Febrile Neutropenia:
A Review of the Guidelines
September 29, 2010
Andrea Beaman, BScPhm, RPh
PharmD Candidate
Learning Objectives
1. Identify predisposing factors and
common pathogens that cause
infections in febrile neutropenic
patients.
2. Review initial investigations that will
help direct therapy in febrile
neutropenic patients.
Learning Objectives
3. Compare recommendations for
empiric antibiotic selections for high
risk and low risk febrile neutropenic
patients.
4. Discuss assessment of response,
treatment modifications and duration
of therapy.
Recent Guidelines
 National Comprehensive Cancer Network
Clinical Practice Guidelines in Oncology.
Prevention and Treatment of CancerRelated Infections v.2.2009
 European Society for Medical Oncology.
Management of Febrile Neutropenia: ESMO
Clinical Practice Guidelines (2010)
 Infectious Disease Society of America. 2002
Guidelines for the Use of Antimicrobial
Agents in Neutropenic Patients with Cancer
(Update expected Winter 2011)
What is the Risk?
Incidence of Febrile Neutropenia
Induction-remission for AML
70-90%
Elderly patients receiving CHOP
35-45%
Patients with NHL
10-20%
Mortality Estimates from Febrile Neutropenia
Solid tumours
5%
Hematological malignancy
Up to 11%
Gram-positive bacteremia
5%
Gram-negative bacteremia
18%
Case Presentation
 A 40 yr old woman diagnosed with locally
advanced breast Ca in Mar/2010
 Plan of care:
 Completed 3 cycles neoadjuvant FEC
q3wk
 Received 2nd cycle Taxotere® q3wk on
Sept 13
 Receiving Neulasta® dose Day 1 postTaxotere®
 Plan for surgery in Nov.
Case Presentation
 Presented on Sept 20th with
Temp=39.5C and feeling “unwell”.
 WBC = 2.2 (4-11), Neutrophil = 0.42 (27.5)
 Creat = 87 (50-100)
 BP 170/60, RR 16
 Ht = 178 cm, Wt = 90.7 kg
Definition of Febrile
Neutropenia
Does this patient have febrile neutropenia?
 Fever: Single oral temperature ≥38.3°C or
persistent temperature ≥38.0 °C for >1 hour.
Temp 39.5 °C
 Neutropenia: ANC <0.5, or ANC <1.0 and a
predicted decline to <0.5 over next 48 hrs.
(ANC= absolute neutrophil count)
ANC 0.42
Predisposing Factors
 Malignancy
 Type
 Advanced/refractory
 Obstructive
 Surgical risk
 Grade of neutropenia
 Disruption of mucosal barriers
 Corticosteroid use
Microbiology
 Mainly gram-positive
organisms (~70%)
 Coagulase-negative
staphylococci
 S. aureus
 S.viridans
 Enterococci
 Gram-negative
organisms
 Coliforms (E.coli,
Klebsiella, Enterobacter)
 P.aeruginosa
 Yeast
 Candida
 Aspergillus
 Viruses
 Herpes simplex (HSV)
 Influenza,
paranifluenza
 CMV
Initial Investigations
 History & physical exam
 Lab assessments
 Diagnostic imaging
 Microbiologic evaluations
Detailed H&P Including
 Chemotherapy
regimen & last dose
given
 Presence of
vascular devices
 Prophylactic
antibiotic
 Steroid use
 Allergies
 Major comorbid
illnesses
 Recent surgical
procedures
 Recent infections or
positive cultures
 Previous antibioticresistant organisms
or bacteraemia
 Recent exposures
Site-Specific H&P
 Oropharynx
 Respiratory system
 GI tract
 Skin
 Genitourinary
 CNS
No mucositis
Mild cough
No N/V/D
No skin lesions, CVAD
Yeast Infection
No CNS symptoms
Lab assessments
 CBC with differential
