CURRICULUM VITAE Full name:Dr. Alan Roland Tumbelaka, Consultant Pediatrician Infectious Diseases and Tropical Pediatrics Address Home:Jl. Duta Indah VIII / 3, Pondok Duta, Depok Telp / fax : , West Java Office:Department of Child Health, Faculty of Medicine, University of Indonesia (FMUI), Jl. Salemba Raya 6, Jakarta Telp / fax : Handphone: Education: M.D., Faculty of Medicine, University of Indonesia, 1977 Pediatrician, Faculty of Medicine University of Indonesia, 1984 Consultant Pediatrician in Infectious and Tropical Diseases,

Research and Training Coordinator, Child Health Dept. FMUI, Member of the FMUI Evidence-based Medicine Teaching team since 2003 Vice Chairman of the Jakarta Branch of Indonesian Society of Pediatricians, 1990 – 2002 National Facilitator for Integrated Management of Childhood Illness courses since WHO Short-term Consultant in Preservice Training for IMCI, College of Medicine, Kathmandu, Nepal, Head of Infection and Tropical Diseases Working Group, Indonesian Society of Pediatricians, Head of Computer Laboratory, FMUI, 2003 – 2005 Head of Division of Infectious Diseases and Tropical Pediatrics, Dept of Child Health, Faculty of Medicine, University of Indonesia, Jakarta, since

Training in Tropical Epidemiology, University of the Phillipines, Manila, October Facilitator of IMCI Intercountry Consultants’ Training Course. WHO, Kathmandu, Nepal, August 6 – 17, 1997 Facilitator of Intercountry Training Course on IMCI. WHO, Kathmandu, Nepal. October 26 – Nov 6, Training of University of Indonesia Super Trainer in Distance Learning. AusAID, Queensland University of Technology, Brisbane 16 July – 1 August Rewards Mahasiswa Teladan FKUI 1977 Dosen Teladan FKUI 1993 Dosen Teladan UI

Edi Hartoyo Alan R. Tumbelaka Infectious Disease and Tropical Pediatrics Working Group Indonesian Pediatrician Society 4

5 1. Definitions and Criteria 2. Initial Evaluation 3. Who should receive empirical Tx? 4. Initial Empirical Antibiotics Considerations ? 5. Initial Antibiotics Recomended Choices? 6. Reassesment Afebrile and Febrile Patient 7. Duration of AntibioticTherapy When to stop? 8. Algorithm for initial management of febrile neutropenia 9. Conclusion OUTLINE

Fever : single oral temp. > C or a temp. > C for > 1 hr Neutropenia : neutrophil count < 500 /mm 3, or account of < 1,000 with a predicted decrease to < Walter at al, Infect Desease Society of America. 2002; 34: Hughes at al, Clin Infect Diss 2002; 52:

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 7 Walter at al, Infect Desease Society of America. 2002; 34: Hughes at al, Clin Infect Diss 2002; 52:

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 8 Hughest et al, Guideline for febrile neutropenia. 2002; 34:

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

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

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 Anerobic Bacteria Bacteroides spp Clostridium spp Fusobacterium spp Propionibacterium spp Peptococcus spp Veillonella spp Peptostreptococcus spp 12 Del Favero at al, Clin infect Dis. 2001; 33: Weinstein et al, J. Clin Microbiol. 2006; 32:2103-6

Bacterial infection Neutropenia :single most important risk factor for infection in cancer. Risk of infection increases 10-fold with declining neutrophil counts < 500/mm % : occult infection 16-20% with neutropenia <100/mm3 have bacteremia 13 Samam MD. Commun Oncol 2006; 3 :

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 14

1. Monotherapy Antipseudomonal Ceph 3 : ceftazidime Ceph 4 : cefepime Carbapenem : imipenem, meropenem 2. Combination Duo therapy without vancomycin Vancomycin plus one or two drugs 15 Lindbad et al, Scand J Infect Dis. 2005; 30: Liat V et al, J Antimimicrobial Chem. 2004; 54:29-31 Hughest et al, Guideline for febrile neutropenia. 2002; 34:

Aminoglycoside + Anti-pseudomonal carboxypenicillin (Piperacillin – Tazobactam + Gentamycin, Tobramycin, Amikacin or Ticarcillin-clavulanic acid + Aminoglycoside) Aminoglycoside + Anti-pseudomonal Cephalosporin Aminoglycoside + Carbapenem 16 Saman K, Commun Oncol. 2006; 3: Bucaneve et al, N Eng J Med. 2005; 353: Combination Therapy Without Vancomycin

17 Reassess after 3-5 days Walter at al. IDSAI Guideline. 2002:34;730-51

Persistence of fever Clinical deterioration Culture results Drug intolerance/side effects 18

Increased bactericidal activity Potential synergistic effects Broader antibacterial spectrum Limits emergence of resistance 19

Drug toxicities Drug interactions Potential cost increase Administration time 20

21 Walter at al. IDSAI Guideline. 2002:34;730-51

22 Reproduced with permission from Hughes et al. Clin Infect Dis 2002;34:730–751

Nonbacterial infection Resistant bacteria Slow response to antibiotics Fungal sepsis Inadequate serum & tissue levels Drug fever 23 Jasic et al, Clin Infect Dis.2006; 42:

No infection identified after 3 days of Rx ANC > 500 for 2 consecutive days Afebrile > 48 hr Clinically well 24 Jasic et al, Clin Infect Dis.2006; 42:

25 Stop if no disease and condition stable Conntinue antibiotik High risk : ANC< 100/mm3, Mucousitis, unstable sign Stop when afebrile for 5- 7 days Lows risk, clinically well Stop Antibiotics 48 h after afebril ANC < 500/mm3 by day 7 DURATION OF ANTIBIOTICS THERAPY Afebrile by day 3-5 ANC≥ 500/mm3 for 2 consecutive days Persistent Fever Reassess Continue for 2 week S top 4 – 5 days after > 500/mm3 ANC < 500/mm3ANC ≥ 500/mm3

Temperature  38.8ºC + neutropenia (<500 neutrophils/mm 3 ) 26 Low risk High risk Oral IVVancomycin not needed Vancomycin needed Ciprofloxacin + Amoxicillin / clavulanate (adults only) Cefepime, Ceftazidime or Carbapenem Monotherapy Aminoglycoside + Antipseudomonal penicillin, Cefepime, Ceftazidime, or Carbapenem Two drugs Vancomycin + Cefepime, Ceftazidime or Carbapenem  Aminoglycoside Vancomycin + Reassess after 3–5 days Reproduced with permission from Hughes et al. Clin Infect Dis 2002;34:730–751

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

28 Guidelines Febrile Neutropenia

Cunha, Antibiotic Essential, 2009

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 30

Thank you for your attention edi & alan 31