febrile%20neutropenia
FEBRILE NEUTROPENIA
Febrile neutropenia is having a fever of ≥38.3 ºC or ≥38 ºC over an hour and neutropenia that is having an absolute neutrophil count (ANC) of <500 neutrophils/mm3 or an ANC <1000 neutrophils/mm3 expected to decline to ≤500 neutrophils/mm3 over the next 48 hours.
The risk of febrile neutropenia is directly proportional to the duration and severity of neutropenia.
Fever is frequently the only indication of infection in the neutropenic patient.

Principles of Therapy

  • Neutropenic patients at the first sign of infection (eg fever) should be treated promptly (within 1 hour after triage from initial presentation) with empiric high-dose, broad-spectrum antibiotics
    • Delay in antibiotic administration is associated with significantly longer hospital stay and increased mortality
  • Goal of initial empirical antibiotic therapy is to prevent serious morbidity and mortality until blood culture results are available to guide specific antibiotic choice
  • The following should be considered when choosing the initial antimicrobial therapy:
    • The most common possible infecting organism
    • Possible sites of infection
    • Local antimicrobial susceptibility patterns
    • Presence of organ dysfunction or comorbid conditions
    • Signs of hypoperfusion (hypotension, decreased urine output, altered sensorium)
    • Drug allergies
    • Patient’s infection risk assessment
    • Previous antimicrobial or antifungal therapy
Chemoprophylaxis
  • Recommended for patients at high-risk for complications based on age, medical history, disease characteristics and chemotherapy regimens for the prevention of febrile neutropenia
Antifungal Therapy
  • Empirical antifungal therapy should be considered in high-risk patients with persistent fever after 4-7 days of broad-spectrum antibiotic treatment, neutropenia expected to last >7 day, with clinical or chest and sinus CT signs of fungal infection, recovery of fungi from any body site, an/or positive serologic test for invasive fungal infection
    • The timing and use of antifungal will need to be determined individually based on the clinical picture
  • Clinically stable patients with no apparent fungal lesion, no Candida or Aspergillus sp isolated from any site and with a neutrophil count that is expected to increase within a few days may not need empiric antifungals

Empiric Antibiotic Therapy

Oral Antibiotics and Outpatient Management

  • Studies have shown that low-risk patients treated with oral antibiotics compared to low-risk patients treated with intravenous (IV) have similar outcomes
  • Advantages: Lower cost, ease of outpatient management, no IV catheter needed, decreased toxicity, less risk of nosocomial infection

Ciprofloxacin + Amoxicillin/clavulanic acid

  • Ciprofloxacin has excellent activity against Gram-negative and atypical pathogens, and the addition of Amoxicillin/clavulanic acid renders this combination effective against aerobic Gram-positive and anaerobic pathogens 
  • Effective alternative to IV monotherapy in appropriately selected low-risk patients
  • Use of Clindamycin instead of Amoxicillin/clavulanic acid is recommended in patients with allergy to Penicillin

Fluoroquinolone

  • Monotherapy may be considered in low-risk patients without history of quinolone prophylaxis, nausea and vomiting, and should be able to tolerate oral medications
  • Evidence from several studies do not support the use of high-dose Ciprofloxacin, Levofloxacin or Ofloxacin and these agents are not recommended for monotherapy
    • Ciprofloxacin’s poor coverage for certain Gram-positive organisms (eg viridans group streptococci, S aureus)
    • Levofloxacin may not adequately cover Pseudomonas sp
    • Moxifloxacin has poor coverage against Pseudomonas sp and should only be considered for patients cleared for Pseudomonas infection
  • Patients receiving fluoroquinolone as prophylaxis should not receive fluoroquinolone as oral empirical therapy

Metronidazole

  • Good activity against anaerobic pathogens

Trimethoprim/sulfamethoxazole (TMP/SMX)

  • May be considered for the treatment of Pneumocystis pneumonia and other pathogens

Intravenous (IV) Monotherapy Antibiotics

  • Preferred treatment option for intermediate- to high-risk patients 
  • Studies in patients with uncomplicated febrile neutropenia have shown no difference between monotherapy and multiple drug therapy
  • Local institutional bacterial susceptibilities should be determined because of the changing antibiotic sensitivities

Cefepime

  • Excellent activity against most Gram-positive and Gram-negative pathogens
  • Vancomycin was shown to be needed less often with Cefepime than with Ceftazidime monotherapy

Ceftazidime

  • No longer used as first-line empirical monotherapy due to decreased activity against Gram-negative and many of Gram-positive pathogens

Imipenem/cilastatin and Meropenem

  • Excellent activity against most Gram-positive, Gram-negative and anaerobic pathogens
  • Preferred agents against extended-spectrum beta-lactamase (ESBL) and Enterobacter infections

Piperacillin/Tazobactam

  • Excellent activity against most Gram-positive, Gram-negative and anaerobic pathogens

Intravenous Combination Therapy

  • Generally, the different 2-drug combinations are considered equally efficacious
  • May be added to the initial regimen for management of complications (pneumonia, hypotension) or antimicrobial resistance
  • Advantages: Potential synergistic effects against particular Gram-negative bacilli and less risk of emergence of drug-resistant organisms during therapy
  • Disadvantages: Lack of activity of some combinations against certain Gram-positive organisms and the nephrotoxicity, ototoxicity and hypokalemia associated with aminoglycosides and carboxypenicillins

