Pneumococcal pneumonia and endotoxemia: An experimental and clinical reappraisal.

BACKGROUND: Circulating endotoxins could result from bacterial digestive translocation during sepsis, thus contributing to uncontrolled systemic inflammation, leading in turn to organ dysfunction. We addressed this issue in the setting of severe pneumococcal pneumonia. METHODS: Endotoxemia was measured in a clinically relevant rabbit model of ventilated pneumococcal pneumonia and in 110 patients with bacteraemic pneumonia, using a patented mass spectrometry (LC-MS/MS) method for detection of 3-OH fatty acids (C10, C12, C14, C16 and C18), which are molecules bound to the lipid A motif of LPS. RESULTS: Whereas higher levels of systemic inflammation and organ dysfunctions were found, there was no significant difference in lipopolysaccharide concentrations when infected rabbits were compared to non-infected ones, or when patients were compared to healthy volunteers. CONCLUSIONS: Seemingly, endotoxins do not drive the overwhelming inflammation associated with severe forms of pneumococcal pneumonia.

Adverse Mechanical Ventilation and Pneumococcal Pneumonia Induce Immune and Mitochondrial Dysfunctions Mitigated by Mesenchymal Stem Cells in Rabbits.

BACKGROUND: Mechanical ventilation for pneumonia may contribute to lung injury due to factors that include mitochondrial dysfunction, and mesenchymal stem cells may attenuate injury. This study hypothesized that mechanical ventilation induces immune and mitochondrial dysfunction, with or without pneumococcal pneumonia, that could be mitigated by mesenchymal stem cells alone or combined with antibiotics. METHODS: Male rabbits underwent protective mechanical ventilation (8 ml/kg tidal volume, 5 cm H2O end-expiratory pressure) or adverse mechanical ventilation (20 ml/kg tidal-volume, zero end-expiratory pressure) or were allowed to breathe spontaneously. The same settings were then repeated during pneumococcal pneumonia. Finally, infected animals during adverse mechanical ventilation received human umbilical cord-derived mesenchymal stem cells (3 × 106/kg, intravenous) and/or ceftaroline (20 mg/kg, intramuscular) or sodium chloride, 4 h after pneumococcal challenge. Twenty-four-hour survival (primary outcome), lung injury, bacterial burden, immune and mitochondrial dysfunction, and lung transcriptomes (secondary outcomes) were assessed. RESULTS: High-pressure adverse mechanical ventilation reduced the survival of infected animals (0%; 0 of 7) compared with spontaneous breathing (100%; 7 of 7) and protective mechanical ventilation (86%; 6 of 7; both P < 0.001), with higher lung pathology scores (median [interquartile ranges], 5.5 [4.5 to 7.0] vs. 12.6 [12.0 to 14.0]; P = 0.046), interleukin-8 lung concentrations (106 [54 to 316] vs. 804 [753 to 868] pg/g of lung; P = 0.012), and alveolar mitochondrial DNA release (0.33 [0.28 to 0.36] vs. 0.98 [0.76 to 1.21] ng/µl; P < 0.001) compared with infected spontaneously breathing animals. Survival (0%; 0 of 7; control group) was improved by mesenchymal stem cells (57%; 4 of 7; P = 0.001) or ceftaroline alone (57%; 4 of 7; P < 0.001) and improved even more with a combination treatment (86%; 6 of 7; P < 0.001). Mesenchymal stem cells reduced lung pathology score (8.5 [7.0 to 10.5] vs. 12.6 [12.0 to 14.0]; P = 0.043) and alveolar mitochondrial DNA release (0.39 (0.34 to 0.65) vs. 0.98 (0.76 to 1.21) ng/µl; P = 0.025). Mesenchymal stem cells combined with ceftaroline reduced interleukin-8 lung concentrations (665 [595 to 795] vs. 804 [753 to 868] pg/g of lung; P = 0.007) compared to ceftaroline alone. CONCLUSIONS: In this preclinical study, mesenchymal stem cells improved the outcome of rabbits with pneumonia and high-pressure mechanical ventilation by correcting immune and mitochondrial dysfunction and when combined with the antibiotic ceftaroline was synergistic in mitigating lung inflammation.

Septic patients without obvious signs of infection at baseline are more likely to die in the ICU.

