EMPIRIC MOULD THERAPY (agents below will cover most Candida sp. as well)

(If suspecting Mucormycosis consult microbiologist)

If mould (e.g. Aspergillus) infection suspected.

First line: Voriconazole 6 mg/kg  i.v. every 12 hour for 2 doses, then 4 mg/kg  i.v. every 12 hours. Dilute in glucose 5% or sodium chloride 0.9% to a concentration of 0.5-5mg/ml and give at a rate not exceeding 3 mg/kg/hour.

Obesity: Use adjusted body weight and adjust the dose based on serum trough concentration to ensure efficacy and avoid toxicity.

NB. In patients with creatinine clearance <50 ml/min accumulation of the voriconazole intravenous vehicle, (SBECD) can occur. Intravenous voriconazole should only be given to these patients if benefit outweighs risk and consider changing to oral therapy as soon as possible.

Voriconazole trough levels should be measured if

• The patient has been on voriconazole for >5 day OR
• Toxicity is suspected OR
• The patient is on or initiated on a drug known to interact with Voriconazole

Please note this must be a white cap blood tube as other types of tubes can affect the result due to the chelating agents contained within them.

• Voriconazole may increase the plasma concentration of tacrolimus and ciclosporin.
• Cardiovascular effects are similar to fluconazole, please refer above.
• Voriconazole is associated with hepatotoxicity

Pre-dose sample taken immediately before administration

Voriconazole levels are a send away test. Please see Test Directory | Edinburgh and Lothians Laboratory Medicine (edinburghlabmed.co.uk) for further details. Reference ranges shown on the report.

If patient is intolerant of voriconazole, consider second line therapy

SECOND LINE: LIPOSOMAL AMPHOTHERICIN: (Ambisome®) 3 mg/kg/day i.v. (single dose over 60 mins). Dilute in glucose 5% to a concentration of 0. 2 – 2mg/ml. 

Give a test dose of Ambisome®before a new course of treatment to exclude anaphylaxis.

Administer 1mg over 10 minutes and then observe patient for at least 30 minutes. If no allergic/anaphylactic reactions, administer the rest of the infusion. Consider premedication with an anti-histamine or hydrocortisone.

(10mg/Kg dosing can be used in cases of Mucormycosis in severe immunocompromise-consult Microbiology)

Obesity: No dose adjustment necessary. Use actual body weight. Maximum dose of 600mg is recommended.

• Monitor electrolytes closely. Amphotericin is associated with hypocalcaemia, hypokalaemia, hypomagnesemia and hyponatraemia. It can also be associated with hypersensitivity reactions and nephrotoxicity.
• No dose adjustment required during renal impairment.
• Increased nephrotoxicity with calcineurin inhibitors (i.e. tacrolimus and ciclosporin).
• Please note that liposomal amphothericin does not penetrate into the kidney. For patients with proven fungal kidney disease resistant to fluconazole, please discuss with a microbiologist.

 

FLUCYTOSINE

Should only be given on microbiological advice and always in combination with another antifungal agent.

Possible indications include cryptococcal infection, intracranial yeast infection or complex renal tract yeast infection. HIV testing should be considered for patients with cryptococcosis in line with national guidance.  

Requires monitoring of serum levels.

Dosing depends on renal function calculated using Cockcroft and Gault. DO NOT USE eGFR. Renal function should be assessed daily in unstable patients and dose adjustments made accordingly. The standard dose is 150 mg/kg/day in 4 divided doses. For patients of 70 kg or greater, doses of flucytosine are “capped” at 2.5 g. Administer each infusion over 40 mins.

