a Departments of Clinical Pharmacy and b Medical Microbiology, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
One of the oldest antifungal agents is 5-fluorocytosine (flucytosine; 5-FC), a fluorinated analogue of cytosine. 5-FC was synthesized in 1957, as a potential anti-tumour agent2 but it was not sufficiently effective against tumours.3 Four years later, 5-FC proved to be active in experimental candidosis and cryptococcosis in mice4 and, in 1968, it was used to treat human candidosis and cryptococcosis.5 In addition to its activity against Candida spp. and Cryptococcus neoformans, 5-FC is active against fungi causing chromoblastomycosis.6
Interest in 5-FC has been renewed as a result of two recent developments: (i) it is now used increasingly in combination with a number of azole antifungal agents, such as ketoconazole, fluconazole and itraconazole; (ii) it plays an important role in a new therapeutic approach in the treatment of certain tumours, especially colorectal carcinoma.
In this article, we review the pharmacology, pharmacokinetics, clinical indications, toxicity and drug interactions of 5-FC. Recent developments in the use of 5-FC are discussed, focusing on the combinations of 5-FC with azole antifungal agents. The possible role of 5-fluorouracil (5-FU) in the toxicity of 5-FC is explored and evaluated.
![]() |
Mechanism of action |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
![]() |
Spectrum of antifungal activity and resistance |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
5-FC is most active against yeasts, including Candida, Torulopsis and Cryptococcus spp., and against the dematiaceous fungi causing chromomycosis (Phialophora and Cladosporium spp.) and Aspergillus spp.14 The MICs of 5-FC vary from 0.1 to c.25 mg/L for these fungal species.
In Emmonsia crescens, Emmonsia parva, Madurella mycetomatis, Madurella grisea, Pyrenochaeta romeroi, Cephalosporium spp., Sporothrix schenckii and Blastomyces dermatitidis, MICs vary from 100 to 1000 mg/L.14 5-FC is also active against some protozoa, including Acanthamoeba culbertsoni both in vitro and in vivo and Leishmania spp. in patients.14
The mode of action of 5-FC and the essential role of cytosine deaminase have been proven in Saccharomyces cerevisiae and C. albicans and are probably also valid for other sensitive fungi.14 However, specific research in this field is lacking.
Resistance
The occurrence of resistance with the use of 5-FC has been widely described and precludes use of 5-FC as a single agent.5,11,17 Two basic mechanisms of resistance can be distinguished: (i) certain mutations can result in a deficiency in the enzymes necessary for cellular transport and uptake of 5-FC or for its metabolism (i.e. cytosine permease, uridine monophosphate pyrophosphorylase or cytosine deaminase);12,18 (ii) resistance may result from increased synthesis of pyrimidines, which compete with the fluorinated antimetabolites of 5-FC and thus diminish its antimycotic activity.12 It has been shown that defective uridine monophosphate pyrophosphorylase is the most frequently occurring type of acquired 5-FC resistance in fungal cells.19
Normark & Schönebeck have reported that two different phenotypes of 5-FC-resistant strains can be recognized:17 strains of resistance phenotype class 1 are not affected by 5-FC at high concentrations (these are the totally (intrinsically) resistant strains), while those of class 2 are susceptible to 5-FC at low concentrations but, after long exposure to 5-FC (even at high concentrations) resistance develops (these are said to be partially resistant or to have acquired resistance). Development of resistance in the latter strains probably results from selection of non-susceptible mutants, leading to a secondary resistant population.12,14
The incidence of resistance to 5-FC varies between species.20 Up to 78% of intrinsically resistant strains are found among pretreatment isolates of C. albicans, unspeciated candida and Torulopsis glabrata. In C. neoformans the incidence of resistance is lower (12%), but in Candida spp. other than C. albicans it is 22%, because of the prevalence of generally less sensitive species such as Candida tropicalis and Candida krusei.20 The exact incidence of primary 5-FC resistance is not clear. Different investigators report rates ranging between 8% and 44% for Candida spp.21 Possible factors contributing to this wide range include the susceptibility methods used, local factors involving use of antifungal agents and differences in the prevalence of various Candida spp.21
![]() |
Pharmacokinetics and dosing |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Dosage must be adjusted in patients with renal impairment. Various recommendations have been made.2225 Daneshmend & Warnock have suggested the following guidelines for the administration of 5-FC to patients with renal insufficiency.22 In patients with a creatinine clearance of >40 mL/min, a standard dose of 37.5 mg/kg every 6 h should be used. If the creatinine clearance is between 20 and 40 mL/min, the recommended dose is 37.5 mg/kg every 12 h. In patients with a creatinine clearance of <20 mL/ minute, the dose of 5-FC should be 37.5 mg/kg once daily. Finally, if the creatinine clearance is <10 mL/min, frequent determinations of 5-FC concentration should be used as guidance for the frequency of dosing.
