Prognostic value of early EEG abnormalities in severe stroke patients requiring mechanical ventilation: a pre-planned analysis of the SPICE prospective multicenter study.

INTRODUCTION: Prognostication of outcome in severe stroke patients necessitating invasive mechanical ventilation poses significant challenges. The objective of this study was to assess the prognostic significance and prevalence of early electroencephalogram (EEG) abnormalities in adult stroke patients receiving mechanical ventilation. METHODS: This study is a pre-planned ancillary investigation within the prospective multicenter SPICE cohort study (2017-2019), conducted in 33 intensive care units (ICUs) in the Paris area, France. We included adult stroke patients requiring invasive mechanical ventilation, who underwent at least one intermittent EEG examination during their ICU stay. The primary endpoint was the functional neurological outcome at one year, determined using the modified Rankin scale (mRS), and dichotomized as unfavorable (mRS 4-6, indicating severe disability or death) or favorable (mRS 0-3). Multivariable regression analyses were employed to identify EEG abnormalities associated with functional outcomes. RESULTS: Of the 364 patients enrolled in the SPICE study, 153 patients (49 ischemic strokes, 52 intracranial hemorrhages, and 52 subarachnoid hemorrhages) underwent at least one EEG at a median time of 4 (interquartile range 2-7) days post-stroke. Rates of diffuse slowing (70% vs. 63%, p = 0.37), focal slowing (38% vs. 32%, p = 0.15), periodic discharges (2.3% vs. 3.7%, p = 0.9), and electrographic seizures (4.5% vs. 3.7%, p = 0.4) were comparable between patients with unfavorable and favorable outcomes. Following adjustment for potential confounders, an unreactive EEG background to auditory and pain stimulations (OR 6.02, 95% CI 2.27-15.99) was independently associated with unfavorable outcomes. An unreactive EEG predicted unfavorable outcome with a specificity of 48% (95% CI 40-56), sensitivity of 79% (95% CI 72-85), and positive predictive value (PPV) of 74% (95% CI 67-81). Conversely, a benign EEG (defined as continuous and reactive background activity without seizure, periodic discharges, triphasic waves, or burst suppression) predicted favorable outcome with a specificity of 89% (95% CI 84-94), and a sensitivity of 37% (95% CI 30-45). CONCLUSION: The absence of EEG reactivity independently predicts unfavorable outcomes at one year in severe stroke patients requiring mechanical ventilation in the ICU, although its prognostic value remains limited. Conversely, a benign EEG pattern was associated with a favorable outcome.

One-Year Outcomes in Patients With Acute Stroke Requiring Mechanical Ventilation.

BACKGROUND: Long-term outcomes of patients with severe stroke remain poorly documented. We aimed to characterize one-year outcomes of patients with stroke requiring mechanical ventilation in the intensive care unit (ICU). METHODS: We conducted a prospective multicenter cohort study in 33 ICUs in France (2017-2019) on patients with consecutive strokes requiring mechanical ventilation for at least 24 hours. Outcomes were collected via telephone interviews by an independent research assistant. The primary end point was poor functional outcome, defined by a modified Rankin Scale score of 4 to 6 at 1 year. Multivariable mixed models investigated variables associated with the primary end point. Secondary end points included quality of life, activities of daily living, and anxiety and depression in 1-year survivors. RESULTS: Among the 364 patients included, 244 patients (66.5% [95% CI, 61.7%-71.3%]) had a poor functional outcome, including 190 deaths (52.2%). After adjustment for non-neurological organ failure, age ≥70 years (odds ratio [OR], 2.38 [95% CI, 1.26-4.49]), Charlson comorbidity index ≥2 (OR, 2.01 [95% CI, 1.16-3.49]), a score on the Glasgow Coma Scale <8 at ICU admission (OR, 3.43 [95% CI, 1.98-5.96]), stroke subtype (intracerebral hemorrhage: OR, 2.44 [95% CI, 1.29-4.63] versus ischemic stroke: OR, 2.06 [95% CI, 1.06-4.00] versus subarachnoid hemorrhage: reference) remained independently associated with poor functional outcome. In contrast, a time between stroke diagnosis and initiation of mechanical ventilation >1 day was protective (OR, 0.56 [95% CI, 0.33-0.94]). A sensitivity analysis conducted after exclusion of patients with early decisions of withholding/withdrawal of care yielded similar results. We observed persistent physical and psychological problems at 1 year in >50% of survivors. CONCLUSIONS: In patients with severe stroke requiring mechanical ventilation, several ICU admission variables may inform caregivers, patients, and their families on post-ICU trajectories and functional outcomes. The burden of persistent sequelae at 1 year reinforces the need for a personalized, multi-disciplinary, prolonged follow-up of these patients after ICU discharge. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03335995.

