Frameshift Mutations in Genes Encoding PBP3 and PBP4 Trigger an Unusual, Extreme β-Lactam Resistance Phenotype in .

In our curated panel of complex isolates, strain AU28442 was unusually highly β-lactam resistant. To explore the molecular mechanisms leading to this phenotype, we performed whole genome sequencing (WGS) and microbiological and biochemical assays. WGS analysis revealed that strain AU28442 produced two β-lactamases, AmpC22 and a novel PenA-like β-lactamase denominated PenA39.

Cefepime-taniborbactam demonstrates potent activity vs with .

Taniborbactam (formerly VNRX-5133) is a novel, investigational boronic acid β-lactamase inhibitor. The combination of cefepime (FEP) with taniborbactam is active against carrying class A, B, C, and/or D enzymes. We assessed the activity of FEP-taniborbactam against clinical strains carrying ( = 50, 100%), of which 78% harbored at least one extended-spectrum β-lactamase (ESBL).

Demographic Differences in Emergency Room Epistaxis Treatment Patterns and Outcomes.

Objective: Investigate the association between demographic characteristics and emergency department (ED) epistaxis management and outcomes.

Study Design: Retrospective cohort study.

Setting: TriNetX US collaborative database.

The interaction of the azetidine thiazole side chain with the active site loop (ASL) 3 drives the evolution of IMP metallo-β-lactamase against tebipenem.

Imipenemase (IMP) metallo-β-lactamases (MBLs) hydrolyze almost all available β-lactams including carbapenems and are not inhibited by any commercially available β-lactamase inhibitor. Tebipenem (TP) pivoxil is the first orally available carbapenem and possesses a unique bicyclic azetidine thiazole moiety located at the R2 position. TP has potent activity against producing extended-spectrum and/or AmpC β-lactamases.

First report of KPC variants conferring ceftazidime-avibactam resistance in Colombia: introducing KPC-197.

Unlabelled: Resistance to ceftazidime-avibactam (CZA) due to carbapenemase (KPC) variants is increasing worldwide. We characterized two CZA-resistant clinical strains by antimicrobial susceptibility test, conjugation assays, and WGS. Isolates belonged to ST258 and ST45, and produced a KPC-31 and a novel variant KPC-197, respectively.

14-Year Epidemiologic study of bloodstream infection incidence and resistance in the Veterans Health Administration system, 2009-2022.

Background: Multidrug resistant (PA) represents a serious threat to hospitalized patients. Characterizing the incidence of PA infection and degree of resistance can inform empiric treatment and preventative measures.

Objectives: We sought to describe trends in incidence and resistance characteristics of PA bloodstream infections (BSI) observed within the Veterans Health Administration (VHA) system and identify factors contributing to higher observed mortality within this population.

Rational Design of Benzobisheterocycle Metallo-β-Lactamase Inhibitors: A Tricyclic Scaffold Enhances Potency against Target Enzymes.

Antimicrobial resistance is a global public health threat. Metallo-β-lactamases (MBLs) inactivate β-lactam antibiotics, including carbapenems, are disseminating among Gram-negative bacteria, and lack clinically useful inhibitors. The evolving bisthiazolidine (BTZ) scaffold inhibits all three MBL subclasses (B1-B3).

Structural role of K224 in taniborbactam inhibition of NDM-1.

Taniborbactam (TAN; VNRX-5133) is a novel bicyclic boronic acid β-lactamase inhibitor (BLI) being developed in combination with cefepime (FEP). TAN inhibits both serine and some metallo-β-lactamases. Previously, the substitution R228L in VIM-24 was shown to increase activity against oxyimino-cephalosporins like FEP and ceftazidime (CAZ).

Association of COVID-19 coinfection with increased mortality among patients with bloodstream infection in the Veterans Health Administration system.

Objective: bloodstream infection (PA-BSI) and COVID-19 are independently associated with high mortality. We sought to demonstrate the impact of COVID-19 coinfection on patients with PA-BSI.

Design: Retrospective cohort study.

Natural protein engineering in the Ω-loop: the role of Y221 in ceftazidime and ceftolozane resistance in -derived cephalosporinase.

A wide variety of clinically observed single amino acid substitutions in the Ω-loop region have been associated with increased minimum inhibitory concentrations and resistance to ceftazidime (CAZ) and ceftolozane (TOL) in -derived cephalosporinase and other class C β-lactamases. Herein, we demonstrate the naturally occurring tyrosine to histidine substitution of amino acid 221 (Y221H) in -derived cephalosporinase (PDC) enables CAZ and TOL hydrolysis, leading to similar kinetic profiles ( = 2.3 ± 0.

Treatment approaches for severe Stenotrophomonas maltophilia infections.

Purpose Of Review: Stenotrophomonas maltophilia is an emerged opportunistic pathogen. Intrinsic multidrug resistance makes treating infections caused by S. maltophilia a great clinical challenge.

Carbonyl Migration in Uronates Affords a Potential Prebiotic Pathway for Pentose Production.

Carbohydrate biosynthesis is fundamental to modern terrestrial biochemistry, but how this collection of metabolic pathways originated remains an open question. Prebiotic sugar synthesis has focused primarily on the formose reaction and Kiliani-Fischer homologation; however, how they can transition to extant biochemical pathways has not been studied. Herein, a nonenzymatic pathway for pentose production with similar chemical transformations as those of the pentose phosphate pathway is demonstrated.

