European society of clinical microbiology and infectious diseases guidelines for antimicrobial stewardship in emergency departments (endorsed by European association of hospital pharmacists).

SCOPE: This European Society of Clinical Microbiology and Infectious Diseases guideline provides evidence-based recommendations to support a selection of appropriate antibiotic use practices for patients seen in the emergency department (ED) and guidance for their implementation. The topics addressed in this guideline are (a) Do biomarkers or rapid pathogen tests improve antibiotic prescribing and/or clinical outcomes? (b) Does taking blood cultures in common infectious syndromes improve antibiotic prescribing and/or clinical outcomes? (c) Does watchful waiting without antibacterial therapy or with delayed antibiotic prescribing reduce antibiotic prescribing without worsening clinical outcomes in patients with specific infectious syndromes? (d) Do structured culture follow-up programs in patients discharged from the ED with cultures pending improve antibiotic prescribing? METHODS: An expert panel was convened by European Society of Clinical Microbiology and Infectious Diseases and the guideline chair. The panel selected in consensus the four most relevant antimicrobial stewardship topics according to pre-defined relevance criteria. For each main question for the four topics, a systematic review was performed, including randomized controlled trials and observational studies. Both clinical outcomes and stewardship process outcomes related to antibiotic use were deemed relevant. The literature searches were conducted between May 2021 and March 2022. In April 2022, the panel members were formally asked to suggest additional studies that were not identified in the initial searches. Data were summarized in a meta-analysis if possible or otherwise summarized narratively. The certainty of the evidence was classified according to the Grading of Recommendations Assessment, Development and Evaluation criteria. The guideline panel reviewed the evidence per topic critically appraising the evidence and formulated recommendations through a consensus-based process. The strength of the recommendations was classified as strong or weak. To substantiate the implementation process, implementation trials or observational studies describing facilitators/barriers for implementation were identified from the same searches and were summarized narratively. RECOMMENDATIONS: The recommendations on the use of biomarkers and rapid pathogen diagnostic tests focus on the initiation of antibiotics in patients admitted through the ED. Their effect on the discontinuation or de-escalation of antibiotics during hospital stay was not reported, neither was their effect on hospital infection prevention and control practices. The recommendations on watchful waiting (i.e. withholding antibiotics with some form of follow-up) focus on specific infectious syndromes for which the primary care literature was also included. The recommendations on blood cultures focus on the indication in three common infectious syndromes in the ED explicitly excluding patients with sepsis or septic shock. Most recommendations are based on very low and low certainty of evidence, leading to weak recommendations or, when no evidence was available, to best practice statements. Implementation of these recommendations needs to be adapted to the specific settings and circumstances of the ED. The scarcity of high-quality studies in the area of antimicrobial stewardship in the ED highlights the need for future research in this field.

Efficacy of an inulin-based treatment on intestinal colonization by multidrug-resistant E. coli: insight into the mechanism of action.

Inulin, an increasingly studied dietary fiber, alters intestinal microbiota. The aim of this study was to assess whether inulin decreases intestinal colonization by multidrug resistant E. coli and to investigate its potential mechanisms of action. Mice with amoxicillin-induced intestinal dysbiosis mice were inoculated with extended spectrum beta-lactamase producing E. coli (ESBL-E. coli). The combination of inulin and pantoprazole (IP) significantly reduced ESBL-E. coli fecal titers, whereas pantoprazole alone did not and inulin had a delayed and limited effect. Fecal microbiome was assessed using shotgun metagenomic sequencing and qPCR. The efficacy of IP was predicted by increased abundance of 74 taxa, including two species of Adlercreutzia. Preventive treatments with A. caecimuris or A. muris also reduced ESBL-E. coli fecal titers. Fecal microbiota of mice effectively treated by IP was enriched in genes involved in inulin catabolism, production of propionate and expression of beta-lactamases. They also had increased beta-lactamase activity and decreased amoxicillin concentration. These results suggest that IP act through production of propionate and degradation of amoxicillin by the microbiota. The combination of pantoprazole and inulin is a potential treatment of intestinal colonization by multidrug-resistant E. coli. The ability of prebiotics to promote propionate and/or beta-lactamase producing bacteria may be used as a screening tool to identify potential treatments of intestinal colonization by multidrug resistant Enterobacterales.

