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

General Therapeutic Principles
  • Neutropenic patients at the first sign of infection (eg fever) should be treated promptly with empiric high-dose, broad-spectrum antibiotics
  • 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 have been given in chemotherapy-treated patients for prevention of episodes of febrile neutroprenia
  • Empirical antifungal therapy should be considered in high-risk patients w/ persistent fever after 4-7 days of broad-spectrum antibiotic treatment
    • The timing & 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

Assessment Prior to Starting Antifungal Agent 

  • Empirical antifungal therapy should be considered in the following settings:
    • With persistent or recurrent fever after 4-7 days of antibiotics
    •  Neutropenia expected to last >7 days
    • With clinical or chest and sinus CT signs of fungal infection
    • Recovery of fungi from any body site
    • Positive serologic test for invasive fungal infection
  • Prior to starting an empiric antifungal agent, patient should be examined for systemic fungal infection
    • Biopsy of lesions
    • X-rays of chest, sinuses
    • Nasal endoscopy, if indicated to investigate sinusitis
    • Cultures
    • CT of the abdomen and chest
  • Empirical antifungal therapy is not recommended in low-risk patients

Pharmacotherapy

Vancomycin Therapy

  • Vancomycin should be used discriminately because of the emergence of Vancomycin-resistant organisms (eg enterococci)
  • In institutions where Gram-positive organisms are common causes of serious infections, Vancomycin should be considered as initial therapy in some high-risk patients but discontinued 24-48 hours later if no such infection is found
  • Consider the use of Vancomycin in the initial empiric therapy in the following:
    • Suspected serious catheter-related infection
    • Pneumonia
    • Hemodynamic instability
    • Skin or soft tissue infection
    • Mucosal damage
    • Verified colonization with penicillin- and cephalosporin-resistant pneumococci or Methicillin-resistant Staphylococcus aureus (MRSA)
    • Positive blood culture for Gram-positive bacteria prior to final identification & susceptibility
    • Evidence of cardiovascular impairment (eg hypotension)
  • Other potential indications for Vancomycin use:
    • Intensive chemotherapy that causes substantial mucosal damage (eg high-dose Cytarabine) or increases the risk of penicillin-resistant streptococcal infections (eg viridans streptococci)
    • Prophylaxis with quinolones for afebrile neutropenic patients prior to fever onset
    • Sudden increase in temperature to >40°C may be predictive of sepsis due to viridans streptococci
    • Persistent fever or clinical deterioration despite empiric antibiotics
  • Reassess need for Vancomycin within 2-3 days of initiation
    • May stop when 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 is recommended

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

Ciprofloxacin + Clindamycin

  • May be appropriate in patients with allergy to Penicillin

Quinolone (alone)

  • Evidence from several studies do not support the use of high-dose Ciprofloxacin, Levofloxacin or Ofloxacin & 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
  • Patients receiving fluoroquinolone as prophylaxis should not receive fluoroquinolone as oral empirical therapy

Intravenous (IV) Monotherapy Antibiotics

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

Cefpirome

  • Active against Pseudomonas aeruginosa, Methicillin-sensitive staphylococci, non-enterococcal streptococci and Haemophilus spp

Ceftazidime

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

Imipenem & Meropenem

  • Excellent activity against viridans streptococci and pneumococci

Piperacillin/Tazobactam

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

Intravenous (IV) Two-drug 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 & hypokalemia associated with aminoglycosides and carboxypenicillins

Aminoglycosides

  • Recommendations regarding the use of once-daily vs multiple-daily dosing have not been established
  • Not used for either empirical therapy or bacteremia in neutropenia due to rapid emergence of resistance in this group of drugs
  • Should be discontinued in high-risk patients on 2-drug therapy if no cause of infection is found

Vancomycin with Mono- or Two-drug Therapy

  • Vancomycin should be used discriminately because of the emergence of Vancomycin-resistant organisms (eg enterococci)
  • Reassess use of Vancomycin at start of therapy & discontinue after 2 days if no susceptible bacteria is recovered from patient

Antifungal Therapy

Amphotericin B Deoxycholate

  • Considered the preferred empiric antifungal therapy in febrile neutropenic patients

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

Caspofungin

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

Itraconazole

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

Fluconazole

  • May be considered in institutions where mold infections eg Aspergillus sp & drug-resistant Candida sp are not common
  • Fluconazole should not be considered if patient has symptoms of sinusitis or X-ray, has evidence of pulmonary infection, has received prophylactic Fluconazole or if Aspergillus was found on culture
  • When the above conditions have been met, Fluconazole may be considered at a dosage of 400-800 mg/day IV
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