Benefits and Harms of Procalcitonin- or C-Reactive Protein-Guided Antimicrobial Discontinuation in Critically Ill Adults With Sepsis: A Systematic Review and Network Meta-Analysis.

OBJECTIVES: In sepsis treatment, antibiotics are crucial, but overuse risks development of antibiotic resistance. Recent guidelines recommended the use of procalcitonin to guide antibiotic cessation, but solid evidence is insufficient. Recently, concerns were raised that this strategy would increase recurrence. Additionally, optimal protocol or difference from the commonly used C-reactive protein (CRP) are uncertain. We aimed to compare the effectiveness and safety of procalcitonin- or CRP-guided antibiotic cessation strategies with standard of care in sepsis. DATA SOURCES: A systematic search of PubMed, Embase, CENTRAL, Igaku Chuo Zasshi, ClinicalTrials.gov , and World Health Organization International Clinical Trials Platform. STUDY SELECTION: Randomized controlled trials involving adults with sepsis in intensive care. DATA EXTRACTION: A systematic review with network meta-analyses was performed. The Grading of Recommendations, Assessments, Developments, and Evaluation method was used to assess certainty. DATA SYNTHESIS: Eighteen studies involving 5023 participants were included. Procalcitonin-guided and CRP-guided strategies shortened antibiotic treatment (-1.89 days [95% CI, -2.30 to -1.47], -2.56 days [95% CI, -4.21 to -0.91]) with low- to moderate-certainty evidence. In procalcitonin-guided strategies, this benefit was consistent even in subsets with shorter baseline antimicrobial duration (7-10 d) or in Sepsis-3, and more pronounced in procalcitonin cutoff of "0.5 µg/L and 80% reduction." No benefit was observed when monitoring frequency was less than half of the initial 10 days. Procalcitonin-guided strategies lowered mortality (-27 per 1000 participants [95% CI, -45 to -7]) and this was pronounced in Sepsis-3, but CRP-guided strategies led to no difference in mortality. Recurrence did not increase significantly with either strategy (very low to low certainty). CONCLUSIONS: In sepsis, procalcitonin- or CRP-guided antibiotic discontinuation strategies may be beneficial and safe. In particular, the usefulness of procalcitonin guidance for current Sepsis-3, where antimicrobials are used for more than 7 days, was supported. Well-designed studies are needed focusing on monitoring protocol and recurrence.

Bacterial sepsis causes more dramatic pathogenetic changes in the Th1 pathway than does viral (COVID-19) sepsis: a prospective observational study of whole blood transcriptomes.

OBJECTIVES: This study aimed to comprehensively compare host responses of patients with bacterial sepsis and those with viral (COVID-19) sepsis by analyzing messenger RNA (mRNA) and microRNA (miRNA) profiles to shed light on their distinct pathophysiological mechanisms. DESIGN: Prospective observational study. SETTING: Whole blood RNA sequencing was used to analyze mRNA and miRNA profiles of patients diagnosed as having bacterial sepsis or viral (COVID-19) sepsis at the Department of Trauma and Emergency Medicine, Osaka University Graduate School of Medicine. PATIENTS: Twenty-two bacterial sepsis patients, 35 viral (COVID-19) sepsis patients, and 15 healthy subjects admitted to the department were included. We diagnosed bacterial sepsis patients according to the sepsis-3 criterion that the Sequential Organ Failure Assessment score must increase to 2 points or more among patients with suspected infections. Viral (COVID-19) sepsis patients were diagnosed using SARS-CoV-2 RT-PCR testing, and presence of pneumonia was assessed through chest computed tomography scans. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: For RNA sequencing, 14,500 mRNAs, 1121 miRNAs, and 2556 miRNA-targeted mRNAs were available for analysis in the bacterial sepsis patients. Numbers of genes showing upregulated: downregulated gene expression (false discovery rate < 0.05, |log2 fold change| > 1.5) were 256:2887 for mRNA, 53:5 for miRNA, and 49:2507 for miRNA-targeted mRNA. Similarly, in viral (COVID-19) sepsis patients, 14,500 mRNAs, 1121 miRNAs, and 327 miRNA-targeted mRNAs were analyzed, with numbers of genes exhibiting upregulated: downregulated gene expression of 672:1147 for mRNA, 3:4 for miRNA, and 165:162 for miRNA-targeted mRNA. This analysis revealed significant differences in the numbers of upregulated and downregulated genes expressed and pathways between the bacterial sepsis and viral (COVID-19) sepsis patients. Bacterial sepsis patients showed activation of the PD-1 and PD-L1 cancer immunotherapy signaling pathway and concurrent suppression of Th1 signaling. CONCLUSION: Our study illuminated distinct molecular variances between bacterial sepsis and viral (COVID-19) sepsis. Bacterial sepsis patients had a greater number of upregulated and downregulated genes and pathways compared to viral (COVID-19) sepsis patients. Especially, bacterial sepsis caused more dramatic pathogenetic changes in the Th1 pathway than did viral (COVID-19) sepsis.

