Antimicrobial Agents in Neutropenic Cancer Patients 

Updated: Sep 16, 2018
  • Author: Alexandre Chan, PharmD, MPH, FCCP, BCPS (AQ-ID), BCOP; more...
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Recommendations

Joint guidelines for the use of antimicrobial agents for prophylaxis and outpatient treatment in neutropenic cancer patients have been issued by the following organizations [1, 2] :

  • American Society of Clinical Oncology (ASCO)
  • Infectious Disease Society of America (IDSA)

Prophylaxis

The ASCO/IDSA guideline recommendations for antimicrobial prophylaxis are as follows [1] :

  • Risk of febrile neutropenia should be systematically assessed, with consideration of patient-related, cancer-related, and treatment-related factors (evidence-based; evidence quality: intermediate; strength of recommendation: strong).

  • Antibiotic prophylaxis with a fluoroquinolone is recommended for patients who are at high risk for febrile neutropenia or profound, protracted neutropenia (eg, most patients with acute myeloid leukemia/myelodysplastic syndromes or hematopoietic stem-cell transplantation [HSCT] treated with myeloablative conditioning regimens) (evidence-based; evidence quality: high; strength of recommendation: moderate).

  • Antibiotic prophylaxis is not routinely recommended for patients with solid tumors (evidence-based; evidence quality: high; strength of recommendation: moderate).

  • Antifungal prophylaxis with an oral triazole or parenteral echinocandin is recommended for patients who are at risk for profound, protracted neutropenia, such as most patients with acute myeloid leukemia/myelodysplastic syndromes  or HSCT. Antifungal prophylaxis is not routinely recommended for patients with solid tumors. Additional distinctions between recommendations for invasive candidiasis and invasive mold infection are provided within the full text of the guideline (evidence-based; evidence quality: intermediate; strength of recommendation: moderate).

  • Prophylaxis (eg, with trimethoprim-sulfamethoxazole [TMP-SMX]) is recommended for patients receiving chemotherapy regimens associated with > 3.5% risk for Pneumocystis jirovecii pneumonia (eg, those with ≥ 20 mg prednisone equivalents daily for ≥ 1 month or those receiving purine analogs) (evidence-based; evidence quality: high; strength of recommendation: strong).

  • Herpes simplex virus–seropositive patients undergoing allogeneic HSCT or leukemia induction therapy should receive prophylaxis with a nucleoside analog (eg, acyclovir) (evidence-based; evidence quality: high; strength of recommendation: strong).

  • Treatment with a nucleoside reverse transcription inhibitor (eg, entecavir or tenofovir) is recommended for patients who are at high risk of hepatitis B virus reactivation (consensus based; evidence quality: intermediate; strength of recommendation: moderate.)

  • Yearly influenza vaccination with inactivated vaccine is recommended for all patients receiving chemotherapy for malignancy and all family and household contacts and health care providers (consensus based; evidence quality: intermediate; strength of recommendation: moderate.)

  • The Expert Panel also supports other vaccination recommendations for immunosuppressed adult oncology patients that are contained in the IDSA guideline for vaccination of the immunosuppressed host [3]  (consensus based; evidence quality: intermediate; strength of recommendation: moderate).

Treatment

The ASCO/IDSA guideline recommendations for outpatient management of fever and neutropenia in adult cancer patients are as follows:

  • In the absence of an alternative explanation, clinicians should assume that fever in a patient with neutropenia from cancer therapy is the result of an infection. 
  •  Fever in neutropenic patients is defined as a single oral temperature of ≥ 38.3°C (101°F) or a temperature of ≥ 38.0°C (100.4°F) sustained over 1 hour.
  • Patients who present with febrile neutropenia within 65 weeks after receiving chemotherapy should be assessed within 15 minutes after triage.

Recommended tests and procedures for the initial assessment (consensus based; evidence quality: low; strength of recommendation: moderate) include the following:

  • Complete blood cell count (CBC) with differential, hemoglobin, and platelet count;
  • Serum creatinine and blood urea nitrogen (BUN)
  • Electrolyte levels
  • Serum lactate
  • Liver function tests (total bilirubin, alkaline phosphatase, transaminases)
  • At least two sets of blood cultures, with samples taken from different sites 
  • Cultures from suspected infection sites (eg, urine, lower respiratory tract, CSF, stool, wounds)
  • Chest imaging study for patients with clinical manifestations of lower respiratory tract infection
  • Patients with a flulike illness in the setting of seasonal community-acquired respiratory illnesses should have a nasopharyngeal swab obtained for detection of influenza. In some of these cases (eg, patients with hematologic malignancy and hematopoietic stem cell transplantation [HSCT], strong consideration should be given to obtaining expanded viral panels for detection of additional respiratory viruses: influenza virus, parainfluenza virus, adenovirus, coronavirus, respiratory syncytial virus, human metapneumovirus, enteroviruses, and rhinovirus.

