SciCombinator

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Concept: Beta-lactam

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Beta-lactam antibiotics form the backbone of treatment for Gram-negative pneumonia in mechanically ventilated patients in the intensive care unit. However, this beta-lactam antibiotic backbone is increasingly under pressure from emerging resistance across all geographical regions, and health-care professionals in many countries are rapidly running out of effective treatment options. Even in regions that currently have only low levels of resistance, the effects of globalization are likely to increase local pressures on the beta-lactam antibiotic backbone in the near future. Therefore, clinicians are increasingly faced with a difficult balancing act: the need to prescribe adequate and appropriate antibiotic therapy while reducing the emergence of resistance and the overuse of antibiotics. In this review, we explore the burden of Gram-negative pneumonia in the critical care setting and the pressure that antibiotic resistance places on current empiric therapy regimens (and the beta-lactam antibiotic backbone) in this patient population. New treatment approaches, such as systemic and inhaled antibiotic alternatives, are on the horizon and are likely to help tackle the rising levels of beta-lactam antibiotic resistance. In the meantime, it is imperative that the beta-lactam antibiotic backbone of currently available antibiotics be supported through stringent antibiotic stewardship programs.

Concepts: Bacteria, Antibiotic resistance, Intensive care medicine, Antibiotic, Penicillin, Beta-lactam antibiotic, Beta-lactam, Antibiotics

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Beta-lactam antibiotics are largely administered by bolus dosing, despite displaying time-dependent pharmacokinetics and pharmacodynamics and there being a strong rationale for continuous administration. The randomised controlled trials conducted to date comparing the mode of betalactam administration have been inconclusive and limited by non-equivalent dosing, unblinded administration and small sample sizes.

Concepts: Pharmacology, Epidemiology, Sample size, Randomized controlled trial, ClinicalTrials.gov, Penicillin, Beta-lactam antibiotic, Beta-lactam

8

Beta-lactamases represent the main bacterial mechanism of resistance to beta-lactam antibiotics and are a significant challenge to modern medicine. We have developed an automated classification and analysis protocol that exploits structure- and sequence-based approaches and which allows us to propose a grouping of serine beta-lactamases that more consistently captures and rationalizes the existing three classification schemes: Classes, (A, C and D, which vary in their implementation of the mechanism of action); Types (that largely reflect evolutionary distance measured by sequence similarity); and Variant groups (which largely correspond with the Bush-Jacoby clinical groups). Our analysis platform exploits a suite of in-house and public tools to identify Functional Determinants (FDs), i.e. residue sites, responsible for conferring different phenotypes between different classes, different types and different variants. We focused on Class A beta-lactamases, the most highly populated and clinically relevant class, to identify FDs implicated in the distinct phenotypes associated with different Class A Types and Variants. We show that our FunFHMMer method can separate the known beta-lactamase classes and identify those positions likely to be responsible for the different implementations of the mechanism of action in these enzymes. Two novel algorithms, ASSP and SSPA, allow detection of FD sites likely to contribute to the broadening of the substrate profiles. Using our approaches, we recognise 151 Class A types in UniProt. Finally, we used our beta-lactamase FunFams and ASSP profiles to detect 4 novel Class A types in microbiome samples. Our platforms have been validated by literature studies, in silico analysis and some targeted experimental verification. Although developed for the serine beta-lactamases they could be used to classify and analyse any diverse protein superfamily where sub-families have diverged over both long and short evolutionary timescales.

Concepts: Evolution, Enzyme, Penicillin, Beta-lactam antibiotic, Beta-lactamase, Beta-lactam

4

Penicillin and related beta-lactams comprise one of our oldest and most widely used antibiotic therapies. These drugs have long been known to target enzymes called penicillin-binding proteins (PBPs) that build the bacterial cell wall. Investigating the downstream consequences of target inhibition and how they contribute to the lethal action of these important drugs, we demonstrate that beta-lactams do more than just inhibit the PBPs as is commonly believed. Rather, they induce a toxic malfunctioning of their target biosynthetic machinery involving a futile cycle of cell wall synthesis and degradation, thereby depleting cellular resources and bolstering their killing activity. Characterization of this mode of action additionally revealed a quality control function for enzymes that cleave bonds in the cell wall matrix. The results thus provide insight into the mechanism of cell wall assembly and suggest how best to interfere with the process for future antibiotic development.

