Febrile Neutropenia: A Review
Download
Report
Transcript Febrile Neutropenia: A Review
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=39.5C 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??