TY - JOUR
T1 - Toxicity of amphotericin B plus flucytosine in 194 patients with cryptococcal meningitis
AU - Stamm, Alan M.
AU - Diasio, Robert B.
AU - Dismukes, William E.
AU - Shadomy, Smith
AU - Cloud, Gretchen A.
AU - Bowles, Cynthia A.
AU - Karam, George H.
AU - Espinel-Ingroff, Ana
N1 - Funding Information:
This work was supported in part by Contract l-Al82570 with the Clinical and Epidemiology Studies Branch, Microbiology and Infectious Diseases Program, National Institute of Allergy and Infectious Diseases; the following grants from the National Institutes of Health: Grant DRR-RR32 to the Clinical Research Center, University of Alabama at Birmingham, Grant RR00036 to the Clinical Research Center, Washington University School of Medicine, Grant RR30 to the Clinical Research Center, Duke University School of Medicine, Grant RR00065 to the Clinical Research Center, Medical College of Virginia, Virginia Commonwealth University, Grant RR01346 to the Clinical Research Center, University of Texas Health Sciences Center, San Antonio, Grant CA13148 from the Comprehensive Cancer Center, University of Alabama at Birmingham, and Grant CA40530 from the National Cancer Institute.
PY - 1987/8
Y1 - 1987/8
N2 - 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 toxocity was associated with peak serum flucytosine levels of 100 μg/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 leve 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 μg/ml.
AB - 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 toxocity was associated with peak serum flucytosine levels of 100 μg/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 leve 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 μg/ml.
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U2 - 10.1016/0002-9343(87)90691-7
DO - 10.1016/0002-9343(87)90691-7
M3 - Article
C2 - 3303926
AN - SCOPUS:0023634292
SN - 0002-9343
VL - 83
SP - 236
EP - 242
JO - The American Journal of Medicine
JF - The American Journal of Medicine
IS - 2
ER -