Febrile neutropenia

Christian Manginstar

CNS
Cardiologic

Sympthomatic
Emergencies

Respiratory
Emergencie
s

Gastrointestina
l

Oncologic
Emergency

Intervensi
Segera
Orthopedic
Emergencies

Hematologic
Emergencies

Infection
Emergencies

Metabolic &
Renal

Neutropenia

Infectio
n

Febrile

Sepsis

Febrile-Neutropenia Penting
Clinical outcomes :
Neutropenia induce
Chemotherapy solid
tumor
25- 40%.

Neutropenia solid tumor :

breast (27%), lung
(16%), ovarian (13%)
and esophageal (13%)
cancers.

Prolonged hospital stay

Increased diagnostic
and treatment costs
Delayed chemotherapy
Chemotherapy dose
reductions
Quality of Life
Increased mortality

Schelenz S et al. Annals of Oncology November 2, 2011

Result :
Regimen : Paclitaxel (18% MBC); Oxaliplatin, 5FU,Leucoforin (23%MCRC); Carboplatin + Paclitaxel
(49%MOC); docetaxel (68%MPC)
FN : 13,1%-20,6%
Hospitalization : 89%-94% first sicle 23-35%, mean
stay 7-7,5 d
Mortality : 3,9-10,3%
Cost : $16,291 - $ 19,456

Risk Infection >> :

ANC : 1000/mm3 < 500/mm3
100/mm3
10% 19%, 28%
<100/mm3 + Sepsis 80% ()

<

Emergency medicine Clinics North America 2009

Prefalensi FN Indonesia (cancer/ Sitostatika)

: (2008) RSCM 15%,
RS Dharmais 26% ( RS. Dharmais
mortalitas 12,5-35,8%) Infection
Eropa 8,7% ........ Why ???
Demam pada pasien neutropenia S.R. Hadinegoro

Neutrophil
Neonatus : (6.000-26.000
sel/mm3)
1 yr 1.500-8.000 cell/mm3)
50-70% cons.
Production 10 triliun 1 d
Age : 12 h in Blood
activation tissue ( 1-2 d )
Fungtion :
Fagositosis
Degranulation protein
(enzim)
NET

Pathophysiology
Absence of Granulocytes
Increase Infection
Disruption

of
Integumentary,
mucosal and
muco-ciliary
barriers
Shifts of inherent
microbial flora

Etiology & Epidemiology

FN : 10-50% during
Chemoth Solid tumor ( >
80% HM)
Infection in 20-30%
Febrile episodes.
Tahun terakhir: > Gr (+)
Drug-resistant gr(-) >>
Infection patients FN

Clinical Practice guideline ISDA

2010

Definisi dan resiko Infeksi pada Neutropeni

Definisi:

Singel oral temp > 38.3oC

(101oF) OR
Repeated oral temps > 38.0oC
(100.4oF) utk 1 jam

ANC < 500/mm3 or <

1000/mm3 < 500/mm3

Active Infection : mucositis,

abdominal pain, perirectal pain
NCCN 2013

Assesment Awal (Triage)

Neutropenia :
Chemoth. Patients with
fever (38oC)
Patients 3 months or <
after bone marrow
transplant

PS :
Tempperatur, pulse,
RR, BP, SaO2, GCS
Sepsis/ syok
resusitasi

Pemeriksaan dan Anamnesa

Sec. Survey :
Chest
Mucous membranes
Skin
Venous access
Peri-anal area
Urinary tract
Gastrointestinal tract
Cat : sign of infection (-)
little or no inflamatory
respoons, or syok/ MODS

Anamnesa:
Type of cancer,
Chemotherapy,
steroid, antibiotic,
surgical procedure,
allergies
( Mengenal Faktor
resiko)

Faktor Resiko
High Risk Patients

:
Haematologic malignancy
Myelosuppresive
Chemoth.
Radio-Chemoth.
Age > 60 th
Co.morbidities (DM)
Kanker pada sumsum
tulang

Luka operasi/ luka terbuka

mucositis
sakit
Pemakaian steroid > 25
mg prednisolon daily
Penurunan neutrophil
count
Riwayat neutropenia
Riwayat opname akibat
infeksi beberapa waktu
sebelumnya

Resiko rendah
Patients cancer dengan :
Solid tumor (non-hematological malignancy)
Tidak tampak sakit
Mucositis (-)
co-morbidities (-)
Neutrofil kembali normal rentang 1 mgg
Normal urine and blood cultur
Normal Chest X-Ray
Kecurigaan sepsis (-)

HIGH RISK
-

Inpatients
Associated co-morbidities
( hypotension,
dehydration, hypoxia )
Uncontrolled / progressive
cancer
Sr. Creatinine > 2 mg/dl

LFT > 3 times normal

HSCT / BMT recipient

Prolonged severe neutropenia

LOW RISK
-

Outpatients

No associated co-morbidities

Good PS ( ECOG 0 1 )

Sr. Creatinine < 2 mg/dl

LFT 3 times normal

Non-transplant, solid tumor or

lymphoma patient

Anticipated duration of
neutropenia
< 7 days

anticipated

* Infectious Diseases Society of America guidelines , 2002.

