Performance of the Cepheid Methicillin-Resistant Staphylococcus aureus/S. aureus Skin and Soft Tissue Infection PCR Assay on Respiratory Samples from Mechanically Ventilated Patients for S. aureus Screening during the Phase 2 Double-Blind SAATELLITE Study.

We investigated the performance of the Xpert methicillin-resistant Staphylococcus aureus (MRSA)/S. aureus skin and soft tissue (SSTI) quantitative PCR (qPCR) assay in SAATELLITE, a multicenter, double-blind, phase 2 study of suvratoxumab, a monoclonal antibody (MAb) targeting S. aureus alpha-toxin, for reducing the incidence of S. aureus pneumonia. The assay was used to detect methicillin-susceptible S. aureus (MSSA) and MRSA in lower respiratory tract (LRT) samples from mechanically ventilated patients. LRT culture results were compared with S. aureus protein A (spa) gene cycle threshold (CT) values. Receiver operating characteristic (ROC) and Youden index were used to determine the CT cutoff for best separation of culture-S. aureus-negative and S. aureus-positive patients. Of 720 screened subjects, 299 (41.5%) were S. aureus positive by qPCR, of whom 209 had culture data: 162 (77.5%) were S. aureus positive and 47 (22.5%) were S. aureus negative. Culture results were negatively affected by antibiotic use and cross-laboratory variability. An inverse linear correlation was observed between CT values and quantitative S. aureus culture results. A spa CT value of 29 (≈2 × 103 CFU/mL) served as the best cutoff for separation between culture-negative and culture-positive samples. The associated area under the ROC curve was 83.8% (95% confidence interval [CI], 78 to 90%). Suvratoxumab provided greater reduction in S. aureus pneumonia or death than placebo in subjects with low S. aureus load (CT ≥ 29; relative risk reduction [RRR], 50.0%; 90% CI, 2.7 to 74.4%) versus the total study population (RRR, 25.2%; 90% CI, -4.3 to 46.4%). The qPCR assay was easy to perform, sensitive, and standardized and provided better sensitivity than conventional culture for S. aureus detection. Quantitative PCR CT output correlated with suvratoxumab efficacy in reducing S. aureus pneumonia incidence or death in S. aureus-colonized, mechanically ventilated patients.

The Extent of Aspergillosis in Critically Ill Patients With Severe Influenza Pneumonia: A Multicenter Cohort Study.

OBJECTIVES: To determine the frequency and prognosis of invasive pulmonary aspergillosis in critically ill patients with severe influenza pneumonia. DESIGN: Retrospective multicenter cohort study. SETTING: Five French ICUs. PATIENTS: Patients with influenza admitted to ICU between 2009 and 2018. MEASUREMENTS AND MAIN RESULTS: Of the 524 patients admitted for severe influenza diagnosed with a positive airway reverse-transcriptase polymerase chain reaction test, 450 (86%) required mechanical ventilation. A lower respiratory tract sample yielded with Aspergillus (Asp+) in 28 patients (5.3%). Ten patients (1.9%) were diagnosed with putative or proven invasive pulmonary aspergillosis, based on the validated AspICU algorithm. A multivariate model was built to identify independent risk factors for Aspergillus-positive pulmonary culture. Factors independently associated with Aspergillus-positive culture were liver cirrhosis (odds ratio = 6.7 [2.1-19.4]; p < 0.01), hematologic malignancy (odds ratio = 3.3 [1.2-8.5]; p = 0.02), Influenza A(H1N1)pdm09 subtype (odds ratio = 3.9 [1.6-9.1]; p < 0.01), and vasopressor requirement (odds ratio = 4.1 [1.6-12.7]; p < 0.01). In-hospital mortality of Asp+ patients was 36% versus 21% in patients without Aspergillus-positive pulmonary culture (p = 0.09). CONCLUSIONS: In this large retrospective multicenter cohort of critically ill patients, putative invasive pulmonary aspergillosis according to AspICU algorithm was a relatively rare complication of influenza. Patients at higher risk of Aspergillus pulmonary colonization included those with liver cirrhosis, hematologic malignancy, H1N1pdm09 influenza A virus, and requiring vasopressors. Our results provide additional data on the controversial association between severe influenza and invasive pulmonary aspergillosis. Reaching a consensual definition of invasive pulmonary aspergillosis becomes mandatory and confers further prospective research.

Effect of an ICU Diary on Posttraumatic Stress Disorder Symptoms Among Patients Receiving Mechanical Ventilation: A Randomized Clinical Trial.

