Febrile Neutropenia

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Febrile Neutropenia

• SIRIPORN PHONGJITSIRI

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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 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 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 Srinagarin 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.
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• 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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• 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

• 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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Vancomycin as Empiric RxWhen to use ?

• Known colonization with MRSA or PRSP
• Clinically suspected serious catheter-related
  infections (eg bacteremia)
• Hypotension or cardiovascular impairment
• Initial positive results of blood culture for G
  bacteria

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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 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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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