UCSF Medical Center Guidelines for Inpatient Management of Febrile Neutropenia

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BACKGROUND:  Neutropenia results in a significant risk of bacterial and fungal infections, especially when neutropenia is profound (ANC <500/µL) and prolonged. Strategies are available that can reduce these risks, even possibly preventing bacterial infections from occurring during these periods of risk. When infections do occur, appropriate changes in antibiotics can improve clinical outcomes. These strategies are based on the local microbiology at UCSF, published literature, and national practice guidelines.

1.0       OBJECTIVE:

1.1            To reduce the incidence of infections during neutropenia.

1.2            To treat infection that arises despite antibiotic prophylaxis.

1.3            To minimize the development of antibiotic-resistant organisms at UCSF.

1.4            To minimize the complications from antibiotic therap

2.0       PERSONNEL/SCOPE:

2.1            Malignant Hematology Attending Physicians

2.2            Malignant Hematology Nurse Practitioners

2.3            Malignant Hematology Pharmacists

2.4            Malignant Hematology Hospitalists

2.5            Transplant Infectious Diseases

2.6            Antimicrobial Stewardship Team

3.0       MATERIALS/EQUIPMENT:

None

4.0       DEFINITIONS/DESCRIPTIONS 

·       * Adjust dose for renal dysfunction. Consult with malignant hematology pharmacists regarding dosing

·       Hemodynamic instability: ≥2 of the following: RR > 22, SBP < 90, HR > 110 or ICU transfer

·       Infectious Disease Pharmacy Pager: 443-9421

·       Transplant Infectious Disease Service Pager: 443-2552

·       ALL: Acute Lymphocytic Leukemia

·       AML: Acute Myelocytic Leukemia

·       ANC:  Absolute Neutrophil Count

·       Cr Cl: Creatinine clearance

·       PO: Orally

·       IV: Intravenous

·       HSCT: Hematopoetic stem cell transplant

·       GVHD: Graft versus host disease

·       AmBisome: Liposomal amphotericin

·       CDI: Clostridium difficile

·       MRSA: methicillin resistant Staphylococcus aureus

·       SBP: Systolic blood pressure

·       RR: Respiratory rate

5.0       POLICIES:   

5.1       Neutropenia is defined as (1) ANC < 500 or (2) < 1000 and likely to fall to < 500 within 48hrs

5.2       Fever in a neutropenic patient is defined as temperature 38.0 degrees Celsius.

5.3       Fever of 38.0 degrees Celsius requires blood cultures and antibiotics.  

6.0      PROCEDURE:

Step 1: Prophylaxis - When neutropenic (ANC < 500, or, < 1000 and likely to fall to < 500 within 48hrs)

1)    Bacterial Prophylaxis: Start levofloxacin 500 mg PO daily*. If patient unable to tolerate PO, may give 500 mg IV daily*.

2)    Fungal prophylaxis: depends on diagnosis and regimen

a)    Autologous HSCT and ALL patients receiving chemotherapy:

i)      Fluconazole 400 mg PO daily*. 

b)    Allogeneic HSCT patients and AML induction or consolidation chemotherapy:

i)      Voriconazole 4 mg/kg PO/IV BID per protocol.

c)    Options for patients intolerant of voriconazole include:

i)      Posaconazole tablets 300 mg PO Q12H x 2 doses, then 300 mg PO QDay (if able to take PO meds, no concern for CYP3A4 interactions), goal trough: 1-5

ii)    Isavuconazonium sulfate 372mg (Isavuconazole 200mg), Q8H x 3 doses then 372mg PO Qd (if able to take PO meds, no concern for CYP3A4 interactions)

iii)   Caspofungin 70mg IV loading dose, then 50 mg IV daily

iv)   AmBisome 1-3 mg/kg IV daily

v)    For paitents with GVHD or other allogeneic HSCT patients on steroids who are unable to take voriconazole, posaconazole, or isavuconazole, amBisome 1mg/kg IV daily is preferred over caspofungin.

3)    Viral prophylaxis: Patients with ALL, Non-Hodgkin lymphoma, and any HSCT patient are to receive acyclovir 400 mg twice daily (or equivalent)

 

New or persistent fever:  Initiate Step 2 and/or Step 3 depending on clinical assessment:

Two central line cultures should be drawn for first neutropenic fever 38.0 C. (one culture if persistently febrile). If a 2nd episode of neutropenic fever occurs distant from the first, then again draw two central line cultures followed by single cultures if persistently febrile.

 Step 2:  New fever and no hemodynamic instability (SBP > 90, HR < 110, or lactate < 2.2 with adequate IV fluid resuscitation, RR < 22) and patient stable for medical ward. If instability is present proceed to Step 3.

1)    Two central line cultures should be drawn for first neutropenic fever 38.0 C. (one culture if persistently febrile). If a 2nd episode of neutropenic fever occurs distant from the first, then again draw two central line cultures followed by single cultures if persistently febrile. Initial cultures should be drawn before antibiotics are started.