Importance: Keeping a diary for patients while they are in the intensive care unit (ICU) might reduce their posttraumatic stress disorder (PTSD) symptoms. Objectives: To assess the effect of an ICU diary on the psychological consequences of an ICU hospitalization. Design, Setting, and Participants: Assessor-blinded, multicenter, randomized clinical trial in 35 French ICUs from October 2015 to January 2017, with follow-up until July 2017. Among 2631 approached patients, 709 adult patients (with 1 family member each) who received mechanical ventilation within 48 hours after ICU admission for at least 2 days were eligible, 657 were randomized, and 339 were assessed 3 months after ICU discharge. Interventions: Patients in the intervention group (n = 355) had an ICU diary filled in by clinicians and family members. Patients in the control group (n = 354) had usual ICU care without an ICU diary. Main Outcomes and Measures: The primary outcome was significant PTSD symptoms, defined as an Impact Event Scale-Revised (IES-R) score greater than 22 (range, 0-88; a higher score indicates more severe symptoms), measured in patients 3 months after ICU discharge. Secondary outcomes, also measured at 3 months and compared between groups, included significant PTSD symptoms in family members; significant anxiety and depression symptoms in patients and family members, based on a Hospital Anxiety and Depression Scale score greater than 8 for each subscale (range, 0-42; higher scores indicate more severe symptoms; minimal clinically important difference, 2.5); and patient memories of the ICU stay, reported with the ICU memory tool. Results: Among 657 patients who were randomized (median [interquartile range] age, 62 [51-70] years; 126 women [37.2%]), 339 (51.6%) completed the trial. At 3 months, significant PTSD symptoms were reported by 49 of 164 patients (29.9%) in the intervention group vs 60 of 175 (34.3%) in the control group (risk difference, -4% [95% CI, -15% to 6%]; P = .39). The median (interquartile range) IES-R score was 12 (5-25) in the intervention group vs 13 (6-27) in the control group (difference, -1.47 [95% CI, -1.93 to 4.87]; P = .38). There were no significant differences in any of the 6 prespecified comparative secondary outcomes. Conclusions and Relevance: Among patients who received mechanical ventilation in the ICU, the use of an ICU diary filled in by clinicians and family members did not significantly reduce the number of patients who reported significant PTSD symptoms at 3 months. These findings do not support the use of ICU diaries for preventing PTSD symptoms. Trial Registration: ClinicalTrials.gov Identifier: NCT02519725.

An early increase in endothelial protein C receptor is associated with excess mortality in pneumococcal pneumonia with septic shock in the ICU.

BACKGROUND: This study investigated changes in plasma level of soluble endothelial protein C receptor (sEPCR) in association with outcome in patients with septic shock. We explored sEPCR for early sepsis prognosis assessment and constructed a scoring system based on clinical and biological data, in order to discriminate between surviving at hospital discharge and non-surviving patients. METHODS: Clinical data and samples were extracted from the prospective "STREPTOGENE" cohort. We enrolled 278 patients, from 50 intensive care units (ICUs), with septic shock caused by pneumococcal pneumonia. Patients were divided into survivors (n = 194) and non-survivors (n = 84) based on in-hospital mortality. Soluble EPCR plasma levels were quantified at day 1 (D1) and day 2 (D2) by ELISA. The EPCR gene A3 haplotype was determined. Patients were followed up until hospital discharge. Univariate and multivariate analyses were performed. A scoring system was constructed using least absolute shrinkage and selection operator (lasso) logistic regression for selecting predictive variables. RESULTS: In-hospital mortality was 30.2% (n = 84). Plasma sEPCR level was significantly higher at D1 and D2 in non-surviving patients compared to patients surviving to hospital discharge (p = 0.0447 and 0.0047, respectively). Early increase in sEPCR at D2 was found in non-survivors while a decrease was observed in the survival group (p = 0.0268). EPCR A3 polymorphism was not associated with mortality. Baseline sEPCR level and its variation from D1 to D2 were independent predictors of in-hospital mortality. The scoring system including sEPCR predicted mortality with an AUC of 0.75. CONCLUSIONS: Our findings confirm that high plasma sEPCR and its increase at D2 are associated with poor outcome in sepsis and thus we propose sEPCR as a key player in the pathogenesis of sepsis and as a potential biomarker of sepsis outcome.

Diagnostic and management of life-threatening Adult-Onset Still Disease: a French nationwide multicenter study and systematic literature review.