Examining the activity of cefepime-taniborbactam against complex and isolated from cystic fibrosis patients in the United States.

The novel clinical-stage β-lactam-β-lactamase inhibitor combination, cefepime-taniborbactam, demonstrates promising activity toward many Gram-negative bacteria producing class A, B, C, and/or D β-lactamases. We tested this combination against a panel of 150 complex (Bcc) and strains. The addition of taniborbactam to cefepime shifted cefepime minimum inhibitory concentrations toward the provisionally susceptible range in 59% of the isolates tested.

Correction: 2-Mercaptomethyl-thiazolidines use conserved aromatic-S interactions to achieve broad-range inhibition of metallo-β-lactamases.

[This corrects the article DOI: 10.1039/D0SC05172A.].

Interactions of hydrolyzed β-lactams with the L1 metallo-β-lactamase: Crystallography supports stereoselective binding of cephem/carbapenem products.

L1 is a dizinc subclass B3 metallo-β-lactamase (MBL) that hydrolyzes most β-lactam antibiotics and is a key resistance determinant in the Gram-negative pathogen Stenotrophomonas maltophilia, an important cause of nosocomial infections in immunocompromised patients. L1 is not usefully inhibited by MBL inhibitors in clinical trials, underlying the need for further studies on L1 structure and mechanism. We describe kinetic studies and crystal structures of L1 in complex with hydrolyzed β-lactams from the penam (mecillinam), cephem (cefoxitin/cefmetazole), and carbapenem (tebipenem, doripenem, and panipenem) classes.

Molecular Mechanisms of Resistance to Ceftazidime/Avibactam in Clinical Isolates of and Pseudomonas aeruginosa in Latin American Hospitals.

Ceftazidime-avibactam (CZA) is the combination of a third-generation cephalosporin and a new non-β-lactam β-lactamase inhibitor capable of inactivating class A, C, and some D β-lactamases. From a collection of 2,727 clinical isolates of ( 2,235) and P. aeruginosa ( 492) that were collected between 2016 and 2017 from five Latin American countries, we investigated the molecular resistance mechanisms to CZA of 127 (18/2,235 [0.

Gating interactions steer loop conformational changes in the active site of the L1 metallo-β-lactamase.

β-Lactam antibiotics are the most important and widely used antibacterial agents across the world. However, the widespread dissemination of β-lactamases among pathogenic bacteria limits the efficacy of β-lactam antibiotics. This has created a major public health crisis.

Selective and Cascade Reporting of Antimicrobial Susceptibility Testing Results and Its Impact on Antimicrobial Resistance Surveillance-National Healthcare Safety Network, April 2020 to March 2021.

Selective or cascade reporting (SR/CR) of antimicrobial susceptibility testing (AST) results is a strategy for antimicrobial stewardship. SR/CR is often achieved by suppressing AST results of secondary drugs in electronic laboratory reports. We assessed the extent of SR/CR and its impact on cumulative antibiograms (CAs) in a large cohort of U.

Boronic Acid Transition State Inhibitors as Potent Inactivators of KPC and CTX-M β-Lactamases: Biochemical and Structural Analyses.

Design of novel β-lactamase inhibitors (BLIs) is one of the currently accepted strategies to combat the threat of cephalosporin and carbapenem resistance in Gram-negative bacteria. oronic cid ransition tate nhibitors (BATSIs) are competitive, reversible BLIs that offer promise as novel therapeutic agents. In this study, the activities of two α-amido-β-triazolylethaneboronic acid transition state inhibitors (S02030 and MB_076) targeting representative KPC (KPC-2) and CTX-M (CTX-M-96, a CTX-M-15-type extended-spectrum β-lactamase [ESBL]) β-lactamases were evaluated.

Measurement of Microcystin Activity in Human Plasma Using Immunocapture and Protein Phosphatase Inhibition Assay.

Microcystins are toxic chemicals generated by certain freshwater cyanobacteria. These chemicals can accumulate to dangerous levels during harmful algal blooms. When exposed to microcystins, humans are at risk of hepatic injury, including liver failure.

Molecular mechanisms leading to ceftolozane/tazobactam resistance in clinical isolates of from five Latin American countries.

Objectives: Identify molecular mechanisms responsible for the non-susceptibility to ceftolozane/tazobactam (TOL) in a group of 158 clinical isolates of from five Latin American countries collected before the introduction of TOL into the clinical practice.

Methods: Clinical isolates of ( = 504) were collected between January 2016 and October 2017 from 20 hospitals located in Argentina, Brazil, Chile, Colombia, and Mexico. Minimum inhibitory concentrations (MICs) to TOL were determined by standard broth microdilution and interpreted according to CLSI breakpoints.

Comparative In Vitro Activity of Ceftolozane/Tazobactam against Clinical Isolates of and from Five Latin American Countries.

Background: Ceftolozane/tazobactam (C/T) is a combination of an antipseudomonal oxyiminoaminothiazolyl cephalosporin with potent in vitro activity against and tazobactam, a known β-lactamase inhibitor. The aim of this study was to evaluate the activity of C/T against clinical isolates of and collected from five Latin American countries between 2016 and 2017, before its clinical use in Latin America, and to compare it with the activity of other available broad-spectrum antimicrobial agents.

Methods: a total of 2760 clinical isolates (508 and 2252 ) were consecutively collected from 20 hospitals and susceptibility to C/T and comparator agents was tested and interpreted following the current guidelines.