Challenging the Dogma of Aggressive Initiation of Antibiotics in Sepsis

Abstract

The Surviving Sepsis Campaign (SSC) was founded in 2002 with the goal of improving the recognition and treatment of patients with sepsis [1 –3]. Through the creation and successful dissemination of guidelines, their efforts have improved sepsis care greatly, although there remains limited evidence for some bundle elements [4,5]. In 2015, the Centers for Medicare & Medicaid Services created their Severe Sepsis and Septic Shock Early Management bundle (SEP-1) based largely on the SSC guidelines [6]. This CMS mandate tied reimbursement to SEP-1 bundle compliance which drove further adoption throughout the United States [7].

The key recommendation of the SSC, and therefore SEP-1, is the aggressive initiation of empiric antibiotics as soon as sepsis is suspected [6 –9]. These recommendations have been criticized recently as encouraging antibiotic overuse [10 –12]. Previous time-to-antibiotic mandates for pneumonia care have led to well-documented instances of overutilization [10]. The current COVID-19 pandemic throws the limitations of such mandates into sharp relief, as many as 64% of COVID-19-positive patients were started on antibacterial agents in one retrospective review [13]. Early antibiotics in this setting have no demonstrated benefit and may be harmful in some patients, as they have no utility against the virus. In cases of diagnostic uncertainty, physicians may feel pressured to prescribe antibiotics in order to avoid CMS non-compliance resulting in a “antibiotics first—questions later” approach [14 –16]. In many cases, once they have been started, it can be difficult to stop antibiotics even in the face of negative cultures [17]. In short, the SSC and SEP-1 recommendations for aggressive empiric antibiotic initiation are fundamentally at odds with the tenets of proper antibiotic stewardship.

The purpose of this paper is to review the current literature supporting the recommendation for aggressive initiation of antibiotic therapy for patients with sepsis or septic shock and its appropriateness in current practice.

Timing of Antibiotics

In 2004, the original SSC guidelines for the management of severe sepsis and septic shock recommended initiation of antibiotic therapy within the first hour after recognition of either condition [8]. This Grade E recommendation was based largely on expert opinion at the time, and no supporting references were given. The most recent SSC guidelines used five manuscripts as the primary basis for the recommendation [9,18 –22]. Of these studies, Barie et al. was the only prospective analysis to identify an increase in the mortality rate with a delay in antibiotic administration (odds ratio [OR] for death 1.02 per 30-minute delay) [18]. Barochia et al. reported that, compared with patients who did not receive bundled sepsis care, those who did were given antibiotics more rapidly and had a lower overall mortality rate [20]. However, the authors did not demonstrate an independent association between aggressive antibiotic administration and a reduced mortality rate [20]. The remining studies all are retrospective cohort analyses [19,21,22]. On the basis of these studies, the most recent guidelines upgrade the recommendation to “strong recommendation, moderate quality evidence” [8]. However, if the 2004 grading system were applied, then the 2016 recommendation would be a Grade D at best [8,9].

The SSC places strong emphasis on a retrospective analysis by Kumar et al., which demonstrated that the duration of hypotension before the initiation of antibiotics was a key determinant of patient survival [19]. Recently, a large retrospective analysis of mandated sepsis care in New York State identified that, in general, delays in antibiotic initiation resulted in a 4% increase in mortality rate per hour (OR 1.04; 95% confidence interval [CI] 1.03–1.06) [23]. However, review of the supplemental material demonstrates that only patients requiring vasopressor drugs were harmed by delays in antibiotic initiation [24]. The timing of antibiotics in patients who did not require vasopressors was not associated with more deaths [24]. Although the SSC cohort analysis by Levy et al. suggested that antibiotic initiation within 3 hours was independently associated with a reduced mortality rate, sepsis and septic shock were not analyzed separately [25].

A growing number of prospective observational studies further suggest that the time to antibiotic administration itself is not associated with poor outcomes [26 –33]. Hranjec et al. attempted to isolate the time-to-antibiotics variable in their 2012 prospective before-and-after study. In their experience, patients in the intensive care unit (ICU) were treated for one year under an “aggressive” antibiotic initiation protocol that included immediate initiation of antibiotics after obtaining appropriate cultures. During the following year, a “conservative” protocol dictated that antibiotics be initiated only after demonstrating objective evidence of infection. Those authors demonstrated an increased mortality rate for patients treated under a “aggressive” antibiotic initiation protocol with an OR for death of 2.5 (95% CI 1.5–4.0) [33]. Additionally, a recent large meta-analysis failed to identify a different mortality benefit to aggressive antibiotic initiation [34].

