Australasian Society for Infectious Diseases

Guidelines for use of antifungal agents in treatment of invasive fungal infection (July 2003)

SUMMARY OF RECOMMENDATIONS FOR TREATMENT

KEY FOR LEVELS OF EVIDENCE   Categories for strength of evidence for or against a recommendation A good evidence to support a recommendation for use B moderate evidence to support a recommendation for use C poor evidence to support a recommendation for or against use D good evidence to support a recommendation against use   Categories indicating the quality of evidence for recommendations I evidence from at least one properly randomised controlled trial II evidence from at least one well-designed clinical trial without randomisation eg from cohort or case controlled studies (preferably from >1 center), from multiple time series or dramatic results in uncontrolled experiments III evidence from opinions of respected authorities on the basis of clinical experience, descriptive studies, or reports of expert committees.

A. Initial therapy for suspected or proven invasive fungal infection (IFI)

• Amphotericin B remains the empiric treatment of choice for invasive fungal infections except for those due to the fungi described in section C below, or in patients with pre-existing renal impairment described in section B (BIII).
  
  Dose of amphotericin B: for a yeast infection 0.7 mg/kg/day (with the exception of C. krusei and C. glabrata where a dose of 1 mg/kg/day is recommended), for a mould infection 1 mg/kg/day.
  
  To minimise renal impairment reduce the number of potentially nephrotoxic drugs co-administered and ensure the patient is well hydrated. Saline pre-hydration should be given if possible (AII).
  
  
• If mould infection is considered unlikely on clinical grounds, fluconazole 400 mg/day may be an alternative if not previously administered for prophylaxis (AI).
  
  
• Voriconazole is an alternative to amphotericin B for the initial treatment of proven acute invasive aspergillosis in the immunocompromised patient (AI).
  
  Dose voriconazole: loading dose of 6 mg/kg/day IV bd for 2 doses and thereafter
  4 mg/kg bd.

• Allow serum creatinine to rise to 0.23mmol/L before ceasing conventional amphotericin B (BII)

• except in patients where renal failure is expected to complicate management of underlying condition: eg renal transplant, haematopoietic stem cell transplant (HSCT), or chemotherapy for haematological malignancy where HSCT is ultimately planned. In these patients stop amphotericin B if serum creatinine reaches 0.15 mmol/L on 2 consecutive days or creatinine clearance falls by 50% or if the rate of creatinine increase has been rapid eg doubling daily.
  
  
• Subsequent therapy if renal impairment reaches these thresholds will depend on clinical setting as follows:
  
  a. For Fever of Unknown Origin (FUO) in neutropenic patients
  
  
  • At low risk for invasive mould infection fluconazole 400 mg/day may be an alternative if not previously administered for prophylaxis (AI).
    
    
  • At high risk for invasive mould infection (eg allogeneic HSCT recipient, patients undergoing therapy for acute leukaemia, patient with >3 weeks Absolute Neutrophil Count (ANC) <0.5 x 10⁹/L)

    Liposomal amphotericin B (AmBisome®) 1 mg/kg/day may be the preferred option (AI). The dose may be increased to 3 mg/kg/day in patients with poor response (BII).

    OR

    Itraconazole loading dose 200 mg IV bd for 2 days then 200mg IV/day in patients being treated for haematological malignancies who have not received itraconazole prophylaxis. After one week of intravenous itraconazole, oral itraconazole cyclodextrin solution 20 mls bd could be substituted. (Not studied in allogeneic HSCT recipients) (AI).

    OR

    Voriconazole. Loading dose of 6 mg/kg/day IV bd for 2 doses then 3 mg/kg IV bd or 200mg orally bd (BI).

    The efficacy of lipid formulations other than AmBisome® are less well evaluated although Amphotericin B lipid complex (Abelcet®) 5 mg/kg/day or Amphotericin B colloidal dispersion (Amphocil®) 3-4 mg/kg/day are alternatives.
    
