• Critically ill patient
• Infection
• Multidrug resistant pathogens
• Septic shock, sepsis, bloodstream infection
• Syndromic molecular diagnosis

• Humans
• Critical Illness/therapy
• Expert Testimony/methods

• Merck

• Culture
• Negative result
• Sepsis
• Shock, septic
• Treatment outcome

• Humans
• Male
• Female
• Prospective Studies
• Sepsis/drug therapy
• Sepsis/mortality
• Aged
• Middle Aged
• Republic of Korea/epidemiology
• Cohort Studies
• Aged, 80 and over
• Intensive Care Units/organization & administration
• Intensive Care Units/statistics & numerical data
• Organ Dysfunction Scores
• Blood Culture/methods
• Blood Culture/statistics & numerical data
• Hospital Mortality
• Registries/statistics & numerical data

• 2019E280500, 2020E280700, 2021-10-026 the Research Program funded by the Korea Disease Control and Prevention Agency
• the 2023 Inje University research grant.
• the Korean Sepsis Alliance (KSA) affiliated with the Korean Society of Critical Care

• Gram-negative
• SLIC
• antibiotic
• blood culture
• sensitivity
• susceptibility

• Humans
• Blood Culture/methods
• Microbial Sensitivity Tests/methods
• Microbial Sensitivity Tests/instrumentation
• Gram-Negative Bacteria/drug effects
• Gram-Negative Bacteria/isolation & purification
• Anti-Bacterial Agents/pharmacology
• Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methods
• Bacteremia/microbiology
• Bacteremia/diagnosis
• Sepsis/diagnosis
• Sepsis/microbiology
• Gram-Negative Bacterial Infections/diagnosis
• Gram-Negative Bacterial Infections/microbiology
• Light

• Higher Specialist Scientist Training Programme), funded by the National Health Service, U.K.

• Pediatric
• culture-negative
• culture-positive
• meta-analysis
• sepsis or septic shock

• Acute lung injury
• Acute respiratory distress syndrome
• Antimicrobial lung tissue penetration
• Ventilator-associated pneumonia

• Animals
• Meropenem/pharmacokinetics
• Meropenem/administration & dosage
• Vancomycin/pharmacokinetics
• Vancomycin/administration & dosage
• Swine
• Anti-Bacterial Agents/pharmacokinetics
• Anti-Bacterial Agents/administration & dosage
• Lung/metabolism
• Lung Injury/drug therapy
• Disease Models, Animal
• Pneumonia/drug therapy
• Female
• Microbial Sensitivity Tests

• A. baumannii
• Drug targets
• Infection
• Multi-drug resistant
• Pathogenesis
• Therapy

• Acinetobacter baumannii/pathogenicity
• Acinetobacter baumannii/drug effects
• Humans
• Acinetobacter Infections/drug therapy
• Acinetobacter Infections/microbiology
• Virulence Factors/metabolism
• Drug Resistance, Multiple, Bacterial
• Anti-Bacterial Agents/therapeutic use
• Anti-Bacterial Agents/pharmacology
• Animals

• acute kidney injury
• continuous venovenous hemofiltration with dialysis
• lactate clearance
• mortality
• plasmapheresis
• sepsis
• survival

• biomarkers
• microbiology
• procalcitonin
• sepsis code

• Bacteremia
• Gram-negative
• Gram-positive
• Machine learning

• Humans
• Gram-Negative Bacterial Infections/diagnosis
• Gram-Negative Bacterial Infections/drug therapy
• Gram-Negative Bacterial Infections/complications
• Sepsis/drug therapy
• Bacteremia/drug therapy
• Shock, Septic/drug therapy
• Anti-Bacterial Agents/therapeutic use

• 81873927 National Natural Science Foundation of China
• 62173212 National Natural Science Foundation of China
• tsqn202103165 Taishan Scholars Program of Shandong Province
• 2020SDUCRCC013 Clinical Research Center of Shandong University

• Antibiotic stewardship
• Community-acquired pneumonia
• Critically ill patients
• Legionella