OBJECTIVE: Early identification of sepsis is mandatory. However, clinical presentation is sometimes misleading given the lack of infection signs. The objective of the study was to evaluate the impact on the 28-day mortality of the so-called "vague" presentation of sepsis. DESIGN: Single centre retrospective observational study. SETTING: One teaching hospital Intensive Care Unit. SUBJECTS: All the patients who presented at the Emergency Department (ED) and were thereafter admitted to the Intensive Care Unit (ICU) with a final diagnosis of sepsis were included in this retrospective observational three-year study. They were classified as having exhibited either "vague" or explicit presentation at the ED according to previously suggested criteria. Baseline characteristics, infection main features and sepsis management were compared. The impact of a vague presentation on 28-day mortality was then evaluated. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among the 348 included patients, 103 (29.6%) had a vague sepsis presentation. Underlying chronic diseases were more likely in those patients [e.g., peripheral arterial occlusive disease: adjusted odd ratio (aOR) = 2.01, (1.08-3.77) 95% confidence interval (CI); p = 0.028], but organ failure was less likely at the ED [SOFA score value: 4.7 (3.2) vs. 5.2 (3.1), p = 0.09]. In contrast, 28-day mortality was higher in the vague presentation group (40.8% vs. 26.9%, p = 0.011), along with longer time-to-diagnosis [18 (31) vs. 4 (11) h, p < 0.001], time-to-antibiotics [20 (32) vs. 7 (12) h, p < 0.001] and time to ICU admission [71 (159) vs. 24 (69) h, p < 0.001]. Whatever, such a vague presentation independently predicted 28-day mortality [aOR = 2.14 (1.24-3.68) 95% CI; p = 0.006]. CONCLUSIONS: Almost one third of septic patient requiring ICU had a vague presentation at the ED. Despite an apparent lower level of severity when initially assessed, those patients had an increased risk of mortality that could not be fully explained by delayed diagnosis and management of sepsis.

Ten-year experience with arterial embolization for peptic ulcer bleeding: N-butyl cyanoacrylate glue versus other embolic agents.

OBJECTIVES: To compare our experience with N-butyl cyanoacrylate glue as the primary embolic agent versus other embolic agents for transcatheter arterial embolization (TAE) in refractory peptic ulcer bleeding and to identify factors associated with early rebleeding and 30-day mortality. METHODS: Retrospective study of 148 consecutive patients comparing the clinical success rate in 78 patients managed with Glubran®2 N-butyl cyanoacrylate metacryloxysulfolane (NBCA-MS) alone or with other agents and 70 with other embolic agents only (coils, microspheres, ethylene-vinyl alcohol copolymer, or gelatin sponge) at a university center in 2008-2019. Univariate and multivariate logistic regression analyses were done to identify prognostic factors. RESULTS: The technical success rate was 95.3% and the primary clinical success was 64.5%. The early rebleeding and day-30 mortality rates were 35.4% and 21.3%, respectively. Rebleeding was significantly less common with than without Glubran®2 (OR, 0.47; 95% CI, 0.22-0.99; p = .047) and significantly more common with coils used alone (OR, 20.4; 95% CI, 10.13-50.14; p = .024). The only other factor independently associated with early rebleeding was having two or more comorbidities (OR, 20.14; 95% CI, 10.01-40.52; p = .047). Day-30 mortality was similar in the two treatment groups. A lower initial hemoglobin level was significantly associated with higher day-30 mortality (OR, 10.38; 95% CI, 10.10-10.74; p = .006). Fluoroscopy time was significantly shorter with Glubran®2 (20.8 ± 11.5 min vs. 35.5 ± 23.4 min, p = .002). Both groups (Glubran®2 vs. other agents) had similar rates of overall complications (10.7% vs. 9.1%, respectively, p = .786). CONCLUSIONS: Glubran®2 NBCA-MS as the primary agent allowed for faster and better clinical success compared to other embolic agents when used for TAE to safely stop refractory peptic ulcer bleeding. KEY POINTS: • Choice of embolic agent for arterial embolization of refractory peptic ulcer bleeding is still debated. We compared our experience with N-butyl cyanoacrylate (NBCA) glue vs. other embolic agents. • The use of Glubran®2 NBCA glue in the endovascular management of refractory peptic ulcer bleeding was significantly faster and more effective, and at least as safe compared to other embolic agents. • NBCA glue offers several advantages compared to other embolic agents and provides rapid hemostasis when used for arterial embolization to treat refractory peptic ulcer bleeding. It should be the first-line therapy.