Comparison of Injuries Associated With Electric Scooters, Motorbikes, and Bicycles in France, 2019-2022.

Importance: Electric scooter (e-scooter) use is increasing in France and in many urban environments worldwide. Yet little is known about injuries associated with use of e-scooters. Objective: To describe characteristics and outcomes of major trauma involving e-scooters. Design, Setting, and Participants: A multicenter cohort study was conducted in France using the national major trauma registry between January 1, 2019, and December 20, 2022. All patients admitted to a participating major trauma center following a road traffic crash (RTC) involving an e-scooter, a bicycle, or a motorbike were included. Exposure: Included patients were compared according to the 3 mechanisms. Main Outcomes and Measures: The primary outcome was trauma severity as defined by the Injury Severity Score (ISS). Secondary outcomes included the trends of the number of patients per year, a comparison of the RTC epidemiologic factors, injury severity, resources used, and in-hospital outcomes. Results: A total of 5233 patients involved in RTCs were admitted (median age, 33 [IQR, 24-48] years; 4629 [88.5%] men; median ISS, 13 [IQR, 8-22]). The population included 229 e-scooter RTCs (4.4%), 4094 motorbike RTCs (78.2%), and 910 bicycle RTCs (17.4%). The number of patients treated following e-scooter RTCs increased by 2.8-fold in 4 years (from 31 in 2019 to 88 in 2022), while bicycle RTCs increased by 1.2-fold and motorbike RTCs decreased by 0.9-fold. At admission, 36.7% of e-scooter users had a blood alcohol content higher than the legal threshold (n = 84) and 22.5% wore a protective helmet (n = 32). Among e-scooter RTCs, 102 patients (45.5%) had an ISS of 16 or higher. This proportion was similar for patients with motorbike RTCs (1557 [39.7%]; P = .10) and bicycle RTCs (411 [47.3%]; P = .69). With a proportion of 25.9% (n = 50), patients with e-scooter RTCs had twice as many severe traumatic brain injuries (Glasgow Coma Scale ≤8) as motorbike RTCs (445 [11.8%]) and a proportion comparable to bicycle RTCs (174 [22.1%]). The mortality of e-scooter RTCs was 9.2% (n = 20), compared with 5.2% (n = 196) (P = .02) for motorbikes and 10.0% (n = 84) (P = .82) for bicycles. Conclusions and Relevance: The findings of this study suggest that trauma involving e-scooters in France has significantly increased over the past 4 years. These patients presented with injury profiles as severe as those of individuals who experienced bicycle or motorbike RTCs, with a higher proportion of severe traumatic brain injury.

Association between combination antibiotic therapy as opposed as monotherapy and outcomes of ICU patients with Pseudomonas aeruginosa ventilator-associated pneumonia: an ancillary study of the iDIAPASON trial.