    Caspofungin has not been evaluated for the empiric treatment of persistent fever in the setting of neutropenia

    
    The agent of choice will depend on individual patient's tolerance, presence of hepatic impairment where liposomal amphotericin B may be better tolerated and requirement for drugs such as rifampicin, which induce metabolism of triazoles and the comparative drug costs. As itraconazole empiric therapy has not been evaluated in allogeneic HSCT recipients, liposomal amphotericin B or voriconazole would be preferred in this setting and itraconazole preferred in patients undergoing treatment for haematological malignancies who have not received itraconazole prophylaxis.

  b. For candidaemia or invasive candidiasis

  • Neutropenic patient: caspofungin (BI), liposomal amphotericin B (AII) 3 mg/kg/day. If the organism is a non-albicans Candida species higher doses may be required. Amphotericin B lipid complex at 5 mg/kg/day or Amphotericin B colloidal dispersion 3-4 mg/kg/day are alternatives (CIII).
    
    
  • Not neutropenic and fluconazole-sensitive organism: Fluconazole 400 mg IV daily (AI). If the organism has intermediate susceptibility to fluconazole and the patient is stable, the dose can be increased to 800 mg/day. Doses should be adjusted for renal function.
    
    
  • Not neutropenic and a fluconazole resistant organism: caspofungin (BI), voriconazole (CIII), or a lipid preparation of amphotericin B (CIII) may be used according to susceptibility of organism, patient tolerance and comparative cost. The maintenance dose of voriconazole is 3mg/kg IV bd for treatment of candidemia.
    
    

  c. For suspected or proven acute invasive aspergillosis

  • Voriconazole loading dose of 6 mg/kg/day IV bd for 2 doses, followed by 4 mg/kg bd (AI).
    
    
  • Liposomal amphotericin B at 3-5 mg/kg/day (BI). If patient not neutropenic and stable, liposomal amphotericin B at 3 mg/kg/day may be adequate (BI).
    
    

  • Caspofungin 70mg load followed by 50 mg/day is an alternative (BII).
    

  • Amphotericin B lipid complex at 5 mg/kg/day, Amphotericin B colloidal dispersion at 3-4 mg/kg/day (BIII).
    

    With current information, voriconazole may be the preferred option. The limitations in the spectrum of activity of these agents should also be considered when treating suspected infection (eg. caspofungin is active against aspergillus and candida only, voriconazole is inactive against Zygomycetes, and amphotericin B is inactive against Scedosporium spp.)
    

a. For other moulds which may be less susceptible to amphotericin B:

• Scedosporium prolificans: voriconazole or itraconazole plus terbinafine 250mg bd as first line treatment (BIII).
  
  
• S. apiospermum and its teleomorph Pseudallescheria boydii: voriconazole or itraconazole.
  
  
• Fusarium spp.: liposomal amphotericin B or other lipid preparation at 5 mg/kg/day (CIII) or voriconazole loading dose of 6 mg/kg/day IV bd for 2 doses followed by 4 mg/kg bd (CIII).
  
  
• Zygomycetes: liposomal amphotericin B or other lipid preparation at 5 mg/kg/day (CIII).

b. For failure of amphotericin B therapy

Failure is defined at day 7-14 of treatment with standard doses of amphotericin B, if there is no improvement in signs or symptoms of infection. (Note: CT changes often worsen in the first 2 weeks of treatment and a decision of failure should not be made on CT findings alone).

• Suspected or proven aspergillosis: voriconazole (BII) caspofungin (BII) amphotericin B lipid complex (BIII), liposomal amphotericin B (CIII) or combination of liposomal amphotericin B and caspofungin (CIII).
  
  
• Cause of infection is unknown: voriconazole (BII), amphotericin B lipid complex at 5 mg/kg/day (BIII) or liposomal amphotericin B at 5 mg/kg/day (CIII) could be considered.
  

Voriconazole would be the preferred choice if the organism causing infection were unknown due to its broader spectrum of activity. If Aspergillus or Candida were suspected Caspofungin would be preferred. If a Zygomycete was suspected a lipid formulation of amphotericin B would be preferred.

c. For infusional toxicity of amphotericin B

eg fevers chills unable to be controlled by pre-medication

Optimal pre-medication may include paracetamol 1g orally 1 hour prior to infusion, phenergen 12.5-25 mg IV, hydrocortisone 50-100 mg IV, pethidine 25 mg IV and anti-emetics (if nausea is a problem) just prior to start of infusion. During an infusion lasting more than 3 hours, more than one dose of pethidine may be required. An infusion may be ceased temporarily or slowed if reactions are problematic. Hydrocortisone may be omitted in appropriate clinical circumstances.