Durlobactam in combination with β-lactams to combat .

() presents significant clinical challenges. This study evaluated the synergistic effects of a β-lactam and β-lactamase inhibitor combination against and explored the underlying mechanisms. Synergy was assessed through MIC tests and time-kill studies, and binding affinities of nine β-lactams and BLIs to eight target receptors (L,D-transpeptidases [LDT] 1-5, D,D-carboxypeptidase, penicillin-binding protein [PBP] B, and PBP-lipo) were assessed using mass spectrometry and kinetic studies.

Application of quality indicators and critical lessons learned assessment as a research approach for the evaluation of rescue missions during terrorist attacks.

In Wuerzburg, Germany, a terrorist attack and a killing rampage occurred five years apart (2016 and 2021). Following a structured evaluation of the rescue mission in 2016, a bundle of quality indicators and ten "lessons learned" were defined. Aim of the presented study was to compare the two rescue missions and to critically review the lessons learned from 2016 for their implementation and feasibility.

Synergistic effects of sulopenem in combination with cefuroxime or durlobactam against .

Unlabelled: () affects patients with immunosuppression or underlying structural lung diseases such as cystic fibrosis (CF). Additionally, poses clinical challenges due to its resistance to multiple antibiotics. Herein, we investigated the synergistic effect of dual β-lactams [sulopenem and cefuroxime (CXM)] or the combination of sulopenem and CXM with β-lactamase inhibitors [BLIs-avibactam (AVI) or durlobactam (DUR)].

Durlobactam, a Diazabicyclooctane β-Lactamase Inhibitor, Inhibits BlaC and Peptidoglycan Transpeptidases of .

Peptidoglycan synthesis is an underutilized drug target in (). Diazabicyclooctanes (DBOs) are a class of broad-spectrum β-lactamase inhibitors that also inhibit certain peptidoglycan transpeptidases that are important in mycobacterial cell wall synthesis. We evaluated the DBO durlobactam as an inhibitor of BlaC, the β-lactamase, and multiple peptidoglycan transpeptidases (PonA1, Ldt, Ldt, Ldt, and Ldt).

Eradicating Pulmonary : The Promise of Dual β-Lactam Therapy.

Macrolide resistance has rendered the treatment of extremely difficult and is fueling a crisis. Recently, there has been dramatically increased incidence of infections by . Select dual β-lactam combinations have shown promising in vitro results.

Inhibiting Mycobacterium abscessus Cell Wall Synthesis: Using a Novel Diazabicyclooctane β-Lactamase Inhibitor To Augment β-Lactam Action.

Mycobacterium abscessus () infections are a growing menace to the health of many patients, especially those suffering from structural lung disease and cystic fibrosis. With multidrug resistance a common feature and a growing understanding of peptidoglycan synthesis in , it is advantageous to identify potent β-lactam and β-lactamase inhibitor combinations that can effectively disrupt cell wall synthesis. To improve existing therapeutic regimens to address serious infections, we evaluated the ability of durlobactam (DUR), a novel diazobicyclooctane β-lactamase inhibitor to restore susceptibilities in combination with β-lactams and provide a biochemical rationale for the activity of this compound.

"One-Two Punch": Synergistic ß-Lactam Combinations for Mycobacterium abscessus and Target Redundancy in the Inhibition of Peptidoglycan Synthesis Enzymes.

Mycobacterium abscessus subsp. abscessus is one of the most difficult pathogens to treat and its incidence in disease is increasing. Dual β-lactam combinations act synergistically in vitro but are not widely employed in practice.

Toxic Metabolic Encephalopathy in Hospitalized Patients with COVID-19.

Background: Toxic metabolic encephalopathy (TME) has been reported in 7-31% of hospitalized patients with coronavirus disease 2019 (COVID-19); however, some reports include sedation-related delirium and few data exist on the etiology of TME. We aimed to identify the prevalence, etiologies, and mortality rates associated with TME in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive patients.

Methods: We conducted a retrospective, multicenter, observational cohort study among patients with reverse transcriptase-polymerase chain reaction-confirmed SARS-CoV-2 infection hospitalized at four New York City hospitals in the same health network between March 1, 2020, and May 20, 2020.

Drug-Resistant Tuberculosis: A Glance at Progress and Global Challenges.

Multidrug-resistant Mycobacterium tuberculosis remains a major public health threat; its management poses a significant economic burden. Treatment requires a programmatic approach with access to laboratory services, second-line medications, and adequate clinical resources. In recent years, we have seen rapid developments in diagnostic techniques with whole genome sequencing-based drug susceptibility prediction now in reach, an array of new drugs that transform treatment regimens to purely oral formulations, and a steady stream of multinational trials that inform us about most efficient combinations.

Insights into the l,d-Transpeptidases and d,d-Carboxypeptidase of Mycobacterium abscessus: Ceftaroline, Imipenem, and Novel Diazabicyclooctane Inhibitors.

is a highly drug-resistant nontuberculous mycobacterium (NTM). Efforts to discover new treatments for infections are accelerating, with a focus on cell wall synthesis proteins ( l,d-transpeptidases 1 to 5 [Ldt to Ldt] and d,d-carboxypeptidase) that are targeted by β-lactam antibiotics. A challenge to this approach is the presence of chromosomally encoded β-lactamase (Bla).

