How Long

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Aguilar-Guisado M, et al.. "Optimisation of empirical antimicrobial therapy in patients with haematological malignancies and febrile neutropenia (How Long study): an open-label, randomised, controlled phase 4 trial". Lancet Haematology. 2017. 4(12):E573-E583.
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Clinical Question

Among patients admitted to hematology wards with high-risk febrile neutropenia and no microbiologic diagnosis, does stopping empiric antibiotics once the patient has been afebrile for 72 hours increase the number of antibiotic-free days compared to continuing antibiotics until neutrophil recovery?

Bottom Line

In high-risk febrile neutropenia negative blood cultures and 72 hours of clinical stability and apyrexia, stopping antibiotics regardless of neutrophil count resulted in a lower total days of empiric antimicrobials without an increase in harm.

Major Points

When patients with hematologic malignancies or stem cell transplantations become febrile while neutropenic, the current guidelines recommend continuing broad-spectrum empiric antimicrobial therapy (EAT) until resolution of fever and neutropenia. For many of these patients, they are expected to have prolonged neutropenia lasting weeks or months, and continuing broad-spectrum antibiotics for such a long duration may be associated with more harm than benefit.

In this trial, the investigators looked at a subset of patients with febrile neutropenia in whom no microbiologic diagnosis is made, and randomized them to stopping antibiotics once afebrile for 72 hours regardless of neutrophil count (experimental group) compared to the current guideline recommendations (control group). In the intention-to-treat analysis, there was an increase in EAT-free days from 13.1 to 16.1 days. There was no apparent increase in mortality or infections during the follow-up period; rather, there appeared to be a decrease in adverse events with the shorter course of antibiotics. However, the study was not powered to detect statistically significant changes in patient-important outcomes such as mortality. The population only included 4 deaths in 157 patients, which is lower than other observational studies of patients with febrile neutropenia.

Guidelines

IDSA Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer (2010): [1]

  • With unexplained febrile neutropenia, empiric antibiotics are traditionally continued until the absolute neutrophil count is greater than 500 cells/mm3 (B-II).
  • Alternatively, following an appropriate course of treatment with clinical resolution of infection, then patients who continue to be neutropenic may use oral fluoroquinolone prophylaxis until marrow recovery (C-III).

ESMO Clinical Practice Guidelines: Management of febrile neutropaenia (2016): [2]

  • Antibiotics should be continued until they have been afebrile for 5-7 days assuming that they have no complications, or, if the patient is high risk (acute leukemia or high-dose chemotherapy), antibiotics should be continued for up to 10 days or until the absolute neutrophil count is ≥0.5 × 109/l (II A).

Design

  • Open-label, multicenter, randomised controlled trial
  • N=157 patients
    • Experimental group (stop at 72 hours of clinical stability) (n=78)
    • Control group (continue until neutrophil recovery) (n=79)
  • Setting: six public academic hospitals in Spain
  • Enrollment: April 10, 2012, to May 31, 2016
  • Mean follow-up: 28 days from beginning of empiric antibiotics
  • Analysis: intention-to-treat
  • Primary outcome: the number of empiric antimicrobial therapy-free days

Population

Inclusion Criteria

  • Adult patients (≥18 years) admitted to the hematology ward of any of the participating centers
  • Any of the following diagnoses: acute leukemia, lymphoproliferative disease, multiple myeloma, myelodysplastic syndrome, bone marrow aplasia and autologous or allogeneic hematopoietic stem cell transplantation
  • High-risk febrile neutropenia, with expected duration of neutropenia ≤0.5x10E9/L of more than 7 days, without etiologic (microbiological) diagnosis, including clinically documented infection or unexplained fever
  • Signed informed consent form
  • Patients who have not previously participated in this trial or, if so,whose final visit took place at least one month before the new inclusion.

