Can Shorter Time to Antibiotic Administration Improve Outcomes in Febrile Neutropenia?

A new protocol consisting of “relatively simple interventions” speeds time to initial receipt of antibiotic therapy for cancer patients experiencing febrile neutropenia (FN), according to results from a report recently published in the Journal of Oncology Practice.

Patients treated through this new protocol also had a shorter time to hospital discharge and an improvement in a host of other endpoints, compared to before the protocol was initiated.

“Fever in the setting of neutropenia in cancer patients is a life-threatening emergency, similar to a heart attack or stroke, and prompt initiation of antibiotics is critical in minimizing mortality,” Mikkael Sekeres, MD, corresponding author on the study and ASH Clinical News Editor-in-Chief, said. To improve outcomes, clinical practice guidelines recommend administering broad-spectrum antibiotics within one hour of fever documentation. Given the increasing number of outpatient chemotherapy regimens, though, patients are more likely to present to the emergency department with FN rather than the outpatient infusion unit – and may face greater delays to antibiotic treatment due to emergency department crowding or inconsistent definition of and treatment regimens for FN. These delays, in turn, can lead to longer hospital stays and poorer survival outcomes.

“For the first time, we were able to demonstrate that instituting a number of simple interventions decreased the time it took for these patients to receive antibiotics from four hours to a little over an hour,” Dr. Sekeres noted.

In the current report, lead author Michael Keng, MD, and colleagues conducted a prospective study of adult patients with cancer who sought treatment in an academic health-care center emergency department to determine if implementation of a new FN protocol could reduce antibiotic delays – and if that would translate to improved quality of care and outcomes for patients.

Patients ≥18 years old who presented with fever to the Cleveland Clinic emergency department between June 2012 and June 2013 were included in the study. Study participants’ time to antibiotic therapy and outcomes were compared with a historical cohort of patients who presented to the Cleveland Clinic emergency department between February 2010 and May 2012, as well as with patients who were directly admitted (those patients who were clinically stable and bypassed the emergency department if FN was suspected).

After reviewing the process that cancer patients encountered when presenting to the emergency department, the investigators identified delays in three areas: time from registration in the emergency department to initial physician evaluation; availability of laboratory results to determine whether the patient was neutropenic; and time to antibiotic administration.

They then developed a febrile neutropenia pathway (FNP) to cut those delays, incorporating the following components:

  • Emergency department reclassification of FN on the Emergency Severity Index to the same level as cerebral-vascular accident or myocardial infarction
  • Triage of FN patients to private rooms at registration rather than waiting rooms
  • Standardization of definition of FN across inpatient and outpatient cancer center and hospital sites
  • Production of an “FN Alert Card,” a wallet-sized card with specific instructions for febrile patients, which could be presented at the emergency department triage desk to alert personnel
  • Creation of a FN chief complaint category and a standardized order set in the emergency medical record (EMR) to eliminate variability in treatment
  • Antibiotic administration before complete blood count confirmation of neutropenia
  • FNP antibiotics made available in emergency department Pyxis dispensing machines to avoid delays in drug transport from the central pharmacy area
  • Education across emergency department and cancer center about the FNP with periodic in-service training and updates at staff meetings

“The interventions we made were not complicated and are in processes that are not specific to Cleveland Clinic,” Dr. Sekeres said. “It took less than 6 months to institute these changes, and the benefits have persisted for years afterward.”

A total of 497 febrile neutropenic episodes occurred in 386 patients during the study period: 276 episodes in 223 patients in the FNP cohort, 107 episodes in 87 patients in the historical cohort, and 114 episodes in 101 direct admission patients. There was some overlap among the three groups.

The most common cancers in the study population were leukemia (24%), lymphoma (22%), breast cancer (9%), head-and-neck cancers (7%), and lung cancer (6%).

Patients in the FNP cohort had significantly shorter time to antibiotic receipt (TTA, the study’s primary endpoint), at a median of 81 minutes – nine minutes shorter than the target TTA of 90 minutes – compared with historical and direct admission cohorts (235 minutes and 169 minutes, respectively; p<0.0001).

More than half (57%) of the FNP patients received antibiotics within 90 minutes and almost one-third (32%) received antibiotics within 60 minutes. For comparison, just 1 percent of patients in the historical cohort and 13 percent of patients in the direct admission cohort met the 90-minute goal, while just two patients in both cohorts were treated within 60 minutes.

Patients in the FNP group had significantly shorter times than the historical and direct admission cohorts for the majority of the study’s secondary endpoints (TABLE), but the reduction in length of hospital stay was not significant.

“By instituting a febrile neutropenia pathway, we were able to decrease the length of hospitalization for patients by approximately one day, thus showing real value from our intervention to patients,” Dr. Sekeres said.

There were, however, limitations of the study. During the course of the study, TTA goals were reduced by the Infectious Diseases Society of America and the American Society of Clinical Oncology – from 90 minutes to 60 minutes. These goals were adjusted accordingly in the study, though it is difficult to determine the impact of any change that occurs during the study period, Dr. Keng and co-authors noted.


Keng M, Thallner E, Elson P, et al. Reducing time to antibiotic administration for febrile neutropenia in the emergency department. J Oncol Practice. 2015;126:486-493.

TABLE. Outcomes of Time Endpoints From ED or Hospital Registration

FNP Cohort, median (range)

Historical cohort, median (range)

Direct admission cohort, median (range) p Value, FNP vs. Historical

p Value, FNP vs. Direct admission

Physician assessment (minutes) 43 (1-226) 73 (12-382) 20 (0-145) <0.001 <0.001
Blood draw (minutes) 44 (1-364) 74 (10-302) 110 (20-392) <0.001 <0.001
Antibiotic order (minutes) 36 (3-426) 141 (18-501) 72 (2-492) <0.001 <0.001
Antibiotic administration (minutes) 81 (9-439) 235 (82-689) 169 (50-679) <0.001 <0.001
Emergency department discharge or hospital admission (hours) 4.4 (0.7-25.0) 6.0 (2.1-18.0) <0.001
Hospital length of stay if admitted (days) 3.3 (0.4-35.4) 4.3 (0.6-33.1) 5.6 (0.1-29.7) 0.26 <0.001
ICU admission, number (%) 18 (7) 8 (8) 5 (4) 0.71 0.42