 BUN, SCr
 Electrolytes
 LFTs
 Urinalysis
WBC=2.2, ANC=0.42,
Hgb=99, Plt=345
BUN=3, SCr=87
Na=139, K=3.6,
Cl=104, HCO3=28
Tbili=16, ALT=117,
AST=76, Alp=84
Normal
Microbiologic evaluations
 Blood cultures x2
 1 catheter + 1 peripheral
 2 catheter
 2 peripheral
 Urine culture
 if symptomatic
 urinary catheter
 or abnormal urinalysis
Blood & urine
cultures Negative
Site-Specific Cultures
 Diarrhea: C.difficile assay, stool microscopy
and culture
 Sputum microscopy and culture
 Aspirate/swab/biopsy of any skin lesions or
CVAD-associated symptoms
 Viral cultures
 Vesicular or ulcerated skin/mucosal lesions
 Throat or nasopharynx for respiratory symptoms
(esp. during outbreaks)
 LP if CNS symptoms
 Fungal cultures
Broad
Spectrum
Patient
Assessment
Organ
Function
AntiPseudomonal
Local
ABx
Susceptibility
Potential
Organisms
Site of
Infection
Initial
Therapy
Allergy
Status
Bactericidal
Previous
ABx
Use
Risk Status Assessment
Low Risk
High Risk
Outpatient at time of fever
Inpatient at time of fever
No acute comorbid illnesses
Significant medical comorbidity
Anticipated short duration of
severe neutropenia
Anticipated severe or prolonged
neutropenia
No renal insufficiency
CrCL <30 ml/min
No hepatic insufficiency
Transaminases ≥5x ULN
Good performance status
Uncontrolled/progressive cancer,
Mucositis grade 3-4
MASCC Risk Index score ≥21
MASCC Risk Index score <21
LOW RISK
Complex infection
MASCC Index
 Multinational Association for Supportive Care in
Cancer
 Prospectively validated tool to rapidly assess risk
before access to neutrophil count.
 Scores 21 are at low risk of complications (max
score 26).
MASCC
Score=26
 MASCC scoring index:









Burden of illness: no or mild symptoms 5
Burden of illness: moderate symptoms 3
Burden of illness: severe symptoms 0
No hypotension (systolic BP >90 mmHg) 5
No chronic obstructive pulmonary disease 4
Solid tumour/lymphoma with no previous fungal infection 4
No dehydration 3
Outpatient status at onset of fever 3
Age <60 years (not valid in children <18 years) 2
Klastersky J,J Clin Oncol 2000; 18:3038–51.
Low Risk Treatment
 Low risk, adult patients
 No focus of infection,
hemodynamically stable
 No systemic symptoms
other than fever
 No organ failure,
pneumonia, soft tissue
infection, CVAD
 Recovering bone
marrow
 Reliable patient
 Vigilant observation
 Access to medical care
24-7
 Return to clinic if
 Positive cultures
 Persistent/recurrent
fever @ 3-5 days
 Unable to tolerate PO
regimen
 Cipro 500 mg PO Q8h +
amoxicillin-clavulanate
500 mg PO Q8h
Principles of High Risk
Treatment
 Inpatient treatment with IV antibiotics
 Coverage for MRSA or resistant Gram-
negative bacteria may be required.
 B-lactam antibiotic in combination
with an aminoglycoside is preferable
to monotherapy with
antipseudomonal cephalosporins.
IV Monotherapy
 Cefepime
 Imipenem-cilastin
 Meropenem**
 Piperacillin-tazobactam** (NCCN)
 Ceftazidime** (with concerns)
**Formulary (all others Non-formulary at THC)
IV Combination Therapy
 Advantages:
 Synergistic effect
against gramnegatives
 Reduced
emergence of
resistance
 Disadvantages:
 Lack of activity
against grampositives?