• Humans
• Anti-Bacterial Agents/therapeutic use
• Retrospective Studies
• Pneumonia, Mycoplasma
• Legionnaires' Disease/diagnosis
• Legionnaires' Disease/drug therapy
• Lactams
• Quinolones
• Antigens, Bacterial
• Community-Acquired Infections/drug therapy
• Influenza, Human
• beta-Lactams

• artificial intelligence
• determinants
• empiric antimicrobials
• neural networks
• sepsis
• septic shock

• SG-001-022021-SPH Management and Science University

• Child
• Humans
• Shock, Septic
• Retrospective Studies
• Intensive Care Units, Pediatric
• Prognosis

• Antimicrobial stewardship
• Infection
• Sepsis

• Diagnosis procedure combination
• Intensive care unit
• Propensity score matching
• Sepsis

• ICU
• LC-MS/MS
• MRM
• antibacterial agents
• multiplex analysis
• therapeutic drug monitoring

• Klebsiella pneumoniae carbapenemase
• carbapenem-resistant Enterobacterales
• ceftazidime-avibactam
• rapid diagnostics

• Humans
• Klebsiella pneumoniae
• Anti-Bacterial Agents/therapeutic use
• Carbapenems/pharmacology
• Klebsiella Infections/drug therapy
• Ceftazidime/therapeutic use
• beta-Lactamases/genetics
• Bacterial Proteins/genetics
• Azabicyclo Compounds/therapeutic use
• Drug Combinations
• beta-Lactamase Inhibitors/therapeutic use
• Bacteremia/drug therapy
• Microbial Sensitivity Tests

• R01 AI090155 NIAID NIH HHS
• P30CA008748 NCI NIH HHS
• P30 CA008748 NCI NIH HHS
• UL1 TR002384 NCATS NIH HHS
• UL1TR002384 NCATS NIH HHS
• Allergan, Inc
• National Institute of Allergy and Infectious Diseases
• National Center for Advancing Translational Sciences
• National Cancer Institute
• National Institutes of Health

• biphasic
• blood stream infection (BSI)
• isothermal amplification
• porous dried blood matrix
• sepsis diagnosis

• Anti-Bacterial Agents/pharmacology
• Candida albicans/genetics
• Candida albicans/isolation & purification
• DNA, Bacterial/blood
• DNA, Fungal/blood
• Dried Blood Spot Testing/methods
• Escherichia coli/genetics
• Escherichia coli/isolation & purification
• Heme/chemistry
• Humans
• Limit of Detection
• Methicillin/pharmacology
• Polymerase Chain Reaction/methods
• Sensitivity and Specificity
• Sepsis/blood
• Sepsis/diagnosis
• Sepsis/microbiology
• Staphylococcus aureus/genetics
• Staphylococcus aureus/isolation & purification
• Stem Cells

• F31 NR010320 NINR NIH HHS
• R01 GM129709 NIGMS NIH HHS
• R21 AI146865 NIAID NIH HHS

Proper selection of susceptible antibiotics in drug-resistant bacteria is critical to treat bloodstream infection. Although biomarkers that guide antibiotic therapy have been extensively evaluated, little is known about host biomarkers targeting in vivo antibiotic susceptibility. Therefore, we aimed to evaluate the trends of hemodynamics and biomarkers in a porcine bacteremia model treated with insusceptible antibiotics compared to those in susceptible models. Extended-spectrum β-lactamase (ESBL)-producing Escherichia coli (E. coli, 5.0 * 10^9 CFU) was intravenously administered to 11 male pigs. One hour after bacterial infusion, pigs were assigned to two groups of antibiotics, ceftriaxone (n = 6) or ertapenem (n = 5). Pigs were monitored up to 7 h after bacterial injection with fluid and vasopressor support to maintain the mean arterial blood pressure over 65 mmHg. Blood sampling for blood culture and plasma acquisition was performed before and every predefined hour after E. coli injection. Cytokine (tumor necrosis factor-α, interleukin [IL]-1β, IL-6, IL-8, IL-10, C-reactive protein, procalcitonin, presepsin, heparan sulfate, syndecan, and soluble triggering receptor expressed on myeloid cells-1 [sTREM-1]) levels in plasma were analyzed using enzyme-linked immunosorbent assays. Bacteremia developed after intravenous injection of E. coli, and negative conversion was confirmed only in the ertapenem group. While trends of other biomarkers failed to show differences, the trend of sTREM-1 was significantly different between the two groups (P = 0.0001, two-way repeated measures analysis of variance). Among hemodynamics and biomarkers, the sTREM-1 level at post 2 h after antibiotics administration represented a significant difference depending on susceptibility, which can be suggested as a biomarker candidate of in vivo antibiotics susceptibility. Further clinical studies are warranted for validation.