BACKGROUND: The optimal treatment duration and the nature of regimen of antibiotics (monotherapy or combination therapy) for Pseudomonas aeruginosa ventilator­associated pneumonia (PA-VAP) remain debated. The aim of this study was to evaluate whether a combination antibiotic therapy is superior to a monotherapy in patients with PA-VAP in terms of reduction in recurrence and death, based on the 186 patients included in the iDIAPASON trial, a multicenter, randomized controlled trial comparing 8 versus 15 days of antibiotic therapy for PA-VAP. METHODS: Patients with PA-VAP randomized in the iDIAPASON trial (short-duration-8 days vs. long-duration-15 days) and who received appropriate antibiotic therapy were eligible in the present study. The main objective is to compare mortality at day 90 according to the antibiotic therapy received by the patient: monotherapy versus combination therapy. The primary outcome was the mortality rate at day 90. The primary outcome was compared between groups using a Chi-square test. Time from appropriate antibiotic therapy to death in ICU or to censure at day 90 was represented using Kaplan-Meier survival curves and compared between groups using a Log-rank test. RESULTS: A total of 169 patients were included in the analysis. The median duration of appropriate antibiotic therapy was 14 days. At day 90, among 37 patients (21.9%) who died, 17 received monotherapy and 20 received a combination therapy (P = 0.180). Monotherapy and combination antibiotic therapy were similar for the recurrence rate of VAP, the number of extra pulmonary infections, or the acquisition of multidrug-resistant (MDR) bacteria during the ICU stay. Patients in combination therapy were exposed to mechanical ventilation for 28 ± 12 days, as compared with 23 ± 11 days for those receiving monotherapy (P = 0.0243). Results remain similar after adjustment for randomization arm of iDIAPASON trial and SOFA score at ICU admission. CONCLUSIONS: Except longer durations of antibiotic therapy and mechanical ventilation, potentially related to increased difficulty in achieving clinical cure, the patients in the combination therapy group had similar outcomes to those in the monotherapy group. TRIAL REGISTRATION: NCT02634411 , Registered 15 December 2015.

Risk factors of second ventilator-associated pneumonia in trauma patients: a retrospective cohort study.

BACKGROUND: Ventilator acquired pneumonia (VAP) is a frequent and serious complication in ICU. Second episodes of VAP are common in trauma patients and may be related to severity of underlying conditions, treatment or bacterial factors of the first VAP. The aim of this study was to identify risk factors of second VAP episodes in trauma injured patients (defined as the development of a new pulmonary infection during or remotely following the first episode). DESIGN: This is a single-center, retrospective cohort study of trauma injured patients who underwent a first episode of VAP between January 1, 2013 and December 31, 2020 at Beaujon Hospital. RESULTS: A total of 533 patients with a first episode of VAP were analyzed, mostly with head and/or thoracic traumatic injury. A second episode of VAP occurred in one hundred sixty-seven patients (31.3%). The main risk factors found was the degree of hypoxemia at the time of the first episode [PaO2/FiO2 ratio 100-200, OR 3.12 (1.77-5.69); < 100, OR 5.80 (2.70-12.8)] and severe traumatic brain injury characterized by an initial GCS ≤ 8 [OR 1.65 (1.01-2.74)]. CONCLUSION: Depth of hypoxemia during the first VAP episode and severity of the initial brain injury are the main risk factors for VAP second episode in trauma injured patients.

Antimicrobial Stewardship for Ventilator Associated Pneumonia in Intensive Care (the ASPIC trial): study protocol for a randomised controlled trial.

INTRODUCTION: Ventilator-associated pneumonia (VAP) remains the leading cause of infections treated in the intensive care units (ICU). In a personalised care approach, we hypothesise that the duration of treatment of VAP can be reduced in function of the response to treatment. METHODS AND ANALYSIS: The Antimicrobial Stewardship for Ventilator-Associated Pneumonia in Intensive Care (ASPIC) trial is a pragmatic national multicentre, phase III, non-inferiority, comparative randomised (1:1) single-blinded clinical trial. Five hundred and ninety adult patients hospitalised in 24 French ICU with a microbiologically confirmed first episode of VAP that received appropriate empirical antibiotic therapy will be included. They will be randomly allocated to standard management with duration of appropriate antibiotic fixed for 7 days according to international guidelines or antimicrobial stewardship based on daily clinical assessment of clinical cure. The assessment of clinical cure will be repeated daily until at least three criteria of clinical cure are met, allowing the discontinuation of antibiotic therapy in experimental group. The primary endpoint is a composite endpoint combining of all-cause mortality measured at day 28, treatment failure or new episode of microbiologically confirmed VAP until day 28.The aim of the study is to demonstrate that a strategy to reduce the duration of antibiotic therapy for VAP based on clinical assessment is safe could lead to changes in practice as part of a personalised therapeutic approach, by reducing exposure to antibiotics and their side effects. ETHICS AND DISSEMINATION: The ASPIC trial has been approved by the French regulatory agency (Agence Nationale de Sécurité du Médicament et des Produits de Santé, ANSM; EUDRACT number 2021-002197-78, 19 August 2021) and an independent ethics committee the Comité de Protection des Personnes Ile-de-France III (CNRIPH : 21.03.25.60729, 10 October 2021) for the study protocol (version ASPIC-1.3; 03 September 2021) for all study centres. Participant recruitment is scheduled to begin in 2022. Results will be published in international peer-reviewed medical journals. TRIAL REGISTRATION NUMBER: NCT05124977.

