Central line-associated bloodstream infections (CLABSIs) occur through four primary mechanisms: extraluminal contamination (skin organisms migrate along the catheter tract, most common in first 10 days), intraluminal contamination (organisms enter through the hub during manipulation, most common after 10 days), hematogenous seeding (distant infection seeds the catheter surface), and infusate contamination (contaminated IV fluids or medications). Staphylococcus epidermidis and S. aureus are the most common pathogens, producing biofilm on catheter surfaces that protects bacteria from antibiotics and host immune defenses. Biofilm formation begins within hours of catheter insertion, creating a matrix of polysaccharides that facilitates bacterial adhesion and proliferation. CLABSI prevention bundles have dramatically reduced infection rates through standardized insertion and maintenance practices.