Febrile neutropenia medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Faizan Sheraz, M.D. [2]

Synonyms and keywords: F and N; fever and neutropenia; FN; hot and low; hot leuk; neutropenic fever; neutropenic fever syndrome; neutropenic sepsis

Overview

Generally, patients with febrile neutropenia are treated with empirical antibiotics until the neutrophil count has recovered (absolute neutrophil counts greater than 500/mm3) and the fever has abated. If there is no improvement in the neutrophil count, treatment may need to continue for two weeks or more. In cases of recurrent or persistent fever, an antifungal agent should be added to the treatment regimen.

Medical Therapy

IDSA Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: Recommendations for Antibiotic Therapy

Class A
"1. High-risk patients require hospitalization for IV empirical antibiotic therapy; monotherapy with an anti- pseudomonal b-lactam agent, such as cefepime, a carbapenem (meropenem or imipenem-cilastatin), or piperacillin-tazobactam, is recommended. (Quality of Evidence: I)"
"2. Vancomycin (or other agents active against aerobic gram- positive cocci) is not recommended as a standard part of the initial antibiotic regimen for fever and neutropenia (A-I). These agents should be considered for specific clinical indications, including suspected catheter-related infection, skin or soft-tissue infection, pneumonia, or hemodynamic instability. (Quality of Evidence: I)"
"3. Most penicillin-allergic patients tolerate cephalosporins, but those with a history of an immediate-type hypersensitivity reaction (eg, hives and bronchospasm) should be treated with a combination that avoids b-lactams and carbapenems, such as ciprofloxacin plus clindamycin or aztreonam plus vancomycin. (Quality of Evidence: II)"
"4. Low-risk patients should receive initial oral or IV empirical antibiotic doses in a clinic or hospital setting; they may be transitioned to outpatient oral or IV treatment if they meet specific clinical criteria. Ciprofloxacin plus amoxicillin-clavulanate in combination is recommended for oral empirical treatment. (Quality of Evidence: I)"
"5. Patients receiving fluoroquinolone prophylaxis should not receive oral empirical therapy with a fluoroquinolone. (Quality of Evidence: III)"
"6. Hospital re-admission or continued stay in the hospital is required for persistent fever or signs and symptoms of worsening infection. (Quality of Evidence: III)"
"7. Modifications to the initial antibiotic regimen should be guided by clinical and microbiologic data. (Quality of Evidence: II)"
"8. Unexplained persistent fever in a patient whose condition is otherwise stable rarely requires an empirical change to the initial antibiotic regimen. If an infection is identified, antibiotics should be adjusted accordingly. (Quality of Evidence: I)"
"9. Documented clinical and/or microbiological infections should be treated with antibiotics appropriate for the site and for the susceptibilities of any isolated organisms. (Quality of Evidence: I)"
"10. If vancomycin or other coverage for gram-positive organisms was started initially, it may be stopped after 2 days if there is no evidence for a gram-positive infection. (Quality of Evidence: II)"
"11. Patients who remain hemodynamically unstable after initial doses with standard agents for neutropenic fever should have their antimicrobial regimen broadened to include coverage for resistant gram-negative, gram-positive, and anaerobic bacteria and fungi. (Quality of Evidence: III)"
"12. Low-risk patients who have initiated IV or oral antibiotics in the hospital may have their treatment approach simplified if they are clinically stable. An IV-to-oral switch in antibiotic regimen may be made if patients are clinically stable and gastrointestinal absorption is felt to be adequate. (Quality of Evidence: I)"
"13. If fever persists or recurs within 48 h in outpatients, hospital re-admission is recommended, with management as for high-risk patients. (Quality of Evidence: III)"
"14. Empirical antifungal coverage should be considered in high-risk patients who have persistent fever after 4–7 days of a broad-spectrum antibacterial regimen and no identified fever source. (Quality of Evidence: II)"
Class C
"1. KPCs: Consider early use of polymyxin-colistin or tigecycline. (Quality of Evidence: III)"
"2. Alternatively, if an appropriate treatment course has been completed and all signs and symptoms of a documented infection have resolved, patients who remain neutropenic may resume oral fluoroquinolone prophylaxis until marrow recovery. (Quality of Evidence: III)"
Class B
"1. Other antimicrobials (aminoglycosides, fluoroquinolones, and/or vancomycin) may be added to the initial regimen for management of complications (eg, hypotension and pneumonia) or if antimicrobial resistance is suspected or proven. (Quality of Evidence: III)"
"2. Modifications to initial empirical therapy may be considered for patients at risk for infection with the following antibiotic-resistant organisms, particularly if the patient’s condition is unstable or if the patient has positive blood culture results suspicious for resistant bacteria. (Quality of Evidence: III)"
i. MRSA: Consider early addition of vancomycin, linezolid, or daptomycin
ii. VRE: Consider early addition of linezolid or daptomycin
iii. ESBLs: Consider early use of a carbapenem
"3. Afebrile neutropenic patients who have new signs or symptoms suggestive of infection should be evaluated and treated as high-risk patients. (Quality of Evidence: III)"
"4. Other oral regimens, including levofloxacin or ciprofloxacin monotherapy or ciprofloxacin plus clindamycin, are less well studied but are commonly used. (Quality of Evidence: III)"
"5. Selected hospitalized patients who meet criteria for being at low risk may be transitioned to the outpatient setting to receive either IV or oral antibiotics, as long as adequate daily follow-up is ensured. (Quality of Evidence: III)"
"6. In patients with clinically or microbiologically documented infections, the duration of therapy is dictated by the particular organism and site; appropriate antibiotics should continue for at least the duration of neutropenia (until ANC is ≥500 cells/mm3) or longer if clinically necessary. (Quality of Evidence: III)"
"7. In patients with unexplained fever, it is recommended that the initial regimen be continued until there are clear signs of marrow recovery; the traditional endpoint is an increasing ANC that exceeds 500 cells/mm3. (Quality of Evidence: II)"


