Read by QxMD icon Read

Carbapenemase inhibitor

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...
October 19, 2016: Expert Opinion on Pharmacotherapy
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
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...
September 8, 2016: Journal of Computer-aided Molecular Design
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
Vincent C C Cheng, Jonathan H K Chen, Simon Y C So, Sally C Y Wong, Pui-Hing Chau, Lisa M W Wong, Radley H C Ching, Modissa M L Ng, Wan-Mui Lee, Ivan F N Hung, Pak-Leung Ho, Kwok-Yung Yuen
OBJECTIVE To study the association between gastrointestinal colonization of carbapenemase-producing Enterobacteriaceae (CPE) and proton pump inhibitors (PPIs). METHODS We analyzed 31,526 patients with prospective collection of fecal specimens for CPE screening: upon admission (targeted screening) and during hospitalization (opportunistic screening, safety net screening, and extensive contact tracing), in our healthcare network with 3,200 beds from July 1, 2011, through December 31, 2015. Specimens were collected at least once weekly during hospitalization for CPE carriers and subjected to broth enrichment culture and multiplex polymerase chain reaction...
September 13, 2016: Infection Control and Hospital Epidemiology
J A Martínez
Directed treatment of infections due to multidrug-resistant Gram-negative bacilli is a difficult task, since it requires the use of a limited number of antibiotics that are often more toxic and possibly less efficacious than β-lactams and fluoroquinolones. Furthermore, there are very few controlled trials informing on the relative efficacy of different therapeutic strategies. As a general rule, it is recommended to use at least two active drugs or a combination with proven synergistic activity in vitro, because several observational studies have associated this practice with better outcomes and as a measure to potentially curb the emergence of further resistance...
September 2016: Revista Española de Quimioterapia: Publicación Oficial de la Sociedad Española de Quimioterapia
Matteo Bassetti, Maddalena Peghin, Davide Pecori
PURPOSE OF REVIEW: Multidrug-resistant (MDR) Enterobacteriaceae are often related to the production of extended-spectrum β-lactamases (ESBLs) and carbapenemases. ESBL and carbapenemase-producing Enterobacteriaceae (CRE), in particular, represent an increasing global threat. Recommendations for the therapeutic management of MDR-related infections, however, are mainly derived from retrospective and nonrandomized prospective studies. The aim of this review is to discuss the challenges in the treatment of patients with infections because of MDR Enterobacteriaceae and provide an expert opinion while awaiting for more definitive data...
August 31, 2016: Current Opinion in Infectious Diseases
K Poole, R George, V Decraene, K Shankar, J Cawthorne, N Savage, W Welfare, A Dodgson
BACKGROUND: Over the past decade, the prevalence of carbapenemase-producing Enterobacteriaceae (CPE) has increased. Whilst basic infection prevention and control practices reduce the risk of transmission, cases of unrecognized carriage pose a potential risk of transmission. AIM: To estimate the prevalence of CPE and explore risk factors associated with colonization within a large teaching hospital with an established CPE outbreak. METHODS: All inpatients that had not previously tested positive for CPE were offered testing...
October 2016: Journal of Hospital Infection
Jose A Hidalgo, Celeste M Vinluan, Nishaal Antony
There has been greater interest in developing additional antimicrobial agents due to the increasing health care costs and resistance resulting from bacterial pathogens to currently available treatment options. Gram-negative organisms including Enterobacteriaceae and Pseudomonas aeruginosa are some of the most concerning threats due to their resistance mechanisms: extended-spectrum beta-lactamase production and Klebsiella pneumoniae carbapenemase enzymes. Ceftazidime is a third-generation broad-spectrum cephalosporin with activity against P...
