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Toxicity of amphotericin B plus flucytosine in 194 patients with cryptococcal meningitis
Abstract:
A multicenter prospective randomized trial of four versus six weeks of amphotericin B, 0.3 mg/kg per day, plus flucytosine, 150 mg/kg per day, was performed with 194 patients with cryptococcal meningitis. One or more toxic drug reactions developed in 103 patients: azotemia (51), renal tubular acidosis (two), leukopenia (30), thrombocytopenia (22), diarrhea (26), nausea/vomiting (10), and hepatitis (13). The four- and six-week regimens were complicated by toxicity in 44 percent and 43 percent of cases, respectively. Toxicity appeared during the first two weeks of therapy in 56 percent and during the first four weeks in 87 percent. Azotemia did not occur more frequently in renal transplant recipients or diabetic patients. Cytopenias did not appear more often in patients with hematologic malignancies or those receiving immunosuppressive therapies. Toxic reactions that contributed to death developed in five patients (two with azotemia, one with pancytopenia, one with hepatitis, one with ileus). Amphotericin B-induced azotemia was not a significant risk factor for the subsequent development of bone marrow, gastrointestinal, or hepatic toxicity attributable to flucytosine. Flucytosine toxicity was associated with peak serum flucytosine levels of 100 micrograms/ml or more during two or more weeks of therapy (p = 0.005). Peak 5-fluorouracil levels were not predictive of toxicity. An initial dose of flucytosine is recommended based on the creatinine clearance: 150 mg/kg per day at a creatinine clearance above 50 ml/minute, 75 mg/kg per day at a creatinine clearance of 26 to 50 ml/minute, and 37 mg/kg per day at a creatinine clearance of 13 to 25 ml/minute. The serum creatinine level should be monitored twice weekly and the creatinine clearance weekly during therapy in order to anticipate changes in serum flucytosine concentration. In addition, it is recommended that the serum flucytosine level be determined two hours after an oral dose once a week, and that the dose be adjusted to maintain a level of 50 to 100 micrograms/ml.
Insights
This study found that both four- and six-week treatment regimens for cryptococcal meningitis using amphotericin B and flucytosine had similar toxicity rates. Monitoring flucytosine levels is crucial to prevent toxicity, especially in patients with impaired kidney function.
Area of Science:
- Infectious Diseases
- Pharmacology
- Nephrology
Background:
- Cryptococcal meningitis is a serious infection, particularly in immunocompromised individuals.
- Standard treatment involves amphotericin B and flucytosine, but drug toxicities are a concern.
- Optimizing treatment duration and dosage is essential for patient outcomes.
Purpose of the Study:
- To compare the toxicity of four-week versus six-week treatment regimens for cryptococcal meningitis.
- To identify risk factors for drug-induced toxicities.
- To establish guidelines for flucytosine dosing and monitoring.
Main Methods:
- A multicenter prospective randomized trial involving 194 patients with cryptococcal meningitis.
- Patients received amphotericin B (0.3 mg/kg/day) plus flucytosine (150 mg/kg/day) for either four or six weeks.
- Adverse events, including azotemia, leukopenia, thrombocytopenia, and hepatitis, were meticulously recorded and analyzed.
Main Results:
- Toxicity rates were similar between the four-week (44%) and six-week (43%) regimens.
- The majority of toxic reactions occurred within the first four weeks of therapy.
- Flucytosine toxicity was associated with peak serum levels ≥100 µg/ml for ≥2 weeks; amphotericin B-induced azotemia did not increase flucytosine toxicity risk.
- Recommended flucytosine dosing based on creatinine clearance and serum level monitoring (50-100 µg/ml) are proposed.
Conclusions:
- Treatment duration of four or six weeks for cryptococcal meningitis with amphotericin B and flucytosine shows comparable toxicity profiles.
- Close monitoring of serum flucytosine levels and dose adjustment based on renal function are critical to minimize toxicity.
- The findings support individualized flucytosine dosing strategies to enhance safety and efficacy.