IMPORTANCE Early and appropriate antibiotic treatment is a keystone in treating patients with sepsis. Despite its importance, blood culture which requires a few days remains as a pillar of diagnostic method for microorganisms and their antibiotic susceptibility. Whether changes in biomarkers and hemodynamics indicate treatment response of susceptible antibiotic compared to resistant one is not well understood to date. In this study using extended-spectrum β-lactamase -producing E. coli bacteremia porcine model, we have demonstrated the comprehensive cardiovascular hemodynamics and trends of plasma biomarkers in sepsis and compared them between two groups with susceptible and resistant antibiotics. While other hemodynamics and biomarkers have failed to differ, we have identified that levels of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) significantly differed between the two groups over time. Based on the data in this study, trends of sTREM-1 obtained before the antibiotics and 2~4 h after the antibiotics could be a novel host biomarker that triggers the step-up choice of antibiotics.

• critical care
• epidemiology
• mortality
• sepsis
• septic shock
• surviving sepsis campaign

• complications
• costs
• hospital-acquired bacterial pneumonia
• nosocomial pneumonia
• pneumonia
• ventilator-associated bacterial pneumonia

Appropriate gentamicin dosing in continuous renal replacement therapy (CRRT) patients remains undefined. This study aimed to develop a population pharmacokinetic (PK) model of gentamicin in CRRT patients and to infer the optimal dosing regimen for gentamicin.

Fourteen CRRT patients dosed with gentamicin were included to establish a population PK model to characterize the variabilities and influential covariates of gentamicin. The pharmacokinetic/pharmacodynamic (PK/PD) target attainment and risk of toxicity for different combinations of gentamicin regimens (3–7 mg/kg q24h) and CRRT effluent doses (30–50 mL/h/kg) were evaluated by Monte Carlo simulation. The probability of target attainment (PTA) was determined for the PK/PD indices of the ratio of drug peak concentration/minimum inhibitory concentration (C_max/MIC > 10) and the ratio of area under the drug concentration–time curve/MIC over 24 h (AUC_0-24h/MIC > 100), and the risk of toxicity was estimated by drug trough concentration thresholds (1 and 2 mg/L).

A one-compartment model adequately described the PK characteristics of gentamicin. Covariates including body weight, age, gender, and CRRT modality did not influence the PK parameters of gentamicin based on our dataset. All studied gentamicin regimens failed to achieve satisfactory PTAs for pathogens with an MIC ≥2 mg/L. A good balance of PK/PD target attainment and risk of toxicity (>2 mg/L) was achieved under 7 mg/kg gentamicin q24h and 40 mL/kg/h CRRT dose for an MIC ≤1 mg/L. CRRT dose intensity had a significant impact on the target attainment of AUC_0-24h/MIC >100 and risk of toxicity.

A combination of 7 mg/kg gentamicin q24h and 40 mL/kg/h CRRT dose might be considered as a starting treatment option for CRRT patients, and drug monitoring is required to manage toxicity.

• CRRT
• critically ill
• gentamicin
• population pharmacokinetics

• Aprendizaje automático
• Artificial intelligence
• Clinical decision support systems
• Inteligencia artificial
• Machine learning
• Sepsis
• Sistemas de apoyo a la decisión clínica

• Clinical Decision-Making
• Humans
• Machine Learning
• Sepsis/diagnosis
• Sepsis/therapy

