Empirical Antibiotic Activity and Outcomes in Pediatric Gram-negative Bloodstream Infections: A Rank-based Composite
Sophie C H Wen1,2, Melissa J Hardy1, Abdullah T Aslan1,3
1The University of Queensland, Centre for Clinical Research, Brisbane, Queensland, Australia.
Insights
Timely active empirical therapy (AET) did not improve clinical outcomes in children with gram-negative bloodstream infections (GNBSI). Composite endpoints are valuable for detecting differences in high-income settings where mortality is low.
Area of Science:
- Pediatric Infectious Diseases
- Clinical Microbiology
- Health Services Research
Background:
- Active empirical therapy (AET) is often recommended for bloodstream infections.
- Low pediatric mortality in high-income countries makes mortality alone an insufficient endpoint for AET studies.
- Composite endpoints combining multiple outcomes may better detect treatment effects.
Purpose of the Study:
- To assess the impact of AET on clinical outcomes in hospitalized children with gram-negative bloodstream infections (GNBSI).
Main Methods:
- Prospective surveillance data from Australian children with GNBSI were analyzed.
- A composite endpoint included mortality, time to death, ICU admission, relapse, and hospitalization duration.
- Inverse probability of treatment weighting and generalized pairwise comparison were used for analysis.
Main Results:
- Active empirical therapy (AET) occurred in 597 episodes, inactive empirical therapy (IET) in 62.
- No significant difference in the composite outcome was found between AET and IET (adjusted win ratio 1.04, p=0.83).
- Individual outcome components showed no significant differences between groups.
Conclusions:
- In high-resource settings, AET did not demonstrate improved outcomes for pediatric GNBSI compared to IET.
- The impact of initial antibiotic activity may be less significant than assumed in these settings.
- Effective therapy remains crucial for severe infections and in low-resource environments.
Background:
Timely active empirical therapy (AET) may improve outcomes following bloodstream infection. In high-income settings, low pediatric mortality following gram-negative bloodstream infection (GNBSI) limits its value as a sole endpoint. Composite measures that incorporate multiple clinically relevant outcomes may detect differences more readily. We assessed the effect of AET on clinical outcomes in pediatric GNBSI.
Methods:
We analyzed data from a prospective surveillance study of hospitalized Australian children with GNBSI. A ranked composite endpoint included 30-day all-cause mortality (30D ACM), time to death, intensive care unit (ICU) admission, relapse, and hospitalization duration. Baseline differences were adjusted using inverse probability of treatment weighting. Generalized pairwise comparison (GPC) generated win statistics. Analyses were stratified by comorbidity, acquisition setting, and organism.
Results:
Active empirical therapy occurred in 597 episodes and inactive empirical therapy (IET) in 62. Median treatment duration was similar (AET 10 vs IET 11 days, P = .44). Generalized pairwise comparison analysis showed an adjusted win ratio of 1.04 (95% CI .72-1.52, P = .83), indicating no significant difference. Contributions from each composite component (AET vs IET) were the following: 30D ACM (2.2% vs 1.3%), time to death (0.02% vs 0.01%), ICU admission (7.5% vs 9.1%), relapse (2.6% vs 1.4%), and hospitalization duration (37.3% vs 36.0%). Stratified estimates were similar for comorbidity and acquisition.
Conclusions:
In this large multicenter pediatric GNBSI cohort, AET was not associated with improved outcomes. In high-resource settings, the impact of initial antibiotic activity may be smaller than traditionally assumed, though timely effective therapy remains essential for severe illness and low-resource settings.
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