MASCC (Multinational Assocoiation for

supportive care)

PENCEGAHAN

Prophylaxis
Langkah Umum :
Cuci tangan
Menjaga kebersihan kulit keseluruhan
( preventing Staph. aureues ).
Menghindari genangan air (Parasit)

Menghindari
makanan
dengan
kandungan bakteri tinggi
Kebersihan mulut

PROPHYLAXIS :
MYELOID GROWTH FACTORS
Colony Stimulating Factors
Sitokin (hormon glikoprotein) mengatur
proliferasi, diferensiasi dan fungsi sel hemopoietik.
types
1.
Granulocyte Colony Stimulating Factors (GCSF)
2.
Granulocyte Macrophage Colony Stimulating
Factors (GM- CSF)
Penggunaan :
Profilaksis : Primer, Sekunder
Terapi

Granulocyte Colony Stimulating Factor (G-CSF)

G-CSF : stimulasi proliferasi, diferensiasi, maturasi sel
progenitor neutrofil, stimulasi neuPD, : waktu transit
me aktivitas neu.

Penggunaan : < 24 j / >24 j

kemoterapi, ANC
1000/mm3 , SC/ infus dex-5% selama 30 mnt
KI : wanita hamil dan menyusui
ES : nyeri tulang >> , ruam, pruritus, leukositosis,
Filgrastim : do : 5 gr/kgBB
Pegfilgasrim : singel dose 6g/cycle

Granulocyte Macrophage Colony

Stimulating Factors (GM- CSF)
GM-CSF = sitokin produce granulosit and monosit :
macrofag dan cell dendritik
Glycoprotein : macrophage, T-cell, mast cell, fibroblast.
Sargramostin :
1.
Induction in AML
2. Stem cell transplant

Waktu pemberian ?
Patient

factor

Chemotherapy
1.
2.
3.

High dose
Dose dense
Standard Dose

.Curative

vs Palliative

.Penyakit

yang mendasari

Faktor Patient
Age

> 65
chemo or radiotherapy
Riwayat neutropenia
Bone marrow involvement
Performance status (ECOG / WHO)
HIV
Renal or liver dysfunction
Riwayat Infeksi sebelumnya

Chemotherapy

Menilai faktor resiko

Terapi CSF pada FN

Apakah dengan GCSF sudah

cukup?
Keganansan

yang

mendasari
Penyakit yang
mendasari
Lamanya neutropenia
Chemotherapy
Intensitas terapi
imunosupresi

Profilaksis
antibiotik

 Prophylactic

antibiotics :

Fluoroquinolone
Cat.
1.
2.

:
Prophylaxis tidak terkait penurunan
bacteremia.
Resistan Quinolone

LEVOFLOXACIN is the preferred drug.

( 2014 update )

THERAPEUTIC

FOLLOW UP DAILY
Riwayat

penyakit dan hasil pemeriksaan

sebelumnya
Laboratorium CBC, Diff count, Platelet, LFT,
RFT, elektrolit, CRP, Procalcitonin, Il-6, Il-8/,
culture
penurunan bakteremia
Data trend demam
Toksisitas terkait obat

FEBRILE NEUTROPENIA
DURATION OF ANTIBIOTIC
THERAPY:

IDSA guidelines , 2002

Anti-Fungal
Mulai

setelah 4 hr FN.
Ampho B gold standard, spectrum
luas.
fluconazole alternative.
CT
scan
and
blood
culture
are
recommended.

Waktu pemberian terapi

Skin/soft tissue: 7-14
days
Sinusitis: 10-21 d
Bacterial pneumonia:
10-21 d
Uncomplicated
bacteremia :

1.
2.
3.
4.
a)
b)

Gram negative: 1014 d

Gram positive: 7-14 d

a)
b)

S.aureus: 2 weeks
kultur darah (-)
Yeast: 2 weeks
kultur darah (-)
mold (aspergillus
etc): min 12 weeks
Viral:
HSV/VZV: 7-10 d
Influenza: 5 d.

