Beneficial effects of early empirical administration of appropriate antimicrobials on survival and defervescence in adults with community-onset bacteremia

Empirical administration of appropriate antimicrobials to septic or infective individuals has remained challenging because of the increased antibiotic resistance in both hospitals and communities [1] as well as atypical presentations in the specific population, such as the elderly [2] and human immunodeficiency virus-infected adults [3]. Particularly in septic patients presenting with a critical illness, inappropriate empirical therapy is associated with increased mortality [4, 5]. Generally, bloodstream infections lead to high morbidity and mortality and substantially contribute to healthcare costs [6]. However, whether appropriate initial antimicrobial administration has beneficial effects on the outcome of patients with bloodstream infections remains debated [4, 7‐11].

To shorten the hospital stay, the timing of defervescence in response to antimicrobial therapy must be addressed. Numerous studies on bacteremia [12] and pneumonia [13, 14] found a significant association between defervescence timing and administration of antimicrobial classes. However, for bloodstream infections, the beneficial effect of rapid administration of appropriate antimicrobial therapy on defervescence remains unclear. Accordingly, we hypothesized that timely appropriate antimicrobial therapy heralds a favorable outcome and speedy defervescence, and a large cohort of adults with community-onset bacteremia was studied.

Bacteremia is associated with substantial morbidity and mortality and thus is typically considered a severe presentation of systemic infections [6]. However, in contrast to the effects of appropriate empirical antibiotic therapy on severe sepsis or septic shock, the potential benefits of appropriate empirical therapy in bacteremia has achieved little consensus. Some studies reported minimal effect [10, 11], whereas some noted a significant reduction of case fatality rates [4, 7‐9]. This controversy may be related to the variations in bacteremia severity, comorbidities, immune status, and distribution of causative microorganisms in the study patients [27]. Similar to two studies of bloodstream infections [7, 8], our results support that appropriate initial antimicrobial therapy could reduce short-term mortality in the setting of community-onset bacteremia.

It has been recognized that antimicrobial delays decreased short-term survival in patients with severe sepsis and septic shock [28, 29]. Likewise, the risk of mortality steadily increased; if appropriate, antimicrobial administration was delayed in our patients with community-onset bacteremia. Our cohort demonstrated that each hour of TtAa delay was associated with an increase in 30-day mortality rate of 0.4% in critically ill patients and 0.3% in all enrolled patients. Consequently, for severe bacteremic episodes, the appropriateness of empirical administration should be emphasized. Therefore, in addition to identifying those critically ill cases of bloodstream infections among febrile visitors at the EDs, timely empirical administration of broad-spectrum antimicrobial agents, epidemiological surveillance, and rapid detection of etiological pathogens and antimicrobial susceptibility is crucial for timely administration of appropriate antimicrobials.

The time gap between the initiation of antimicrobial administration and defervescence has been assessed as an outcome parameter in response to antimicrobial therapy in previous investigations of bloodstream infections [12, 30, 31]. Focusing on this outcome vastly linked to the hospital stay, our cohort highlighted the temporal association between the defervescence timing and the appropriateness of empirical antimicrobial therapy was evident in not only non-critically ill cases, but also critically ill ones at initial presentations. Such a therapeutic benefit of timely appropriate therapy also can be noted in the subgroup patients with variable bacteremic sources or causative pathogens. In other words, the association of delayed defervescence and inappropriate empirical antimicrobials was clearly and reasonably demonstrated herein.

Similar to several ED-based investigations of bloodstream infections [32, 33], the bacteremia source of urinary or biliary infections was a protective factor against mortality in our cohort, whereas bacteremia due to pneumonia was a crucial determinant of fatality. From our suspect, major reasons for the differences in the prognoses between these bacteremia sources may have been the different proportions for three most powerful prognostic factors recognized here, in terms of bacteremia severity at initial presentations, comorbidity severity, and adequate source control. For instance, compared with patients with bacteremia due to urosepsis, patients with bacteremic pneumonia had a significantly higher tendency to have a critical illness at ED arrival (228/473, 48.2% vs. 133/1034, 12.9%; P < 0.001), severe underlying diseases (i.e., fatal comorbidities) (159/473, 33.6% vs. 173/1034, 16.7%; P < 0.001), and inadequate source control (11/473, 2.3% vs. 8/1034, 0.8%; P = 0.01).

In addition to the timing of appropriate antimicrobial administration, the role of adequate source control for complicated bloodstream infections was examined herein. Consistent with published studies on severe sepsis [25] and complicated bacteremia [26], we found that inadequate source control was an independent determinant of short-term mortality. Although an association between adequate source control and the TtD was not evident in the literature, it is reasonable to assume individuals with inadequate source control have delayed defervescence. In our cohort, patients with inadequate source control for complicated bacteremia accounted only for the minority (2.4%), but the median TtD was longer in those with inadequate source control than in those who received adequate source control, irrespective of the appropriateness of empirical antimicrobial administration (appropriate, 11 vs. 4 h, P < 0.001; inappropriate, 84 vs. 74 h, P < 0.001). Therefore, to accurately assess the effect of the TtAa on the TtD, patients with inadequate source control was reasonably excluded from our analyses.

This study possesses several limitations. First, its retrospective and observational nature is the main limitation. However, the study cohort was large, and the record discrepancy was minimized by discussion between the chart reviewers during the capture of clinical information. Valuable information on the interaction between the TtAa and TtD has therefore been provided. Second, antimicrobial therapy is a cornerstone of clinical management for patients with bloodstream infections. Similar to the positive attitude on the appropriateness of empirical antimicrobial administration on patient outcomes [4, 7‐11], our study had no detailed information of early goal-directed therapy and the sepsis bundle as covariates. Superior to these established reports, the impact of inadequate source control for complicated bacteremia was firstly highlighted herein. Third, in the analysis of the effect of antimicrobial therapy on patient survival, we excluded those with uncertain outcome. Although the chance that the excluded cases of unknown outcome were too severe to return the healthcare system is substantial, only 148 (4.4%) of 3342 adults with community-onset bacteremia were excluded and trivial selection bias is thus expected. Fourth, to prevent interference from several covariates linked to the TtD, patients with initial afebrile presentation or hypothermia, those with steroid therapy for severe sepsis or adrenal insufficiency, and those without adequate source control were excluded. Therefore, caution should be exercised in interpreting the effects of TtAa delay on the TtD. Finally, because the study hospitals were localized in southern Taiwan, a lack of an independent validation is one of the study limitations, and our results may not be extended to other population with variable infection sources, proportions of antimicrobial-resistant microorganisms, or bacteremia severity. However, several clinical predictors of short-term mortality identified in our cohort, including specific bacteremia sources (such as bacteremic pneumonia) and comorbidities (such as liver cirrhosis and malignancies), are consistent with earlier reports involving ED bacteremia [32, 33]. More importantly, the study findings from our large bacteremia cohort highlight that adults with community-onset bacteremia requires early administration of appropriate antimicrobials to achieve favorable outcomes and therapeutic efficacies, as noted before [16, 28, 29]. Additionally, the beneficial influence of rapid administration of appropriate antimicrobials on defervescence was the novelty for patients with bloodstream infections.

Regardless of bacteremia severity, early administration of appropriate antimicrobials is a crucial determinant of short-term outcomes in patients with community-onset bacteremia. Additionally, rapid administration of appropriate antimicrobials facilitated defervescence. Therefore, to achieve a favorable outcome and rapid defervescence, epidemiological surveillance, rapid pathogen identification, and the incorporation of broad-spectrum antimicrobial as empirical therapy into an antibiotic stewardship program should be considered, particularly in critically ill patients.