Search results for "beta-Lactams"

DALI: Defining Antibiotic Levels in Intensive Care Unit Patients: Are Current -Lactam Antibiotic Doses Sufficient for Critically Ill Patients?

2014

Background. Morbidity and mortality for critically ill patients with infections remains a global healthcare problem. We aimed to determine whether α-lactam antibiotic dosing in critically ill patients achieves concentrations associated with maximal activity and whether antibiotic concentrations affect patient outcome.Methods. This was a prospective, multinational pharmacokinetic point-prevalence study including 8 α-lactam antibiotics. Two blood samples were taken from each patient during a single dosing interval. The primary pharmacokinetic/pharmacodynamic targets were free antibiotic concentrations above the minimum inhibitory concentration (MIC) of the pathogen at both 50% (50% f TMIC) an…

Therapeutic Strategies To Counteract Antibiotic Resistance in MRSA Biofilm‐Associated Infections

2021

Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as one of the leading causes of persistent human infections. This pathogen is widespread and is able to colonize asymptomatically about a third of the population, causing moderate to severe infections. It is currently considered the most common cause of nosocomial infections and one of the main causes of death in hospitalized patients. Due to its high morbidity and mortality rate and its ability to resist most antibiotics on the market, it has been termed a “superbug”. Its ability to form biofilms on biotic and abiotic surfaces seems to be the primarily means of MRSA antibiotic resistance and pervasiveness. Importantly, more tha…

Sequence type 101 (ST101) as the predominant carbapenem-non-susceptible Klebsiella pneumoniae clone in an acute general hospital in Italy.

2012

Klebsiella pneumoniae is one of the most common multidrug-resistant (MDR) Gram-negative organisms worldwide, responsible for high morbidity and mortality both in hospitals and alternative healthcare settings. Recently, increasing use of carbapenems has promoted the emergence and dissemination of carbapenem-non-susceptible MDR K. pneumoniae strains. All of the CNSKP strains isolated between January 2009 and December 2011 in the General Hospital of Prato (Prato, Italy) were studied. Our findings indicate that, unlike previously reported by other authors from different regions of Italy, K. pneumoniae producing KPC-2 and belonging to ST101 have been established in the area of Prato, Tuscany, It…

New β-Lactam-β-Lactamase Inhibitor Combinations.

2020

The limited armamentarium against drug-resistant Gram-negative bacilli has led to the development of several novel β-lactam-β-lactamase inhibitor combinations (BLBLIs). In this review, we summarize their spectrum of in vitro activities, mechanisms of resistance, and pharmacokinetic-pharmacodynamic (PK-PD) characteristics. A summary of available clinical data is provided per drug. Four approved BLBLIs are discussed in detail. All are options for treating multidrug-resistant (MDR) Enterobacterales and Pseudomonas aeruginosa Ceftazidime-avibactam is a potential drug for treating Enterobacterales producing extended-spectrum β-lactamase (ESBL), Klebsiella pneumoniae carbapenemase (KPC), AmpC, an…

Synthesis of enantiopure pyrrolidine-derived peptidomimetics and oligo-beta-peptides via nucleophilic ring-opening of beta-lactams.

2006

The synthesis of the two enantiomers of pyrrolidine-derived spiro beta-lactams by resolution with D- and L-Boc phenylalanine is described. The potential of these optically active spiro beta-lactams on the synthesis of peptidomimetics as analogues of melanostatin is evaluated. Theoretical studies of several models, at the Becke3LYP/6-31+G* level of theory, together with previous experimental evidences from our group, gathered by NMR, allow us to design structures that can efficiently mimic some biologically active peptide-type molecules. On the other hand, the spiro beta-lactams have shown their utility in the preparation of beta-peptides. As an example, a homo-tetra-beta-peptide was synthes…

Role of Protein Flexibility in Enzymatic Catalysis:  Quantum Mechanical−Molecular Mechanical Study of the Deacylation Reaction in Class A β-Lactamases

2002

We present a theoretical study of a mechanism for the hydrolysis of the acyl-enzyme complex formed by a class A beta-lactamase (TEM1) and an antibiotic (penicillanate), as a part of the process of antibiotic's inactivation by this type of enzymes. In the presented mechanism the carboxylate group of a particular residue (Glu166) activates a water molecule, accepting one of its protons, and afterward transfers this proton directly to the acylated serine residue (Ser70). In our study we employed a quantum mechanics (AM1)-molecular mechanics partition scheme (QM/MM) where all the atoms of the system were allowed to relax. For this purpose we used the GRACE procedure in which part of the system …

Asymmetric Synthesis of Spirocyclic β-Lactams through Copper-Catalyzed Kinugasa/Michael Domino Reactions

2018

The first copper-catalyzed highly chemo-, regio-, diastereo-, and enantioselective Kinugasa/Michael domino reaction for the desymmetrization of prochiral cyclohexadienones is described. In the presence of a chiral copper catalyst, alkyne-tethered cyclohexadienones couple with nitrones to generate the chiral spirocyclic lactams with excellent stereoselectivity (up to 97 % ee, >20:1 dr). The new method provides direct access to versatile highly functionalized spirocyclic β-lactams possessing four contiguous stereocenters, including one quaternary and one tetra-substituted stereocenter.

Should continuous infusion of β‐lactam antibiotics be the first‐line approach?

1997

Preparation of Carbon-14 Labeled 2-(2-mercaptoacetamido)-3-phenylpropanoic Acid as Metallo-beta-lactamases Inhibitor (MBLI), for Coadministration wit…

2019

Aim and Objective: Bacteria could become resistant to β-lactam antibiotics through production of β- lactamase enzymes like metallo-β-lactamase. 2-(2-mercaptoacetamido)-3-phenylpropanoic acid was reported as a model inhibitor for this enzyme. In order to elucidate the mechanism of action in the body’s internal environment, preparation of a labeled version of 2-(2-mercaptoacetamido)-3-phenylpropanoic acid finds importance. In this regard, we report a convenient synthetic pathway for preparation of carbon-14 labeled 2-(2- mercaptoacetamido)-3-phenylpropanoic acid. Materials and Methods: This study was initiated by using non-radioactive materials. Then, necessary characterization was performed…

Controlled rearrangement of lactam-tethered allenols with brominating reagents: a combined experimental and theoretical study on α- versus β-keto lac…

2011

N-Bromosuccinimide (NBS) smoothly promotes the ring expansion of lactam-tethered allenols to efficiently afford cyclic α- or β-ketoamides with good yields and high chemo-, regio-, and diastereoselectivity, through controlled C-C bond cleavage of the β- or γ-lactam nucleus. Interestingly, in contrast to the rearrangement reactions of 2-azetidinone-tethered allenols, which lead to the corresponding tetramic acid derivatives (β-keto lactam adducts) as the sole products, the reactions of 2-indolinone-tethered allenols under similar conditions give quinoline-2,3-diones (α-keto lactam adducts) as the exclusive or major products. To rationalize the experimental observations, theoretical studies ha…