Transition matrices model as a way to better understand and predict intra-hospital pathways of covid-19 patients.

Since January 2020, the SARS-CoV-2 pandemic has severely affected hospital systems worldwide. In Europe, the first 3 epidemic waves (periods) have been the most severe in terms of number of infected and hospitalized patients. There are several descriptions of the demographic and clinical profiles of patients with COVID-19, but few studies of their hospital pathways. We used transition matrices, constructed from Markov chains, to illustrate the transition probabilities between different hospital wards for 90,834 patients between March 2020 and July 2021 managed in Paris area. We identified 3 epidemic periods (waves) during which the number of hospitalized patients was significantly high. Between the 3 periods, the main differences observed were: direct admission to ICU, from 14 to 18%, mortality from ICU, from 28 to 24%, length of stay (alive patients), from 9 to 7 days from CH and from 18 to 10 days from ICU. The proportion of patients transferred from CH to ICU remained stable. Understanding hospital pathways of patients is crucial to better monitor and anticipate the impact of SARS-CoV-2 pandemic on health system.

Comparison of 8 versus 15 days of antibiotic therapy for Pseudomonas aeruginosa ventilator-associated pneumonia in adults: a randomized, controlled, open-label trial.

PURPOSE: Duration of antibiotic therapy for ventilator-associated pneumonia (VAP) due to non-fermenting Gram-negative bacilli (NF-GNB), including Pseudomonas aeruginosa (PA) remains uncertain. We aimed to assess the non-inferiority of a short duration of antibiotics (8 days) vs. prolonged antibiotic therapy (15 days) in VAP due to PA (PA-VAP). METHODS: We conducted a nationwide, randomized, open-labeled, multicenter, non-inferiority trial to evaluate optimal duration of antibiotic treatment in PA-VAP. Eligible patients were adults with diagnosis of PA-VAP and randomly assigned in 1:1 ratio to receive a short-duration treatment (8 days) or a long-duration treatment (15 days). A pre-specified analysis was used to assess a composite endpoint combining mortality and PA-VAP recurrence rate during hospitalization in the intensive care unit (ICU) within 90 days. RESULTS: The study was stopped after 24 months due to slow inclusion rate. In intention-to-treat population (n = 186), the percentage of patients who reached the composite endpoint was 25.5% (N = 25/98) in the 15-day group versus 35.2% (N = 31/88) in the 8-day group (difference 9.7%, 90% confidence interval (CI) -1.9%-21.2%). The percentage of recurrence of PA-VAP during the ICU stay was 9.2% in the 15-day group versus 17% in the 8-day group. The two groups had similar median days of mechanical ventilation, of ICU stay, number of extra pulmonary infections and acquisition of multidrug-resistant (MDR) pathogens during ICU stay. CONCLUSIONS: Our study failed to show the non-inferiority of a short duration of antibiotics in the treatment of PA-VAP, compared to a long duration. The short duration strategy may be associated to an increase of PA-VAP recurrence. However, the lack of power limits the interpretation of this study.

Empiric antimicrobial therapy for early-onset pneumonia in severe trauma patients.