![]() |
Clinical uses and trial results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Cryptococcosis
The superiority of the combination of amphotericin B and 5-FC over either drug alone in cryptococcal meningitis has been described in case series,30 as well as in randomized trials.29,3135 Bennett et al.29 found, in non-HIV-infected patients, that the combination of amphotericin B (0.3 mg/ kg/day) and 5-FC (150 mg/kg/day) administered for 6 weeks was superior to amphotericin B alone (0.4 mg/kg/day) administered for 10 weeks. A similar trial evaluating the same combined regimen showed that treatment for 6 weeks rather than 4 weeks was required for most patients.31 The authors suggested that 4 weeks' treatment may be used in non-immunocompromised patients with favourable prognostic signs, including a cerebrospinal fluid (CSF) cryptococcal antigen titre of <1:8 following treatment.31
Several studies have been conducted in HIV-infected patients with cryptococcosis. In a retrospective study, the course and outcome of 89 eligible patients were reported.36 Forty-nine patients received a combination of 5-FC and amphotericin B, while 40 were treated with amphotericin B alone. There was a trend towards a higher survival rate in the group of patients treated with the combination.36 However, the relative efficacy of clearance of cryptococcal antigen from the CSF was not assessed and 5-FC concentrations were not monitored, so it is difficult to interpret the role of 5-FC. In a randomized study of a small population (42 patients, of whom 20 were eventually used in the study), the combination of amphotericin B and 5-FC was more effective than monotherapy with fluconazole.37 Recently, the results of a randomized, double-blind multicentre trial, in which patients with a first episode of HIV-associated cryptococcal meningitis were treated with high-dose amphotericin B (0.7 mg/kg/day) with or without 5-FC (100 mg/kg/ day) for 2 weeks, were published.32 The combination of high-dose amphotericin B and 5-FC was associated with an increased rate of CSF sterilization and a decreased mortality 2 weeks after treatment.
In the treatment of cryptococcal meningitis, 5-FC may in the future be combined with ketoconazole, fluconazole or itraconazole, although currently these combinations are not satisfactory.38 Ketoconazole, amphotericin B, 5-FC and combinations of these drugs have been compared for chronic cryptococcal meningitis in steroid-treated rabbits.39 The combination of ketoconazole and amphotericin B was at least as effective as the combination of amphotericin B and 5-FC after a 2 week treatment regimen. In a mouse model of cryptococcal meningitis, the combination of 5-FC and fluconazole resulted in a significantly higher survival rate and a lower colony count of C. neoformans in brain tissue than either drug alone.40 However, such synergy between these two antifungal agents was not found in a study of experimental cryptococcal meningitis in rabbits.41 Recently, it has been shown that HIV-infected patients with cryptococcal meningitis might benefit from the combination of 5-FC and fluconazole.42 There have also been reports that show the superiority of a combination of amphotericin B and 5-FC over monotherapy with fluconazole.37 Furthermore, in a randomized study of AIDS patients with cryptococcal meningitis treated with either fluconazole or amphotericin B, it has been shown that fluconazole was as effective as amphotericin B.43 Itraconazole is less effective than the combination of amphotericin B and 5-FC in achieving a complete response in the initial therapy in AIDS patients with cryptococcal meningitis. A complete response was observed in five of 12 patients using itraconazole and in all 10 patients treated with amphotericin B and 5-FC.44 The combination of 5-FC and amphotericin B is also effective against large cryptococcal intracerebral masses (cryptococcomas).45
Candidosis
Monotherapy with 5-FC in cases of systemic or disseminated candidosis has been shown to be effective in adults as well as in neonates and premature infants.5,19 However, resistance to 5-FC in Candida spp. is not rare and thus monotherapy of such infections with 5-FC is not recommended.
