4.06 - Febrile Neutropenia

Haematopoietic Stem Cell Transplantation (HSCT), Haematology and Oncology

Febrile Neutropenia: Neutrophils < 0.5 x 109/L, or < 1 x 109/L with a predicted decline to  < 0.5 x 109/L,+ fever ≥ 38⁰C.

Low risk patients: Anticipate < 7 days profound neutropenia, no co morbidities, can take orally, accessible to hospital care.

High-risk patients: Anticipate ≥ 7 days and profound neutropenia (ANC < 1 x 109/L) ± significant medical co-morbid conditions.


A) Adults

Disease / Etiology

Preferred

Alternative

Comments

Low Risk (Outpatient)

 
Co-amoxiclav 625 mg PO q12H
± Ciprofloxacin 750 mg PO q12H
If colonized by P aeruginosa previously

 
Duration: 3 - 5 days or until afebrile
Treat till counts > 1 x 109/L.

High Risk - Stable Patient

 
Initial fever

 
Piperacillin / Tazobactam 4.5 gm IV q8H
± Amikacin 15 mg/kg IV q24H
± Vancomycin 15 - 20 mg/kg IV q12H*


Cefepime 2 gm IV q8H
± Amikacin 15 mg/kg IV q24H

Duration: until neutrophils count recovers (> 1 x 109/L).

*Vancomycin is not recommended as a standard part of the initial antibiotic regimen. Only consider for: known MRSA colonizer, suspected catheter-related infection, skin or soft-tissue infection, or in shock.
Stop after 48 hours if no evidence of gram positive cocci.

Persistent fever
or new fever after 4 - 7 days
or deterioration of clinical signs
Consider VRE, resistant gram negative bacilli


Change or upgrade to Imipenem 500 mg IV q6H
± Vancomycin 15 - 20 mg/kg IV q12H
 

Consider Invasive Fungal Infections if new clinical signs or symptoms suggestive and/or if fever persists ≥ 7 - 10 days.

Received none or only Fluconazole antifungal prophylaxis.
Sinus ± chest CT not suggestive of fungal infection.


Add antifungal to above:
Caspofungin 70 mg IV single dose Day 1 then 50 mg IV q24H

Anidulafungin 200 mg IV single dose then 100 mg IV q24H
OR
Amphotericin B 0.7 - 1 mg/kg IV q24H
OR
Liposomal Amphotericin B
3 - 5 mg/kg IV q24H

Duration:
If culture positive, for two weeks from first negative culture and until neutrophil recovers.

Repeat fungal culture EOD if positive for candidaemia and no evidence of invasive disease.

If there is no positive cultures but is CT scan / biopsy proven, continue until off immunosuppressant or no further chemotherapy.
 
Sinus ± chest CT suggestive of fungal infection.


Voriconazole 6 mg/kg IV q12H for 2 doses then 3 mg/kg IV q12H


Caspofungin 70 mg IV single
dose Day 1
then 50 mg IV q24H

Received Voriconazole or Posaconazole prophylaxis

Amphotericin B
0.7 - 1 mg/kg IV q24H
OR
Liposomal Amphotericin B
3 - 5 mg/kg IV q24H

High Risk - Unstable Patient

 
Initial fever

 
Imipenem 1 gm IV q8H
± Vancomycin 15 - 20 mg/kg IV q12H

 
Piperacillin / Tazobactam 4.5 g IV q8H
± Amikacin 15 mg/kg IV q24H
± Vancomycin 15 - 20 mg/kg IV q12H

 
Treatment in HDU setting.
 
