Dr. Santosa, Sp.

PD-KHOM,FINASIM
Division Hematology Medical Oncology,
Dept of Internal Medicine, Dr. Kariadi
Hospital/Diponegoro University Semarang
Email: santosaiva@yahoo.com;
hemasemarang@yahoo.com
 Definisi Demam Neutropenia:
Demam:
suhu sekurang-kurangnya 38.30 C atau
suhu sekurang-kurangnya 380C, pada dua
waktu, dalam hubungannya dengan:
Hitung NEUTROFIL absolut: (ANC)
< 0.5 x 109 sel/L atau
 1.0 x 109 dan diprediksi turun < 0.5 x 109
sel/L
ingaratnam S. et al. Internal Medicine Journal 2011;41 (Suppl 1):75-81
● unspesific symptom

● Abdominal pain

● treatment delay; Mortality 70%.

 complications of cancer chemotherapy
 major cause of morbidity
 healthcare resource use
 compromised efficacy resulting from delays
and dose reductions in chemotherapy.
◙ clinical infection 50%
◙ Microbial 25%.
 Gram negative,
 Pseudomonas aeruginosa
 Escherichia coli
 Klebsiella spp
Overall mortality rates are 5% in patients with
solid tumours (1% in lowrisk patients) and as high
as 11% in some haematological malignancies.
Prognosis is worst in patients with proven
bacteraemia, with mortality rates of 18% in
Gram-negative and 5% in Gram-positive
bacteraemia.
Mortality varies according to the MASCC
prognostic index (detailed further down): as low
as 3% if the MASCC score is >21, but as high as
36% if the MASCC score is <21
◙ Coagulase-negative Staphylococcus
 Methicillin-resistant Staphylococcus aureus
 Vancomycin-resistant Enterococcus
 Penicillin-resistant Streptococcus pneumoniae

Sesitifity pattern and local infection
 necrotizing mucositis
 perirectal abcess/cellulitis
 intra-abdominal atau pelvic infection
 typhilitis (necrotizing neutropenic colitis)
 sinus atau periodontal abcess
 anaerobic bacteremia.
◙ Candida
◙ Aspergillus
◙ Herpes simplex or zoster
 skin eruption
 encephalitis
 Meningitis
 myelitis
 esophagitis
 pneumonia
 hepatitis
 rythema multiforme / or ocular syndromes
◙ other cytomegalovirus, Epstein-Barr virus,
respiratory syncytial and influenza A viruses.
 Mainly gram-positive  Yeast
organisms (~70%)  Candida
 Coagulase-negative
staphylococci
 Aspergillus
 S. aureus  Viruses
 S.viridans  Herpes simplex (HSV)
 Enterococci  Influenza, paranifluenza
 Gram-negative organisms
 CMV
 Coliforms (E.coli, Klebsiella,
Enterobacter)
 P.aeruginosa
 Incidence 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%

FEBRILE NEUTROPENIA ; CHEMO REGIMENT

REGIMENT FN RATE
ABVD 2-10 %
CHOP 20-40%
LYMPHOHA SALVAGE 30-60%
AML INDUCTION 100%
AML CONSOLIDATION > 85%
 Malignancy
 Type
 Advanced/refractory
 Obstructive (lung, urinary tract)
 Surgical risk
 Grade of neutropenia
 Disruption of mucosal barriers
 Corticosteroid use
 History & physical exam
 Lab assessments
 Diagnostic imaging
 Microbiologic evaluations
 Chemotherapy  Major comorbid
regimen & last dose illnesses
 Recent surgical
given
 Presence of vascular procedures
 Recent infections or
devices positive cultures
 Prophylactic antibiotic  Previous antibiotic-
 Steroid use
resistant organisms or
 Allergies bacteraemia
 Recent exposures
 Oropharynx Mucositis??
 Respiratory system cough ???
 GI tract Nausea, vomitus,
 Skin diarhea??
 Genitourinary skin lesions??, CVAD??
 CNS Yeast Infection???
CNS symptoms???
 CBC with differential

 Ureum, Creatinien
 Electrolytes

 LFTs
 Urinalysis
 Blood cultures , 2 set
 1 catheter + 1 peripheral
 2 catheter
 2 peripheral
 Urine culture
 if symptomatic
 urinary catheter
 or abnormal urinalysis
 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
 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).

Klastersky J,J Clin Oncol 2000; 18:3038–51.