Skin and soft tissue infection in neutropenic fever

  • Treatment of skin and soft tissue infection in neutropenic fever[1]
  • 1. Initial episode
  • 2. Recurrent or persistent
  • Empiric treatment
  • 2.1 Antibacterial therapy
  • Preferred regimen (1): Vancomycin 30–60 mg/kg/day IV in 2–4 divided doses (Target serum trough concentrations of 15–20 µg/mL in severe infections)
  • Preferred regimen (2): Daptomycin 4–6 mg/kg/day IV (Covers VRE, strains nonsusceptible to vancomycin may be cross-resistant to daptomycin)
  • Preferred regimen (3): Linezolid 600 mg q12h IV (100% oral bioavailability; so oral dose same as IV dose. Covers VRE and MRSA)
  • Preferred regimen (4): Colistin 5 mg/kg IV loaing dose, THEN 2.5 mg/kg q12h IV (Nephrotoxic; does not cover gram-positives or anaerobes, Proteus, Serratia, Burkholderia)
  • 2.2 Antifungal therapy
  • Preferred regimen (1): Fluconazole 100–400 mg PO q24h OR Fluconazole 800 mg IV loading dose, THEN 400 mg qd (Candida krusei and Candida glabrata are resistant)
  • Preferred regimen (2): Voriconazole 400 mg PO bid in 2 doses, then 200 mg q12h OR Voriconazole 6 mg/kg IV q12h for 2 doses, THEN 4 mg/kg IV q12h (Accumulation of cyclodextrin vehicle with IV formulation with renal insufficiency)
  • Preferred regimen (3): Posaconazole 400 mg PO bid with meals (Covers Mucorales)
  • Preferred regimen (4): Lipid complex Amphotericin-B 5 mg/kg/day IV (Not active against fusaria)
  • Preferred regimen (5): Liposomal Amphotericin-B 3–5 mg/kg/day IV (Not active against fusaria)
  • Culture directed antimicrobial therapy
  • Candida
  • Aspergillus
  • Fusarium
  • Dissemianted HSV or VZV