BACKGROUND: Adult-onset Still disease (AOSD) is a rare systemic inflammatory disorder. A few patients develop organ complications that can be life-threatening. Our objectives were to describe the disease course and phenotype of life-threatening AOSD, including response to therapy and long-term outcome. METHODS: A multicenter case series of intensive care medicine (ICU) patients with life-threatening AOSD and a systematic literature review. RESULTS: Twenty patients were included. ICU admission mostly occurred at disease onset (90%). Disease manifestations included fever (100%), sore throat (65%), skin rash (65%), and arthromyalgia (55%). Serum ferritin was markedly high (median: 29,110 ng/mL). Acute respiratory failure, shock and multiple organ failure occurred in 15 (75%), 10 (50%), and 7 (35%) cases, respectively. Hemophagocytosis was demonstrated in eight cases. Two patients died. Treatment delay was significant. All patients received corticosteroids. Response rate was 50%. As second-line, intravenous immunoglobulins were ineffective. Anakinra was highly effective. After ICU discharge, most patients required additional treatment. Literature analysis included 79 cases of AOSD with organ manifestations, which mainly included reactive hemophagocytic syndrome (42%), acute respiratory failure (34%), and cardiac complications (23%). Response rate to corticosteroids was 68%. Response rates to IVIgs, cyclosporin, and anakinra were 50%, 80%, and 100%, respectively. CONCLUSIONS: AOSD should be recognized as a rare cause of sepsis mimic in patients with fever of unknown origin admitted to the ICU. The diagnosis relies on a few simple clinical clues. Early intensive treatment may be discussed. IVIgs should be abandoned. Long-term prognosis is favorable.

Epidemiology, risk factor, species distribution, antifungal resistance and outcome of Candidemia at a single French hospital: a 7-year study.

Candidemia remains a major cause of disease worldwide and is associated with a high mortality rate. We conducted a retrospective study of candidemia at Nantes Hospital, France, between 2004 and 2010. A total of 191 episodes (n = 188 patients) were reviewed. Incidence, demographics, risk factors, antifungal management, species identification, in vitro susceptibility and 12 weeks survival were analysed. Global incidence of candidemia was 0.37‰ admissions. Higher incidences were observed in haematology (6.65‰) and intensive care units (2‰). Central venous catheter and antibiotic exposure were the most frequent risk factors (77% and 76% respectively). Candida albicans was the predominant species (51.8%) followed by C. parapsilosis (14.5%), C. glabrata (9.8%), C. tropicalis (9.8%) and C. krusei (4.1%). However, species distribution differed significantly between medical units with frequency of C. tropicalis being higher in haematology compared to other medical units. Fluconazole and caspofungin were the main antifungals given as first-line therapy. Although not significant, 12 weeks mortality rate was 30.9%, being higher for C. tropicalis (44.4%) than for C. parapsilosis (16%). Acquired azole or echinocandin resistance was noted in some isolates, underlining the need for systematic antifungal susceptibility testing in patients with candidemia. These epidemiological findings will be of interest for antifungal stewardship at our hospital.

Rifampin use in acute community-acquired meningitis in intensive care units: the French retrospective cohort ACAM-ICU study.

INTRODUCTION: Bacterial meningitis among critically ill adult patients remains associated with both high mortality and frequent, persistent disability. Vancomycin was added to treatment with a third-generation cephalosporin as recommended by French national guidelines. Because animal model studies had suggested interest in the use of rifampin for treatment of bacterial meningitis, and after the introduction of early corticosteroid therapy (in 2002), there was a trend toward increasing rifampin use for intensive care unit (ICU) patients. The aim of this article is to report on this practice. METHODS: Five ICUs participated in the study. Baseline characteristics and treatment data were retrospectively collected from charts of patients admitted with a diagnosis of acute bacterial meningitis during a 5-year period (2004-2008). The ICU mortality was the main outcome measure; Glasgow Outcome Scale and 3-month mortality were also assessed. RESULTS: One hundred fifty-seven patients were included. Streptococcus pneumoniae and Neisseria meningitidis were the most prevalent causative microorganisms. The ICU mortality rate was 15%. High doses of a cephalosporin were the most prevalent initial antimicrobial treatment. The delay between admission and administration of the first antibiotic dose was correlated with ICU mortality. Rifampin was used with a cephalosporin for 32 patients (ranging from 8% of the cohort for 2004 to 30% in 2008). Administration of rifampin within the first 24 h of hospitalization could be associated with a lower ICU survival. Statistical association between such an early rifampin treatment and ICU mortality reached significance only for patients with pneumococcal meningitis (p=0.031) in univariate analysis, but not in the logistic model. CONCLUSIONS: We report on the role of rifampin use for patients with community-acquired meningitis, and the results of this study suggest that this practice may be associated with lower mortality in the ICU. Nevertheless, the only independent predictors of ICU mortality were organ failure and pneumococcal infection. Further studies are required to confirm these results and to explain how rifampin use would reduce mortality.

Does PaCO2 correction have an impact on survival of patients with chronic respiratory failure and long-term non-invasive ventilation?

