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Carbapenemase inhibitor

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https://www.readbyqxmd.com/read/29232103/game-changers-new-%C3%AE-lactamase-inhibitor-combinations-targeting-antibiotic-resistance-in-gram-negative-bacteria
#1
Karen Bush
Recent regulatory approvals for the β-lactam inhibitor combinations of ceftazidime-avibactam and meropenem-vaborbactam have provided two novel therapeutic options for the treatment of multidrug-resistant infections caused by Gram-negative bacteria. Most importantly, these combination agents have satisfied an important medical need related to antibiotic-resistant Klebsiella pneumoniae that produce serine carbapenemases, especially the Klebsiella pneumoniae carbapenemase (KPC) enzymes. Both combinations contain non-β-lactam β-lactamase inhibitors of novel chemical classes not previously developed as antibacterial agents, the diazabicyclooctanes and cyclic boronic acid derivatives...
December 12, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29230684/imipenem-relebactam-and-meropenem-vaborbactam-two-novel-carbapenem-%C3%AE-lactamase-inhibitor-combinations
#2
REVIEW
George G Zhanel, Courtney K Lawrence, Heather Adam, Frank Schweizer, Sheryl Zelenitsky, Michael Zhanel, Philippe R S Lagacé-Wiens, Andrew Walkty, Andrew Denisuik, Alyssa Golden, Alfred S Gin, Daryl J Hoban, Joseph P Lynch, James A Karlowsky
Relebactam (formerly known as MK-7655) is a non-β-lactam, bicyclic diazabicyclooctane, β-lactamase inhibitor that is structurally related to avibactam, differing by the addition of a piperidine ring to the 2-position carbonyl group. Vaborbactam (formerly known as RPX7009) is a non-β-lactam, cyclic, boronic acid-based, β-lactamase inhibitor. The structure of vaborbactam is unlike any other currently marketed β-lactamase inhibitor. Both inhibitors display activity against Ambler class A [including extended-spectrum β-lactamases (ESBLs), Klebsiella pneumoniae carbapenemases (KPCs)] and class C β-lactamases (AmpC)...
December 12, 2017: Drugs
https://www.readbyqxmd.com/read/29228202/activity-of-ceftazidime-avibactam-against-problem-enterobacteriaceae-and-pseudomonas-aeruginosa-in-the-uk-2015-16
#3
David M Livermore, Danièle Meunier, Katie L Hopkins, Michel Doumith, Robert Hill, Rachel Pike, Peter Staves, Neil Woodford
Background: Ceftazidime/avibactam combines an established oxyimino-cephalosporin with the first diazabicyclooctane β-lactamase inhibitor to enter clinical use. We reviewed its activity against Gram-negative isolates, predominantly from the UK, referred for resistance investigation in the first year of routine testing, beginning in July 2015. Methods: Isolates were as received from referring laboratories; there is a bias to submit those with suspected carbapenem resistance...
December 8, 2017: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/29216350/italian-nationwide-survey-on-pseudomonas-aeruginosa-from-invasive-infections-activity-of-ceftolozane-tazobactam-and-comparators-and-molecular-epidemiology-of-carbapenemase-producers
#4
Tommaso Giani, Fabio Arena, Simona Pollini, Vincenzo Di Pilato, Marco Maria D'Andrea, Lucia Henrici De Angelis, Matteo Bassetti, Gian Maria Rossolini
Objectives: Pseudomonas aeruginosa is a major cause of severe healthcare-associated infections and often shows MDR phenotypes. Ceftolozane/tazobactam is a new cephalosporin/β-lactamase inhibitor combination with potent activity against P. aeruginosa. This survey was carried out to evaluate the susceptibility of P. aeruginosa, circulating in Italy, to ceftolozane/tazobactam and comparators and to investigate the molecular epidemiology of carbapenemase-producing strains. Methods: Consecutive non-replicate P...
December 5, 2017: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/29186432/bacterial-zincophore-s-s-ethylenediamine-n-n-disuccinic-acid-is-an-effective-inhibitor-of-mbls
#5
Anna Proschak, Jan Kramer, Ewgenij Proschak, Thomas A Wichelhaus
Objectives: Carbapenemases such as MBLs are spreading among Gram-negative bacterial pathogens. Infections due to these MDR bacteria constitute a major global health challenge. Therapeutic strategies against carbapenemase-producing bacteria include β-lactamase inhibitor combinations. [S,S]-ethylenediamine-N,N'-disuccinic acid (EDDS) is a chelator and potential inhibitor of MBLs. We investigated the activity of EDDS in combination with imipenem against MBL-producing bacteria in vitro as well as in vivo...
November 23, 2017: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/29144958/isolation-of-blandm-producing-enterobacteriaceae-in-a-public-hospital-in-salvador-bahia-brazil
#6
Maria Goreth Barberino, Silvia de Araujo Cruvinel, Célio Faria, Marco Aurélio Salvino, Márcio Oliveira
Carbapenemases have great importance in the global epidemiological scenario since infections with carbapenemase-producing bacteria are associated with high mortality, especially in hospitalized patients in intensive care units. This study describes two microorganisms producers of the New Delhi Metallo-b-lactamase (NDM), Klebsiella pneumoniae and Citrobacter freundii, from two patients admitted to a public hospital in Salvador, Bahia. These are the first clinical cases of NDM described in microorganisms in the north and northeast Brazil...