In vitro and in animal models, amphotericin B and 5-FC show synergic activity against a number of different Candida spp.,46,47 so this combination is also used. Chronic infections such as candidal endophthalmitis48 and endocarditis49 can be treated with the combination of amphotericin B and 5-FC for long periods of time, in conjunction with surgery. The use of a combination of 5-FC and amphotericin B for the treatment of hepatosplenic candidosis has also been reported.50 Furthermore, it has been shown in a retrospective study that patients with candidal meningitis respond well to the combination of amphotericin B and 5-FC.51 5-FC in combination with amphotericin B is beneficial in patients with candidal peritonitis associated with continuous ambulatory peritoneal dialysis, if the catheter cannot be removed.52 Finally, in the treatment of uncomplicated candidal cystitis, 5-FC has been used alone as well as in combination with amphotericin B.53 The role of 5-FC in the treatment of candidal urinary tract infections has been reviewed recently:53 the use of 5-FC for this indication is limited by the drug's toxicity and, perhaps, it should only be used under unusual circumstances or when azole-resistant organisms are involved.52
It should be stressed that no randomized trials have been conducted to determine whether combination therapy with 5-FC and amphotericin B is superior to monotherapy with either amphotericin B or fluconazole for invasive candidal infections. Even so, combination therapy with amphotericin B and 5-FC is recommended for the following types of invasive candidosis: meningitis, hepatosplenic candidosis, endophthalmitis, endocarditis and peritonitis, especially those caused by C. tropicalis, Candida parapsilosis, C. krusei or Candida guilliermondii (which are inherently less susceptible to amphotericin B than C. albicans).19
Future developments in the use of 5-FC in the treatment of candidosis lie in its combination with ketoconazole, fluconazole and itraconazole.5456 5-FC and itraconazole act synergically in a murine candidosis model.56 Fluconazole and the combination of itraconazole and 5-FC have been shown to be equally effective,55 whereas fluconazole has been shown to be more effective than 5-FC alone for the treatment of oesophageal candidosis in HIV-infected patients.54 In surgical patients with deep-seated candida mycoses, the combination of amphotericin B and 5-FC eliminated the organism earlier than fluconazole alone, although the cure rates of the two patient groups were similar.57 In intensive care unit patients with pneumonia or sepsis due to Candida spp. and treated with fluconazole or with amphotericin B and 5-FC, no differences in clinical outcome were observed. However, the combination of amphotericin B and 5-FC was more effective than fluconazole for the treatment of patients with candida peritonitis and eradicated the infecting yeast better.58
Aspergillosis
5-FC is often added to amphotericin B in the treatment of invasive aspergillosis, primarily in cases of aspergillosis refractory to amphotericin B alone.53 However, there is no clear evidence that this combination is more effective than amphotericin B alone.53 Pulmonary aspergillosis has been effectively treated with 5-FC monotherapy. However, large comparative trials are lacking.
Chromoblastomycosis
The treatment of chromoblastomycosis caused by dematiaceous moulds has been hampered by the relative paucity of effective agents and particularly by the in vitro resistance of many of these moulds to amphotericin B.19 In a small series from the USA and a larger series from Brazil, 5-FC has been shown to be effective as monotherapy for chromoblastomycosis.53 Furthermore, there are case reports in which chromoblastomycosis has been cured with the combination of oral and topical 5-FC59 and with the combination of oral ketoconazole and 5-FC after monotherapy with ketoconazole had failed.60
Other mycoses
The combination of 5-FC and amphotericin B can also be used in the treatment of phaeohyphomycosis of the central nervous system, specifically caused by Xylohypha bantiana.45 5-FC is not effective in the treatment of blastomycosis, coccidioidomycosis, histoplasmosis or sporotrichosis.19
Cancer therapy
5-FC may have a new role in the treatment of different types of cancer, especially colorectal carcinoma. One of the new and promising therapeutic approaches that takes advantage of the effectiveness of 5-FU and minimizes its systemic toxicity is the use of an enzyme/prodrug combination in which 5-FC is combined with an Escherichia coli gene that encodes the enzyme cytosine deaminase.61 It is hoped that this combination will deliver high local concentrations of 5-FU at the tumour site. The topic of 5-FC and cancer therapy will not be explored further in this review.