Impact of emergency physician performed ultrasound in the evaluation of adult patients with acute abdominal pain: a prospective randomized bicentric trial.

BACKGROUND: Abdominal pain is common in patients visiting the emergency department (ED). The aim of this study was to assess the diagnostic contribution of point-of-care ultrasound (POCUS) in patients presenting to the ED with acute abdominal pain. METHODS: We designed an interventional randomized, controlled, open label, parallel-group, trial in two French EDs. We included adult patients presenting to the ED with acute abdominal pain. Exclusion criteria were a documented end-of-life, an immediate need of life-support therapy and pregnant or breast-feeding women. Patients were randomized in the experimental group (i.e., workup including POCUS) or control group (usual care). The primary objective of the study was to assess the added value of POCUS on diagnostic pathway in the ED, according to the diagnostic established a posteriori by an adjudication committee. The primary endpoint was the proportion of exact preliminary diagnosis between the 2 groups. The preliminary diagnosis made after clinical examination and biological results with POCUS (intervention arm) or without POCUS (usual care) was considered exact if it was similar to the adjudication committee diagnosis. RESULTS: Between June 2021 11th and June 2022 23th, 256 patients were randomized, but five were not included in the primary analysis, leaving 125 patients in the POCUS group and 126 patients in the usual care group (130 women and 121 men, median [Q1-Q3] age: 42 [30;57]). There was no difference for exact diagnosis between the two groups (POCUS 70/125, 56% versus control 78/126 (62%), RD 1.23 [95% CI 0.74-2.04]). There was no difference in the accuracy for the diagnosis of non-specific abdominal pain nor number of biological or radiological exams. Diagnostic delays and length of stay in the ED were also similar. CONCLUSIONS: In this trial, systematic POCUS did not improve the rate of diagnostic accuracy in unselected patients presenting to the ED with acute abdominal pain. However, as it was a safe procedure, further research should focus on patients with suspected etiologies where POCUS is particularly useful. TRIAL REGISTRATION:  This trial was registered on ClinicalTrials.gov on 2022/07/20 ( https://clinicaltrials.gov/study/NCT04912206?id=NCT04912206&rank=1 ) (NCT04912206).

Pantoprazole promotes sustained intestinal carriage of multidrug-resistant Escherichia coli in amoxicillin-treated mice.

AIMS: The main objective of this study was to compare extended-spectrum ß-lactamase (ESBL) Escherichia coli fecal titers during 12 days between two groups: mice who received proton pump inhibitors (PPIs) and those that did not. METHODS AND RESULTS: We tested three different in vivo models: model 1, high inoculum (106 CFU ml-1); model 2, low inoculum (102 CFU ml-1); and model 3, low inoculum and 2-day amoxicillin wash-out. There was no significant difference between the two groups in fecal ESBL E. coli titers in models 1 and 2. The fecal titers of ESBL E. coli were probably too high to show differences in colonization related to PPI treatment. By introducing a 2-day wash-out period after stopping amoxicillin (model 3), the fecal ESBL E. coli titers were higher in the PPI-treated mice during 12 days (3 log versus 11 log day CFU g-1; P < 0.05). This result highlighted that PPIs promote stable ESBL E. coli digestive carriage in mice. Fecal quantitative PCR showed that mice with low ESBL E. coli fecal titers had a much higher concentration of equol-producing bacteria, Muribaculum sp., and Adlercreutzia caecimuris. CONCLUSIONS: Pantoprazole treatment promotes sustained digestive carriage of ESBL E. coli in amoxicillin-treated mice.

Comparison of the global prevalence and trend of human intestinal carriage of ESBL-producing Escherichia coli between healthcare and community settings: a systematic review and meta-analysis.

