The purpose of this study is to describe an unexpected degree of differences between expiratory occlusion plateau pressure (EPO) and airway opening pressure (Pawo) measured level of intrinsic positive end-expiratory pressure above externally applied (auto-PEEP) that was found in six critically ill patients. In six patients (ten studies), the presence and degree of auto-PEEP found during the EPO maneuvers was not confirmed by Pawo measurements. In five studies, flow tracings showed prolonged near zero flow toward end expiration and a slow rise to plateau during the EPO maneuver.

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Study: No Evidence for Superior Time Trial Performances in the “Epo Era” Another newly published study.. Challenges the "speeds are down" discourse since the epo-era with a historical...

The beta-lactamase inhibitory properties of 6-acetylmethylene penicillanic acid (6-AMPA) were investigated and compared with those of other beta-lactamase inhibitors. 6-AMPA inhibited the TEM-1, TEM-2, SHV-1, PSE-1, PSE-2, PSE-3, PSE-4, OXA-2, OXA-3, and Staphylococcus aureus beta-lactamases. It also inhibited the chromosomally-mediated beta-lactam

Beta-lactam antibiotics exhibit the most common treatment for bacterial infections and continue to be the prominent cause of resistance to beta-lactam antibiotics among Gram-negative bacteria world…

Pharmacological and Pharmaceutical Sciences, Department of

Novel β-lactamase inhibitors have extended the reach of new and existing β-lactams against multidrug-resistant bacteria expressing β-lactamases. The efficacy of these combination therapeutics relies ...

Beta-lactamase inhibitors are increasingly used to counteract microbial resistance to beta-lactam antibiotics mediated by beta-lactamase enzymes. These inhibitors compete with the beta-lactam drug for the same binding site of the beta-lactamase, thereby generating an inherent evolutionary tradeoff: enzyme mutations that increase its activity against the beta-lactam drug also increase its susceptibility towards the inhibitor. It is unclear how common and accessible are mutants that escape this adaptive tradeoff. Here, systematically constructing and phenotyping a deep mutant library of the ampC beta-lactamase gene of Escherichia coli , we identified escape mutations, which even in the presence of the enzyme inhibitor allow growth at beta-lactam concentrations far exceeding the native inhibitory levels of the wildtype strain. Importantly, while such escape mutations appear for combinations of avibactam with some beta-lactam drugs, for other drugs escape phenotypes are completely restricted. Amplicon sequencing of the selected mutant pool identified these escape mutations and showed that they are rare and drug specific. For the combination of avibactam with aztreonam, an escape phenotype was conferred via multiple substitutions in a single conserved amino acid (Tyr 150). In contrast, a different set of mutations showed an escape phenotype for cefepime, and no escape mutants appeared for piperacillin. The differential adaptive potential of ampC to combinations of avibactam and different beta-lactam drugs can help guide drug treatments that are more resilient to evolution of resistance.

Beta-lactam antibiotics include penicillins, cephalosporins and related compounds. As a group, these drugs are active against many gram-positive, gram-negative and anaerobic organisms. Information based on

β-lactam antibiotics are the most widely used antimicrobial agents since the discovery of benzylpenicillin in the 1920s. Unfortunately, these life-saving antibiotics are vulnerable to inactivation by continuously evolving β-lactamase enzymes that are primary resistance determinants in multi-drug resistant pathogens. The current study exploits the strategy of combination therapeutics and aims at identifying novel β-lactamase inhibitors that can inactivate the β-lactamase enzyme of the pathogen while allowing the β-lactam antibiotic to act against its penicillin-binding protein target. Inhibitor discovery applied the Site-Identification by Ligand Competitive Saturation (SILCS) technology to map the functional group requirements of the β-lactamase CMY-10 and generate pharmacophore models of active site. SILCS-MC, Ligand-grid Free Energy (LGFE) analysis and Machine-learning based random-forest (RF) scoring methods were then used to screen and filter a library of 700,000 compounds. From the computational screens 74 compounds were subjected to experimental validation in which β-lactamase activity assay, in vitro susceptibility testing, and Scanning Electron Microscope (SEM) analysis were conducted to explore their antibacterial potential. Eleven compounds were identified as enhancers while 7 compounds were recognized as inhibitors of CMY-10. Of these, compound 11 showed promising activity in β-lactamase activity assay, in vitro susceptibility testing against ATCC strains (E. coli, E. cloacae, E. agglomerans, E. alvei) and MDR clinical isolates (E. cloacae, E. alvei and E. agglomerans), with synergistic assay indicating its potential as a β-lactam enhancer and β-lactamase inhibitor. Structural similarity search against the active compound 11 yielded 28 more compounds. The majority of these compounds also exhibited β-lactamase inhibition potential and antibacterial activity. The non-β-lactam-based β-lactamase inhibitors identified in the current study have the potential to be used in combination therapy with lactam-based antibiotics against MDR clinical isolates that have been found resistant against last-line antibiotics.

