Febrile neutropenia

Resident Survival Guide

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

Febrile neutropenia is a condition characterized by a decrease in neutrophils (neutropenia) associated with the development of fever, the latter indicating the presence of an infection. The majority of patients have no identifiable site of infection and no positive culture results. Nonetheless, urgent treatment with empirical antibiotics is recommended in light of the possibility of rapid progression.

Historical Perspective

In 1966, Bodey et al. first described the quantitative association between leukocyte counts and the incidence of infection in a study of acute leukemia which demonstrated that the risk and the type of infection are related to the severity and duration of granulocytopenia. Infection risk begins to increase when the absolute neutrophil count (ANC) decreases to less than 1000 cells/mm³ and rises markedly when the ANC drops to less than 500 cells/mm³. When the causative pathogen is identifiable, bacterial or viral etiology predominates within the first seven days of neutropenic fever, while infection with antibiotic-resistant bacteria or invasive fungi occurs more often in the setting of protracted neutropenia.

Pathophysiology

A number of factors pose an increased risk for infections in cancer patients:

• Absolute or functional leukopenia

Leukocytes, particularly neutrophils, constitute one of the front-line defense mechanisms against invading microorganisms. Chemotherapy is associated with both qualitative and quantitative deficits in circulating neutrophils by lowering neutrophil counts and impairing chemotaxis and phagocytosis, respectively.

• Altered microbiota

Microbiota that inhabit the skin, respiratory tract, and digestive tract may be altered by cancer and its treatment or the use of antibiotics.

• Breaches of natural barriers

Mucositis may occur as a direct adverse effect of chemotherapy or radiotherapy and disrupt the barrier function of the endothelial lining. Indwelling catheters and implanted devices allow access of skin commensals into blood or subcutaneous tissues or serve as a biofilm which bacteria can colonize. Solid tumors that overgrow their blood supply may undergo necrosis and form a nidus for infection.

• Immune defects associated with specific primary malignancies

Patients with leukemias, non-Hodgkin's lymphoma, or myelodysplastic syndrome may be leukopenic due to malignant infiltration or marrow dysfunction. Absolute or functional hypogammaglobulinemia predisposes patients with chronic lymphocytic leukemia or multiple myeloma to recurrent sinopulmonary infections and septicemia caused by encapsulated pathogens such as Streptococcus pneumoniae and Haemophilus influenza. An increased risk of infection has also been observed in patients with Hodgkin's lymphoma as a result of defective cell-mediated immunity.

• Hyposplenism

Production of opsonizing antibodies takes place in the spleen. Hyposplenism, either as a complication of graft-versus-host disease or irradiation, may contribute to overwhelming infection with encapsulated bacteria.

• Lymphotoxicity

High-dose corticosteroids affect the distribution and function of lymphocytes as well as other immunocytes. Fludarabine, an adenosine analogue, depletes CD4+ lymphocytes and increases the risk of listeriosis, mycobacterial infections, and opportunistic infections. Therapy with alemtuzumab, a humanized monoclonal antibody targeting CD52 on lymphocytes, heightened the risk for a wide variety of infections. In addition, the use of anti-CD20 monoclonal antibodies such as rituximab and ofatumumab has been associated with an escalated risk for hepatitis B virus reactivation.

Causes

Table 1. Common Bacterial Pathogens in Neutropenic Patients
Gram-Positive Pathogens
Coagulase-negative staphylococci Staphylococcus aureus, including methicillin-resistant strains Enterococcus species, including vancomycin-resistant strains Viridans group streptococci Streptococcus pneumoniae Streptococcus pyogenes
Gram-Negative Pathogens
Escherichia coli Klebsiella species Enterobacter species Pseudomonas aeruginosa Citrobacter species Acinetobacter species Stenotrophomonas maltophilia

Bloodstream infections caused by endogenous flora and reactivation of latent infections account for a majority of initial febrile episode in neutropenic patients with cancer. Common bacterial isolates that cause bacteremia in the setting of neutropenia are listed in Table 1. Certain endogenous microorganisms may be reactivated and exit latency during immunosuppression. These include herpes simplex virus, varicella-zoster virus, Epstein-Barr virus, cytomegalovirus, hepatitis B and C viruses, and Mycobacterium tuberculosis. Exogenous pathogens carried by contaminated blood products, medical equipment and devices, water sources, and health care workers represent less common sources of infection. These include Clostridium difficile, respiratory syncytial virus, vancomycin-resistant enterococci, and other multidrug resistant bacteria.