Persistent fever 
or new fever after 4 - 7 days

 
Consider add Vancomycin 15 - 20 mg/kg IV q12H
+ Antifungal as above (for stable patients)

   


B) Paediatrics

Disease / Etiology

Preferred

Alternative

Comments

 
Non-neutropenic fever, stable patient, no previous infection, no infective foci:
Staph epidermidis (MSSE)
Staph aureus (MSSA)
Streptococcus viridians
Enterobacteriaceae
Pseudomonas
Enterococcus

 
Cloxacillin 50 mg/kg (max 2gm) IV q6H
+
Gentamicin 5 mg/kg (max 240 mg) IV single daily dose
 
Ceftriaxone 50 - 80 mg/kg/day IV in 1 - 2 divided doses
 
Targeted therapy:

Non-VRE:
Vancomycin 15 mg/kg IV q8H

Enterococcus faecium (VRE):
Linezolid 10 mg/kg IV q8H (max 600 mg)
 
Suspected in-dwelling venous catheter as source:
Staph aureus (MRSA)
Staph epidermidis (MRSE)

 
Vancomycin 15 mg/kg (max 1gm) IV q8H
 
Linezolid 10 mg/kg (max 600 mg) IV q8H
 
Monitor Vancomycin blood levels and renal function.

Excellent CSF penetration (70%) for Linezolid.
 
Febrile Neutropenia
(ANC < 1.0 x 109
/L)

CONS:
Staph aureus / MRSA
Streptococcus spp
Enterococcus spp


Gram negatives:
Escherichia coli
Klebsiella pneumoniae
Pseudomonas aeruginosa
Enterobacter spp
Acinetobacter baumanii
Strenotrophomonas maltophilia
Citrobacter spp


Fungal:
Candida spp
Aspergillus spp



Stable Patient:
Piperacillin / Tazobactam 100 mg/kg (Piperacillin component) (max 4 gm) IV q6 - 8H

For HSCT patients:
Cefepime 50 mg/kg (max 2 gm) IV q8H

Unstable Patient / Previous MRSA Isolated:

Meropenem 40 mg/kg (max 2 gm) IV q8H
+
Vancomycin 15 mg/kg (max 1 gm) IV q8H

Stable Patient:
Meropenem 20 mg/kg (max 2 gm) IV q8H
+
Gentamicin
1 week - 10 years old:
8 mg/kg IV q24H Day 1, then 6 mg/kg IV q24H
> 10 years old:
7 mg/kg IV q24H Day 1, then 5 mg/kg IV q24H
OR
Amikacin
1 week to 10 years old:
25 mg/kg IV q24H Day 1, then 18 mg/kg IV q24H
> 10 years old:
20 mg/kg IV q24H Day 1, then 15 mg/kg (max 1.5 gm) q24H

Documented fungaemia OR
No clinical improvement / febrile still after 72 hour of Meropenem
ADD Amphotericin B 1 mg/kg IV once daily 4 - 6 hours infusion

Monitor renal function.

Targeted Specific Pathogens

 
Pneumocystis jirovecii (PCP)
 
Co-trimoxazole 5 mg/kg (Trimethoprim component) (max 160 mg) IV q6H

 
Pentamidine 4 mg/kg IV q24H (given slowly over 1 hour in D5W)
Risk of severe hypotension


Duration of treatment: 21 days.

Prednisolone 1 - 2 mg/kg/day (max 80 mg) in 2 divided doses in first week; then taper over next 2 weeks


Candida spp
(Other than C. glabrata and C. krusei)
 
Stable haemodynamics
Fluconazole 3 - 6 mg/kg (max 200 mg) IV / PO q12H
OR
Amphotericin B 1 mg/kg IV q24H
 
Unstable haemodynamics, recent azoles exposure, unknown Candida spp
Caspofungin 70 mg/m2 (max 70 mg) q24H on Day 1 followed by 50 mg/m2 (max 50 mg) q24H
OR
Liposomal Amphotericin B 3 - 5 mg/kg IV q24H

Consider removal of CVC.

Duration of treatment: ≥ 21 days on average or for ≥ 2 weeks following first negative blood culture.

