Background: Staphylococcus aureus remains a common cause of ventilatorassociated pneumonia, with little change in infection rates over the past 15 years. This phase 2 study evaluated suvratoxumab, an anti-alpha-toxin monoclonal antibody, in reducing incidence of S. aureus pneumonia in intensive care unit (ICU) subjects on mechanical ventilation (MV). Methods:We did a multicenter, single-dose, randomized, placebo-controlled, doubleblind, phase 2 pilot trial in 9 countries. Eligible subjects were patients in an ICU ≥18 years of age, currently intubated and on MV, positive for S. aureus lower respiratory tract (LRT) colonization as assessed by polymerase chain reaction (PCR) of endotracheal aspirate, and with no diagnosis of new-onset pneumonia. Subjects were excluded if they had confirmed or suspected acute ongoing staphylococcal disease; had received anti-S. aureus antibiotics for >48 hours; had a CPIS ≥6, APACHE-II score ≥25, a SOFA score ≥9; or had active pulmonary disease that would impair the ability to diagnose pneumonia. Subjects were screened for S. aureus lower respiratory tract (LRT) colonization using real-time polymerase chain reaction (PCR).Colonized subjects were randomly assigned 1:1:1 to a single intravenous infusion of suvratoxumab 2000 mg, 5000 mg or placebo. Randomization was stratified by country and by whether subjects received anti-S. aureus systemic antibiotic therapy. Based on pre-defined PK criteria, the 2000 mg arm was discontinued upon the recommendation of the data monitoring committee at an interim analysis. Primary efficacy endpoint was incidence of S. aureus pneumonia, adjudicated by a blinded independent panel, through 30 days post dose in the modified intent-to-treat study population. Primary safety endpoints were Francois et al. Suvratoxumab Ph2 (NCT02296320) D3 5 treatment-emergent AEs assessed through 30 and 90 days, treatment-emergent SAEs, adverse events of special interest, and new onset chronic disease, all assessed through 190 days. Findings: PCR screening of 737 ICU subjects identified 213 with S. aureus colonization; of these, 96 were randomized to receive suvratoxumab 5000 mg and 100 to placebo. At 30 days, 17/96 (17•7%) suvratoxumab and 26/100 (26•0%) placebo subjects had developed S. aureus pneumonia (relative risk reduction, 31.9%; 90% confidence interval [CI], −7•5 to 56•8; P = 0•166). At 30 days, incidences of treatmentemergent adverse events (AEs) and serious AEs were similar in suvratoxumab and placebo groups (90•6% [87/96] vs. 90•0% [90/100] and 37•5% [36/96] vs 32•0% [32/100], respectively). At 90 and 190 days, incidence of treatment-emergent AEs was still similar in suvratoxumab and placebo groups (92.

Objectives: To determine the impact of chronic obstructive pulmonary disease (COPD) on incidence, microbiology, and outcomes of ventilator-associated lower respiratory tract infections (VA-LRTI). Methods: Planned ancillary analysis of TAVeM study, including 2960 consecutive adult patients who received invasive mechanical ventilation (MV) > 48 h. COPD patients (n = 494) were compared to non-COPD patients (n = 2466). The diagnosis of ventilator-associated tracheobronchitis (VAT) and ventilator-associated pneumonia (VAP) was based on clinical, radiological and quantitative microbiological criteria. Results: No significant difference was found in VAP (12% versus 13%, p = 0.931), or VAT incidence (13% versus 10%, p = 0.093) between COPD and non-COPD patients. Among patients with VA-LRTI, Escherichia coli and Stenotrophomonas maltophilia were significantly more frequent in COPD patients as compared with non-COPD patients. However, COPD had no significant impact on multidrug-resistant bacteria incidence. Appropriate antibiotic treatment was not significantly associated with progression from VAT to VAP among COPD patients who developed VAT, unlike non-COPD patients. Among COPD patients, patients who developed VAT or VAP had significantly longer MV duration (17 days (9–30) or 15 (8–27) versus 7 (4–12), p < 0.001) and intensive care unit (ICU) length of stay (24 (17–39) or 21 (14–40) versus 12 (8–19), p < 0.001) than patients without VA-LRTI. ICU mortality was also higher in COPD patients who developed VAP (44%), but not VAT(38%), as compared to no VA-LRTI (26%, p = 0.006). These worse outcomes associated with VA-LRTI were similar among non-COPD patients. Conclusions: COPD had no significant impact on incidence or outcomes of patients who developed VAP or VAT.

The clinical course of intensive care unit (ICU) patients may be complicated by a large spectrum of lower respiratory tract infections (LRTI), defined by specific epidemiological, clinical and microbiological aspects.A European network for ICU-related respiratory infections (ENIRRIs), supported by the European Respiratory Society, has been recently established, with the aim at studying all respiratory tract infective episodes except community-acquired ones. A multicentre, observational study is in progress, enrolling more than 1000 patients fulfilling the clinical, biochemical and radiological findings consistent with a LRTI. This article describes the methodology of this study. A specific interest is the clinical impact of non-ICU-acquired nosocomial pneumonia requiring ICU admission, non-ventilator-associated LRTIs occurring in the ICU, and ventilator-associated tracheobronchitis. The clinical meaning of microbiologically negative infectious episodes and specific details on antibiotic administration modalities, dosages and duration are also highlighted. Recently released guidelines address many unresolved questions which might be answered by such large-scale observational investigations. In light of the paucity of data regarding such topics, new interesting information is expected to be obtained from our network research activities, contributing to optimisation of care for critically ill patients in the ICU.

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