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Mark G Wise, Elizabeth Horvath, Katherine Young, Daniel F Sahm, Krystyna M Kazmierczak
PURPOSE: To understand the diversity of porin disruption in Klebsiella pneumoniae, the major outer membrane protein (OMP) porins, OmpK35 and OmpK36, were examined in a set of isolates that did not harbour traditional carbapenem-hydrolysing enzymes, but nevertheless tested non-susceptible to ertapenem. METHODS: A world-wide collection of Klebsiella pneumoniae isolates that were part of the Study for Monitoring Antimicrobial Resistance Trends (SMART) surveillance project over the years 2008-2014 were characterised with regard to their β-lactamase gene carriage and potential permeability defects...
March 2018: Journal of Medical Microbiology
Yafei Ye, Lijuan Xu, Yanping Han, Zhe Chen, Cailin Liu, Liang Ming
Carbapenemase-producing 'super bacteria', particularly NDM-1 and its variants, have become a major public health concern worldwide. The present study aimed to explore the molecular mechanism for carbapenem resistance of clinical Enterobacteriaceae isolates. Seventy-eight non-repeated Enterobacteriaceae strains resistant to any carbapenem were screened at the First Affiliated Hospital of Zhengzhou University (Zhengzhou, China) between December 2011 and December 2015. Outer membrane porin (OMP) proteins were detected using SDS-PAGE...
January 2018: Experimental and Therapeutic Medicine
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
Alejandra Vera-Leiva, Sergio Carrasco-Anabalón, Celia A Lima, Nicolás Villagra, Mariana Domínguez, Helia Bello-Toledo, Gerardo González-Rocha
OBJECTIVES: KPC-producing strains present a wide range of MICs of carbapenems; this variation may be due to different gene expression levels of the blaKPC and porin genes, associated with efflux-pumps and the production of ESBLs and/or AmpC β-lactamase. The aim of this study was to determine the role of efflux-pumps inhibited by PAβN in the resistance to carbapenems in Chilean clinical isolates of K. pneumoniae harbouring the gene blaKPC. METHODS: Minimum Inhibitory Concentration (MIC) was determined by the agar dilution method for imipenem, meropenem, ertapenem and ciprofloxacin in the presence and absence of PAβN (25mg/L)...
December 21, 2017: Journal of Global Antimicrobial Resistance
Toyotaka Sato, Kazuki Harada, Masaru Usui, Yuzo Tsuyuki, Tsukasa Shiraishi, Yutaka Tamura, Shin-Ichi Yokota
Transmission of tigecycline-nonsusceptible pathogenic Enterobacteriaceae from companion animals to human should be a concern because tigecycline is a last-line drug for treating multidrug-resistant Enterobacteriaceae in human medicine. However, tigecycline susceptibility of Enterobacteriaceae isolated from companion animals has not been investigated. In this study, we investigated the tigecycline susceptibility of Klebsiella pneumoniae complex and Escherichia coli isolates from dogs and cats, and evaluated their human pathogenicity potential...
December 12, 2017: Microbial Drug Resistance: MDR: Mechanisms, Epidemiology, and Disease
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)...
January 2018: Drugs
Naina Adren Pinto, Roshan D'Souza, In Sik Hwang, Jongrak Choi, Yong Ha In, Hyung Soon Park, Choong-Min Ryu, Dongeun Yong, Kyungwon Lee
To detect the outer membrane protein (OMP), which plays a key role in carbapenem resistance, whole-genome and transcriptome analysis of the clinical carbapenem-resistant Klebsiella pneumoniae was carried out. The index strain lacked both OmpK35 and OmpK36, whereas the other strains lacked only OmpK35. After SDS-PAGE, the putative OMP bands were excised and identified as OmpA and OmpK36. MALDI-TOF MS showed peaks at ∼36 and ∼38 kDa that corresponded to OmpA and OmpK36, respectively. In all the strains except YMC2014/03/P345, the ∼38 kDa peaks were present...
October 17, 2017: Oncotarget
Dongxu Sun, Debora Rubio-Aparicio, Kirk Nelson, Michael N Dudley, Olga Lomovskaya
Vaborbactam (formerly RPX7009) is a new β-lactamase inhibitor based on a cyclic boronic acid pharmacophore with potent inhibitory activity against <u>K</u> lebsiella<u>p</u>neumoniae <u>c</u>arbapenemases (KPC). It has been developed in combination with meropenem. The objective of these studies was to identify the concentrations of both agents associated with the selection or prevention of single-step mutations leading to reduced sensitivity to the combination and to characterize the selected mutations...