Fungal infections often take place in the setting of prolonged or profound neutropenia after administration of empirical therapy. Candidiasis may range in severity from mucosal or cutaneous infection to septicemia, endocarditis, or disseminated infection. Aspergillus, on the contrary, typically causes life-threatening infection of the sinuses and lungs, particularly after protracted neutropenia.

Epidemiology and Demographics

Approximately 10% to 50% of patients with solid tumors and more than 80% of those with hematologic malignancies will develop fever during courses of cytotoxic chemotherapy. However, an infectious etiology can be established in a minority of patients, and clinically defined infections occur in 20% to 30% of febrile episodes.

Over the past few decades, there has been a shift in the spectrum of bacterial isolates from patients with febrile neutropenia. Gram-negative organisms prevailed in the era when cytotoxic chemotherapy was initially introduced, whereas Gram-positive skin flora including coagulase-negative staphylococci evolved as the most common isolates after widespread use of indwelling catheters and prophylactic antibiotics. In addition, there has been a drift in susceptibility patterns, with resistance seen in the general population of hospitalized patients now emerging in febrile neutropenic patients.

Risk Factors

NCCN Overall Infection Risk Categories

The National Comprehensive Cancer Network (NCCN) devised a set of overall infection risk categories (low, intermediate, and high) in patients with cancer based on factors such as the underlying malignancy, disease status (eg, active disease, disease in remission), duration of neutropenia, prior exposure to chemotherapy, and intensity of immunosuppressive therapies.

Low risk for infectious complications

Patients with solid tumors undergoing standard chemotherapy regimens and who have an anticipated duration of neutropenia less than 7 days are considered at low risk for infectious complications.

Intermediate risk for infectious complications

Intermediate risk refer to patients with an anticipated duration of neutropenia of 7 to 10 days. Patients with lymphoma, multiple myeloma, or CLL; autologous HSCT recipients; or patients receiving treatment with purine analogue-containing regimens are also considered intermediate risk.

High risk for infectious complications

Patients with an anticipated duration of neutropenia longer than 10 days, patients undergoing intensive induction/consolidation therapy for acute leukemias, patients receiving treatment with alemtuzumab-containing regimens, allogeneic HSCT recipients, and those with GVHD following allogeneic HSCT are categorized as high risk for infectious complications.

Complications

Table 2. Medical Complications Considered Serious
Hypotension: systolic blood pressure less than 90 mmHg or need for pressor support to maintain blood pressure Respiratory failure: arterial oxygen pressure less than 60 mmHg while breathing room air or need for mechanical ventilation Intensive care unit admission Disseminated intravascular coagulation Confusion or altered mental state Congestive cardiac failure seen on chest x-ray and requiring treatment Bleeding severe enough to require transfusion Arrhythmia or ECG changes requiring treatment Renal failure requiring investigation and/or treatment with IV fluids, dialysis, or any other intervention Other complications judged serious and clinically significant by the investigator†
† All reviewed by one investigator. Viral or fungal, microbiologically documented primary infection during the febrile episode, without any described complication and resolving under therapy, was considered a part of the infectious process and was not considered a serious complication.

High-risk patients as assessed by clinical judgment criteria or MASCC Risk Index are more likely to develop serious complications of febrile neutropenia including intensive care unit admission, confusion, cardiac complications, respiratory failure, renal failure, hypotension, bleeding, and death (Table 2).

Diagnosis

Diagnostic Criteria

The definitions of fever and neutropenia are used to identify patients in whom empirical antibiotic therapy must be initiated. However, neutropenic patients represent a heterogeneous population and treatment may be considered even when they do not meet these specific criteria. Clinical judgment based on parameters in risk assessment also plays a critical role in tailoring the management.

Fever

Fever is defined as a single oral temperature measurement of ≥38.3°C (101°F) or a temperature of ≥38.0°C (100.4°F) sustained over a 1-hour period.

Neutropenia

Neutropenia is defined as an absolute neutrophil count (ANC) of <500 cells/mm³ or an ANC that is expected to decrease to <500 cells/mm³ during the next 48 hours.

Profound neutropenia

Neutropenia in which the ANC is <100 cells/mm³; a manual reading of the blood smear is required to confirm this degree of neutropenia.

Functional neutropenia

Functional neutropenia refers to patients whose hematologic malignancy results in qualitative defects (impaired phagocytosis and killing of pathogens) of circulating neutrophils. These patients should also be considered to be at increased risk for infection, despite a normal neutrophil count.