![]() |
Toxicity and drug interactions |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Gastrointestinal side effects
Gastrointestinal side effects, the most common and least harmful side effects associated with 5-FC treatment, include nausea, diarrhoea and, occasionally, vomiting and diffuse abdominal pain. They occur in approximately 6% of patients treated with 5-FC.6 Although these side effects are usually not severe, two cases of ulcerative colitis and bowel perforation have been reported.6,53
Hepatotoxicity
Hepatotoxicity can occur during 5-FC treatment. In most cases it involves increases in serum concentrations of transaminases and alkaline phosphatase.7,28,30 The incidence of hepatotoxicity is not clear: most reports quote incidences of between 0 and 25%,7,29,62 although a recent study by our own group showed that hepatotoxicity could occur in up to 41% of patients.28 This apparent higher incidence of hepatotoxicity may have resulted from the definition of hepatotoxicity being stricter than that used in earlier studies, or increases in liver enzymes may not have been caused only by 5-FC, given the underlying illnesses in the patients investigated.
The increases in liver enzymes can usually be reversed if the dose of 5-FC is reduced and sometimes even when the dose is unchanged.14 Increases in the concentration of bilirubin in serum and swelling of the liver have also been reported rarely, but can be reversed by discontinuing 5-FC treatment.14 However, two cases of severe liver necrosis have occurred in patients who received 5-FC for treatment of candidal endocarditis.14
The mechanism of 5-FC's hepatotoxicity is unknown, but it seems to be concentration-dependent, predictable, possibly avoidable with careful maintenance of peak 5-FC concentrations below 100 mg/L, and reversible with temporary discontinuation of the drug or a reduction in dose.19,62 Not all patients with high 5-FC concentrations will experience hepatotoxicity.19
Bone-marrow depression
The most severe toxicity associated with 5-FC treatment is bone-marrow depression. There have been several reports of serious or life-threatening leucocytopenia, thrombocytopenia and/or pancytopenia.6365 In the study by Kauffman & Frame,63 four of 15 patients treated with 5-FC developed bone-marrow toxicity (leucocytopenia in three and pancytopenia in one patient). All four patients had peak serum 5-FC concentrations of 125 mg/L immediately preceding and during the initial period of bonemarrow depression, and 5-FC serum concentrations remained at >125 mg/L for 214 days in three patients. Although reduction in the serum concentrations of 5-FC resolved the bone-marrow depression in three patients, one patient died as a result of bone-marrow aplasia.63
Several other studies have shown that 5-FC concentrations >100 mg/L are toxic.29,34 The largest study that examined 5-FC toxicity involved 194 patients who were also given amphotericin B.62 This study showed that bonemarrow depression (granulocytopenia and/or thrombocytopenia) occurred in 12 (60%) of 20 patients with 5-FC concentrations >100 mg/L, and in eight (12%) of 65 patients with 5-FC concentrations <100 mg/L. Bonemarrow depression became apparent in the first 2 weeks of therapy in 51% of these cases and during the first 4 weeks in 91% of these cases.62 Patients who have an underlying haematological disorder or who have undergone radiation treatment or myelosuppressive therapy are particularly likely to develop bone-marrow depression after 5-FC treatment.53
Symptomatic HIV-infected patients may be more intolerant to 5-FC than patients without AIDS. A high incidence of bone-marrow depression has been described in these patients.36 However, other studies have failed to show any difference in the rate of adverse effects in HIV-infected and uninfected patients.35
Mechanism of toxicity
The mechanism of toxicity of 5-FC is still not fully understood. It is likely that some of the side effects caused by 5-FC, for example hepatotoxicity and bone-marrow depression, are dose-dependent, although not all reports support this theory. Furthermore, it has been postulated that conversion of 5-FC to certain metabolites, especially 5-FU, could be one of the mechanisms of development of 5-FC-associated toxicity.
It has been shown that patients treated with 5-FC have detectable amounts of 5-FU in their urine66 and serum.67 5-FU is known to cause bone-marrow depression and gastrointestinal complications, as seen with 5-FC therapy.67 In addition, it has been shown that 5-FU concentrations in patients treated with 5-FC are comparable to those in patients treated with 5-FU.68
Diasio et al. found that 5-FU concentrations in the serum of two healthy volunteers during the 6 h after oral administration of 2 g of 5-FC ranged from 10 to 400 ng/mL.67 They also measured 5-FU concentrations in the serum of seven patients treated for cryptococcal meningitis with amphotericin B and 5-FC, of whom five had experienced haematological or other toxicity during 5-FC treatment. 5-FU concentrations ranged between 2 and 3060 ng/mL and in 20 of the 41 were >1000 ng/mL, a concentration that is in the range found after cancer chemotherapeutic doses and known to be associated with haematological toxicity. Moreover, it was found that the ratios of 5-FU concentration to 5-FC concentration varied from 0.11% to 3.45% and the ratio was >1% in 21 of the samples analysed.67
Harris et al. examined the capacity of the human intestinal microflora to convert 5-FC to 5-FU using an in vitro semicontinuous culture system that mimicked the intestinal microflora.69 The culture system was dosed with radiolabelled 5-FC initially and after 2 weeks' chronic exposure to 5-FC (50 mg/day). No detectable production of 5-FU was observed up to 8 h after the acute dose. However, at 24 h and at all times for 4 days, increasing concentrations of 5-FU were detected. The authors concluded that enzyme(s) responsible for deamination of 5-FC to 5-FU can be induced in the intestinal microflora by chronic exposure to 5-FC and that this conversion may provide a mechanism by which 5-FC toxicity may occur.