PURPOSE: The bacterial ecology involved in early pneumonia of severe trauma patients is mostly commensal and would allow wide use of narrow-spectrum antibiotics. We describe risk factors for treatment failure of severe trauma patients' pneumonia with the use of narrow-spectrum antimicrobial therapy in order to develop a score that could help clinicians to determine which patients might be treated with narrow-spectrum antibiotics. METHODS: A retrospective, observational, monocentric cohort study was conducted of severe trauma patients requiring mechanical ventilation for > 48 h and developing a first episode of microbiologically confirmed pneumonia occurring within the first 10 days after admission. RESULTS: Overall, 370 patients were included. The resistance rate against narrow-spectrum antibiotics (amoxicillin/clavulanic acid) was 22.7% (84 pneumonia). In a multivariate analysis, two independent risk factors were associated with this resistance: prior antimicrobial therapy ≥ 48 h (OR 4.00; 95 CI [2.39; 6.75]) and age ≥ 30y (OR 2.10; 95 CI [1.21; 3.78]). We created a prediction score that defined patient with one or two risk factors at high risk of resistance. This score presented a sensitivity of 0.92 [0.88; 0.94], a specificity of 0.33 [0.28; 0.38], a positive predictive value of 0.29 [0.24; 0.33] and a negative predictive value of 0.93 [0.90; 0.95]. CONCLUSION: Simple risk factors may help clinicians to identify severe trauma patients at high risk of pneumonia treatment failure with the use of narrow-spectrum antimicrobial therapy and, thus, use better tailored empiric therapy and limit the use of unnecessary broad-spectrum antimicrobial therapy.

ISS is not an appropriate tool to estimate overtriage.

PURPOSE: The aim of this work is to study a cohort of patients of ISS < 15 admitted to a TC, and to determine the number of patients that ultimately benefited from the skills and resources specific of a level 1 trauma center. METHODS: Retrospective study from a prospective cohort of patients admitted to TC (Beaujon Hospital, APHP) for suspected severe trauma from January 2011 to December 2017. The main outcome criterion was the use of surgery or interventional radiology within the first 24 h after admission of patients with ISS < 15. The secondary outcomes were stratified into severe (mortality, resuscitation care, length of stay in intensive care units) and non-severe criteria (mild head injury, hospital discharge or transfer within 24 h). RESULTS: Of 3035 patients admitted during the study period, 1409 with an ISS < 15 were included, corresponding to a theoretical overtriage rate of 46.4%. Among these, 611 patients (43.4%) underwent emergency intervention within the first 24 h (586 surgical interventions, 19 direct transfers to the operating theater and 6 acts of interventional radiology), 238 (16.9%) of patients presented with severe and 531 (38%) with non-severe outcome criteria. CONCLUSION: This work demonstrates that in a cohort of patients classified as ISS < 15 admitted to a TC, a considerable amount of TC-specific resources are required, and patients present with severe outcome criteria despite being classified as overtriaged. These results suggest that triage of trauma patients should be based on resource use and clinical outcome rather than anatomic criteria.

Prediction models of methicillin sensitive Staphylococcus aureus ventilator associated pneumonia relapse in trauma and brain injury patients: A retrospective analysis.

PURPOSE: To describe the incidence and risk factors of methicillin sensitive Staphylococcus aureus ventilator associated pneumonia (MSSA-VAP) relapse in trauma and non-traumatic brain injury patients. MATERIALS AND METHODS: Retrospective observational monocentric cohort study of consecutive ICU patients who developed a first episode of MSSA-VAP after trauma and non-traumatic brain injury. MSSA-VAP relapse encompass MSSA-VAP treatment failure (persistence or recurrence of MSSA) or other pathogen - VAP. RESULTS: A total of 165 patients (71% of trauma and 29% of non-traumatic brain injury) with MSSA-VAP were included. MSSA-VAP relapse occurred in 54 (33%) patients, including 28 (17%) MSSA-VAP treatment failure and 46 (28%) other pathogen-VAP. Empirical first-line antibiotic therapy was appropriate in 96% of cases. In multivariate analysis, the presence of Streptococcus species (Odds ratio [OR] 7.37) and oropharyngeal flora (OR 3.64) as initial MSSA co-pathogen, suggested aspiration at the time of admission and independently predicted MSSA-VAP treatment failure. Initial Glasgow coma scale (OR 0.89), need for emergent surgery (OR 5.71) and the presence of an acute respiratory distress syndrome at the time of the first MSSA-VAP (3.99), independently predicted the onset of other pathogen - VAP. CONCLUSION: Early and simple factors may help to identify patients with high-risk of MSSA-VAP relapse.