Microbiologically defined infection

This can include both

1. bacteremia, either with a single organism or polymicrobial infection, but without a definable nonhematogenous site of infection, and
2. a microbiologically defined site of infection (e.g., pneumonia, cellulitis) with or without concomitant bacteremia.

Clinically defined infection

This is designated when a site of infection is diagnosed (e.g., pneumonia,cellulitis) but its microbiologic pathogenesis either cannot be proven or is inaccessible to examination.

Unexplained fever

In the neutropenic patient, this is defined as a new fever that is not accompanied by either clinical or microbiologic evidence of infection.

History

Pertinent history should include new site-specific symptoms, prior use of antimicrobial agents, potential infection exposures, previous documented infections or pathogen colonization, catheter or device placement, and co-existence of noninfectious causes of fever, such as blood product administration. Underlying co-morbidities, such as diabetes, chronic obstructive lung disease, and/or recent procedures, should also be noted.

Signs and Symptoms

In neutropenic patients, manifestations secondary to inflammation are attenuated and fever is often the only clue indicative of an underlying infection.

Physical Examination

The physical examination should focus on potential sites of infection.

Skin

Induration and erythema may be minimal. Pustule formation are uncommon in the absence of neutrophils.

Throat

Examination of the oropharynx may reveal ulcers or plaques suggestive of herpes or candidiasis. Mucositis owing to cytotoxic chemotherapy may be indistinguishable from herpetic gingivostomatitis.

Lungs

Auscultation of the lungs may reveal minimal adventitial sounds.

Abdomen

Abdominal pain in neutropenic patients may herald an intraabdominal catastrophe secondary to neutropenic enterocolitis or tumor necrosis.

Other

Examination of catheter sites may disclose erythema, tenderness, or discharge.

Laboratory Tests

Complete blood cell count with differential white cell count and levels of serum creatinine and urea nitrogen are required for determining the severity of neutropenia and monitoring potential drug toxicity. These tests should be performed at least every 3 days during the initial course of antibiotic treatment. At least weekly monitoring of transaminase levels is advisable for patients with suspected hepatocellular injury or cholestatic disease. Routine test of inflammation markers, such as C-reactive protein, IL-6, IL-8, or procalcitonin, to guide clinical decisions is not recommended.

At least two sets of blood culture samples, each consisting of ~20 mL of blood divided into 1 aerobic and 1 anaerobic blood culture bottle, should be obtained from both a peripheral vein and from each catheter lumen. In pediatric patients, the total sample limit would be 7 mL for a 10-kg patient and 28 mL for a 40-kg patient. Drawing blood samples from both peripheral vein and catheter may help determine the source of infection. Culture for coagulase-negative staphylococci requires two positive results to be considered a "true positive." After initial defervescence occurs with empirical treatment, any recrudescent fever should be evaluated as a new episode of possible infection.

Stool

A stool specimen in a patient with diarrhea should be evaluated with Clostridium difficile toxin assays. There is limited value in sending a stool specimen for bacterial pathogen cultures or for ova and parasite examination for most patients unless there has been recent travel to or residence in areas of endemicity.

Urine

Culture of urine samples is indicated if signs or symptoms of urinary tract infection exist, a urinary catheter is in place, or the findings of urinalysis are abnormal.

Cerebrospinal Fluid

Examination and culture of the cerebrospinal fluid is indicated if meningitis is suspected. Platelet transfusion may be considered prior to lumbar puncture if thrombocytopenia is a concern.

Skin Biopsy

Biopsy of skin lesions suspected of infection should be performed for Gram staining and culture.

Respiratory Specimens

Sputum samples for routine bacterial culture should be obtained from patients with productive cough. Specimens obtained by bronchoalveolar lavage (BAL) are recommended for patients with a pulmonary infiltrate of uncertain etiology. Polymerase chain reaction testing, rapid antigen testing, or culture on nasal wash or BAL samples should be performed for respiratory viruses (including adenovirus, influenza A and B virus, respiratory syncytial virus, and parainfluenza virus) in patients with suggestive signs or symptoms during the winter season.

Imaging Studies

Chest radiography should be reserved for patients with symptoms of respiratory tract infection. CT scan of the head, sinuses, abdomen, and pelvis may be performed if clinically indicated.