Efficacy of Carbapenems Compared With Noncarbapenem Broad-Spectrum Beta-Lactam Antibiotics as Initial Antibiotic Therapy Against Sepsis: A Nationwide Observational Study.

OBJECTIVES: As causative pathogens are not usually identified at the time of initiating antibiotics in sepsis, carbapenems are commonly used as an initial treatment. To reduce indiscriminate use of carbapenems, the efficacy of alternative empiric regimens, such as piperacillin-tazobactam and the fourth-generation cephalosporins, should be elucidated. This study aimed to evaluate survival effect associated with carbapenems as initial therapy for sepsis compared with these antibiotics. DESIGN: Multicenter retrospective observational study. SETTING: Tertiary hospitals in Japan. PATIENTS: Adult patients diagnosed as having sepsis from 2006 to 2019. INTERVENTIONS: Administration of carbapenems as initial antibiotic therapy. MEASUREMENTS AND MAIN RESULTS: This study used data of adult patients with sepsis extracted from a large-scale database in Japan. Patients were divided into two groups as follows: patients receiving carbapenems and patients receiving noncarbapenem broad-spectrum beta-lactam antibiotics as initial treatment. In-hospital mortality was compared between the groups by a logistic regression model adjusted by an inverse probability treatment weighting using propensity scores. To evaluate heterogeneity of effects according to patient characteristics, we also fitted logistic models in several subgroups. Among 7,392 patients with sepsis, 3,547 patients received carbapenems, and 3,845 patients received noncarbapenem agents. The logistic model showed no significant association between carbapenem therapy and lower mortality (adjusted OR 0.88, p = 0.108). Subgroup analyses suggested that there were significant survival benefits associated with carbapenem therapy in patients with septic shock, in ICUs, or with mechanical ventilation ( p for effect modifications: < 0.001, 0.014, and 0.105, respectively). CONCLUSIONS: Compared with the noncarbapenem broad-spectrum antibiotics, carbapenems as an initial therapy for sepsis were not associated with significantly lower mortality.

Impact of Gram stain results on initial treatment selection in patients with ventilator-associated pneumonia: a retrospective analysis of two treatment algorithms.

BACKGROUND: Ventilator-associated pneumonia (VAP) is a common and serious problem in intensive care units (ICUs). Several studies have suggested that the Gram stain of endotracheal aspirates is a useful method for accurately diagnosing VAP. However, the usefulness of the Gram stain in predicting which microorganisms cause VAP has not been established. The purpose of this study was to evaluate whether a Gram stain of endotracheal aspirates could be used to determine appropriate initial antimicrobial therapy for VAP. METHODS: Data on consecutive episodes of microbiologically confirmed VAP were collected from February 2013 to February 2016 in the ICU of a tertiary care hospital in Japan. We constructed two hypothetical empirical antimicrobial treatment algorithms for VAP: a guidelines-based algorithm (GLBA) based on the recommendations of the American Thoracic Society-Infectious Diseases Society of America (ATS-IDSA) guidelines and a Gram stain-based algorithm (GSBA) which limited the choice of initial antimicrobials according to the results of bedside Gram stains. The GLBA and the GSBA were retrospectively reviewed for each VAP episode. The initial coverage rates and the selection of broad-spectrum antimicrobial agents were compared between the two algorithms. RESULTS: During the study period, 219 suspected VAP episodes were observed and 131 episodes were assessed for analysis. Appropriate antimicrobial coverage rates were not significantly different between the two algorithms (GLBA 95.4% versus GSBA 92.4%; p = 0.134). The number of episodes for which antimethicillin-resistant Staphylococcus aureus agents were selected as an initial treatment was larger in the GLBA than in the GSBA (71.0% versus 31.3%; p < 0.001), as were the number of episodes for which antipseudomonal agents were recommended as an initial treatment (70.2% versus 51.9%; p < 0.001). CONCLUSIONS: Antimicrobial treatment based on Gram stain results may restrict the administration of broad-spectrum antimicrobial agents without increasing the risk of treatment failure. TRIAL REGISTRATION: UMIN-CTR, UMIN000026457 . Registered 8 March 2017 (retrospectively registered).

