1. Edi Hartoyo Alan R. Tumbelaka Infectious Disease and Tropical Pediatrics Working Group Indonesian Pediatrician Society 1

2. 2 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

3. Fever : single oral temp. > 38.3 0 C or a temp. >38.0 0 C for > 1 hr Neutropenia : neutrophil count < 500 /mm 3, or account of < 1,000 with a predicted decrease to < 500 3 Walter at al, Infect Desease Society of America. 2002; 34: 731-751 Hughes at al, Clin Infect Diss 2002; 52: 551-73

4. 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 4 Walter at al, Infect Desease Society of America. 2002; 34: 731-751 Hughes at al, Clin Infect Diss 2002; 52: 551-73

5. 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 5 Hughest et al, Guideline for febrile neutropenia. 2002; 34: 734-752

6. Blood C/S : central line & peripheral Chest X-Ray Urine C/S Stool C/S Biopsy cultures Viral studies 6 2. INITIAL EVALUATION

7. URTI Dental sepsis Mouth ulcers Skin sores Exit site of central venous catheters Anal fissures GI 7

8. Gram-positive bacteria (60-70%) Staphylococcus spp : MSSA,MRSA, Enterococcus faecalis/faecium Corynebacterium spp Bacillus spp Stomatococcus mucilaginosus 8

9. 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 9 Del Favero at al, Clin infect Dis. 2001; 33: 1295-301 Weinstein et al, J. Clin Microbiol. 2006; 32:2103-6

10. 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 10 Samam MD. Commun Oncol 2006; 3 : 585-591

11. 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 11

12. 1. Monotherapy Antipseudomonal Ceph 3 : ceftazidime Ceph 4 : cefepime Carbapenem : imipenem, meropenem 2. Combination Duo therapy without vancomycin Vancomycin plus one or two drugs 12 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

13. Aminoglycoside + Anti-pseudomonal carboxypenicillin (Piperacillin – Tazobactam + Gentamycin, Tobramycin, Amikacin or Ticarcillin-clavulanic acid + Aminoglycoside) Aminoglycoside + Anti-pseudomonal Cephalosporin Aminoglycoside + Carbapenem 13 Saman K, Commun Oncol. 2006; 3:585-591 Bucaneve et al, N Eng J Med. 2005; 353:977-987 Combination Therapy Without Vancomycin

14. 14 Reassess after 3-5 days Walter at al. IDSAI Guideline. 2002:34;730-51

15. Persistence of fever Clinical deterioration Culture results Drug intolerance/side effects 15

16. Increased bactericidal activity Potential synergistic effects Broader antibacterial spectrum Limits emergence of resistance 16

17. Drug toxicities Drug interactions Potential cost increase Administration time 17

18. 18 Walter at al. IDSAI Guideline. 2002:34;730-51

19. 19 Reproduced with permission from Hughes et al. Clin Infect Dis 2002;34:730–751

20. Nonbacterial infection Resistant bacteria Slow response to antibiotics Fungal sepsis Inadequate serum & tissue levels Drug fever 20 Jasic et al, Clin Infect Dis.2006; 42:597-607

21. No infection identified after 3 days of Rx ANC > 500 for 2 consecutive days Afebrile > 48 hr Clinically well 21 Jasic et al, Clin Infect Dis.2006; 42:597-607

22. 22 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 Stop 4 – 5 days after > 500/mm3 ANC < 500/mm3ANC ≥ 500/mm3

23. Terature  38.8ºC) + neutropenia (<500 neutrophils/mm 3 ) 23 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

24. 24 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

25. 25 Guidelines Febrile Neutropenia

26. Cunha, Antibiotic Essential, 2009

27. 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 27

28. Thank you for your attention edi & alan 28