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 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

Episodes by diagnosis

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

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

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

Positive Blood Cultures

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

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

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 Therapy Antimicrobial Mean Duration No. of Episodes IV 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 1 IV + PO Amphotericin 19 1 + PO Itraconazole 60 PO 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: 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