Bone Marrow Toxicity Associated with 5-Fluorocytosine Therapy

121

137

In vivo pharmacodynamic parameters have been characterized for a variety of antibacterial agents. These parameters have been studied in correlation with in vivo outcomes in order to determine (i) which dosing parameter is predictive of outcome and (ii) the magnitude of that parameter associated with efficacy. Very little is known of the pharmacodynamics of antifungal agents. We used a neutropenic murine model of disseminated candidiasis to correlate the pharmacodynamic parameters ( Groups of mice were treated with fourfold escalating total doses of 5-FC ranging from 1.56 to 400 mg/kg of body weight/day divided into one, two, four, or eight doses over 24 h. Increasing doses produced minimal concentration-dependent killing ranging from 0 to 0.9 log 10 CFU/kidneys. 5-FC did, however, produce a dosedependent suppression of growth after levels in serum had fallen below the MIC. The fungistatic dose increased from 6 to 8 mg/kg with dosing every 3 and 6 h to 70 mg/kg at with dosing every 24 h. Nonlinear regression analysis was used to determine which pharmacodynamic parameter best correlated with efficacy. Time above the MIC was the parameter best predictive of outcome, while AUC/MIC was only slightly less predictive (time above MIC, R 2 ‫؍‬ 85%; AUC/MIC, R 2 ‫؍‬ 77%; peak level/MIC, R 2 ‫؍‬ 53%). Maximal efficacy was observed when levels exceeded the MIC for only 20 to 25% of the dosing interval. If one considers drug kinetics in humans, these results suggest reevaluation of current dosing regimens.

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

In Vivo Characterization of the Pharmacodynamics of Flucytosine in a Neutropenic Murine Disseminated Candidiasis Model

Andes

Ogtrop

2000

121

137

“…However, only a limited number of effective agents, e.g., amphotericin B and 5-fluorocytosine, have been available, and various problems have been associated with their usage (5,8,9,12,14,18,22,26). Recently, imidazole compounds have been reported to have antifungal properties (7,13,23, 27), and the clinical efficacy of compounds such as miconazole, miconazole nitrate, and ketoconazole (formerly designated R41,400), is under investigation (10,11,24,25).…”

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confidence: 99%

In vitro activities of miconazole, miconazole nitrate, and ketoconazole alone and combined with rifampin against Candida spp. and Torulopsis glabrata recovered from cancer patients

Moody¹,

Young²,

Morris³

et al. 1980

A total of 440 fresh clinical isolates of yeasts from cancer patients were tested by an agar dilution technique against miconazole, miconazole nitrate, and ketoconazole individually and combined with 5 ,ug of rifampin per ml. Most strains of Candida albicans were susceptible to 0.5 jig or less of the imidazoles per ml. Candida tropicalis required 2 to 4 jig of miconazole and its nitrate base per ml for inhibition and was resistant to ketoconazole. The 100% minimal inhibitory concentration of the imidazoles for Candida krusei was 1 jig/ml. Susceptiblty to 4 jug of miconazole and miconazole nitrate per ml occurred in 73 and 87% of Torulopsis glabrata strains, respectively, and none was susceptible to ketoconazole. Miconazole was most effective against the Candida spp., whereas its nitrate base was most active against T. glabrata. Synergy was observed when rifampin was combined with miconazole and miconazole nitrate but was not observed when rifampin was combined with ketoconazole. Synergy occurred most frequently when rifampin was combined with miconazole nitrate.Neutropenic cancer patients undergoing antineoplastic chemotherapy occasionally develop fungal infections which necessitate the institution of prompt and effective antifungal therapy (6,8,19). However, only a limited number of effective agents, e.g., amphotericin B and 5-fluorocytosine, have been available, and various problems have been associated with their usage (5,8,9,12,14,18,22,26). Recently, imidazole compounds have been reported to have antifungal properties (7,13,23, 27), and the clinical efficacy of compounds such as miconazole, miconazole nitrate, and ketoconazole (formerly designated R41,400), is under investigation (10,11,24,25). As the antifungal properties of amphotericin B and 5-fluorocytosine against some fungi have been enhanced by combining these agents with rifampin (1, 3, 4, 15-18, 20, 21), it was important to determine whether rifampin also exerted a synergistic effect on the antifungal properties of these currently available imidazoles. This study was designed to compare the in vitro susceptibilities of fresh clinical isolates of Candida spp. and Torulopsis glabrata recovered from cancer patients to these imidazoles with those of the same isolates when the agents were combined with rifampin. MATERIALS AND METHODSFungal strains. A total of 440 strains of yeasts, which included Candida albicans, Candida tropicalis, Candida krusei, and T. glabrata recovered from clinical specimens from cancer patients, were tested; isolation and identification were performed by the Hazleton Laboratories, Vienna, Va. The isolates were collected consecutively from a variety of clinical sources over a 6-month period, but no more than one of a fungal species from an individual patient was included in the test strains. Before testing, strains were grown on Sabouraud agar slants for 48 h at 30°C. Inocula were prepared by suspending the growth in sterile physiological saline to a turbidity that transmitted 90% of light at 530 nm on a Coleman Junior spectropho...

“…However, toxicity does develop in patients treated with 5-FC and is seen most commonly in the setting of hig serum concentrations (>125 "g/ml), such as may occur with renal dysfunction (1,8). Besides gstrointestinal side effects, the manifestations of clinical toxicity include leukopenia and thrombocytopenia (1,8), which is similar to the toxicity associated with the anticancer drug 5-FU (2). Evidence that 5-FU might account for the clinical toxicity of 5-FC was suggested in previous studies in which catabolites of 5-FU were detected in the urine of patients being treated with 5-FC (9,11,16) and was most recently supported by the detection of elevated levels of 5-FU in 5-FC-treated patients who had developed myelosuppression (3).…”

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confidence: 98%

“…On the other hand, human cells could not convert 5-PC to 5-FU, and thus, there could be no interflerence of nucleic acid synthesis and thus no toxicity (9). However, toxicity does develop in patients treated with 5-FC and is seen most commonly in the setting of hig serum concentrations (>125 "g/ml), such as may occur with renal dysfunction (1,8). Besides gstrointestinal side effects, the manifestations of clinical toxicity include leukopenia and thrombocytopenia (1,8), which is similar to the toxicity associated with the anticancer drug 5-FU (2).…”

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confidence: 99%

5-fluorocytosine susceptibility of pathogenic fungi in the presence of allopurinol: potential for improving the therapeutic index of 5-fluorocytosine

Kerkering¹,

Schwartz²,

Espinel-Ingroff³

et al. 1983

The minimal inhibitory concentration of 5-fluorocytosine in 18 pathogenic fungal isolates was not altered by either allopurinol (100 microM) or oxypurinol (100 microM). Since allopurinol at this level clinically has been demonstrated to interfere with 5-fluorouracil anabolism, thereby reducing toxicity owing to 5-fluorouracil, allopurinol may be useful in counteracting the 5-fluorouracil-induced myelotoxicity observed in patients being treated with 5-fluorocytosine without interfering with the antifungal activity of 5-fluorocytosine.