The theory of conversion of 5-FC to 5-FU by the intestinal microflora was strengthened by a study in which the relationship between the gut flora status and the in vivo 5-FC conversion to 5-FU was investigated by fluorine-19 magnetic resonance spectroscopy analysis (19F-NMR) of the urine of two patients treated with 5-FC and amphotericin B.70 Although 5-FU itself was not detectable in urine samples, there was a direct relationship between 5-FU metabolites and gut flora status. The authors stated that the fact that 5-FU was not detectable in the urine of the patients was a result of the fast degradation process of 5-FU occurring primarily in the liver and of the intrinsic insensitivity of the NMR method used.70
In addition to the possibility of conversion of 5-FC to 5-FU by the human intestinal microflora, it has recently been shown that considerable amounts of 5-FU may be present in some 5-FC intravenous solutions as a result of both impurities in the raw material and the formation of 5-FU from 5-FC upon sterilization and storage.71
Monitoring toxicity
It is widely believed that, during treatment with 5-FC, careful attention to drug dosage and 5-FC concentrations is important. Measurement of serum drug concentrations is necessary if high doses of 5-FC are being used or if prolonged therapy is required. Furthermore, dosage reduction and therapeutic drug monitoring (TDM) are required in patients with renal failure or those receiving nephrotoxic agents (such as amphotericin B), or experiencing haematological or gastrointestinal toxicity.6
Currently, therapeutic drug monitoring of 5-FC is routinely performed in many institutions to assure effective 5-FC levels in the individual patient, to avoid resistance and to prevent serious dose-limiting toxicity. Usually, in patients treated intermittently with 5-FC, target trough and peak concentrations of 2550 and 50100 mg/L, respectively, are considered adequate. In patients treated with continuous 5-FC infusion, a serum concentration of 50 mg/L is recommended.
Drug interactions
The antimycotic activity of 5-FC has been shown to be competitively inhibited by cytarabine (cytosine arabinoside) if co-administered to patients.72 Inhibition may result from 5-FC being taken up by susceptible cells by the same transport system.9 Therefore, therapy with cytarabine is a contraindication to the use of 5-FC.
Since the most harmful side effects of 5-FC (i.e. bone-marrow depression and hepatotoxicity) can be elicited by many other agents, it is necessary to be cautious when 5-FC has to be co-administered with drugs that could enhance these side effects, such as immunosuppressive or cytostatic agents. Furthermore, drugs that are known to be myelosuppressive, such as zidovudine, should be used with caution in patients receiving 5-FC.73 However, there is no evidence that concomitant administration of 5-FC with immunosuppressive or cytostatic agents produces synergy of bone-marrow depression or hepatotoxicity.22
Concomitant administration of aluminium hydroxide or magnesium hydroxide suspension delays the absorption of 5-FC. However, this has only a small effect on total bioavailability.23
Drugs that impair glomerular filtration will decrease the elimination of 5-FC and thus prolong the half-life of the drug. Probably the most important and most common drug interaction is the concomitant administration of 5-FC and amphotericin B. In the treatment of a number of systemic fungal infections, 5-FC is combined with amphotericin B in order to enhance the antifungal activity of both.19,29 However, amphotericin is highly nephrotoxic and concomitant use of 5-FC and amphotericin B will thus lead to an increase in 5-FC serum concentrations and 5-FC half-life.
![]() |
Notes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2 . Duschinsky, R., Pleven, E. & Heidelberger, C. (1957). The synthesis of 5-fluoropyrimidines. Journal of the American Chemical Society 79, 455960.
