Febrile Neutropenia in Paediatric Oncology – What do the rest do?

Janis Chamberlain

Paediatric Haematology / Oncology

JHCH Grand Rounds August 2005

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

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

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

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

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

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

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

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

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

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

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

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

Results

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+)

Patient Characteristics CHARACTERISTIC 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

2

0

Central line (% of patients) 86

Episodes by diagnosis

Wilms

Other

AML

ALL

NHL

NB

Ewings

Hodgkins

OsteosarcomaBrain Tumour

010203040506070

% o

f p

ati

en

ts

<0.1 0.1 <0.2 0.2 <0.5 0.5 <1.0

Cell Count

Beginning of episode

Neutrophil

Monocyte

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

ANTIMICROBIALS- First line antibiotics

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

Second line therapy

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

Positive cultures

30% of episodes had positive blood cultures

69 different pathogens during 39% of episodes

0 2 4 6 8 10 12 14 16 18

No. of Episodes

Xanthomonas Maltophilia

Strep sp.

Staph sp.

Stomatococcus Mucilaginosus

Pseudomonas sp.

Klebsiella Pneumoniae

Enterobacter cloacoe

E. Coli

CMV PCR

Candida sp.

Acinetobacter Iwoffii

Mic

ro-o

rganis

m Positive Blood Cultures

Site specific isolatesOrganism Site No. of isolates

RESPIRATORY Candida albicans Sputum 1

CMV Throat swab 1

Influenza A NPA 1

Pantoea Sputum 1

Parainfluenza NPA 1

Pneumocystis Sputum 1

Rhinovirus NPA 3

GASTROINTESTINAL Adenovirus Stool 1

C. difficile Stool 2

Candida sp. Stool 2

Enterobacter sp. Stool 1

Klebsiella oxytoca Stool 1

RENAL CMV Urine 1

Enterococcus Faecalis Urine 1

SKIN Enterococcus Faecalis Skin 1

Herpes Simplex Lip lesion 3

Staph aureus Skin wound swab 2

Varicella Zoster Skin swab 1

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

0

10

20

30

40

50

60

% o

f pati

ents

No central line Portacath External CentralLine

Total episodes

Staph Positive Blood CultureStaph Negative Blood Culture

0

10

20

30

40

50

% o

f p

ati

en

ts

<0.1 0.1 <0.2 0.2 <0.5 0.5 <1.0 1.0+

Cell count

End of episode

Neutrophils

Monocytes

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

Outpatient Antimicrobial TherapyAntimicrobial Mean Duration No. of EpisodesIV Ceftriaxone / Ambisome 7 1 Ceftriaxone 13 1 Cotrimoxazole 4 1 Ambisome 22 1 Ceftriaxone / Tobramycin 5 4 Ceftriaxone / Tobramycin / Teicoplanin 5 1 Ceftriaxone / Teicoplanin 10 1 Teicoplanin 7 1IV + PO Amphotericin 19 1 + PO Itraconazole 60PO Augmentin 10 1 Augmentin Duo / Ciprofloxacin 9, 8, 10, 8 4 Clindamycin n/s 1 Acyclovir 12 (+n/s) 2 Valacyclovir 21 1 Flucloxacillin 15, 9 2 Keflex 10 1

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

Potential Difficulties

What is standard of care? What antibiotic combination? Lack of funding for outpatient care Consensus

Acknowledgements:

M Giles JHCH Newcastle

A Kain WCH Adelaide

Y Hastings RCH Brisbane

Dr L Hesketh Wellington

Dr R Suppiah Mater Hospital Brisbane

L Pearson CHW Westmead