Benefit profile of recombinant human soluble thrombomodulin in sepsis-induced disseminated intravascular coagulation: a multicenter propensity score analysis.

INTRODUCTION: The safety and efficacy of recombinant human soluble thrombomodulin (rhTM) have been demonstrated, with promising evidence suggestive of efficacy for patients with severe sepsis involving coagulopathy in a phase IIb randomized controlled trial. However, the benefit profiles of rhTM have not been elucidated. The purpose of this study was to explore whether patients with greater disease severity, determined according to the Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) scores, would experience treatment benefit from rhTM administration. METHODS: This was a post hoc, subgroup analysis of a multicenter retrospective cohort study conducted in three Japanese tertiary referral hospitals. Patients with sepsis-induced disseminated intravascular coagulation (DIC) who required ventilator management were included. We stratified patients into several strata according to disease severity, determined by APACHE II and SOFA scores, using classification and regression trees for survival data. Intervention effects, expressed as hazard ratios (HR), were analyzed using Cox regression analysis adjusted for a propensity model to detect subgroup heterogeneity of the effects of rhTM on in-hospital mortality. RESULTS: Participants were 162 patients with sepsis-induced DIC; 68 of these patients received rhTM and 94 did not. After adjusting for imbalances, rhTM administration was significantly associated with reduced mortality in high-risk patients (APACHE II: 24 to 29; HR: 0.281; 95% confidence interval (CI): 0.093 to 0.850; P = 0.025). A similar nonsignificant tendency was observed in the very high-risk subset (APACHE II: ≥30; HR: 0.529; 95% CI: 0.202 to 1.387; P = 0.195) but was not evident in the moderate-risk subset of patients (APACHE II: <24; HR: 0.814; 95% CI: 0.351 to 1.884; P = 0.630). A similar tendency was observed in analysis of SOFA scores (moderate-risk subset (SOFA: <11), P = 0.368; high-risk subset (SOFA: ≥11), P = 0.042). CONCLUSIONS: Survival benefit was observed with rhTM treatment in sepsis-induced DIC and high risk of death according to baseline APACHE II and SOFA scores.

[A Case of Invasive Ductal Carcinoma in the Fat Replacement of the Pancreatic Body and Tail].

A 56 year-old woman with obesity (BMI3 2) and diabetes mellitus was diagnosed with right renal cell carcinoma. She underwent right nephrectomy 1 year ago. Seven months after surgery, CT revealed a rapidly growing mass near the spleen. The mass showed slight accumulation of FDG (SUVmax=2.4) on PET-CT. Since the lesion grew rapidly and was not enhanced in the early phase of enhanced CT, we diagnosed pancreatic cancer. Distal pancreatectomy and splenectomy were performed. The final pathological diagnosis was invasive ductal carcinoma in the fat replacement of the pancreatic body and tail. Postoperatively, the patient had no complications such as pancreatic fistula or aggravation of glucose intolerance. She received postoperative chemotherapy with gemcitabine. Since she developed pulmonary artery thrombosis, postoperative chemotherapy was interrupted after 8 courses. Thirty-two months after the surgery, she was still living without any recurrence. Acinar cells were absent in the fat replacement of the pancreas, but the pancreatic duct cells were still present. There was carcinoma in situ in the main pancreatic duct surrounding chronic inflammation. Fat replacement itself could be potentially precursor of the pancreatic cancer.

