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. > 38.3 0C or a temp. >38.0 0C for > 1 hr Neutropenia : neutrophil count < 500 /mm3
, or a count of < 1,000 with a predicted 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 3 days of Rx
ANC > 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