Background

Like many other medications, dosages of antifungal agents may be adjusted in patients with compromised kidney or liver function to minimize potential toxicities associated with drug accumulation. Drug interactions can also require a change in antifungal dosing. Fortunately, the effects of impaired kidney and liver function on antifungal concentrations in the body can be anticipated based on the pharmacokinetic properties of the specific antifungal agent; i.e. its absorption, distribution, and pathway for elimination from the body. In certain situations, measuring the serum drug concentration of an antifungal agent can provide some guidance for dosage adjustment or in the assessment of potential for toxic effects.

Antifungal Dosage Adjustment in Renal Dysfunction

Although renal function can be assessed by a number of tests and procedures, (E):creatinine clearance (an indicator of the glomerular filtration rate or GFR) is typically considered to be the guiding factor for dosage adjustment. Typically, fixed adjustments in the dose or duration are made for antifungals predominantly cleared through the kidney (i.e. fluconazole, flucytosine) as the GFR rate declines. However, these ranges encompass up to a ten-fold range in renal function and may not be optimal for all patients. Therefore, antifungal dosing should always be individualized on the basis of kidney and liver function, medical status of the patient, and severity of the infection.

In patients with chronic renal failure who are receiving intermittent dialysis, the degree of drug removal is dependent upon the type of dialysis (peritoneal versus hemodialysis), the dialysis prescription (e.g., dialysis membrane composition, filter surface area, dialysate composition and flow rate) and the physiochemical characteristics of the drug (e.g., molecular weight, membrane permeability or water solubility, etc.). A more detailed description of factors that effect the dialysis of drugs can be found (A):here. Critically-ill patients with renal failure generally require continuous dialysis or continuous renal replacement therapy (CRRT), which can be provided by a number of methods (e.g., continuous atriovenous hemofiltration, CAVH; continuous venovenous hemofiltration, CVVH; continuous atriovenous hemodialysis, CAVD; continuous venovenous hemodialysis, CVVD; continuous atriovenous hemofiltration, CAVHDF; slow continuous ultrafiltration, SCUF; continuous venovenous high-flux hemodialysis, CVVHFD). Because of the multiple techniques employed in CRRT and variability in individual patient circumstances, clinicians should always refer to the primary literature for assistance with the dosing of specific antifungals. General guidance for adjustment of antifungal dosages in the setting of renal dysfunction is summarized below.

Antifungal Dosing in Renal Impairment

Drug Dose normal renal function GFR > 50 GFR 10-50 GFR < 10 Hemodialysis CAPD CRRT
Amphotericin B 0.25-1.5 mg/kg q24h q24h q24h q24-q36h None Dose for GFR < 10 Dose for GFR 10-50
ABLC 5 mg/kg q24h q24h q24h q24-q36h None Dose for GFR < 10 Dose for GFR 10-50
ABCD 3-5 mg/kg/day q24h q24h q24-q36h None Dose for GFR < 10 Dose for GFR 10-50
L-AMB 3-5 mg/kg q24h q24h q24h q24-q36h None Dose for GFR < 10 Dose for GFR 10-50
Flucytosine 37.5 mg/kg q6h q6h q12h-24h q24-q48h Dose after dialysis 0.5-1 g/d Dose for GFR 10-50
Ketoconazole 200-400 mg q24h 100% dose or interval 100% dose or interval 100% dose or interval Full dose or interval 100% dose or interval Dose for GFR < 10
Fluconazole 100-800 mg q24h 100% dose or interval 50% dose or interval 50% dose or interval 100% after dialysis Dose for GFR < 10 Dose for GFR < 10
Itraconazole 200-400 mg q12h 100% dose or interval 100% dose or interval IV not recommended* 100% dose or interval

IV not recommended*

 100% dose/interval Dose for GFR 10-50
Voriconazole 6 mg/kg IV x 2 doses then 4 mg/kg q12h or 200 mg PO q12h 100% dose or interval 100% dose or interval

IV not recommended*

 IV not recommended* 100% dose or interval 100% dose or interval Dose for GFR 10-50
Posaconazole 600-800 mg day in divided doses q24h q24h q24h q24h Dose for GFR < 10 100% dose or interval
Caspofungin 70 mg initial dose, then 50 mg daily q24h q24h q24h q24h Dose for GFR < 10 100% dose or interval
Micafungin 50-150 m daily q24h q24h q24h q24h Dose for GFR < 10 100% dose or interval
Anidulafungin 100-200 mg initial dose, then 50-100 mg daily q24h q24h q24h q24h Dose for GFR < 10 100% dose or interval

* Due to accumulation of the cyclodextran vehicle, which is minimally dialyzable
Source: (A):2004 Dialysis of Drugs and (E):The Renal Drug Book.