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

Class A

"1. Laboratory tests should include a CBC count with differential leukocyte count and platelet count; measurement of serum levels of creatinine and blood urea nitrogen; and measurement of electrolytes, hepatic transaminase enzymes, and total bilirubin. (Quality of Evidence: III)"

"2. At least 2 sets of blood cultures are recommended, with a set collected simultaneously from each lumen of an existing CVC, if present, and from a peripheral vein site; 2 blood culture sets from separate venipunctures should be sent if no central catheter is present. (Quality of Evidence: III)"

"3. Culture specimens from other sites of suspected infection should be obtained as clinically indicated. (Quality of Evidence: III)"

"4. A chest radiograph is indicated for patients with respiratory signs or symptoms. (Quality of Evidence: III)"

Class C

"1. Blood culture volumes should be limited to <1% of total blood volume (usually ~70 mL/kg) in patients weighing <40 kg. (Quality of Evidence: III)"

Risk Assessment

Table 3. MASCC Risk Index Score
Characteristic Burden of febrile neutropenia with no or mild symptomsa No hypotension (systolic blood pressure >90 mmHg) No chronic obstructive pulmonary diseaseb Solid tumor or hematologic malignancy w/o prior fungal infectionc No dehydration requiring parenteral fluids Burden of febrile neutropenia with moderate symptomsa Outpatient status Age <60 years	Weight 5 5 4 4 3 3 3 2
The maximum value of the score is 26. a Burden of febrile neutropenia refers to the general clinical status of the patient as influenced by the febrile neutropenic episode. It should be evaluated on the following scale: no or mild symptoms (score of 5); moderate symptoms (score of 3); and severe symptoms or moribund (score of 0). Scores of 3 and 5 are not cumulative. b Chronic obstructive pulmonary disease means active chronic bronchitis, emphysema, decrease in forced expiratory volumes, need for oxygen therapy and/or steroids and/or bronchodilators requiring treatment at the presentation of the febrile neutropenic episode. c Previous fungal infection means demonstrated fungal infection or empirically treated suspected fungal infection.

Infectious Diseases Society of America (IDSA) recommends that either the clinical judgment criteria or the MASCC assessment tool can be used to stratify risk for patients presenting with fever and neutropenia. Risk assessment should then inform decisions about the type of regimen and appropriate venue for delivery of empirical antibiotics, as well as the timing of hospital discharge. High-risk patients should initially receive IV empirical antibiotic therapy in the hospital, whereas low-risk patients may be candidates for oral and/or outpatient empirical antibiotic therapy.

Clinical Judgment Criteria

Patients with febrile neutropenia can be stratified at presentation into those with high-risk versus low-risk for complications of severe infection by the clinical judgment criteria as follows:

High-Risk Patient by Clinical Judgment Criteria

Patients with any of the following criteria are considered to be at high risk for serious complications during fever and neutropenia:

• Profound neutropenia (ANC ≤100 cells/mm³) anticipated to extend >7 days
• Presence of any co-morbid medical problems including but not limited to:

— Hemodynamic instability

— Oral or gastrointestinal mucositis that interferes with swallowing or causes severe diarrhea

— Gastrointestinal symptoms, including abdominal pain, nausea and vomiting, or diarrhea

— Neurologic or mental-status changes of new onset d Intravascular catheter infection, especially catheter tunnel infection

— New pulmonary infiltrate or hypoxemia, or underlying chronic lung disease

• Evidence of hepatic insufficiency (defined as aminotransferase levels greater than 5 times of normal values) or renal insufficiency (defined as a creatinine clearance of less than 30 mL/min).

High-risk patients should be hospitalized and receive intravenous empirical antibiotic therapy.

Low-Risk Patient by Clinical Judgment Criteria

Patients with all of the following criteria are considered to be at low risk for serious complications during fever and neutropenia:

• Neutropenia expected to resolve within 7 days
• No active medical co-morbidity
• Stable and adequate hepatic function and renal function.

In general, any patient who does not strictly fulfill criteria for being at low risk should be treated according to guidelines for high-risk patients. Low-risk patients may be candidates for oral and/or outpatient empirical antibiotic therapy.

MASCC Risk Index

The Multinational Association for Supportive Care in Cancer (MASCC) scoring system is a summation of weighted factors, including patient age, history, outpatient or inpatient status, acute clinical signs, the presence of medical comorbid conditions, and severity of fever and neutropenia as assessed by burden of illness. The MASCC Risk Index can be used to identify subgroups of febrile neutropenic patients with high-risk (score <21) or low-risk (score ≥21) for serious complications and death (Table 3). It is also a means to determine which patients require prolonged hospitalization and which may be candidates for oral or once-daily IV regimens and/or for early discharge from the hospital to complete the antibiotic course as outpatients. A fundamental difficulty with the MASCC Risk Index is the indistinct nature of its major criteria: the "burden of febrile neutropenia" and associated symptoms. Without a clear standardized definition of this ‘‘burden’’ of disease, uniform application of the MASCC Risk Index may be confusing.

