scholarly journals Antimicrobial resistance conferred by OXA-48 β-lactamases:towards a detailed mechanistic understanding

2021 ◽  
Author(s):  
Viivi H. A. Hirvonen ◽  
James Spencer ◽  
Marc W. van der Kamp
Keyword(s):  
Bacterial Infections ◽  
Gram Negative Bacteria ◽  
Carbapenem Resistant ◽  
Open Research ◽  
Resistance To Penicillin ◽  
Research Questions ◽  
Mechanistic Basis ◽  
Healthcare Associated ◽  
The Relationship ◽  
Detailed Picture

OXA-48-type β-lactamases are now routinely encountered in bacterial infections caused by carbapenem-resistant Enterobacterales. These enzymes are of high and growing clinical significance due to the importance of carbapenems in treatment of healthcare-associated infections by Gram-negative bacteria, the wide and increasing dissemination of OXA-48 enzymes on plasmids, and the challenges posed by their detection. OXA-48 confers resistance to penicillin (which is efficiently hydrolyzed) and carbapenem antibiotics (more slowly broken down). In addition to the parent enzyme, a growing array of variants of OXA-48 is now emerging. The spectrum of activity of these variants varies, with some hydrolyzing expanded-spectrum oxyimino-cephalosporins. The growth in importance and diversity of the OXA-48 group has motivated increasing numbers of studies that aim to elucidate the relationship between structure and specificity and establish the mechanistic basis for β-lactam turnover in this enzyme family. In this review we collate recently published structural, kinetic, and mechanistic information on the interactions between clinically relevant β-lactam antibiotics and inhibitors with OXA-48 β-lactamases. Collectively, these studies are starting to form a detailed picture of the underlying bases for the differences in β-lactam specificity between OXA-48 variants, and the consequent differences in resistance phenotype. We focus specifically on aspects of carbapenemase and cephalosporinase activities of OXA-48 β-lactamases and discuss β-lactamase inhibitor development in this context. Throughout the review, we also outline key open research questions for future investigation.

scholarly journals An overview of carbapenem, its resistance and therapeutic options for infections caused by carbapenem resistant bacteria

2020 ◽  
Vol 9 (9) ◽  
pp. 1454
Author(s):  
Hari P. Nepal ◽  
Rama Paudel
Keyword(s):  
Bacterial Infections ◽  
Carbapenem Resistance ◽  
Therapeutic Options ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Beta Lactam ◽  
Gram Negative ◽  
Penicillin Binding Proteins ◽  
Carbapenem Resistant ◽  
The World

Carbapenems are beta-lactam drugs that have broadest spectrum of activity. They are commonly used as the drugs of last resort to treat complicated bacterial infections. They bind to penicillin binding proteins (PBPs) and inhibit cell wall synthesis in bacteria. Important members that are in clinical use include doripenem, ertapenem, imipenem, and meropenem. Unlike other members, imipenem is hydrolyzed significantly by renal dehydropeptidase; therefore, it is administered together with an inhibitor of renal dehydropeptidase, cilastatin. Carbapenems are usually administered intravenously due to their low oral bioavailability. Most common side effects of these drugs include nausea, vomiting, diarrhea, skin rashes, and reactions at the infusion sites. Increasing resistance to these antibiotics is being reported throughout the world and is posing a threat to public health.  Primary mechanisms of carbapenem resistance include expulsion of drug and inactivation of the drug by production of carbapenemases which may not only hydrolyze carbapenem, but also cephalosporin, penicillin, and aztreonam. Resistance especially among Gram negative bacteria is of much concern since there are only limited therapeutic options available for infections caused by carbapenem resistant Gram-negative bacterial pathogens. Commonly used drugs to treat such infections include polymyxins, fosfomycin and tigecycline.

scholarly journals Treatment Options for Carbapenem-resistant Gram-negative Bacterial Infections

2019 ◽  
Vol 69 (Supplement_7) ◽  
pp. S565-S575 ◽  
Author(s):  
Yohei Doi
Keyword(s):  
Bacterial Infections ◽  
Treatment Options ◽  
Clinical Development ◽  
Gram Negative Bacteria ◽  
First Line ◽  
Safe Alternative ◽  
New Agents ◽  
Gram Negative ◽  
Carbapenem Resistant

AbstractAntimicrobial resistance has become one of the greatest threats to public health, with rising resistance to carbapenems being a particular concern due to the lack of effective and safe alternative treatment options. Carbapenem-resistant gram-negative bacteria of clinical relevance include the Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumannii, and more recently, Stenotrophomonas maltophilia. Colistin and tigecycline have been used as first-line agents for the treatment of infections caused by these pathogens; however, there are uncertainties regarding their efficacy even when used in combination with other agents. More recently, several new agents with activity against certain carbapenem-resistant pathogens have been approved for clinical use or are reaching late-stage clinical development. They include ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, plazomicin, eravacycline, and cefiderocol. In addition, fosfomycin has been redeveloped in a new intravenous formulation. Data regarding the clinical efficacy of these new agents specific to infections caused by carbapenem-resistant pathogens are slowly emerging and appear to generally favor newer agents over previous best available therapy. As more treatment options become widely available for carbapenem-resistant gram-negative infections, the role of antimicrobial stewardship will become crucial in ensuring appropriate and rationale use of these new agents.