Exclusion Criteria

  • Fever with etiologic diagnosis, including an infection with microbiological diagnosis and fever with non-infectious etiology (e.g. transfusion or drug-related, graft-versus-host disease, or underlying disease)
  • History of epilepsy
  • History of tendon disorders related to fluoroquinolones
  • Pregnancy or breastfeeding
  • HIV infection
  • Renal dysfunction with creatinine clearance less than 30 mL/min
  • Patients receiving CYP3A5 substrates (e.g. ergot alkaloids, terfenadine, astemizole, cisapride, pimozide or quinidine, rifampin, carbamazepine, phenobarbital, high doses of ritonavir, or St. John's wort)

Baseline Characteristics

From the experimental group:

  • Age: 52 years
  • Sex: 54%
  • Hematologic disease and treatment
    • Acute leukemia: 51% (39% in control)
      • Induction/reinduction: 31%
      • Other chemotherapy: 10%
      • Autologous HSCT: 4%
      • Allogeneic HSCT: 6%
    • Lymphoma: 29% (37% in control)
      • Chemotherapy: 6%
      • Autologous HSCT: 22%
      • Allogeneic HSCT: 2%
    • Chronic lymphocytic leukemia: 3%
      • Chemotherapy: 3%
    • Multiple myeloma: 9% (18% in control)
      • Chemotherapy: 0%
      • Autologous HSCT: 8%
      • Allogeneic HSCT: 1%
    • Myelodysplastic syndrome: 3%
      • Allogeneic HSCT: 3%
    • Other diagnosis: 5%
      • Chemotherapy: 1%
      • Autologous HSCT: 4%
    • By treatment
      • Chemotherapy or immunosuppression: 50% (39% in control)
      • Autologous HSCT: 37% (54% in control)
      • Allogeneic HSCT: 12% (6% in control)
  • Clinical focus of fever
    • Unknown: 40%
    • Oral mucositis: 18%
    • Abdominal: 19%
    • Pulmonary: 9%
    • Perianal: 3%
    • Other: 14%
  • Median duration of neutropenia: 14 days

Interventions

All patients were started on antipseudomonal EAT according to local protocols. In the experimental group, antimicrobials were stopped once the patient met all criteria for 72 hours: resolution of fever, resolution of signs and symptoms of infection, and normal vital signs. In the control group, patients were also required to have a neutrophil count greater than 0.5 × 109 cells/L before antimicrobials were stopped.

Outcomes

Primary Outcome

EAT-free days
16.1 days (SD 6.3) vs. 13.6 days (SD 7.2) (absolute difference of -2.4 days; 95% CI -4.6 to -0.3; P 0.026)

Secondary Outcomes

Safety endpoints
Crude mortality: 1 death vs. 3 deaths (P 0.62)
Days of fever: 5.7 days vs. 6.3 days (P 0.53)
Infections by end of follow-up
Bacterial infections: 39% vs. 46%
Viral infections: 17% vs. 11%
Fungal infections: 22% vs. 37%

Adverse Events

Serious adverse events
All serious adverse events: 14% vs. 34%
Non-infectious adverse events: 5% vs 14%
Infectious adverse events: 9% vs. 20%
Specific adverse events of note
Mucositis: 36% vs. 25%
Diarrhea: 29% vs. 30%
Nausea and vomiting: 26% vs. 28%
Fatigue: 23% vs. 15%
Cough: 14% vs. 9%
Acute kidney injury: 4% vs. 8%

Criticisms

  • A single center recruited 83% of the patients, possibly limiting its external validity.
  • By necessity, it used an open-label design, although allocation concealment was maintained.
  • EAT-free days as an outcome may not be important to patients.
  • The trial was not powered to detect an effect on mortality.

Funding

Publicly funded by the Spanish Ministry of Economy, Industry and Competitiveness, with support from other Spanish and European public institutions.

Further Reading

  1. Freifeld AG, et al. "Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America". Clinical Infectious Diseases. 2011;52(4):e56-93.
  2. Klastersky J, et al. "Management of Febrile Neutropaenia: ESMO Clinical Practice Guidelines". Annals of Oncology. 2016;27(suppl 4):v111-v118.