Examining the Evidence for Escalating Antimicrobial Regimens in Febrile Oncology and Hematopoietic Stem Cell Transplant Patients Admitted to the PICU: An Observational Study*

Abstract

OBJECTIVES: To examine whether escalating antimicrobial treatment in pediatric oncology and hematopoietic cell transplantation (HSCT) patients admitted to the PICU is supported by culture data or affects patient outcomes. DESIGN: Retrospective cross-sectional study. SETTING: Quaternary care PICU. PATIENTS: Patients younger than 18 years old who were admitted to the PICU at Boston Children’s Hospital from 2012 to 2017 with a diagnosis of cancer or who had received HSCT and who had suspected sepsis at the time of PICU admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 791 PICU admissions for 544 patients that met inclusion criteria, 71 (9%) had escalation of antimicrobial therapy. Median Pediatric Logistic Organ Dysfunction (PELOD) score was higher in the escalation group (4 vs 3; p = 0.01). There were 14 admissions (20%) with a positive culture in the escalation group and 110 (15%) in the no escalation group (p = 0.31). In the escalation group, there were only 2 (3%) cultures with organisms resistant to the initial antimicrobial regimen, compared with 28 (4%) cultures with resistant organisms in the no escalation group (p = 1). Mortality in the escalation group was higher (17%) compared with the nonescalation group (5%; p < 0.001). The escalation group had more acute kidney injury (AKI) (25%) during treatment compared with the no escalation group (15%; p = 0.04), although this difference was not statistically significant when controlling for age, neutropenia, and PELOD-2 score (odds ratio, 1.75; 95% CI, 0.95–3.08; p = 0.06). CONCLUSIONS: Few patients who had escalation of antimicrobials proved on culture data to have an organism resistant to the initial antimicrobials, and more patients developed AKI during escalated treatment. While the escalation group likely represents a sicker population, whether some of these patients would be safer without escalation of antimicrobial therapy warrants further study.

To Broaden or Not to Broaden? Answers on Appropriate Antimicrobial Escalations for Pediatric Hematopoietic Cell Transplant Patients Remain Out of Reach*

“…Due to the small number of patients with antimicrobial escalations, further subgroup analyses focused on only the escalations including antimicrobials with a higher risk of nephrotoxicity is likely not feasible; however, a larger study may be able to evaluate this risk. Furthermore, although the study may have been underpowered to detect a true significant increase in AKI risk using multivariable modeling, recent data suggest the association between stage 1 AKI with worse outcomes is present only when a patient meets both the criteria for increased creatinine as well as reduced urine output (9), which was not the AKI criterion used in the study by Prince et al (6), potentially leading to misclassification bias of the outcome. Therefore, we also propose that future studies use this more inclusive definition for stage 1 AKI or focus on stage 2 or higher AKI when measuring the association of an exposure with increased risk of AKI.…”

“…In this issue of Pediatric Critical Care Medicine, Prince et al (6) explore whether antimicrobial escalation in HSCT patients admitted to the PICU with suspected sepsis is supported by subsequent blood culture data and investigate the impact of antimicrobial escalations on mortality and on the risk of developing at least stage 1 acute kidney injury (AKI) per Kidney Disease Improving Global Outcomes definitions (7). In this single-center analysis of 544 patients with 791 PICU admissions, less than 10% of the PICU admissions had an escalation of antimicrobial therapy.…”

“…However, evaluation of AKI as an outcome may be most accurate when the antimicrobials defined as the exposure are known to have a higher risk of nephrotoxicity (8). In review of eTable 5 in Prince et al (6), most of the antimicrobials listed as new agents for children with antimicrobial escalations have a low reported frequencyof AKI associated with their use (e.g., ampicillin, azithromycin, cefepime, ceftriaxone, ciprofloxacin, clindamycin, daptomycin, fluconazole, linezolid, levofloxacin, meropenem, metronidazole, micafungin, voriconazole), leading to potential misclassification bias the exposure. Due to the small number of patients with antimicrobial escalations, further subgroup analyses focused on only the escalations including antimicrobials with a higher risk of nephrotoxicity is likely not feasible; however, a larger study may be able to evaluate this risk.…”

“…Prince et al (6) draw needed attention to the paucity of information about patterns of antimicrobial use in critically ill HSCT patients and the importance of balancing the risks of escalating antimicrobials with the potential benefit of treating possible resistant organisms while awaiting culture results, particularly when the frequency of resistant organisms may be low. We agree that future studies should continue to question our practice surrounding the treatment of sepsis in this vulnerable patient population with the intent of further optimizing care and patient outcomes.…”

“…However, this is a very challenging question to answer and would require a complex study design and statistical analyses to address the heterogeneity of prior exposures in the patient population, define a complex exposure with regard to antimicrobials escalated, account for severity of illness at the time of PICU transfer, and handle the complexities surrounding residual confounding. Prince et al ( 6) ask a much-needed question with results that warrant further investigation; however, due to the single-center retrospective design, the high potential for misclassification bias, and multiple confounders, the study by Prince et al (6) alone cannot inform changes in our practice in this vulnerable population just yet.…”