ANTIMICROBIAL THERAPY OF FEBRILE NEUTROPENIA

Edi HartoyoAlan R. Tumbelaka

Infectious Disease and Tropical Pediatrics Working Group Indonesian Pediatrician Society

1. Definitions and Criteria2. Initial Evaluation3. Who should receive empirical Tx? 4. Initial Empirical Antibiotics Considerations ? 5. Initial Antibiotics Recomended Choices? 6. Reassesment Afebrile and Febrile Patient7. Duration of AntibioticTherapy When to stop? 8. Algorithm for initial management of febrile

neutropenia9. Conclusion

OUTLINE

1. Definitions and Criteria

Fever : single oral temp. > 38.3 0C ora temp. >38.0 0C for > 1 hr

Neutropenia : neutrophil count < 500 /mm3 , or account of < 1,000 with a predicted decrease to < 500

Walter at al, Infect Desease Society of America. 2002; 34: 731-751Hughes at al, Clin Infect Diss 2002; 52: 551-73

Febrile NeutropeniaLow 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

Walter at al, Infect Desease Society of America. 2002; 34: 731-751Hughes at al, Clin Infect Diss 2002; 52: 551-73

High Risk Patients

• Parenteral antibiotics + close monitoring• Haematological malignancies• Severe and prolonged neutropenia > 10 d• Evidence of shock / dehydration• Mucositis preventing oral hydration• Complex focal infection eg CVL site infection• Respiratory / gastrointestinal involvement• Need for blood products• Renal / hepatic insufficiency • Change in mental status

Hughest et al, Guideline for febrile neutropenia. 2002; 34: 734-752

Preantibiotic Investigations

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

2. INITIAL EVALUATION

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

Febrile NeutropeniaBacterial causes

• Gram-positive bacteria (60-70%)

Staphylococcus spp : MSSA,MRSA, Enterococcus faecalis/faecium Corynebacterium spp Bacillus spp Stomatococcus mucilaginosus

• Gram-negative bacilli (30-40%) Escherichia coli Klebsiella spp : ESBL Pseudomonas aeruginosa Enterobacter spp Acinetobacter spp Citrobacter spp Stenotrophomonas maltophilia

• Anerobic BacteriaBacteroides spp Clostridium spp Fusobacterium spp Propionibacterium spp Peptococcus spp Veillonella spp Peptostreptococcus sppDel Favero at al, Clin infect Dis. 2001; 33: 1295-301

Weinstein et al, J. Clin Microbiol. 2006; 32:2103-6

3. WHO SHOULD RECEIVE EMPIRICAL TX?

• Bacterial infection • Neutropenia :single most important risk factor for infection in cancer. • Risk of infection increases 10-fold with declining neutrophil counts < 500/mm3• 48-60% : occult infection • 16-20% with neutropenia<100/mm3 have bacteremia

Samam MD. Commun Oncol 2006; 3 : 585-591

4. 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

5. Initial Empiric Antibiotics Recommended choices 1. Monotherapy

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

2. Combination • Duo therapy without vancomycin• Vancomycin plus one or two drugs

Lindbad et al, Scand J Infect Dis. 2005; 30: 237-43Liat V et al, J Antimimicrobial Chem . 2004; 54:29-31Hughest et al, Guideline for febrile neutropenia. 2002; 34: 734-752

• Aminoglycoside + Anti-pseudomonal carboxypenicillin (Piperacillin – Tazobactam + Gentamycin, Tobramycin, Amikacin or Ticarcillin-clavulanic acid + Aminoglycoside)• Aminoglycoside + Anti-pseudomonal Cephalosporin• Aminoglycoside + Carbapenem

Saman K, Commun Oncol. 2006; 3:585-591Bucaneve et al, N Eng J Med. 2005; 353:977-987