scholarly journals Etiology and Antimicrobial Resistance of Secondary Bacterial Infections in Patients Hospitalized With COVID-19 in Wuhan, China: A Retrospective Analysis

2020 ◽  
Author(s):  
Jie Li ◽  
Junwei Wang ◽  
Yi Yang ◽  
Peishan Cai ◽  
Jingchao Cao ◽  
...  
Keyword(s):  
Antimicrobial Resistance ◽  
Bacterial Infections ◽  
Virus Disease ◽  
Considerable Proportion ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Carbapenem Resistant ◽  
Union Hospital ◽  
Critical Patients ◽  
Resistance Rates

Abstract Background: A considerable proportion of patients hospitalized with corona virus disease 2019 (COVID-19) have acquired secondary bacterial infections (SBIs). We report the etiology and antimicrobial resistance of bacteria to provide theoretical basis for appropriate infection therapy.Methods: In the retrospective study, we reviewed electronic medical records of all the patients hospitalized with COVID-19 in the Wuhan Union hospital from January 27 to March 17, 2020. According to the inclusion and exclusion criteria, patients who acquired SBIs were enrolled. Demographic, clinical course, etiology and antimicrobial resistance data of the SBIs were collected. Outcomes were also compared between patients who were classified as severe on admission and those who were classified as critical.Results: 6.8% (102/1495) of the patients with COVID-19 had acquired SBIs and almost half of them (50, 49.0%) died during hospitalization. Compared with the severe patients, the critical patients had a higher chance of SBIs. 159 strains of bacteria were isolated, 85.5% of which were Gram-negative bacteria. The top three bacteria of SBIs were A. baumannii (35.8%), K. pneumoniae (30.8%) and Staphylococcus (8.8%). The isolation rate of carbapenem-resistant A. baumannii and K. pneumoniae were 91.2% and 75.5%, respectively. Meticillin resistance was in 100% of Staphylococcus, and vancomycin resistance was not found. Conclusions: SBIs may occur in patients hospitalized with COVID-19 and lead to high mortality. The incidence of SBIs was associated with the grade on admission. Gram-negative bacteria, especially A. baumannii and K. pneumoniae, were the main bacteria and the resistance rates of the major isolated bacteria were generally high.

scholarly journals Multiscale simulations identify origins of differential carbapenem hydrolysis by the OXA-48 β-lactamase

2021 ◽  
Author(s):  
Viivi Hirvonen ◽  
Tal Moshe Weizmann ◽  
Adrian Mulholland ◽  
James Spencer ◽  
Marc van der Kamp
Keyword(s):  
Water Molecule ◽  
Bacterial Infections ◽  
Enzyme Reaction ◽  
Subtle Change ◽  
Conformational Substates ◽  
Multi Scale ◽  
Hydrogen Bonding Pattern ◽  
Carbapenem Resistant ◽  
New Antibiotics ◽  
Healthcare Associated

OXA-48 β-lactamases are frequently encountered in bacterial infections caused by carbapenem-resistant Gram-negative bacteria. Due to the importance of carbapenems in treatment of healthcare-associated infections, and the increasingly wide dissemination of OXA-48-like enzymes on plasmids, these β-lactamases are of high clinical significance. Notably, OXA-48 hydrolyses imipenem more efficiently than other commonly used carbapenems, such as meropenem. Here, we use extensive multi-scale simulations of imipenem and meropenem hydrolysis by OXA-48 to dissect the dynamics and to explore differences in reactivity of the possible conformational substates of the respective acylenzymes. QM/MM simulations of the deacylation reaction for both substrates demonstrate that deacylation is favoured when the 6α-hydroxyethyl group is able to hydrogen bond to the water molecule responsible for deacylation, but disfavoured by increasing hydration of either oxygen of the carboxylated Lys73 general base. Differences in free energy barriers calculated from the QM/MM simulations correlate well with the experimentally observed differences in hydrolytic efficiency between meropenem and imipenem. We conclude that the impaired breakdown of meropenem, compared to imipenem, which arises from a subtle change in the hydrogen bonding pattern between the deacylating water molecule and the antibiotic, is most likely induced by the meropenem 1-methyl group. In addition to increased insights into carbapenem breakdown by OXA β-lactamases, which may aid design of new antibiotics or inhibitors, our approach exemplifies the combined use of atomistic simulations in determining the possible different enzyme-substrate substates, and their influence on enzyme reaction kinetics.

scholarly journals When Computational Representation Meets Neuroscience: A Survey on Brain Encoding and Decoding

2021 ◽  
Author(s):  
Lu Cao ◽  
Dandan Huang ◽  
Yue Zhang
Keyword(s):  
Language Processing ◽  
Research Field ◽  
Language Models ◽  
Research Progress ◽  
Artificial Intelligent ◽  
Comprehensive Review ◽  
Open Research ◽  
Research Questions ◽  
The Relationship ◽  
Computational Representation

