ANTIMICROBIAL THERAPY OF FEBRILE NEUTROPENIA
Edi HartoyoAlan R. Tumbelaka
Infectious Disease and Tropical Pediatrics Working Group Indonesian Pediatrician Society
1. Definitions and Criteria2. Initial Evaluation3. Who should receive empirical Tx? 4. Initial Empirical Antibiotics Considerations ? 5. Initial Antibiotics Recomended Choices? 6. Reassesment Afebrile and Febrile Patient7. Duration of AntibioticTherapy When to stop? 8. Algorithm for initial management of febrile
neutropenia9. Conclusion
OUTLINE
1. Definitions and Criteria
Fever : single oral temp. > 38.3 0C ora 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: 731-751Hughes at al, Clin Infect Diss 2002; 52: 551-73
Febrile NeutropeniaLow 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: 731-751Hughes 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
Preantibiotic Investigations
• Blood C/S : central line & peripheral • Chest X-Ray • Urine C/S • Stool C/S • Biopsy cultures • Viral studies
2. INITIAL EVALUATION
Possible sites of infection• URTI • Dental sepsis • Mouth ulcers • Skin sores • Exit site of central venous catheters • Anal fissures • GI
Febrile NeutropeniaBacterial causes
• Gram-positive bacteria (60-70%)
Staphylococcus spp : MSSA,MRSA, Enterococcus faecalis/faecium Corynebacterium spp Bacillus spp Stomatococcus mucilaginosus
• Gram-negative bacilli (30-40%) Escherichia coli Klebsiella spp : ESBL Pseudomonas aeruginosa Enterobacter spp Acinetobacter spp Citrobacter spp Stenotrophomonas maltophilia
• Anerobic BacteriaBacteroides spp Clostridium spp Fusobacterium spp Propionibacterium spp Peptococcus spp Veillonella spp Peptostreptococcus sppDel Favero at al, Clin infect Dis. 2001; 33: 1295-301
Weinstein et al, J. Clin Microbiol. 2006; 32:2103-6
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
4. Initial Empiric AntibioticsConsiderations
• 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
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: 237-43Liat V et al, J Antimimicrobial Chem . 2004; 54:29-31Hughest et al, Guideline for febrile neutropenia. 2002; 34: 734-752
• 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; 3:585-591Bucaneve et al, N Eng J Med. 2005; 353:977-987
Combination Therapy Without Vancomycin
Selection of initial antibiotic therapy
M onotherapyCef t az id ime
Cef epime or
Car bapenems
T wo Drugs+ A minoglycos ide
or
2 lac t ams
Vancomycinnot needed
Vancomycin plusCephs / car bap
+/ -
aminoglycos ide
Vancomycinneeded
ff ff ff ff ff ff ff ff ff ff ff ff ff
Child with Fever + N eutropeniaff ff ff ff ff ff ff ff ff ff ff ff ff ff ff
Reassess after 3-5 days
Walter at al. IDSAI Guideline. 2002:34;730-51
Initial Antibiotic ModificationsConsiderations
• Persistence of fever • Clinical deterioration • Culture results • Drug intolerance/side effects
Combination TherapyAdvantages
• Increased bactericidal activity • Potential synergistic effects • Broader antibacterial spectrum • Limits emergence of resistance
Combination TherapyDisadvantages
• Drug toxicities • Drug interactions • Potential cost increase • Administration time
6. Reassessment – Afebrile patient
ConsiderPO ant ibiot ics
Low Risk
Cont inue sameI V ant ibiot ics
H igh r isk
N o et iology
A dj usttherapy
Et iology ident ifi ed
ff ff ff ff ff ff ff ff ff ff ff ff ffA f ebrile within the fi rst 3- 5 days of t reatment
ff ff ff ff ff ff ff ff ff ff ff ff ff ff ff
Walter at al. IDSAI Guideline. 2002:34;730-51
Reassessment – Febrile Patient
I f no changein pat ientcondit ion
D/ C vanco
Cont inue sameA nt ibiot ics
CoverES BL T ype 1 lactamase
I f progressivedisease
I f cr iter ia f orVancomycin
Change A nt ibiot ics A dd ant if ungaldrug
ff ff ff ff ff ff ff ff ff ff ff ff ffFebrile f or the fi rst 3- 5 days of t reatment
O r new onset f ever
Reproduced with permission from Hughes et al. Clin Infect Dis 2002;34:730–751
Persistent FeverCauses • 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
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
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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
Reassess
Continue for 2 weekStop 4 – 5 days after > 500/mm3
ANC < 500/mm3ANC ≥ 500/mm3
Algorithm for initial management of febrile neutropenia
Terature 38.8ºC) + neutropenia (<500 neutrophils/mm3)
Low risk High risk
Oral IV Vancomycin 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
Guide for the management of patients with persistent fever during antibiotic therapy
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
Guidelines Febrile Neutropenia
Antibiotics penetration :
Cunha, Antibiotic Essential, 2009
Febrile NeutropeniaConclusions
• 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
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Thank you
for your attention
edi & alan