Lowbury Lecture 2021: tales of the unexpected in antibiotic resistance

Since the 1990s few new antibiotics have become available; during the same period the appearance and spread of bacteria no longer susceptible to first- and second-line antibiotics has accelerated; indeed some bacterial infections have become untreatable with existing antibiotics. Control of antibiotic resistance is multifactorial, and includes restrictive antibiotic use and good infection control. This lecture addresses three aspects of antibiotic resistance, with reference to the Netherlands, that illustrate the complexity of antibiotic resistance epidemiology. Initially selective decontamination of the digestive tract (SDD) was not adopted in the Netherlands because of concern about antibiotic resistance. However, three trials showed that SDD regimens, including four days of systemic cephalosporins, gave better clinical outcomes with no effect on antibiotic-resistant bacteria. Many predictions have been made about the impact of infections with antibiotic-resistant bacteria on human health. However, the situation is complex, because the risk factors for infection with multidrug-resistant bacteria are also risk factors for poor clinical outcome. A study in eight Dutch hospitals estimated the mortality attributable to antibiotic resistance as close to zero. Concern about the emergence of resistance in Staphylococcus aureus has limited the universal use of mupirocin to prevent surgical site infections. However, the risk may have been overstated, and universal decolonization with mupirocin and chlorhexidine has now become standard of care in patients undergoing cardiothoracic or orthopaedic surgery in many Dutch hospitals. Prophylactic antibiotics can improve patient outcomes with acceptable risks of promoting resistance

Oropharyngeal decontamination in intensive care patients: less is not more

Ventilator-associated pneumonia (VAP) is a common cause of morbidity, antibiotic use, increased length of stay and, possibly, increased mortality in ICU patients. Colonization of the oropharyngeal cavity with potentially pathogenic micro-organisms is instrumental in the pathogenesis of VAP, and selective oropharyngeal decontamination (SOD) with antibiotics (AB-SOD) or antiseptics, such as chlorhexidine gluconate (CHX-SOD), has been associated with reduced incidences of VAP. In a recent issue of Critical Care Scannapieco and colleagues investigated differences in oropharyngeal colonization between mechanically ventilated patients receiving oropharyngeal decontamination with 0.12% CHX-SOD either once or twice daily compared to placebo. CHX-SOD was associated with a reduction in Staphylococcus aureus colonization, but the study was underpowered to demonstrate a reduction in VAP incidence. We urgently need well-designed and adequately powered studies to evaluate the potential benefits of CHX-SOD on patient outcome in ICUs

Analysis of melting and flow in the hot-end of a material extrusion 3D printer using X-ray computed tomography

This paper presents in-situ X-ray computed tomography (CT) experiments used to study the flow behavior within a conventional hot-end of a fused filament fabrication printer. Three types of experiments were performed to better understand the melt and flow behavior. In one experiment, 360{\deg} CT scans were conducted, focusing on the air gap between the filament and the nozzle wall. In a second experiment, the flow profile inside the nozzle was studied using radiography. To provide a good contrast to the surrounding nozzle material, filament was prepared containing small amounts of tungsten powder as a contrast agent. During a third test, the extruder forces were measured and compared with the X-ray results and the predictions of a numerical simulation. The CT scans showed that at higher filament speeds, less area of the nozzle wall is in contact with the melt. This means that a larger part of the barrel section is occupied by an air gap between the solid filament and the nozzle wall. In contrast to the filament speed, the influence of the heater temperature shows no discernible effect on the part of the nozzle filled with melt. Radiographic evaluation of the velocity profile revealed a parabolic distribution under the studied conditions, closely matching numerical simulations modeling the flow as isothermal and non-Newtonian. The study's findings offer potential for improving nozzle design. Furthermore, the presented experimental method can serve as a valuable tool for future validation of more complex numerical simulations

Why sensitive bacteria are resistant to hospital infection control.

Background: Large reductions in the incidence of antibiotic-resistant strains of Staphylococcus aureus and Clostridium difficile have been observed in response to multifaceted hospital-based interventions. Reductions in antibiotic-sensitive strains have been smaller or non-existent. It has been argued that since infection control measures, such as hand hygiene, should affect resistant and sensitive strains equally, observed changes must have largely resulted from other factors, including changes in antibiotic use. We used a mathematical model to test the validity of this reasoning. Methods: We developed a mechanistic model of resistant and sensitive strains in a hospital and its catchment area. We assumed the resistant strain had a competitive advantage in the hospital and the sensitive strain an advantage in the community. We simulated a hospital hand hygiene intervention that directly affected resistant and sensitive strains equally. The annual incidence rate ratio ( IRR) associated with the intervention was calculated for hospital- and community-acquired infections of both strains. Results: For the resistant strain, there were large reductions in hospital-acquired infections (0.1 ≤ IRR ≤ 0.6) and smaller reductions in community-acquired infections (0.2 ≤ IRR ≤  0.9). These reductions increased in line with increasing importance of nosocomial transmission of the strain. For the sensitive strain, reductions in hospital acquisitions were much smaller (0.6 ≤ IRR ≤ 0.9), while communityacquisitions could increase or decrease (0.9 ≤ IRR ≤ 1.2). The greater the importance of the community environment for the transmission of the sensitive strain, the smaller the reductions. Conclusions: Counter-intuitively, infection control interventions, including hand hygiene, can have strikingly discordant effects on resistant and sensitive strains even though they target them equally, following differences in their adaptation to hospital and community-based transmission. Observed lack of effectiveness of control measures for sensitive strains does not provide evidence that infection control interventions have been ineffective in reducing resistant strains

