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ANTIMICROBIAL THERAPY OF FEBRILE NEUTROPENIA

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 T x ?

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ANTIMICROBIAL THERAPY OF FEBRILE NEUTROPENIA

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  1. Edi Hartoyo Alan R. Tumbelaka Infectious Disease and Tropical Pediatrics Working Group Indonesian Pediatrician Society ANTIMICROBIAL THERAPY OF FEBRILE NEUTROPENIA

  2. 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

  3. 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

  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 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

  5. 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

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

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

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

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

  10. 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

  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 4. Initial Empiric AntibioticsConsiderations

  12. 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

  13. 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

  14. Selection of initial antibiotic therapy 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 Initial Antibiotic ModificationsConsiderations

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

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

  18. 6. Reassessment – Afebrile patient Walter at al. IDSAI Guideline. 2002:34;730-51

  19. Reassessment – Febrile Patient 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 Persistent FeverCauses 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 7. Duration of AntibioticTherapyWhen to stop? Jasic et al, Clin Infect Dis .2006; 42:597-607

  22. 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

  23. Low risk High risk Terature38.8ºC) + neutropenia(<500 neutrophils/mm3) Oral Vancomycin needed IV Vancomycin not needed Monotherapy Two drugs Vancomycin + Ciprofloxacin+Amoxicillin / clavulanate (adults only) • Aminoglycoside + • Antipseudomonal penicillin, • 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

  24. 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

  25. Guidelines Febrile Neutropenia

  26. Antibiotics penetration : 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 Febrile NeutropeniaConclusions

  28. Thank you for your attention edi & alan

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