2016: Drug Design, Development and Therapy
Marco Falcone, David Paterson
During the last decade infections caused by MDR Gram-negative bacteria (GNB) have become increasingly prevalent. Because of their high morbidity and mortality rates, these infections constitute a serious threat to public health worldwide. Ceftazidime/avibactam is a new approved agent combining ceftazidime and a novel β-lactamase inhibitor with activity against various β-lactamases produced by MDR GNB. Avibactam has a spectrum of inhibition of class A and C β-lactamases, including ESBLs, AmpC and Klebsiella pneumoniae carbapenemase (KPC) enzymes...
October 2016: Journal of Antimicrobial Chemotherapy
Mariana Castanheira, Paul R Rhomberg, Robert K Flamm, Ronald N Jones
Klebsiella pneumoniae carbapenemase (KPC)-producing isolates have become increasingly prevalent worldwide, and these organisms are often multidrug resistant, limiting the therapeutic options available for treating infections. We evaluated the activity of meropenem combined with the serine β-lactamase inhibitor vaborbactam (formerly RPX7009) against 315 serine carbapenemase-producing Enterobacteriaceae (CPE) isolates by use of checkerboard-designed panels to assess the optimal inhibitor concentration (range tested, 0...
September 2016: Antimicrobial Agents and Chemotherapy
Yunliang Zhang, Xiaoyan Lin, Karen Bush
Eravacycline is a novel, fully synthetic fluorocycline antibiotic of the tetracycline class being developed for the treatment of complicated urinary tract infections and complicated intra-abdominal infections. Eravacycline has activity against many key Gram-negative pathogens, including Enterobacteriaceae resistant to carbapenems, cephalosporins, fluoroquinolones and β-lactam/β-lactamase inhibitor combinations, including strains that are multidrug-resistant. Carbapenem-resistant Enterobacteriaceae (CRE) isolates from 2010 to 2013 (n=110) were characterized for carbapenemase genes by PCR and sequencing...
August 2016: Journal of Antibiotics
Marie Titecat, Xiaofei Liang, Chul-Jin Lee, Audrey Charlet, Didier Hocquet, Thierry Lambert, Jean-Marie Pagès, René Courcol, Florent Sebbane, Eric J Toone, Pei Zhou, Nadine Lemaitre
OBJECTIVES: Inhibitors of uridine diphosphate-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC, which catalyses the first, irreversible step in lipid A biosynthesis) are a promising new class of antibiotics against Gram-negative bacteria. The objectives of the present study were to: (i) compare the antibiotic activities of three LpxC inhibitors (LPC-058, LPC-011 and LPC-087) and the reference inhibitor CHIR-090 against Gram-negative bacilli (including MDR and XDR isolates); and (ii) investigate the effect of combining these inhibitors with conventional antibiotics...
October 2016: Journal of Antimicrobial Chemotherapy
Karen Bush, Patricia A Bradford
β-Lactams are the most widely used class of antibiotics. Since the discovery of benzylpenicillin in the 1920s, thousands of new penicillin derivatives and related β-lactam classes of cephalosporins, cephamycins, monobactams, and carbapenems have been discovered. Each new class of β-lactam has been developed either to increase the spectrum of activity to include additional bacterial species or to address specific resistance mechanisms that have arisen in the targeted bacterial population. Resistance to β-lactams is primarily because of bacterially produced β-lactamase enzymes that hydrolyze the β-lactam ring, thereby inactivating the drug...
2016: Cold Spring Harbor Perspectives in Medicine
Pawel Nowak, Paulina Paluchowska
Acinetobacter baumannii is a Gram-negative, glucose-non-fermenting, oxidase-negative coccobacillus, most commonly associated with the hospital settings. The ability to survive in adverse environmental conditions as well as high level of natural and acquired antimicrobial resistance make A. baumannii one of the most important nosocomial pathogens. While carbapenems have long been considered as antimicrobials of last-resort, the rates of clinical A. baumannii strains resistant to these antibiotics are increasing worldwide...
