Critical care antifungal guidance

Candida infections and azoles/echinocandin dosing recommendations

For Haematology patients see Haematology guidance on intranet here.

For Transplant patients or immunosuppressed patients seek specialist advice.

Actual therapy may be modified after discussion with microbiology.

FLUCONAZOLE: Fluconazole is the 1^st line treatment for invasive candidiasis where fluconazole resistance is unlikely.

Indications:

PROVEN - Invasive candidiasis caused by fluconazole-sensitive candida species.
PRE-EMPTIVE - Gastrointestinal perforation or anastomotic leak with Septic Shock and multiple organ failure (and a positive serum beta-D-glucan assay if available) OR
Multiple site growth/colonisation of fluconazole-sensitive candida.
EMPIRIC - treatment of suspected invasive candidiasis AND septic shock with multiple organ failure AND fluconazole-resistance is unlikely, (i.e. no recent history of fluconazole/azole therapy or known recent colonisation with fluconazole-sensitive candida species).

Intravenous loading dose - 12mg/kg (rounded to the nearest 50mg). Typically, 800mg daily.

Maximum loading dose of 1200mg.

then

Intravenous maintenance dose – 6mg/kg (rounded to the nearest 50mg) once daily (typically, fluconazole 400mg once daily).

Maximum maintenance dose of 600mg

Increased intravenous exposure dose (when directed by Microbiology): 12mg/kg (rounded to the nearest 50mg) once daily. Typically, 800mg once daily

Maximum maintenance dose of 1200mg

Maximum infusion rate is 20milligrams/minute.

Duration of therapy – If candidaemia, 14 days from 1^st negative blood culture.

Caution: If creatinine clearance < 10ml/min – 50% of daily i.v. fluconazole dose.
Fluconazole is removed by CVVHD, therefore dose as for normal renal function.
Fluconazole may increase the plasma concentration of tacrolimus.
It is associated with dysrhythmias, particularly prolonged QT internal on ECG, which may lead to torsades de pointes. Monitor ECG daily.

ECHINOCANDINS

Indications (NB Echinocandins do not reach therapeutic concentrations in urine, hence are not suitable for treatment of urinary tract candidiasis):

PROVEN - Invasive candidiasis caused by fluconazole-resistant candida species (i.e. Candida galbrata, Candida krusei).
- Please note that Candida auris is a multidrug resistant organism, which is usually susceptible to echinocadins. High risk patients include those repatriated with invasive devises in situ.
EMPIRIC - treatment of suspected invasive candidiasis when severely unwell and fluconazole resistance is probable (i.e. recent fluconazole prophylaxis/treatment or known colonisation with fluconazole-resistant candida species). De-escalate to fluconazole if appropriate when culture results available.

ANDILAFUNGIN

Day 1 Loading dose – anidulafungin 200mg i.v. (over 3 hours)

then

Day 2 onwards – anidulafungin 100mg i.v. daily (over 1.5 hours) thereafter.

No dose adjustment is required during hepatic or renal impairment. Does not interact with calcineurin inhibitors i.e. tacrolimus, ciclosporin.
Please note that echinocandins do not penetrate eye or CNS. If there is evidence that these organs are affected (Candida endophthalmitis), please discuss with Microbiology to adjust treatment.
For the treatment of candidaemia in neutropenic patients, consult the haematology guidelines on the intranet here.

Mould infections and other antifungals dosing recommendations

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, sulfobutylether-ß-cyclodextran (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.

Mycology reference laboratory:service user handbook - GOV.UK(for Microbiology/Pharmacy information).

If patient is intolerant of voriconazole, consider second line therapy

SECOND LINE: LIPOSOMAL AMPHOTHERICIN: (Tillomed brand) 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 Tillomed before a new course of treatment to exclude anaphylaxis.

Administer 1mg intravenously 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.

In patients (including those with a BMI>30) with Mucormycosis or treatment failure, consider doses ≥ 5mg/kg/day after consultation with Microbiology. Use actual body weight. Maximum dose is 600mg. Monitor for signs of toxicity.

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. Intravenous flucytosine is no longer available. Oral flucytosine 500mg tablets are available as an unlicenced medicine.

Possible indications include cryptococcal infection, intracranial yeast infection or complex renal tract yeast infection.

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. When using the oral preparation, pleaser round dose to nearest 500mg tablet.