T cell dysfunction in elderly ARDS patients based on miRNA and mRNA integration analysis.

Background: Acute respiratory distress syndrome (ARDS) is respiratory failure that commonly occurs in critically ill patients, and the molecular mechanisms underlying its pathogenesis and severity are poorly understood. We evaluated mRNA and miRNA in patients with ARDS and elucidated the pathogenesis of ARDS after performing mRNA and miRNA integration analysis. Methods: In this single-center, prospective, observational clinical study of patients with ARDS, peripheral blood of each patient was collected within 24 hours of admission. Sequencing of mRNA and miRNA was performed using whole blood from the ARDS patients and healthy donors. Results: Thirty-four ARDS patients were compared with 15 healthy donors. Compared with the healthy donors, 1233 mRNAs and 6 miRNAs were upregulated and 1580 mRNAs and 13 miRNAs were downregulated in the ARDS patients. For both mRNA and miRNA-targeted mRNA, canonical pathway analysis showed that programmed death-1 (PD-1) and programmed cell death ligand 1 (PD-L1) cancer immunotherapy pathway was most activated and the Th2 pathway was most suppressed. For mRNA, the Th1 pathway was most suppressed. miR-149-3p and several miRNAs were identified as upstream regulators. Conclusion: miRNAs regulated the PD-1 and PD-L1 cancer immunotherapy pathway and Th2 pathway through miRNA interference action of mRNA. Integrated analysis of mRNAs and miRNAs showed that T cells were dysfunctional in ARDS patients.

Using novel micropore technology combined with artificial intelligence to differentiate Staphylococcus aureus and Staphylococcus epidermidis.

Methods for identifying bacterial pathogens are broadly categorised into conventional culture-based microbiology, nucleic acid-based tests, and mass spectrometry. The conventional method requires several days to isolate and identify bacteria. Nucleic acid-based tests and mass spectrometry are relatively rapid and reliable, but they require trained technicians. Moreover, mass spectrometry requires expensive equipment. The development of a novel, inexpensive, and simple technique for identifying bacterial pathogens is needed. Through combining micropore technology and assembly machine learning, we developed a novel classifier whose receiver operating characteristic (ROC) curve showed an area under the ROC curve of 0.94, which rapidly differentiated between Staphylococcus aureus and Staphylococcus epidermidis in this proof-of-concept study. Morphologically similar bacteria belonging to an identical genus can be distinguished using our method, which requires no specific training, and may facilitate the diagnosis and treatment of patients with bacterial infections in remote areas and in developing countries.

Atypical and non-classical CD45RBlo memory B cells are the majority of circulating SARS-CoV-2 specific B cells following mRNA vaccination or COVID-19.

Resting memory B cells can be divided into classical or atypical groups, but the heterogenous marker expression on activated memory B cells makes similar classification difficult. Here, by longitudinal analysis of mass cytometry and CITE-seq data from cohorts with COVID-19, bacterial sepsis, or BNT162b2 mRNA vaccine, we observe that resting B cell memory consist of classical CD45RB+ memory and CD45RBlo memory, of which the latter contains of two distinct groups of CD11c+ atypical and CD23+ non-classical memory cells. CD45RB levels remain stable in these cells after activation, thereby enabling the tracking of activated B cells and plasmablasts derived from either CD45RB+ or CD45RBlo memory B cells. Moreover, in both COVID-19 patients and mRNA vaccination, CD45RBlo B cells formed the majority of SARS-CoV2 specific memory B cells and correlated with serum antibodies, while CD45RB+ memory are activated by bacterial sepsis. Our results thus identify that stably expressed CD45RB levels can be exploited to trace resting memory B cells and their activated progeny, and suggest that atypical and non-classical CD45RBlo memory B cells contribute to SARS-CoV-2 infection and vaccination.

Can Gram staining be a guiding tool for optimizing initial antimicrobial agents in bacterial infections?

