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 NeutropeniaBacterial infection Neutropenia :single most important risk factor for infection in cancer pts. Risk of infection increases 10-fold with declining neutrophil counts< 500/mm348-60% : occult infection 16-20% with neutropenia

Initial Empiric AntibioticsRationale 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 NeutropeniaLevel of Fever & NeutropeniaFever : 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 NeutropeniaEvaluation 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 AntibioticsConsiderations Broad spectrum of bactericidal activity Local prevalence, susceptibility patternAntibiotic toxicity : well-tolerated, allergy Host factors : severity of presentation Prior antibiotic usage Antibiotic costs Ease of administration

Febrile NeutropeniaBacterial 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 HospitalReviewed febrile neutropenia adult pts. with hematologic malignancy illness18% FUO which may associated with underlying disease 36% UTI 25% skin & soft tissue infection21% bacteremiaPathogens : K. pneumoniae , E. coli , Pseudomonas aeruginosa , Acinetobacter spp. , StaphylococcusMortality 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 AntibioticsRecommended choices Monotherapy Duotherapy without vancomycinVancomycin 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

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

Oral Antibiotics and Outpatient Management

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

Febrile NeutropeniaLow RiskANC > 100 /mm3Normal CXR Duration of neutropenia < 7 d Resolution of neutropenia

Monotherapy Choices Ceph 3 : ceftazidime Ceph 4 : cefepime Carbapenem : imipenem , meropenemIDSA guidelines-2002

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

Combination TherapyDisadvantagesDrug toxicities Drug interactions Potential cost increase Administration time

Combination TherapyChoices Aminoglycoside + Anti-pseudomonal carboxypenicillinAminoglycoside + Anti-pseudomonal cephalosporinAminoglycoside + Carbapenem

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

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

Persistent FeverCauses Nonbacterial infectionResistant bacteria Slow response to antibiotics Fungal sepsis Inadequate serum & tissue levels Drug fever

Persistent Fever > 5 DaysChoices 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 TherapyWhen to stop? No infection identified after 3 days of Rx ANC > 500 for 2 consecutive days Afebrile > 48 hr Clinically well

Febrile NeutropeniaConclusions Significant morbidity & mortality Choice of initial empiric therapy dependent on epidemiologic & clinical factors Monotherapy as efficacious as combination RxModifications upon reassessment Duration dependent on ANC