The dysregulated innate immune response in severe COVID-19 pneumonia that could drive poorer outcome.

BACKGROUND: Although immune modulation is a promising therapeutic avenue in coronavirus disease 2019 (COVID-19), the most relevant targets remain to be found. COVID-19 has peculiar characteristics and outcomes, suggesting a unique immunopathogenesis. METHODS: Thirty-six immunocompetent non-COVID-19 and 27 COVID-19 patients with severe pneumonia were prospectively enrolled in a single center, most requiring intensive care. Clinical and biological characteristics (including T cell phenotype and function and plasma concentrations of 30 cytokines) and outcomes were compared. RESULTS: At similar baseline respiratory severity, COVID-19 patients required mechanical ventilation for significantly longer than non-COVID-19 patients (15 [7-22] vs. 4 (0-15) days; p = 0.0049). COVID-19 patients had lower levels of most classical inflammatory cytokines (G-CSF, CCL20, IL-1ß, IL-2, IL-6, IL-8, IL-15, TNF-α, TGF-ß), but higher plasma concentrations of CXCL10, GM-CSF and CCL5, compared to non-COVID-19 patients. COVID-19 patients displayed similar T-cell exhaustion to non-COVID-19 patients, but with a more unbalanced inflammatory/anti-inflammatory cytokine response (IL-6/IL-10 and TNF-α/IL-10 ratios). Principal component analysis identified two main patterns, with a clear distinction between non-COVID-19 and COVID-19 patients. Multivariate regression analysis confirmed that GM-CSF, CXCL10 and IL-10 levels were independently associated with the duration of mechanical ventilation. CONCLUSION: We identified a unique cytokine response, with higher plasma GM-CSF and CXCL10 in COVID-19 patients that were independently associated with the longer duration of mechanical ventilation. These cytokines could represent the dysregulated immune response in severe COVID-19, as well as promising therapeutic targets. ClinicalTrials.gov: NCT03505281.

CXCL10 could drive longer duration of mechanical ventilation during COVID-19 ARDS.

BACKGROUND: COVID-19-related ARDS has unique features when compared with ARDS from other origins, suggesting a distinctive inflammatory pathogenesis. Data regarding the host response within the lung are sparse. The objective is to compare alveolar and systemic inflammation response patterns, mitochondrial alarmin release, and outcomes according to ARDS etiology (i.e., COVID-19 vs. non-COVID-19). METHODS: Bronchoalveolar lavage fluid and plasma were obtained from 7 control, 7 non-COVID-19 ARDS, and 14 COVID-19 ARDS patients. Clinical data, plasma, and epithelial lining fluid (ELF) concentrations of 45 inflammatory mediators and cell-free mitochondrial DNA were measured and compared. RESULTS: COVID-19 ARDS patients required mechanical ventilation (MV) for significantly longer, even after adjustment for potential confounders. There was a trend toward higher concentrations of plasma CCL5, CXCL2, CXCL10, CD40 ligand, IL-10, and GM-CSF, and ELF concentrations of CXCL1, CXCL10, granzyme B, TRAIL, and EGF in the COVID-19 ARDS group compared with the non-COVID-19 ARDS group. Plasma and ELF CXCL10 concentrations were independently associated with the number of ventilator-free days, without correlation between ELF CXCL-10 and viral load. Mitochondrial DNA plasma and ELF concentrations were elevated in all ARDS patients, with no differences between the two groups. ELF concentrations of mitochondrial DNA were correlated with alveolar cell counts, as well as IL-8 and IL-1ß concentrations. CONCLUSION: CXCL10 could be one key mediator involved in the dysregulated immune response. It should be evaluated as a candidate biomarker that may predict the duration of MV in COVID-19 ARDS patients. Targeting the CXCL10-CXCR3 axis could also be considered as a new therapeutic approach. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03955887.

Outcomes of Transcatheter Arterial Embolization with a Modified N-Butyl Cyanoacrylate Glue for Spontaneous Iliopsoas and Rectus Sheath Hematomas in Anticoagulated Patients.