The emergence of multidrug-resistant organisms poses a significant threat to global public health, making the optimization of antimicrobial use crucial. Antimicrobial therapy is often initiated in emergency rooms (ERs) and intensive care units (ICUs), where patients are at high risk of infection. Prompt antimicrobial selection is essential in these facilities, and point-of-care testing can guide the appropriate initial antimicrobial therapy. Gram staining, a quick and inexpensive method, was previously used for point-of-care testing by physicians in the 1980s but was discontinued in 1988 in the United States. However, in Japan, the clinical practice of Gram stain-based antimicrobial therapy by physicians has continued in a limited number of hospitals. Several studies undertaken in Japan have shown that Gram staining carried out by trained physicians can reduce the overuse of broad-spectrum antimicrobial agents in ERs and ICUs without worsening patients' outcomes. Gram stain-based antimicrobial therapy reduced unnecessary use of carbapenems in the ER. Furthermore, Gram staining has been shown to significantly reduce the overuse of broad-spectrum antimicrobials without worsening clinical cure and mortality for patients with ventilator-associated pneumonia in the ICU. The classic technique of Gram staining has regained its usefulness through persistent clinical practice in Japan. It is hoped that Japanese researchers in this field will demonstrate to the world the efficacy of the classic technique of Gram staining in addressing this critical problem. Gram staining carried out by trained physicians could serve as a valuable means of optimizing antimicrobial treatment in ERs and ICUs.

Comparison of Quantitative Values of Headspace Gas Chromatography--Mass Spectrometry and a Formate Quantification Kit in Blood Formate Quantification.

Methanol poisoning is caused by the toxicity of formate, a by-product of methanol metabolism. Measurement of blood formate concentrations is required for emergency treatment and investigation of the cause of death. In this study, we measured concentrations of formate in the plasma of a patient with methanol poisoning using headspace gas chromatography--mass spectrometry (HS-GC--MS) and a formate assay kit. Results showed a discrepancy as the quantitative values of the kit were higher than those of HS-GC--MS. Metabolic profiling of low-molecular-weight organic compounds in patient plasma samples showed that the concentrations of lactate were correlated with the values obtained using the kit. We observed a progression when lactate and lactate dehydrogenase were added to the kit reaction simultaneously, even in the absence of formate. Moreover, disulfiram, an aldehyde dehydrogenase inhibitor, suppressed the values of patient plasma samples in the formate assay kit, implying that formate production from remaining methanol in patient plasma samples via formaldehyde occurred during the kit reaction. The reactions of the kit with lactate and methanol were undesirable for accurate measurement of formate concentration in the sample. However, considering that elevated concentrations of lactate and remaining methanol both cause acidosis and are dangerous to the body, cross-reactions with lactate and methanol in the formate assay kit may be acceptable for rapid diagnosis in facilities where HS-GC--MS and other physical and chemical equipment are unavailable.

Classification of patients with COVID-19 by blood RNA endotype: a prospective cohort study.

IMPORTANCE: In this study, whole-blood RNAs (prolactin and toll-like receptor 3) involved in the prognosis of patients with COVID-19 were identified. The RNA endotypes classified by these important RNAs highlight the possibility of stratifying the COVID-19 patient population and the need for targeted therapy based on these phenotypes.

Short- versus prolonged-course antibiotic therapy for sepsis or infectious diseases in critically ill adults: a systematic review and meta-analysis.

BACKGROUND: The 2016 International Guidelines for the Management of Sepsis and Septic Shock recommend antibiotic therapy for 7-10 days for most patients with sepsis. However, evidence on critically ill patients is limited. Thus, we conducted the first systematic review and meta-analysis comparing the effectiveness and adverse events of shorter- (≤1 week) with longer-course antibiotics in adults with critical infections including sepsis. METHODS: We searched the MEDLINE, Cochrane Central Register of Controlled Trials, and Igaku Chuo Zasshi databases for randomised controlled trials (RCTs) and observational studies (OSs) from inception to 31 March 2021. RESULTS: We included 6 of 3,766 identified articles, incorporating data from 4 RCTs and 2 OSs (1,721 patients) in meta-analyses. Three RCTs and one OS focussed on ventilator-associated pneumonia, and one RCT and one OS investigated intra-abdominal infections. The severity score levels were similar to that of sepsis, but no study comprehensively focussing on sepsis was found. There were no significant differences in mortality at a maximum follow-up of 30 days (RR 1.08, 95%CI 0.80-1.46); 28-day mortality, clinical cure, the occurrence of new events, and the emergence of resistant organisms between the groups in the RCTs. The OSs findings were consistent. The quality of evidence was assessed as very low to moderate using the GRADE approach, with no uniform description of severity scores, sepsis, or adverse events. CONCLUSIONS: Shorter, fixed-duration antibiotic therapy for clinically heterogeneous sepsis or severe infections was not associated with poorer outcomes, but the overall quality of evidence was poor.

