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 This is an original JCO publication from 2013. Please visit the JCO website to access the full article.


Antimicrobial Prophylaxis and Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy


 

 Authors
Christopher R. Flowers, Jerome Seidenfeld, Eric J. Bow, Clare Karten, Charise Gleason, Douglas K. Hawley, Nicole M. Kuderer, Amelia A. Langston, Kieren A. Marr, Kenneth V.I. Rolston, and Scott D. Ramsey

BOTTOM LINE

 

 

Interventions

  • Antibacterial and/or antifungal prophylaxis for afebrile outpatients with neutropenia from treatment for malignancy
  • Identification of oncology outpatients with fever and neutropenia (FN) at low risk for medical complications
  • Initial empiric therapy in the outpatient setting to treat FN in patients at low risk for medical complications

 

Target Audience

  • Medical oncologists, primary care physicians, and oncology nurses

 

Key Recommendations

  • Only use antibacterial and antifungal prophylaxis if neutrophils are expected to remain < 100/ µL for > 7 days, unless other factors (see text and Table 2) increase risks for complications or mortality
  • An oral fluoroquinolone is preferred for antibacterial prophylaxis and an oral triazole for antifungal prophylaxis
  • Interventions such as footwear exchange, protected environments, respiratory or surgical masks, neutropenic diet, or nutritional supplements are not recommended because evidence is lacking of clinical benefits to patients from their use
  • Assess risk for medical complications in patients with FN using the Multinational Association for Supportive Care in Cancer (MASCC) score (see Table 3) or Talcott’s rules; score > 21 or Talcott’s group 4 with no other risk factors (see text and Table 4) defines low risk
  • An oral fluoroquinolone plus amoxicillin/clavulanate (or plus clindamycin for those with penicillin allergy) is recommended for initial empiric therapy, unless fluoroquinolone prophylaxis was used before fever developed (see text for alternatives)

 

Methods

  • An Expert Panel was convened to develop clinical practice guideline recommendations based on a review of evidence from a systematic review of the medical literature.

 

Additional Information

The complete guideline along with Data Supplements, including evidence tables, and clinical tools and

resources can be found at www.asco.org/guidelines/outpatientfn.

 

 

SUMMARY OF RECOMMENDATIONS

 

 

Clinical Question

Recommendations

A.  What interventions are appropriate to prevent infections in oncology patients who have received chemotherapy as inpatients or outpatients, and who are, or are anticipated to become, neutropenic as outpatients?

A-1.  How should risk of developing a febrile neutropenic episode (FNE) be assessed in such patients who are not yet febrile? What clinical characteristics identify patients who should be offered antimicrobial prophylaxis?

Recommendation A-1:  Since evidence to address this question was unavailable from trials limited to outpatients, the Panel considered evidence from studies on inpatients or mixed populations, and recommends the following, based on such evidence and members’ expert opinion.

A-1a. FNE risk should be systematically assessed (in consultation with infectious disease specialists as needed) including patient-related, cancer-related, and treatment-related factors (see Table 2).  G-CSF prophylaxis should be used before neutropenia develops for patients who meet criteria specified  in  ASCO’s WBC growth factors guideline.

A-1b. Clinicians should consider antibacterial prophylaxis only for patients expected to experience profound neutropenia (defined as ANC <100/µL) likely to last for ≥7 days.  The Panel does not recommend routine antibacterial prophylaxis if neutropenia is less severe or of shorter duration, the usual course with current chemotherapy regimens for solid tumors.  Thus, the Panel does not recommend routine use of antibacterial prophylaxis for patients with solid tumors undergoing conventional chemotherapy with or without biologics (e.g., trastuzumab, bevacizumab, or cetuximab).

A-1c. Limit antifungal prophylaxis (for decreasing invasive fungal infections (IFI) due to opportunistic yeast or mold species) to patients receiving chemotherapy expected to cause profound neutropenia (ANC <100/µL) for ≥7 days which confers substantial risk (>6-10%) for IFI.  Antifungal prophylaxis is not recommended for patients with solid tumors receiving conventional-dose chemotherapy with or without biologics (e.g., trastuzumab, bevacizumab, or cetuximab).