Sepsis is a potentially dangerous infection that requires prompt identification and treatment. Emergency medicine physicians must grasp the clinical signs and laboratory results of direct and indirect organ failure, the source of infection management, and the criteria for treating sepsis and septic shock. The pathogenesis of sepsis is connected to inflammation and an excess of reactive oxygen and nitrogen species, which activate the pathogen-associated molecular pattern (PAMP)-pattern recognition receptor (PRR) and damage-associated molecular pattern (DAMP)-PRR signaling pathways. The development of rapid, sensitive, and precise techniques for sepsis diagnosis might be aided by nanotechnology, a part of nanomedicine. Nanoparticles (NPs) such as magnetic NPs, gold NPs, fluorescent (silica and quantum dots), and lipid-based NPs have all been discussed to contribute to the detection of sepsis-related microbial infections. Because of the intrinsic and unique features of these nano-sized systems, researchers are evaluating nanotechnology-based alternatives for sepsis control. Recent advances in nanotechnology-based technologies for sepsis detection and management are discussed in this study.

Databases (PubMed, Medline, PMC, Google Scholar) were used to source various studies that were carried out on sepsis in terms of assessment, types, diagnosis, and treatment controversies, with more attention being given with a focus on the most recent data, principles, and management guidelines. Priority was also given to studies published within the last 11 years, using keywords such as "sepsis guidelines," "sepsis clinical," "septic risk factors," "sepsis and nano technology," "nano particles," "sepsis controversies," and "nano diagnostic" in the search. After a filtration process, the eight most relevant studies were selected to be included in this review. The filtration process included the use of both inclusion and exclusion criteria. The excluded studies were pediatric populations, obstetrical populations, and nanotechnology advancements dealing with other fields not relating to sepsis. The selected studies were also undertaken through a quality appraisal process using corresponding assessment tools. The selected articles were all highly informative about sepsis and the processes of diagnosis and treatment that are currently in use as well as those that are still being developed or implemented. Furthermore, we look at how nanomedicine in the application of nanomaterials can be employed to efficiently manage sepsis.

The Surviving Sepsis Campaign recommends the administration of antibiotics within 1 hour of triage time in sepsis patients. The purpose of this study was to determine the factors affecting the time to first dose antibiotics in sepsis patients presenting to the emergency department (ED).

We conducted a prospective observational study on factors affecting the time to first dose antibiotics in patients with sepsis presenting to the ED over a period of 7 months (July 2019 to January 2020). The purpose of this study was to determine the factors affecting the time to first dose antibiotics in sepsis patients.

During the study period, a total of 410 patients with a mean age of 51.6 years were presented to the ED with sepsis. Majority was triaged to priority 1 (84.8%). The median door to antibiotic time was 50 minutes (IQR, 40–90). Two-thirds (68%) of the patients (279) received antibiotics within 60 minutes. The blood culture positivity rate was 22.9%, and the contamination rate was 6%. The most common factors for the delay were atypical presentation (36.6%) and unknown focus of infection (36.6%). Triage to non-acute areas of the ED (priority 2) was associated with delayed antibiotic administration [odds ratio (OR), 7.3; 95% confidence interval (CI), 4.03–13.36; p-value <0.001]. Patients presented with cellulitis and necrotizing soft tissue infection (NSTI) had received antibiotics within an hour compared to other diagnoses (18.3 vs 8.4%; OR, 2.4; 95% CI, 1.2–4.9; p = 0.009).

Two-thirds of our patients received their first dose of antibiotics within an hour of presentation to the ED. Triage to lower priorities was an independent risk factor for delay in first-dose antibiotic administration, and patients presented with an obvious focus of infections like cellulitis and NSTI received their first dose of antibiotic much earlier when compared to other diagnoses.

Joseph JV, Madhiyazhagan M, Roshan R, Dhanapal SG, Arul S, Abhilash KPP. Factors Affecting the Time to First Dose Antibiotic in Sepsis in Acute Emergency. Indian J Crit Care Med 2021;25(10):1155–1160.