Evaluation of urinary extravasation after non-operative management of traumatic renal injury: a multi-center retrospective study.

PURPOSE: Urinary extravasation is one of the major complications after non-operative management of traumatic renal injury and may lead to urinary tract infection and sepsis. The purpose of this study was to evaluate these factors in patients with traumatic renal injury. METHODS: This was a multi-center, retrospective, observational study performed at three tertiary referral hospitals in Osaka prefecture. We included patients with traumatic renal injury transported to the centers between January 2008 and December 2018. We excluded patients who either died or underwent nephrectomy within 24 h after admission. We investigated the occurrence of urinary extravasation and the related factors after traumatic renal injury using multivariable logistic regression analysis. RESULTS: In total, 146 patients were eligible for analysis. Their median age was 44 years and 68.5% were male. Their median Injury Severity Score was 17. Renal injuries were graded as American Association for Surgery of Trauma (AAST) grade I in 33 (22.6%), II in 27 (18.5%), III in 38 (26.0%), IV in 28 (19.2%), and V in 20 (13.7%) patients. Urinary extravasation was diagnosed in 26 patients (17.8%) and was statistically significantly associated with AAST grades IV-V (adjusted odds ratio, 33.8 [95% confidence interval 7.12-160], p < 0.001). CONCLUSION: We observed urinary extravasation in 17.8% of patients with non-operative management of traumatic renal injury and the diagnosed was made in mostly within 7 days after admission. In this study, the patients with AAST grade IV-V injury were associated with having urinary extravasation.

Significance of interferon signaling based on mRNA-microRNA integration and plasma protein analyses in critically ill COVID-19 patients.

We evaluated mRNA and miRNA in COVID-19 patients and elucidated the pathogenesis of COVID-19, including protein profiles, following mRNA and miRNA integration analysis. mRNA and miRNA sequencing was done on admission with whole blood of 5 and 16 healthy controls (HCs) and 10 and 31 critically ill COVID-19 patients (derivation and validation cohorts, respectively). Interferon (IFN)-α2, IFN-ß, IFN-γ, interleukin-27, and IFN-λ1 were measured in COVID-19 patients on admission (day 1, 181 critical/22 non-critical patients) and days 6-8 (168 critical patients) and in 19 HCs. In the derivation cohort, 3,488 mRNA and 31 miRNA expressions were identified among differentially expressed RNA expressions in the patients versus those in HCs, and 2,945 mRNA and 32 miRNA expressions in the validation cohort. Canonical pathway analysis showed the IFN signaling pathway to be most activated. The IFN-ß plasma level was elevated in line with increased severity compared with HCs, as were IFN-ß downstream proteins, such as interleukin-27. IFN-λ1 was higher in non-critically ill patients versus HCs but lower in critical than non-critical patients. Integration of mRNA and miRNA analysis showed activated IFN signaling. Plasma IFN protein profile revealed that IFN-ß (type I) and IFN-λ1 (type III) played important roles in COVID-19 disease progression.

Effect of Gram Stain-Guided Initial Antibiotic Therapy on Clinical Response in Patients With Ventilator-Associated Pneumonia: The GRACE-VAP Randomized Clinical Trial.