A-1d. Patients receiving chemotherapy regimens associated with >3.5% risk for pneumonia due to Pneumocystis jirovecii  (e.g., those with ≥20 mg of prednisone equivalents daily for ≥1 month, or those based on purine analogs) are eligible for prophylaxis.

A-1e. Antiviral prophylaxis should be considered for patients known to be at substantial risk for reactivation of hepatitis B virus (HBV) infection.

A-1f. Prophylaxis to prevent reactivation of infection due to Herpesviruses (Herpes simplex virus or Herpes zoster virus) is recommended for seropositive patients undergoing therapy for certain hematologic malignancies (see details in text).

A-1g. Seasonal influenza immunization is recommended for all patients receiving chemotherapy for malignancy, and for all family and household contacts.

A-2.  What antimicrobial drug classes should be used to prevent infection in afebrile neutropenic outpatients who should be offered prophylaxis?

Recommendation A-2:  Since evidence to address this question was unavailable from trials limited to outpatients, the Panel considered evidence from studies on inpatients or mixed populations, and recommends the following based on such evidence and members’ expert opinion.

A-2a. Antibacterial prophylaxis should use an orally administered, systemically absorbed fluoroquinolone, to prevent invasive infection by Gram-negative bacilli of outpatients with profound neutropenia expected for ≥7 days associated with severe mucositis (e.g., from primary or salvage remission-induction therapy for acute leukemia, dose-intensive post-remission consolidation for acute leukemia, or hematopoietic stem cell transplantation).  Prophylaxis may be less effective in environments where >20% of Gram-negative bacilli are resistant to fluoroquinolones.

A-2b. Use an orally-administered triazole antifungal or an echinocandin parenterally-administered in the outpatient setting as prophylaxis against opportunistic yeast infection of those with profound neutropenia and mucositis expected to last for ≥7 days in environments with >10% risk of invasive Candida infection.  A mold-active triazole is recommended in environments with a substantial risk (>6%) for invasive aspergillosis.

A-2c. Prophylaxis with trimethoprim-sulfamethoxazole should only be used if risk for pneumonia due to Pneumocystis jirovecii is >3.5% (e.g., patients given regimens with ≥20 mg of prednisone equivalents daily for ≥1 month, or those based on purine analogs).  Additional details and alternatives for patients with sulfa-based hypersensitivities are provided in the text.

A-2d. Lamivudine is recommended as prophylaxis in patients at substantial risk for reactivation of HBV infection.

A-2e. A nucleoside analog is recommended to prevent herpesvirus infection in those at risk.

A-2f.  Influenza immunization should utilize trivalent inactivated vaccine.  In select circumstances following proven exposure of a susceptible cancer patient, a neuraminidase inhibitor (e.g., oseltamivir, zanamivir) may be offered.

A-3.  What additional precautions are appropriate to prevent exposure of neutropenic but afebrile outpatients with a malignancy to infectious agents or organisms?

Recommendation A-3:  Since direct evidence was unavailable from randomized trials, the Panel considered evidence from uncontrolled and retrospective studies and based the following recommendations on such evidence and members’ expert opinion.

 

A-3a. All healthcare workers should follow hand hygiene guidelines including handwashing practices to reduce exposure through contact transmission, and respiratory hygiene/cough etiquette guidelines to reduce exposure through droplet transmission.

 

A-3b. Outpatients with neutropenia due to cancer therapy should avoid prolonged contact with environments that have high concentrations of airborne fungal spores (e.g., construction and demolition sites).

 

A-3c. None of the following measures are routinely necessary to prevent infection of afebrile outpatients with a malignancy and neutropenia: protected environments (HEPA filters with or without laminar air flow); respiratory or surgical masks (to prevent invasive aspergillosis); footwear exchange at entry and exit; and the “neutropenic diet” or similar.   nutritional interventions.  Gowning and gloving should be only be considered in accordance with local Infection Prevention and Control practices for antibiotic-resistant organisms such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, or extended-spectrum ß-lactamase-producing and carbapenemase-producing Gram-negative bacilli.