Aminoglycosides

  • Eg Amikacin, Gentamicin, Tobramycin
  • Combined with recommended initial IV antimicrobials for high-risk patients and resistant diseases
  • Once-daily dosing is preferred to lessen the risk of renal toxicities
  • Should be discontinued in high-risk patients on combination therapy if no cause of infection is found

Vancomycin

  • Should be used discriminately because of the emergence of Vancomycin-resistant organisms (eg enterococci)
  • Should only be considered for patients with suspected serious catheter-related infection, pneumonia, hemodynamic instability, skin or soft tissue infection, mucosal damage, known colonization with penicillin/cephalosporin-resistant pneumococci or MRSA, or positive blood culture for Gram-positive bacteria prior to final identification and susceptibility
  • Reassess need for Vancomycin within 2-3 days of initiation and discontinue if there is absence of clinical response or catheter-related infection and cultures for Gram-positive bacteria or MRSA are negative 

Linezolid, Daptomycin

  • Recommended for Vancomycin-resistant infections or for whom Vancomycin is not an option

Special Regimens

  • MRSA: Vancomycin, Linezolid, Daptomycin
  • Vancomycin-resistant: Linezolid, Daptomycin, Quinupristin/dalfopristin
  • ESBL-producing Gram-negative bacilli: Carbapenem (Imipenem, Meropenem)
  • Carbapenemase-producing bacteria: Colistin, Tigecycline

Antifungal Therapy

Amphotericin B Formulations

  • Effective antifungal activity against Candida sp, Aspergillus sp (excluding Aspergillus terreus), Zygomycetes sp, rarer molds, C neoformans and dimorphic fungi
Amphotericin B deoxycholate (AmB-D)
  • Considered the preferred empiric antifungal therapy in patients with febrile neutropenia

Amphotericin B Lipid Complex (ABLC)

  • With less infusional and renal toxicity compared to AmB-D

Liposomal Amphotericin B (L-AMB)

  • Comparative trials have shown that L-AMB is not substantially more effective than AmB-D but there is less drug-related toxicity

Azoles

Fluconazole

  • May be considered in institutions where mold infections (eg Aspergillus sp) and drug-resistant Candida sp are not common
  • Fluconazole should not be considered if patient has symptoms or radiologic evidence of sinusitis, evidence of pulmonary infection, has received prophylactic Fluconazole, or if positive for Aspergillus on culture
  • Recommended dose: 400-800 mg/day IV

Isavuconazonium sulfate

  • A prodrug of the triazole antifungal Isavuconazole, is effective against invasive aspergillosis and mucormycosis in cancer patients and those with history of HCT

Itraconazole

  • Has been shown to be as effective against Candida, Aspergillus sp, dimorphic fungi, C neoformans and some rarer molds but not as toxic as Amphotericin B when used as empiric therapy

Posaconazole

  • Effective against Candida, Aspergillus sp, some Zygomycetes sp, dimorphic fungi, C neoformans and some rarer molds in neutropenic patients

Voriconazole

  • Effective against Candida, Aspergillus sp, dimorphic fungi, C neoformans and some rarer molds
  • Primary treatment of invasive aspergillosis
  • Has poor coverage against Zygomycetes sp
  • Has less infusional and renal toxicity but with increased incidence of transient visual changes and hallucinations

Echinocandins

  • Eg Anidulafungin, Caspofungin, Micafungin 
  • Has been shown to be as effective and is generally better tolerated than L-AMB
  • Primary treatment of invasive candidiasis and candidemia

Myeloid Growth Factors (MGFs)

  • In febrile neutropenia patients at high risk for infection-associated complications or with prognostic features predictive of poor clinical outcomes, adjunctive therapy using MGFs should be considered especially if with no history of prophylactic G-CSF use
  • Treatment with MGFs may also be considered for patients with radiation-induced myelosuppression following hematopoietic acute radiation syndrome (H-ARS)
  • Recommended therapeutic MGFs include Filgrastim and its biosimilars, and Sargramostim
    • For patients given or currently receiving prophylactic Filgrastim or its biosimilar, treatment with the same agent should be continued
    • Sargramostim is the only FDA-approved granulocyte-macrophage colony-stimulating factor (GM-CSF) used for the treatment of febrile neutropenia
      • Molgramostim, another GM-CSF, is currently undergoing clinical studies to prove its use in febrile neutropenia
      • Studies showed that there is significantly less adverse effects seen in Sargramostim use compared to Molgramostim
  • Further studies are needed to prove the use of Pegfilgrastim and its biosimilars as therapeutic agents for febrile neutropenia, but may be used for patients with radiation-induced myelosuppression following hematopoietic acute radiation syndrome (H-ARS) to help reduce the duration of severe neutropenia
    • Patients previously or currently receiving prophylactic Pegfilgrastim or its biosimilar should not receive any additional G-CSF
  • Indications for use of therapeutic MGFs include presence of any of the following:
    • Sepsis syndrome
    • Advanced age (>65 years of age)
    • ANC <100/μL (<0.1 x 109/L)
    • Neutropenia duration expected to be >10 days
    • Pneumonia or other clinically documented infections
    • Invasive fungal infection
    • Hospitalization during appearance of fever
    • History of febrile neutropenia
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