Importance: Gram staining should provide immediate information for detecting causative pathogens. However, the effect of Gram staining on restricting the initial antibiotic choice has not been investigated in intensive care units (ICUs). Objective: To compare the clinical response to Gram stain-guided restrictive antibiotic therapy vs guideline-based broad-spectrum antibiotic treatment in patients with ventilator-associated pneumonia (VAP). Design, Setting, and Participants: This multicenter, open-label, noninferiority randomized clinical trial (Gram Stain-Guided Antibiotics Choice for VAP) was conducted in the ICUs of 12 tertiary referral hospitals in Japan from April 1, 2018, through May 31, 2020. Patients aged 15 years or older with a VAP diagnosis and a modified Clinical Pulmonary Infection Score of 5 or higher were included. The primary analysis was based on the per-protocol analysis population. Interventions: Patients were randomized to Gram stain-guided antibiotic therapy or guideline-based antibiotic therapy (based on the 2016 Infectious Disease Society of America and American Thoracic Society clinical practice guidelines for VAP). Main Outcomes and Measures: The primary outcome was the clinical response rate; clinical response was defined as completion of antibiotic therapy within 14 days, improvement or lack of progression of baseline radiographic findings, resolution of signs and symptoms of pneumonia, and lack of antibiotic agent readministration, with a noninferiority margin of 20%. Secondary outcomes were the proportions of antipseudomonal agents and anti-methicillin-resistant Staphylococcus aureus (MRSA) agents as initial antibiotic therapies; 28-day mortality, ICU-free days, ventilator-free days; and adverse events. Results: In total, 206 patients (median [IQR] age, 69 [54-78] years; 141 men [68.4%]) were randomized to the Gram stain-guided group (n = 103) or guideline-based group (n = 103). Clinical response occurred in 79 patients (76.7%) in the Gram stain-guided group and 74 patients (71.8%) in the guideline-based group (risk difference, 0.05; 95% CI, -0.07 to 0.17; P < .001 for noninferiority). Reduced use of antipseudomonal agents (30.1%; 95% CI, 21.5%-39.9%; P < .001) and anti-MRSA agents (38.8%; 95% CI, 29.4%-48.9%; P < .001) was observed in the Gram stain-guided group vs guideline-based group. The 28-day cumulative incidence of mortality was 13.6% (n = 14) in the Gram stain-guided group vs 17.5% (n = 18) in the guideline-based group (P = .39). Escalation of antibiotics according to culture results was performed in 7 patients (6.8%) in the Gram stain-guided group and 1 patient (1.0%) in the guideline-based group (P = .03). There were no significant differences between the groups in ICU-free days, ventilator-free days, and adverse events. Conclusions and Relevance: Results of this trial showed that Gram stain-guided treatment was noninferior to guideline-based treatment and significantly reduced the use of broad-spectrum antibiotics in patients with VAP. Gram staining can potentially ameliorate the multidrug-resistant organisms in the critical care setting. Trial Registration: ClinicalTrials.gov Identifier: NCT03506113.

Impact of beta-lactamase detection reagent on rapid diagnosis of ESBL-producing pathogens using urine samples of patients with Gram-negative bacteriuria.

INTRODUCTION: The rapid increase of extended-spectrum beta-lactamase (ESBL)-producing pathogens makes it difficult to choose appropriate antimicrobials in patients with Gram-negative bacterial infection. The Cica-beta reagent (Kanto Chemical, Tokyo, Japan) is a chromogenic test that detects ESBLs from bacterial colonies. This study aimed to reveal whether Cica-beta reagent could detect ESBLs directly from urine samples to facilitate rapid diagnosis of antibiotic susceptibility. METHODS: A prospective study was conducted from July 2019 to November 2019. Patients in whom urine culture tests were performed were eligible. Each urine sample was centrifuged, and the pellet was mixed with Cica-beta reagent. The test was considered positive when the enzymatic reaction turned from yellow to red or orange. RESULTS: In total, 350 urine samples were analysed. Urinary tract infection (UTI) was diagnosed in 214 patients. ESBL-producing Enterobacterales were isolated from 79 samples. The Cica-beta test showed sensitivity of 79.8% and specificity of 99.3% in patients with Gram-negative bacteriuria. Sensitivity and specificity improved to 90.2% and 100%, respectively, in patients with UTI. CONCLUSION: The Cica-beta test could be an efficient test for the detection of ESBL-producing pathogens in urine. By providing immediate information about ESBLs, it might be a useful point-of-care test to guide appropriate antimicrobial use in patients with UTI.

