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The use of inadequate empirical antimicrobial therapy is common in intensive care unit patients and contributes to a number of poor outcomes. Selecting appropriate antimicrobial therapy is complicated by many factors, including the large number of agents available, the presence of resistant organisms, and the general desire among practitioners to use the most focused therapy available. An important aspect of appropriate antimicrobial use is prompt initiation of adequate empirical therapy, which has been shown to improve mortality rates in hospitalized patients with pneumonia and other serious infections. Other key strategies include streamlining antimicrobial therapy when a pathogen is identified and switching from intravenous to oral therapy when clinically indicated. In addition, antibiotic rotation (or cycling) has been evaluated in several trials as a means to minimize resistance. Promoting appropriate antimicrobial therapy ultimately will require a multidisciplinary, system-oriented, institution-specific approach because each intensive care unit has its own unique flora and antimicrobial resistance patterns.