June 8, 2016: Folia Histochemica et Cytobiologica
Meredith Hackel, Krystyna M Kazmierczak, Daryl J Hoban, Douglas J Biedenbach, Samuel K Bouchillon, Boudewijn L M de Jonge, Gregory G Stone
Increasing resistance in Gram-negative bacilli, including Klebsiella spp., has reduced the utility of broad-spectrum cephalosporins. Avibactam, a novel non-β-lactam β-lactamase inhibitor, protects β-lactams from hydrolysis by Gram-negative bacteria that produce extended-spectrum β-lactamases (ESBLs) and serine carbapenemases, including Ambler class A and/or class C and some class D enzymes. In this analysis, we report the in vitro activity of ceftazidime-avibactam and comparators against multidrug-resistant (MDR) Klebsiella spp...
August 2016: Antimicrobial Agents and Chemotherapy
Juan A Vallejo, Marta Martínez-Guitián, Juan C Vázquez-Ucha, Concepción González-Bello, Margarita Poza, John D Buynak, Christopher R Bethel, Robert A Bonomo, German Bou, Alejandro Beceiro
OBJECTIVES: Carbapenemases are the most important mechanism responsible for carbapenem resistance in Enterobacteriaceae. Among carbapenemases, OXA-48 presents unique challenges as it is resistant to β-lactam inhibitors. Here, we test the capacity of the compound LN-1-255, a 6-alkylidene-2'-substituted penicillanic acid sulfone, to inhibit the activity of the carbapenemase OXA-48. METHODS: The OXA-48 gene was cloned and expressed in Klebsiella pneumoniae and Escherichia coli in order to obtain MICs in the presence of inhibitors (clavulanic acid, tazobactam and sulbactam) and LN-1-255...
August 2016: Journal of Antimicrobial Chemotherapy
Daniele V de Oliveira, Sueli T Van Der Sand
Some bacteria from the Enterobacteriaceae family are showing a significant capability to disseminate β-lactams resistance mechanisms among them, and these same mechanisms can be carried out from the hospital environment to superficial water. The aim of this study was to evaluate different phenotypic methods for the detection β-lactamases production by enterobacteria isolated from the anthropogenic environment: hospital wastewater and from a stream that cross the city of Porto Alegre. The applied tests were the modified Hodge test (MHT) and phenotypic tests with the following inhibitors: carbapenemase-phenylboronic acid (APB), metallo-β-lactamase-EDTA, AmpC β-lactamase-cloxacillin, and the confirmatory test for extended-spectrum β-lactamase (ESBL)-clavulanic acid...
July 2016: Current Microbiology
Ya-Ping Pan, Yuan-Hong Xu, Zhong-Xin Wang, Ya-Ping Fang, Ji-Lu Shen
Efflux pump systems are one of the most important mechanisms conferring multidrug resistance in Pseudomonas aeruginosa. MexAB-OprM efflux pump is one of the largest multi-drug resistant efflux pumps with high-level expression, which is controlled by regulatory genes mexR, nalC, and nalD. This study investigated the role of efflux pump MexAB-OprM in 75 strains of carbapenem-resistant P. aeruginosa and evaluated the influence of point mutation of the regulatory genes. The minimum inhibitory concentrations of imipenem and meropenem, with or without MC207110, an efflux pump inhibitor, were determined by agar dilution method to select the positive strains for an overexpressed active efflux pump...
August 2016: Archives of Microbiology
Bradley J Gardiner, Yoav Golan
Avibactam, a novel β-lactamase inhibitor, has recently been co-formulated with ceftazidime and approved for use in patients with complicated intra-abdominal and urinary tract infections, where no better treatment alternative exists. The basis for its FDA approval has been the extensive clinical experience with ceftazidime and the demonstration in vitro and in animal models that the addition of avibactam reverses resistance to ceftazidime in extended-spectrum β-lactamase and some carbapenemase-producing Enterobacteriaceae...
2016: Expert Review of Anti-infective Therapy
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"