Febrile Neutropenia Xử trí

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 IV have similar outcomes. The advantages of oral antibiotics are lower cost, ease of outpatient management, no IV catheter needed, decreased toxicity, and 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. These are an effective alternative to IV monotherapy in appropriately selected low-risk patients. The use of Clindamycin instead of Amoxicillin/clavulanic acid is recommended in patients with an allergy to Penicillin.

Fluoroquinolone

Fluoroquinolone monotherapy may be considered in low-risk patients without a history of quinolone prophylaxis, nausea and vomiting, and who should be able to tolerate oral medications. This has good activity against Gram-negative and atypical organisms (eg Legionella spp). Evidence from several studies does not support the use of high-dose Ciprofloxacin, Levofloxacin or Ofloxacin and these agents are not recommended for monotherapy. Ciprofloxacin has 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

Metronidazole has good activity against anaerobic pathogens.

Trimethoprim/sulfamethoxazole (TMP/SMX)

Trimethoprim/sulfamethoxazole may be considered for the treatment of Pneumocystis pneumonia and other pathogens, including Toxoplasma gondii and Nocardia.

Intravenous (IV) Monotherapy Antibiotics

Intravenous (IV) monotherapy antibiotics is the 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. A 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

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Cefepime has 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

Ceftazidime is no longer used as first-line empirical monotherapy due to its decreased activity against Gram-negative and many Gram-positive pathogens.

Imipenem/cilastatin and Meropenem

Imipenem/cilastatin and Meropenem have excellent activity against most Gram-positive, Gram-negative and anaerobic pathogens. These are preferred agents against extended-spectrum beta-lactamase (ESBL) and Enterobacter infections.

Piperacillin/tazobactam

Piperacillin/tazobactam has excellent activity against most Gram-positive, Gram-negative and anaerobic pathogens.

Intravenous (IV) Combination Therapy

Generally, two-drug combinations are considered equally efficacious. These may be added to the initial regimen for management of complications (pneumonia, hypotension) or antimicrobial resistance. The advantages are the potential synergistic effects against particular Gram-negative bacilli and less risk of emergence of drug-resistant organisms during therapy. The disadvantages are the lack of activity of some combinations against certain Gram-positive organisms and the nephrotoxicity, ototoxicity and hypokalemia associated with aminoglycosides and carboxypenicillins.

Aminoglycosides

Example drugs: Amikacin, Gentamicin, Tobramycin

Aminoglycosides have activity against Gram-negative pathogens. These may be combined with recommended initial IV antimicrobials for high-risk patients and resistant diseases. A once-daily dosing is preferred to lessen the risk of renal toxicities. These should be discontinued in high-risk patients on combination therapy if no cause of infection is found.

Linezolid, Daptomycin

Linezolid or Daptomycin is recommended for Vancomycin-resistant infections or for whom Vancomycin is not an option.

Tedizolid

Tedizolid has less hematologic toxicity compared to Linezolid.

Vancomycin

Vancomycin should be used discriminately because of the emergence of Vancomycin-resistant organisms (eg enterococci). This 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 the need for Vancomycin within 2 to 3 days of initiation and discontinue if there is an absence of clinical response or catheter-related infection and cultures for Gram-positive bacteria or MRSA are negative.

Special Regimens

The special regimens are: MRSA (Vancomycin, Linezolid, Daptomycin); Vancomycin-resistant (Linezolid, Daptomycin, Quinupristin/Dalfopristin); ESBL-producing Gram-negative bacilli (Carbapenem [Imipenem, Meropenem]); and Carbapenemase-producing bacteria (Colistin, Tigecycline).

EMPIRIC ANTIFUNGAL THERAPY

Empirical antifungal therapy with coverage for molds should be considered in high-risk patients with persistent fever after 4 to 7 days of broad-spectrum antibiotic treatment, neutropenia expected to last >7 days, clinical or chest and sinus computed tomography (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 antifungals 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.

Amphotericin B Formulations

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Amphotericin B has effective antifungal activity against Candida sp, Aspergillus sp (excluding Aspergillus terreus), Mucorales sp, rarer molds, C neoformans and dimorphic fungi.