3 . Heidelberger, C., Griesbach, L., Montag, B. J., Mooren, D., Cruz, O., Schnitzer, R. J. et al. (1958). Studies on fluorinated pyrimidines. II. Effects on transplanted tumors. Cancer Research 18, 30517.[ISI]
4 . Grunberg, E., Titsworth, E. & Bennett, M. (1963). Chemotherapeutic activity of 5-fluorocytosine. Antimicrobial Agents and Chemotherapy 3, 5668.
5 . Tassel, D. & Madoff, M. A. (1968). Treatment of Candida sepsis and Cryptococcus meningitis with 5-fluorocytosine. A new antifungal agent. Journal of the American Medical Association 206, 8302.[Medline]
6 . Benson, J. M. & Nahata, M. C. (1988). Clinical use of systemic antifungal agents. Clinical Pharmacy 7, 42438.[ISI][Medline]
7 . Bennet, J. E. (1977). Flucytosine. Annals of Internal Medicine 86, 31921.[ISI][Medline]
8 . Polak, A. & Scholer, H. J. (1980). Mode of action of 5-fluorocytosine. Revue de l'Institute Pasteur de Lyon 13, 23344.
9 . Polak, A. & Grenson, M. (1973). Evidence for a common transport system for cytosine, adenine and hypoxanthine in Saccharomyces cerevisiae and Candida albicans. European Journal of Biochemistry 32, 27682.[ISI][Medline]
10 . Vanden Bossche, H., Willemsens, G. & Marichal, P. (1987). Anti-Candida drugsthe biochemical basis for their activity. Critical Reviews in Microbiology 15, 5772.[Medline]
11 . Polak, A. & Scholer, H. J. (1975). Mode of action of 5-fluorocytosine and mechanisms of resistance. Chemotherapy 21, 11330.[ISI][Medline]
12 . Polak, A. (1977). 5-Fluorocytosinecurrent status with special references to mode of action and drug resistance. Contributions to Microbiology and Immunology 4, 15867.[Medline]
13 . Bennett, J. E. (1996). Antifungal agents. In Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th edn, (Hardman, J. G., Limbird, L. E., Molinoff, P. B., Ruddon, R. W. & Goodman Gilman, A., Eds), pp. 117590. McGrawHill, New York.
14 . Scholer, H. J. (1980). Flucytosine. In Antifungal Chemotherapy, (Speller, D. C. E., Ed.), pp. 35106. Wiley, Chichester.
15 . Waldorf, A. R. & Polak, A. (1983). Mechanisms of action of 5-fluorocytosine. Antimicrobial Agents and Chemotherapy 23, 7985.[ISI][Medline]
16 . Diasio, R. B., Bennett, J. E. & Myers, C. E. (1978). Mode of action of 5-fluorocytosine. Biochemical Pharmacology 27, 7037.[ISI][Medline]
17 . Normark, S. & Schönebeck, J. (1973). In vitro studies of 5-fluorocytosine resistance in Candida albicans and Torulopsis glabrata. Antimicrobial Agents and Chemotherapy 2, 11421.[ISI][Medline]
18 . Fasoli, M. & Kerridge, D. (1988). Isolation and characterization of fluoropyrimidine-resistant mutants in two Candida species. Annals of the New York Academy of Sciences 544, 2603.[Medline]
19 . Francis, P. & Walsh, T. J. (1992). Evolving role of flucytosine in immunocompromised patients: new insights into safety, pharmacokinetics, and antifungal therapy. Clinical Infectious Diseases 15, 100318.[ISI][Medline]
20 . Medoff, G. & Kobayashi, G. S. (1980). Strategies in the treatment of systemic fungal infections. New England Journal of Medicine 302, 14555.[ISI][Medline]
21 . Armstrong, D. & Schmitt, H. J. (1990). Older drugs. In Chemotherapy for Fungal Diseases, (Ryley, J. F., Ed.), pp. 43954. Springer-Verlag, Berlin.