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

Class A

"1. Assessment of risk for complications of severe infection should be undertaken at presentation of fever. Risk assessment may determine the type of empirical antibiotic therapy (oral vs IV), venue of treatment (inpatient vs outpatient), and duration of antibiotic therapy. (Quality of Evidence: II)"

"2. Most experts consider high-risk patients to be those with anticipated prolonged (>7 days duration) and profound neutropenia (absolute neutrophil count [ANC] ≤100 cells/mm3 following cytotoxic chemotherapy) and/or significant medical co-morbid conditions, including hypotension, pneumonia, new-onset abdominal pain, or neurologic changes. Such patients should be initially admitted to the hospital for empirical therapy. (Quality of Evidence: II)"

"3. Low-risk patients, including those with anticipated brief (≤7 days duration) neutropenic periods or no or few co-morbidities, are candidates for oral empirical therapy. (Quality of Evidence: II)"

Class B

"1. Formal risk classification may be performed using the Multinational Association for Supportive Care in Cancer (MASCC) scoring system. (Quality of Evidence: I) i. High-risk patients have a MASCC score <21. All patients at high risk by MASCC or by clinical criteria should be initially admitted to the hospital for empirical antibiotic therapy if they are not already inpatients. ii. Low-risk patients have a MASCC score ≥21. Carefully selected low-risk patients may be candidates for oral and/or outpatient empirical antibiotic therapy."

Treatment

Generally, patients with febrile neutropenia are treated with empirical antibiotics until the neutrophil count has recovered (Absolute neutrophil counts greater than 500/mm3) and the fever has abated; if the neutrophil count does not improve, treatment may need to continue for two weeks or occasionally more. In cases of recurrent or persistent fever, an antifungal agent should be added.

Guidelines issued in 2002 by the Infectious Diseases Society of America recommend the use of particular combinations of antibiotics in specific settings; mild low-risk cases may be treated with a combination of oral co-amoxiclav and ciprofloxacin, while more severe cases require cephalosporins with activity against Pseudomonas aeruginosa (e.g. cefepime), or carbapenems (imipenem or meropenem). A subsequent meta-analysis published in 2006 found that cefepime was associated with more negative outcomes, and that carbapenems (while causing a higher rate of pseudomembranous colitis) were the most straightforward in use.

In 2010, an updated guidelines was issued by the Infectious Diseases Society of America, recommending use of cefepime, carbapenems (meropenem and imipenem/cilastatin), piperacillin/tazobactam for high risk patients and co-amoxiclav and ciprofloxacin for low risk patients. Patients who do not strictly fulfill the criteria of 'low risk patients' should be admitted to the hospital and treat as high risk patients.

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

Class A

"1. High-risk patients require hospitalization for IV empirical antibiotic therapy; monotherapy with an anti- pseudomonal b-lactam agent, such as cefepime, a carbapenem (meropenem or imipenem-cilastatin), or piperacillin-tazobactam, is recommended. (Quality of Evidence: I)"

"2. 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 (A-I). These agents should be considered for specific clinical indications, including suspected catheter-related infection, skin or soft-tissue infection, pneumonia, or hemodynamic instability. (Quality of Evidence: I)"

"3. Most penicillin-allergic patients tolerate cephalosporins, but those with a history of an immediate-type hypersensitivity reaction (eg, hives and bronchospasm) should be treated with a combination that avoids b-lactams and carbapenems, such as ciprofloxacin plus clindamycin or aztreonam plus vancomycin. (Quality of Evidence: II)"

"4. Low-risk patients should receive initial oral or IV empirical antibiotic doses in a clinic or hospital setting; they may be transitioned to outpatient oral or IV treatment if they meet specific clinical criteria. Ciprofloxacin plus amoxicillin-clavulanate in combination is recommended for oral empirical treatment. (Quality of Evidence: I)"

"5. Patients receiving fluoroquinolone prophylaxis should not receive oral empirical therapy with a fluoroquinolone. (Quality of Evidence: III)"

"6. Hospital re-admission or continued stay in the hospital is required for persistent fever or signs and symptoms of worsening infection. (Quality of Evidence: III)"

