1. CURRICULUME VITAE NAMA : Dr. Edi Hartoyo, Sp.A
TEMPAT/TGL LAHIR : Brebes, 05 Juli 1964
JABATAN : Staf Bag./SMF IKA RSUD Ulin Banjarmasin
JENIS KELAMIN : Laki-laki
ALAMAT RUMAH : Jl. Raya Sadewa No. 23 Komp. Perumnas Permai Banjarmasin
PENDIDIKAN DAN PELATIHAN :
Lulus pendidikan S 1 tahun 1991 di FK. Unissula Semarang
Lulus pendidikan Spesialis Anak tahun 2002 di FK. UGM Yogyakarta
Fellowship PICU (FK. UNDIP, tahun 2004)
Fellowship Penyakit Infeksi dan Pediatric Tropic (FK. UI, tahun2008)
Workshop Biomolekuler Vaccine (FK. UGM, tahun 2006)
Workshop Biomolekuler Penyakit Infeksi (FK. UGM, tahun 2003)
Workshop Metodologi Penelitian (FK. UI, tahun 2008)

2. ANTIMICROBIAL THERAPY OF FEBRILE NEUTROPENIA
Antibiotic Usage in Children
ANTIMICROBIAL THERAPY OF FEBRILE NEUTROPENIA
Unit Kerja Koordinasi Infeksi dan Penyakit Tropis

3. OUTLINE Definitions and Criteria Initial Evaluation
Who should receive empirical Tx?
Initial Empirical Antibiotics Considerations?
Initial Antibiotics Recomended Choices?
Reassesment Afebrile and Febrile Patient
Duration of Antibiotic Therapy When to stop?
Algorithm for initial management of febrile neutropenia
Conclusion

4. 1. DEFINITION AND CRITERIA
Fever : singel oral temp. > C or
a temp. > C for > 1 hr
Neutropenia : neutrophil count < 500 /mm3 , or
account of < 1,000 with a predicted decrease to < 500
Walter at al, Infect Desease Society of America. 2002; 34:
Hughes at al, Clin Infect Diss 2002; 52: 4

5. RISK FACTOR

7. LOW RISK ANC > 100 /mm3 Normal CXR Duration of neutropenia < 7 d
Resolution of neutropenia <10 d
No appearance of illness
No comorbidity complications
Malignancy in remission
Walter at al, Infect Desease Society of America. 2002; 34:
Hughes at al, Clin Infect Diss 2002; 52: 7

8. HIGH RISK PATIENTS Parenteral antibiotics + close monitoring
Haematological malignancies
Severe and prolonged neutropenia > 10 d
Evidence of shock / dehydration
Mucositis preventing oral hydration
Complex focal infection eg CVL site infection
Respiratory / gastrointestinal involvement
Need for blood products
Renal / hepatic insufficiency
Change in mental status
Hughest et al, Guideline for febrile neutropenia. 2002; 34:

9. 2. INITIAL EVALUATION Preantibiotic Investigations
Blood C/S : central line & peripheral
Chest X-Ray
Urine C/S
Stool C/S
Biopsy cultures
Viral studies
Preantibiotic Investigations 9

10. POSSIBLE SITES OF INFECTION
URTI
Dental sepsis
Mouth ulcers
Skin sores
Exit site of central venous catheters
Anal fissures GI 10

11. FEBRILE NEUTROPENIA BACTERIAL CAUSES
Gram-positive bacteria (60-70%)
Staphylococcus spp : MSSA,MRSA,
Enterococcus faecalis/faecium
Corynebacterium spp
Bacillus spp
Stomatococcus mucilaginosus 11

12. Gram-negative bacilli (30-40%) Escherichia coli Klebsiella spp : ESBL
Pseudomonas aeruginosa
Enterobacter spp
Acinetobacter spp
Citrobacter spp
Stenotrophomonas maltophilia 12

13. Propionibacterium spp Peptococcus spp Veillonella spp
Anerobic Bacteria
Bacteroides spp
Clostridium spp
Fusobacterium spp
Propionibacterium spp
Peptococcus spp
Veillonella spp
Peptostreptococcus spp
Del Favero at al, Clin infect Dis. 2001; 33:
Weinstein et al, J. Clin Microbiol. 2006; 32:2103-6 13