B.    Which oncology patients with fever and neutropenia are appropriate candidates for outpatient management?

B-4.  What clinical characteristics should be used to select patients for outpatient empiric therapy?

Recommendation B- 4: Since medical complications occurred in up to 11% of patients identified as low-risk for medical complications of FN in studies validating risk indices or scoring systems, the Panel considers inpatient treatment the standard approach for managing an FNE.  However, outpatient management may be acceptable for carefully selected patients.  When considering a patient with an FNE for outpatient management, the Panel recommends beginning the evaluation with a systematic risk assessment using a validated index.  The Multinational Association for Supportive Care in Cancer (MASCC) risk index (Table 3) has been evaluated most thoroughly of the available risk indices for adults; Talcott’s rules have also been validated in prospective studies.  However, the FNE should be managed in the hospital if the clinician has any reservations with respect to an index’s accuracy for an individual, even if the patient is classified as low risk (MASCC score ≥21 or Talcott Group 4).  Table 4 lists additional factors to take into account when assessing risk for medical complications in the setting of outpatient FNE management.  Patients meeting any of the criteria listed in Table 4, those with MASCC score <21, or those in Talcott Groups 1-3 should not be managed as outpatients.  Moreover, neither a currently available risk index nor the criteria in Table 4 should substitute for clinical judgment when deciding whether or not a given patient with FNE should be admitted to the hospital for inpatient management.

B-5.  Should outpatients with fever and neutropenia at low-risk for medical complications receive their initial dose(s) of empiric antimicrobial(s) in the hospital or clinic and be observed, or can some selected for outpatient management be discharged immediately after evaluation?

Recommendation B-5:  The duration of observation before outpatients were discharged varied considerably among studies that directly compared inpatient versus outpatient empiric therapy or oral versus IV regimens in outpatients.  Lacking evidence from direct comparisons, the Panel relied on members’ expert opinion to recommend that the first dose of empiric therapy be administered within 1 hr after triage from initial presentation in the clinic, emergency room, or hospital department, after fever has been documented in a neutropenic patient and pre-treatment blood samples have been drawn.  Similarly, the Panel recommends that patients identified as low risk and selected for outpatient management be observed for at least 4 hr before discharge, to verify they are stable and can tolerate the regimen they will receive.

B-6.  What psychosocial and logistical requirements must be met to permit outpatient management of patients with fever and neutropenia?

Recommendation B-6:  Since direct comparative evidence was unavailable for any of these factors, the Panel relied on members’ expert opinion to recommend that an oncology patient with fever and neutropenia during or after chemotherapy should meet each of the following criteria to receive empiric therapy as an outpatient:

  1. residence ≤1 hour or ≤30 miles (48 km) from clinic or hospital;
  2. patient’s primary care physician or oncologist agrees to outpatient management;
  3. able to comply with logistical requirements, including frequent clinic visits;
  4. family member or care giver at home 24 hours each day;
  5. 24-hour a day access to a telephone and transportation;
  6. no prior history of non-compliance with treatment protocols.

C.  What interventions are indicated for oncology patients with an FNE who can be managed as outpatients?

C-7.  What diagnostic procedures are recommended?

Recommendation C-7:  Based on members’ expert opinion, the Panel recommends that in the absence of an alternative explanation, fever in a patient with neutropenia from cancer therapy should be assumed to be due to a bacterial infection.  The initial diagnostic approach should maximize the chances of establishing a clinical and microbiologic diagnosis that may affect antibacterial choice and prognosis.  The Panel also recommends systematically evaluating the patient to identify the infectious agent and the anatomic focus (see text for details).

C-8.  What antibacterials are recommended for outpatient empiric therapy?

