Neutropenic Fever CID 2011; 52 (4):e56-e93.
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Transcript of Neutropenic Fever CID 2011; 52 (4):e56-e93.
Learning Objectives
Definition and classification– Identify appropriate patient– Classify risk and type
Etiology / Microbiology– Understand what you are evaluating for– What “bugs” do you need to worry about
Clinical evaluation
Management– Antibiotic selection, escalation, de-escalation– Antibiotic duration
Definitions
Fever:– Single oral temperature of ≥ 101°F (38.3°C)– Temperature ≥ 100.4°F (38.0°C) over 1 hour
Neutropenia:– ANC < 500 cells/mm3
– Expected ANC < 500 cells/mm3 within the next 48 hours
Chemotherapy Induced Neutropenia
Risk Stratification
High Risk
ANC ≤ 100 anticipated > 7 days
Hemodynamic instability
Oral or GI mucositis interfering with swallowing or causing diarrhea
Neurologic/MS changes – new onset
Intravascular catheter infection
New pulmonary infiltrate, hypoxemia or underlying chronic lung disease
Hepatic or renal insufficiency
MASCC < 21
Low Risk
Neutropenia anticipated ≤ 7 days
No active medical co-morbidity
Adequate hepatic and renal function
Multinational Assoc for Supportive Care in Cancer Risk-Index Score (MASCC) ≥ 21 of 26.
Burden of febrile neutropenia 0,3,5
No hypotension 5
No COPD 4
Solid or Heme w/o fungus 4
No IVF 3
Outpatient 3
Age < 60 2
Classification
Initial neutropenic fever– Typically coincides with neutrophil nadir– Standard protocol – concern for bacterial infection
Persistent neutropenic fever– Fever despite 5 days of broad-spectrum antibacterials– Complex management – concern for fungal infection
Recrudescent neutropenic fever– Fever that recurs following initial response – Wide differential
Etiology / Microbiology
InfectiousBacterial translocation– Intestinal– Oropharyngeal
Community-acquired– Respiratory viruses
Healthcare-associated– MDR organisms– C. diff
Opportunistic– Herpes virus reactivation– Fungal
Non-infectiousUnderlying malignancy
Blood products
Tumor lysis
Hematoma
Thrombosis
Phlebitis
Atelectasis
Viscus obstruction
Drug fever
Myeloid reconstitution
Clinical Evaluation
Symptoms and signs of inflammation may be minimal or absent in the severely neutropenic patient
Cellulitis with minimal to no erythemaPulmonary infection without discernable infiltrate on radiographMeningitis without pleocytosis in the CSFUrinary tract infection without pyuriaPeritonitis - abdominal pain without fever or guarding
Sickles, Arch Intern Med 1975; 135;715-9
The Work Up
Physical Exam:Periodontium
Palate
Lung
Abdomen
Perineum
Skin
Tissue around the nails
BM biopsy site
Blood cultures x2
UA and Urine Cx
CXR
Targeted workup– C.diff– Exit site cultures– Catheter tip cultures – CT Abdomen/Pelvis
Ecthyma Gangrenosum
Bacteria:
Pseudomonas
GNR
Staphylococcus aureus
Fungus:
Aspergillus
Fusarium
Initial Neutropenic Fever
Empiric antibiotics:– Pseudomonas and Streptococcus coverage
Cefepime OR Zosyn OR Imipenem
+/- Aminoglycoside
+/- Vancomycin
Coverage of bacteria– Gram-negative organisms
Pseudomonas aeruginosa, E. coli, Klebsiella
– Gram-positive organisms (60%)Coag neg Staph, Viridans Streptococcus, MRSA Corynebacterium jeikeium
Empiric Vancomycin
Management Algorithm
65 AML s/p induction chemotherapy – HD 12 neutropenic fever.Physical exam unremarkable. Vitals = SIRS. CXR negative.
HD 13 – Remains febrile. Clinically stable. Cultures negative.
Start Vanco/Cefepime/Amikacin Blood Culture x2
Any Change in Management?
Management Algorithm
65 AML s/p induction chemotherapy – HD 12 neutropenic fever.Physical exam unremarkable. Vitals = SIRS. CXR negative.
HD 13 – Remains febrile. Clinically stable. Cultures negative.
Start Vanco/Cefepime/Amikacin Blood Culture x2
Blood Culture x2 Continue Vanco/Cefepime/Amikacin
HD 14 – Afebrile. Cx negative. HD 14 – Cx E.coli (pan-S)
Management Algorithm
65 AML s/p induction chemotherapy – HD 12 neutropenic fever.Physical exam unremarkable. Vitals = SIRS. CXR negative.
HD 13 – Remains febrile. Clinically stable. Cultures negative.
Start Vanco/Cefepime/Amikacin Blood Culture x2
Blood Culture x2 Continue Vanco/Cefepime/Amikacin
HD 14 – Afebrile. Cx negative. HD 14 – Afebrile. Cx E.coli (pan-S)
Cefepime Cefazolin
Continue antibiotics until ANC > 500.