Observational studies in this area have a major flaw; i.e., delays in antibiotic therapy likely reflect delays in either recognition of sepsis or other aspects of care such as appropriate resuscitation or source control [19,21,22,35]. Emergency department-based studies are at particular risk because the time to presentation can be highly variable. Filbin et al. suggest that presenting symptomatology, classified as “explicit” or “vague,” was not only a key determinant in their ultimate outcome but also likely an important confounding variable [36]. Filbin et al. noted that not only did patients with “vague” symptoms receive antibiotics later (1.6 hours versus 0.8 hours; p < 0.01), but these patients also had a higher overall mortality rate (34% versus 16%; p < 0.01). On multivariable analysis, vague symptomatology, not time-to-antibiotics, was associated with death [36]. Similarly, Kushimoto et al. demonstrated that the entire sepsis bundle, not just antibiotic administration, was affected by the presenting temperature; in their study, time-to-antibiotic exposure was not associated with death [37]. Finally, Blot et al. suggest that delays in oxygenation assessment ultimately led to delays in antibiotic therapy, again finding no association between antibiotic exposure and death when accounting for this confounding factor [38].

Contrary to the SSC guidelines, the only randomized trial evaluating the timing of antibiotics in the literature demonstrates no effect on the mortality rate. This 2018 study, conducted by Alam et al., randomized 2,672 patients with suspected sepsis to receive either immediate initiation of antibiotics in the ambulance before arriving at the hospital or to antibiotics after arrival at the hospital. The group that received antibiotics after arrival had their first dose delayed by a median of 96 minutes. There was no difference in 28-day or 90-day mortality rate between patients who received antibiotics early versus after arrival at the hospital. Moreover, there was no difference in outcomes regardless of the severity of illness, including patients in septic shock [39].

Implications for Antibiotic Stewardship

The negative impact of the SSC and SEP-1 recommendations on antibiotic stewardship is clear when viewed through the lens of diagnostic uncertainty. The underlying assumption of these recommendations, namely that sepsis is frequently and reliably identifiable in real time, is incorrect. Sepsis commonly is diagnosed only in retrospect [12]. Indeed, in one prospective study, 43% of patients who were treated for sepsis ultimately were found to have been unlikely ever to have had sepsis when re-evaluated retrospectively [40]. Aggressive application of the SSC and SEP-1 recommendations results in many patients receiving antibiotics who do not have an infectious cause for their organ dysfunction.

De-escalation strategies should restrain antibiotic usage and serve as a reasonable second check in cases of diagnostic uncertainty [41 –43]. However, in practice, de-escalation is applied infrequently even in the face of negative cultures [17,44 –46]. Deshpande et al. report hospital-wide de-escalation rates of only 2%–35% in a cohort of more than 14,000 patients with cultures negative for pneumonia [45]. In this cohort, even the lowest risk patients had de-escalation rates of <50% [45].

If we cannot count on reliable de-escalation or cessation of antibiotics, even in the face of negative cultures, then we must conclude that thoughtful initiation is the key to reducing avoidable antibiotic exposure. In septic shock, there are some data to support aggressive antibiotic initiation with subsequent de-escalation. However, in suspected sepsis without shock, the same approach does not result in improved outcomes. If we accept diagnostic uncertainty as part of our sepsis treatment pathway, it becomes clear that our current “one-size-fits-all” approach to antibiotic initiation is unnecessary and may be harmful [10,12].

Conclusion

For almost two decades, the SSC has recommended aggressive antibiotic initiation based on data quality that is marginal at best. Coupled with the power of a CMS mandate, this recommendation has fueled unrestrained antibiotic use in the United States. As we have demonstrated, there is limited observational evidence to support aggressive antibiotic initiation in septic shock, and almost no evidence to support such a recommendation in septic patients presenting without shock. Although the SSC guidelines and SEP-1 mandate must be recognized for increasing awareness of sepsis care, the time has come to improve these recommendations. All physicians, particularly surgeons, who manage septic patients, should lead the charge in raising the quality of evidence in this field and improving antibiotic stewardship.

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