Background and objective: Non-invasive ventilation (NIV) improves survival of patients with chronic respiratory failure (CRF). Most often, pressure settings are made to normalize arterial blood gases. However, this objective is not always achieved due to intolerance to increased pressure or poor compliance. Few studies have assessed the effect of persistent hypercapnia on ventilated patients' survival. Data from the Pays de la Loire Respiratory Health Research Institute cohort were analyzed to answer this question. Study design and methods: NIV-treated adults enrolled between 2009 and 2019 were divided into 5 subgroups: obesity-hypoventilation syndrome (OHS), COPD, obese COPD, neuromuscular disease (NMD) and chest wall disease (CWD). PaCO2 correction was defined as the achievement of a PaCO2 < 6 kPa or a 20% decrease in baseline PaCO2 in COPD patients. The endpoint was all-cause mortality. Follow-up was censored in case of NIV discontinuation. Results: Data from 431 patients were analyzed. Median survival was 103 months and 148 patients died. Overall, PaCO2 correction was achieved in 74% of patients. Bivariate analysis did not show any survival difference between patients who achievedPaCO2 correction and those who remained hypercapnic: overall population: p = 0.74; COPD: p = 0.97; obese COPD: p = 0.28; OHS: p = 0.93; NMD: p = 0.84; CWD: p = 0.28. Conclusion: Moderate residual hypercapnia under NIV does not negatively impact survival in CRF patients. In individuals with poor tolerance of pressure increases, residual hypercapnia can therefore be tolerated under long-term NIV. Larger studies, especially with a higher number of patients with residual PaCO2 > 7 kPa, are needed to confirm these results.

Effect of SARS-CoV-2 infection and pandemic period on healthcare-associated infections acquired in intensive care units.

OBJECTIVES: To compare the occurrence of healthcare-associated infections acquired in intensive care units (HAI-ICUs) in France among patients with COVID-19 and those without it in 2020 and the latter with that in patients before the COVID-19 pandemic. METHODS: Multicentre HAI-ICU surveillance network (REA-REZO) data were used to identify 3 groups: 2019 patients (2019Control), a COVID-19 group (2020Cov), and a non-COVID-19 group (2020NonCov). The primary outcome was the occurrence of HAI-ICU (ventilator-associated pneumonia [VAP], bloodstream infections [BSIs], catheter-related bacteraemia). Standardized infection ratios of VAP were calculated for each quarter in 2020 and compared with those in 2019. RESULTS: A total of 30 105 patients were included in 2020: 23 798 in the 2020NonCov group, 4465 in 2020Cov group, and 39 635 patients in the 2019Control group. The frequency of VAP was strikingly greater in the 2020Cov group: 35.6 (33.4-37.8) episodes/1000 days of mechanical ventilation versus 18.4 (17.6-19.2) in the 2020NonCov group. VAP standardized infection ratio was high in 2020 patients, particularly during the 2 quarters corresponding to the 2 waves. BSI/1000 days were more frequent in the 2020Cov group (6.4% [6.4-6.4%] vs. 3.9% [3.8-3.9%] in the 2020NonCov group). VAP and BSI were also more frequent in the 2020NonCov group than in the 2019Control group. The microbial epidemiology was only slightly different. DISCUSSION: The data presented here indicate that HAI-ICUs were more frequent during the COVID-19 period, whether the patients were admitted for COVID-19 or, to a lesser extent, for another cause. This implies that managing patients with severe disease in a pandemic context carries risks for all patients.

Contribution of Transcutaneous PCO2 in Obesity Hypoventilation Syndrome.

BACKGROUND: More and more patients have obesity-hypoventilation syndrome (OHS) because of the increasing prevalence of obesity. The accuracy of transcutaneous PCO2 (PtcCO2 ) has recently been validated. However, no study evaluated the interest of measuring systematically nocturnal PtcCO2 in the follow-up of patients with OHS and home mechanical ventilation to detect residual nocturnal hypoventilation. We aimed to evaluate the contribution of nocturnal PtcCO2 to assess nocturnal hypoventilation compared with current routine examinations, that is, daytime arterial blood gases and nocturnal pulse oximetry. METHODS: A prospective monocentric pilot study was conducted from August 2018 to November 2019. Patients with stable OHS and who were treated with home noninvasive ventilation for at least 6 months were eligible to participate. After oral consent, we performed both diurnal arterial blood gases and combined home oximetry and capnography. The primary end point was the presence of residual nocturnal hypoventilation, defined as PaCO2 > 45 mm Hg or bicarbonate ≥ 27 mmol/L, SpO2 < 90% for ≥ 10% of the night, or PtcCO2 > 49 mm Hg for ≥ 10% of the night. RESULTS: A total of 32 subjects were included. Twenty-nine subjects with nocturnal PtcCO2 were analyzed. Eighteen of the 29 subjects showed residual nocturnal hypoventilation. The association of diurnal arterial blood gases and nocturnal pulse oximetry revealed nocturnal hypoventilation in only 9 subjects. Among the 19 subjects with both normal blood gases and normal nocturnal pulse oximetry, 11 had nocturnal hypoventilation with transcutaneous capnography. Only one subject presented with hypoventilation symptoms (asthenia). CONCLUSIONS: The assessment of PtcCO2 in comparison with nocturnal pulse oximetry and arterial blood gases provides important information for the diagnosis of residual nocturnal hypoventilation in the subjects with OHS who were ventilated at home.