Continuous Pneumatic Regulation of Tracheal Cuff Pressure to Decrease Ventilator-associated Pneumonia in Trauma Patients Who Were Mechanically Ventilated: The AGATE Multicenter Randomized Controlled Study.

BACKGROUND: Ventilator-associated pneumonia (VAP) is the most frequent health care-associated infection in severely ill patients, and aspiration of contaminated oropharyngeal content around the cuff of the tracheal tube is the main route of contamination. RESEARCH QUESTION: Is continuous regulation of tracheal cuff pressure using a pneumatic device superior to manual assessment three times daily using a portable manometer (routine care) in preventing VAP in patients with severe trauma? STUDY DESIGN AND METHODS: In this open-label, randomized controlled superiority trial conducted in 13 French ICUs, adults (age ≥ 18 years) with severe trauma (Injury Severity Score > 15) and requiring invasive mechanical ventilation for ≥ 48 h were enrolled. Patients were randomly assigned (1:1) via a secure Web-based random number generator in permuted blocks of variable sizes to one of two groups according to the method of tracheal cuff pressure control. The primary outcome was the proportion of patients developing VAP within 28 days following the tracheal intubation, as determined by two assessors masked to group assignment, in the modified intention-to-treat population. This study is closed to new participants. RESULTS: A total of 434 patients were recruited between July 31, 2015, and February 15, 2018, of whom 216 were assigned to the intervention group and 218 to the control group. Seventy-three patients (33.8%) developed at least one episode of VAP within 28 days following the tracheal intubation in the intervention group compared with 64 patients (29.4%) in the control group (adjusted subdistribution hazard ratio, 0.96; 95% CI, 0.76-1.20; P = .71). No serious adverse events related to the use of the pneumatic device were noted. INTERPRETATION: Continuous regulation of cuff pressure of the tracheal tube using a pneumatic device was not superior to routine care in preventing VAP in patients with severe trauma. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT02534974; URL: www.clinicaltrials.gov.

Implementation of French Recommendations for the Prevention and the Treatment of Hospital-acquired Pneumonia: A Cluster-randomized Trial.

BACKGROUND: We determined whether an audit on the adherence to guidelines for hospital-acquired pneumonia (HAP) can improve the outcomes of patients in intensive care units (ICUs). METHODS: This study was conducted at 35 ICUs in 30 hospitals. We included consecutive, adult patients hospitalized in ICUs for 3 days or more. After a 3-month baseline period followed by the dissemination of recommendations, an audit on the compliance to recommendations (audit period) was followed by a 3-month cluster-randomized trial. We randomly assigned ICUs to either receive audit and feedback (intervention group) or participate in a national registry (control group). The primary outcome was the duration of ICU stay. RESULTS: Among 1856 patients enrolled, 602, 669, and 585 were recruited in the baseline, audit, and intervention periods, respectively. The composite measures of compliance were 47% (interquartile range [IQR], 38-56%) in the intervention group and 42% (IQR, 25-53%) in the control group (P = .001). As compared to the baseline period, the ICU lengths of stay were reduced by 3.2 days in the intervention period (P = .07) and by 2.8 days in the control period (P = .02). The durations of ICU stay were 7 days (IQR, 5-14 days) in the control group and 9 days (IQR, 5-20 days) in the intervention group (P = .10). After adjustment for unbalanced baseline characteristics, the hazard ratio for being discharged alive from the ICU in the control group was 1.17 (95% confidence interval, .69-2.01; P = .10). CONCLUSIONS: The publication of French guidelines for HAP was associated with a reduction of the ICU length of stay. However, the realization of an audit to improve their application did not further improve outcomes. CLINICAL TRIALS REGISTRATION: NCT03348579.

