Febrile Neutropenia

Question 1

Risk of infection increases with the _____ and _____ of neutropenia

Answer 1

1. severity
2. duration

• Greatest risk of infection occurring in patients who experience profound, prolonged neutropenia after chemotherapy [ASCO/IDSA 2018 CPC Update: Outpatient Management of Fever and Neutropenia]

Question 2

What other factors increase risk of infection in neutropenic patients?

Answer 2

• risk of infection in this patient population include impaired integrity of mucocutaneous barriers—catheters or mucositis
• type of treatment or conditioning regimens
• metabolic perturbations, such as diabetes or uremia
• the presence of immunomodulating viruses
• the presence of graft-versus-host disease (GVHD)
• perturbation of the microbiome

Question 3

• Rate of major complications in Febrile Neutropenic syndromes = ____%.
• Rate of mortality?

Answer 3

• 25 - 30% (eg, hypotension, acute renal, respiratory, heart failure)
• Mortality up to 11%.
  
  • In addition, in the setting of severe sepsis or septic shock, hospital mortality may be as high as 50%.
  • ASCO/IDSA 2018 CPC Update: Outpatient Management of Fever and Neutropenia

Question 4

What is the recommended initial diagnostic approach for patients with fever who are seeking emergency medical care within 6 weeks of receiving chemotherapy?

Answer 4

• Assume fever is due to infection.
• Approach

1. H&P
2. CBC with diff, electrolytes, Cr, BUN, lactate, LFTs,
3. At least two sets of blood cultures from different anatomic sites, including a peripheral site as well as one line lumen of a central venous catheter, if present
   
   • although the Expert Panel recognizes that that some centers may modify this practice and use only peripheral cultures, given the potential for false-positive results with blood cultures from the line lumen of a central venous catheter.
4. Culture from other sites (urine, lower resp tract, CSF, stool, wounds, or drains as indicated)
5. Chest imaging study for patients
6. nasopharyngeal swab obtained for detection of influenza.
   
   • In some settings, such as patients with such symptoms in the setting of 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).
7. Assessment should occur soon (ie, within 15 minutes) after triage
8. The first dose of empirical therapy should be administered within 1 hour after triage from initial presentation.
   
   • Patients who are seen in clinic or the emergency department for FN and whose degree of risk has not yet been determined to be high or low within 1 hour should receive an initial IV dose of therapy while undergoing evaluation.

ASCO/IDSA 2018 CPC Update: Outpatient Management of Fever and Neutropenia

Question 5

• Which patients with FN are at low risk of medical complications and are, therefore, candidates for outpatient management?
• What are some scoring systems and how do they compare to each other?

Answer 5

• Clinical judgment should be used when selecting candidates for outpatient management (even with MASCC score ≥ 21) . Factors to consider when assessing risk for medical complications in the setting of outpatient management of FN are outlined in Table 1 of ASCO/IDSA 2018 Outpt Mgmt of fever and neutropenia in adults.
• Scoring systems
  
  • The MASCC index (Table 2) or Talcott’s rules (Table 3) are recommended tools for identifying patients who may be candidates for outpatient management.
  • The Clinical Index of Stable Febrile Neutropenia (CISNE; Table 4) may be used as an additional tool to determine the risk of major complications among the group of patients with solid tumors who have undergone mild- to moderate-intensity chemotherapy and who appear to be clinically stable, assuming close proximity to an appropriate medical facility that can provide 24-hour access CISNE demonstrated better performance characteristics than the MASCC index and Talcott’s rules.
• Patients with FN who are infected by fluoroquinolone-resistant, gram-negative pathogens that are also coresistant to b-lactams/cephalosporins should be treated as inpatients with a carbapenem based regimen that likely requires multiple doses per day.
• Patients colonized with or suspected of having MRSA, 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.

ASCO/IDSA 2018 CPC Update: Outpatient Management of Fever and Neutropenia

Question 6

• What psychosocial and logistic recommendations must be met for patients to be eligible for outpatient management?
• How should patients be monitored for outpatient management?
• When should patients be evaluated for in-patient management?

Answer 6

1. Patients with FN who are eligible for discharge and outpatient management must also meet the following psychosocial and logistic requirements:
   
   • 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
2. The following additional measures are 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
3. Patients should be evaluated for admission to the hospital if any of the following occur:
   
   • patients do not 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.