Risk stratification is required to determine the management of patients with fever and neutropenia, including the route of antibiotic therapy (oral vs. IV), its duration, and the choice of inpatient or outpatient care. Widely accepted indications of high risk include either or both of the following:

  • Chemotherapy-related neutropenia that is expected to be prolonged (duration > 7 days) and profound (absolute neutrophil count [ANC] < 100 cells/μL
  • Significant  medical co-morbid conditions  (eg, hypotension, pneumonia, new-onset abdominal pain, neurologic changes)

Risk assessment recommendations are as follows:

  •   The Multinational Association for Supportive Care in Cancer (MASCC) scoring system or Talcott's rules can be used for a formal assessment of risk; a MASCC score < 21 indicates high risk
  • Clinical judgment should be used when selecting candidates for outpatient management. Patients with significant co-morbidity may not be candidates for outpatient treatment, even if their MASCC score is ≥ 21.
  • In patients with solid tumors who have undergone mild- to moderate-intensity chemotherapy, who appear to be clinically stable, and who are in close proximity to an appropriate medical facility that can provide 24-hour access, the Clinical Index of Stable Febrile Neutropenia (CISNE) may be used as an additional tool to determine the risk of major complications.
  • Patients infected with fluoroquinolone-resistant, gram-negative pathogens that are also coresistant to β-lactams/cephalosporins should receive inpatient treatment with a carbapenem-based regimen that likely requires multiple doses per day.

  • Patients colonized with, or suspected of having methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococcus (VRE) , or Stenotrophomonas maltophilia infection should be considered as candidates for inpatient management.

  • Patients undergoing HSCT or induction therapy for acute leukemia are unlikely to be appropriate candidates for outpatient therapy.

  • Patients whose degree of risk has not yet been determined to be high or low within 1 hour after triage should receive an initial IV dose of therapy while undergoing evaluation

The guidelines also include the following consensus-based recommendations regarding psychosocial and logistic requirements:that patients must meet to be eligible for discharge and outpatient management: 

  • Residence ≤ 1 hour or ≤ 30 miles (48 km) from clinic or hospital
  • Patient’s primary care physician or oncologist agrees to outpatient management
  • Able to comply with logistic requirements, including frequent clinic visits
  • Family member or caregiver at home 24 h/d
  • Access to a telephone and transportation 24 h/d
  • No history of noncompliance with treatment protocols

Antibiotic agents

Recommendations are as follows:

  • Monotherapy with an antipseudomonal β-lactam agent, such as cefepime, a carbapenem (eg, meropenem or imipenem-cilastatin), or piperacillin-tazobactam
  • Other antimicrobials (eg, aminoglycosides, fluoroquinolones, vancomycin) may be added for management of complications (eg, hypotension, pneumonia) or if antimicrobial resistance is suspected or proven.
  • Vancomycin (or other agents active against aerobic gram-positive cocci) is not recommended as a standard part of the initial antibiotic regimen for fever and neutropenia; such agents should be considered for specific clinical indications, including suspected catheter-related infection, skin or soft-tissue infection, pneumonia, or hemodynamic instability.

Early addition of the following modifications to initial empirical therapy may be considered for patients at risk for infection with antibiotic-resistant organisms, particularly if the patient’s condition is unstable or if the patient has positive blood-culture results suspicious for resistant bacteria (consensus based; evidence quality: low;  strength of recommendation: strong):

  • MRSA - Vancomycin, linezolid, or (if there is no evidence of pneumonia) daptomycin
  • VRE - Llinezolid or daptomycin.○ESBLs: Consider early use of a carbapenem.
  • Extended-spectrum β-lactamase (ESBL)–producing gram-negative bacteria - Carbapenem
  • Carbapenemase-producing organisms, including  Klebsiella pneumoniae carbapenemase KPCs: Polymyxin-colistin or tigecycline, or a newer β-lactam with activity against resistant gram-negative organisms 

Patients should be observed for ≥ 4 hours before discharge. Patients with febrile neutropenia who are at low risk of medical complications, in whom fever is responding to inpatient IV empirical antibiotic treatment, and hwo remain clinically stable, are considered eligible for transition to an outpatient regimen.

Follow-up

The following additional measures are also recommended:

  • Frequent evaluation for at least 3 days in clinic or at home
  • Daily or frequent telephone contact to verify (by home thermometry) that fever resolves
  • Monitoring of ANC and platelet count for myeloid reconstitution
  • Frequent return visits to clinic

Patients who are undergoing outpatient management should be evaluated for admission to the hospital if any of the following occur:

  • Failure to defervesce after 2 to 3 days of an initial, empirical, broad-spectrum antibiotic regimen
  • Fever recurrence after a period of defervescence
  • New signs or symptoms of infection
  • Use of oral medications is no longer possible or tolerable
  • Change in the empirical regimen or an additional antimicrobial drug becomes necessary
  • Microbiologic tests identify species not susceptible to the initial regimen
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