Dosage adjustment of fluconazole during continuous renal replacement therapy (CAVH, CVVH, CAVHD, CVVHD)

Abstract

Continuous arterio-venous haemofiltration (CAVH), continuous veno-venous haemofiltration (CVVH), continuous arterio-venous haemodialysis (CAVHD) and continuous veno-venous haemodialysis (CVVHD) are increasingly used in patients with acute renal failure (ARF). The elimination rate of fluconazole varies considerably depending on the procedure used. (In Germany, fluconazole is approved for the treatment of life-threatening fungal infections caused by Candida spp. and Cryptococcus neoformans at a dosage of up to 800 mg day-1.) The elimination rate of fluconazole by CVVHD depends on the combined dialysate/ultrafiltrate flow rate, but is much higher than achieved with CVVH and intermittent dialysis, with a fluconazole clearance in patients with CVVHD 2 l h-1 exceeding the values of healthy persons. To achieve therapeutic plasma levels during continuous renal replacement therapy, the same loading dose as in patients without renal failure should be administered, followed by a maintenance dose that is adjusted for anuric patients by multiplying by a factor that takes into account the extracorporeal elimination of the absorbed dose (CAVH, CVVH x 2.2, ultrafiltrate flow 0.5 l h-1; CAVHD, CVVHD x 3.8, combined dialysate/ultrafiltrate flow 1.5 l h-1). Despite the broad therapeutic margin of fluconazole, drug monitoring is recommended to achieve therapeutic drug levels in life-threatening indications because there have been only a few investigations of this, all involving relatively low dosages (up to 200 mg day-1).

Randomized Trial of Micafungin for the Prevention of Invasive Fungal Infection in High-Risk Liver Transplant Recipients

“…Drug–drug interactions with fluconazole complicate dosing with the immunosuppressants ciclosporin, tacrolimus, and sirolimus [32]. Fluconazole requires dose adjustment in patients receiving RRT, as the procedure results in a significant clearance of fluconazole, which varies depending on the technique used [33, 34]. Although nephrotoxicity risk is reduced with liposomal amphotericin B compared with amphotericin B deoxycholate [15, 17], it may still limit its use [20, 35], especially in recipients with renal dysfunction.…”

Population Pharmacokinetics of Fluconazole in Critically Ill Patients Receiving Continuous Venovenous Hemodiafiltration: Using Monte Carlo Simulations To Predict Doses for Specified Pharmacodynamic Targets

“…3D to F). Several studies have previously recommended a daily dose of 800 mg with CVVHDF (4,8,12,14,20,22,26,36,39). However, due to study design and analysis methods, these recommendations do not accurately identify between-subject variability, the effect of covariates such as filter age, or the likely probability of attainment at steady state.…”

“…It is normally extensively reabsorbed by the kidneys (9), and it has previously been validated as a marker for renal reabsorption (35). However, in patients with severely impaired kidney function, the ability for tubular reabsorption is unlikely, and it could considerably alter the clearance of fluconazole when combined with continuous RRT (8,20,26,38,39). As a consequence, this could significantly influence the fAUC 0-24 /MIC ratio of fluconazole, thereby compromising its desired therapeutic response.…”

Antifungal Dosing in Dialysis and Continuous Renal Replacement Therapy

“…A number of pharmacokinetic characteristics predict that fluconazole will be significantly removed during RRT: these include a low molecular weight, relatively small volume of distribution, low degree of protein binding, and elimination of unmetabolized drug through predominantly renal mechanisms (Table 1). A number of studies have shown that fluconazole is readily removed during various types of RRT, including IHD, CVVH, CVVHD, and CVVHDF [14][15][16][17][18]. Indeed, the total systemic clearance of fluconazole during CVVHDF at ultrafiltration rates of 1 to 2 L per hour may exceed that of patients with normal renal function, and up to 88% to 99% of the administered fluconazole dose may be removed over a 24-hour period [14,16].…”