Implementation of a Pragmatic Biomarker-Driven Algorithm to Guide Antibiotic Use in the Pediatric Intensive Care Unit: the Optimizing Antibiotic Strategies in Sepsis (OASIS) II Study

Abstract

Background Biomarkers can facilitate safe antibiotic discontinuation in critically ill patients without bacterial infection. Methods We tested the ability of a biomarker-based algorithm to reduce excess antibiotic administration in patients with systemic inflammatory response syndrome (SIRS) without bacterial infections (uninfected) in our pediatric intensive care unit (PICU). The algorithm suggested that PICU clinicians stop antibiotics if (1) C-reactive protein <4 mg/dL and procalcitonin <1 ng/mL at SIRS onset and (2) no evidence of bacterial infection by exam/testing by 48 hours. We evaluated excess broad-spectrum antibiotic use, defined as administration on days 3–9 after SIRS onset in uninfected children. Incidence rate ratios (IRRs) compared unadjusted excess length of therapy (LOT) in the 34 months before (Period 1) and 12 months after (Period 2) implementation of this algorithm, stratified by biomarker values. Segmented linear regression evaluated excess LOT among all uninfected episodes over time and between the periods. Results We identified 457 eligible SIRS episodes without bacterial infection, 333 in Period 1 and 124 in Period 2. When both biomarkers were below the algorithm’s cut-points (n = 48 Period 1, n = 31 Period 2), unadjusted excess LOT was lower in Period 2 (IRR, 0.53; 95% confidence interval, 0.30–0.93). Among all 457 uninfected episodes, there were no significant differences in LOT (coefficient 0.9, P = .99) between the periods on segmented regression. Conclusions Implementation of a biomarker-based algorithm did not decrease overall antibiotic exposure among all uninfected patients in our PICU, although exposures were reduced in the subset of SIRS episodes where biomarkers were low.

Nonparametric Maximum Likelihood Estimation Under a Likelihood Ratio Order

“…A primary goal of the study was to assess whether CRP, which had previously been found to be predictive of bacterial infection (Downes et al, 2017), could be used to determine when antibiotic therapy could be safely ended. Additional details of the study design and results of the primary analysis may be found in Downes et al (2018).…”

Use of a Procalcitonin-guided Antibiotic Treatment Algorithm in the Pediatric Intensive Care Unit

“…These findings were similar to the OASIS II Study in which investigators found the biggest impact among a subgroup of patients with low biomarker levels at onset of systemic inflammatory response syndrome (SIRS). 17 In many of our subgroup analyses, including patients with pneumonia and possible sepsis, we found shorter DOT in the PCT vs. usual care arm, but these were not statistically significant differences, likely due to small sample sizes.…”

Utility of Procalcitonin as a Biomarker for Sepsis in Children

“…To our knowledge, there are no published RCTs comparing PCT-based discontinuation to standard-of-care treatment in older pediatric patients. However, observational studies are available (62). One study evaluated the impact of an algorithm on antibiotic use in critically ill children with SIRS (62).…”

“…However, observational studies are available (62). One study evaluated the impact of an algorithm on antibiotic use in critically ill children with SIRS (62). The algorithm indicated cessation of antibiotics at 24 to 48 h if PCT levels determined at SIRS onset were Ͻ1 ng/ml and CRP levels were Ͻ4 mg/dl, microbiological cultures were negative, and there were no focal signs of infection present on evaluation.…”

“…The algorithm indicated cessation of antibiotics at 24 to 48 h if PCT levels determined at SIRS onset were Ͻ1 ng/ml and CRP levels were Ͻ4 mg/dl, microbiological cultures were negative, and there were no focal signs of infection present on evaluation. Although antibiotic use was not decreased among all patients with SIRS (P ϭ 0.76), implementation of this algorithm was associated with a significant reduction in days of therapy in the subset of patients who had both CRP and PCT levels below the defined cutoff points, i.e., 129.9/1,000 days versus 301.2/ 1,000 days (incidence rate ratio, 0.43 [95% CI, 0.26 to 0.71]) (62). While observational, this study demonstrates the potential utility of PCT measurements to allow for safe antibiotic de-escalation in pediatric patients at low risk for bacterial infection.…”