Febrile Neutropenia

SIRIPORN PHONGJITSIRI

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?

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?

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 < 500/mm3

48-60% : occult infection

16-20% with neutropenia<100/mm3
have bacteremia

Initial Empiric Antibiotics

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

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?

Febrile Neutropenia
Level of Fever & Neutropenia
Fever : single oral temp. >
temp. >38.0 0C for >

38.3 0C or a

1 hr

Neutropenia : neutrophil count

mm3 , or a count of <

< 500 /

1,000 with a predi

cted decrease to < 500

Febrile Neutropenia
Evaluation

History
Physical examination : minimal signs
Risk assessment
Investigations

Possible sites of infection

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

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

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?

Initial Empiric Antibiotics

Considerations

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

Febrile Neutropenia
Bacterial causes (EORTC)
Gram-positive bacteria (60-70%)
Gram-negative bacilli (30-40%)

Gram-positive Bacteria
Staphylococcus spp :
MSSA,MRSA,
Streptococcus spp : viridans
Enterococcus faecalis/faecium
Corynebacterium spp
Bacillus spp
Stomatococcus mucilaginosus

Gram-negative Bacteria

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

 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.

 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 1999;38:9-16

Initial Empiric Antibiotics

Recommended choices
Monotherapy
Duotherapy without vancomycin
Vancomycin plus one or two drugs

 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.1999;341:305-311

 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)

Kern WV et al. N Engl J Med.1999;341:312-318

Oral Antibiotics and Outpatient

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

Febrile Neutropenia
Low 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

Monotherapy
Choices
Ceph 3 : ceftazidime
Ceph 4 : cefepime
Carbapenem : imipenem , meropenem

IDSA guidelines-2002

Combination Therapy
Advantages

Increased bactericidal activity

Potential synergistic effects
Broader antibacterial spectrum
Limits emergence of resistance

Combination Therapy
Disadvantages

Drug toxicities
Drug interactions
Potential cost increase
Administration time

Combination Therapy
Choices
Aminoglycoside + Anti-pseudomonal
carboxypenicillin
Aminoglycoside + Anti-pseudomonal
cephalosporin
Aminoglycoside + Carbapenem

Vancomycin as Empiric Rx
When to use ?
Known colonization with MRSA or PRSP
Clinically suspected serious catheterrelated infections (eg bacteremia)
Hypotension or cardiovascular impairment
Initial positive results of blood culture for G
+ bacteria

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?

Initial Antibiotic Modifications

Considerations

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

Persistent Fever
Causes

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

Persistent Fever > 5 Days

Choices of Mx
Continue initial Rx
Change or add antibiotics
Add an antifungal drug(Ampho B)

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?

Duration of Antibiotic Therapy

When to stop?
No infection identified after
ANC >

3 days of Rx

500 for 2 consecutive days

Afebrile > 48 hr

Clinically well

Febrile Neutropenia
Conclusions
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