1. Febrile Neutropenia in Paediatric Oncology – What do the rest do?
Janis Chamberlain
Paediatric Haematology / Oncology
JHCH Grand Rounds August 2005

2. Febrile neutropenia (FN) in paediatric oncology
commonest cause of unplanned hospital admissions for paediatric patients on therapy for cancer
mortality rate 1%
morbidity
significant cost

3. FN – what is it? Many definitions of both fever and neutropenia
EG. Infectious Diseases Society of America Guidelines
fever ; single oral temperature ≥ 38.3°C
temperature ≥ 38.0°C for at least an hour
neutropenia; < 0.5 x 109/L or
< 1.0 x 109/L with a predicted decrease to < 0.5 x 109/L
neutropenic patients who are unwell but afebrile, and non-neutropenic febrile patients expected to become neutropenic, => treat as per FN PRN

4. Infectious Diseases Society of America Guidelines
Initial monotherapy with cefepime, ceftazidime, imipenem or meropenem,
Or aminoglycoside + antipseudomonal penicillin, cephalosporin or carbapenem
Initial Vancomycin + added antibiotics only if;
suspected catheter related infection
potential for severe mucositis
known colonisation with penicillin and cephalosporin-resistant pneumococci or MRSA
gram positive organisms awaiting sensitivity
cardiovascular compromise

5. Guidelines continued …
If used as initial therapy, Vancomycin should be given with cefepime or ceftazidime, +/- an aminoglycoside, or with carbapenem +/- an aminoglycoside, or with an anti-pseudomonal penicillin and an aminoglycoside
Add antifungal at day 5

6. High Risk Patients Parenteral antibiotics + close monitoring
Haematological malignancies
Severe and prolonged neutropenia
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

7. Low Risk Patients
Clinical basis / biochemical marker / laboratory parameter unique to patients with significant infection
Select good candidates for outpatient therapy
Absolute monocyte count > 155/mm3
C-reactive protein < 90mg/L
No single marker or system

8. Low Risk Patients Solid tumours receiving conventional chemotherapy
patients without AML, Burkitt’s Lymphoma or ALL in induction
expected duration of neutropenia ≤ 7 days
clinically and haemodynamically stable
unexplained or simple infection
no other significant comorbidities

9. Outpatient FN therapy
Increasingly, published trials are supporting the efficacy of outpatient therapy
Less cost
Preferred by most families
Reduced nosocomial infection risk
Reduced administration of broad-spectrum antibiotics and associated drug resistance
Reduced treatment-related toxicity

10. Out-patient Antibiotics
Adequate institutional and community infrastructure
Trained health professionals 1) at discharge from hospital and 2) at regular review in the home / hospital setting
Detect early deterioration / lack of response to minimise morbidity and mortality
Family selection; compliance, transportation, geography
24hr advice and emergency care
Antimicrobials chosen on patient condition, ease of administration and local sensitivities

11. Febrile Neutropenia Audit: Prospective audit of FN episodes treated in Australia and New Zealand tertiary paediatric oncology referral centres
Janis Chamberlain, Elizabeth Smibert, Jane Skeen, Frank Alvaro
­­Australian and New Zealand Children’s Haematology/Oncology Group

12. Aim
There are currently no published national guidelines for the treatment of FN in children
Clarify current practice
Supportive Care Committee of the Australian and New Zealand Children’s Haematology Oncology Group (ANZCHOG)
Prospective audit of current management practices of febrile neutropenia in paediatric oncology patients
Treated in all of the major paediatric oncology units in Australia and New Zealand

13. Method All tertiary centres in Aust/NZ invited to participate
Prospective audit
Proforma mailed to each of the 12 ANZCHOG members
Clinicians or data managers asked to collect clinical and microbial data regarding patients admitted with FN episodes
Audit undertaken over an 8 week period

14. Results

15. Results 11 centres participated 127 episodes 114 patients
Median neutrophil count 0 x 109 /L
Median monocyte count 0 x 109 /L
Median duration of hospital stay - 6 days (range 1-43+)

16. Patient Characteristics
VALUE
Number of febrile episodes
127
Number of patients
114
Median age years (range)
6.6 (0.8 to 19.1yrs)
Sex (%) Male 56
Underlying disease (% of diagnosis)
Leukaemia
Lymphoma
Brain tumour
Solid tumour 54 12 13 21
Bone Marrow Transplant (% of episodes)
Autologous
Peripheral Collection
Bone Marrow Harvest
Allogenic
Matched related donor
Matched unrelated donor
Cord 6 2 1
Central line (% of patients) 86