• Antibiotics
• Blood culture
• Emergency department
• Sepsis
• qSOFA

• Age Factors
• Anti-Bacterial Agents/administration & dosage
• Anti-Bacterial Agents/adverse effects
• Anti-Bacterial Agents/pharmacokinetics
• Anti-Bacterial Agents/therapeutic use
• Bacterial Infections/drug therapy
• Biomarkers
• C-Reactive Protein/analysis
• Drug Monitoring/methods
• Healthy Volunteers
• Humans
• Inflammation Mediators/blood
• Interleukin-6/blood
• Lipopolysaccharide Receptors/blood
• Lipopolysaccharides/pharmacology
• Metabolic Clearance Rate
• Models, Biological
• Peptide Fragments/blood
• Procalcitonin/blood

• Antibacterial
• ICU
• PCT-based
• mortality
• sepsis

The development of new strategic therapies for multidrug-resistant bacteria, like the use of non-antimicrobial approaches and/or drugs repurposed to be used as monotherapies or in combination with clinically relevant antibiotics, has become urgent. A therapeutic alternative for infections by multidrug-resistant Gram-negative bacilli (MDR-GNB) is immune system modulation to improve the infection clearance. We showed that immunocompetent mice pretreated with tamoxifen at 80 mg/kg/d for three days and infected with Acinetobacter baumannii, Pseudomonas aeruginosa, or Escherichia coli in peritoneal sepsis models showed reduced release of the monocyte chemotactic protein-1 (MCP-1) and its signaling pathway interleukin-18 (IL-18), and phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2). This reduction of MCP-1 induced the reduction of migration of inflammatory monocytes and neutrophils from the bone marrow to the blood. Indeed, pretreatment with tamoxifen in murine peritoneal sepsis models reduced the bacterial load in tissues and blood, and increased mice survival from 0% to 60–100%. Together, these data show that tamoxifen presents therapeutic efficacy against MDR A. baumannii, P. aeruginosa, and E. coli in experimental models of infection and may be a new candidate to be repurposed as a treatment for GNB infections.

• animal model
• bacteria
• immune system
• infection
• repurposing drug
• tamoxifen

• Aetiology
• Bacteraemia
• Bloodstream infection
• Epidemiology
• Healthcare-associated

• Pseudomonas aeruginosa
• RNA-Seq
• Ribo-seq
• colistin
• ribosome profiling
• tobramycin

• P 33617 Austrian Science Fund FWF

• Sepsis
• nosocomial infections
• post-operative complications
• surgery

• A-2020-061 Landspítali Háskólasjúkrahús

• Antimicrobial resistance
• Nanodiagnostics
• Nanotechnology
• Nanotherapeutics
• Sepsis

• Drug Delivery Systems
• Humans
• Nanoparticles
• Nanotechnology/methods
• Sepsis/diagnosis
• Sepsis/therapy

• CHS

• antibiotic susceptibility test
• bacterial isolation
• hydrogel
• microwell
• morphology

• 30-Day mortality
• Antibiotics
• Epidemiology
• National database
• Sepsis

• MBEC
• MIC
• biofilms
• ciprofloxacin
• sub-MIC
• uropathogenic Escherichia coli

• Higher Education Commission Pakistan and Quaid-i-Azam University, Islamabad

• Sepsis
• antimicrobial stewardship
• antimicrobial therapy
• de-escalation
• early antibiotics
• septic Shock
• timing

• Aprendizaje automático
• Artificial intelligence
• Clinical decision support systems
• Inteligencia artificial
• Machine learning
• Sepsis
• Sistemas de apoyo a la decisión clínica

Rapid identification from positive blood cultures is standard of care (SOC) in many clinical microbiology laboratories. The GenMark Dx ePlex Blood Culture Identification Gram-Positive (BCID-GP) Panel is a multiplex nucleic acid amplification assay based on competitive DNA hybridization and electrochemical detection using eSensor technology. This multicenter study compared the investigational-use-only (IUO) BCID-GP Panel to other methods of identification of 20 Gram-positive bacteria, four antimicrobial resistance genes, and both Pan Candida and Pan Gram-Negative targets that are unique to the BCID-GP Panel.