November 13, 2017: Brazilian Journal of Infectious Diseases
https://www.readbyqxmd.com/read/29133551/copper-ions-and-coordination-complexes-as-novel-carbapenem-adjuvants
#7
Karrera Y Djoko, Maud E S Achard, Minh-Duy Phan, Alvin W Lo, Manfredi Miraula, Sasiprapa Prombhul, Steven J Hancock, Kate M Peters, Hanna Sidjabat, Patrick N Harris, Nataša Mitić, Timothy R Walsh, Gregory J Anderson, William M Shafer, David L Paterson, Gerhard Schenk, Alastair G McEwan, Mark A Schembri
Carbapenem-resistant Enterobacteriaceae are an urgent threat to global human health. These organisms produce β-lactamases with carbapenemase activity, such as the metallo-β-lactamase NDM-1, which is notable due to its association with mobile genetic elements and the lack of a clinically useful inhibitor. Here we examined the ability of copper to inhibit the activity of NDM-1 and explored the potential of a copper coordination complex as a mechanism to efficiently deliver copper as an adjuvant in clinical therapeutics...
November 13, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29115680/mastdiscs-combi-carba-plus-a-simple-discrimination-method-for-carbapenemase-producing-enterobacteriaceae-including-oxa-48-type-producers
#8
Yusuke Ohsaki, Ryoichi Kubo, Jonathan Hobson, Mya Davies, Shunsuke Osaka, Wataru Hayashi, Yui Taniguchi, Shota Koide, Yukiko Nagano, Noriyuki Nagano
Not only detection of carbapenemases but also identification of their types accurately and rapidly in Enterobacteriaceae is still a major challenge for clinical laboratories in order to prevent the intrusion and the transmission of carbapenemase-producing Enterobacteriaceae. This study aimed to evaluate the performance of the MASTDISCS® combi Carba plus disc system in the identification of different carbapenemase types, including OXA-48-type carbapenemase for which no specific enzyme inhibitors have so far been available...
November 8, 2017: Microbiology and Immunology
https://www.readbyqxmd.com/read/29110143/pharmacological-aspects-and-spectrum-of-action-of-ceftazidime-avibactam-a-systematic-review
#9
REVIEW
Felipe Francisco Tuon, Jaime L Rocha, Marcelo R Formigoni-Pinto
PURPOSE: Ceftazidime-avibactam is an antimicrobial association active against several Enterobacteriaceae species, including those resistant to carbapenem. Considering the importance of this drug in the current panorama of multidrug-resistant bacteria, we performed a systematic review about ceftazidime-avibactam with emphasis on clinical and pharmacological published data. METHODS: A systematic search of the medical literature was performed. The databases searched included MEDLINE, EMBASE and Web of Science (until September 2017)...
November 7, 2017: Infection
https://www.readbyqxmd.com/read/29089425/klebsiella-pneumoniae-carbapenemase-2-kpc-2-substitutions-at-ambler-position-asp179-and-resistance-to-ceftazidime-avibactam-unique-antibiotic-resistant-phenotypes-emerge-from-%C3%AE-lactamase-protein-engineering
#10
Melissa D Barnes, Marisa L Winkler, Magdalena A Taracila, Malcolm G Page, Eric Desarbre, Barry N Kreiswirth, Ryan K Shields, Minh-Hong Nguyen, Cornelius Clancy, Brad Spellberg, Krisztina M Papp-Wallace, Robert A Bonomo
The emergence of Klebsiella pneumoniae carbapenemases (KPCs), β-lactamases that inactivate "last-line" antibiotics such as imipenem, represents a major challenge to contemporary antibiotic therapies. The combination of ceftazidime (CAZ) and avibactam (AVI), a potent β-lactamase inhibitor, represents an attempt to overcome this formidable threat and to restore the efficacy of the antibiotic against Gram-negative bacteria bearing KPCs. CAZ-AVI-resistant clinical strains expressing KPC variants with substitutions in the Ω-loop are emerging...
October 31, 2017: MBio
https://www.readbyqxmd.com/read/29059308/potential-of-high-dose-cefepime-tazobactam-against-multiresistant-gram-negative-pathogens
#11
David M Livermore, Shazad Mushtaq, Marina Warner, Simon J Turner, Neil Woodford
Background: Early β-lactamase inhibitors were combined with established penicillins, but different combinations may be more appropriate to counter current β-lactamase threats, with development facilitated by the US Generating Antibiotic Incentives Now (GAIN) Act. Cefepime/tazobactam is especially attractive, combining an AmpC-stable cephalosporin with a clinically established inhibitor, active against ESBLs and suitable for high-dose administration. Methods: Organisms (n = 563) were clinical isolates submitted to the UK national reference laboratory...
October 20, 2017: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/29020404/colistin-vs-ceftazidime-avibactam-in-the-treatment-of-infections-due-to-carbapenem-resistant-enterobacteriaceae
#12
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
#13
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
#14
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
#15
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
#16
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 Acinetobacter 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 multidrug-resistant A...
November 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
#17
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 describe regional differences in therapy for bloodstream infection (BSI) caused by extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-E) or carbapenemase-producing Enterobacteriaceae (CPE). Patients (n = 1482) in 12 countries from an observational study of BSI caused by ESBL-E or CPE were included. 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 (BLBLIs) or carbapenems, targeted use of BLBLIs 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
#18
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
#19
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
#20
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
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