Objectives: The widespread intestinal carriage of ESBL-producing Escherichia coli (ESBL E. coli) among both patients and healthy individuals is alarming. However, the global prevalence and trend of this MDR bacterium in healthcare settings remains undetermined. To address this knowledge gap, we performed a comparative meta-analysis of the prevalence in community and healthcare settings. Methods: Our systematic review included 133 articles published between 1 January 2000 and 22 April 2021 and indexed in PubMed, EMBASE or Google Scholar. A random-effects meta-analysis was performed to obtain the global pooled prevalence (community and healthcare settings). Subgroup meta-analyses were performed by grouping studies using the WHO regions and 5 year intervals of the study period. Results: We found that 21.1% (95% CI, 19.1%-23.2%) of inpatients in healthcare settings and 17.6% (95% CI, 15.3%-19.8%) of healthy individuals worldwide carried ESBL E. coli in their intestine. The global carriage rate in healthcare settings increased 3-fold from 7% (95% CI, 3.7%-10.3%) in 2001-05 to 25.7% (95% CI, 19.5%-32.0%) in 2016-20, whereas in community settings it increased 10-fold from 2.6% (95% CI, 1.2%-4.0%) to 26.4% (95% CI, 17.0%-35.9%) over the same period. Conclusions: The global and regional human intestinal ESBL E. coli carriage is increasing in both community and healthcare settings. Carriage rates were generally higher in healthcare than in community settings. Key relevant health organizations should perform surveillance and implement preventive measures to address the spread of ESBL E. coli in both settings.

In vitro and in vivo activity of new strains of Bacillus subtilis against ESBL-producing Escherichia coli: an experimental study.

AIMS: The gastro-intestinal tract is a major reservoir of extended-spectrum beta-lactamase (ESBL) producing Escherichia coli. Bacillus spores may be used as probiotics to decrease digestive colonization by ESBL-E. coli. Our aim was to assess the in vitro and in vivo activity of new Bacillus strains against ESBL-E. coli. METHODS AND RESULTS: We screened the in vitro activity of 50 Bacillus strains against clinical isolates of ESBL-E. coli and selected B. subtilis strains CH311 and S3B. Both strains decreased ESBL-E. coli titers by 4 log10 CFU L-1 in an in vitro model of gut content, whereas the B. subtilis CU1 strain did not. In a murine model of intestinal colonization by ESBL-E. coli, CH311 and S3B did not decrease fecal titers of ESBL-E. coli. Ten sequences of putative antimicrobial peptides were identified in the genomes of CH311 and S3B, but not in CU1. CONCLUSIONS: Two new B. subtilis strains showed strong in vitro activity against ESBL-E. coli. SIGNIFICANCE AND IMPACT OF STUDY: Despite strong in vitro activities of new B. subtilis strains against ESBL-E. coli, intestinal colonisation was not altered by curative Bacillus treatment even if their spores proved to germinate in the gut. Thus, this work underlines the importance of in vivo experiments to identify efficient probiotics. The use of potential antimicrobial compounds identified by genome sequencing remains an attractive alternative to explore.

Impact of Phage Therapy on Multidrug-Resistant Escherichia coli Intestinal Carriage in a Murine Model.

