Febrile neutropenia primary prevention

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Synonyms and keywords: F and N; fever and neutropenia; FN; hot and low; hot leuk; neutropenic fever; neutropenic fever syndrome; neutropenic sepsis

Overview

According to the NCCN Overall Infection Risk Categories, antimicrobial prophylaxis with fluoroquinolones may be considered in intermediate-risk or high-risk patients. Antifungal, antiviral, and anti-Pneumocystis jirovecii prophylaxis should be initiated in a targeted populations based upon the history, comorbidity, and serology.

Primary Prevention

Table 4. Antimicrobial Prophylaxis for Cancer-Related Infections
Low Risk
Bacterial - None Fungal - None Viral - None except positive HSV serology
Intermediate Risk
Bacterial - Consider fluoroquinolone prophylaxis Fungal - Consider antifungals during neutropenia and for anticipated mucositis Viral - During neutropenia and at least 30 days after HSCT
High Risk
Bacterial - Consider fluoroquinolone prophylaxis Fungal - Consider antifungals during neutropenia and for anticipated mucositis Viral - During neutropenia and at least 30 days after HSCT; also consider pre-emptive therapy against CMV or HBV
Table 5. Antifungal Prophylaxis in Patients with Cancer
Disease/Therapy ALL AML MDS Autologous HSCT with mucositis Allogenic HSCT GVHD	Antifungal prophylaxis Fluconazole Posaconazole Posaconazole Fluconazole or micafungin Fluconazole or micafungin Posaconazole

Low risk for infectious complications

Antimicrobial prophylaxis is not routinely recommended in these patients. Antiviral agents may be considered in low risk patients with prior HSV episodes (Table 4).

Intermediate risk for infectious complications

For the intermediate risk patients, antibacterial prophylaxis with fluoroquinolones should be considered. Herpes simplex virus prophylaxis should be given during periods of neutropenia, and for autologous HSCT recipients, until at least 30 days following transplant. Prophylaxis for varicella zoster virus should be maintained for at least 1 year after HSCT. Antifungals may be considered during periods of neutropenia and for anticipated mucositis for intermediate risk patients.

High risk for infectious complications

For the high risk patients, antibacterial prophylaxis with fluoroquinolones should be considered. Herpes simplex virus prophylaxis should be given during periods of neutropenia, and for autologous HSCT recipients, until at least 30 days following transplant. Prophylaxis for varicella zoster virus should be maintained for at least 1 year after HSCT. Antifungals may be considered during periods of neutropenia for ALL, AML/MDS, allogeneic HSCT recipients, or patients with significant GVHD receiving immunosuppressive therapy. In addition, allogeneic HSCT recipients, patients with ALL, and patients treated with alemtuzumab are all at increased risk for infection with Pneumocystis jirovecii.

Antibacterial Prophylaxis

Levofloxacin (500-750 mg oral or IV daily) significantly reduce episodes of fever and the number of documented infections, particularly gram-negative bacillary infections, among high-risk patients with cancer expected to develop profound neutropenia >7 days in duration. The NCCN Guidelines advise that fluoroquinolone prophylaxis (levofloxacin is preferred) be considered in patients with an expected duration of neutropenia (ANC <1000 cells/mm³) for more than 7 days. This is in agreement with the recommendations of the IDSA guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Among patients with neutropenia who are at lowe risk of infectious complications, the main benefit of antibacterial prophylaxis is a reduction in fever rather than in documented infections.

According to the NCCN guidelines, prophylaxis for pneumococcal infection with penicillin should be initiated 3 months after HSCT and be continued until at least 1 year following transplant regardless of prior administration of pneumococcal vaccines. Prophylaxis should be continued in patients with chronic GVHD until immunosuppressive therapy has been discontinued.

Antifungal Prophylaxis

The rationale for antifungal prophylaxis is to prevent fungal infections in a targeted group of high-risk patients (Table 5). Therapeutic drug monitoring (TDM) for the pharmacokinetic evaluation is generally recommended for patients receiving triazoles other than fluconazole. Currently, there is no sufficient evidence to support the use of TDM for the evaluation of polyenes or echinocandins.

Antiviral Prophylaxis

Herpes Simplex Virus

Herpes simplex virus (HSV) prophylaxis should be administered in patients with positive serology undergoing chemotherapy for acute leukemia during the period of neutropenia and in patients receiving hematopoietic stem cell transplantation (HSCT) for at least 30 days. A longer duration of pre-emptive therapy may be considered in allogenic HSCT recipients with severe graft-versus-host disease. For patients receiving alemtuzumab-containing regimens, HSV prophylaxis is advised until at least 2 months after completion of therapy or until CD4+ cell counts are 200 cells/mm³ or more, whichever occurs later. Prophylaxis against HSV may also be considered in patients with protracted neutropenia or patients receiving high-dose corticosteroids or fludarabine. Acyclovir or valacyclovir is the initial drug of choice, whereas foscarnet is reserved for resistant strains.

