Febrile Neutropenia

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Febrile Neutropenia

• SIRIPORN PHONGJITSIRI,MD
• Pediatric Infectious Division
• Queen Sirikit National Institute of Child Health
• June 28,2007

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Febrile Neutropenia

• Who should receive empirical Rx?
• When should empirical Rx be started?
• What is appropriate initial Rx?
• How should initial Rx be modified?
• How long should empirical Rx be continued?

3
Febrile Neutropenia

• Who should receive empirical Rx?
• When should empirical Rx be started?
• What is appropriate initial Rx?
• How should initial Rx be modified?
• How long should empirical Rx be continued?

4
Febrile Neutropenia

• Bacterial infection
• Neutropenia single most important risk factor
  for infection in cancer pts.
• Risk of infection increases 10-fold with
  declining neutrophil counts lt 500/mm3
• 48-60 occult infection
• 16-20 with neutropenialt100/mm3 have bacteremia

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Initial Empiric AntibioticsRationale

• Severe risk of bacterial sepsis
• Insensitivity of diagnostic tests
• Delays in identification of pathogens

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Febrile Neutropenia

• Who should receive empirical Rx?
• When should empirical Rx be started?
• What is appropriate initial Rx?
• How should initial Rx be modified?
• How long should empirical Rx be continued?

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Febrile NeutropeniaLevel of Fever Neutropenia

• Fever single oral temp. gt 38.3 0C or a temp.
  gt38.0 0C for gt 1 hr
• Neutropenia neutrophil count lt 500 /mm3 , or a
  count of lt 1,000 with a predicted decrease to lt
  500

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Febrile NeutropeniaEvaluation

• History
• Physical examination minimal signs
• Risk assessment
• Investigations

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Possible sites of infection

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

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Preantibiotic Investigations

• Blood C/S central line peripheral
• Chest X-Ray
• Urine C/S
• Stool C/S
• Biopsy cultures
• Viral studies

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Febrile Neutropenia

• Who should receive empirical Rx?
• When should empirical Rx be started?
• What is appropriate initial Rx?
• How should initial Rx be modified?
• How long should empirical Rx be continued?

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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

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Febrile NeutropeniaBacterial causes (EORTC)

• Gram-positive bacteria (60-70)
• Gram-negative bacilli (30-40)

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Gram-positive Bacteria

• Staphylococcus spp MSSA,MRSA,
• Streptococcus spp viridans
• Enterococcus faecalis/faecium
• Corynebacterium spp
• Bacillus spp
• Stomatococcus mucilaginosus

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Gram-negative Bacteria

• Escherichia coli
• Klebsiella spp ESBL
• Pseudomonas aeruginosa
• Enterobacter spp
• Acinetobacter spp
• Citrobacter spp
• Stenotrophomonas maltophilia

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Anerobic Bacteria

• Bacteroides spp
• Clostridium spp
• Fusobacterium spp
• Propionibacterium spp
• Peptococcus spp
• Veillonella spp
• Peptostreptococcus spp

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• Retrospective study in Srinagarind Hospital
• Reviewed febrile neutropenia adult pts. with
  hematologic malignancy illness
• 18 FUO which may associated with underlying
  disease
• 36 UTI
• 25 skin soft tissue infection
• 21 bacteremia
• Pathogens K. pneumoniae , E. coli , Pseudomonas
  aeruginosa , Acinetobacter spp. , Staphylococcus
• Mortality rate 24 higher in microbiological
  documented gr.

Siriluck Anunnatsiri,M.D.
18

• Retrospective reviewed trend of bacterial
  infection of children with admitted in
  Ramathibodi hospital 89 pts.
• The incidence of positive culture was 13.6
• Most of the organism isolated were Salmonella sp.
  21 , K. pneumoniae 16 and P. aeruginosa 10.5

Punpanich W, et al. Thai J Pediatr 1999389-16
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Initial Empiric AntibioticsRecommended choices

• Monotherapy
• Duotherapy without vancomycin
• Vancomycin plus one or two drugs

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Oral Antibiotics and Outpatient Management

• Low risk hospitalized febrile neutropenia
  pts.were assigned to receive either an oral
  regimen(amoxicillin-clavulanate plus
  ciprofloxacin) or IV ceftazidime. The success
  rate was 71 in the oral regimen and 67 in IV gr.