17. Episodes by diagnosis

19. ANTIMICROBIALS- First line antibiotics
Cefepime + Gentamicin
Cefepime + Flucloxacillin
Cefepime + Gentamicin + Flucloxacillin
Ceftazadime
Tazocin + Gentamicin
Tazocin + Cefepime + Tobramycin
Piperacillin + Amikacin
Piperacillin + Amikacin + Acyclovir
Meropenem + Metronidazole + Flucloxacillin
Ceftriaxone + Tobramycin + Teicoplanin
Ceftriaxone + Tobramycin
Vancomycin + Meropenem
Timentin + Cefalothin + Gentamicin
Timentin + Gentamicin
Ceftriaxone
Timentin + Gentamicin + Metronidazole
Vancomycin + Timentin + Gentamicin
Cefepime + Tobramycin

20. Second line therapy ANTIMICROBIAL No. of EPISODES Vancomycin 21
Amphotericin 6
Meropenem 8
Metronidazole 3
Teicoplanin 3
Acyclovir 3
Amikacin 3
Flucloxacillin 3
Gentamicin 2
Ceftazidime 1
Tazocin 1
Cefotaxime 1
Erythromycin 1
Penicillin 1
Ceftriaxone 1
Fluconazole 1
High dose Bactrim 1

21. Results 18 different first line antibiotics
39% of episodes no change to first line antibiotics
Persistent fever most common reason for change to first line antibiotics
Second most common reason was response to culture result
Anti-fungals introduced in 18% of episodes
Introduced at median of 6 days after commencement of antibiotics

22. Positive cultures 30% of episodes had positive blood cultures
69 different pathogens during 39% of episodes

23. Positive Blood Cultures

24. Site specific isolates
Organism
Site
No. of isolates
RESPIRATORY Candida albicans
Sputum 1
CMV
Throat swab
Influenza A
NPA
Pantoea
Parainfluenza
Pneumocystis
Rhinovirus 3
GASTROINTESTINAL Adenovirus
Stool
C. difficile 2
Candida sp.
Enterobacter sp.
Klebsiella oxytoca
RENAL CMV
Urine
Enterococcus Faecalis
SKIN Enterococcus Faecalis
Skin
Herpes Simplex
Lip lesion
Staph aureus
Skin wound swab
Varicella Zoster
Skin swab

25. Venous access status / blood culture positivity
Venous access status / blood culture positivity * One patient had Candida albicans cultured from unspecified type of central line.

27. Discharge 6 centres discharged patients on therapeutic antibiotics
Outpatient antibiotics were used in a total of 21% of episodes
Almost all patients discharged on oral antibiotics were afebrile at time of discharge
Median ANC at d/c in patients discharged on oral antibiotics was 0.6 x x 109 /L
G-CSF was utilised in 48% of patients as part of protocol and 12% in response to the febrile illness

28. Outpatient Antimicrobial Therapy
Antimicrobial Mean Duration No. of Episodes IV
Ceftriaxone / Ambisome
Ceftriaxone
Cotrimoxazole
Ambisome
Ceftriaxone / Tobramycin
Ceftriaxone / Tobramycin / Teicoplanin 5 1
Ceftriaxone / Teicoplanin
Teicoplanin
IV + PO
Amphotericin
+ PO Itraconazole 60 PO
Augmentin
Augmentin Duo / Ciprofloxacin 9, 8, 10, 8 4
Clindamycin n/s 1
Acyclovir (+n/s) 2
Valacyclovir
Flucloxacillin 15, 9 2
Keflex

29. Future Directions ?Future national study
Standard of treatment
Interventional study examining the safety and failure of out-patient antibiotics
Reducing the use of external CVL in favour of ports (including double lumen ports)
Biochemical marker for severe life threatening infections

30. Potential Difficulties
What is standard of care?
What antibiotic combination?
Lack of funding for outpatient care
Consensus

31. Acknowledgements: Dr L Hesketh M Giles Wellington JHCH Newcastle
Dr R Suppiah
Mater Hospital Brisbane
L Pearson
CHW Westmead
M Giles
JHCH Newcastle
A Kain
WCH Adelaide
Y Hastings
RCH Brisbane