Neutropenic fever, prophylaxis

  • Neutropenic fever, prophylaxis[2]
  • 1.Low risk (standard chemotherapy regimen for soild tumor, anticipated neutropenia < 7 days)
  • Antibacterial agent: none
  • Antifungal agent: none
  • Antiviral agent: none unless prior HSV episode
  • 2. Intermediate risk (autologous HSCT, lymphoma, multiple myeloma, CLL, Purine analog therapy [i.e., Fludarabine, Clofarabine, Nelarabine, Cladribine], anticipated neutropenia 7-10 days)
  • 2.1 Antibacterial agent: consider fluroquinolone prophylaxis
  • 2.2 Antifungal agent: consider fluconozole during neutropenia and for anticipated mucositis
  • 2.3 Antiviral agent:
  • 2.3.1 HSV prophylaxis
  • 2.3.2 VZV prophylaxis
  • Preferred regimen (1): Acyclovir 800 mg PO bid (in allogeneic HSCT)
  • Preferred regimen (2): Famciclovir 250 mg PO bid
  • Preferred regimen (3): Valacyclovir 500 mg PO bid-tid
Note (1): Antiviral agents should be administered during active therapy and for at least 30 days after HSCT.
Note (2): Consider VZV prophylaxis for at least 1 year after allogeneic HSCT and for at least 6-12 months after autologous HSCT.
  • 3.High risk (acute leukemia, Alemutuzumab therapy, in allogenic HSCT including cord blood, GVHD treated with high dose steriods, anticipated neutropenia > 10 days)
  • 3.1 Antibacterial agent: Levofloxacin 500-750 mg PO/IV q24h
  • 3.2 Antifungal agent:
  • 3.2.1 ALL
  • 3.2.2 MDS or AML
  • Preferred regimen: Posaconazole EC 300 mg bid on day 1 and then 300 mg IV q day after or IV 300 mg q day after
  • Alternative regimen: Voriconazole 6mg/kg IV q 12 h X 2 doses then 4 mg/kg q 12 h until resolution of neutropenia
  • Alternative regimen: Fluconazole in adult with normal renal function 400mg IV/PO q24h
  • Alternative regimen: Amphotericin B until resolution of neutropenia
  • 3.2.3 Autologous HSCT with mucositis
  • Preferred regimen: Fluconazole 400mg IV/PO q24h (in adult with normal renal function) OR Micafungin 50-100mg/ d IV until resolution of neutropenia
  • 3.2.4 Allogenic HSCT
  • Preferred regimen: Fluconazole 400mg IV/PO q24h (in adult with normal renal function) OR Micafungin 50-100mg/ d IV until resolution of neutropenia
  • Alternative regimen (1): Itraconazole
  • Alternative regimen (2): Voriconazole 6mg/kg IV q 12 h X 2 doses then 4 mg/kg q 12 h
  • Alternative regimen (3): Posaconazole EC 300 mg bid on day 1 and then 300 mg IV q day after or IV 300 mg q day after
  • Alternative regimen (4): Amphotericin B continue during neutropenia and for at least 75 days after transplant
  • 3.2.5 Significant GVHD
  • Preferred regimen: Posaconazole EC 300 mg bid on day 1 and then 300 mg IV q day after or IV 300 mg q day after
  • Alternative regimen (1): Voriconazole6mg/kg IV q 12 h X 2 doses then 4 mg/kg q 12 h
  • Alternative regimen (2): Echinocandin
  • Alternative regimen (3): Amphotericin B until resolution of Significant GVHD
  • 3.3 Antiviral agent:
  • 3.3.1 Acute Leukemia
  • HSV prophylaxis
  • Proteasome inhibitors
  • VZV prophylaxis
  • Preferred regimen (1): Acyclovir 800 mg PO bid (in allogeneic HSCT)
  • Preferred regimen (2): Famciclovir 250 mg PO bid
  • Preferred regimen (3): Valacyclovir 500 mg PO bid-tid
Note (1): Antiviral agents should be administered during active therapy and for at least 30 days after HSCT.
Note (2): Consider VZV prophylaxis for at least 1 year after allogeneic HSCT and for at least 6-12 months after autologous HSCT.