DRUGS REVIEW

Perbandingan terapi Antibiotik

Piperacillin-tazobactam

lactamase inhibitor)

(comb : penicillin +

Broad spectrum gram(-), gram(+) & anaerobic

Use for intra-abdominal
Not recommended for meningitis (poor CSF
penetration)

Imipenem-cilastin (Carbapenem)
Broad spectrum gram(-), gram(+) & anaerobic and
ESBL coverage
Use for intra-abdominal source
Risk of seizures in CNS malignancy or renal
impairment

 Meropenem

Broad spectrum gram(-), gram(+) &

anaerobic
Use for intra-abdominal source
Preferred for meningitis/CNS infection

Ceftazidime (Gen-3 Cephalosphorin)

Poor gram(+) activity
streptococcal infections
No activity against anaerobes, enterococcus
Good CSF penetration

 Aminoglycosides
Gram(-), synergy with beta-lactams against
S.aureus and Enterococcus
Nephrotoxicity, ototoxicity

Ciprofloxacin (gen-2 Fluorokuinolon)

Gram(-)
anaerobic (-), less gram(+)

Anti- fungals
NCCN recommens:
fluconazole :

Profilaksis azol sebelumnya (-),

low risk aspergillosis invasif
azole-resistant Candida rendah.

Dosing:

150 mg PO daily x 14 dose for vaginal candidiasis

200 mg PO daily x14 days for candidal
pyelonephritis
400 mg PO daily prophylaxis for neutropenic
patients

NCCN Recommends :
Tambahkan

Vorikonazol, amfoterisin B jika

sudah menerima azole sebelumnya dengan
klinis candida albican

Voriconazole 6 mg/kg IV 12h x2 doses then 4 mg/kg

IV/PO q12h
Amphotericin 3-5 mg/kg IV daily

ANC
setidaknya 14 hr

Pemberian

>

1000/mm3

atau

Antiviral drugs

(-) Provilaksis antivirus

Pertimbangkan acyclovir (famiciclovir or valacyclovir)
HSV (hematologic malignancy)
Pada BMT pengobatan CMV dgn ganciclovir
Oral vesicular lesions: HSV
Esophageal lesions: HSV, CMV
Skin lesions: VZ
Pneumonia: Influenza
CNS : HSV

Acyclovir:

Ganciclovir:

CMV treatment: 5 mg/kg IV Q12h x2 weeks then 5

mg/kg IV Q24h x2-4 weeks

Foscarnet:

Mucocutaneous HSV: 5 mg/kg IV Q8h

Single dermatomal VZ: 800 mg PO 5x/day or 5 mg/kg IV
Q8h
Disseminated VZV or HSV: 10 mg/kg IV Q8h

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)

CNS
CT

+/- MRI
LP recommended
Empiric therapy:
Anti-pseudomonal CSF (ceftazidime, meropenem)
Vancomycin pilihan pertama, especially if neurosurgical.
Adjuvant dexamethasone
For suspected Abscess, tambahkan metronidazole.
Use cotrimoxazole, if suspect toxoplasma and nocardia

Pneumonia
Px. tambahan: Chest radiographs+ blood culture
Cultures

: sputum
Nasal wash for respiratory virus
Legionella antigen test
BAL
High risk CT chest to define infiltrates

anti-pseudomonal diberikan
atypical bacteria azithromycin/ fluroquinolones
MRSA vancomycin
Aspergilosis antifungal (voriconazole / amphotericin
B) if high risk

Gastrointestinal Symptoms
Abdominal pain
CT Abdominal
ALP, transaminases, bilirubin, amylase, lipase
anaerobic + anti-pseudomonal
Anti-fungal prophylaxis as candida.
Diarrhoea
cultures feses
C.difficile
suspected,
nasogastric

oral

metronidazole

Neutropenic Colitis kasus emergency kematian, Sebaiknya dikelola

secara konservatif

Vascular Access Device

Urinary tract symptoms

Urine

culture
Urinalysis
No additional therapy until pathogen
identified

Invasive Fungal Infection

INVASIVE CANDIDIASIS

Fluconazole/Echinocandin pada non-neutropenic

pts.
Echinocandin / Capsofungin iv is drug of
choice (IDSA update) pada neutropenic patients.
Fluconazole , bila sensitive (C. albicans and
parapsilosis)
Ampho B pada meningitis and endocarditis.

Vaksinasi
IDSA guidelines
Vaksin hidup yang dilemahkan diberikan 3 bln post
Kemo/radioTh/
Ideal diberikan 2 mgg sblm kemo/radioth.
Vaksin influenza diberikan setiap tahun
Pneumococcal, meningococcal vaccine diberikan pada
patients splenectomy, hypogammaglobulinemia and B
cell malignancies.

Kesimpulan

FN dapat dicegah
kedaruratan Onkologi

dan diperlakukan sebagai suatu

FN bersifat indifidual pada setiap penderita.

Setiap lembaga harus memiliki pedoman dan pola kuman

serta sensitifitas sebagai bagian penatalaksanaan FN.

Universal precautions harus diterapkan dengan ketat pada

penatalaksanaan FN.

Walau sesuatu sudah tampak jelas adanya,

tidak selalu demikian dengan yang
sesungguhnya terjadi

Only GOD Know

Management