December 2017: Antimicrobial Agents and Chemotherapy
Litty Babu, Siva R Uppalapati, Murali H Sripathy, Prakash N Reddy
Safety and protective efficacy of recombinant multi-epitope subunit vaccine (r-AK36) was evaluated in a mouse model. Recombinant AK36 protein comprised of immunodominant antigens from outer membrane proteins (Omp's) of Klebsiella pneumoniae namely OmpA and OmpK36. r-AK36 was highly immunogenic and the hyperimmune sera reacted strongly with native OmpA and OmpK36 proteins from different K. pneumoniae strains. Hyperimmune sera showed cross-reactivity with Omp's of other Gram-negative organisms. Humoral responses showed a Th2-type polarized immune response with IgG1 being the predominant antibody isotype...
2017: Frontiers in Microbiology
Rasha Barwa, Mona Shaaban
BACKGROUND: Emergence of carbapenems-resistant K. pneumoniae represents a serious challenge for antimicrobial therapy. OBJECTIVE: The aim of this research is to determine different mechanisms mediating the emergence of K. pneumoniae isolates with high-level carbapenem resistance. METHOD: A total of 80 K. pneumoniae isolates were purified from sputum and urine specimens. The minimum inhibitory concentrations (MICs) of imipenem and meropenem were determined by broth microdilution method...
2017: Open Microbiology Journal
Kirk Nelson, Peera Hemarajata, Dongxu Sun, Debora Rubio-Aparicio, Ruslan Tsivkovski, Shangxin Yang, Robert Sebra, Andrew Kasarskis, Hoan Nguyen, Blake M Hanson, Shana Leopold, George Weinstock, Olga Lomovskaya, Romney M Humphries
Ceftazidime-avibactam is an antibiotic with activity against serine beta-lactamases, including Klebsiella pneumoniae carbapenemase (KPC). Recently, reports have emerged of KPC-producing isolates resistant to this antibiotic, including a report of a wild-type KPC-3 producing sequence type 258 Klebsiella pneumoniae that was resistant to ceftazidime-avibactam. We describe a detailed analysis of this isolate, in the context of two other closely related KPC-3 producing isolates, recovered from the same patient. Both isolates encoded a nonfunctional OmpK35, whereas we demonstrate that a novel T333N mutation in OmpK36, present in the ceftazidime-avibactam resistant isolate, reduced the activity of this porin and impacted ceftazidime-avibactam susceptibility...
October 2017: Antimicrobial Agents and Chemotherapy
C Vuotto, F Longo, C Pascolini, G Donelli, M P Balice, M F Libori, V Tiracchia, A Salvia, P E Varaldo
AIMS: Multidrug-resistant Klebsiella pneumoniae has become a relevant healthcare-associated pathogen. Capsule, type 1 and 3 fimbriae (mrkA gene), type 2 quorum-sensing system (luxS), synthesis of D-galactan I (wbbM), LPS transport (wzm) and poly-beta-1,6-N-acetyl-D-glucosamine (pgaA) seem involved in K. pneumoniae biofilm. Nonenzymatic antibiotic resistance is related to nonexpression or mutation of porins (OmpK35 and OmpK36), and efflux pump (acrB) overexpression. The aim of this study was to analyse some virulence factors of K...
July 21, 2017: Journal of Applied Microbiology
Wenzi Bi, Haiyang Liu, Rhys A Dunstan, Bin Li, Von Vergel L Torres, Jianming Cao, Lijiang Chen, Jonathan J Wilksch, Richard A Strugnell, Trevor Lithgow, Tieli Zhou
The rise in diversity of antimicrobial resistance phenotypes seen in Klebsiella pneumoniae is becoming a serious antibiotic management problem. We sought to investigate the molecular characteristics and clinical implications of extensively drug-resistant (XDR) K. pneumoniae isolated from different nosocomial bloodstream infections (BSIs) patients from July 2013 to November 2015. Even in combination treatment, meropenem did not protect against mortality of BSIs patients (P = 0.015). In contrast, tigecycline in combination with other antimicrobial agents significantly protected against mortality (P = 0...