Amphotericin B deoxycholate (AmB-D)

Amphotericin B deoxycholate is considered the preferred empiric antifungal therapy in patients with febrile neutropenia.

Amphotericin B Lipid Complex (ABLC)

Amphotericin B lipid complex has less infusional and renal toxicity compared to Amphotericin B deoxycholate.

Liposomal Amphotericin B (L-AMB)

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

Azoles

Fluconazole

Fluconazole is effective against Candida sp, coccidioidomycosis and C neoformans. This 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.

Isavuconazonium sulfate

Isavuconazonium sulfate, a prodrug of the triazole antifungal Isavuconazole, is effective against invasive aspergillosis and mucormycosis in cancer patients and those with a history of HCT.

Itraconazole

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

Posaconazole is effective against Candida, Aspergillus sp, some Mucorales spp, dimorphic fungi, C neoformans and some rarer molds in neutropenic patients. The United States Food and Drug Administration (US FDA)-approved antifungal for invasive aspergillosis.

Voriconazole

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Voriconazole is effective against Candida, Aspergillus sp, dimorphic fungi, C neoformans and some rarer molds. This is the primary treatment of invasive aspergillosis and has poor coverage against Mucorales spp. This has less infusional and renal toxicity but with increased incidence of transient visual changes and hallucinations. Long-term use may increase the risk for squamous cell carcinoma and hyperphosphatemia.

Echinocandins

Example drugs: Anidulafungin, Caspofungin, Micafungin

Echinocandins has been shown to be as effective and is generally better tolerated than liposomal Amphotericin B. These are the primary treatment for invasive candidiasis and candidemia and may be used for invasive aspergillosis.

MYELOID GROWTH FACTORS (MGFs)

The indications for use of therapeutic myeloid growth factors include the presence of any of the following: Sepsis syndrome; advanced age (>65 years old); 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; and a 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 myeloid growth factors should be considered especially if with no history of prophylactic granulocyte colony-stimulating factor (G-CSF) use.







The recommended therapeutic myeloid growth factors include Filgrastim and its biosimilars, Sargramostim and Tbo-filgrastim. For patients given or currently receiving prophylactic Filgrastim or its biosimilar, treatment with the same agent should be continued. Sargramostim is the only US FDA-approved granulocyte-macrophage colony-stimulating factor (GM-CSF) used for the treatment of febrile neutropenia. Molgramostim, another granulocyte-macrophage colony-stimulating factor, is currently undergoing clinical studies to prove its use in febrile neutropenia. Studies showed that there are significantly less adverse effects seen in Sargramostim use compared to Molgramostim. Further studies are needed to prove the use of Eflapegrastim-xnst, Efbemalenograstim alfa-vuxw, 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, to help reduce the duration of severe neutropenia. Patients previously or currently receiving prophylactic Pegfilgrastim or its biosimilar, Eflapegrastim-xnst, or Efbemalenograstim alfa-vuxw should not receive any additional granulocyte colony-stimulating factor.

Vaccination

Annual influenza vaccination, either in inactivated or recombinant form, is recommended in all patients with hematologic or solid tumor malignancies. Vaccination against coronavirus disease 2019 (COVID-19) is recommended in all individuals diagnosed with cancer or those with a history of cancer treatment. All pneumococcal vaccine-naive newly diagnosed cancer patients should receive pneumococcal conjugate vaccine (PCV20). Additional pneumococcal polysaccharide vaccine (PPSV23) is not needed for vaccine-naive patients given PCV20. If PCV15 was initially administered, PPSV23 should be given at least 8 weeks later. Patients who have previously received PPSV23, can receive either PCV20 (preferred) or PCV15, while those previously given PCV13 only can receive PCV20 after at least 1 year. If PCV13 and 1 or 2 doses of PPSV23 were previously administered, the patient may be given PCV20 after 5 years.

Please see Pneumonia - Community-Acquired disease management chart for further information.