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.
CVVHD	37.5mg/kg (capped at 2.5g/dose) 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 levels 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 before oral dose

Peak – 2 hours post oral dose

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.

The flucytosine dose and interval should be adjusted in order to produce peak serum concentrations of approximately 50 to 100 mg/L and trough concentrations of 20 to 40 mg/L. Levels > 100mg/L are toxic.

Please contact the clinical pharmacy team for advice on dose adjustment if serum levels are outwith these ranges.

Alternative Antifungal Treatment Options (when IV Flucytosine not available)^{13, 14, 15}

Indication	Treatment	Alternative Options	Notes
Cryptococcal infection (e.g. meningitis)	Oral flucytosine + IV liposomal amphotericin B	Liposomal IV amphotericin B + high-dose IV fluconazole 12mg/kg/day	Consider voriconazole if fluconazole resistance or intolerance is present
Intracranial yeast infection	Oral flucytosine + IV liposomal amphotericin B	Liposomal IV amphotericin B ± IV voriconazole	Ensure CNS penetration; consult microbiology for tailored therapy
Complex renal tract yeast infection	Oral flucytosine. Used in selected cases on microbiology advice as part of dual therapy along with IV fluconazole or IV Amphotericin B (non-liposomal, Fungizone brand)	Monotherapy with IV fluconazole (if susceptible), or IV Amphotericin B (non-liposomal, Fungizone brand)	Echinocandins usually not suitable (Anidulafungin)

References

1. IV flucytosine. www.renaldrugdatabase.com.FLUCYTOSINE .Last updated 31/12/25. Accessed
02/02/2026

2. IV fluconazole. www.renaldrugdatabase.com. FLUCONAZOLE. Last updated 18/12/25. Accessed
02/02/2026.

3. Amphotericin B Tillomed, liposomal 50mg powder for dispersion for infusion. Amphotericin B Tillomed
liposomal 50 mg powder for dispersion for infusion - Summary of Product Characteristics (SmPC) -
(emc) | 15711. Last updated, 23/11/25. Accessed 02/02/2026.

4. Anidulafungin (Ecalta). Anidulafungin 100 mg powder for concentrate for solution for infusion - Summary
of Product Characteristics (SmPC) - (emc) (medicines.org.uk). Last updated 14/04/23. Accessed
02/02/2026.

5. Voriconazole (Vfend® ). Voriconazole Pfizer 200 mg powder for solution for infusion - Summary of
Product Characteristics (SmPC) - (emc) (medicines.org.uk). Last updated 06/01/26.
Accessed 02/02/2026.

6. Fluconazole. Fluconazole 2 mg/ml solution for infusion - Summary of Product Characteristics (SmPC) -
(emc) | 15231. Last updated 08/04/2024. Accessed 02/02/2026

7. 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.

8. 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.

9. 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.

10. Management of candidemia and invasive candidiasis in adults. Management of candidemia and invasive
candidiasis in adults - UpToDate. Accessed 14/6/2023.

11. Amsden J, Slain D. Dosing antifungals in obesity: A literature review. Current fungal infection reports.
2019;13:21-32.

12. AFST_BP_v10.0_200204_updatd_links_200924.pdf (eucast.org)

13. Global guideline for the diagnosis and management of candidiasis: an initiative of the ECMM in
cooperation with ISHAM and ASM. Cornely et al. Lancet Infect Dis. 2025 e280-293

14. EACS Guidelines.Cryptococcosis. Diagnosis and treatment. B.https://eacs.sanfordguide.com/en/eacshiv/eacs-section4/ois/cryptococcosis

15. https://www.nhstaysideadtc.scot.nhs.uk/Antibiotic%20site/pdf%20docs/Antifungal%20Guidance.pdf

16. Ting M et al. Evaluation of total body weight versus adjusted body weight liposomal amphotericin B
dosing in obese patients. Animicrobial Agents and Chemotherapy. 2021;65 (9)

17. Anocitil (flucytosine) 500mg tablets. Summary of Product Characteristics. Vaiatris Medical. Reviewed April 2024. HA693 part4v6.pdf

Last reviewed: 02/02/2026

Next review date: 02/02/2029

Author(s): Lothian Critical Care Infection Group.

Version: 6.0

Approved By: Antimicrobial Management Committee