This is an ongoing prospective observational study conducted since September 2006 in 46 departments coming from 31 hospitals in Greece. From these departments, 21 are mixed surgical/medical ICUs; 20 are departments of internal medicine; and five are departments of general surgery. The protocol was approved by the Ethics Committee of each hospital. Written informed consent was collected from all patients or from first-degree relatives for patients unable to consent. Patients with community-acquired sepsis admitted to the general ward or with hospital-acquired sepsis developing in the ICU at least 48 hours after ICU admission are enrolled in this study. Participating departments were not obliged to report all cases of sepsis admitted since the beginning of the study. Data referring to patients with BSIs due to sepsis collected until March 2013 were analyzed in the current manuscript.
Inclusion criteria were: a) age ≥18 years; b) at least two signs of the systemic inflammatory response syndrome; and c) presence of BSI. Exclusion criteria were: a) infection by the human immunodeficiency virus; b) neutropenia defined as less than 1000 neutrophils/mm3 due to causes other than sepsis; c) death of patients before the results of blood cultures were available.
The following signs of SIRS were considered for study enrollment : a) core temperature >38°C or <36°C, b) pco2 < 32 mmHg or more than 20 breaths/min, c) pulse rate >90/min, and d) white blood cells >12,000/mm3 or <4,000/mm3 or >10% of band forms. Patients were classified as suffering from sepsis, severe sepsis and septic shock according to standard definitions .
BSI was considered as the isolation of at least one Gram-negative or Gram-positive or one fungal species from blood sampled from a peripheral vein. If coagulase-negative Staphylococcus spp (CoNS) and other common skin flora were isolated, they were considered as skin contaminants if they were isolated in a single blood culture. When CoNS was isolated both from a central and a peripheral vein with the same antibiogram, it was considered true pathogen.
When no underlying infection was diagnosed despite intense clinical and radiological work-out, BSI was considered primary. In all other cases it was considered secondary to another infection. For the cases of secondary BSIs, diagnosis of acute pyelonephritis, community-acquired pneumonia, intraabdominal infections, ventilator-associated pneumonia and acute bacterial skin and soft tissues infections were done by standard definitions –.
Only one septic episode for each patient was studied. Polymicrobial BSI was identified when at least two different microorganisms were isolated from blood within a 48-h period. The following information were recorded: demographics; Acute Physiology and Chronic Health Evaluation (APACHE) II score; laboratory examinations; source of BSI; administered antimicrobial agents; isolated pathogens from the bloodstream and their antibiogram; co-existing diseases; predisposing conditions; and 28-day outcome expressed as crude mortality. Prior exposure to an antimicrobial agent was elaborated both by the patients’ case history and by monitoring of the prescribed drugs over the last three months.
For blood culturing, 10 ml of blood was inoculated into ready-prepared culture vials (bioMérieux, Marcy l’Etoile, France) and incubated into the Vitek 2 automated system. The same system reported for identification of microorganisms and for susceptibility testing by measurement of the minimum inhibitory concentrations (MICs) of antimicrobials onto pre-coated microplates. Susceptibility was reported based on the CLSI susceptibility criteria. For species of Staphylococcus aureus susceptibility to methicillin was defined by the inhibition of growth around a disk of 30 μg of cefoxitin after plating onto Muller-Hinton agar. Susceptibility of Gram-negative species to colistin was assessed by a similar way using a 10 μg disk.
Administered antimicrobial therapy was considered appropriate when the isolated microorganism was susceptible to at least one of the administered antimicrobials. Any bloodstream isolate resistant to at least three drugs of different classes was considered multidrug-resistant (MDR).
Episodes of BSIs were studied into two equal study time periods; from September 2006 until December 2009 and from January 2010 until April 2013. In each study period, patients were divided into two groups: those admitted with sepsis in the emergency department and who were hospitalized in the general ward (GW) and into those who developed sepsis at least 48 hours after ICU admission. Comparisons between groups were done by the X2 test for qualitative variables and by the Student’s “t-test” for the quantitative variables. In order to assess factors related with BSI by one MDR pathogen, univariate analysis was done only for the GW group. Those factors with a p value of significance lower than 0.100 entered as independent variables into a logistic regression analysis model. Odds ratios (ORs) and 95% confidence intervals (CI) were determined.
Only patients in the GW with BSIs by fully susceptible Gram-negative isolates of both study periods were analyzed for the secondary endpoint. As such de-escalation therapy was considered as a switch to a drug class covering a narrower spectrum of microorganisms. The decision for de-escalation was made according to the discretion of the attending physicians. Patients of each study period were divided into the de-escalation arm and into the non-de-escalation arm. Survival of each arm was measured by Kaplan-Meier analysis; comparisons were done by the log-rank test. Since the study was observational, to assess the impact of sepsis severity on final outcome, forward Cox-logistic regression analysis was done; presence of severe sepsis/shock, age, gender, history of at least one underlying disease and de-escalation were entered as independent variables in the equation. Hazard ratios (HRs) and 95% CIs were determined. Any p value below 0.05 was considered significant.