18. 3. WHO SHOULD RECEIVE EMPIRICAL TX?
Bacterial infection
Neutropenia :single most important risk factor for
infection in cancer.
Risk of infection increases 10-fold with declining
neutrophil counts < 500/mm3
48-60% : occult infection
16-20% with neutropenia <100/mm3 have
bacteremia
Samam MD. Commun Oncol 2006; 3 : 18

19. 4. INITIAL EMPIRIC ANTIBIOTICS CONSIDERATIONS
Broad spectrum of bactericidal activity
Local prevalence, susceptibility pattern
Antibiotic toxicity : well-tolerated, allergy
Host factors : severity of presentation
Prior antibiotic usage
Antibiotic costs
Ease of administration 19

21. 5. INITIAL EMPIRIC ANTIBIOTICS RECOMMENDED CHOICES
1. Monotherapy
Antipseudomonal Ceph 3 : ceftazidime
Ceph 4 : cefepime
Carbapenem : imipenem , meropenem
2. Combination
Duo therapy without vancomycin
Vancomycin plus one or two drugs
Lindbad et al, Scand J Infect Dis. 2005; 30:
Liat V et al, J Antimimicrobial Chem ; 54:29-31
Hughest et al, Guideline for febrile neutropenia. 2002; 34: 21

23. COMBINATION THERAPY WITHOUT VANCOMYCIN
Aminoglycoside + Anti-pseudomonal
Carboxypenicillin (Piperacillin – Tazobactam +
Gentamycin, Tobramycin, Amikacin or
Ticarcillin-clavulanic acid + Aminoglycoside)
Cephalosporin
Aminoglycoside + Carbapenem
Saman K, Commun Oncol. 2006; 3:
Bucaneve et al, N Eng J Med. 2005; 353: 23

26. SELECTION OF INITIAL ANTIBIOTIC THERAPY
Reassess after 3-5 days
Walter at al. IDSAI Guideline. 2002:34;730-51 26

27. INITIAL ANTIBIOTIC MODIFICATIONS CONSIDERATIONS
Persistence of fever
Clinical deterioration
Culture results
Drug intolerance/side effects 27

28. COMBINATION THERAPY ADVANTAGES
Increased bactericidal activity
Potential synergistic effects
Broader antibacterial spectrum
Limits emergence of resistance 28

29. COMBINATION THERAPY DISADVANTAGES
Drug toxicities
Drug interactions
Potential cost increase
Administration time 29

30. 6. REASSESSMENT – AFEBRILE PATIENT
Walter at al. IDSAI Guideline. 2002:34;730-51 30

31. REASSESSMENT – FEBRILE PATIENT
Reproduced with permission from Hughes et al. Clin Infect Dis 2002;34:730–751 31

33. PERSISTENT FEVER CAUSES
Nonbacterial infection
Resistant bacteria
Slow response to antibiotics
Fungal sepsis
Inadequate serum & tissue levels
Drug fever
Jasic et al, Clin Infect Dis .2006; 42: 33

34. 7. DURATION OF ANTIBIOTIC
THERAPY WHEN TO STOP?
No infection identified after 3 days of Rx
ANC > 500 for 2 consecutive days
Afebrile > 48 hr
Clinically well
Jasic et al, Clin Infect Dis .2006; 42: 34

35. DURATION OF ANTIBIOTICS THERAPY
Afebrile by day 3-5
Persistent Fever
ANC≥ 500/mm3 for 2 consecutive days
ANC < 500/mm3 by day 7
ANC ≥ 500/mm3
ANC < 500/mm3
Stop Antibiotics 48 h after afebril
Lows risk, clinically well
High risk : ANC< 100/mm3, Mucousitis, unstable sign
Stop 4 – 5 days after > 500/mm3
Continue for 2 week
Reassess
Stop when afebrile for
5- 7 days
Conntinue antibiotik
Reassess
Stop if no disease and condition stable

