spectrum B1 enzyme SPM-1...
January 22, 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29356380/phenyl-boronic-acids-development-led-to-validated-leads-active-in-clinical-strains-overexpressing-kpc-2-a-step-against-bacterial-resistance
#16
Giuseppe Celenza, Mattia Vicario, Pierangelo Bellio, Linciano Pasquale, Mariagrazia Perilli, Antonio Oliver, Jesus Blazquez, Laura Cendron, Donatella Tondi
The emergence and dissemination of multi drug resistant (MDR) pathogens resistant to near all available antibiotics poses a significant threat in clinical therapy. Among them, Klebsiella pneumoniae clinical isolates overexpressing KPC-2 carbapenemase are the most worrisome, extending bacterial resistance to last resort carbapenems. In this study we investigate the molecular recognition requirements in KPC-2 active site by small phenyl boronic acid derivatives. Four new phenyl boronic acid derivatives were designed and tested vs KPC-2...
January 22, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29322236/-urosepsis
#17
Mathias W Pletz, Sebastian Weis, Christina Forstner, Florian Wagenlehner
Urosepsis is defined as a severe disease due to organ failure caused by a urinary tract infection. An empirical antibiotic therapy should be instigated within the first hour after diagnosis. Urine cultures and blood cultures should be performed before antibiotic treatment. Further diagnostics should be carried out at an early stage to enable an interventional focus control in the case of urinary tract obstruction or abscess formation, if necessary. Gram-negative pathogens are most frequently isolated. Extended spectrum beta-lactamase (ESBL) forming bacteria as a cause of urosepsis are increasing...
January 2018: Der Urologe. Ausg. A
https://www.readbyqxmd.com/read/29311069/single-dose-pharmacokinetics-and-safety-of-meropenem-vaborbactam-in-subjects-with-chronic-renal-impairment
#18
Christopher M Rubino, Sujata M Bhavnani, Jeffery S Loutit, Brooke Lohse, Michael N Dudley, David C Griffith
Vaborbactam is a member of a new class of β-lactamase inhibitors with inhibitory activity against serine carbapenemases (e.g., Klebsiella pneumoniae carbapenemase) that has been developed in combination with meropenem. The pharmacokinetics of the combination was evaluated in 41 subjects with chronic renal impairment in a phase 1, open-label, single-dose study. Subjects were assigned to one of five groups based on renal function: normal (creatinine clearance of ≥90 ml/min), mild (estimated glomerular filtration rate [eGFR] of 60 to 89 ml/min/1...
March 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29276104/determination-of-mic-and-disk-diffusion-quality-control-guidelines-for-meropenem-vaborbactam-a-novel-carbapenem-boronic-acid-%C3%AE-lactamase-inhibitor-combination
#19
Erik Munson, Michael D Huband, Mariana Castanheira, Kelley A Fedler, Robert K Flamm
Meropenem-vaborbactam is a carbapenem/cyclic boronic acid β-lactamase inhibitor combination primarily active against Gram-negative bacilli, including those harboring class A serine carbapenemases such as Klebsiella pneumoniae carbapenemase (KPC). A Clinical and Laboratory Standards Institute M23-A4 (Tier 2) quality control study established broth microdilution and disk diffusion ranges for reference strains. Two KPC-producing K. pneumoniae ATCC strains are recommended for quality control testing.
April 2018: Diagnostic Microbiology and Infectious Disease
https://www.readbyqxmd.com/read/29274802/susceptibility-testing-and-detection-of-%C3%AE-lactam-resistance-mechanisms-in-enterobacteriaceae-a-multicentre-national-proficiency-study
#20
María Díez-Aguilar, María-Carmen Conejo, María-Isabel Morosini, Núria Tormo Palop, Concepción Gimeno, Rafael Cantón, Álvaro Pascual
A nationwide study was developed to evaluate the ability of 60 Spanish clinical microbiology laboratories to predict the underlying β-lactam resistance mechanisms of 12 Enterobacteriaceae strains (CCS01-CCS12). Results obtained by two reference laboratories were compared with those reported by the participant laboratories that used their own routine susceptibility testing methodology. Clinical and Laboratory Standards Institute (CLSI) interpretive criteria were used in 53.3% of centres, whilst 46.7% used European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria...
April 2018: International Journal of Antimicrobial Agents
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