Pathophysiology of Escherichia coli pneumonia: Respective contribution of pathogenicity islands to virulence.

Ventilator-associated pneumonia (VAP) remains the most frequent life-threatening nosocomial infection. Enterobacteriaceae including Escherichia coli are increasingly involved. If a cumulative effect of pathogenicity islands (PAIs) has been shown for E. coli virulence in urinary tract or systemic infections, very little is known regarding pathophysiology of E. coli pneumonia. This study aimed to determine the role of each of the 7 PAIs present in pathogenic E. coli strain 536 in pneumonia pathophysiology. We used mutant strains to screen pathophysiological role of PAI in a rat pneumonia model. We also test individual gene mutants within PAI identified to be involved in pneumonia pathogenesis. Finally, we determined the prevalence of these genes of interest in E. coli isolates from feces and airways of ventilated patients. Only PAIs I and III were significantly associated with rat pneumonia pathogenicity. Only the antigen-43 (Ag43) gene in PAI III was significantly associated with bacterial pathogenicity. The prevalence of tested genes in fecal and airway isolates of ventilated patients did not differ between isolates. In contrast, genes encoding Ag43, the F17-fimbriae subunits, HmuR and SepA were more prevalent in VAP isolates with statistical significance for hmuR when compared to airway colonizing isolates. The E. coli PAIs involved in lung pathogenicity differed from those involved in urinary tract and bloodstream infections. Overall, extraintestinal E. coli virulence seems to rely on a combination of numerous virulence genes that have a cumulative effect depending on the infection site.

Impact of the duration of antibiotics on clinical events in patients with Pseudomonas aeruginosa ventilator-associated pneumonia: study protocol for a randomized controlled study.

BACKGROUND: Ventilator-associated pneumonia (VAP) accounts for 25% of infections in intensive care units. Compared to a long duration (LD) of antibiotic therapy, a short duration (SD) has a comparable clinical efficacy with less antibiotic use and less multidrug-resistant (MDR) pathogen emergence, with the exception of documented VAP of non-fermenting Gram-negative bacilli (NF-GNB), including Pseudomonas aeruginosa (PA). These results have led the American Thoracic Society to recommend SD therapy for VAP, except for PA-VAP. Thus the beneficial effect of SD therapy in PA-VAP is still a matter of debate. We aimed to assess the non-inferiority of a short duration of antibiotics (8 days) versus prolonged antibiotic therapy (15 days) in PA-VAP. METHODS/DESIGN: The impact of the duration of antibiotics on clinical events in patients with Pseudomonas aeruginosa ventilator-associated pneumonia (iDIAPASON) trial is a randomized, open-labeled non-inferiority controlled trial, conducted in 34 French intensive care units (ICUs), comparing two groups of patients with PA-VAP according to the duration (8 days or 15 days) of effective antibiotic therapy against PA. The primary outcome is a composite endpoint combining day 90 mortality and PA-VAP recurrence rate during hospitalization in the ICU. Furthermore, durations of mechanical ventilation and hospitalization, as well as number and types of extrapulmonary infections or acquisition of MDR pathogens during the hospitalization in the ICU will be recorded. Recurrence with predefined criteria (clinical suspicion of VAP associated with a positive quantitative culture of a respiratory sample) will be evaluated by two independent experts. DISCUSSION: Demonstrating that an SD (8 days) versus LD (15 days) therapy strategy in PA-VAP treatment is safe and not associated with an increased mortality or recurrence rate could lead to a change in practices and guidelines in the management of antibiotic therapy of this frequent ICU complication. This strategy could lead to decreased antibiotic exposure during hospitalization in the ICU and in turn reduce the acquisition and the spread of MDR pathogens. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02634411 . Registered on 19 November 2015.

Population pharmacokinetics of micafungin in ICU patients with sepsis and mechanical ventilation.

