Febrile neutropenia

Christian Manginstar
 CNS

Cardiologic Gastrointestinal

Sympthomatic Oncologic Hematologic

Emergencies Emergencies
Emergency

Intervensi
Respiratory
Emergencies Segera Infection
Emergencies
Neutropenia Infection Febrile Sepsis

Orthopedic Metabolic &

Emergencies Renal
 Febrile-Neutropenia Penting

Clinical outcomes :
Neutropenia induce Prolonged hospital stay
Chemotherapy solid
tumor Increased diagnostic
25- 40%. and treatment costs
Delayed chemotherapy
Chemotherapy dose
Neutropenia solid tumor : reductions
breast (27%), lung (16%),
ovarian (13%) and Quality of Life
esophageal (13%) Increased mortality
cancers.

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

Result :
Regimen : Paclitaxel (18% MBC); Oxaliplatin, 5-
FU,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 ( 1-3 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: All Infxns Severe Infxns Bacteremia

Singel oral temp > 38.3oC
(101oF) OR 5
Repeated oral temps > 4,5
38.0 C (100.4 F) utk 1 jam
o o
4
3,5
ANC < 500/mm3 or <
3
1000/mm3 < 500/mm3 2,5
2
Active Infection : mucositis, 1,5
abdominal pain, perirectal pain
1
NCCN 2013
0,5
0
0 100 500 1000
Assesment Awal (Triage)

Neutropenia : PS :
Chemoth. Patients with Tempperatur, pulse, RR,
fever (38oC) BP, SaO2, GCS
Patients 3 months or <
after bone marrow Sepsis/ syok
transplant resusitasi
Pemeriksaan dan Anamnesa
Sec. Survey :
Chest
Mucous membranes Anamnesa:
Skin Type of cancer,
Venous access Chemotherapy,
Peri-anal area steroid, antibiotic,
Urinary tract surgical procedure,
Gastrointestinal tract allergies

Cat : sign of infection (-)

little or no inflamatory
respoons, or syok/ MODS
Faktor Resiko
High Risk Patients : Luka operasi/ luka terbuka
Haematologic malignancy
Myelosuppresive Chemoth.
Radio-Chemoth.
Age > 60 th
Co.morbidities (DM)
Kanker pada sumsum
tulang
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
LOW RISK
- Inpatients
- Outpatients
- Associated co-morbidities
( hypotension, dehydration, - No associated co-morbidities
hypoxia )
- Good PS ( ECOG 0 1 )
- Uncontrolled / progressive
- Sr. Creatinine < 2 mg/dl
cancer
- LFT 3 times normal
- Sr. Creatinine > 2 mg/dl
- Non-transplant, solid tumor or
- LFT > 3 times normal
lymphoma patient
- HSCT / BMT recipient
- Anticipated duration of
- Prolonged severe neutropenia neutropenia
anticipated < 7 days

* 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. High dose
2. Dose dense
3. 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
Profilaksis
Lamanya neutropenia
antibiotik
Chemotherapy
Intensitas terapi
imunosupresi
 Prophylactic antibiotics :
Fluoroquinolone
Cat. :
1. Prophylaxis tidak terkait penurunan
bacteremia.
2. 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
1. Skin/soft tissue: 7-14 S.aureus: 2 weeks
days kultur darah (-)
2. Sinusitis: 10-21 d Yeast: 2 weeks
3. Bacterial pneumonia: kultur darah (-)
10-21 d mold (aspergillus
etc): min 12 weeks
4. Uncomplicated
Viral:
bacteremia :
a) HSV/VZV: 7-10 d
a) Gram negative: 10-
14 d b) Influenza: 5 d.
b) Gram positive: 7-14 d
DRUGS REVIEW
Perbandingan terapi Antibiotik
Piperacillin-tazobactam (comb : penicillin
+ lactamase inhibitor)
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

Pemberian ANC > 1000/mm3 atau setidaknya

14 hr
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:
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

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)
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, oral metronidazole +
nasogastric

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 dan diperlakukan sebagai suatu

kedaruratan Onkologi

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