Risk of recurrent cefepime-resistant bacterial infection during febrile neutropenia in pediatric oncology and hematopoietic cell transplantation
Authors: Pham Thanh , Wolf Josh , Morton Ted H , Ramilo Octavio , Maron Gabriela , Hayden Randall T , Glasgow Heather L , Cross Shane J 
Published: January 2025

Abstract

Corresponding author: Thanh Pham, 262 Danny Thomas Pl, Memphis, TN 38105, thanh.pham@stjude.org, 503-380-8576
Alternate corresponding author: Shane Cross, 262 Danny Thomas Pl, Memphis, TN 38105, shane.cross@stjude.org, 901-595-3300
The authors have no conflicts of interest to declare.

Background
Children receiving chemotherapy or hematopoietic cell transplantation (HCT) are at high risk for life-threatening antibiotic-resistant bacterial infections. Patients who present with febrile neutropenia (FN) following a recent resistant infection may be at uniquely elevated risk of having another resistant infection. Therefore, national and international guidelines recommend clinicians consider modifying initial antibiotic regimens based on prior multidrug-resistant infections. However, broader spectrum empiric therapy has significant risks at the individual and community level, and not all subsequent episodes of FN are associated with another antibiotic resistant infection; some have susceptible infections or no bacterial infection. Therefore, there is uncertainty about appropriate empiric antibiotic regimens during subsequent FN episodes in patients with past resistant infection, and no high-quality published data are available for the absolute risk of recurrent resistant bacteria during FN in this patient population. We aimed to fill this knowledge gap by evaluating the risk of cefepime-resistant bacterial infections during FN episodes occurring within 6 months after cefepime-resistant bacteremia in pediatric patients with cancer.

Methods
This was an IRB-approved retrospective cohort study of children and adolescents (&lt;25 years) who had an episode of cefepime-resistant Gram-negative bacteremia identified between January 2010 and September 2022 at St. Jude Children’s Research Hospital, a pediatric comprehensive cancer center in Memphis, TN. We abstracted demographic, oncologic information, clinical presentation, laboratory data, microbiology data and antibiotic information for the index bacteremia episode, and for all subsequent discrete FN episodes occurring within 6 months. FN episodes were excluded if they did not meet definition of FN or if there was not at least seven prior days of fever-free without treatment antibiotics or non-standard prophylactic antibiotics. We estimated the proportion of FN episodes with microbiologically-documented caused by cefepime-resistant Gram-negative bacteria with 95% confidence intervals, and identified risk factors for recurrent resistant infection.

Results
We identified 150 evaluable episodes in 75 participants; 77 index episodes and 73 recurrent episodes. Descriptive data for demographics, clinical presentation and initial outcome data are shown in Table 1.
Recurrent cefepime-resistant infection occurred in 29/73 (40%) of FN episodes (95%CI 29-51%). Hypotension, fluid bolus, or chills/rigors were significantly associated with an increased risk of cefepime-resistant infection in recurrent episodes (P = 0.01, P =0.01, and P = 0.046 respectively). The absence of any high-risk clinical features (hypotension, fluid bolus, severe abdominal pain, chills/rigors) markedly reduced the risk (5/28 [18%] vs. 24/45 [53%]; P = 0.003).

Conclusions
Children and adolescents with cancer presenting with FN after a recent cefepime-resistant bacteremia are at high risk of having another cefepime-resistant infection. Those without high-risk features at presentation are at markedly lower risk. Further research should aim to validate these findings, with the aim of developing risk-stratification models to guide empiric treatment.
Table 1. Characteristics of included participants

Table 2. Characteristics of recurrent episodes