Recommendation C-8:  Patients with cancer, fever, and neutropenia and at low risk for medical complications by criteria of Recommendation B-4, may be given oral empiric therapy with a fluoroquinolone (ciprofloxacin or levofloxacin) plus amoxicillin/clavulanate (or plus clindamycin for those with penicillin allergy).  However, a fluoroquinolone is not recommended for initial empiric therapy of neutropenic cancer patients who develop fever

after receiving fluoroquinolone-based antibacterial prophylaxis, or in environments where the prevalence of fluoroquinolone resistance is >20%.  For these patients, and if deemed appropriate by the treating physician, intravenous therapy is recommended with a regimen suitable for outpatient administration, provided they meet clinical and other criteria for outpatient management (see Recommendations B-4 & C-9).

 

Hospitalized stable and responding low-risk patients receiving intravenously administered initial empiric antibacterial therapy, particularly those classified as having unexplained fever and neutropenia, may be considered for stepdown to an orally administered regimen and early discharge for outpatient follow-up and monitoring.

 

For patients with fever and neutropenia from cancer therapy who are at high risk for medical complications, the Panel recommends hospitalization for intravenous antimicrobial therapy and endorses the most recent (2010) recommendations from IDSA.12

C-9.  What additional measures are recommended for outpatient management?

Recommendation C-9:  The literature review did not identify any studies comparing outcomes of outpatient management for patients with fever and neutropenia with or without specific logistical measures, or with different frequencies of contact or evaluation.  Based on members’ expert opinion, the following are recommended as prudent and sensible measures for outpatient management:

  1. frequent evaluation for at least 3 days, in clinic or at home;
  2. daily or frequent telephone contact to verify (by home thermometry) that fever resolves;
  3. monitoring of ANC and platelet count for myeloid reconstitution;
  4. frequent return visits to clinic.
  5. Patients should be evaluated for admission to the hospital if any of the following occur:  persistent neutropenic fever syndrome; fever recurs; new signs or symptoms of infection appear; use of oral medications are no longer possible or tolerable; a change in the empiric regimen or an additional antimicrobial drug becomes necessary; microbiologic tests identify species not susceptible to initial regimen.

C-10. How should the persistent neutropenic fever syndrome (PNF) be managed?

Recommendation C-10:  Low-risk patients who fail to defervesce after 2-3 days of an initial empirical broad-spectrum antibiotic regimen should be re-evaluated to detect and treat a new or progressing anatomical site of infection and considered for hospitalization.

Abbreviations:  ANC, absolute neutrophil count; ASCO, American Society of Clinical Oncology; cont., continued; FNE, febrile neutropenic episode; FUO, unexplained fever and neutropenia (also termed fever of unknown origin; G-CSF, granulocyte colony stimulating factor; HBV, hepatitis B virus; HEPA, high efficiency particulate air; IDSA, Infectious Disease Society of America; IFI, invasive fungal infections; IV, intravenous; MASCC, Multinational Association for Supportive Care in Cancer; WBC, white blood cell;

 

 

 

 

 

ASCO Guideline Disclaimer: The clinical practice guidelines and other guidance published herein are provided by the American Society of Clinical Oncology, Inc. (“ASCO”) to assist practitioners in clinical decision making. The information therein should not be relied upon as being complete or accurate, nor should it be considered as inclusive of all proper treatments or methods of care or as a statement of the standard of care. With the rapid development of scientific knowledge, new evidence may emerge between the time information is developed and when it is published or read. The information is not continually updated and may not reflect the most recent evidence. The information addresses only the topics specifically identified therein and is not applicable to other interventions, diseases, or stages of diseases. This information does not mandate any particular course of medical care. Further, the information is not intended to substitute for the independent professional judgment of the treating physician, as the information does not account for individual variation among patients. Recommendations reflect high, moderate or low confidence that the recommendation reflects the net effect of a given course of action.  The use of words like “must,” “must not,” “should,” and “should not” indicate that a course of action is recommended or not recommended for either most or many patients, but there is latitude for the treating physician to select other courses of action in individual cases. In all cases, the selected course of action should be considered by the treating physician in the context of treating the individual patient. Use of the information is voluntary.  ASCO provides this information on an “as is” basis, and makes no warranty, express or implied, regarding the information. ASCO specifically disclaims any warranties of merchantability or fitness for a particular use or purpose. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of this information or for any errors or omissions.


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