 Toxicity
IV Combination Therapy
 Aminoglycoside + (meropenem,
imipenem-cilastin or piperacillintazobactam)
 Aminoglycoside + (cefepime or
ceftazidime)
 Ciprofloxacin + (meropenem,
imipenem-cilastin or piperacillintazobactam)
IV Therapy Options:
Comparison
 Piperacillin-tazobactam
 Broad spectrum gram(-), gram(+) & anaerobic
coverage
 Use for intra-abdominal source
 Not recommended for meningitis (poor CSF
penetration)
 Imipenem-cilastin
 Broad spectrum gram(-), gram(+) & anaerobic
and ESBL coverage
 Use for intra-abdominal source
 Risk of seizures in CNS malignancy or renal
impairment
IV Therapy Options:
Comparison
 Meropenem
 Broad spectrum gram(-), gram(+) & anaerobic
and ESBL coverage
 Use for intra-abdominal source
 Preferred for meningitis/CNS infection
 Ceftazidime
 Poor gram(+) activity
 Breakthrough streptococcal infections
 No activity against anaerobes, enterococcus
 Good CSF penetration
IV Treatment Options:
Comparison
 Aminoglycosides
 Gram(-) coverage, synergy with beta-lactams
against S.aureus and Enterococcus
 Nephrotoxicity, ototoxicity
 Ciprofloxacin
 Gram(-) and atypical bacterial coverage
 No anaerobic coverage, less gram(+) activity
than other options
 Good clinical studies as empirical PO or IV
therapy
 Avoid in patients recently treated with quinolone
prophylaxis
Vancomycin
 Vancomycin not routinely recommended for
empiric therapy
 Use should be limited to specific indications:
 clinically suspected serious catheter-related infection
 known colonization with MRSA or pcn/ceph-resistant





pneumococci
gram-positive bacteremia pending further C&S
hypotension or other cardiovascular impairment
soft-tissue infection
risk factors for viridans strep bacteremia (severe mucositis +
prophylaxis with Septra or Cipro)
Reassess Vancomycin after 24-48 hours
THC protocol:
 Ceftazidime 2g IV q8h
 Gentamicin 120 mg IV q12h x2 doses,
then Pharmacist to dose
Case Patient Gentamicin Dosing:
 ABW=90.7 kg, Ht = 178 cm
 IBW=70.7 kg, DW=78.8 kg
 SCr=73, CrCl=92 ml/min
 Gentamicin once daily dosing appropriate
 Dose: Age 16-65: 6 mg/kg (DW)/dose = 460 mg IV
 Frequency: CrCl >60 ml/min: Q24h
Antifungals as Empiric
Therapy?
 Clinical suspicion: High risk patients with
prolonged neutropenia and site-specific
symptoms:
 Oral thrush: Mucositis mouthwash , Fluconazole
 Esophageal lesions: Fluconazole
 Sinus/nasal symptoms and suspicious CT/MRI:
Amphotericin B
 Pneumonia: voriconazole, amphotericin B
 Empiric treatment required based on H&P as
positive cultures can take several days.
Antifungals Added Later?
 IDSA recommends consider antifungal
if febrile after 3-5 days and remains
neutropenic
 Amphotericin B is preferred
 Fluconazole may be acceptable at
institutions with low rates of mold
infections or drug-resistant Candida
species
Antifungals Added Later?
NCCN recommends:
 Add fluconazole if
 no prior azole antifungal prophylaxis,
 low risk for invasive aspergillosis and
 low rates of azole-resistant Candida.
 Dosing:
 150 mg PO x1 dose for vaginal candidiasis
 200 mg PO daily x14 days for candidal pyelonephritis
 800 mg x1 then 400 mg daily x14 days from first negative
culture for candidiasis (not recommended if received
prophylaxis)
 400 mg PO daily prophylaxis for neutropenic patients
Antifungals Added Later?
NCCN Recommends
 Add voriconazole, liposomal amphotericin B
or an echinocandin if already exposed to
an azole or known to be colonized with nonalbicans Candida.
 Voriconazole 6 mg/kg IV q12h x2 doses then 4
mg/kg IV/PO q12h
 Amphotericin B 3-5 mg/kg IV daily
 Caspofungin 70 mg IV x1 then 50 mg IV daily; 70
mg IV daily for aspergillosis
 Continue until neutropenia has resolved, or
for at least 14 days in patients with a
demonstrated fungal infection.
Case Presentation
 Does she need antifungal coverage?
 Symptomatic vaginal yeast infection,
unsuccessfully treated
 Fluconazole 200 mg PO x1 dose given.
 Clotrimazole Vaginal ovule daily x3
days with prn use of cream.