22 . Daneshmend, T. K. & Warnock, D. W. (1983). Clinical pharmacokinetics of systemic antifungal drugs. Clinical Pharmacokinetics 8, 1742.[ISI][Medline]
23 . Cutler, R. E., Blair, A. D. & Kelly, M. R. (1978). Flucytosine kinetics in subjects with normal and impaired renal function. Clinical Pharmacology and Therapeutics 24, 33342.[ISI][Medline]
24 . Block, E. R., Bennett, J. E., Livoti, L. G., Klein, W. J., MacGregor, R. R. & Henderson, L. (1974). Flucytosine and amphotericin B: hemodialysis effects on the plasma concentration and clearance. Studies in man. Annals of Internal Medicine 80, 6137.[ISI][Medline]
25 . Schönebeck, J., Polak, A., Fernex, M. & Scholer, H. J. (1973). Pharmacokinetic studies on the oral antimycotic agent 5-fluorocytosine in individuals with normal and impaired kidney function. Chemotherapy 18, 32136.[ISI][Medline]
26 . Gillum, J. G., Johnson, M., Lavoie, S. & Venitz, J. (1995). Flucytosine dosing in an obese patient with extrameningeal cryptococcal infection. Pharmacotherapy 15, 2513.[ISI][Medline]
27 . Muther, R. S. & Bennett, W. M. (1980). Peritoneal clearance of amphotericin B and 5-fluorocytosine. Western Journal of Medicine 133, 15760.[ISI][Medline]
28 . Vermes, A., van der Sijs, I. H. & Guchelaar, H.-J. (2000). Flucytosine: correlation between toxicity and pharmacokinetic parameters. Chemotherapy 46, 8694.[ISI][Medline]
29 . Bennett, J. E., Dismukes, W. E., Duma, R. J., Medoff, G., Sande, M. A., Gallis, H. et al. (1979). A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptococcal meningitis. New England Journal of Medicine 301, 12631.[Abstract]
30 . Harder, E. J. & Hermans, P. E. (1975). Treatment of fungal infections with flucytosine. Archives of Internal Medicine 135, 2317.[Abstract]
31 . Dismukes, W. E., Cloud, G., Gallis, H. A., Kerkering, T. M., Medoff, G., Craven, P. C. et al. (1987). Treatment of cryptococcal meningitis with combination amphotericin B and flucytosine for four as compared with six weeks. New England Journal of Medicine 317, 33441.[Abstract]
32
.
van der Horst, C. M., Saag, M. S., Cloud, G. A., Hamill, R. J., Graybill, J. R., Sobel, J. D. et al. (1997). Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases, Mycoses Study Group. New England Journal of Medicine 337, 1521.
33 . Schmutzhard, E. & Vejajjiva, A. (1988). Treatment of cryptococcal meningitis with high dose, long-term combination amphotericin B and flucytosine. American Journal of Medicine 85, 7378.
34 . Utz, J. P., Garriques, I. L., Sande, M. A., Warner, J. F., Mandell, G. L., McGehee, R. F. et al. (1975). Therapy of cryptococcosis with a combination of flucytosine and amphotericin B. Journal of Infectious Diseases 132, 36873.[ISI][Medline]
35 . Zuger, A., Louie, E., Holzman, R. S., Simberkoff, M. S. & Rahal, J. J. (1986). Cryptococcal disease in patients with the acquired immunodeficiency syndrome. Diagnostic features and outcome of treatment. Annals of Internal Medicine 104, 23440.[ISI][Medline]
36 . Chuck, S. L. & Sande, M. A. (1989). Infections with Cryptococcus neoformans in the acquired immunodeficiency syndrome. New England Journal of Medicine 321, 7949.[Abstract]
37 . Larsen, R. A., Leal, M. A. & Chan, L. S. (1990). Fluconazole compared with amphotericin B plus flucytosine for cryptococcal meningitis in AIDS. A randomized trial. Annals of Internal Medicine 113, 1837.[ISI][Medline]
38 . Aberg, J. A. & Powderly, W. G. (1997). Cryptococcal disease: implications of recent clinical trials on treatment and management. AIDS Clinical Review, 22948.