ASCO/IDSA 2018 CPC Update: Outpatient Management of Fever and Neutropenia

Question 7

• Should patients with FN who are appropriate candidates for outpatient management receive their initial dose(s) of empirical antimicrobial(s) in the hospital or clinic and be observed, or can they be discharged immediately after evaluation?

Answer 7

• In patients with fever and neutropenia who are appropriate candidates for outpatient management, the first dose of empirical therapy should be administered in the clinic, emergency department, or hospital department after fever has been documented and pretreatment blood samples drawn.
  
  • Patients should be observed for >=4 hours before discharge.
  • Patients with FN and a low risk of medical complications, in whom fever is responding to inpatient IV empirical antibiotic treatment and the patient remains clinically stable, are considered eligible for transition to an outpatient regimen.
    
    • ASCO/IDSA 2018 CPC Update: Outpatient Management of Fever and Neutropenia

Question 8

What antimicrobials are recommended for outpatient empirical therapy in patients with FN?

Answer 8

• For patients with FN who are undergoing outpatient antibiotic treatment
  
  • oral empirical therapy with a fluoroquinolone (ie, ciprofloxacin or levofloxacin) plus amoxicillin/clavulanate (or plus clindamycin for those with a penicillin allergy) is recommended.
    
    • The use of a fluoroquinolone alone as initial empirical therapy for outpatient management of FN is not recommended; however, some studies have shown that monotherapy may be effective in low-risk outpatients.
• In the setting of a high prevalence of ESBL-producing gram-negative bacilli or fluoroquinolone resistance,
  
  • hospital admission and initial empirical antibacterial treatment with a carbapenem should be considered.
• Similarly, in a setting of high prevalence of other resistant organisms such as MRSA and VRE and concern for specific, active infection with entities such as pneumonia-causing pathogens or central line–associated bloodstream infection, hospital admission and targeted therapy should be considered.
• ASCO/IDSA 2018 CPC Update: Outpatient Management of Fever and Neutropenia

Question 9

If low-risk outpatients with FN do not defervesce after 2 to 3 days of an initial, empirical, broad-spectrum antibiotic regimen, should they be considered for hospitalization or continue to be treated on an outpatient basis?

Answer 9

• Low-risk outpatients with FN who do not defervesce after 2 to 3 days of an initial, empirical, broad-spectrum antibiotic regimen should be re-evaluated to detect and treat a new or progressing anatomic site of infection and be considered for hospitalization.
• Patients should also be evaluated for admission to the hospital if any of the following occur:
  
  • 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
  • blood cultures drawn on presentation become positive
  • microbiologic tests identify species not susceptible to the initial regimen.
• ASCO/IDSA 2018 CPC Update: Outpatient Management of Fever and Neutropenia

Question 10

Definition of

• neutropenia
• severe neutropenia
• profound neutropenia.
• fever in neutropenic patients
• protracted neutropenia

Answer 10

• Neutropenia = ANC < 1,000/mL (equivalent to < 1.0 x 10^9/L)
• Severe neutropenia = ANC < 500/mL (equivalent to < 0.5 x 10^9/L)
• Profound neutropenia = ANC < 100/mL (equivalent to , 0.1 x 10^9/L)
• 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
• Protracted neutropenia if it lasts >= 7 days
• Outpatient Management of Fever and Neutropenia in Adults
  Treated for Malignancy: American Society of Clinical
  Oncology and Infectious Diseases Society of America Clinical
  Practice Guideline Update (JCO 2018)
• Antimicrobial Prophylaxis for Adult Patients With Cancer-
  Related Immunosuppression: ASCO and IDSA Clinical
  Practice Guideline Update (JCO 2018)

Question 11

What empiric antibiotics should be used FN?

Answer 11

• Monotherapy with an antipseudomonal beta-lactam agent:
  
  • cefepime, a carbapenem (eg, meropenem or imipenem-cilastatin), or piperacillin-tazobactam, is recommended.
• Other antimicrobials (eg, aminoglycosides, fluoroquinolones, vancomycin) may be added to the initial regimen for management of complications (eg, hypotension, pneumonia) or if antimicrobial resistance is suspected or proven.
• ASCO/IDSA 2018 CPC Update: Outpatient Management of Fever and Neutropenia

Question 12

When should vancomycin be added to empiric antibiotic regimen for FN?