When to Add Antiviral Therapy
 Oral vesicular lesions: HSV
 Esophageal lesions: HSV, CMV
 Skin lesions: VZV
 Pneumonia: Influenza
 CNS symptoms: HSV
Antiviral Doses
 Acyclovir:
 Mucocutaneous HSV: 5 mg/kg IV Q8h
 Single dermatomal VZV: 800 mg PO 5x/day or 5 mg/kg IV Q8h
 Disseminated VZV or HSV: 10 mg/kg IV Q8h
 Valacyclovir:
 HSV or VZV treatment: 1g PO Q8h
 Ganciclovir:
 CMV treatment: 5 mg/kg IV Q12h x2 weeks then 5 mg/kg IV Q24h
x2-4 weeks
 Foscarnet:
 Acyclovir-resistant HSV: 40 mg/kg IV Q8h
 CMV treatment: 90 mg/kg IV Q12h x2 weeks then 120 mg/kg IV
Q24h x2-4 weeks
 Oseltamivir:
 Influenza: 75 mg PO Q12h
(reduced doses required in renal impairment)
Pneumonia
Additional Tests:
Include coverage for:
sputum cultures
 atypical bacteria with
Nasal wash for respiratory
viruses
Legionella urine antigen test
Consider BAL



If high risk consider
adding
CT chest to define infiltrates
ID Consult

azithromycin
P.jirovecii with Septra
MRSA with vancomycin or
linezolid
adding antiviral therapy
(influenza outbreak)
mold-active antifungal
(voriconazole or liposomal
amphotericin B) if high risk
Gastrointestinal Symptoms
Abdominal pain
 Abdominal CT or
ultrasound
 ALP, transaminases,
bilirubin, amylase,
lipase
 Ensure anaerobic
coverage
Diarrhea
 C.difficile assay,
(rotavirus &
norovirus?)
 Consider stool
bacterial cultures
+/- parasite exam
 Metronidazole if
C.difficile suspected
Urinary tract symptoms
 Urine culture
 Urinalysis
 No additional therapy until pathogen
identified
CNS Symptoms
 ID consult
 Neurology consult
 CT +/- MRI
 LP recommended
Empiric therapy:
 Anti-pseudomonal
penicillin that enters
CSF (ceftazidime,
meropenem)
 Vancomycin
 Ampicillin unless using
meropenem
 For encephalitis add
high dose acyclovir
Assessment of Response
Daily assessment until afebrile and ANC
0.5:
 Fever
 CBC
 Renal function
 Clinical Symptoms
Case Presentation
Assessment of Response
Sept 21
Sept 22
Sept 23
WBC 3.6
ANC 0.9
SCr=75
CrCl 92 ml/min
Temp=37
WBC 4.0
ANC 1.4
SCr=73
WBC 5.4
ANC 3.7
Temp=37.4
Temp=37.7
Urine C&S
negative, CXR
clear
Gent trough
0.4
Decision to
discharge in
24hr.
Duration of Therapy
 Afebrile and ANC 0.5 x48 hrs:
 Low risk patients, no source of infection identified: can
discontinue abx
 High risk patients or with documented infection: continue
tailored therapy 7 days
 Afebrile but ANC <0.5 after 5-7 days:
 low risk: can discontinue abx
 high risk: continue abx until ANC 0.5 or 14 days in pts not
expecting ANC recovery.
 Febrile:
 Neutropenic: continue abx at least 14 days, reassess for
non-response
 Non-neutropenic: discontinue abx 4-5 days after ANC >0.5
if no source of infection identified
IDSA 2002 Guidelines for the Use of
Antimicrobial Agents in Neutropenic
Patients with Cancer
Follow up for Non-Responsive
Patients
 Febrile but otherwise stable
 If non-neutropenic consider d/c abx 4-5 days
after ANC >0.5
 Consider antifungal therapy with activity against
mold if fever continuing ≥4-5 days.
 Febrile and clinically unstable
 Broaden coverage to include anaerobes,
resistant gram negative rods, resistant gram
positive organisms
 Ensure coverage of Candida
 Consider antifungal therapy with activity against
mold if fever continuing ≥4 days of therapy
 ID consult
Duration of Therapy for
Documented Infection
 Skin/soft tissue: 7-14 days
 Sinusitis: 10-21 days
 Bacterial pneumonia: 10-21 days
Duration of Therapy for
Documented Infection
 Uncomplicated bacteremia:
 Gram negative: 10-14 days
 Gram positive: 7-14 days
 S.aureus: at least 2 weeks after first
negative blood culture and normal TEE
 Yeast: ≥2 weeks after first negative blood
culture
Duration of Therapy for
Documented Infection
 mold (aspergillus etc): min 12 weeks
 Viral:
 HSV/VZV: 7-10 days
 Influenza: ≥5 days.
Where do we go from
here?
 The role of oral therapy and IV
monotherapy?
 Antibiotic lock solutions for CVADs
 The role of G-CSFs
 Updated IDSA Guidelines
Questions??