OBJECTIVES: To identify the factors associated with the interindividual pharmacokinetic (PK) variability of micafungin and to evaluate the probability of reaching the previously determined PK/pharmacodynamic efficacy thresholds (AUC/MIC >5000 for non-parapsilosis Candida sp. and ≥285 for Candida parapsilosis) with the recommended 100 mg daily dose in ICU patients with sepsis and mechanical ventilation. METHODS: One hundred patients were included and 436 concentrations were available for PK analysis performed with NONMEM software. PTA was determined by Monte Carlo simulations. RESULTS: Micafungin obeyed a two-compartment model with first-order elimination from the central compartment. Mean parameter estimates (percentage interindividual variability) were 1.34 L/h (34%) for clearance (CL), 11.80 L (38%) and 7.68 L (39%) for central (Vc) and peripheral (Vp) distribution volumes, respectively, and 4.67 L/h (37%) for distribution clearance. CL, Vc and Vp increased by 14% when the albumin level was ≤25 g/L and CL decreased by 25% when SOFA score was ≥10. Body weight was related to CL, Vc and Vp by allometric models. PTA was ≥90% in Candida albicans and Candida glabrata infections, except when the MIC was ≥0.015 mg/L, and ranged between 0% and 40% for C. parapsilosis infections with MIC ≥0.5 mg/L. CONCLUSIONS: A possible increase in the dose should be evaluated for infections due to C. parapsilosis and for infections due to C. albicans and C. glabrata with MICs ≥0.015 mg/L.

Empirical Micafungin Treatment and Survival Without Invasive Fungal Infection in Adults With ICU-Acquired Sepsis, Candida Colonization, and Multiple Organ Failure: The EMPIRICUS Randomized Clinical Trial.

Importance: Although frequently used in treating intensive care unit (ICU) patients with sepsis, empirical antifungal therapy, initiated for suspected fungal infection, has not been shown to improve outcome. Objective: To determine whether empirical micafungin reduces invasive fungal infection (IFI)-free survival at day 28. Design, Setting, and Participants: Multicenter double-blind placebo-controlled study of 260 nonneutropenic, nontransplanted, critically ill patients with ICU-acquired sepsis, multiple Candida colonization, multiple organ failure, exposed to broad-spectrum antibacterial agents, and enrolled between July 2012 and February 2015 in 19 French ICUs. Interventions: Empirical treatment with micafungin (100 mg, once daily, for 14 days) (n = 131) vs placebo (n = 129). Main Outcomes and Measures: The primary end point was survival without proven IFI 28 days after randomization. Key secondary end points included new proven fungal infections, survival at day 28 and day 90, organ failure, serum (1-3)-ß-D-glucan level evolution, and incidence of ventilator-associated bacterial pneumonia. Results: Among 260 patients (mean age 63 years; 91 [35%] women), 251 (128, micafungin group; 123, placebo group) were included in the modified intent-to-treat analysis. Median values were 8 for Sequential Organ Failure Assessment (SOFA) score, 3 for number of Candida-colonized sites, and 99 pg/mL for level of (1-3)-ß-D-glucan. On day 28, there were 82 (68%) patients in the micafungin group vs 79 (60.2%) in the placebo group who were alive and IFI free (hazard ratio [HR], 1.35 [95% CI, 0.87-2.08]). Results were similar among patients with a (1-3)-ß-D-glucan level of greater than 80 pg/mL (n = 175; HR, 1.41 [95% CI, 0.85-2.33]). Day-28 IFI-free survival in patients with a high SOFA score (>8) was not significantly different when compared between the micafungin vs placebo groups (HR, 1.69 [95% CI, 0.96-2.94]). Use of empirical micafungin decreased the rate of new invasive fungal infection in 4 of 128 patients (3%) in the micafungin group vs placebo (15/123 patients [12%]) (P = .008). Conclusions and Relevance: Among nonneutropenic critically ill patients with ICU-acquired sepsis, Candida species colonization at multiple sites, and multiple organ failure, empirical treatment with micafungin, compared with placebo, did not increase fungal infection-free survival at day 28. Trial Registration: clinicaltrials.gov Idenitfier: NCT01773876.