Febrile%20neutropenia Treatment

• Neutropenic patients at the first sign of infection (eg fever) should be treated promptly (within 1 hour after triage from initial presentation) with empiric 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
• Monotherapy with an antipseudomonal beta-lactam, a 4th generation cephalosporin, or a carbapenem is recommended; a 2nd Gram-negative agent may be added in patients with complications, suspected or at high risk for drug resistance
• For patients with worsening disease, treatment escalation to include coverage for resistant Gram-negative, Gram-positive and anaerobic bacteria is recommended
• Treatment de-escalation should be considered in patients with stable disease and good response to initial treatment after 24-48 hours and without a clinical or microbiologic indication to continue a 2nd agent
• Empirical antibiotics may be discontinued in high-risk patients with negative blood cultures at 48 hours, who are afebrile for at least 24 hours and have evidence of marrow recovery, and in low-risk patients with negative blood cultures at 72 hours, who have assured follow-up and are afebrile for at least 24 hours, regardless of marrow recovery status
• Early discharge may be considered in low-risk patients with negative blood cultures at 24-36 hours and afebrile for at least 24 hours, and for high-risk patients with negative blood cultures at 48 hours and afebrile for at least 24 hours regardless of marrow recovery status and will follow up

• Recommended for patients at high-risk for complications based on age, medical history, disease characteristics and chemotherapy regimens for the prevention of febrile neutropenia

• 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 days, with clinical or chest and sinus CT signs of fungal infection, recovery of fungi from any body site, and/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

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
• Prolonged infusion administration strategy for IV beta-lactam antibiotics may improve microbiologic and clinical cure especially in pathogens with higher minimum inhibitory concentrations (MIC)

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 1st-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, periorbital cellulitis, 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

Empiric 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

• 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

• Effective against Candida sp, coccidioidomycosis and C neoformans
• 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)

• 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
• 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, Tbo-filgrastim 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