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The majority of nosocomial bloodstream infections in critically ill patients originate from an infected central venous catheter (CVC). Catheter-related bloodstream infections (CRBSIs) cause significant morbidity and mortality and increase the cost of care. The most frequent causative organisms for CRBSI are coagulase-negative staphylococci (CoNSs), Staphylococcus aureus, enterococci, and Candida species. The path to infection frequently includes migration of skin organisms at the insertion site into the cutaneous catheter tract, resulting in microbial colonization of the catheter tip and formation of biofilm. Evidence-based strategies for the prevention of CRBSI include behavioral and educational interventions, effective skin antisepsis coupled with maximum barrier precautions, the use of antiseptic dressings, and the use of antiseptic or antibiotic impregnated catheters. Achieving and maintaining very low rates of CRBSI requires a multidisciplinary approach involving the entire health care team, the use of novel technologies in patients with the highest risk of CRBSI, and frequent reeducation of staff.