Serogroup B meningococcal vaccination (quadrivalent MenACWY vaccine series, monovalent meningococcal serogroup B vaccine series) is recommended in patients at increased risk for meningococcal disease. Two doses of the MenACWY vaccine are given at least 8 weeks apart. Serogroup B vaccine is available in a 2- or 3-dose series, depending on the vaccine formulation used. Patients with ongoing risk for meningococcal disease should receive a booster dose 5 years after completing the primary series and every 5 years thereafter. PCV20 or PCV15 should not be given with meningococcal conjugate vaccine, quadrivalent (MenACWY-D) but can be given with MenACWY-CRM. Recombinant 3-dose human papillomavirus vaccine is recommended for patients <26 years old, and may be considered in patients >26 to ≤45 years of age. A vaccine against respiratory syncytial virus (RSV) was recently approved for patients ≥60 years of age and should be considered for cancer patients belonging to this age group. The diphtheria/tetanus/acellular pertussis (DTaP) vaccine is recommended to be given every 10 years. Other recommended inactivated vaccines include H influenzae type b (Hib), hepatitis A, hepatitis B and polio vaccine to be given 6 to 12 months after hematopoietic cell transplant. Recombinant zoster vaccine is recommended for adult patients aged ≥50 years and those ≥18 years who are at increased risk for herpes zoster 50 to 70 days after autologous hematopoietic cell transplant and may be considered after allogeneic hematopoietic cell transplant. Live vaccines such as measles, mumps, rubella (MMR), varicella and zoster vaccines may be considered ≥24 months after hematopoietic cell transplant if the patient is negative for GVHD or ongoing immunosuppression and seronegative for respective disease.

CHEMOPROPHYLAXIS

Chemoprophylaxis is recommended for patients at high risk for complications based on their age, medical history, disease characteristics and chemotherapy regimens for the prevention of febrile neutropenia.

Antimicrobials

Antimicrobials have been used for a long time as chemoprophylaxis but it led to the emergence of resistant strains that limited their efficacy. The following should be considered when choosing the initial antimicrobial prophylactic agent: Emergence of multidrug-resistant organisms; disruption of the microbiome which may affect patient's immune response; and antibiotic toxicities.

Antibiotics

Fluoroquinolone prophylaxis is recommended for intermediate- and high-risk patients with febrile neutropenia or profound neutropenia. The use of fluoroquinolones is discouraged in low-risk patients. This should be considered in patients with >7 days expected duration of neutropenia. Trimethoprim/sulfamethoxazole or an oral third-generation cephalosporin is an alternative treatment for patients with intolerance to fluoroquinolones. The use of Ciprofloxacin or Levofloxacin in cancer patients undergoing intensive chemotherapy is recommended based on recent update of the Cochrane meta-analysis.

Antifungals

Antifungals are recommended for patients at intermediate and high risk for febrile neutropenia or profound/protracted neutropenia. Pneumocystis pneumonia (PCP) prophylaxis may be considered for intermediate- to high-risk patients with a history of allogeneic hematopoietic cell transplant, autologous hematopoietic cell transplant, or those with acute lymphocytic leukemia (ALL). These recommended antipneumocystic prophylactic agents include Trimethoprim/sulfamethoxazole (preferred), Atovaquone, Dapsone, or Pentamidine.

These are recommended antifungal prophylactic agents based on disease for patients at intermediate to high risk for infection include ALL (Fluconazole or Micafungin/Caspofungin/Anidulafungin); alternative agent includes Amphotericin B; myelodysplastic syndrome or acute myeloid leukemia (AML) (Posaconazole); alternative agents include Voriconazole, Isavuconazole, Fluconazole, Micafungin/Caspofungin/Anidulafungin or Amphotericin B; autologous hematopoietic cell transplant with mucositis (Fluconazole or Micafungin/Caspofungin/Anidulafungin); allogeneic hematopoietic cell transplant (Fluconazole or Micafungin/Caspofungin/Anidulafungin); alternative agents include Posaconazole, Voriconazole, Isavuconazole or Amphotericin B; and graft-versus-host disease (GVHD) (Posaconazole); alternative agents include Voriconazole, any echinocandin, Amphotericin B or Isavuconazole.

