Monitoring Amphotericin B and Fluconazole Concentrations in the Plasma and Cerebrospinal Fluid of Patients with Cryptococcal Meningitis

Abstract

Objectives: To determine whether amphotericin B (AmB) and fluconazole cross the blood-brain barrier in a similar manner in patients with HIV-associated cryptococcal meningitis based on the cerebrospinal fluid (CSF)/plasma drug ratio through a comparative study. Methods: This prospective, open-label clinical protocol included 21 male and female patients, 28-55 years of age. The patients were infected with HIV (CD4 50-200 cells/mL) and cryptococcal meningitis and were receiving AmB (1 mg/kg daily, infusion of four hours; 6-10 weeks) and fluconazole (400 mg 12 qh; until CSF was negative for fungal growth). The patients were informed in detail about all procedures to be performed in the hospital, including blood and CSF sample collection, if required. The study protocol was approved by the hospital’s ethical committee. Plasma samples were obtained by centrifugation at 2800 g for 30 min, and CSF samples were collected by the physician to relieve symptoms caused by intracranial hypertension. The drug concentrations of both antifungal agents were determined in the biological samples using HPLC. Results: The mean drug plasma: CSF concentrations were 2.30:0.3 μg/mL and 31.7:19.4 μg/mL for AmB and fluconazole, respectively. The CSF:plasma ratios were 0.20 (AmB) and 0.67 (fluconazole). Conclusions: Unlike fluconazole, the conventional AmB formulation did not reach the optimum CSF drug concentration. However, a high-dose regimen of fluconazole contributes to the outcome of HIV inpatients with severe cryptococcal meningitis.

Keywords

• open-label clinical protocol included 21 male and female patients
• 28-55 years of age. The patients were infected with HIV (CD4 50-200 cells/mL) and cryptococcal meningitis and were receiving AmB (1 mg/kg daily
• infusion of four hours; 6-10 weeks) and fluconazole (400 mg 12 qh; until CSF was negative for fungal growth). The patients were informed in detail about all procedures to be performed in the hospital
• including blood and CSF sample collection
• if required. The study protocol was approved by the hospital’s ethical committee. Plasma samples were obtained by centrifugation at 2800 g for 30 min
• and CSF samples were collected by the physician to relieve symptoms caused by intracranial hypertension. The drug concentrations of both antifungal agents were determined in the biological samples using HPLC. Results: The mean drug plasma: CSF concentrations were 2.30:0.3 μg/mL and 31.7:19.4 μg/mL for AmB and fluconazole
• respectively. The CSF:plasma ratios were 0.20 (AmB) and 0.67 (fluconazole). Conclusions: Unlike fluconazole
• the conventional AmB formulation did not reach the optimum CSF drug concentration. However
• Amphotericin B
• fluconazole
• cerebrospinal fluid/plasma ratio
• HIV infection and cryptococcal meningitis