INTRODUCTION: The growing resistance of bacteria to antibiotics is a major global public health concern. An important reservoir of this resistance is the gut microbiota. However, limited data are available on the ability of phage therapy to reduce the digestive carriage of multidrug-resistant bacteria. MATERIALS AND METHODS: Four novel lytic phages were isolated in vitro for efficacy against an extended-spectrum beta-lactamase-producing (ESBL) Escherichia coli strain also resistant to carbapenems through a carbapenemase OXA-48. The first step was to develop models of ESBL E. coli digestive carriage in mice. The second step was to test the efficacy of an oral and rectal phage therapy (a cocktail of four phages or microencapsulated phage) to reduce this carriage. RESULTS: The two most intense models of digestive carriage were obtained by administering amoxicillin (0.5 g·L-1) continuously in the drinking water (Model 1) or pantoprazole (0.1 g·L-1) continuously in the drinking water, combined with amoxicillin (0.5 g·L-1), for the first 8 days (Model 2). Oral administration of the phage cocktail to Model 1 resulted in a transient reduction in the concentration of ESBL E. coli in the faeces 9 days after the bacterial challenge (median = 5.33 × 108 versus 2.76 × 109 CFU·g-1, p = 0.02). In contrast, in Model 2, oral or oral + rectal administration of this cocktail did not alter the bacterial titre compared to the control (area under the curve, AUC, 3.49 × 109; 3.41 × 109 and 3.82 × 109 for the control, oral and oral + rectal groups, respectively; p-value > 0.8 for each two-by-two group comparison), as well as the administration of an oral microencapsulated phage in Model 1 (AUC = 8.93 × 109 versus 9.04 × 109, p = 0.81). CONCLUSIONS: Oral treatment with amoxicillin promoted digestive carriage in mice, which was also the case for the addition of pantoprazole. However, our study confirms the difficulty of achieving efficacy with phage therapy to reduce multidrug-resistant bacterial digestive carriage in vivo.

Probiotics impact the antibiotic resistance gene reservoir along the human GI tract in a person-specific and antibiotic-dependent manner.

Antimicrobial resistance poses a substantial threat to human health. The gut microbiome is considered a reservoir for potential spread of resistance genes from commensals to pathogens, termed the gut resistome. The impact of probiotics, commonly consumed by many in health or in conjunction with the administration of antibiotics, on the gut resistome is elusive. Reanalysis of gut metagenomes from healthy antibiotics-naïve humans supplemented with an 11-probiotic-strain preparation, allowing direct assessment of the gut resistome in situ along the gastrointestinal (GI) tract, demonstrated that probiotics reduce the number of antibiotic resistance genes exclusively in the gut of colonization-permissive individuals. In mice and in a separate cohort of humans, a course of antibiotics resulted in expansion of the lower GI tract resistome, which was mitigated by autologous faecal microbiome transplantation or during spontaneous recovery. In contrast, probiotics further exacerbated resistome expansion in the GI mucosa by supporting the bloom of strains carrying vancomycin resistance genes but not resistance genes encoded by the probiotic strains. Importantly, the aforementioned effects were not reflected in stool samples, highlighting the importance of direct sampling to analyse the effect of probiotics and antibiotics on the gut resistome. Analysing antibiotic resistance gene content in additional published clinical trials with probiotics further highlighted the importance of person-specific metagenomics-based profiling of the gut resistome using direct sampling. Collectively, these findings suggest opposing person-specific and antibiotic-dependent effects of probiotics on the resistome, whose contribution to the spread of antimicrobial resistance genes along the human GI tract merit further studies.

A murine model to study the gut bacteria parameters during complex antibiotics like cefotaxime and ceftriaxone treatment.

BACKGROUND: The globally increasing resistance due to extended-spectrum beta-lactamase producing Enterobacteriaceae is a major concern. The objective of this work was to develop a murine model to study the gut bacteria parameters during complex antibiotics like cefotaxime and ceftriaxone treatment and to compare the fecal carriage of ESBL-producing Enterobacteriaceae. METHODS: SWISS mice were treated either with ceftriaxone or with cefotaxime or with NaCl 0.9% as a control group from day 1 to day 5. We performed a gavage at day 4 with a Klebsiella pneumonia CTX-M9. We collected stools and performed pharmacological measurements, cultures and 16S rRNA gene amplification and sequencing during the 12 days of the stool collection. RESULTS: Mice treated with ceftriaxone were more colonized than mice treated with cefotaxime after gavage (p-value = 0.008; Kruskal-Wallis test). Ceftriaxone and cefotaxime were both excreted in large quantity in gut lumen but they drove architecture of the gut microbiota in different trajectories. Highest levels of colonization were associated with particular microbiota composition using principal coordinate analysis (PCoA) which were more often achieved in ceftriaxone-treated mice and which were preceded by highest fecal antibiotics concentrations in both cefotaxime or ceftriaxone groups. Using LEfSe, we found that twelve taxa were significantly different between cefotaxime and ceftriaxone-treated mice. Using SplinectomeR, we found that relative abundances of Klebsiella were significantly higher in CRO than in CTX-treated mice (p-value = 0.01). CONCLUSION: Ceftriaxone selects a particular microbial community and its substitution for cefotaxime could prevent the selection of extended-spectrum beta-lactamase producing Enterobacteriaceae.

