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
  • 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

  • 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


  • 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

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


  • Excellent activity against viridans streptococci and pneumococci
  • Vancomycin was shown to be needed less often with Cefepime than with Ceftazidime monotherapy


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

Imipenem/cilastatin and Meropenem

  • Excellent activity against viridans streptococci and pneumococci


  • Has been used as monotherapy but has not been studied as extensively as the above agents

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)
  • 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


  • 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


  • 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 
  • For Vancomycin-resistant infections or for whom Vancomycin is not an option, Linezolid or Daptomycin is recommended

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 deoxycholate

  • Considered the preferred empiric antifungal therapy in patients with febrile neutropenia

Liposomal Amphotericin B

  • Comparative trials have shown that liposomal Amphotericin B is not substantially more effective than Amphotericin B deoxycholate but there is less drug-related toxicity


  • Has been shown to be as effective and is generally better tolerated than liposomal Amphotericin B


  • Has been shown to be as effective but not as toxic as Amphotericin B when used as empiric therapy


  • 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
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