2)    During influenza season (Oct-March) consider influenza testing and empiric therapy

a)    See IDMP website – treatment of influenza:http://idmp.ucsf.edu/

3)    Discontinue levofloxacin (or prophylactic antibacterial medication)

4)    Start cefepime 2 g IV Q8 hrs*

a)    If patient has history of immediate-type hypersensitivity reaction (eg, hives and bronchospasm) aztreonam 2g IV Q8 hrs* plus vancomycin 15-20 mg/kg IV Q12* may be used instead of cefepime (Note that vancomycin must be given in this case, even in instances where it would not normally be prescribed, due to the lack of gram-positive coverage by aztreonam).

5)    Assess for risk factors for MRSA infection: bacterial pneumonia, skin and soft tissue infection, evidence of central line infection, recent systemic MRSA infection

a)    If MRSA risk present, also start vancomycin 15-20 mg/kg IV Q12 hrs*

6)    If fevers persist but patient is clinically stable and cultures are negative, do not broaden antibacterial coverage

7)    At 48hrs, discontinue vancomycin if cultures do not grow a resistant gram positive organism and there is no evidence of a resistant gram positive infection

8)    Continue cefepime until:

a)    Cultures negative, fever resolved, and adequate treatment course (up to 10 total days or earlier if neutropenia has resolved) completed. Then discontinue cefepime and return to Step 1 (levofloxacin)

9)    If work-up reveals infectious organism or site of infection, change antibiotics to target this entity and treat until:

a)    Fever resolved and appropriate treatment course for infectious etiology is completed. Then discontinue antibiotics and return to Step 1 (levofloxacin)

10)If fever persists despite 4-7 days of antibiotics and no fever source has been identified, proceed to Step 4 (antifungal work-up)

Step 3:  New or persistent fevers in the setting of sepsis with hemodynamic instability (documented or suspect bacterial infection with ≥2 of: RR > 22, SBP < 90, HR > 110, or lactate > 2.2 persistent despite adequate IV fluid resuscitation) or ICU transfer

1)    Discontinue levofloxacin and start cefepime 2 g IV Q8 hrs*

a)    If already on cefepime, discontinue cefepime, start meropenem 1 g IV Q8 hrs*

2)    Start or continue vancomycin 15-20 mg/kg IV Q12 hrs*

3)    If the patient remains hemodynamically unstable after 24hrs despite the above:

a)    If on cefepime, discontinue cefepime and start meropenem 1 g IV Q8 hrs*

b)    Consider adding tobramycin 7 mg/kg IV Q24 hrs.

i)      Drug levels should be drawn 6-14 hrs after administration and compared to the nomogram on the antibiotic dosing card or the IDMP website (http://idmp.ucsf.edu/aminoglycoside-dosing-and-monitoring-recommendations). Contact malignant hematology pharmacists regarding appropriate dosing and monitoring.

c)    If on fluconazole prophylaxis and high risk for candidemia: Consider discontinuation of fluconazole and starting caspofungin 70 mg IV loading dose, then 50 mg IV Q24 hrs

i)      Candidemia risk factors: recent intra-abdominal procedure, current TPN, > 7 days of broad spectrum antibiotics, long-term central line, known candida colonization

4)    If remains hemodynamically unstable after 48 hrs:

a)    Consult with Transplant Infectious Disease service is recommended

b)    Proceed to Step

5)    If improves and hemodynamically stable with negative cultures/work-up after 48hrs:

a)    Discontinue vancomycin

b)    Discontinue tobramycin (if started)

c)    Discontinue caspofungin after 96hrs if cultures are negative (if started)

d)    Continue meropenem or change to pipercillin/tazobactam 4.5g IV Q6 hrs* to complete 10-day abx course from the point of clinical stability. Then discontinue antibiotic and return to Step 1 (levofloxacin).

6)    If improvement and hemodynamically stable and if work-up reveals infectious organism or site of infection, change antibiotics to target this entity and treat until:

a)    Fever resolved and appropriate treatment course for infectious etiology is completed. Then discontinue antibiotics and return to Step 1 (levofloxacin)

Step 4: New or persistent fevers despite 4-7 days of antibiotics and current/recent neutropenia > 7 days or radiology compatible with invasive fungal infection. Also if persistent hemodynamic instability despite broad spectrum antibiotics (step 3).

1)    Consultation with the Transplant Infectious Diseases service is recommended

2)    Evaluate patient with chest CT and/or sinus CT and serum galactomannan level.

a)    Consider additional fungal serologies based on exposure history.