An Evidence-Based Narrative Review of the Emergency Department Management of Acute Hyperkalemia.

BACKGROUND: The normal range for potassium is within narrow limits. Hyperkalemia is an electrolyte disorder that frequently affects patients in the emergency department (ED), and can result in significant morbidity and mortality if not identified and treated rapidly. OBJECTIVE: This article provides an evidence-based narrative review of the management of hyperkalemia, with focused updates for the emergency clinician. METHODS: We searched in MEDLINE, EMBASE, Web of Science, and Scopus databases for articles in English published in peer-reviewed journals and indexed up until May 2020. We used multiple search terms, including hyperkalemia, potassium, acute hyperkalemia, emergency department, dyskalemia, potassium disorders, kidney disease, epidemiology, electrolyte disturbance, severe hyperkalemia, and emergency management. DISCUSSION: In the ED, interventions aimed to protect patients from the immediate dangers of elevated serum potassium are divided into the following: stabilizing cardiac membrane potentials, reducing serum potassium levels through shift from the extracellular fluid to intracellular fluid, and elimination of potassium through excretion via urinary or fecal excretion. Calcium is widely recommended to stabilize the myocardial cell membrane, but additional research is necessary to establish criteria for use, dosages, and preferred solutions. Redistribution of potassium ions from the bloodstream into the cells is based on intravenous insulin or nebulized ß2-agonists. CONCLUSIONS: Hyperkalemia is a frequent electrolyte disorder in the ED. Because of the risk of fatal dysrhythmia due to cardiac membrane instability, hyperkalemia is a medical emergency. There is a lack of scientific evidence on the optimal management of hyperkalemia and more research is needed to establish optimal strategies to manage acute hyperkalemia in the emergency department.

Gut microbiome signatures of nursing home residents carrying Enterobacteria producing extended-spectrum ß-lactamases.

BACKGROUND: The prevalence of extended beta-lactamase producing Enterobacteriaceae (ESBL-E) has been constantly increasing over the last few decades. These microorganisms that have acquired broad antibiotic resistance are now common human pathogens. Changes in the gut microbiome, induced by antibiotics or other drugs, enable expansion of these microorganisms, but the mechanisms are not yet fully understood. OBJECTIVES: The main objective was to identify specific bacteria and functional pathways and genes characterizing the gut microbiome of nursing home residents carrying ESBL-E, using metagenomics. SUBJECTS AND METHODS: We included 144 residents living in two different nursing homes. All fecal samples were screened for ESBL-E and gut microbiome was characterized using shallow shotgun metagenomic DNA sequencing. RESULTS: Ten nursing home residents were colonized by ESBL-E, namely Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae species, and were compared to non-carriers. We found that ESBL-E carriers had an alteration in within-sample diversity. Using a bootstrap algorithm, we found that the gut microbiome of ESBL-E carriers was depleted in butyrate-producing species, enriched in succinate-producing species and enriched in pathways involved in intracellular pH homeostasis compared to non-carriers individuals. Several energy metabolism pathways were overrepresented in ESBL-E carriers suggesting a greater ability to metabolize multiple microbiota and mucus layer-derived nutrients. CONCLUSIONS: The gut microbiome of ESBL-E carriers in nursing homes harbors specific taxonomic and functional characteristics, conferring an environment that enables Enterobacteriaceae expansion. Here we describe new functional features associated with ESBL-E carriage that could help us to elucidate the complex interactions leading to colonization persistence in the human gut microbiota.

Modeling the risk of fluoroquinolone resistance in non-severe community-onset pyelonephritis.

