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During the 1980s and 1990s, sepsis research propelled dozens of potential therapeutic candidates into clinical trials without a single novel therapeutic approach entering the clinical arena. After the publication of the landmark PROWESS trial in 2001, which showed survival benefit associated with the use of recombinant activated protein C for treatment of severe sepsis, there have been a series of positive sepsis intervention trials studying intensive glycemic control, low-dose steroid therapy, and early goal-directed therapy. The fact that the efficacy of these interventions is not restricted to certain types of infection should not detract from the importance of a full understanding of the microbial epidemiology of sepsis. Empirical antimicrobial therapy remains the mainstay of sepsis treatment. Furthermore, among a number of promising novel therapies that are in phase II and III clinical trials, several have pathogen-specific modes of action. The optimal targeting of antibiotics and such novel treatments toward the specific patient groups who will benefit represents a major challenge to reducing sepsis mortality. This requires detailed, up-to-date, and local epidemiological data. It is becoming increasingly clear that the nature of the infection underlying sepsis is a major determinant of outcome, and future trials of sepsis interventions, guided by high-quality data on microbial epidemiology, may well have to focus on subgroups of patients with different forms of infection. Finally, with the rapidly increasing challenge of antimicrobial resistance and the paucity of novel antibiotics, particularly for infections with gram-negative pathogens, it is more important than ever that we properly understand the forces that drive changes in the microbial epidemiology of sepsis.

Tracking the Microbes in Sepsis: Advancements in Treatment Bring Challenges for Microbial Epidemiology