3)    If abdominal symptoms present or above testing negative, consider abdominal CT

4)    If CT abnormalities found, biopsy or targeted microbiologic testing (eg, BAL) is recommended to establish diagnosis

a)    If BAL is performed, BAL galactomannan should be ordered

5)    Discontinue fluconazole prophylaxis, start voriconazole 6 mg/kg PO Q12 hrs x 2 doses, then 4 mg/kg PO Q12 hrs. If already on voriconazole, check voriconazole trough (goal 2-5 mcg/ml)

a)    Check LFTs when starting or changing dose of voriconazole.

b)    Check voriconazole trough after 5-7 days at any new dose.

c)    Voriconazole may also be given IV if necessary.

d)    Depending on the clinical situation and suspicion for invasive fungal infection, various options to consider in consultation with the Transplant ID service:

i)      Concern for aspergillus: add caspofungin 70mg IV x 1 dose, then 50mg IV Q24 hrs to voriconazole

ii)    Concern for mucor: Discontinue voriconazole, start amBisome 5 mg/kg IV Q24 hrs +/- caspofungin

6)    If hemodynamically stable with positive fungal work-up or resolution of fever after 3-5 days of antifungal therapy:

a)    Continue antifungal agent, treatment duration based on type of infection

b)    If no documented bacterial infection, discontinue broad spectrum antibiotics and return to Step 1 (levofloxacin)

7)    If hemodynamically stable with persistent fevers despite 3-5 days of antifungals:

a)    Continue antibacterials per steps above

b)    Discontinue antifungal agent

c)    Additional fever work-up

d)    Consider Transplant ID consult

CDI diagnosis: If at any point during above algorithm, a clinical syndrome consistent with CDI is diagnosed, the following are recommended:

1)    Treat per UCSF CDI guidelines (see http://idmp.ucsf.edu/news/updated-ucsfmcvasfzsfgh-guidelines-c-difficile...)

2)     Strongly consider using the narrowest systemic antibiotics for the shortest duration.

7.0      MEASURABLE OUTCOMES:

1)    The antibiotic algorithm at UCSF is reviewed annually by a team including malignant hematology physicians, the antimicrobial stewardship team, and the microbiology lab.

2)    Antibiotic use is monitored regularly by the antimicrobial stewardship team

3)    The incidence of infections with various organisms and the patterns of antibiotic sensitivity are tracked. In particular, we review the incidence of bloodstream infections with:

a)    Gram positive bacteria

b)    Gram negative bacteria

c)    Candida species

4)    We also track the incidence of:

a)    CDI

b)    Vancomycin-resistant enterococcus (VRE)

c)    Extended spectrum beta-lactamase (ESBL) enterobacteriacae

d)    Carbapenem-resistant enterobacteriacae (CRE)

 

8.0      REFERENCES:

·      Antibiotic Algorithm for Neutropenic Patients, UCSF Adult Leukemia and BMT Programs

·      P&P 133.230: Antimicrobial Management of Critically Ill Patients, UCSF Pharmacy Manual

·      P&P 4.1: Guidelines for the Care of the Immunocompromised Patient, UCSF Infection Control Manual

·      Infectious Disease Management Program at UCSF: http://idmp.ucsf.edu/  

·      NCCN Guidelines on the Prevention and Treatment of Cancer-Related Infections. Version 2.2015

 

·      Freifeld et al. Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: 2010 Update by the Infectious Diseases Society of America. Clinical Infectious Diseases 2011;52(4):e56–e93

 

·      Averbuch et al. European guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of growing resistance: summary of the 2011 4th European Conference on Infections in Leukemia. Haematologica. 2013. 98(12):1826-35

·      Paul et al. Cochrane Database Syst Rev. 2014 Issue 1. Art: CD003914

9.0      APPENDICES:

9.1      Flowchart for the management of neutropenic fever: click here

SOP REVISION HISTORY PAGE

 

Date

Revision

 

10/20/03

 

New

2/13/07

Format change and change of antibiotic algorithym

03/22/10

Updated revision number, header and footer, date and name change

1/27/11

Revisions include:

1.    Change imipenem to meropenem in antibiotic algorithm.

2.    Clarified use of tobramycin.

3.    Alternative antibiotic use in patients with cephalosporin allergy.

1/27/12

Revisions include:

1.    Options for patients intolerant to voriconazole

2.    Change vancomycin dosing to 15.20 mg/kg

3.    Consultation with ID Service

4.    Biopsy recommendation

5.    Meropenem and Tobramycin dosing

6.    Appendix

1/21/14

Change Moxifloxacin to Levofloxacin due to increase in pseudomonas rate. Change Tobramycin to daily dosing. Update Appendix. Delete step 5 as only one case per year.

10/27/15

Added definition of neutropenic fever and when blood cultures to be drawn. Amended Appendix 9.1 for consistency with this SOP.

5/24/2016

Changed definition of neutropenia to include ANC<1000 and expected to fall to <500

Defined stable and unstable

Changed recommendations for when vancomycin should be initiated

Changed recommendations for duration of IV therapy for neutropenic fever

Changed recommendations for escalation of therapy in stable patients with neutropenic fever

Added a flowsheet to assist with decision making