Estimating whether the individual probability of being infected by a fluoroquinolone resistant isolate is higher than 10% may help to choose the empirical treatment of pyelonephritis. We aimed to model the risk of fluoroquinolone resistance in women with community-onset pyelonephritis. Women with non-severe community-onset pyelonephritis were prospectively recruited in 4 French emergency departments of 2 districts. Adjusted odds ratios (aOR) and 95% confidence intervals were estimated through multivariate logistic regression. Among 190 patients, 19 (10%) were infected by a fluoroquinolone resistant isolate. Fluoroquinolone resistance was more frequent in district #2 (17%) than in district #1 (3%). Independent risk factors for fluoroquinolone resistance were district (adjusted OR, 7.0 (2.2-31.9)), and in the 6 previous months, urinary tract infection (UTI, aOR, 3.9 (1.3-11.5)) and vesical catheterization (aOR, 4.7 (0.5-33.3)). A specific model was derived to identify district #2 patients with a low (10% or lower) probability of being infected by a fluoroquinolone resistant isolate. Independent risk factors were residency in long-term care facility (aOR, 3.3 (0.7-13.5)), and in the 6 previous months, UTI (adjusted OR, 3.1 (0.9-10.7)) and home nursing care (aOR, 3.4 (0.6-17.0)). For 63 (67%) patients, the predicted probability of fluoroquinolone resistance was 0.10; among these patients, 6 (10%) actually had a fluoroquinolone resistant isolate. Locally derived predictive models may be used to identify patients with a low probability of fluoroquinolone resistance and guide the empirical antimicrobial therapy of non-severe community-onset pyelonephritis.

The effects of inulin on gut microbial composition: a systematic review of evidence from human studies.

BACKGROUND: Inulin, consisting of repetitive fructosyl units linked by ß(2,1) bonds, is a readily fermentable fiber by intestinal bacteria that generates large quantities of short-chain fatty acids (SCFA). In individuals with constipation, it was reported that inulin ingestion was associated with a significant increase in stool frequency, suggesting a potential impact of inulin on human gut microbiota composition. Progress in high-throughput technologies allow assessment of human-associated microbiomes in terms of diversity and taxonomic or functional composition, and can identify changes in response to a specific supplementation. Hence, to understand the effects of inulin on the human gut microbiome is pivotal to gain insight into their mechanisms of action. METHODS: Here, we conducted a systematic review of human studies in adult individuals showing the effects of inulin on the gut microbiome. We searched in MEDLINE, EMBASE, Web of Science, and Scopus databases for articles in English published in peer-reviewed journals and indexed up until March 2019. We used multiple search terms capturing gut microbiome, gut microflora, intestinal microbiota, intestinal flora, gut microbiota, gut flora, microbial gut community, gut microbial composition, and inulin. RESULTS: Overall, nine original articles reported the effects of inulin on microbiome composition in adult humans, most of them being randomized, double-blind, placebo-controlled trials (n = 7). Studies varied significantly in design (3 studies associated inulin and oligofructose), supplementation protocols (from 5 to 20 gr per day of inulin consumed) and in microbiome assessment methods (16S sequencing, n = 7). The most consistent change was an increase in Bifidobacterium. Other concordant results included an increase in relative abundance of Anaerostipes, Faecalibacterium, and Lactobacillus, and a decrease in relative abundance of Bacteroides after inulin supplementation. CONCLUSIONS: Our systematic review assessed the evidence for the effects of inulin supplementation on the human gut microbiome. However, these in vivo studies did not confirm in vitro experiments as the taxonomic alterations were not associated with increase in short-chain fatty acids levels.

Correction to: Incidence of hyperkalemia in the emergency department: a 10-year retrospective study.

In the original publication of the article, the 3rd author name was swapped. The correct author name should read as Damien Masson.

US Immigration Is Associated With Rapid and Persistent Acquisition of Antibiotic Resistance Genes in the Gut.

Little is known about the effect of human migration on gut microbiome antibiotic resistance gene (ARG) carriage. Using deep shotgun stool metagenomics analysis, we found a rapid increase in gut microbiome ARG richness and abundance in women from 2 independent ethnic groups relocating from Thailand to the United States.