Background: Flucytosine (5-FC) is widely used in combination therapy with amphotericin B for treatment of cryptococcal meningitis. However, the potential for gastrointestinal, hepatic and myelo-toxicites limits its use. The risk of toxicity is especially elevated when serum levels exceed 100μg/mL. Levels of 40-50 μg/mL correlate with antifungal efficacy and are seldom associated with toxicity. Unfortunately, serum levels are difficult to obtain for many centers and the results may not return for timely adjustment of dosage in patients with abnormal renal function. As 5-FC is eliminated almost exclusively by the kidney, at a given dose, serum drug levels are expected to be directly proportional to renal function. A simple measurement of prediction of levels may help guide dosage pending the results of serum levels. Methods: The medical records of all adult patients at the Washington Hospital Center whose steady state serum 5-FC levels were measured from January 1, 2001 through February 31, 2003 (study period) were retrospectively reviewed. During the study period, steady state 5-FC levels were analyzed in 14 serum samples from 6 patients. Renal function, 5-FC dosage and serum 5-FC levels were evaluated. Assays for serum 5-FC levels were performed at a reference laboratory (Mayo Medical Laboratories) using High Performance Liquid Chromatography. Renal function was determined by the Cockcroft-Gault formula for estimating creatinine clearance (CrCl). Results: All patients were adults who were treated for disseminated cryptococcosis. 5-FC dosages ranged from 27 to 100 mg/kg/d. Measured 5-FC levels ranged from 9.9 to 85 μg/mL. Estimated CrCl ranged from 30 to 114 mL/min. To correct for variability in administered dosages, serum levels were multiplied by a factor of standardized/ administered dose. For a given dose, serum levels were inversely proportional to CrCl. The dose needed to achieve a target level was directly proportional CrCl in (mL/min). When renal function was normal or moderately impaired, the dose of drug (in mg/kg/d) that yielded a serum drug level of approximately 40- 50 μg/mL was nearly equivalent to the measured CrCl (in mL/min). Conclusions: Knowledge of the direct relationship between CrCl and the dose of 5-FC needed to achieve therapeutic drug levels in patients with normal or moderately impaired renal function may help clinicians to optimize its antifungal efficacy while minimizing its toxicity.
Full conference title:
15th Annual Focus on Fungal Infections
- FFI 15th (2005)