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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 16418 Telp / fax : +62-21-8714112, West Java
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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 16418 Telp / fax : +62-21-8714112, West Java E-mail: alanrt@yahoo.com , alan.roland@ui.ac.id Office : Department of Child Health, Faculty of Medicine, University of Indonesia (FMUI), Jl. Salemba Raya 6, Jakarta 10430 Telp / fax : +62-21-3914126 Handphone: +62-811-106609 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, 1993
Research and Training Coordinator, Child Health Dept. FMUI, 1999 - 2003 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 1977. WHO Short-term Consultant in Preservice Training for IMCI, College of Medicine, Kathmandu, Nepal, 1998. Head of Infection and Tropical Diseases Working Group, Indonesian Society of Pediatricians, 2002 - 2005. 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 2004 - 2008
Training in Tropical Epidemiology, University of the Phillipines, Manila, October 1987. Facilitator of IMCIIntercountry Consultants’ Training Course. WHO, Kathmandu, Nepal, August 6 – 17, 1997 Facilitator of Intercountry Training Course on IMCI. WHO, Kathmandu, Nepal. October 26 – Nov 6, 1998. Training of University of Indonesia Super Trainer in Distance Learning. AusAID, Queensland University of Technology, Brisbane 16 July – 1 August 2005. Rewards MahasiswaTeladanFKUI 1977 DosenTeladanFKUI 1993 DosenTeladan UI 1993
Edi Hartoyo Alan R. Tumbelaka Infectious Disease and Tropical Pediatrics Working Group Indonesian Pediatrician Society ANTIMICROBIAL THERAPY OF FEBRILE NEUTROPENIA
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 AntibioticTherapyWhen to stop? • Algorithm for initial management of febrile neutropenia • Conclusion
Fever : single 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 Definitions and Criteria Walter at al, Infect Desease Society of America. 2002; 34: 731-751 Hughes at al, Clin Infect Diss 2002; 52: 551-73
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 Febrile NeutropeniaLow Risk Walter at al, Infect Desease Society of America. 2002; 34: 731-751 Hughes at al, Clin Infect Diss 2002; 52: 551-73
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 Blood C/S : central line & peripheral Chest X-Ray Urine C/S Stool C/S Biopsy cultures Viral studies Preantibiotic Investigations
Possible sites of infection URTI Dental sepsis Mouth ulcers Skin sores Exit site of central venous catheters Anal fissures GI
Gram-positive bacteria (60-70%) Staphylococcus spp : MSSA,MRSA, Enterococcus faecalis/faecium Corynebacterium spp Bacillus spp Stomatococcus mucilaginosus Febrile NeutropeniaBacterial causes
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 Del Favero at al, Clin infect Dis. 2001; 33: 1295-301 Weinstein et al, J. Clin Microbiol. 2006; 32:2103-6
3. WHOSHOULDRECEIVEEMPIRICALTX? 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
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 4. Initial Empiric AntibioticsConsiderations
1. Monotherapy Antipseudomonal Ceph 3 : ceftazidime Ceph 4 : cefepime Carbapenem : imipenem , meropenem 2. Combination Duotherapy without vancomycin Vancomycin plus one or two drugs 5. Initial Empiric AntibioticsRecommended choices 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
Combination Therapy Without Vancomycin Aminoglycoside + Anti-pseudomonal carboxypenicillin (Piperacillin – Tazobactam + Gentamycin, Tobramycin, Amikacin or Ticarcillin-clavulanic acid + Aminoglycoside) Aminoglycoside + Anti-pseudomonal Cephalosporin Aminoglycoside + Carbapenem Saman K, Commun Oncol. 2006; 3:585-591 Bucaneve et al, N Eng J Med. 2005; 353:977-987
Selection of initial antibiotic therapy 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 Initial Antibiotic ModificationsConsiderations
Increased bactericidal activity Potential synergistic effects Broader antibacterial spectrum Limits emergence of resistance Combination TherapyAdvantages
Drug toxicities Drug interactions Potential cost increase Administration time Combination TherapyDisadvantages
6. Reassessment – Afebrile patient Walter at al. IDSAI Guideline. 2002:34;730-51
Reassessment – Febrile Patient 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 Persistent FeverCauses Jasic et al, Clin Infect Dis .2006; 42:597-607
No infection identified after 3 days of Rx ANC > 500 for 2 consecutive days Afebrile > 48 hr Clinically well 7. Duration of AntibioticTherapyWhen to stop? Jasic et al, Clin Infect Dis .2006; 42:597-607
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
Low risk High risk Temperature38.8ºC + neutropenia(<500 neutrophils/mm3) Oral Vancomycinneeded IV Vancomycinnot needed Monotherapy Two drugs Vancomycin + Ciprofloxacin+Amoxicillin / clavulanate(adults only) • Aminoglycoside + • Antipseudomonalpenicillin, • Cefepime, • Ceftazidime,or • Carbapenem • Cefepime, • Ceftazidime or • Carbapenem Algorithm for initial management of febrile neutropenia • Vancomycin • + • Cefepime, • Ceftazidimeor • Carbapenem • Aminoglycoside Reassess after 3–5 days Reproduced with permission from Hughes et al. Clin Infect Dis 2002;34:730–751
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 Continueinitial antibiotics Change antibiotics Antifungal drug, with or without antibiotic change • If no change in patient's condition (consider stopping vancomycin) • If progressive disease or • If criteria for vancomycinare met 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
Antibiotics penetration : 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 Febrile NeutropeniaConclusions
Thank you for your attention edi & alan