Development of a Predictive Dosing Nomogram to Achieve PK/PD Targets of Amikacin Initial Dose in Critically Ill Patients: A Non-Parametric Approach.

French guidelines recommend reaching an amikacin concentration of ≥8 × MIC 1 h after beginning infusion (C1h), with MIC = 8 mg/L for probabilistic therapy. We aimed to elaborate a nomogram guiding clinicians in choosing the right first amikacin dose for ICU patients in septic shock. A total of 138 patients with 407 observations were prospectively recruited. A population pharmacokinetic model was built using a non-parametric, non-linear mixed-effects approach. The total body weight (TBW) influenced the central compartment volume, and the glomerular filtration rate (according to the CKD-EPI formula) influenced its clearance. A dosing nomogram was produced using Monte Carlo simulations of the amikacin amount needed to achieve a C1h ≥ 8 × MIC. The dosing nomogram recommended amikacin doses from 1700 mg to 4200 mg and from 28 mg/kg to 49 mg/kg depending on the patient's TBW and renal clearance. However, a Cthrough ≤ 2.5 mg/L 24 h and 48 h after an optimal dose of amikacin was obtained with probabilities of 0.20 and 0.81, respectively. Doses ≥ 30 mg/kg are required to achieve a C1h ≥ 8 × MIC with MIC = 8 mg/L. Targeting a MIC = 8 mg/L should depend on local ecology.

Propofol Infusion syndrome during refractory status epilepticus in a young adult: successful ECMO resuscitation.

BACKGROUND: Propofol infusion syndrome (PRIS) is a rare but serious complication of propofol administration consisting of metabolic disorder with acidosis, often leading to fatal cardiovascular collapse. METHODS: A case of PRIS is described in a 17-year-old female with refractory status epilepticus (RSE) who was receiving high-dose propofol for seizure control and sedation. RESULTS: Metabolic syndrome was observed with renal failure, severe metabolic acidosis, and rhabdomyolysis after 58 h of propofol infusion at a maximum dose of 8.8 mg/kg/h. It was not initially associated with circulatory failure. Propofol was stopped immediately, and brief bradycardia was observed. The patient was started on continuous hemofiltration resulting in correction of the metabolic disorder. However, cardiocirculatory failure occurred a few hours later. Her clinical evolution and biological assessments were typical of PRIS. Extracorporeal membrane oxygenation (ECMO) was initiated despite the presence of cardiocirculatory arrest. Cardiocirculatory function improved rapidly, and the patient was weaned off ECMO after 5 days. No severe neurologic effects were observed, and she left the intensive care unit after 36 days, returning home after 2 months. CONCLUSIONS: Careful consideration should be given before prescribing propofol as first-line therapy for RSE, and this drug should be avoided altogether if high doses are required. Close biochemical monitoring is needed if propofol is used for more than a few hours, so that PRIS can be recognized promptly. Immediate discontinuation of propofol is essential, and early hemofiltration should be initiated. ECMO should be considered in cases of cardiocirculatory failure.

Improving the Diagnosis of the Frontal Variant of Alzheimer's Disease with the DAPHNE Scale.

BACKGROUND: The frontal variant of Alzheimer's disease (fAD) is poorly understood and poorly defined. The diagnosis remains challenging. The main differential diagnosis is the behavioral variant of frontotemporal degeneration (bvFTD). For fAD, there is some dissociation between the clinical frontal presentation and imaging and neuropathological studies, which do not always find a specific involvement of the frontal lobes. DAPHNE is a behavioral scale, which demonstrated excellent performance to distinguish between bvFTD and AD. OBJECTIVE: The aim of the present study was to assess the reliability of this new tool to improve the clinical diagnosis of fAD. METHODS: Twenty fAD patients and their caregivers were prospectively included and were compared with 36 bvFTD and 22 AD patients. RESULTS: The three main behavioral disorders in the fAD patients were apathy, loss of empathy, and disinhibition. Three disorders were discriminant because they were less frequent and less severe in the fAD patients than in the bvFTD patients, namely hyperorality, neglect, and perseverations. This specific pattern of behavioral disorders was corroborated by SPECT or 18FDG PET-CT scan that showed that patients with fAD could have a medial frontal hypoperfusion, whereas in bvFTD patients the orbitofrontal cortex was the main involved region, with more diffuse hypoperfusion. CONCLUSION: We demonstrated that DAPHNE had good sensitivity and good specificity to discriminate between the three groups and in particular between fAD and bvFTD patients. DAPHNE is a quick tool that could help clinicians in memory clinics not only to differentiate bvFTD from typical AD but also from fAD.