  • Alemutuzumab Therapy, allogenic HSCT ,GVDH requiring steriod treatment
  • HSV prophylaxis
  • VZV prophylaxis
  • Preferred regimen (1): Acyclovir 800 mg PO bid (in allogeneic HSCT)
  • Preferred regimen (2): Famciclovir 250 mg PO bid
  • Preferred regimen (3): Valacyclovir 500 mg PO bid-tid
Note (1): Antiviral agents should be administered during active therapy and for at least 30 days after HSCT.
Note (2): Consider VZV prophylaxis for at least 1 year after allogeneic HSCT and for at least 6-12 months after autologous HSCT.
  • Anti CMV prophylaxis
  • Allogenic stem cell transplant (surveillance period: 1-6 months after transplant, GVDH requiring therapy)
  • Preferred regimen: Valganciclovir900 mg daily PO OR Ganciclovir5 mg / kg IV q 12 h for 2 weeks followed by 5-6mg / kg daily for at least an additional 2-4 weeks and resolution of all symptoms
  • Alternative regimen: Foscarnet 60 mg / kg IV q 8-12 h for 7 d followed by 90-120mg / kg daily until day 100 after HSCTOR Cidofovir IV
  • Alemtuzumab therapy (suveillance period: for a minimum of 2 months after alemtuzumab)
  • Preferred regimen: Valganciclovir 900 mg daily PO OR Ganciclovir5 mg / kg IV q 12 h for 2 weeks followed by 5-6mg / kg daily for at least an additional 2-4 weeks and resolution of all symptoms
  • Alternative regimen: Foscarnet 60 mg / kg IV q 8-12 h for 7 d followed by 90-120mg / kg daily until day 100 after HSCT OR Cidofovir IV
  • Anti Pneumocystis prophylaxis
  • Duration of prophylaxis:
  • Allogenic stem cell recipients: for at least 6 months and while receving immunosuppresive therapy
  • Acute lymphocytic leukemia: throughout anti-leukemic therapy
  • Alemtuzumab therapy: for a minimum of 2 months after Alemtuzumab and until CD4 count > 200 cells/mcL
Note: Anti-Pneumocystis prophylaxis may be considered in (1) recipients of purine analog therapy and other T-cell-depleting agents; (2) recipients of prolonged corticosteroids or receiving temozolomide + radiation therapy; and (3) autologous stem cell recipients.
  • HBV prophylaxis
  • Allogenic stem cell transplant, Anti CD20 or Anti CD52 monoclonal antibodies
  • Therapy considerations
  • ID consult to determine possible antiviral prophylaxis, consider delayed transplant if active infection
  • Antiviral therapy
  • Preferred regimen (1): Entecavir0.5 mg PO q24h ( nucleoside- treatment- naive with compensated liver disease) or 1 mg PO 24 h ( lamivudine - refractory or known Lamivudine or telbivudine resistance mutation or decompensated liver disease
  • Preferred regimen (2): Tenofovir300 mg PO q 24 h
  • Preferred regimen (3): Lamivudine 100mg PO q 24 h
  • Preferred regimen (4): Adefovir 10mg PO q 24 h
  • Preferred regimen (5): Telbivudine60 mg PO q 24 h
  • Surveillance
  • At least 6-12 months following conclusion of treatment
  • Prophylaxis in HIV
  • Chemotherapy, targeted therapies
  • Therapy considerations
  • ID consult to adjust dosing and regimen for concurrent treatment
  • Antiviral therapy
  • Preferred regimen: antiretroviral therapy
  • Surveillance
  • Monthly during therapy then as clinically indicated

References

  1. ↑ Stevens DL, Bisno AL, Chambers HF, Dellinger EP, Goldstein EJ, Gorbach SL; et al. (2014). "Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the infectious diseases society of America". Clin Infect Dis. 59 (2): 147–59. doi:10.1093/cid/ciu296. PMID 24947530.
  2. ↑ "neutropenic fever prophylaxis" (PDF).
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