Freifeld A et al. N Engl J Med.1999341305-311
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Kern WV et al. N Engl J Med.1999341312-318
Oral Antibiotics and Outpatient Management

• Low risk adults and a very small number of
  children with febrile neutropenia were enrolled.
  Treatment was successful in 86 of pts.treated
  with oral therapy (ciprofloxacin
  amoxicillin-clavulanate) and 84 of those in IV
  gr.(ceftriaxone amikacin)

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Oral Antibiotics and Outpatient Management

• Current studies potentially be safe and
  effective in low-risk patients

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Febrile NeutropeniaLow Risk

• ANC gt 100 /mm3
• Normal CXR
• Duration of neutropenia lt 7 d
• Resolution of neutropenia lt10 d
• No appearance of illness
• No comorbidity complications
• Malignancy in remission

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Monotherapy Choices

• Ceph 3 ceftazidime
• Ceph 4 cefepime
• Carbapenem imipenem , meropenem

IDSA guidelines-2002
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Combination TherapyAdvantages

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

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Combination TherapyDisadvantages

• Drug toxicities
• Drug interactions
• Potential cost increase
• Administration time

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Combination TherapyChoices

• Aminoglycoside Anti-pseudomonal
  carboxypenicillin
• Aminoglycoside Anti-pseudomonal cephalosporin
• Aminoglycoside Carbapenem

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Therapy options for febrile neutropenic patients
(contd)

• In a study comparing meropenem and ceftazidime
  for the empiric therapy of febrile neutropenia in
  paediatric cancer patients, both treatment
  options were found to be equally effective
• Monotherapy with meropenem was as effective as a
  combination of ceftazidime and amikacin for the
  empiric treatment of fever in persistently
  neutropenic cancer patients (including paediatric
  patients)

Fleischhack et al. J Antimicrob Chemother
200147841853 Cometta et al. Antimicrob Agents
Chemother 19964011081115
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Algorithm for initial management of febrile
neutropenia
Fever (temperature ?38.8ºC) neutropenia (lt500
neutrophils/mm3)
Low risk
High risk
Vancomycin not needed
Vancomycin needed
Oral
CiprofloxacinAmoxicillin / clavulanate
(adults only)
Monotherapy
Two drugs
Vancomycin

• Cefepime,
• Ceftazidime or
• Carbapenem

• Aminoglycoside
• Antipseudomonal penicillin,
• Cefepime,
• Ceftazidime,or
• Carbapenem

• Vancomycin
• Cefepime,
• Ceftazidimeor
• Carbapenem
• ? Aminoglycoside

Reassess after 35 days
Reproduced with permission from Hughes et al.
Clin Infect Dis 200234730751
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Algorithm for initial management of febrile
neutropenia
Clinically suspected catheter infection Colonizati
on by penicillin/cephalosporin-resistant
pneumococci or MRSA Bacteremia by GPC
Hypotension or other evidence of cardiovascular
impairment Potential severe mucositis
Fever (temperature ?38.8ºC) neutropenia (lt500
neutrophils/mm3)
Low risk
High risk
Vancomycin not needed
Vancomycin needed
Oral
CiprofloxacinAmoxicillin / clavulanate
(adults only)
Monotherapy
Two drugs
Vancomycin

• Cefepime,
• Ceftazidime or
• Carbapenem

• Aminoglycoside
• Antipseudomonal penicillin,
• Cefepime,
• Ceftazidime,or
• Carbapenem

• Vancomycin
• Cefepime,
• Ceftazidimeor
• Carbapenem
• ? Aminoglycoside

Reassess after 35 days
Reproduced with permission from Hughes et al.
Clin Infect Dis 200234730751
31
Febrile Neutropenia

• Who should receive empirical Rx?
• When should empirical Rx be started?
• What is appropriate initial Rx?
• How should initial Rx be modified?
• How long should empirical Rx be continued?

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Initial Antibiotic ModificationsConsiderations

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

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Persistent FeverCauses

• Nonbacterial infection
• Resistant bacteria
• Slow response to antibiotics
• Fungal sepsis
• Inadequate serum tissue levels
• Drug fever

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Persistent Fever gt 5 DaysChoices of Mx

• Continue initial Rx
• Change or add antibiotics
• Add an antifungal drug(Ampho B)

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Guide for the management of patients with
persistent fever during antibiotic therapy
Persistent fever during first 35 days of
treatment no aetiology
Reassess patient on Days 35
Antifungal drug, with or without antibiotic
change
Change antibiotics
Continue initial antibiotics
If febrile through Days 57 and resolution of
neutropenia is not imminent

• If progressive disease or
• If criteria for vancomycin are met

• If no change in patient's condition (consider
  stopping vancomycin)

Reproduced with permission from Hughes et al.
Clin Infect Dis 200234730751
36
Febrile Neutropenia

• Who should receive empirical Rx?
• When should empirical Rx be started?
• What is appropriate initial Rx?
• How should initial Rx be modified?
• How long should empirical Rx be continued?

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Duration of Antibiotic TherapyWhen to stop?

• No infection identified after 3 days of Rx
• ANC gt 500 for 2 consecutive days
• Afebrile gt 48 hr
• Clinically well

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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