  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

Paesmans M, Klastersky J. Risk Assessment in Adult Cancer Patients with Febrile Neutropenia: A Review of Methods and of Risk-adapted Empiric
Treatments. HOSPITAL CHRONICLES 2007, 2(2): 66–73
Hughes WT, Armstrong D, Bodey GP, Bow EJ, Brown AE, Calandra T. 2002 Guidelines for the Use of Antimicrobial Agents in Neutropenic Patients with
Cancer. Clin Infect Dis 2002;34(6):730-51.
Naurois JD, Basso N, Gill MJ, Marti FM, Cullen MH, Roila F. Management of febrile neutropenia: ESMO Clinical Recommendations. Annals of
Oncology 2010
 Low risk, adult patients  Vigilant observation
 No focus of infection,  Access to medical care 24-7
hemodynamically stable  Return to clinic if
 No systemic symptoms other  Positive cultures
than fever  Persistent/recurrent fever @ 3-5
 No organ failure, pneumonia, days
soft tissue infection, CVAD  Unable to tolerate PO regimen
 Recovering bone marrow  Cipro 500 mg PO Q8h +
 Reliable patient amoxicillin-clavulanate 500 mg
PO Q8h
 Moxifloxacin 400 mg PO daily
 If penicillin allergic, substitute
clindamycin 300 mg PO q6h for
amoxicillin-clavulanate
 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.
 Anticipated, prolonged (>7-d duration), and
profound neutropenia (ANC <100/µL)
following cytotoxic chemotherapy
 Significant medical comorbidities, including
hypotension, pneumonia, new-onset
abdominal pain, or neurologic changes
 Anticipated brief (<7-d duration) period of
neutropenia
 ANC greater than 100/µL and absolute monocyte
count greater than 100/µL
 Normal findings on chest radiograph
 Outpatient status at the time of fever onset
 No associated acute comorbid illness
 No hepatic or renal insufficiency
 Early evidence of bone marrow recovery
This must include an agent with antipseudomonal
activity.
The following antibiotics are appropriate as
monotherapy
 Piperacillin-tazobactam  4.5 g IV q6h or
 Cefepime 2 g IV q8h or
 Meropenem  1 g IV q8h or
 Imipenem-cilastatin  500 mg IV q6h
 Piperacillin-tazobactam
No single agent has shown superiority in the empiric
treatment of febrile neutropenia.
 Dual antibiotic for complicated cases
 hypotension or
 Pneumonia or
 suspected or proven antimicrobial resistance.

 Piperacillin-tazobactam 4.5 g IV q6h plus  an aminoglycoside

 or
 Cefepime 2 g IV q8h plus  an aminoglycoside  or
 Meropenem 1 g IV q8h plus  an aminoglycoside  or
 Imipenem-cilastatin 500 mg IV q6h plus an aminoglycoside
 Aminoglycoside options:
 Gentamicin  2 mg/kg IV q8h or 5 mg/kg q24h or
 Amikacin  15 mg/kg/day or
 Tobramycin  2 mg/kg q8h
 Clinically suspected serious catheter-related infections (eg,
bacteremia, cellulitis)
 Known colonization with penicillin- and cephalosporin-
resistant pneumococci or methicillin-resistant Staphylococcus
aureus (MRSA)
 Blood culture positive for gram-positive bacteria
 Hypotension
 Severe mucositis, if prior fluoroquinolone prophylaxis
provided 

doses 15 mg/kg IV q12h)

 MRSA – Vancomycin, linezolid, or daptomycin
 Vancomycin-resistant enterococcus (VRE) – 
Linezolid or daptomycin
 Extended-spectrum beta-lactamase (ESBL)–
producing gram-negative bacteria – A carbepenem
(eg, imipenem, meropenem)
 Carbapenemase-producing  organisms
(eg, Klebsiella pneumoniaecarbapenemase) –
polymyxin-colistin  or tigecycline
 Empiric antifungal therapy:
 Amphotericin B liposomal complex 3 mg/kg q24h or
 Voriconazole 6 mg/kg q12h X 2 doses, then 4 mg/kg q12
h or
 Posaconazole 200 mg PO q6h for 7d, then 400 mg PO
q12h or
 Itraconazole 200 mg IV q12h for 2d, then 200 mg IV or PO
q24h for 7d, then 400 mg PO q24h thereafter or
 Caspofungin 70 mg IV for 1 dose, then 50 mg IV q24h or
 Micafungin 100-150 mg IV q24h or
 Anidulafungin 200 mg IV for 1 dose, then 100 mg IV q24h
Patients already on antifungal prophylaxis
should be switched to a different class if fever
persists.
Continue therapy for 2 weeks if patient has
stabilized and no infectious nidus is identified.
Talcott JA, Siegel RD, Finberg R, Goldman L. J Clin Oncol 1992 Feb;10(2):316-22.
Naurois JD, Basso N, Gill MJ, Marti FM, Cullen MH, Roila F. Management of febrile neutropenia: ESMO Clinical
Recommendations. Annals of Oncology 2010