Safe at First, But Not Reaching Second: Implications of Delayed Second Doses of Antimicrobials in Patients Presenting to Emergency Departments With Sepsis*

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Ever since groundbreaking study by Kumar et al (1) correlating time of antibiotic initiation with outcome in septic shock, early initiation of appropriate antimicrobial therapy has become a cornerstone of sepsis management guidelines and performance improvement (2, 3). Initial antimicrobial administration within 3 hours is a key element of sepsis bundles in the U.S. Centers for Medicare and Medicaid Services National Hospital Inpatient Quality Measures (4). Institutions have devoted significant resources into improving compliance with first dose antimicrobial administration guidelines, with the expectation that improvements will translate into improved patient outcomes (5). Despite intense focus on the initial antimicrobial dose, there is limited information on what happens after that. Do patients get their subsequent doses on time? If they do not, why not and what are the consequences?
The study by Leisman et al (6) is an effort to understand the epidemiology of second antimicrobial doses in sepsis through a retrospective analysis of second dose administration using a single institutional database of patients presenting to an emergency department (ED) with sepsis and septic shock. The primary finding is that overall one third of second doses were significantly delayed. Not surprisingly, delays were most common with the shortest interval (every 6 hr) agents. Seventy-two percentage of these doses were delayed with median delay time of nearly 4 hours. However, 47% of patients with 8-hour intervals and a quarter of patients with 12-hour intervals also experienced significant delays. There was an association of dose delays with boarding of patients in the ED. This is consistent with previous observations of increased mortality in ICU patients boarded in the ED and the high prevalence of delayed and missed orders in boarders (7, 8). Although these observed delays could be related to care processes unique to the study institution, it is reasonable to assume that similar issues in care delivery can also be found elsewhere. Implementation of early sepsis bundles and the need to meet stringent quality performance measures results in intense scrutiny of sepsis bundles from hospital administrations. A common approach of sepsis quality improvement programs is to create expedited care pathways, employing dedicated personnel, web or electronic health record-based flow sheets, alerts and reminders, and other clinical decision support tools to achieve the time specific demands of these bundles (5). Once early goals have been achieved, care processes might no longer proceed in an “expedited” manner and revert to “standard” care outside of the bundle. Interestingly, this study found a small paradoxical negative correlation of bundle adherence with timeliness of second doses. Without a specific antimicrobial fast track system, there are many potential impediments to timely delivery of subsequent antibiotic doses (9). These include ordering delays especially if second doses are not bundled into the initial orders, delays in pharmacy processing, delays in drug dispensing and delivery and in drug administration. Such delays may be even more common in ED boarded patients, where delineation for responsibility of care may be blurred. Boarded ED patients are also frequently on the move, leaving the ED for imaging, interventional procedures, and for surgery, and patient movement introduces additional challenges for timely antimicrobial dispensing. Although antimicrobial stewardship initiatives were not felt to be an issue in this study, optimal implementation of antimicrobial stewardship in the ED remains particularly challenging, and programs with stringent prior authorization requirements agents may provide additional barriers to timely redosing of specific agents (10).

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