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 Cancer-
Related 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 post-
Taxotere®
 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 (2-
7.5)
 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  Yeast
organisms (~70%)  Candida
 Coagulase-negative
staphylococci  Aspergillus
 S. aureus  Viruses
 S.viridans
 Herpes simplex (HSV)
 Enterococci
 Influenza,
 Gram-negative paranifluenza
organisms
 CMV
 Coliforms (E.coli,
Klebsiella, Enterobacter)
 P.aeruginosa
 Initial Investigations
 History & physical exam
 Lab assessments
 Diagnostic imaging
 Microbiologic evaluations
 Detailed H&P Including
 Chemotherapy  Major comorbid
regimen & last dose illnesses
given  Recent surgical
 Presence of
procedures
vascular devices  Recent infections or
positive cultures
 Prophylactic
 Previous antibiotic-
antibiotic resistant organisms
 Steroid use or bacteraemia
 Allergies  Recent exposures
 Site-Specific H&P
 Oropharynx No mucositis
 Respiratory system Mild cough
 GI tract No N/V/D
 Skin No skin lesions, CVAD
 Genitourinary Yeast Infection
 CNS No CNS symptoms
 Lab assessments
 CBC with differential WBC=2.2, ANC=0.42,
Hgb=99, Plt=345
 BUN, SCr BUN=3, SCr=87
 Electrolytes Na=139, K=3.6,
Cl=104, HCO3=28
 LFTs
Tbili=16, ALT=117,
AST=76, Alp=84
 Urinalysis Normal
 Microbiologic evaluations
 Blood cultures x2
 1 catheter + 1 peripheral
 2 catheter
 2 peripheral
Blood & urine
 Urine culture cultures Negative
 if symptomatic
 urinary catheter
 or abnormal urinalysis
 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
 Patient
Assessment
Broad Site of
Spectrum Infection

Anti- Organ
Pseudomonal Function
Initial
Therapy
Local
Allergy
ABx
Status
Susceptibility

Previous
Potential
ABx
Organisms
Bacteri- Use
cidal
 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 Anticipated severe or prolonged

severe neutropenia 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 scoring index:
MASCC Score=26
 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  Vigilant observation
 No focus of infection,  Access to medical care
hemodynamically stable 24-7
 No systemic symptoms  Return to clinic if
other than fever  Positive cultures
 No organ failure,  Persistent/recurrent
pneumonia, soft tissue fever @ 3-5 days
infection, CVAD  Unable to tolerate PO
 Recovering bone regimen
marrow  Cipro 500 mg PO Q8h +
 Reliable patient 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:  Disadvantages:
 Synergistic effect  Lack of activity
against gram- against gram-
negatives positives?
 Reduced  Toxicity
emergence of
resistance
 IV Combination Therapy
 Aminoglycoside + (meropenem,
imipenem-cilastin or piperacillin-
tazobactam)
 Aminoglycoside + (cefepime or
ceftazidime)
 Ciprofloxacin + (meropenem,
imipenem-cilastin or piperacillin-
tazobactam)
 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 non-
albicans 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 azithromycin
viruses  P.jirovecii with Septra
Legionella urine antigen test  MRSA with vancomycin or
Consider BAL linezolid
 adding antiviral therapy
(influenza outbreak)
If high risk consider
 mold-active antifungal
adding (voriconazole or liposomal
CT chest to define infiltrates amphotericin B) if high risk
ID Consult
 Gastrointestinal Symptoms
Abdominal pain Diarrhea
 Abdominal CT or  C.difficile assay,
ultrasound (rotavirus &
 ALP, transaminases, norovirus?)
bilirubin, amylase,  Consider stool
lipase bacterial cultures
 Ensure anaerobic +/- parasite exam
coverage  Metronidazole if
C.difficile suspected
 Urinary tract symptoms
 Urine culture
 Urinalysis
 No additional therapy until pathogen
identified
 CNS Symptoms
 ID consult Empiric therapy:
 Neurology consult  Anti-pseudomonal
 CT +/- MRI penicillin that enters
 LP recommended
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 WBC 4.0 WBC 5.4
ANC 0.9 ANC 1.4 ANC 3.7
SCr=75 SCr=73
CrCl 92 ml/min
Temp=37 Temp=37.4 Temp=37.7
Urine C&S Gent trough Decision to
negative, CXR 0.4 discharge in
clear 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??