262 - A Systematic Review and Meta-Analysis of the Impact of Delayed Appropriate Antibiotic Therapy on Mortality in Patients with Gram-Positive Bacteremia

Background: Antibiotic resistance is common and frequently leads to unintentional delays in appropriate antibiotic therapy. The detrimental impact of delayed therapy is well-accepted, but the majority of evidence focuses on gram-negative infections. A review and synthesis of the evidence evaluating the impact of delayed appropriate antibiotic therapy in serious gram-positive infections does not exist. Such data would define the scope of the problem in this important patient population where antibiotic resistance is common. The objective of this systematic review and meta-analysis was to assess the impact of delayed appropriate antibiotic therapy on mortality in patients with gram-positive bacteremia.

Methods: Pubmed and Embase were searched from inception to March 30, 2020 to identify clinical studies of patients with bacteremia due to staphylococci, enterococci, or streptococci that reported the association between delayed appropriate antibiotic therapy and mortality.  Three independent reviewers screened search results. Study quality was assessed via Newcastle-Ottawa Assessment Scale. Meta-analyses evaluating association between delayed therapy and mortality were conducted via random effects models in Review Manager 5.3. The primary analysis included unadjusted effect estimates from studies reporting unadjusted data. Secondary analysis included adjusted effect estimates from studies adjusting for confounding.

Results: Of 3684 search results, 16 cohort studies encompassing 4173 bacteremias were included. Ten studies involved S. aureus, 5 enterococci, and 2 S. pneumoniae. One-third (33.7%) of the 3659 patients in the primary analysis received delayed appropriate antibiotic therapy. The primary meta-analysis of 15 studies reporting unadjusted data showed a statistically significant association between delayed therapy and mortality (figure 1).  Results from secondary analysis using adjusted point estimates from 9 studies were similar (figure 2).Figure 1. Forrest plot of meta-analysis of unadjusted association between delayed therapy and mortality
Figure 2. Forrest plot of meta-analysis of covariate adjusted association between delayed therapy and mortality


Conclusion: Delayed appropriate therapy was common and associated with increased mortality in patients with gram-positive bacteremia. These findings underscore the need for continued antimicrobial stewardship efforts to ensure expeditious appropriate antibiotic therapy for patients with gram-positive bacteremia.