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PurposeHospital-acquired bacterial pneumonia (HABP) is a critical concern in hospitals with ventilator-associated bacterial pneumonia (VABP) remaining the most common infection in the ICU, often due to Staphylococcus aureus, an increasingly difficult to treat pathogen. Anti-infective monoclonal antibodies (mAb) may provide new, promising treatment options. This randomized, double-blinded, placebo-controlled study aimed at assessing the safety and pharmacokinetics of AR-301, an S. aureus alpha toxin-neutralizing mAb, and exploring its clinical and microbiologic outcomes when used adjunctively with standard-of-care antibiotics.MethodsEligibility in this trial required microbiologically confirmed severe S. aureus pneumonia, including HABP, VABP or CABP, treated in the ICU and an APACHE II score ≤ 30. Standard-of-care antibiotics selected by the investigators were administered to all patients in the study following clinical and microbiologic confirmation of S. aureus pneumonia. Adjunctive treatment of AR-301 was to start < 36 h after onset of severe pneumonia. AR-301 was administered to four sequentially ascending dose cohorts. The placebo cohort received antibiotics and a placebo buffer. Clinical outcomes were adjudicated by a blinded committee. S. aureus eradication was declared based on a negative follow-up culture and presumed to be negative when no culture was obtained in the presence of clinical improvement.ResultsThirteen ICUs enrolled 48 patients, with pneumonia attributable to MRSA in six subjects. The study drug displayed a favorable safety profile: Of 343 AEs reported, 8 (2.3%) were deemed related, none serious. In a post hoc subgroup analysis of VABP patients receiving AR-301, ventilation duration was shorter for AR-301-treated patients compared with the placebo group. Overall, there was a trend toward a better and faster microbiologic eradication at day 28. The PK profile of AR-301 is consistent with that of a human IgG1 mAb, with a plasma half-life of about 25 days.ConclusionsAdjunctive treatment of severe S. aureus HABP with anti-staphylococcal mAbs appears feasible and suggests some clinical benefits, but larger randomized studies are needed to better define its safety and efficacy.

Background Adrenomedullin (ADM) regulates vascular tone and endothelial permeability during sepsis. Levels of circulating biologically active ADM (bio-ADM) show an inverse relationship with blood pressure and a direct relationship with vasopressor requirement. In the present prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock 1 (, AdrenOSS-1) study, we assessed relationships between circulating bio-ADM during the initial intensive care unit (ICU) stay and short-term outcome in order to eventually design a biomarker-guided randomized controlled trial. Methods AdrenOSS-1 was a prospective observational multinational study. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use, and need for renal replacement therapy. AdrenOSS-1 included 583 patients admitted to the ICU with sepsis or septic shock. Results Circulating bio-ADM levels were measured upon admission and at day 2. Median bio-ADM concentration upon admission was 80.5 pg/ml [IQR 41.5–148.1 pg/ml]. Initial SOFA score was 7 [IQR 5–10], and 28-day mortality was 22%. We found marked associations between bio-ADM upon admission and 28-day mortality (unadjusted standardized HR 2.3 [CI 1.9–2.9]; adjusted HR 1.6 [CI 1.1–2.5]) and between bio-ADM levels and SOFA score ( p < 0.0001). Need of vasopressor/inotrope, renal replacement therapy, and positive fluid balance were more prevalent in patients with a bio-ADM > 70 pg/ml upon admission than in those with bio-ADM ≤ 70 pg/ml. In patients with bio-ADM > 70 pg/ml upon admission, decrease in bio-ADM below 70 pg/ml at day 2 was associated with recovery of organ function at day 7 and better 28-day outcome (9.5% mortality). By contrast, persistently elevated bio-ADM at day 2 was associated with prolonged organ dysfunction and high 28-day mortality (38.1% mortality, HR 4.9, 95% CI 2.5–9.8). Conclusions AdrenOSS-1 shows that early levels and rapid changes in bio-ADM estimate short-term outcome in sepsis and septic shock. These data are the backbone of the design of the biomarker-guided AdrenOSS-2 trial. Trial registration ClinicalTrials.gov, NCT02393781 . Registered on March 19, 2015.

Community-acquired pneumonia (CAP) is one of the leading causes of healthcare utilisation and death worldwide. Treatment according to evidence-based clinical guidelines can reduce mortality, antibiotic exposure and length of hospital stay related to CAP. Several studies, including a pilot study from one of our sites, indicate that physicians show a low grade of guideline adherence when managing patients with CAP. To improve the guideline-based treatment of patients with CAP admitted to hospital, we designed a quality improvement study. Four process indicators were combined in a CAP care bundle: chest X-ray, CURB-65 severity score, lower respiratory tract samples and antibiotics within 8 hours from admission. After a 4-month baseline period, we applied multiple interventions at three hospitals during 8 months. Progression in our process indicators was measured continuously and compared with a control site without interventions. After the 8-month intervention period, we continued with a 4-month follow-up period to assess the sustainability of the improvements. The care bundle utilisation rate within 8 hours increased from 11% at baseline to 41% in the follow-up period at the intervention sites, whereas it remained below 3% at the control site. The most considerable improvements have been observed regarding documentation of CURB-65 (34% at baseline, 68% at follow-up) and the collection of lower respiratory tract samples (43% at baseline, 63% at follow-up). Our study has demonstrated poor adherence to CAP guidelines at all sites at baseline. After implementing multiple tailored interventions, guideline adherence increased substantially. In conclusion, we recommend that CAP guidelines should be actively adapted in order to be followed in a daily routine.