36. ALGORITHM FOR INITIAL MANAGEMENT OF FEBRILE NEUTROPENIA
Temperature 38,3ºC +
neutropenia (<500 neutrophils/mm3)
Low risk
High risk
Vancomycin not needed
Vancomycin needed
Oral IV
Ciprofloxacin + Amoxicillin / clavulanate (adults only)
Monotherapy
Two drugs
Vancomycin +
Cefepime,
Ceftazidime or
Carbapenem
Aminoglycoside +
Antipseudomonal penicillin,
Cefepime,
Ceftazidime, or
Carbapenem
Vancomycin +
Cefepime,
Ceftazidime or
Carbapenem
 Aminoglycoside
Reassess after 3–5 days
Reproduced with permission from Hughes et al. Clin Infect Dis 2002;34:730–751 36

37. GUIDE FOR THE MANAGEMENT OF PATIENTS WITH PERSISTENT FEVER DURING ANTIBIOTIC THERAPY
Persistent fever during first 3–5 days of treatment: no aetiology
Reassess patient on Days 3–5
Continue initial antibiotics
Change antibiotics
Antifungal drug, with or without antibiotic change
If progressive disease or
If criteria for vancomycin are met
If no change in patient's condition (consider stopping vancomycin)
If febrile through Days 5–7 and resolution of neutropenia is not imminent
Reproduced with permission from Hughes et al. Clin Infect Dis 2002;34:730–751

38. GUIDELINES FEBRILE NEUTROPENIA

39. Aytaç S, Yildirim Í, Ceyhan M, Çetin M, Tuncer M, Kara A, Cengiz AB, Seçmeer G, Yetgin S. Risks and outcome of fungal infection in neutropenic children with hematologic diseases. Turk J Pediatr 2010;52:
January to December = a total of 52 patients and 221 febrile neutropenic episodes were evaluated.
Anti Fungal Therapy was started in 96 (43%) of the 221 episodes.
Amphotericin B and fluconazole were used in 44 (46%) and 52 (54%) febrile neutropenic episodes, respectively.
Microbiologically or histopathologically evident fungal infections were detected in 35 of 96 febrile neutropenic episodes. 39

40. The mortality rate due to fungal infection was higher in
patients with AA (7/8 patients) and AML (7/12 patients) than in ALL
patients
(1/32). Mortality for the whole group was 28%.
Mortality rate was compared between the two treatment groups
(amphotericin B vs fluconazole), significant higher in patients receiving
amphotericin B [n=14 (93%) and n=l (7%), respectively].

41. FEBRILE NEUTROPENIA CONCLUSIONS
Significant morbidity & mortality
Choice of initial empiric therapy dependent on
epidemiologic & clinical factors
Monotherapy as efficacious as combination Rx
Modifications upon reassessment
Duration dependent on ANC 41

42. FEBRILE NEUTROPENIA CONCLUSIONS
At least one-half of neutrofenic patient who become febrile have an
established or ocult infection.
Sign and symptoms of infection are often subtle in neutropenic patient
because lack of inflamatory respons
More gram (+) organisms increasingly drug resistent pathogens, and
uncommon organisms are now the rise.
Neutrophil recovery is the most important factor in deciding when to
discontinue therapy.
Newer antifungal agent, which are effective and less toxis, are available for
neutropenic patient 42

43. TERIMAKASIH
ATAS
PERHATIANNYA

44. Soal Definisi demam adalah bila suhu oral :
≥38,30C atau suhu ≥380C selama 1 jam
Suhu > 37,50C
Suhu > 38 0C
Suhu > 38,5 0C
Suhu > 39 0C
Neutrophenia bila ANC:
< 500 sel/mm3
< 500 sel/mm3 atau < 1000 sel/mm3 dengan prediksi terjadi penurunan < 500 sel/mm3
< 100 sel /mm3
< 1000 sel/mm3
< 250 sel/mm3
Penyebab infeksi bakteri gram negatif pada febrile neutropenia:
Streptoccocus pneumonia
Streptoccocus pyogenes`
E. Coli
Stapyloccocus pyogenes
Corynebacterium species

45. Soal Pada low risk febrile neutropenia antibiotik oral terpilih:
Amoksilin-asam clavulanic
Amoksilin
Cyprofloxasin
Azitromicin
Klorampenikol
Keuntungan terapi antibiotik kombinasi pada febrile neutropenia:
Efek sinergis dari antibiotik
Efek samping minimal
Cost terapi lebih murah
Mudah terjadi resistensi
Lama pengobatan pendek