Management Algorithm
65 AML s/p induction chemotherapy – HD 12 neutropenic fever.Physical exam unremarkable. Vitals = SIRS. CXR negative.
HD 13 – Remains febrile. Clinically stable. Cultures negative.
Start Vanco/Cefepime/Amikacin Blood Culture x2
Blood Culture x2 Continue Vanco/Cefepime/Amikacin
HD 14 – Remains febrile. Clinically stable. Cultures negative.
Any Change in Management?
Management Algorithm
65 AML s/p induction chemotherapy – HD 12 neutropenic fever.Physical exam unremarkable. Vitals = SIRS. CXR negative.
HD 13 – Remains febrile. Clinically stable. Cultures negative.
Start Vanco/Cefepime/Amikacin Blood Culture x2
Blood Culture x2 Continue Vanco/Cefepime/Amikacin
HD 14 – Remains febrile. Clinically stable. Cultures negative.
Blood Culture x2 Continue Cefepime
HD 15 – Remains febrile. Clinically stable. Cultures negative.
Any Change in Management?
Early Management Summary
D/C vanco after 48 hours if no evidence of GP infection.
No need to perform more BC after first 48-72 hours if patient clinically stable and no new symptoms.
Can simplify regimen if organism isolated. No need to double cover Pseudomonas if sensitive to monotherapy.
Median time to defervescence ~5 days.
Treatment duration typically until ANC > 500.
If clinical worsening:– Aggressive diagnostics– Modify antibiotics to cover for resistant organisms– Start anti-Candida therapy
Persistent Neutropenic Fever
65 AML s/p induction chemotherapy – HD 12 neutropenic fever.Physical exam unremarkable. Vitals = SIRS. CXR negative.
HD 17 – Remains febrile. Clinically stable. Cultures negative.
Vanco/Cefepime/Amikacin
HD 14 - Cefepime
Any Change in Management?
Persistent Neutropenic Fever
Up to 1/3 of patients with persistent neutropenic fever after 7d Abx have invasive fungal infection.
Most common: Candida & Aspergillus
Look for a source:
CT Chest and Sinus
Fungal blood cultures
Galactomannan or b-D-Glucan
Biopsy suspicious skin lesions
Fungus 101
YEAST:
Candida, Cryptococcus
MOLD:
Aspergillus, Mucor
Invasive Mold
Aspergillus
Zygomyces
Mucor
Rhizopus
Absidia
Fusarium
Halo sign Air crescent sign
Halo sign, air crescent sign, cavitating nodule Invasive mold
Abnormal CT chest BAL with biopsy or IR guided biopsy
Invasive Fungal Pneumonia
Anti-Fungal Therapy
Empiric:– Normal CT chest and/or sinus– Non-specific infiltrate on CT chest– No other evidence of invasive fungus– USE: Caspofungin or Amphotericin
Presumed or Definite Invasive Aspergillus:– Classic CT chest findings (no previous Voriconazole)– Positive culture or biopsy with typical hyphae– Positive Galactomannan– USE: Voriconazole
Persistent Fever
65 AML s/p induction chemotherapy – HD 12 neutropenic fever.Physical exam unremarkable. Vitals = SIRS. CXR negative.
HD 17 – Remains febrile. Clinically stable. Cultures negative.
Vanco/Cefepime/Amikacin
Cefepime
CT Chest & Sinus, Galactomannan Continue Cefepime. Start anti-mold.
Consult ID
Invasive mold infection No invasive mold infection
Voriconazole / Amphotericin Echinocandin / Amphotericin
Case
65 M AML s/p induction chemotherapy with daunorubicin and cytarabine.
Develops fever 12 days after completion of induction chemotherapy. He notes some non-specific abdominal pain and reports diarrhea x2 days (C.diff negative x1).
Fever to 39OC, HR 110, BP 90/50.
Looks ill, diffuse mild abd tenderness
Next Steps
Blood Cx x2
UA and Urine Cx
PA/LAT CXR
Empiric Abx – Vanco/Cefepime/Amikacin
Results
Blood Cultures negative x 24 hours
UA and Urine Cx negative
CXR negative
C.diff EIA negative
He develops septic shock ~30 hours later
CT Abd/Pelvis
Blood Cultures x2 – anaerobic bottle: Clostridium septicum
Neutropenic Colitis
Typhlitis– ANC < 500, usually AML– Abdominal pain– Diarrhea initially, ileus later– CT or US with bowel wall thickening– Rule-out C.diff– Need anaerobic coverage:
Zosyn, Imipenem, Cefepime + Flagyl
Summary
Neutropenic fever – definition and classification– High risk versus Low risk– Initial, Persistent, Recrudescent
Etiology / Microbiology– Bacterial translocation, CAI, HAI, opportunistic
Clinical evaluation– Neutropenia = lack of inflammation
Management– Initial NF – need Pseudomonas and Strep coverage– De-escalate empiric therapy after 48-72 hours– Persistent/Recrudescent NF – think fungal infection– Duration until ANC > 500