Catastrophic adult-onset Still's disease as a distinct life-threatening clinical subset: case-control study with dimension reduction analysis.

OBJECTIVES: Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder. Diagnosing AOSD can be challenging, as disease presentation and clinical course are highly heterogeneous. For unclear reasons, a few patients develop life-threatening complications. Our objective was to determine whether these cases resulted from therapeutic delay or could represent a peculiar AOSD subset. METHODS: We conducted a multicentre retrospective study of 20 AOSD patients with organ failure requiring intensive care unit admission and 41 control AOSD patients without organ failure. Clinico-biological data at hospital admission were explored using supervised analyses and unsupervised dimension reduction analysis (factor analysis of mixed data, FAMD). RESULTS: Disease duration before admission was shorter in patients with life-threatening AOSD (median, 10 vs 20 days, p = 0.007). Disease duration before AOSD therapy initiation also tended to be shorter (median, 24 vs 32 days, p = 0.068). Despite this shorter disease duration, FAMD, hierarchical clustering and univariate analyses showed that these patients exhibited distinctive characteristics at first presentation, including younger age; higher frequency of splenomegaly, liver, cardiac and/or lung involvement; less frequent arthralgia; and higher ferritin level. In multivariate analysis, 3 parameters predicted life-threatening complications: lack of arthralgia, younger age and shorter time between fever onset and hospitalisation. CONCLUSION: This study suggests that life-threatening complications of AOSD occur very early, in a peculiar subset, which we propose to name catastrophic adult-onset Still's disease (CAOSD). Its exact burden may be underestimated and remains to be clarified through large multicentre cohorts. Further studies are needed to identify red flags and define the optimal therapeutic strategy.

Efficacy and safety of suvratoxumab for prevention of Staphylococcus aureus ventilator-associated pneumonia (SAATELLITE): a multicentre, randomised, double-blind, placebo-controlled, parallel-group, phase 2 pilot trial.

BACKGROUND: Staphylococcus aureus remains a common cause of ventilator-associated pneumonia, with little change in incidence over the past 15 years. We aimed to evaluate the efficacy of suvratoxumab, a monoclonal antibody targeting the α toxin, in reducing the incidence of S aureus pneumonia in patients in the intensive care unit (ICU) who are on mechanical ventilation. METHODS: We did a multicentre, randomised, double-blind, placebo-controlled, parallel-group, phase 2 pilot trial at 31 hospitals in Belgium, the Czech Republic, France, Germany, Greece, Hungary, Portugal, Spain, and Switzerland. Eligible patients were in the ICU, aged ≥18 years, were intubated and on mechanical ventilation, were positive for S aureus colonisation of the lower respiratory tract, as assessed by quantitative PCR (qPCR) analysis of endotracheal aspirate, and had not been diagnosed with new-onset pneumonia. Patients were excluded if they had confirmed or suspected acute ongoing staphylococcal disease; had received antibiotics for S aureus infection for more than 48 h within 72 h of randomisation; had a Clinical Pulmonary Infection Score of 6 or higher; had an acute physiology and chronic health evaluation II score of 25 or higher with a Glasgow coma scale (GCS) score of more than 5, or an acute physiology and chronic health evaluation II score of at least 30 with a GCS score of 5 or less; had a Sequential Organ Failure Assessment score of 9 or higher; or had active pulmonary disease that would impair the ability to diagnose pneumonia. Colonised patients were randomly assigned (1:1:1), by use of an interactive voice or web response system, to receive either a single intravenous infusion of suvratoxumab 2000 mg, suvratoxumab 5000 mg, or placebo. Randomisation was done in blocks of size four, stratified by country and by whether patients had received systemic antibiotics for S aureus infection. Patients, investigators, and study staff involved in the treatment or clinical evaluation of patients were masked to patient assignment. The primary efficacy endpoint was the incidence of S aureus pneumonia at 30 days, as determined by a masked independent endpoint adjudication committee, in all patients who received their assigned treatment (modified intention-to-treat [ITT] population). Primary safety endpoints were the incidence of treatment-emergent adverse events at 30 days, 90 days, and 190 days after treatment, and the incidence of treatment-emergent serious adverse events, adverse events of special interest, and new-onset chronic disease at 190 days after treatment. All primary safety endpoints were assessed in the modified ITT population. This trial is registered with ClinicalTrials.gov (NCT02296320) and the EudraCT database (2014-001097-34). FINDINGS: Between Oct 10, 2014, and April 1, 2018, 767 patients were screened, of whom 213 patients with confirmed S aureus colonisation of the lower respiratory tract were randomly assigned to the suvratoxumab 2000 mg group (n=15), the suvratoxumab 5000 mg group (n=96), or the placebo group (n=102). Two patients in the placebo group did not receive treatment after randomisation because their clinical conditions changed and they no longer met the eligibility criteria for dosing. As adjudicated by the data monitoring committee at an interim analysis, the suvratoxumab 2000 mg group was discontinued on the basis of predefined pharmacokinetic criteria. At 30 days after treatment, 17 (18%) of 96 patients in the suvratoxumab 5000 mg group and 26 (26%) of 100 patients in the placebo group had developed S aureus pneumonia (relative risk reduction 31·9% [90% CI -7·5 to 56·8], p=0·17). The incidence of treatment-emergent adverse events at 30 days were similar between the suvratoxumab 5000 mg group (87 [91%]) and the placebo group (90 [90%]). The incidence of treatment-emergent serious adverse events at 30 days were also similar between the suvratoxumab 5000 mg group (36 [38%]) and the placebo group (32 [32%]). No significant difference in the incidence of treatment-emergent adverse events between the two groups at 90 days (89 [93%] in the suvratoxumab 5000 mg group vs 92 [92%] in the placebo group) and at 190 days (93 [94%] vs 93 [93%]) was observed. 40 (40%) patients in the placebo group and 50 (52%) in the suvratoxumab 5000 mg group had a serious adverse event at 190 days. In the suvratoxumab 5000 mg group, one (1%) patient reported at least one treatment-emergent serious adverse event related to treatment, two (2%) patients reported an adverse event of special interest, and two (2%) reported a new-onset chronic disease. INTERPRETATION: In patients in the ICU receiving mechanical ventilation with qPCR-confirmed S aureus colonisation of the lower respiratory tract, the incidence of S aureus pneumonia at 30 days was not significantly lower following treatment with 5000 mg suvratoxumab than with placebo. Despite these negative results, monoclonal antibodies still represent one promising therapeutic option to reduce antibiotic consumption that require further exploration and studies. FUNDING: AstraZeneca, with support from the Innovative Medicines Initiative Joint Undertaking.