Answer 12

• Vancomycin (or other agents active against aerobic gram-positive cocci) is not recommended as a standard part of the initial antibioticregimen for fever and neutropenia.
• These agents should be considered for specific clinical indications, including suspected catheter-related infection, skin or soft-tissue infection, pneumonia, or hemodynamic instability.
• ASCO/IDSA 2018 CPC Update: Outpatient Management of Fever and Neutropenia

Question 13

1. When should you make modifications to initial empiric antibiotic therapy?
2. Risk factors of resistant bacteria?
3. Antibiotics for these resistant bacteria?

Answer 13

1. 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.
   
   • Methicillin-resistant Staphylococcus aureus (MRSA)
   • Vancomycin-resistant Enterococcus (VRE)
   • Extended-spectrum b-lactamase (ESBL)–producing gram-negative bacteria
   • Carbapenemase-producing organisms, including Klebsiella pneumoniae carbapenemase (KPC).
2. Risk factors for resistant bacteria include previous infection or colonization with the organism and treatment in a hospital with high rates of endemicity
3. Antibiotics for resistant bacteria:
   
   • MRSA: Consider early addition of vancomycin, linezolid, or, in the absence of evidence for pneumonia, daptomycin.
   • VRE: Consider early addition of linezolid or daptomycin.
   • ESBLs: Consider early use of a carbapenem.
   • KPCs: Consider early use of polymyxin-colistin or tigecycline, or a newer B-lactam with activity against resistant gram-negative organisms as a less toxic and potentially more effective alternative.
4. ASCO/IDSA 2018 CPC Update: Outpatient Management of Fever and Neutropenia

Question 14

Does antibacterial prophylaxis with a fluoroquinolone, compared with placebo, no intervention, or another class of antibiotic, reduce the incidence of and mortality as a result of febrile episodes in patients with cancer?

Answer 14

1. Antibacterial prophylaxis with fluoroquinolone should be given patients who are at high risk for FN (table 2 of JCO 2018 CPG) or profound, protracted neutropenia
   
   • Examples: patients with acute myeloid leukemia/myelodysplastic syndromes (AML/ MDS) or HSCT treated with myeloablative conditioning regimens.
   • Antibiotic prophylaxis is not routinely recommended for patients with solid tumors.
   • Antibacterial prophylaxis is recommended during the expected period of neutropenia in patients who meet the proposed criteria for use
   • Antibacterial prophylaxis is not recommended for patients
     who are at low risk of profound, protracted neutropenia
   • Antibacterial and antifungal prophylaxis would generally not
     be indicated when CSF prophylaxis effectively reduces the
     depth and duration of neutropenia
   • Fluoroquinolone resistance rates among community-acquired Enterobacteriaceae isolates in theUnited States have risen from, 1% to as high as 30% during the decade from the late 1990s to 2009
     
     • GI colonization by fluoroquinolone-resistant—and
       extended-spectrum b-lactamase–positive—gram-negative bacilli has been a risk factor for bacteremic events in the setting of GI mucositis, and fluoroquinolone resistance may result in inappropriate initial empirical antibacterial therapy and increased all-cause mortality
     • The activity of fluoroquinolone prophylaxis on the intestinal microbiome is to select not only for fluoroquinolone resistant, gram-negative bacilli, but also for Clostridium difficile and enterococci.
   • Quinolone prophylaxis resulted in significant reductions in
     all-cause mortality and febrile episodes/patients in both high and low risk groups
     
     • benefits do not outweigh the harm in all patients in the low risk groups
     • Fluoroquinolone prophylaxis may also be recommended for some patients with solid tumors or lymphoma who are expected to experience profound neutropenia for at least 7 days and for whom granulocyte CSF is not being prescribed.
   • Fluoroquinolones were recommended
     over trimethoprim-sulfamethoxazole (TMP-SMX) in the
     previous version of this guideline because the former drug class results in fewer adverse events that lead to discontinuation of treatment.
2. Antimicrobial Prophylaxis for Adult Patients With Cancer-
   Related Immunosuppression: ASCO and IDSA Clinical
   Practice Guideline Update (JCO 2018)

Question 15

What ABX can you give to patients who are intolerant or allergic to fluoroquinolones for antibiotic prophylaxis for immunosuppressed patients?

Answer 15

For patients who are intolerant or allergic to fluoroquinolones,
cefpodoxime has been used as an alternative agent for neutropenic
prophylaxis

Question 16

Does antifungal prophylaxis with an oral triazole or parenteral echinocandin, compared with no prophylaxis or another treatment option, reduce the incidence of and mortality as a result of febrile episodes in patients with cancer?