Cockroft and Gault Equation: CrCl (ml/min) =( (140- age)  x weight (kg) x 1 . 04(female) or 1 . 23 (male))/Serum creatinine (micromols/litre)

Creatinine clearance	Dose
> 40 ml/min	37.5 mg/kg (capped at 2. 5g/dose) 6 hourly
20-40 ml/min	37.5mg/kg (capped at 2. 5g/dose) 12 hourly
10-20 ml/min	37.5mg/kg (capped at 2. 5g/dose) 24 hourly
<10 ml/min	37.5mg/kg (capped at 2. 5 g) as a single dose then adjust regimen according to levels.
CVVH	37.5mg/kg (capped at 2. 5g/dose) every 24 hourly
Haemodialysis	2.5g as a single dose and then no further doses should be given until after the patient is next dialysed. Monitor level pre-dialysis, post-dialysis and post dose. Levels may not be available immediately and therefore a clinical decision should be made as to whether to wait for the post dialysis level or to administer a further dose. Adjust regimen according to levels. (Flucytosine is dialysed).

FLUCYTOSINE SERUM LEVELS

Trough – immediately pre dose 

Peak – 30-60 mins after end of infusion 

When?

3-4 days after therapy commences, or sooner if patient has renal impairment.

It takes at least 24 hours for serum levels to reach steady state. Therefore serum levels should only be taken after a minimum of 24 hours of therapy.

How?

Liaise with microbiology, Mon-Thurs. Arrange 24 hours in advance

Flucytosine levels are a send away test. Please see Test Directory | Edinburgh and Lothians Laboratory Medicine (edinburghlabmed.co.uk) for further details. Reference ranges shown on the report.

References

1. Ashley C, Dunleavy A. Eds. The Renal Drug Handbook. 5thth ed. Radcliffe Medical Press. 2019.
2. Amphotericin (Ambisome®).AmBisome Liposomal 50 mg Powder for dispersion for infusion - Summary of Product Characteristics (SmPC) - (emc) (medicines.org.uk) Accessed 29/06/2023.
3. Liposomal amphotericin B: Drug information - UpToDate Accessed 14/6/2023
4. Anidulafungin (Ecalta). Anidulafungin 100 mg powder for concentrate for solution for infusion - Summary of Product Characteristics (SmPC) - (emc) (medicines.org.uk). Accessed 29/06/2023.
5. Anidulafungin: Drug information - UpToDate Accessed 14/6/2023.
6. Voriconazole (Vfend® ). Voriconazole Pfizer 200 mg powder for solution for infusion - Summary of Product Characteristics (SmPC) - (emc) (medicines.org.uk). Accessed 29/06/2023.
7. Voriconazole: Drug information - UpToDate. Accessed 14/6/2023.
8. Fluconazole 2 mg/ml solution for infusion - Summary of Product Characteristics (SmPC) - (emc) (medicines.org.uk)
9. Fluconazole: Fluconazole: Drug information - UpToDate Accessed 14/6/2023.
10. Pappas P, Kauffman C A et al. Clinical Practice guidelines for the Management of Candidiasis. Clinical Infectious Diseases 2009;48:503-35.
11. Walsh T J,  Anaissie E J et  al. Treatment of Aspergillosis: Clinical Practice Guidelines of the Infectious Disease Society of America.  Clinical  Infectious Diseases 2008;46:327-60.
12. Bailly S, Bouadma L et al. Failure of Empirical Systemic Antifungal Therapy in Mechanically Ventilated Critically ill Patients. American Journal of Critical  Care  Medicine. 2015;191:10:1139-1146.
13. Martin-Loeches I et al ESICM/ESCMID task force on practical management of invasive candidiasis in critically ill patients. Intensive Care Medicine 2019;45(6):789-805.
14. SAPG & HIS. Good Practice Recommendations for treatment of candidaemia and the use of antifungal agents. https://www.sapg.scot/guidance-qi-tools/good-practice-recommendations/antifungals/Accessed 07/07/2019.
15. Management of candidemia and invasive candidiasis in adults. Management of candidemia and invasive candidiasis in adults - UpToDate. Accessed 14/6/2023.
16. Amsden J, Slain D. Dosing antifungals in obesity: A literature review. Current fungal infection reports. 2019;13:21-32.
17. 0_200204_updatd_links_200924.pdf (eucast.org)