Efficacy of doripenem in the treatment of Pseudomonas aeruginosa experimental pneumonia versus imipenem and meropenem.

OBJECTIVES: The aim of this study was to compare doripenem with imipenem and meropenem in an experimental rabbit model of Pseudomonas aeruginosa pneumonia and then to compare different doripenem doses and methods of intravenous administration. METHODS: Using a rabbit experimental model of pneumonia, efficacy was assessed following 2 days of treatment by colony counts of different tissues (lung, spleen and blood culture). RESULTS: Mean pulmonary bacterial loads were 3.17 ± 0.53, 3.42 ± 0.61 and 2.75 ± 0.59 log(10) cfu/g for imipenem, doripenem (0.5 g three times daily) and meropenem, respectively, compared with 7.57 ± 0.99 cfu/g for control animals. At a higher dose (1 g three times daily), doripenem showed significantly better efficacy (2.70 ± 0.65 log(10) cfu/g) than the standard regimen of doripenem. Sterilization of spleen cultures was achieved with standard regimens of imipenem (1 g three times daily) and a higher dose of doripenem. CONCLUSIONS: In this model of P. aeruginosa pneumonia, doripenem had an efficacy equivalent to that of meropenem and imipenem at a high dose of 1 g three times a day and lower efficacy at a standard dose (0.5 g three times daily) than the other two agents in terms of bacteria cultivated from spleens. Doripenem is a new drug that offers new therapeutic options, especially for difficult-to-treat infections such as pneumonia due to non-fermenting Gram-negative bacteria.

Impact of Confinement on the Burden of Caregivers of Patients with the Behavioral Variant of Frontotemporal Dementia and Alzheimer Disease during the COVID-19 Crisis in France.

INTRODUCTION: The clinical presentation of the behavioral variant of frontotemporal dementia (bvFTD) differs from that of Alzheimer disease (AD), with major impairments in behavioral functions in bvFTD and cognitive impairment in AD. Both behavioral disturbances in bvFTD and cognitive impairment in AD contribute to caregiver burden. OBJECTIVE: To investigate the impact of home confinement during the COVID-19 crisis on the burden of caregivers of bvFTD or AD patients. METHODS: During the COVID-19 lockdown in France, neurologists and neuropsychologists from the Memory Center of Nantes Hospital conducted teleconsultations for 38 AD patients and 38 bvFTD patients as well as for their caregivers. During these consultations, caregivers were invited to rate the change in their burden during home confinement. They were also invited to rate behavioral or emotional changes in the patients during, compared with before, the confinement. RESULTS: Twenty-two bvFTD caregivers and 14 AD caregivers experienced an increase in burden. For bvFTD caregivers, this increased burden occurred regardless of behavioral changes, while AD caregivers experienced an increased burden related to changes in patients' neuropsychiatric symptoms. Among the whole cohort, 2 factors were associated with increased caregiver burden: behavioral change and bvFTD. CONCLUSION: The results demonstrate that during home confinement in the COVID-19 crisis, neuropsychiatric symptoms were the core factor that impacted caregiver burden in different ways depending on the disease.