Concepts: Bacteria, Enzyme, Cell wall, Antibiotic, Penicillin, Beta-lactam antibiotic, Beta-lactamase, Beta-lactam

3

Broilers and broiler meat products are highly contaminated with extended spectrum beta-lactamase (ESBL) or plasmid-mediated AmpC beta-lactamase producing Escherichia coli and are considered to be a source for human infections. Both horizontal and vertical transmission might play a role in the presence of these strains in broilers. As not much is known about the presence of these strains in the whole production pyramid, the epidemiology of ESBL/AmpC-producing E. coli in the Dutch broiler production pyramid was examined. Cloacal swabs of Grandparent stock (GPS) birds (one-/two-days (breed A and B), 18 and 31 weeks old (breed A)), one-day old Parent stock birds (breed A and B) and broiler chickens of increasing age (breed A) were selectively cultured to detect ESBL/AmpC-producing isolates. ESBL/AmpC-producing isolates were found at all levels in the broiler production pyramid in both broiler breeds examined. Prevalence was already relatively high at the top of the broiler production pyramid. At broiler farms ESBL/AmpC producing E. coli were still present in the environment of the poultry house after cleaning and disinfection. Feed samples taken in the poultry house also became contaminated with ESBL/AmpC producing E. coli after one or more production weeks. The prevalence of ESBL/AmpC-positive birds at broiler farms increased within the first week from 0-24% to 96-100% independent of the use of antibiotics and stayed 100% until slaughter. In GPS breed A, prevalence at 2 days, 18 weeks and 31 weeks stayed below 50% except when beta-lactam antibiotics were administered. In that case prevalence increased to 100%. Interventions minimizing ESBL/AmpC contamination in broilers should focus on preventing horizontal and vertical spread, especially in relation to broiler production farms.

Concepts: Escherichia coli, Chicken, Penicillin, Beta-lactam antibiotic, Beta-lactamase, Beta-lactam, Cephalosporin, Broiler

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To describe medical negligence and malpractice cases in which a patient with a known penicillin allergy received a beta-lactam and experienced an adverse reaction related to the beta-lactam.

Concepts: Physician, Penicillin, Beta-lactam antibiotic, Beta-lactamase, Beta-lactam, Medical malpractice

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 Cross-reactivity is anticipated between penicillins or cephalosporins and carbapenems as all have a beta lactam ring but the true incidence of IgE-mediated cross-reactivity is not known.

Concepts: Penicillin, Beta-lactam antibiotic, Beta-lactamase, Beta-lactam, Cephalosporin, Carbapenem, Lactam

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Background. Morbidity and mortality for critically patients with infections remains a global healthcare problem. We aimed to determine whether beta-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 beta-lactam antibiotics. Two blood samples were taken from each patient during a single dosing interval. The primary pharmacokinetic/pharmacodynamic targets were free antibiotic concentrations was above the minimum inhibitory concentration (MIC) of the pathogen at both 50% (50% f T>MIC) and 100% (100% f T>MIC) of the dosing interval. We used skewed logistic regression to describe the effect of antibiotic exposure on patient outcome. Results. We included 384 patients (361 evaluable patients) across 68 hospitals. The median (interquartile range) age was 61 (48-73) years and Acute Physiology and Chronic Health Evaluation II score was 18 (14-24) and 65% of patients were male. Of the 248 patients treated for infection, 16% did not achieve 50% f T>MIC and these patients were 32% less likely to have a positive clinical outcome (odds ratio: 0.68, p=0.009). Positive clinical outcome was associated with increasing 50% f T>MIC and 100% f T>MIC ratios (odds ratios: 1.02 and 1.56, respectively, p<0.03), with significant interaction with sickness severity status. Conclusions. Infected critically ill patients may have adverse outcomes as a result of antibiotic inadequate exposure and as such a paradigm change to more personalised antibiotic dosing may be necessary to improve outcomes for these most seriously ill patients.

Concepts: Logit, Epidemiology, Illness, Antibiotic, Penicillin, Beta-lactam antibiotic, Odds, Beta-lactam

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Critically ill patients undergoing aggressive fluid resuscitation and treated empirically with hydrosoluble time-dependent beta-lactam antibiotics are at risk for sub-therapeutic plasma concentrations. The aim of this study was to assess the impact of two covariates - creatinine clearance (Clcr) and cumulative fluid balance (CFB) on pharmacokinetics/pharmacodynamics (PK/PD) target attainment within a week of treatment with meropenem (ME) or piperacillin/tazobactam (PIP/TZB).

Concepts: Illness, Covariate, Time-varying covariate, Penicillin, Beta-lactam antibiotic, Beta-lactamase, Beta-lactam

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Piperacillin is a beta-lactam antibiotic of penicillin family. Some penicillins were report-ed as occupational diseases cause, but piperacillin anaphylaxis with occupational sensi-tization is rare. We describe the case of a female nurse with recurrent anaphylaxis in last few months without apparent cause, only in work environment. Latex allergy was excluded after negative latex glove provocation. Later during diagnostic workup, the patient reported a similar reaction minutes after piperacillin preparation. She denied any previous antibiotic therapeutic exposure. Skin prick tests (SPT) to beta-lactams were positive to piperacillin, penicillin G and major and minor determinants. SPT to cefuroxime was negative but intradermic test was positive. The patient has indication for beta-lactams eviction and for adrenaline auto-injector kit. No further reactions occurred after patient’s transfer to another department with minimum possible exposure. Allergic risk prevention is essential and must be rapidly implemented to avoid incapacitating occupational diseases development.

Concepts: Medicine, Penicillin, Beta-lactam antibiotic, Beta-lactamase, Beta-lactam, Cephalosporin, Determinant, Beta-lactam antibiotics