Intravenous to Oral switch permissible after 5 days of IV therapy, where circumstances permit, provided clinical improvement.
Caspofungin: useful in renal impaired
Liposomal Amphotericin B is no more effective than Amphotericin B as an antifungal.
For other anti-fungals : Consult ID

 
Aspergillus spp
 
Amphotericin B
1 - 1.5 mg/kg IV q24H

Caspofungin 70 mg/m2 (max 70 mg) on Day 1, followed by 50 mg/m2 (max 50 mg) IV q24H 


Fluconazole has no activity against Aspergillus spp.
Voriconazole is available if patient can afford. Advantage of faster IV to oral switch. Consult ID. Ophthalmological assessment and monitoring.
 
Zygomycetes (Moulds) :
Mucor
Rhizopus


 
Liposomal Amphotericin B 
3 - 5 mg/kg IV q24
H
 
Children > 12 years old:
Posaconazole 200 mg PO q6H
 
Voriconazole and Caspofungin not effective against moulds.
Consult ID.

Posaconazole is not available in UMMC.


 
Fusarium spp
 
Liposomal Amphotericin B 
3 - 5 mg/kg IV q24
H
OR
Voriconazole 7 - 9 mg/kg (max 200 mg) IV q12H

 
Children > 12 years old:
Posaconazole 200 mg PO q6H

Consult ID.

Posaconazole is not available in UMMC. 

 
Stenotrophomonas maltophilia
 
Co-trimoxazole 5 mg/kg (Trimethoprim component) IV q6H

Older children:
Ciprofloxacin 10 mg/kg (max 400 mg) IV q8H

Minocycline 4 mg/kg initially PO, then 2 mg/kg (max 100 mg) PO q12H
Avoid in < 12 years old; deposited in teeth

 
Avoid Ciprofloxacin if possible < 18 years old. Risk of ruptured tendo-archilles and arthropathies.

Often susceptible to Colistin Methanesulfonate (CMS).
Consult ID.
 
Acinetobacter baumanii
 
Carbapenems if susceptible
Imipenem 20 mg/kg IV q8H

Ampicillin / Sulbactam
25 - 50 mg/kg (Ampicillin component) IV q6H


Colistin Methanesulfonate (CMS)
Consult ID.

Non-MDR Acinetobacter spp may be susceptible to 3rd generation or 4th generation Cephalosporins and respiratory Quinolones. However, their use is not encouraged as resistance develops quickly.

Varicella zoster

Post-Exposure Prophylaxis
Effective up to 96H following exposure.

Varicella Immunoglobulin:

Weight Dose
≤ 2 kg 62.5 units
2.1 - 10 kg 125 units
10.1 - 20 kg 250 units
20.1 - 30 kg 375 units
30.1 - 40 kg 500 units
> 40.1 kg 625 units

Valacyclovir 20 mg/kg (max 1 gm) PO q8H for 5 days

Treatment
Acyclovir 10 mg/kg (max 800 mg) IV q8H for 7 - 10 days

 
IV Immunoglobulin (IVIG) 400 mg/kg.
Effectiveness variable.

Treatment
Foscarnet 40 mg/kg IV q8H for 7 - 10 days
 
Oral Acyclovir (unlike Valacyclovir) is poorly absorbed and requires very frequent dosing; not suitable for prophylaxis in immunocompromised.

 

 
Cytomegalovirus (CMV) Retinitis

Initial Therapy
Ganciclovir 5 mg/kg IV q12H for 14 - 21 days

Secondary Prophylaxis:
Valganciclovir 16 mg/kg q24H PO for 2 - 3 weeks

Initial Therapy
Foscarnet 60 mg/kg IV q8H for 14 - 21 days, then 90 - 120 mg/kg daily for chronic suppressive therapy
 
Repeat induction regimen if CMV retinitis progresses while on therapy.

Use of Valacyclovir for prophylaxis not FDA approved.

Valganciclovir is not available as standard formulary in UMMC.