β-Lactam antibiotics act by binding to penicillin-binding proteins (PBPs), thus inhibiting bacterial cell wall synthesis. Increasingly, however, these antibiotics are rendered ineffective because of degradation by β-lactamases. This family of enzymes, which are produced by gram-positive and...

nic acid, tazobactam, and sulbactam. New BLIs molecules have been developed to face the need of compounds that are active against multidrug or pandrug resistant gram-negative pathogens. The aim of this review is to summarize the new generation of BLIs and β-lactams combinations. Recent findings A number of new molecules with activity against Ambler class A (e.g., extended-spectrum β-lactamases, serine carbapenemases), class C (e.g., AmpC), or class D (e.g., oxacillinase-48) have been recently approved in combination with old β-lactams for the treatment of multidrug-resistant bacteria, and other agents are under investigation. These new compounds include diazabicyclooctanones non-β-lactam inhibitors (e.g., avibactam, relebactam, nacubactam) and boronic acid inhibitors (e.g., vaborbactam). Summary Newly approved and investigational new BLIs are expected to offer many advantages for the management of patients with multidrug-resistant gram-negative pathogens. Promising characteristics of new compounds include high activity against multi drug resistance gram-negative bacteria and a favorable safety profile....

Nature Reviews Microbiology - In this Review, Bush and Bradford describe medically relevant β-lactamase families and various combinations of a β-lactam with a β-lactamase...

The increasing incidence and prevalence of multi-drug resistance (MDR) among contemporary Gram-negative bacteria represents a significant threat to human health. Since their discovery, β-lactam antibiotics have been a major component of the armamentarium against these serious pathogens. Unfortunately, a wide range of β-lactamase enzymes have emerged that are capable of inactivating these powerful drugs. In the past 30 years, a major advancement in the battle against microbes has been the development of β-lactamase inhibitors, which restore the efficacy of β-lactam antibiotics (e.g., ampicillin/sulbactam, amoxicillin/clavulanate, ticarcillin/clavulanate, and piperacillin/tazobactam). Unfortunately, many newly discovered β-lactamases are not inactivated by currently available inhibitors. Is there hope? For the first time in many years, we can anticipate the development and introduction into clinical practice of novel inhibitors. Although these inhibitors may still not be effective for all β-lactamases, their introduction is still welcome. This review focuses on the novel β-lactamase inhibitors that are closest to being introduced in the clinic.

WASHINGTON – Beta-lactams were noninferior to fluoroquinolones or trimethoprim-sulfamethoxazole for step-down pyelonephritis treatment.

'I am unaware of any textbook which provides such comprehensive coverage of the field and doubt that this work will be surpassed in the foreseeable future, if ever!'From the foreword by Robert C. Moellering, Jr., M.D, Shields Warren-Mallinckrodt Professor of Medical Research, Harvard Medical School, USA Kucers' The Use of Antibiotics is the leading major reference work in this vast andrapidly developing field. More than doubled in length compared to the fifth edition, thesixth edition comprises 3000 pages over 2-volumes in order to cover all new and existing therapies, and emerging drugs not yet fully licensed. Concentrating on the treatment of infectious diseases, the content is divided into 4 sections: antibiotics, anti-fungal drugs, anti-parasitic drugs and anti-viral drugs, and is highly structured for ease of reference.Within each section, each chapter is structured to cover susceptibility, formulations and dosing (adult and paediatric), pharmacokinetics and pharmacodynamics, toxicity and drug distribution, detailed discussion regarding clinical uses, a feature unique to this title.Compiled by an expanded team of internationally renowned and respected editors, witha vast number of contributors spanning Europe, Africa, Asia, Australia, South America,the US and Canada, the sixth edition adopts a truly global approach. It will remaininvaluable for anyone using antimicrobial agents in their clinical practice and provides in a systematic and concise manner all the information required when treating infectionsrequiring antimicrobial therapy.Kucers' The Use of Antibiotics is available free to purchasers of the books as an electronic version on line or on your desktop: It provides access to the entire 2-volume print material It is fully searchable, so you can find the relevant information you need quickly Live references are linked to PubMed referring you to the latest journal material Customise the contents - you can highlight sections and make notes Comments can be shared with colleagues/tutors for discussion, teaching and learning The text can also be reflowed for ease of reading Text and illustrations copied will be automatically referenced to Kucers' The Use of Antibiotics