Source: Antimicrobial Prophylaxis for Adult Patients With Cancer-
Related Immunosuppression: ASCO and IDSA Clinical
Practice Guideline Update (JCO 2018)

Answer 16

• Recommendation #1: 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 AML/MDS or undergoing HSCT. Prophylaxis is not routinely recommended for patients with solid tumors.
  
  • Qualifying statements
    
    • Antifungal prophylaxis is recommended during the expected period of neutropenia in those patients who are anticipated to have profound, protracted neutropenia and grade III or IV mucositis where the risk for invasive candidiasis is high.
    • Clinicians should be able to differentiate the risks for invasive candidiasis from the risks for invasive mold infection. Fluconazole, which is active against yeast but not mold, has for the most part been effective in reducing the risks of the former, but not the latter.
      
      • Examples of mold-active agents include echinocandins and other azole antifungals, such as posaconozole, voriconozole, or isavuconazole.
    • A mold-active triazole is recommended where the risk of invasive aspergillosis is > 6%, such as in patients with AML/ MDS during the neutropenic period associated with chemotherapy.
    • Invasive mold infection risk is now observed to be greater in late-stage postallogeneic SCT, and a mold-active antifungal should be considered in this context (eg, posaconazole) and/or in the context of GVHD
    • Antifungal prophylaxis is not recommended for patients who are at low risk of profound, protracted neutropenia
    • Antibacterial and antifungal prophylaxis would generally not be indicated when CSF prophylaxis effectively reduces the depth and duration of neutropenia
• Recommendation #2: Prophylaxis is recommended (eg, TMP-SMX) for patients receiving chemotherapy regimens associated with > 3.5% risk for PNA from Pneumocystis jirovecii (eg, those with >= 20 mg prednisone equivalents daily for >= 1 month or those on the basis of purine analogs)
  
  • Qualifying statement
    
    • Alternatives such as dapsone, aerosolized pentamidine, or atovaquone are options for individuals who may be hypersensitive to sulfonamides or unable to tolerate TMPSMX for other reasons.
• Antimicrobial Prophylaxis for Adult Patients With Cancer-
  Related Immunosuppression: ASCO and IDSA Clinical
  Practice Guideline Update (JCO 2018)

Question 17

Does antiviral prophylaxis reduce the incidence of immunosuppression-related viral infections in patients with cancer compared with no prophylaxis or another treatment option?

Source: Antimicrobial Prophylaxis for Adult Patients With Cancer-
Related Immunosuppression: ASCO and IDSA Clinical
Practice Guideline Update (JCO 2018)

Answer 17

• Recommendation #1: Herpes simplex virus–seropositive patients undergoing allogeneic HSCT or leukemia induction therapy should receive antiviral prophylaxis with a nucleoside analog (eg, acyclovir).
• Recommendation #2: Treatment with a nucleoside reverse
  transcription inhibitor (eg, entecavir or tenofovir) is recommended
  for patients at high risk of hepatitis B virus reactivation
  
  • Qualifying statement: Recommendations related to universal testing and in-depth treatment algorithms for hepatitis B virus are included in the ASCO Provisional Clinical Opinion on Hepatitis B Virus Screening for Patients With Cancer Before Therapy
• Recommendation #3: Yearly influenza vaccination with
  inactivated quadrivalent vaccine is recommended for all patients
  receiving chemotherapy for malignancy. Optimal timing of vaccination for patients being treated for cancer is not established, but serologic responses may be best between chemotherapy cycles (> 7 days after the last treatment) or > 2 weeks before chemotherapy starts.
  
  • Influenza vaccination is also recommended for all family and household contacts and health care providers.
  • Individuals older than 65 years should receive the high-dose vaccine.
  • Currently, there are insufficient data to recommend the high-dose vaccine in compromised hosts younger than 65 years.
• Recommendation #4: The Expert Panel also supports other
  vaccination recommendations for immunosuppressed adult oncology patients that are contained within the IDSA guideline for vaccination of the immunosuppressed host
• Source: Antimicrobial Prophylaxis for Adult Patients With Cancer-
  Related Immunosuppression: ASCO and IDSA Clinical
  Practice Guideline Update (JCO 2018)

Question 18

Do additional precautions, such as hand hygiene, air filtration,
or a neutropenic diet, reduce the risk of infection in neutropenic
patients with cancer compared with no or other additional precautions?