Varicella Zoster Virus

Herpes zoster occurs primarily in patients with defective cell-mediated immunity. Varicella zoster virus (VZV) prophylaxis is advisable for seropositive patients for at least one year after allogenic or autologous HSCT and should be continued if immunosuppressive therapy is administered. Patients undergoing therapy with T-cell–depleting agents such as alemtuzumab or fludarabine should also receive prophylaxis against VZV. In addition, the use of proteasome inhibitors including carfilzomib and bortezomib is associated with a heightened risk for VZV reactivation. Acyclovir, valacyclovir, or famciclovir is generally considered the agent of choice in these settings.

Cytomegalovirus

Cytomegalovirus (CMV) may occur as a primary infection in seronegative patients or result from reactivation in patients with positive serology. Prevention of CMV disease after allogeneic HSCT can be accomplished with use of either prophylactic or preemptive therapy. Prophylactic strategy entails the use of antiviral agents in all allogenic HSCT recipients if either the donor or recipient is seropositive for CMV. Pre-emptive therapy involves active surveillance (i.e., detection of CMV DNA or p65 antigen in the peripheral circulation) and deployment of antiviral agents such as ganciclovir, foscarnet, or cidofovir. CMV surveillance is recommended in allogenic HSCT recipients for at least 6 months after transplantation and in chronic GVHD requiring immunosuppressive therapy and until the CD4+ count is 100 cells/mm³ or more. Patients receiving alemtuzumab therapy should undergo routine surveillance for CMV reactivation and weekly monitoring during therapy and at least 2 months after completion of treatment. Upon confirmation of CMV antigenemia, pre-emptive therapy with valganciclovir, ganciclovir, foscarnet, or cidofovir should be administered for at least 2 weeks and until CMV is undetectable.

Hepatitis B Virus

High risk groups for hepatitis B virus (HBV) infection refer to patients with HBsAg+ serology or with prior resolved HBV infection (HBsAg-, HBsAb+, HBcAb+ serology) or with increasing HBV viral load planned for allogeneic HSCT, anti-CD20, or anti-CD52 monoclonal antibody therapy. In HBsAg+ or HBcAb+ individuals, baseline quantitative PCR for HBV DNA should be obtained. In allogeneic HSCT candidates with active HBV infection, the transplant should be delayed and antiviral therapy should be administered for 3 to 6 months prior to conditioning. Candidates with no active HBV infection should undergo monitoring of HBV DNA with antiviral prophylaxis throughout HSCT procedure and at least 6 to 12 months after transplant. Routine surveillance for HBV DNA and antiviral prophylaxis for at least 6 to 12 months following the last dose of therapy are recommended in HBsAg+ or HBcAb+ patients with hematologic malignancies receiving monoclonal antibodies such as rituximab, ofatumumab, or alemtuzumab. The choice of antiviral agents such as adefovir, entercavir, lamivudine, telbivudine, or tenofovir should be based upon efficacy, resistance, and safety profile.

Prophylaxis for Pneumocystis jirovecii

Antipneumocystis prophylaxis is recommended for allogenic HSCT recipients for at least 6 months and while receiving immunosuppressive therapy. For patients with acute lymphocytic leukemia, prophylactic therapy should be continued throughout antileukemic therapy. Individuals undergoing alemtuzumab treatment should also receive prophylaxis against Pneumocystis jirovecii for a minimum of two months after the last dose and until CD4+ count is greater than 200 cells/mm³. Trimethoprim/sulfamethoxazole (TMP/SMX) is considered as the treatment of choice; atovaquone, dapsone, or pentamidine may be used if the patient cannot tolerate TMP/SMX. Prophylaxis is also advisable in patients receiving concomitant temozolomide and radiotherapy and should be continued until recovery from lymphopenia.

