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Sepsis (formerly severe sepsis [1]) is increasingly recognized as a global health threat and is associated with substantial morbidity and mortality [2]. Sepsis is currently defined as life-threatening organ dysfunction due to dysregulated host response to infection [1], and is considered a medical emergency [2, 3]. Following the demonstrated outcome benefits of timely initiation of antimicrobial therapy and circulatory support in a small randomized sepsis trial [4], the Surviving Sepsis Campaign (SSC), a collaborative initiative by professional societies, has introduced serially updated guidelines on time-sensitive care bundles for sepsis including, among other elements, initiation of broad-spectrum antibiotics within 1 h of patient’s presentation (e.g. time of triage in the Emergency Department) and initial provision of at least 30 mL/kg of intravenous fluids in patients with sepsis-induced hypoperfusion (defined as hypotension and/or serum lactate level ≥ 4 mmol/L) [3]. Increasing compliance with bundle-based care was associated with improved patient outcomes [5]. More recently, the SSC has updated its guidelines, introducing a 1-h bundle where the abovementioned fluid resuscitation was also to be initiated within 1 h of presentation [6]. This update brought forth progressively increasing opposition to the advocated bundled care and, specifically, to both early antimicrobial therapy [7] and the recommended fluid administration to all those with sepsis-induced hypoperfusion [8]. The concerns raised about the latter two interventions focused predominantly on limitations of supporting evidence and risks of adverse impact of such broad guidance for treatment of a syndromic condition, with ongoing challenges in its precise diagnosis. The specific arguments brought by the opponents of administration of timed antimicrobial therapy in patients considered septic include the following. 1) Even among patients with a diagnosis of septic shock, a considerable proportion (11.6%) was found to have non-infectious etiology after 24 following ICU admission [9]. 2) An overly broad mandate for administration of antibiotics will increase antimicrobial resistance, especially if clinicians will feel pressured to administer antibiotics to patients who are not infected [7]. 3) Previous studies showing increased risk of death with hourly delays in antibiotic therapy were retrospective with expected uncontrolled confounders [7]. However, other perspectives on the contemporary data on sepsis care should be considered by clinicians when contemplating use and initial timing of antibiotics in patients suspected to be septic. 1) The large number of observational studies showing increased risk of death with progressive delay of initial antimicrobial therapy in septic patients [10, 11] do not represent a therapeutic equipoise and thus a randomized trial on timing of initial antibiotics in sepsis is unlikely due to ethical considerations, while early administration of antibiotics in severe bacterial and fungal infection is biologically plausible; thus, it is unlikely that higher level of evidence for timing of initial antibiotics in suspected sepsis is forthcoming. 2) Although unnecessary, prolonged antimicrobial therapy will undoubtedly increase development of antimicrobial resistance, there are no reports demonstrating the association of an empiric single initial dose of antibiotics (or that for the first 24 48 h) for suspected sepsis or septic shock with increasing antimicrobial resistance at institutional or population-level. Crucially, no study to date has demonstrated that the risk of initial antimicrobial therapy in a patient suspected to have sepsis or septic shock, but shown later to have no infectious etiology outweighs the risk of delay of proper antimicrobial therapy in a patient with suspected sepsis/septic shock, with ultimately confirmed infection. 3) There are no reports to suggest that data definitely confirming or excluding an infectious cause in a patient with suspected sepsis/septic shock can be routinely expected within 3 6 h after initial presentation. It is, moreover, inconceivable that a clinician will delay initial antimicrobial therapy for several hours once a patient with new life-threatening organ dysfunction is suspected to have a potentially treatable infectious etiology. Importantly, even in the setting of a clinical trial of septic shock, with heightened pre-enrollment scrutiny, a specific site of infection could not be identified in 12.7% of enrolled patients [12] and microbial etiology could not be demonstrated in 36% [13]. When addressing use of initial weight-based intravenous Manuscript submitted May 2, 2019, accepted May 23, 2019

Time-Sensitive Therapeutic Interventions at Diagnosis of Sepsis: Should Guidelines Be Confined to High-Level Evidence?