Review on the biological degradation of polymers in various environments

Biodegradable plastics can make an important contribution to the struggle against increasing environmental pollution through plastics. However, biodegradability is a material property that is influenced by many factors. This review provides an overview of the main environmental conditions in which biodegradation takes place and then presents the degradability of numerous polymers. Polylactide (PLA), which is already available on an industrial scale, and the polyhydroxyalkanoates polyhydroxybutyrate (PHB) and polyhydroxybutyrate-co-valerate (PHBV), which are among the few plastics that have been proven to degrade in seawater, will be discussed in detail, followed by a summary of the degradability of further petroleum-, cellulose-, starch-, protein- and CO2-based biopolymers and some naturally occurring polymers

Within-Host Evolution of the Dutch High-Prevalent<i> Pseudomonas aeruginosa</i> Clone ST406 during Chronic Colonization of a Patient with Cystic Fibrosis

This study investigates adaptation of ST406, a prevalent P. aeruginosa clone, present in 15% of chronically infected cystic fibrosis (CF) patients in the Netherlands, in a newly infected CF patient during three years using whole genome sequencing (WGS), transcriptomics, and phenotypic assays, including biofilm formation. WGS-based phylogeny demonstrates that ST406 is genetically distinct from other reported CF related strains or epidemic clones. Comparative genomic analysis of the early (S1) and late (S2) isolate yielded 42 single nucleotide polymorphisms (SNPs) and 10 indels and a single 7 kb genomic fragment only found in S2. Most SNPs and differentially expressed genes encoded proteins involved in metabolism, secretion and signal transduction or transcription. SNPs were identified in regulator genes mexT and exsA and coincided with differential gene expression of mexE and mexF, encoding the MexE/F efflux pump, genes encoding the type six secretion system (T6SS) and type three secretion system (T3SS), which have also been previously implicated in adaptation of other P. aeruginosa strains during chronic infection of CF lungs. The observation that genetically different strains from different patients have accumulated similar genetic adaptations supports the concept of adaptive parallel evolution of P. aeruginosa in chronically infected CF patients. Phenotypically, there was loss of biofilm maturation coinciding with a significant lower level of transcription of both bfmR and bfmS during chronic colonization. These data suggest that the high-prevalent Dutch CF clone ST406 displays adaptation to the CF lung niche, which involves a limited number of mutations affecting regulators controlling biofilm formation and secretion and genes involved in metabolism. These genes could provide good targets for anti-pseudomonal therapy

New methods to analyse microarray data that partially lack a reference signal

BACKGROUND: Microarray-based Comparative Genomic Hybridisation (CGH) has been used to assess genetic variability between bacterial strains. Crucial for interpretation of microarray data is the availability of a reference to compare signal intensities to reliably determine presence or divergence each DNA fragment. However, the production of a good reference becomes unfeasible when microarrays are based on pan-genomes.When only a single strain is used as a reference for a multistrain array, the accessory gene pool will be partially represented by reference DNA, although these genes represent the genomic repertoire that can explain differences in virulence, pathogenicity or transmissibility between strains. The lack of a reference makes interpretation of the data for these genes difficult and, if the test signal is low, they are often deleted from the analysis. We aimed to develop novel methods to determine the presence or divergence of genes in a Staphylococcus aureus multistrain PCR product microarray-based CGH approach for which reference DNA was not available for some probes. RESULTS: In this study we have developed 6 new methods to predict divergence and presence of all genes spotted on a multistrain Staphylococcus aureus DNA microarray, published previously, including those gene spots that lack reference signals. When considering specificity and PPV (i.e. the false-positive rate) as the most important criteria for evaluating these methods, the method that defined gene presence based on a signal at least twice as high as the background and higher than the reference signal (method 4) had the best test characteristics. For this method specificity was 100% and 82% for MRSA252 (compared to the GACK method) and all spots (compared to sequence data), respectively, and PPV were 100% and 76% for MRSA252 (compared to the GACK method) and all spots (compared to sequence data), respectively. CONCLUSION: A definition of gene presence based on signal at least twice as high as the background and higher than the reference signal (method 4) had the best test characteristics, allowing the analysis of 6-17% more of the genes not present in the reference strain. This method is recommended to analyse microarray data that partially lack a reference signal

Тарикъатлар хусусиетлери

В статье проанализированы в историко-хронологическом и диахроническом аспектах весьма важный социальный институт – суфийские братства и их деятельность. Работа посвящена по преимуществу особенностям и характерным чертам практического (прагматического, или рефлекторного) суфизма, который функционально осуществляется через братства, а не специфике суфизма интеллектуального, то есть не его религиозно-философским и этико-моральным доктринам и положениям