Combination Therapy Without Vancomycin

Selection of initial antibiotic therapy

M onotherapyCef t az id ime

Cef epime or

Car bapenems

T wo Drugs+ A minoglycos ide

or

2 lac t ams

Vancomycinnot needed

Vancomycin plusCephs / car bap

+/ -

aminoglycos ide

Vancomycinneeded

ff ff ff ff ff ff ff ff ff ff ff ff ff

Child with Fever + N eutropeniaff ff ff ff ff ff ff ff ff ff ff ff ff ff ff

Reassess after 3-5 days

Walter at al. IDSAI Guideline. 2002:34;730-51

Initial Antibiotic ModificationsConsiderations

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

Combination TherapyAdvantages

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

Combination TherapyDisadvantages

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

6. Reassessment – Afebrile patient

ConsiderPO ant ibiot ics

Low Risk

Cont inue sameI V ant ibiot ics

H igh r isk

N o et iology

A dj usttherapy

Et iology ident ifi ed

ff ff ff ff ff ff ff ff ff ff ff ff ffA f ebrile within the fi rst 3- 5 days of t reatment

ff ff ff ff ff ff ff ff ff ff ff ff ff ff ff

Walter at al. IDSAI Guideline. 2002:34;730-51

Reassessment – Febrile Patient

I f no changein pat ientcondit ion

D/ C vanco

Cont inue sameA nt ibiot ics

CoverES BL T ype 1 lactamase

I f progressivedisease

I f cr iter ia f orVancomycin

Change A nt ibiot ics A dd ant if ungaldrug

ff ff ff ff ff ff ff ff ff ff ff ff ffFebrile f or the fi rst 3- 5 days of t reatment

O r new onset f ever

Reproduced with permission from Hughes et al. Clin Infect Dis 2002;34:730–751

Persistent FeverCauses • Nonbacterial infection• Resistant bacteria • Slow response to antibiotics • Fungal sepsis • Inadequate serum & tissue levels • Drug fever Jasic et al, Clin Infect Dis .2006; 42:597-607

7. 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

Jasic et al, Clin Infect Dis .2006; 42:597-607

22

Stop if no disease and condition stable

Conntinue antibiotik

High risk : ANC< 100/mm3, Mucousitis,

unstable sign

Stop when afebrile for 5- 7 days

Lows risk, clinically well

Stop Antibiotics 48 h after afebril

ANC < 500/mm3 by day 7

DURATION OF ANTIBIOTICS THERAPY

Afebrile by day 3-5

ANC≥ 500/mm3 for 2 consecutive days

Persistent Fever

Reassess

Reassess

Continue for 2 weekStop 4 – 5 days after > 500/mm3

ANC < 500/mm3ANC ≥ 500/mm3

Algorithm for initial management of febrile neutropenia

Terature 38.8ºC) + neutropenia (<500 neutrophils/mm3)

Low risk High risk

Oral IV Vancomycin not needed

Vancomycin needed

Ciprofloxacin+

Amoxicillin / clavulanate (adults only)

• Cefepime,• Ceftazidime

or• Carbapenem

Monotherapy

Aminoglycoside

+• Antipseudomonal

penicillin,• Cefepime,• Ceftazidime,

or • Carbapenem

Two drugs

Vancomycin+

• Cefepime, • Ceftazidime

or• Carbapenem

Aminoglycoside

Vancomycin +

Reassess after 3–5 days

Reproduced with permission from Hughes et al. Clin Infect Dis 2002;34:730–751

Guide for the management of patients with persistent fever during antibiotic therapy

Reproduced with permission from Hughes et al. Clin Infect Dis 2002;34:730–751

Antifungal drug, with or without

antibiotic change

If febrile through Days

5–7 and resolution of

neutropenia is not imminent

Persistent fever during first 3–5 days of treatment: no aetiology

Reassess patient on Days 3–5

• If progressive disease or

• If criteria for vancomycin are met

Change antibiotics

If no change in patient's condition (consider stopping

vancomycin)

Continue initial

antibiotics

Guidelines Febrile Neutropenia

Antibiotics penetration :

Cunha, Antibiotic Essential, 2009

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

28

Thank you

for your attention

edi & alan