Timing of appropriate empirical antimicrobial administration and outcome of adults with community-onset bacteremia

Despite improvements in hemodynamic support and antibiotic therapy, bacteremia is still associated with high morbidity and mortality, which contribute substantially to healthcare costs [1]. Community-onset bacteremia, with an annual incidence of 0.82% in a population-based study [2], is a common problem for clinicians. In addition to early establishment of vascular access, fluid resuscitation, and removal of infection source, particularly in critically ill patients, antimicrobial therapy has been regarded as one of the mainstays of bacteremia treatment [3]. Although most investigations have concluded that early administration of appropriate antimicrobials could be linked to a favorable prognosis in the individuals with bacteremia [4‐7], several studies have not identified the survival benefit of early appropriate antimicrobial therapy [8, 9]. Furthermore, the timing of the first dose of appropriate antibiotics remains a controversial point, and thus appropriate empirical antimicrobial therapy has been defined as the interval between bacteremia onset and antimicrobial administration, ranging widely from <24 hours to <48 hours in previous reports [7, 10, 11]. To our knowledge, the Surviving Sepsis Campaign (SCC) “International guidelines for the management of severe sepsis and septic shock” recommend that an appropriate antimicrobial therapy be administered within the first 1 hour of recognition of severe sepsis or septic shock [3]. However, focusing on patients with bacteremia, the question “what priority is early enough for appropriate antibiotic administration?” has been debated. Therefore, to describe the beneficial effects of appropriate empirical antimicrobial administration on clinical outcome and to further achieve the “optimum timing” of appropriate antimicrobial administration, we compared the outcome impact of different time cutoffs from emergence department (ED) triage to appropriate antimicrobial administration for adults with community-onset bacteremia.

Bacteremia is associated with substantial morbidity and mortality and early interventions are often emphasized [1, 14]. However, the estimates of potential benefits of appropriate empirical antibiotic treatment vary widely in the literature, from no effect [8, 9] to significant reduction in fatality with an odds ratio of up to 6 [4‐7]. Such a controversy may be related to variations in sepsis severity, comorbidities and the immune status of study cohorts, and the distribution of causative microorganisms [24]. Similar to previous reports dealing with the crucial relationship between patient outcomes and the appropriateness of empirical antimicrobial therapy for specific pathogens, such as Gram-negative bacilli [25], E. coli [26, 27], K. pneumoniae [27], S. aureus [28], or bloodstream infections [5, 6], our results support that appropriate empirical antimicrobial therapy reduces short-term mortality in patients with community-onset bacteremia. Of importance, in accordance with increasing bacteremia severity, appropriate antimicrobials should be given as soon as possible.

Several investigations have attempted to answer the question “How early is enough to administer appropriate antimicrobials in patients with severe infection?” However, different TtAa cutoffs were determined in heterogeneous patient populations reported in the literature. First, for patients with severe Legionella pneumophila pneumonia, delays >8 hours between appropriate antimicrobial administration and ICU admission resulted in increased mortality [29]. Second, in another study of patients with cancer and septic shock, a delay of >2 hours from ICU admission was associated with a poor prognosis [30]. Finally, in a study of ED patients with severe sepsis and septic shock, a TtAa <1 hour led to a better short-term survival rate [18].

To our knowledge, the present study was the first one focusing on community-onset bacteremia to prioritize antimicrobial therapy in the initial therapeutic strategy. Similar to a previous report of hospital-based bloodstream infection [7], the “optimum timing” of appropriate antimicrobial administration was determined as the first 48 hours after arrival at the ED. Furthermore, consistent with the SSC recommendations [3], this time should be shortened to 1 hour in critically ill patients. However, the administration of in vitro effective antimicrobials to treat bloodstream infections should be as early as possible to achieve optimal treatment of bacterial infections. Any delay in the administration of appropriate drugs should be avoided, if there is a suspicion of severe sepsis or septic shock.

This study has several limitations. First, antimicrobial therapy is one of the cornerstones of therapeutic strategies for patients with bloodstream infection. Nevertheless, for critically ill patients with the complications of severe sepsis and septic shock, other elements of early goal-directed therapy, such as central venous pressure, mean arterial pressure, and central venous oxygen saturation, were not evaluated as covariates in this study. Second, in the assessment of the primary endpoint and analysis of the impact of antimicrobial therapy, we excluded patients with incomplete clinical information and those receiving inappropriate antibiotic dosage or route of administration. As a result, only 16 patients were excluded and thus the selection bias was expected to be minimal. Third, as previous investigations dealing with the effects of the appropriateness of empirical antimicrobial administration on patient outcome [4‐9], no detailed information was available in our study on early resuscitation. However, the majority (1663, 70.8%) of the 2349 patients with community-onset bacteremia received the first dose of appropriate antimicrobials within one hour of arrival at the ED, and the study population were believed to be managed according to the SSC recommendations. Thus, the clinical outcomes of the patients receiving appropriate antimicrobial therapy at different time points after arrival at the ED could be compared with each other. Fourth, as noted before [4‐9], no analyses of source control were performed in the present study. However, taking the cases of urosepsis as the example, in those with or without interventions for source control, such as percutaneous nephrolithotomy or nephrectomy, the 28-day crude mortality rate was not different (4/48, 8.3% vs. 35/700, 5.0%; P = 0.31), indicative of standard quality of clinical care in the study hospital. Finally, as this study was conducted at one hospital, the critical TtAa cutoffs we identified may not be generalizable to other communities with variable infection sources or severity of community-onset bacteremia. However, our findings highlight that more severely ill patients with bacteremia require earlier administration of appropriate antimicrobials to achieve a favorable outcome.

Our results demonstrate that the elapsed time from arrival at the ED to the administration of appropriate antimicrobials is a crucial determinant of short-term outcomes in patients with community-onset bacteremia. The optimum timing of appropriate antimicrobial administration in mildly ill patients was the first 48 hours after arrival at the ED. With increasing severity of bacteremia, this time should be limited to the first 1 hour in critically ill patients. Therefore, to achieve a favorable outcome in critically ill patients, epidemiological surveillance, rapid pathogen identification, or the incorporation of broad-spectrum antimicrobials as empirical therapy into an antibiotic stewardship program should be considered.