Nasal high-flow preoxygenation for endotracheal intubation in the critically ill patient: a randomized clinical trial.

PURPOSE: Preoxygenation with high-flow therapy by nasal cannulae (HFNC) is now widespread in the intensive care unit (ICU). However, no large randomized study has assessed its relevance in non-severely hypoxemic patients. In a randomized controlled trial (PROTRACH study), we aimed to evaluate preoxygenation with HFNC vs. standard bag-valve mask oxygenation (SMO) in non-severely hypoxemic patients during rapid sequence intubation (RSI) in the ICU. METHODS: Randomized controlled trial including non-severely hypoxemic patients requiring intubation in the ICU. Patients received preoxygenation by HFNC or SMO during RSI. HFNC was maintained throughout the intubation procedure whereas SMO was removed to perform laryngoscopy. The primary outcome was the lowest pulse oximetry (SpO2) throughout the intubation procedure. Secondary outcomes included drop in SpO2, adverse events related to intubation, and outcome in the ICU. RESULTS: A total of 192 patients were randomized. In the intent-to-treat analysis, 184 patients (HFNC n = 95; SMO n = 89), the median [IQR] lowest SpO2 was 100% [97; 100] for HFNC and 99% [95; 100] for the SMO group (P = 0.30). Mild desaturation below 95% was more frequent with SMO (23%) than with HFNC (12%) (RR 0.51, 95% CI 0.26-0.99, P = 0.045). There were fewer adverse events in the HFNC group (6%) than in the SMO group (19%) (RR 0.31, 95% CI 0.13-0.76, P = 0.007), including fewer severe adverse events, respectively 6 (6%) and 14 (16%) with HFNC and SMO (RR 0.38, 95% CI 0.15-0.95, P = 0.03). CONCLUSIONS: Compared with SMO, preoxygenation with HFNC in the ICU did not improve the lowest SpO2 during intubation in the non-severely hypoxemic patients but led to a reduction in intubation-related adverse events. TRIAL REGISTRATION: Clinical trial Submission: 7 March 2016. Registry name: Benefits of high-flow nasal cannulae oxygen for preoxygenation during intubation in non-severely hypoxemic patients: the PROTRACH study. Clinicaltrials.gov identifier: NCT02700321. Eudra CT: 2015-A00145-44. CPP: 15/13-975 (Comité de protection des personnes de Rennes). URL registry: https://clinicaltrials.gov/ct2/show/record/NCT02700321 .

Fatal coinfection with Legionella pneumophila serogroup 8 and Aspergillus fumigatus.

Legionella pneumophila is an important cause of community-acquired and nosocomial pneumonia. We report on a patient who simultaneously developed L. pneumophila serogroup 8 pneumonia and Aspergillus fumigatus lung abscesses. Despite appropriate treatments, Aspergillus disease progressed with metastasis. Coinfections caused by L. pneumophila and A. fumigatus remain exceptional. In apparently immunocompetent patients, corticosteroid therapy is a key risk factor for aspergillosis.

Risk factors and outcomes of infected pancreatic necrosis: Retrospective cohort of 148 patients admitted to the ICU for acute pancreatitis.

OBJECTIVE: The primary objective of this article is to identify risk factors for infected pancreatic necrosis (IPN) in patients admitted to the intensive care unit (ICU) for severe acute pancreatitis. We also described outcomes of IPN. BACKGROUND: Acute pancreatitis is common and associated with multiple, potentially life-threatening complications. Over the last decade, minimally invasive procedures have been developed to treat IPN. METHODS: We retrospectively studied consecutive patients admitted for severe acute pancreatitis to the ICUs of the Nantes University Hospital in France, between 2012 and 2015. Logistic regression was used to evaluate potential associations linking IPN to baseline patient characteristics and outcomes. RESULTS: Of the 148 included patients, 26 (17.6%) died. IPN developed in 62 (43%) patients and consistently required radiological, endoscopic, and/or surgical intervention. By multivariate analysis, factors associated with IPN were number of organ failure (OF) (for ≥ 3: OR, 28.67 (6.23-131.96), p < 0.001) and portosplenomesenteric venous thrombosis (OR, 8.16 (3.06-21.76)). CONCLUSION: IPN occurred in nearly half our ICU patients with acute pancreatitis and consistently required interventional therapy. Number of OFs and portosplenomesenteric venous thrombosis were significantly associated with IPN. Early management of OF may reduce IPN incidence, and management of portosplenomesenteric venous thrombosis should be investigated.