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)

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

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

1. DEFINITION AND CRITERIA Fever : singel oral temp. > 38.3 0C or a temp. >38.0 0C 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: 731-751 Hughes at al, Clin Infect Diss 2002; 52: 551-73 4

RISK FACTOR

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: 731-751 Hughes at al, Clin Infect Diss 2002; 52: 551-73 7

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: 734-752

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

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

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

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

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: 1295-301 Weinstein et al, J. Clin Microbiol. 2006; 32:2103-6 13

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 : 585-591 18

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

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: 237-43 Liat V et al, J Antimimicrobial Chem . 2004; 54:29-31 Hughest et al, Guideline for febrile neutropenia. 2002; 34: 734-752 21

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; 3:585-591 Bucaneve et al, N Eng J Med. 2005; 353:977-987 23

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

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

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

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

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

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

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; 42:597-607 33

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; 42:597-607 34

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

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

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

GUIDELINES FEBRILE NEUTROPENIA

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;52:121-125. January 2004 to December 2005 = 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

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].

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

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

TERIMAKASIH ATAS PERHATIANNYA

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

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