IDSA Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: Recommendations for Antibacterial Prophylaxis

Class A

"1. Levofloxacin and ciprofloxacin have been evaluated most comprehensively and are considered to be roughly equivalent, although levofloxacin is preferred in situations with increased risk for oral mucositis-related invasive viridans group streptococcal infection. A systematic strategy for monitoring the development of fluoroquinolone resistance among gram- negative bacilli is recommended. (Quality of Evidence: II)"

"2. Addition of a gram-positive active agent to fluoroquinolone prophylaxis is generally not recommended. (Quality of Evidence: I)"

"3. Antibacterial prophylaxis is not routinely recommended for low-risk patients who are anticipated to remain neutropenic for <7 days. (Quality of Evidence: III)"

Class B

"1. Fluoroquinolone prophylaxis should be considered for high-risk patients with expected durations of prolonged and profound neutropenia (ANC ≤100 cells/mm3 for >7 days). (Quality of Evidence: I)"

IDSA Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: Recommendations for Antifungal Prophylaxis

Class A

"1. Empirical antifungal therapy and investigation for invasive fungal infections should be considered for patients with persistent or recurrent fever after 4–7 days of antibiotics and whose overall duration of neutropenia is expected to be <7 days. (Quality of Evidence: I)"

"2. In low-risk patients, the risk of invasive fungal infection is low, and therefore routine use of empirical antifungal therapy is not recommended. (Quality of Evidence: III)"

"3. Prophylaxis against Candida infection is recommended in patient groups in whom the risk of invasive candidal infection is substantial, such as allogeneic hematopoietic stem cell transplant (HSCT) recipients or those undergoing intensive remission-induction or salvage-induction chemotherapy for acute leukemia. Fluconazole, itraconazole, voriconazole, posaconazole, micafungin, and caspofungin are all acceptable alternatives. (Quality of Evidence: I)"

"4. Prophylaxis against Aspergillus infection in pre- engraftment allogeneic or autologous transplant recipients. (Quality of Evidence: III)"

"5. Antifungal prophylaxis is not recommended for patients in whom the anticipated duration of neutropenia is <7 days. (Quality of Evidence: III)"

Class C

"1. A mold-active agent is recommended in patients with anticipated prolonged neutropenic periods of at least 2 weeks, or a prolonged period of neutropenia immediately prior to HSCT. (Quality of Evidence: III)"

Class B

"1. Data are insufficient to recommend a specific empirical antifungal agent for a patient already receiving anti- mold prophylaxis, but switching to a different class of anti- mold antifungal that is given intravenously should be considered. (Quality of Evidence: III)"

"2. Preemptive antifungal management is acceptable as an alternative to empirical antifungal therapy in a subset of high- risk neutropenic patients. Those who remain febrile after 4–7 days of broad-spectrum antibiotics but are clinically stable, have no clinical or chest and sinus computed tomography (CT) signs of fungal infection, have negative serologic assay results for evidence of invasive fungal infection, and have no recovery of fungi (such as Candida or Aspergillus species) from any body site may have antifungal agents withheld. Antifungal therapy should be instituted if any of these indicators of possible invasive fungal infection are identified. (Quality of Evidence: II)"

"3. Prophylaxis against invasive Aspergillus infections with posaconazole should be considered for selected patients >13 years of age who are undergoing intensive chemotherapy for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) in whom the risk of invasive aspergillosis without prophylaxis is substantial. (Quality of Evidence: I)"

IDSA Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: Recommendations for Antiviral Prophylaxis

Class A

"1. Herpes simplex virus (HSV)–seropositive patients undergoing allogeneic HSCT or leukemia induction therapy should receive acyclovir antiviral prophylaxis. (Quality of Evidence: I)"

"2. Yearly influenza vaccination with inactivated vaccine is recommended for all patients being treated for cancer. (Quality of Evidence: II)"

"3. Influenza virus infection should be treated with neuraminidase inhibitors if the infecting strain is susceptible. (Quality of Evidence: II)"

Class C

"1. Antiviral treatment for HSV or varicella-zoster virus (VZV) infection is only indicated if there is clinical or laboratory evidence of active viral disease. (Quality of Evidence: III)"

"2. In the setting of an influenza exposure or outbreak, neutropenic patients presenting with influenza-like illness should receive treatment empirically. (Quality of Evidence: III)"

Class B

"1. Respiratory virus testing (including testing for influenza, parainfluenza, adenovirus, respiratory syncytial virus [RSV], and human metapneumovirus) and chest radiography are indicated for patients with upper respiratory symptoms (eg, coryza) and/or cough. (Quality of Evidence: III)"

"2. Optimal timing of vaccination is not established, but serologic responses may be best between chemotherapy cycles (>7 days after the last treatment) or >2 weeks before chemotherapy starts. (Quality of Evidence: III)"

"3. Routine treatment of RSV infection in neutropenic patients with upper respiratory disease should not be given. (Quality of Evidence: III)"

IDSA Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: Recommendations for Adjunctive Therapy

Class A

"1. Prophylactic use of myeloid colony-stimulating factors (CSFs; also referred to as hematopoietic growth factors) should be considered for patients in whom the anticipated risk of fever and neutropenia is ≥20%. (Quality of Evidence: II)"

Class B

"1. CSFs are not generally recommended for treatment of established fever and neutropenia. (Quality of Evidence: II)"