Source: Antimicrobial Prophylaxis for Adult Patients With Cancer-
Related Immunosuppression: ASCO and IDSA Clinical
Practice Guideline Update (JCO 2018)

Answer 18

• Recommendation #1: All health care workers should comply with hand hygiene and respiratory hygiene/cough etiquette guidelines to reduce the risk for aerosol- and direct or indirect contact–based transmission of pathogenic micro-organisms in the health care setting.
• Recommendation #2: Outpatients with neutropenia from cancer therapy should avoid prolonged contact with environments that have high concentrations of airborne fungal spores (eg, construction and demolition sites, intensive exposure to soil through gardening or digging, or household renovation).
• Recommendation #3:The Expert Panel continues to endorse the ASCO recommendations from the previous version of this guideline, including recommendations from the US Centers for Disease Control and Prevention for hand hygiene and the prevention of infection in outpatient settings and recommendations against interventions, such as footwear exchange, protected environments, respiratory or surgical masks, neutropenic diet, or nutritional supplements, for which evidence of clinical benefit is lacking.
  
  • Studies included in the previous version of this review of high-efficiency particulate air– filtered protected environments, respiratory masks, footwear exchange,
    and dietary interventions did not demonstrate any significant differences in outcomes, although protected environments may play a limited role in the prevention of airborne acquisition of infections, such as invasive mold, in the event that the patient remains in the protected environment and does not import an
    infection from previous exposure. Included in this update is a new meta-analysis of neutropenic diets—that is, diets that generally include cooked foods and restrict raw fruit, vegetables, fish meat, and soft cheese, which did not show a protective benefit with
    intervention.
• Source: Antimicrobial Prophylaxis for Adult Patients With Cancer-
  Related Immunosuppression: ASCO and IDSA Clinical
  Practice Guideline Update (JCO 2018)

Question 19

Bacteria from cultures of patients with FN?

Answer 19

• Currently, coagulase-negative staphylococci are the most common species identified in blood cultures, but the frequency of drug-resistant Gram-negative bacterial infections is increasing.
• However, blood and other cultures are negative and the causative organism and site of infection remain uncertain in many oncology patients with fever.
• ASCO 2013 CPG: Antimicrobial Prophylaxis and Management of Fever and Neutropenia in Outpatients

Question 20

What is the MASCC scoring system?

Answer 20

Question 21

What are the Talcott’s rules?

Answer 21

Question 22

What’s the risk of serious complications occuring in low risk (defined by MASCC or Talcott’s rules?)

Answer 22

• serious complications developed
  
  • ≤ 11% of patients classified as low risk by MASCC score ≥ 21
  • 7% of patients in Talcott’s group 4.
• The MASCC score and Talcott’s classification were derived and validated in heterogeneous samples; patient has solid tumors, acute leukemia, or had undergone bone marrow transplant

Question 23

What is the CISNE scoring system?

Answer 23

The Clinical Index of Stable Febrile Neutropenia (CISNE)

Question 24

Risk of FN should be systematically assessed (in consultation with infectious disease specialists as needed), including patient-, cancer-, and treatment-related factors.

Give patient risk factors for FN

Answer 24

JCO 2018: Antimicrobial Prophylaxis for Adult Patients With Cancer- Related Immunosuppression: ASCO and IDSA Clinical
Practice Guideline Update

Question 25

Risk of FN should be systematically assessed (in consultation with infectious disease specialists as needed), including patient-, cancer-, and treatment-related factors.

Cancer-related risk of FN?

Answer 25

JCO 2018: Antimicrobial Prophylaxis for Adult Patients With Cancer- Related Immunosuppression: ASCO and IDSA Clinical
Practice Guideline Update

Question 26

Risk of FN should be systematically assessed (in consultation with infectious disease specialists as needed), including patient-, cancer-, and treatment-related factors.

Give treatment-related factors

Answer 26

JCO 2018: Antimicrobial Prophylaxis for Adult Patients With Cancer- Related Immunosuppression: ASCO and IDSA Clinical
Practice Guideline Update

Question 27

Summary slide for antibacterial and antifungal prophylaxis in immunosuppressed patients

Source: Antimicrobial Prophylaxis for Adult Patients With Cancer-
Related Immunosuppression: ASCO and IDSA Clinical
Practice Guideline Update (JCO 2018)

Answer 27

Question 28

Summary slide for antiviral prophylaxis in immunosuppressed patients

Source: Antimicrobial Prophylaxis for Adult Patients With Cancer-
Related Immunosuppression: ASCO and IDSA Clinical
Practice Guideline Update (JCO 2018)

Answer 28