Antivirals

Patients at intermediate to high risk for infection may be given antiviral prophylaxis (Acyclovir, Famciclovir, Ganciclovir, Valacyclovir, Valganciclovir) for herpes simplex and varicella during active therapy. Patients with lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), or a history of autologous hematopoietic cell transplant or purine analog therapy at intermediate risk for infection may be given prophylaxis against herpes simplex virus (HSV) during active therapy or longer depending on the degree of immunosuppression, and may consider varicella zoster virus (VZV) prophylaxis for at least 6 to 12 months after autologous hematopoietic cell transplant. For patients with acute leukemia at high risk for infections, HSV prophylaxis may be considered. Patients at high risk for infections may be given prophylaxis against VZV during active proteosome inhibitor therapy. Patients with history of Alemtuzumab therapy, allogeneic hematopoietic cell transplant, or GVHD that required corticosteroid use, HSV prophylaxis may also be considered for a minimum of 2 months after Alemtuzumab therapy and until CD4 is ≥200 cells/mcL, or VZV prophylaxis for at least 1 year after allogeneic hematopoietic cell transplant.

Primary prophylaxis with Letermovir may be considered in allogeneic HCT recipients at high risk for cytomegalovirus (CMV) reactivation or disease. Once CMV reactivation has been detected, initiate preemptive therapy with Valganciclovir or Ganciclovir. For patients who are intolerant or unresponsive to Ganciclovir therapy, Foscarnet or Cidofovir may be considered. Oral Oseltamivir and inhaled Zanamivir may be given as antiviral prophylaxis for influenza A and B. For patients who cannot tolerate oral Oseltamivir and inhaled Zanamivir, IV Peramivir may be considered. Prophylaxis using nucleoside reverse transcriptase inhibitor Entecavir (preferred) or Tenofovir (preferred) or Lamivudine should be considered in patients at high risk for hepatitis B reactivation.

Granulocyte Colony-Stimulating Factors (G-CSFs)

Example drugs: Filgrastim (biosimilars Filgrastim-aafi, Filgrastim-sndz, Tbo-filgrastim), Lenograstim, Pegfilgrastim (biosimilars Pegfilgrastim-bmez, Pegfilgrastim-cbqv, Pegfilgrastim-jmdb), Eflapegrastim-xnst, Efbemalenograstim alfa-vuxw

Granulocyte colony-stimulating factors are recommended as prophylaxis in patients currently receiving systemic chemotherapy with fever and neutropenia at high risk for infection-associated complications or with prognostic factors for poor clinical outcome. These should be used with caution during administration in patients given concurrent chemoradiotherapy. These may be considered in patients currently undergoing high-intensity chemotherapy with intermediate risk if patients have ≥1 of the following: History of chemotherapy or radiotherapy, persistent neutropenia, bone marrow involvement, recent surgery, open wounds, liver impairment (bilirubin >2), renal dysfunction (creatinine clearance <50), and advanced age (>65 years of age). These may be considered in patients with low risk but not to be used routinely. These should not be used in febrile neutropenia patients with prior treatment of long-lasting prophylactic Pegfilgrastim, Eflapegrastim-xnst or Efbemalenograstim alfa-vuxw. It was shown to reduce the risk of febrile neutropenia by at least 50% in patients with solid tumors without significant effect on tumor response or overall survival. These can also be used in patients with decreased bone marrow reserve due to extensive radiotherapy or in patients who are neutropenic due to HIV. Primary prophylaxis with Filgrastim or Pegfilgrastim has shown success in recent meta-analysis of randomized controlled trials. Secondary prophylaxis is indicated if dose reduction is below threshold or delay of chemotherapy is undesirable. These are associated with mild to moderate bone pain, splenic rupture (rare), increased risk for AML and myelodysplastic syndrome and other toxicities (eg acute respiratory distress syndrome, alveolar hemorrhage, hemoptysis). Pegfilgrastim administration increases bone marrow and spleen fluorodeoxyglucose (FDG) uptake, which may affect positron emission tomography (PET) and CT scan results and interpretation.