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Association of White Blood Cell Count with Treatment Response to Cefepime vs Piperacillin-Tazobactam
Daniel I Rzewnicki1, Rishi Chanderraj2,3,4, Edward T Qian5,6
1Department of Medicine, Emory University, Atlanta, GA.
Rationale:
Empiric anti-pseudomonal coverage is an important part of treatment of sepsis, but there is limited data to guide antibiotic selection. The antibiotic choice on renal outcomes (ACORN) randomized trial found no difference in mortality when comparing cefepime and piperacillin-tazobactam, while an Instrumental Variable (IV) study found improved mortality with cefepime.
Objective:
To determine if white blood cell (WBC) count modifies the effect of antibiotic choice on mortality.
Methods:
We conducted post-hoc sub-group analyses of the ACORN trial and the IV study comparing cefepime to piperacillin-tazobactam. We performed regression modeling of interaction between treatment group and WBC on 28-day mortality with adjustment for relevant covariates, with evaluation for heterogeneity of treatment effect through likelihood ratio testing.
Measurements:
The main outcome was 28-day mortality in both cohorts. Secondary outcomes in the secondary analysis of the ACORN trial included highest stage of acute kidney injury on an ordinal scale, a composite outcome of major adverse kidney events, and incidence of coma or delirium within 14 days.
Main Results:
There was a significant interaction between WBC and treatment group in predicting 28-day mortality in both the ACORN trial and the IV study (odds ratio [OR] 0.95, 95% confidence interval [CI] 0.92-0.98, p = <0.01 and OR 0,95, CI 0.94-0.96, P < .01, respectively), with likelihood ratio testing revealing better model fit with inclusion of the interaction term (F = 8.17, p = <0.01 and F = 42.9, P < .01, respectively). In the ACORN cohort, patients with a baseline WBC count of 16 or higher had significantly lower odds of mortality when treated with piperacillin-tazobactam compared to cefepime (OR 0.51, CI 0.29-0.90).
Conclusions:
WBC modified the effect of antibiotic choice on mortality in two large clinical studies. Further research is needed to confirm this effect in prospective studies and to determine if WBC count could be used for predictive enrichment in future trials of anti-pseudomonal antibiotics.
Insights
White blood cell (WBC) count significantly impacts sepsis treatment outcomes. Patients with higher WBC counts receiving piperacillin-tazobactam showed lower mortality compared to cefepime in the ACORN trial.
Area of Science:
- Critical Care Medicine
- Infectious Diseases
- Pharmacology
Background:
- Empiric anti-pseudomonal coverage is crucial for sepsis management, yet optimal antibiotic selection remains under-investigated.
- The Antibiotic Choice On Renal Outcomes (ACORN) trial found no mortality difference between cefepime and piperacillin-tazobactam, while an Instrumental Variable (IV) study suggested cefepime superiority.
Purpose of the Study:
- To investigate whether white blood cell (WBC) count modifies the effect of antibiotic choice on mortality in sepsis patients.
- To analyze the interaction between WBC count and antibiotic treatment on 28-day mortality.
Main Methods:
- Post-hoc subgroup analyses were conducted on data from the ACORN randomized trial and an IV study.
- Regression modeling assessed the interaction between treatment groups (cefepime vs. piperacillin-tazobactam) and WBC count on 28-day mortality.
- Likelihood ratio testing evaluated heterogeneity of treatment effects.
Main Results:
- A significant interaction between WBC count and antibiotic choice was observed in both cohorts, influencing 28-day mortality.
- Patients with a baseline WBC count of 16 or higher in the ACORN cohort had significantly lower mortality odds with piperacillin-tazobactam versus cefepime (OR 0.51, CI 0.29-0.90).
Conclusions:
- White blood cell count significantly modifies the impact of antibiotic choice on sepsis-related mortality.
- Further prospective research is warranted to confirm these findings and explore WBC count for predictive enrichment in future anti-pseudomonal antibiotic trials.
