Microbiological outcomes and antibiotic overuse in Emergency Department patients with suspected sepsis.

OBJECTIVE: To study the presence of bacterial disease and antibiotic use in patients in the emergency department (ED) included in the local sepsis protocol. METHODS: An observational retrospective cohort study. Adults aged > 18 years, presenting to the ED of a large teaching hospital, from 1 January to 1 June 2011, with more than two SIRS criteria and a clinical suspicion of sepsis were included. RESULTS: Bacterial disease was suspected or confirmed in only 71% of all the patients with suspected sepsis (2008 definition) and consequently treated with antibiotics. Most of these patients (58%) suffered from systemic inflammatory response syndrome (SIRS) without signs of organ dysfunction, hypotension or hypoperfusion. Despite absence of bacterial disease in 29% of the patients after rigorous diagnostics, median antibiotic treatment in this group was still seven days (IQR 4-10). CONCLUSIONS: Standard sepsis detection using SIRS criteria and clinical suspicion identified patients with suspected or confirmed bacterial disease in 71% of the cases. A significant proportion of patients were exposed to prolonged antibiotic use without proof of bacterial disease. This study illustrates the difficulties in correctly identifying bacterial disease and sepsis, and shows that overuse of antibiotics may be the consequence.

The impact of antigen density and antibody affinity on antibody-dependent cellular cytotoxicity: relevance for immunotherapy of carcinomas.

Antibody-dependent cellular cytotoxicity (ADCC) is considered to be the major mechanism through which tumour cells, upon treatment with anti-tumour MAbs, are eliminated in vivo. However, the relative importance of various parameters that influence the efficacy of ADCC is unclear. Here we present in vitro data on the impact of MAb affinity and antigen density on ADCC, as obtained by comparison of two MAbs against the tumour-associated antigen Ep-CAM. The low-affinity MAb 17-1A (Ka = 5 x 10(7)M(-1)) currently used for therapy, and the high-affinity MAb 323/A3 (Ka = 2 x 10(9) M(-1)), were compared in ADCC experiments against murine and human tumour target cells transfected with the Ep-CAM cDNA under the control of an inducible promoter to enable regulation of the target antigen expression levels. Data obtained from these studies revealed that the high-affinity MAb, in contrast to the low-affinity MAb, could mediate killing of tumour cells with low antigen expression levels. Even at comparable MAb-binding levels, ADCC mediated by the high-affinity MAb was more effective. The kinetics of ADCC was also found to be determined by the level of antigen expression, and by the affinity and the concentration of the MAb used. The efficacy of ADCC with both low- and high-affinity MAbs further depended on adhesive interactions between effector and target cells mediated by CD18. However, at every given MAb concentration these interactions were of less importance for the high-affinity MAb than for the low-affinity MAb. As heterogeneity of a target antigen expression is a common feature of all tumours, and some tumour cells express very low levels of the antigen, the use of high-affinity MAbs in immunotherapy may significantly improve the clinical results obtained to the present date in the treatment of minimal residual disease.