Real human language mechanisms and the artificial intelligent language processing methods are two independent systems. Exploring the relationship between the two can help develop human-like language models and is also beneficial to reveal the neuroscience of the reading brain. The flourishing research in this interdisciplinal research field calls for surveys to systemically study and analyze the recent successes. However, such a comprehensive review still cannot be found, which motivates our work. This article first briefly introduces the interdisciplinal research progress, then systematically discusses the task of brain decoding from the perspective of simple concepts and complete sentences, and also describes main limitations in this field and put forward with possible solutions. Finally, we conclude this survey with certain open research questions that will stimulate further studies.

scholarly journals Infections with Carbapenem-Resistant Gram-Negative Bacteria are a Serious Problem Among Critically Ill Children: A Single-Centre Retrospective Study

Pathogens ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 69 ◽  
Author(s):  
Fatih Aygun ◽  
Fatma Deniz Aygun ◽  
Fatih Varol ◽  
Cansu Durak ◽  
Haluk Çokuğraş ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Critically Ill ◽  
Bacterial Infections ◽  
Invasive Mechanical Ventilation ◽  
Critically Ill Children ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Carbapenem Resistant ◽  
Culture Positive

Children in paediatric intensive care units (PICUs) are vulnerable to infections because invasive devices are frequently used during their admission. We aimed to determine the prevalence, associated factors, and prognosis of infections in our PICU. This retrospective study evaluated culture results from 477 paediatric patients who were treated in the PICU between January 2014 and March 2019. Ninety patients (18.9%) had bacterial infections, with gram-negative bacteria being the predominant infectious agents. Culture-positive patients were younger than culture-negative patients, and age was related to mortality and various clinical factors. Culture-positive bacterial infections in the PICU were associated with increased use of invasive mechanical ventilation (odds ratio(OR); 2.254), red blood cell (RBC) transfusions (OR:2.624), and inotropic drugs (OR:2.262). Carbapenem resistance was found in approximately one-third of gram-negative bacteria, and was most common in tracheal aspirate specimens and cases involving Klebsiella spp. Total parenteral nutrition was a significant risk factor (OR:5.870). Positive blood culture results were associated with poorer patient survival than other culture results. These findings indicate that infections, especially those involving carbapenem-resistant bacteria, are an important issue when treating critically ill children.

scholarly journals Cefiderocol for Extensively Drug-Resistant Gram-Negative Bacterial Infections: Real-world Experience From a Case Series and Review of the Literature

2020 ◽  
Vol 7 (6) ◽  
Author(s):  
Sandra Zingg ◽  
G Jacopo Nicoletti ◽  
Sabine Kuster ◽  
Milena Junker ◽  
Andreas Widmer ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Case Reports ◽  
Case Series ◽  
Gram Negative Bacteria ◽  
Drug Resistant ◽  
Gram Negative ◽  
Carbapenem Resistant ◽  
Extensively Drug Resistant ◽  
Health Care Associated Infections ◽  
Tract Infections

Abstract Cefiderocol is a new siderophore cephalosporin with activity against carbapenem-resistant gram-negative bacteria. Data on its clinical efficacy are limited to complicated urinary tract infections. We present a series of 3 patients successfully treated with cefiderocol for complicated health care–associated infections and review published case reports.

scholarly journals Clinical Treatment Options for Carbapenem-resistant Gram-negative Infections in China: a Single Centre Real-world Experience

2021 ◽  
Author(s):  
Ruanmei Sheng ◽  
Xuemin Wang ◽  
Yanqiang Hou ◽  
Jun Liu ◽  
Zhiwen Yang
Keyword(s):  
Success Rate ◽  
Bacterial Infections ◽  
Clinical Success ◽  
Treatment Options ◽  
Clinical Success Rate ◽  
Gram Negative Bacteria ◽  
Single Centre ◽  
Gram Negative ◽  
Carbapenem Resistant ◽  
Clinical Strategies

Abstract Carbapenem-resistant gram-negative bacteria constitute a serious threat to public health worldwide. However, as a result of the complexities of clinical therapy, antibiotic options against carbapenem-resistant pathogens have not yet been fully standardized. Here, we conducted a retrospective study in 65,000 inpatients over a 2-year period that involved a total of 86 patients from whom carbapenem-resistant gram-negative bacteria were isolated. Monotherapy using trimethoprim/ sulfamethoxazole, amikacin, meropenem, and/or doxycycline in our hospital exhibited a clinical success rate of 83.3% for carbapenem-resistant Klebsiella pneumoniae, monotherapy using moxifloxacin, piperacillin/tazobactam, cefepime, and/or ceftazidime for carbapenem-resistant Pseudomonas aeruginosa exhibited a clinical success rate of 77.7%, and monotherapy using cefoperazone/sulbactam or combination therapy with tigecycline and cefoperazone/sulbactam for carbapenem-resistant Acinetobacter baumannii exhibited a clinical success rate of 62.1%. Our findings highlight the clinical strategies used in our hospital to successfully treat carbapenem-resistant gram-negative bacterial infections.

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