"7. Modifications to the initial antibiotic regimen should be guided by clinical and microbiologic data. (Quality of Evidence: II)"

"8. Unexplained persistent fever in a patient whose condition is otherwise stable rarely requires an empirical change to the initial antibiotic regimen. If an infection is identified, antibiotics should be adjusted accordingly. (Quality of Evidence: I)"

"9. Documented clinical and/or microbiological infections should be treated with antibiotics appropriate for the site and for the susceptibilities of any isolated organisms. (Quality of Evidence: I)"

"10. If vancomycin or other coverage for gram-positive organisms was started initially, it may be stopped after 2 days if there is no evidence for a gram-positive infection. (Quality of Evidence: II)"

"11. Patients who remain hemodynamically unstable after initial doses with standard agents for neutropenic fever should have their antimicrobial regimen broadened to include coverage for resistant gram-negative, gram-positive, and anaerobic bacteria and fungi. (Quality of Evidence: III)"

"12. Low-risk patients who have initiated IV or oral antibiotics in the hospital may have their treatment approach simplified if they are clinically stable. An IV-to-oral switch in antibiotic regimen may be made if patients are clinically stable and gastrointestinal absorption is felt to be adequate. (Quality of Evidence: I)"

"13. If fever persists or recurs within 48 h in outpatients, hospital re-admission is recommended, with management as for high-risk patients. (Quality of Evidence: III)"

"14. Empirical antifungal coverage should be considered in high-risk patients who have persistent fever after 4–7 days of a broad-spectrum antibacterial regimen and no identified fever source. (Quality of Evidence: II)"

Class C

"1. KPCs: Consider early use of polymyxin-colistin or tigecycline. (Quality of Evidence: III)"

"2. Alternatively, if an appropriate treatment course has been completed and all signs and symptoms of a documented infection have resolved, patients who remain neutropenic may resume oral fluoroquinolone prophylaxis until marrow recovery. (Quality of Evidence: III)"

Class B

"1. Other antimicrobials (aminoglycosides, fluoroquinolones, and/or vancomycin) may be added to the initial regimen for management of complications (eg, hypotension and pneumonia) or if antimicrobial resistance is suspected or proven. (Quality of Evidence: III)"

"2. Modifications to initial empirical therapy may be considered for patients at risk for infection with the following antibiotic-resistant organisms, particularly if the patient’s condition is unstable or if the patient has positive blood culture results suspicious for resistant bacteria. (Quality of Evidence: III)" i. MRSA: Consider early addition of vancomycin, linezolid, or daptomycin ii. VRE: Consider early addition of linezolid or daptomycin iii. ESBLs: Consider early use of a carbapenem

"3. Afebrile neutropenic patients who have new signs or symptoms suggestive of infection should be evaluated and treated as high-risk patients. (Quality of Evidence: III)"

"4. Other oral regimens, including levofloxacin or ciprofloxacin monotherapy or ciprofloxacin plus clindamycin, are less well studied but are commonly used. (Quality of Evidence: III)"

"5. Selected hospitalized patients who meet criteria for being at low risk may be transitioned to the outpatient setting to receive either IV or oral antibiotics, as long as adequate daily follow-up is ensured. (Quality of Evidence: III)"

"6. In patients with clinically or microbiologically documented infections, the duration of therapy is dictated by the particular organism and site; appropriate antibiotics should continue for at least the duration of neutropenia (until ANC is ≥500 cells/mm3) or longer if clinically necessary. (Quality of Evidence: III)"

"7. In patients with unexplained fever, it is recommended that the initial regimen be continued until there are clear signs of marrow recovery; the traditional endpoint is an increasing ANC that exceeds 500 cells/mm3. (Quality of Evidence: II)"

Prophylaxis

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)"

Guideline Sources

• Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: 2010 Update by the Infectious Diseases Society of America

• Antimicrobial Prophylaxis and Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: American Society of Clinical Oncology Clinical Practice Guideline

• Guideline for the Management of Fever and Neutropenia in Children with Cancer and/or Undergoing Hematopoietic Stem-Cell Transplantation: American Society of Clinical Oncology Endorsement

• Prevention and Treatment of Cancer-Related Infections: National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology

• Management of Febrile Neutropenia: European Society for Medical Oncology Clinical Recommendations

See Also

• Neutropenia
• Leukopenia
• Fever
• Myelosuppression
• Chemotherapy

External Links

• Febrile neutropenia entry in the NCI Dictionary of Cancer Terms