3.06 - Febrile Neutropenia [updated]

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
(within the last 6 months)

 
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 q6H
± Amikacin 15 mg/kg IV q24H
± Vancomycin 15 - 20 mg/kg IV q8 - 12H*


Cefepime 2 gm IV q8H
± Amikacin 15 mg/kg IV q24H
OR Gentamicin 5mg/kg IV q24H

Duration: until neutrophils count recovers (> 1 x 109/L).
(May consider stop empirical antimicrobial therapy (EAT) by 7 days.

*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 Meropenem 1g  IV q8H
± Vancomycin 15 - 20 mg/kg IV q8 - 12H
 

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:
Micafungin 100mg IV single dose Day1 and q24h

**Anidulafungin 200 mg IV single dose then 100 mg IV q24H
OR
Amphotericin B 0.7 - 1 mg/kg IV q24H
OR
Amphotericin B Lipid complex
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.

**not available in UMMC
 
Sinus ± chest CT suggestive of fungal infection.


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


Amphotericin B 0.7-1mg/kg IV q24H

Received Voriconazole or Posaconazole prophylaxis

Amphotericin B
0.7 - 1 mg/kg IV q24H
OR
Amphotericin B Lipid Complex
5 mg/kg IV q24H

High Risk - Unstable Patient

 
Initial fever

 
Meropenem 1 gm IV q8H
± Vancomycin 15 - 20 mg/kg IV q8 - 12H

 
Piperacillin / Tazobactam 4.5 g IV q6H
± Amikacin 15 mg/kg IV q24H
± Vancomycin 15 - 20 mg/kg IV q8 - 12H

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

 
Consider add Vancomycin 15 - 20 mg/kg IV q8 - 12H
+ Antifungal as above (for stable patients)

   

Antimicrobial prophylaxis in patient with neutropenia

Herpes Simplex Virus (HSV)/ Varicella-Zoster Virus (VZV)                         Aciclovir 400-800mg PO q12H  Valaciclovir 500mg PO q12H Patients who are seropositive for HSV and who are undergoing allogeneic Hematopoietic Cell Transplant (HCT) or induction chemotherapy for acute leukaemia should receive antiviral prophylaxis.

Duration: continued until recovery of the white blood cell count or resolution of mucositis, whichever occurs later; it can be extended for a longer period in patients with frequent recurrent HSV infections or in those with graft-versus-host disease (GVHD).

In HCT recipients who are seropositive for VZV should receive antiviral prophylaxis. Duration: continue for one year or longer in those with chronic GVHD and/or who require ongoing immunosuppressant

Pneumocystis pneumonia Co-Trimoxazole (480mg) PO 1-2 tablets q24H

Or

Co-Trimoxazole (480mg) PO 2 tablets q24H three times per week

 Dapsone 100mg PO q24H  


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/dose (max 2gm) IV q6H
+
Gentamicin 5 mg/kg/dose (max 240 mg) IV q24H
 
Ceftriaxone 50mg/kg/dose IV q12H
 

 
Suspected in-dwelling venous catheter as source:
Staph aureus (MRSA)
Staph epidermidis (MRSE)

 
Vancomycin 15 mg/kg (max 1gm) IV q8H
 

 
Monitor Vancomycin blood levels and renal function.

 
Febrile Neutropenia


Gram positive:
Staph aureus / MRSA
Streptococcus spp
Enterococcus spp


Gram negative:
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/dose (Piperacillin component) (max 4 gm) IV q8H

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

Unstable Patient / Previous MRSA Isolated:

Meropenem 20-40 mg/kg/dose

(max 2 gm) IV q8H


±


Vancomycin 15 mg/kg/dose (max 1 gm) IV q8H
 



Documented fungaemia OR

No clinical improvement / febrile still after 96 hours of antibiotics

ADD Fluconazole 6-12mg/kg/dose IV q24H OR Amphotericin B 1 mg/kg IV q24H 4 - 6 hours infusion

Monitor renal function.
.

Targeted Specific Pathogens

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

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

Duration of treatment: 21 days (can change to oral).

(Moderate to severe) Consider Prednisolone 1 - 2 mg/kg/day (max 80 mg) q12H in first week; then taper over next 2 weeks


Candida spp
(Other than C. glabrata and C. krusei)
 

Stable haemodynamics
Fluconazole 6-12 mg/kg/dose IV / PO q24H


OR
Amphotericin B 1 mg/kg/dose IV q24H
 

Unstable haemodynamics, recent azoles exposure, unknown Candida spp
Micafungin 2mg/kg/dose (max 100 mg) IV q24H


OR

Lipid complex Amphotericin B 5mg/kg/dose IV q24H

Consider removal of CVC.

Repeat blood culture every 72 hours till a negative culture.

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

Liposomal Amphotericin B is no more effective than Amphotericin B as an antifungal.


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

Voriconazole 9 mg/kg/dose (max 350 mg) IV q12H x 2 doses followed by 8mg/kg/dose IV q12H


Fluconazole has no activity against Aspergillus spp.


Renal function monitoring 
 
Stenotrophomonas maltophilia

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

Older children:

Levofloxacin 8mg/kg/dose IV q12H
 
Avoid Fluroquinolone group if possible < 18 years old. Risk of ruptured tendo-archilles and arthropathies.


 
Acinetobacter baumanii
 

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


 




Varicella zoster

Post-Exposure Prophylaxis
Effective up to 10 days following exposure.

Varicella Immunoglobulin (undetectable VZ antibodies) :

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

Acyclovir 20mg/kg/dose PO q6H for 7 days


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

Acyclovir 20mg/kg/dose PO q6h for 7 – 10 days or until no new lesions for 48 hours



 
IV Immunoglobulin G (IVIG) 400 mg/kg.

 

 
Cytomegalovirus (CMV) Infection

Ganciclovir 5 mg/kg/dose IV q12h for 14 - 21 days