External Validation of the Two Newly Proposed Criteria for Assessing Coagulopathy in Sepsis.

BACKGROUND: Two different criteria for evaluating coagulopathy in sepsis were recently released: sepsis-induced coagulopathy (SIC) and sepsis-associated coagulopathy (SAC). Although both use universal haemostatic markers of platelet count and pro-thrombin time, significance and usefulness of these criteria remain unclear. OBJECTIVE: This article validates and evaluates the significance of SIC and SAC criteria compared with the International Society on Thrombosis and Haemostasis (ISTH) overt disseminated intravascular coagulation (DIC) and Japanese Association for Acute Medicine (JAAM) DIC criteria. METHODS: Clinical characteristics of patients from a nationwide Japanese cohort were classified by SIC, SAC or DIC status and relations between criteria were examined. We evaluated associations between in-hospital mortality and anticoagulant therapy according to the SIC, SAC or DIC status to clarify the significance of criteria for introducing anticoagulants. Intervention effects were analysed by Cox regression analysis adjusted by propensity scoring. RESULTS: Incidences of coagulopathy diagnosed by SIC and JAAM DIC were similar, whereas those of SAC and ISTH overt DIC were about half of the former two (61.4%, 60.8% vs. 45.3%, 29.3%). Severity and mortality of all criteria were almost comparable. For validating initiation of anticoagulation, favourable effects of anticoagulant therapy were observed only in sub-sets with, and not without, coagulopathy diagnosed by all four criteria. Slight non-significant differences between anticoagulant groupings were found in ISTH overt DIC- and SAC-negative populations, suggesting that some patients even 'without' these criteria may benefit from anticoagulant therapy. CONCLUSION: Newly developed SIC diagnostic criteria for coagulopathy may be valuable in detecting appropriate candidates for anticoagulant therapy in sepsis and a useful alternative to conventional DIC scoring systems.

GRam stain-guided Antibiotics ChoicE for Ventilator-Associated Pneumonia (GRACE-VAP) trial: rationale and study protocol for a randomised controlled trial.

BACKGROUND: Optimising the use of antibiotic agents is a pressing challenge to overcoming the rapid emergence and spread of multidrug-resistant pathogens in intensive care units (ICUs). Although Gram staining may possibly provide immediate information for predicting pathogenic bacteria, Gram stain-guided initial antibiotic treatment is not well established in the ICU setting. We planned the GRam stain-guided Antibiotics ChoicE for Ventilator-Associated Pneumonia (GRACE-VAP) trial to investigate whether Gram staining can safely restrict the use of broad-spectrum antibiotics in patients with ventilator-associated pneumonia (VAP), which is one of the most common hospital-acquired infections in ICUs. METHODS/DESIGN: The GRACE-VAP trial is a multicentre, randomised, open-label parallel-group trial to assess the non-inferiority of Gram stain-guided initial antibiotic treatment to guidelines-based initial antibiotic treatment for the primary endpoint of clinical response rate in patients with VAP. Secondary endpoints include the coverage rates of initial antibiotic therapies, the selected rates of anti-pseudomonal agents and anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) agents as initial antibiotic therapies, 28-day all-cause mortality, ICU-free days, ventilator-free days and adverse events. Patients are randomly assigned to receive Gram stain-guided treatment or guidelines-based treatment at a ratio of 1:1. In the Gram stain group, results of Gram staining of endotracheal aspirate are used to guide the selection of antibiotics. In the guidelines group, the combination of an anti-pseudomonal agent and an anti-MRSA agent is administered. A total sample size of 200 was estimated to provide a power of 80% with a one-sided alpha level of 2.5% and a non-inferiority margin of 20%, considering 10% non-evaluable patients. DISCUSSION: The GRACE-VAP trial is expected to reveal whether Gram staining can reduce the use of broad-spectrum antibiotics without impairing patient outcomes and thereby provide evidence for an antibiotic selection strategy in patients with VAP. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03506113 . Registered on 29 March 2018. University Hospital Medical Information Network, UMIN000031933. Registered on 26 March 2018.