PURPOSE: To assess the efficacy and safety of n-butyl cyanoacrylate methacryloxy sulfolane (NBCA-MS) transcatheter arterial embolization for anticoagulation-related soft-tissue bleeding and to evaluate predictive factors of clinical success and 30-day mortality. MATERIALS AND METHODS: A retrospective review of 50 anticoagulated patients (25 male; mean age, 71.7 y ± 14.2; range, 19-87 y) who underwent emergent Glubran 2 NBCA-MS embolization for iliopsoas hematomas (IPHs; n = 38), rectus sheath hematomas (n = 11), or both (n = 1) between 2011 and 2016 was performed. Inclusion criteria were active bleeding on computed tomography (CT) and anticoagulation. The mean number of red blood cell (RBC) units transfused was 4.8 ± 3.2 (range, 0-14), median hemoglobin level before embolization was 9.7 g/dL (range, 6.2-18 g/dL), and median "mean blood pressure" (MBP) was 62.5 mm Hg (range, 58.3-75 mm Hg). Mean International Normalized Ratio before intervention was 2.5 ± 1.5 (range, 1.0-6.9). Angiograms revealed extravasation in 44 of 50 patients (88%). Mean hematoma volume was 1,119.2 cm3 ± 863.5 (range, 134.0-3,589.0 cm3). RESULTS: Technical success was achieved in 100% of patients, and 30-day clinical success was achieved in 66% of patients. Recurrent bleeding and mortality rates within 30 days of embolization were 34% and 44%, respectively. No complications related to the embolization procedure occurred. Lower MBP (P = .003), greater number of RBC units transfused (P = .003), greater volume of hematoma (P = .04), and IPH location (P = .02) were associated with decreased clinical success. Clinical failure (P = .00002), lower MBP (P = .004), greater number of RBC units transfused (P = .002), and IPH location (P = .01) were significantly associated with higher 30-day mortality rates. CONCLUSIONS: Transcatheter arterial embolization with NBCA-MS is safe and effective in treating refractory soft-tissue bleeding in anticoagulated patients despite the high mortality rates associated with this patient population.

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.

Significance of Prior Digestive Colonization With Extended-Spectrum ß-Lactamase-Producing Enterobacteriaceae in Patients With Ventilator-Associated Pneumonia.

OBJECTIVES: Ventilator-associated pneumonia is frequent in ICUs. Extended-spectrum ß-lactamase-producing Enterobacteriaceae are difficult-to-treat pathogens likely to cause ventilator-associated pneumonia. We sought to assess the interest of screening for extended-spectrum ß-lactamase-producing Enterobacteriaceae rectal carriage as a way to predict their involvement in ventilator-associated pneumonia. DESIGN: A retrospective cohort study of patients with suspected ventilator-associated pneumonia in a medical ICU was conducted. PATIENTS: Every patient admitted between January 2006 and August 2013 was eligible if subjected to mechanical ventilation for more than 48 hours. Each patient with suspected ventilator-associated pneumonia was included in the cohort. Active surveillance culture for extended-spectrum ß-lactamase-producing Enterobacteriaceae detection was routinely performed in all patients at admission and then weekly throughout the study period. Extended-spectrum ß-lactamase colonization was defined by the isolation of at least one extended-spectrum ß-lactamase-producing Enterobacteriaceae from rectal swab culture. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 587 patients with suspected ventilator-associated pneumonia, 40 (6.8%) were colonized with extended-spectrum ß-lactamase-producing Enterobacteriaceae prior to the development of pneumonia. Over the study period, 20 patients (3.4%) had ventilator-associated pneumonia caused by extended-spectrum ß-lactamase-producing Enterobacteriaceae; of whom, 17 were previously detected as being colonized with extended-spectrum ß-lactamase-producing Enterobacteriaceae. Sensitivity and specificity of prior extended-spectrum ß-lactamase-producing Enterobacteriaceae colonization as a predictor of extended-spectrum ß-lactamase-producing Enterobacteriaceae involvement in ventilator-associated pneumonia were 85.0% and 95.7%, respectively. The positive and negative predictive values were 41.5% and 99.4%, respectively. The positive likelihood ratio was 19.8. CONCLUSIONS: Screening for extended-spectrum ß-lactamase-producing Enterobacteriaceae digestive colonization by weekly active surveillance cultures could reliably exclude the risk of the involvement of such pathogens in patients with ventilator-associated pneumonia in low-prevalence area.

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.

In vivo efficacy of ceftaroline fosamil in a methicillin-resistant panton-valentine leukocidin-producing Staphylococcus aureus rabbit pneumonia model.

Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil, is a cephalosporin with broad-spectrum in vitro activity against Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Streptococcus pneumoniae (MDRSP), and common Gram-negative pathogens. This study investigated the in vivo activity of ceftaroline fosamil compared with clindamycin, linezolid, and vancomycin in a severe pneumonia model due to MRSA-producing Panton-Valentine leukocidin (PVL). A USA300 PVL-positive clone was used to induce pneumonia in rabbits. Infected rabbits were randomly assigned to no treatment or simulated human-equivalent dosing with ceftaroline fosamil, clindamycin, linezolid, or vancomycin. Residual bacterial concentrations in the lungs and spleen were assessed after 48 h of treatment. PVL expression was measured using a specific enzyme-linked immunosorbent assay (ELISA). Ceftaroline, clindamycin, and linezolid considerably reduced mortality rates compared with the control, whereas vancomycin did not. Pulmonary and splenic bacterial titers and PVL concentrations were greatly reduced by ceftaroline, clindamycin, and linezolid. Ceftaroline, clindamycin, and linezolid were associated with reduced pulmonary tissue damage based on significantly lower macroscopic scores. Ceftaroline fosamil, clindamycin, and, to a lesser extent, linezolid were efficient in reducing bacterial titers in both the lungs and spleen and decreasing macroscopic scores and PVL production compared with the control.

Empirical antifungal therapy with an echinocandin in critically-ill patients: prospective evaluation of a pragmatic Candida score-based strategy in one medical ICU.

BACKGROUND: Invasive candidiasis (IC) is a life-threatening ICU-acquired infection. A strong correlation between time to antifungal therapy (AFT) administration and outcome has been established. Empirical therapy benefit should be balanced with the risk of echinocandin overuse. We assessed therefore a decision rule that aimed at guiding empirical therapy. METHODS: A 45-month prospective cohort study in a teaching medical ICU. All of the patients with suspected IC (uncontrolled sepsis despite broad spectrum antibiotics without any bacterial proven infection in patients with Candida score ≥ 3 points including multifocal Candida sp. colonization) were eligible. The primary endpoint was proven IC diagnosis (i.e., candidemia) following treatment onset. Timing of AFT administration was also investigated in those latter patients. Antifungal therapy step-down and discontinuation was done according to international guidelines in patients with candidemia. Otherwise, echinocandin discontinuation was encouraged in patients without proven IC, excepting when a clinical improvement was achieved without any other explanation that antifungals initiation (i.e., probable IC). In addition, a survival multivariate analysis using a Cox model was conducted. RESULTS: Fifty-one patients were given an echinocandin with respect to our decision rule. Among them, candidemia was diagnosed thereafter in 9 patients. Over the same period, antifungal therapy was triggered by candidemia announcement (i.e., definite therapy) in 12 patients who did not fulfill criteria for empirical therapy before. Time elapsed from candidemia onset to echinocandin therapy initiation was shortened (0.4 [0.5] vs. 2.4 [2.8] hours; p = 0.04) when it was given empirically. In addition, 18 patients clinically improved under empirical antifungal therapy without any obvious other explanation, despite IC remained unproven. Moreover, echinocandin exposure duration was independently related to survival in those patients. Over the same period, our predefined criteria for empirical therapy were overruled in 55 cases. None of them develop IC thereafter. Finally, Our decision rule allowed IC early recognition of proven/probable IC with sensitivity, specificity, positive and negative predictive value of 69.2%, 82.1%, 69.2% and 82.1%, respectively. CONCLUSION: Implementation of pragmatic guidelines for empirical AFT based on CS and fungal colonization assessment could be useful in selecting patients who really benefit from an echinocandin.

Predicting outcome in patients with sepsis: new biomarkers for old expectations.

Early prediction of the outcome of patients with sepsis could be helpful in guiding therapies but remains challenging. Presepsin, a new sepsis biomarker whose elevation as early as day 1 is well correlated with 28-day mortality, could be considered to this end.

Impact of prior statin therapy on the outcome of patients with suspected ventilator-associated pneumonia: an observational study.