2017: Frontiers in Microbiology
Naina Adren Pinto, Roshan D'Souza, In Sik Hwang, Jongrak Choi, Yong Ha In, Hyung Soon Park, Choong-Min Ryu, Dongeun Yong, Kyungwon Lee
To detect the outer membrane protein (OMP), which plays a key role in carbapenem resistance, whole-genome and transcriptome analysis of the clinical carbapenem-resistant Klebsiella pneumoniae was carried out. The index strain lacked both OmpK35 and OmpK36, whereas the other strains lacked only OmpK35. After SDS-PAGE, the putative OMP bands were excised and identified as OmpA and OmpK36. MALDI-TOF MS showed peaks at ~36 and ~38 kDa that corresponded to OmpA and OmpK36, respectively. In all the strains except YMC2014/03/P345, the ~38 kDa peaks were present...
July 5, 2017: Oncotarget
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 MICs against 100 CRE isolates that underwent whole-genome sequencing. Klebsiella pneumoniae carbapenemases (KPCs) were the most common carbapenemases. Forty-six isolates carried extended-spectrum β-lactamases (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 metallo-β-lactamase (MBL) producers...
September 2017: Antimicrobial Agents and Chemotherapy
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
Anastasia I Lev, Evgeny I Astashkin, Rima Z Shaikhutdinova, Mikhail E Platonov, Nikolay N Kartsev, Nikolay V Volozhantsev, Olga N Ershova, Edward A Svetoch, Nadezhda K Fursova
Hospital Klebsiella pneumoniae strains (n = 196) were collected in 2012-16 from the patients of a Moscow neurosurgical intensive care unit. Klebsiella pneumoniae strains were multidrug-resistant and carried beta-lactamase genes blaSHV (97.4% of strains), blaCTX-M (84.7%), blaTEM (56.1%), blaOXA-48-like (49.0%) and blaNDM-1 (one strain), class 1 integrons (43.4% of strains) and porin protein ompK36 gene (100% of strains). The ompK36 porin protein gene disruption by insertion sequence (IS) elements and OmpK36 production loss in two strains were detected in this study...
May 1, 2017: FEMS Microbiology Letters
Zhen Shen, Baixing Ding, Meiping Ye, Peng Wang, Yingmin Bi, Shi Wu, Xiaogang Xu, Qinglan Guo, Minggui Wang
Objectives: To investigate mechanisms for the decreased susceptibility to ceftazidime/avibactam in KPC-producing Klebsiella pneumoniae (KPC-KP). Methods: A total of 24 isolates, 8 each with ceftazidime/avibactam MICs of 4-8, 1-2 and ≤0.5 mg/L, were randomly selected from 214 clinical isolates of KPC-KP, and the β-lactamase hydrolysis activity and porin expression profiles were determined. Plasmid profile and relative expression and copy number of the bla KPC gene were also analysed...
July 1, 2017: Journal of Antimicrobial Chemotherapy
Ryan K Shields, M Hong Nguyen, Ellen G Press, Liang Chen, Barry N Kreiswirth, Cornelius J Clancy
Ceftazidime-avibactam resistance is mediated by blaKPC-3 mutations, which restore carbapenem susceptibility. We subjected Klebsiella pneumoniae isolates with different blaKPC-3 mutations (n = 5) or wild-type blaKPC-3 (n = 2) to serial passages with meropenem. The meropenem MIC against each isolate increased. Mutations in the ompK36 porin gene evolved in 5 isolates. Among isolates with D179Y substitutions in KPC-3, blaKPC-3 mutations reverted to wild type, were replaced by new mutations, or were retained. Carbapenem treatment of ceftazidime-avibactam-resistant K...
May 2017: Antimicrobial Agents and Chemotherapy
Mariana Castanheira, Rodrigo E Mendes, Helio S Sader
Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae isolates have been increasingly reported worldwide, and therapeutic options to treat infections caused by these organisms are limited. We evaluated the activity of ceftazidime-avibactam and comparators against 456 Enterobacteriaceae isolates carrying blaKPC collected from 79 U.S. hospitals during 2012 to 2015. Overall, ceftazidime-avibactam (MIC50/90, 0.5/2 μg/ml; 99.3% susceptible) and tigecycline (MIC50/90, 0.5/1 μg/ml; 98.9% susceptible at ≤2 μg/ml) were the most active agents...
March 2017: Antimicrobial Agents and Chemotherapy
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