Rapid identification from positive blood cultures is standard of care (SOC) in many clinical microbiology laboratories. The GenMark Dx ePlex Blood Culture Identification Gram-Positive (BCID-GP) Panel is a multiplex nucleic acid amplification assay based on competitive DNA hybridization and electrochemical detection using eSensor technology. This multicenter study compared the investigational-use-only (IUO) BCID-GP Panel to other methods of identification of 20 Gram-positive bacteria, four antimicrobial resistance genes, and both Pan Candida and Pan Gram-Negative targets that are unique to the BCID-GP Panel. Ten microbiology laboratories throughout the United States collected residual, deidentified positive blood culture samples for analysis. Five laboratories tested both clinical and contrived samples with the BCID-GP Panel. Comparator identification methods included each laboratory’s SOC, which included matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) and automated identification systems as well as targeted PCR/analytically validated real-time PCR (qPCR) with bidirectional sequencing. A total of 2,342 evaluable samples (1,777 clinical and 565 contrived) were tested with the BCID-GP Panel. The overall sample accuracy for on-panel organisms was 89% before resolution of discordant results. For pathogenic Gram-positive targets (Bacillus cereus group, Enterococcus spp., Enterococcus faecalis, Enterococcus faecium, Staphylococcus spp., Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus lugdunensis, Listeria spp., Listeria monocytogenes, Streptococcus spp., Streptococcus agalactiae, Streptococcus anginosus group, Streptococcus pneumoniae, and Streptococcus pyogenes), positive percent agreement (PPA) and negative percent agreement (NPA) ranged from 93.1% to 100% and 98.8% to 100%, respectively. For contamination rule-out targets (Bacillus subtilis group, Corynebacterium, Cutibacterium acnes, Lactobacillus, and Micrococcus), PPA and NPA ranged from 84.5% to 100% and 99.9% to 100%, respectively. Positive percent agreement and NPA for the Pan Candida and Pan Gram-Negative targets were 92.4% and 95.7% for the former and 99.9% and 99.6% for the latter. The PPAs for resistance markers were as follows: mecA, 97.2%; mecC, 100%; vanA, 96.8%; and vanB, 100%. Negative percent agreement ranged from 96.6% to 100%. In conclusion, the ePlex BCID-GP Panel compares favorably to SOC and targeted molecular methods for the identification of 20 Gram-positive pathogens and four antimicrobial resistance genes in positive blood culture bottles. This panel detects a broad range of pathogens and mixed infections with yeast and Gram-negative organisms from the same positive blood culture bottle.

• Gram-positive bacteria
• blood culture
• eSensor technology
• identification
• multiplex nucleic acid test
• resistance marker

• APACHE
• Appropriateness
• Empirical antibiotics
• ICU
• Infection
• Length of stay
• Malaysia
• Resistance
• Risk factors
• Sepsis

Sepsis is a medical emergency and life-threatening condition due to a dysregulated host response to infection, which is time-dependent and associated with unacceptably high mortality. Thus, when treating suspicious or confirmed cases of sepsis, clinicians must initiate broad-spectrum antimicrobials within the first hour of diagnosis. Optimizing antibiotic use is essential to ensure successful outcomes and to reduce adverse antibiotic effects, as well as preventing drug resistance. All likely pathogens involved should be considered to provide an appropriate antibiotic coverage. Clinicians must investigate on the previous risk of multidrug-resistant (MDR) pathogens, and the principle of individualized dosing should replace the principle of standard dosing. The loading dose is an initial higher dose of an antibiotic for all patients, yet an individualized treatment approach for further doses should be implemented according to pharmacokinetics (PK)/pharmacodynamics (PD) and the presence of renal/liver dysfunction. Extended or continuous infusion of beta-lactams and therapeutic drug monitoring (TDM) can help to achieve therapeutic levels of antimicrobials. Reevaluation of duration and appropriateness of treatment at regular intervals are also necessary. De-escalation and shortened courses of antimicrobials must be considered for most patients, except in some justified circumstances. Leadership, teamwork, antimicrobial stewardship (AS) frameworks, guideline’s recommendations on the optimal duration of treatments, de-escalation, and novel diagnostic stewardship approaches will help us to improve patients’ quality of care.

• Sepsis
• antimicrobial stewardship (AS)
• antimicrobial therapy
• de-escalation
• early antibiotics
• early antimicrobial therapy in sepsis
• sepsis treatment
• septic shock
• timing

• ESBL
• carbapanems
• carbapenem-resistant
• intra-abdominal infection
• outcomes

• Continuous infusion
• Critically ill
• Loading dose
• Maintenance dose
• Vancomycin