INTRODUCTION: Ventilator-associated pneumonia (VAP) is the most commonly acquired infection in intensive care units (ICU). Its outcome is related, at least in part, to the host's response. Statins have anti-inflammatory effects and may thus improve the outcome. We aimed to assess the impact of prior statin use in the setting of VAP. METHODS: A six-year cohort study was conducted in a French ICU at a teaching hospital. All of the patients with suspected VAP were included. Baseline characteristics, outcomes, statin exposure, and the description of suspected episodes were collected prospectively. The primary endpoint was 30-day mortality. Patients who were taking statins before admission to the ICU whether or not treatment was continued thereafter ('previous users' group) were compared to those without prior statin therapy ('statin-naive' group). A survival analysis using a Cox model was conducted in the whole cohort and in the subgroup of prior statin users. RESULTS: Among the 349 patients included, 93 (26.6%) had taken statins. At baseline, these patients were at higher risk of complications than statin-naive ones (for example, older, more likely to be men and to have underlying diseases, greater simplified acute physiology score II (SAPS II)). There was, however, no difference regarding severity at the time VAP was suspected (sequential organ failure assessment (SOFA): 9.0 (4.0 to 16.0) versus 8.0 (4.0 to 17.0); P = 0.11). Nonetheless, 30-day mortality in statin users was not different from that in statin-naive patients (35.5% versus 26.2%, respectively; adjusted hazard ratio (HR) = 1.23 (0.79 to 1.90) 95% confidence interval (CI); P = 0.36). In contrast, after limiting analysis to prior statin users and adjusting for potential confounders, those who continued the treatment had better survival than those who did not (HR = 0.47; (0.22 to 0.97) 95% CI; P = 0.04). CONCLUSIONS: Statin continuation in prior users could provide protective effects in patients with suspected VAP.

Impact of the prone position in an animal model of unilateral bacterial pneumonia undergoing mechanical ventilation.

BACKGROUND: The prone position (PP) has proven beneficial in patients with severe lung injury subjected to mechanical ventilation (MV), especially in those with lobar involvement. We assessed the impact of PP on unilateral pneumonia in rabbits subjected to MV. METHODS: After endobronchial challenge with Enterobacter aerogenes, adult rabbits were subjected to either "adverse" (peak inspiratory pressure = 30 cm H2O, zero end-expiratory pressure; n = 10) or "protective" (tidal volume = 8 ml/kg, 5 cm H2O positive end-expiratory pressure; n = 10) MV and then randomly kept supine or turned to the PP. Pneumonia was assessed 8 h later. Data are presented as median (interquartile range). RESULTS: Compared with the supine position, PP was associated with significantly lower bacterial concentrations within the infected lung, even if a "protective" MV was applied (5.93 [0.34] vs. 6.66 [0.86] log10 cfu/g, respectively; P = 0.008). Bacterial concentrations in the spleen were also decreased by the PP if the "adverse" MV was used (3.62 [1.74] vs. 6.55 [3.67] log10 cfu/g, respectively; P = 0.038). In addition, the noninfected lung was less severely injured in the PP group. Finally, lung and systemic inflammation as assessed through interleukin-8 and tumor necrosis factor-α measurement was attenuated by the PP. CONCLUSIONS: The PP could be protective if the host is subjected to MV and unilateral bacterial pneumonia. It improves lung injury even if it is utilized after lung injury has occurred and nonprotective ventilation has been administered.

Invasive infections due to Candida norvegensis and Candida inconspicua: report of 12 cases and review of the literature.

Candida inconspicua and Candida norvegensis are two closely related species rarely involved in invasive infections. The purpose of this study was to depict the epidemiologic and clinical characteristics of candidemia due to these emerging fluconazole less susceptible species. A retrospective analysis of the epidemiology of C. inconspicua and C. norvegensis during the period 2006-2010 was initiated in six French University hospitals. From this, demographics, clinical, diagnostic and therapeutic data of C. inconspicua or C. norvegensis candidemia were recorded and compared to the observations reported in the literature. C. inconspicua was more frequently isolated compared to C. norvegensis (ratio 2.6) but from the same preferential body sites: mainly digestive (56.4% and 48.37%, respectively, for C. inconspicua and C. norvegensis) and respiratory (26% and 28.2%, respectively). Thirteen cases of candidemia were recorded and five additional cases were found in the literature. Hematogical malignancy was the main underlying disease (n = 12). Associated factors were the presence of a vascular catheter (n = 18), broad-spectrum antibiotics (n = 15), and neutropenia (n = 14). In 13 cases (72%), prior colonization was noted before the candidemia diagnosis. Combining the results for the two species, Minimal Inhibitory Concentrations (MIC50) of amphotericin B, fluconazole, voriconazole and caspofungin were 0.125, 48, 0.25, and 0.19 mg/l, respectively. These two species must be added to the growing list of emerging Candida species poorly susceptible to fluconazole.