The effect of respiratory viral assay panel on antibiotic prescription patterns at discharge in adults admitted with mild to moderate acute exacerbation of COPD: a retrospective before- after study.

Background: Despite well-defined criteria for use of antibiotics in patients presenting with mild to moderate Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD), their overuse is widespread. We hypothesized that following implementation of a molecular multiplex respiratory viral panel (RVP), AECOPD patients with viral infections would be more easily identified, limiting antibiotic use in this population. The primary objective of our study was to investigate if availability of the RVP decreased antibiotic prescription at discharge among patients with AECOPD.

Drug-Resistant Tuberculosis: Challenges and Progress.

Antimicrobial resistance is a natural evolutionary process, which in the case of Mycobacterium tuberculosis is based on spontaneous chromosomal mutations, meaning that well-designed combination drug regimens provided under supervised therapy will prevent the emergence of drug-resistant strains. Unfortunately, limited resources, poverty, and neglect have led to the emergence of drug-resistant tuberculosis throughout the world. The international community has responded with financial and scientific support, leading to new rapid diagnostics, new drugs and regimens in advanced clinical development, and an increasingly sophisticated understanding of resistance mechanisms and their application to all aspects of TB control and treatment.

Kinetic and Structural Characterization of the Interaction of 6-Methylidene Penem 2 with the β-Lactamase from Mycobacterium tuberculosis.

Mycobacterium tuberculosis is intrinsically resistant to most β-lactam antibiotics because of the constitutive expression of the blaC-encoded β-lactamase. This enzyme has extremely high activity against penicillins and cephalosporins, but weaker activity against carbapenems. The enzyme can be inhibited by clavulanate, avibactam, and boronic acids.

Inhibiting the β-Lactamase of Mycobacterium tuberculosis (Mtb) with Novel Boronic Acid Transition-State Inhibitors (BATSIs).

BlaC, the single chromosomally encoded β-lactamase of Mycobacterium tuberculosis, has been identified as a promising target for novel therapies that rely upon β-lactamase inhibition. Boronic acid transition-state inhibitors (BATSIs) are a class of β-lactamase inhibitors which permit rational inhibitor design by combinations of various R1 and R2 side chains. To explore the structural determinants of effective inhibition, we screened a panel of 25 BATSIs to explore key structure-function relationships.

Can inhibitor-resistant substitutions in the Mycobacterium tuberculosis β-Lactamase BlaC lead to clavulanate resistance?: a biochemical rationale for the use of β-lactam-β-lactamase inhibitor combinations.

The current emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis calls for novel treatment strategies. Recently, BlaC, the principal β-lactamase of Mycobacterium tuberculosis, was recognized as a potential therapeutic target. The combination of meropenem and clavulanic acid, which inhibits BlaC, was found to be effective against even extensively drug-resistant M.

Reappraising the use of β-lactams to treat tuberculosis.

The emergence of multidrug-resistant and extensively drug-resistant tuberculosis calls for novel approaches to treatment. Recent studies have shown that BlaC, the β-lactamase of Mycobacterium tuberculosis, is the major determinant of β-lactam resistance. This review invites the reader to explore evidence in order to answer the questions: can β-lactam and β-lactamase inhibitors adequately treat M.

Are we ready for novel detection methods to treat respiratory pathogens in hospital-acquired pneumonia?

Hospital-acquired pneumonia represents one of the most difficult treatment challenges in infectious diseases. Many studies suggest that the timely administration of appropriate, pathogen-directed therapy can be lifesaving. Because results of culture and antimicrobial susceptibility testing can take 48 h or longer, physicians currently rely on clinical, epidemiological, and demographic factors to assist with the choice of empiric therapy for antibiotic-resistant pathogens.

Transcriptome-based antigen identification for Neisseria meningitidis.

The identification of suitable antigens is crucial to successful vaccine development based on subunit approaches. While many methods exist for the identification of vaccine candidates which are surface-exposed or secreted, immunogenic and conserved, contain B and T cell epitopes, most of these have a major drawback: they do not yield any information on whether the antigen is indeed expressed by the pathogen during infection. However, DNA microarrays offer a novel tool for the investigation of the transcriptional activity of all genes of a pathogenic microorganism under in vivo conditions.

Transcriptome analysis of Neisseria meningitidis during infection.

Neisseria meningitidis is the cause of septicemia and meningococcal meningitis. During the course of infection, N. meningitidis encounters multiple environments within its host, which makes rapid adaptation to environmental changes a crucial factor for neisserial pathogenicity.

Analysis of the heat shock response of Neisseria meningitidis with cDNA- and oligonucleotide-based DNA microarrays.

Oligonucleotide- and cDNA-based microarrays comprising a subset of Neisseria meningitidis genes were assessed for study of the meningococcal heat shock response and found to be highly suitable for transcriptional profiling of N. meningitidis. Employing oligonucleotide arrays encompassing the entire genome of N.