39 . Perfect, J. R. & Durack, D. T. (1982). Treatment of experimental cryptococcal meningitis with amphotericin B, 5-fluorocytosine, and ketoconazole. Journal of Infectious Diseases 146, 42935.[ISI][Medline]
40 . Allendoerfer, R., Marquis, A. J., Rinaldi, M. G. & Graybill, J. R. (1991). Combined therapy with fluconazole and flucytosine in murine cryptococcal meningitis. Antimicrobial Agents and Chemotherapy 35, 7269.[ISI][Medline]
41 . Kartalija, M., Kaye, K., Tureen, J. H., Liu, Q., Tauber, M. G., Elliot, B. R. et al. (1996). Treatment of experimental cryptococcal meningitis with fluconazole: impact of dose and addition of flucytosine on mycologic and pathophysiologic outcome. Journal of Infectious Diseases 173, 121621.[ISI][Medline]
42 . Larsen, R. A., Bozzette, S. A., Jones, B. E., Haghighat, D., Leal, M. A., Forthal, D. et al. (1994). Fluconazole combined with flucytosine for treatment of cryptococcal meningitis in patients with AIDS. Clinical Infectious Diseases 19, 7415.[ISI][Medline]
43 . Saag, M. S., Powderly, W. G., Cloud, G. A., Robinson, P., Grieco, M. H., Sharkey, P. K. et al. (1992). Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. New England Journal of Medicine 326, 839.[Abstract]
44 . de Gans, J., Portegies, P., Tiessens, G., Eeftinck Schattenkerk, J. K., van Boxtel, C. J., van Ketel, R. J. et al. (1992). Itraconazole compared with amphotericin B plus flucytosine in AIDS patients with cryptococcal meningitis. AIDS 6, 18590.[ISI][Medline]
45 . Lyman, C. A. & Walsh, T. J. (1992). Systemically administered antifungal agents. A review of their clinical pharmacology and therapeutic applications. Drugs 44, 935.[ISI][Medline]
46 . Medoff, G., Comfort, M. & Kobayashi, G. S. (1971). Synergistic action of amphotericin B and 5-fluorocytosine against yeast-like organisms. Proceedings of the Society for Experimental Biology and Medicine 138, 5714.
47 . Montgomerie, J. Z., Edwards, J. E. & Guze, L. B. (1975). Synergism of amphotericin B and 5-fluorocytosine for Candida species. Journal of Infectious Diseases 132, 826.[ISI][Medline]
48 . Schmid, S., Martenet, A. C. & Oelz, O. (1991). Candida endophthalmitis: clinical presentation, treatment and outcome in 23 patients. Infection 19, 214.[ISI][Medline]
49 . Record, C. O., Skinner, J. M., Sleight, P. & Speller, D. C. E. (1971). Candida endocarditis treated with 5-fluorocytosine. British Medical Journal i, 2624.
50 . Thaler, M., Pastakia, B., Shawker, T. H., O'Leary, T. & Pizzo, P. A. (1988). Hepatic candidiasis in cancer patients: the evolving picture of the syndrome. Annals of Internal Medicine 108, 88100.[ISI][Medline]
51 . Smego, R. A., Perfect, J. R. & Durack, D. T. (1984). Combined therapy with amphotericin B and 5-fluorocytosine for Candida meningitis. Reviews of Infectious Diseases 6, 791801.[ISI][Medline]
52 . Struijk, D. G., Krediet, R. T., Boeschoten, E. W., Rietra, P. J. & Arisz, L. (1987). Antifungal treatment of Candida peritonitis in continuous ambulatory peritoneal dialysis patients. American Journal of Kidney Diseases 9, 6670.[ISI][Medline]
53 . Patel, R. (1998). Antifungal agents. Part I. Amphotericin B preparations and flucytosine. Mayo Clinic Proceedings 73, 120525.[ISI][Medline]
54 . Barbaro, G., Barbarini, G. & Di Lorenzo, G. (1995). Fluconazole vs. flucytosine in the treatment of esophageal candidiasis in AIDS patients: a double-blind, placebo-controlled study. Endoscopy 27, 37783.[ISI][Medline]
55
.
Barbaro, G., Barbarini, G. & Di Lorenzo, G. (1996). Fluconazole vs. itraconazoleflucytosine association in the treatment of esophageal candidiasis in AIDS patients. A double-blind, multicenter placebo-controlled study. Chest 110, 150714.
56 . Polak, A. (1987). Combination therapy of experimental candidiasis, cryptococcosis, aspergillosis and wangiellosis in mice. Chemotherapy 33, 38195.[ISI][Medline]
57 . Kujath, P., Lerch, K., Kochendorfer, P. & Boos, C. (1993). Comparative study of the efficacy of fluconazole versus amphotericin B/flucytosine in surgical patients with systemic mycoses. Infection 21, 37682.[ISI][Medline]
58 . Abele-Horn, M., Kopp, A., Sternberg, U., Ohly, A., Dauber, A., Russwurm, W. et al. (1996). A randomized study comparing fluconazole with amphotericin B/5-flucytosine for the treatment of systemic Candida infections in intensive care patients. Infection 24, 42632.[ISI][Medline]
59 . Morison, W. L., Connor, B. & Clayton, Y. (1974). Successful treatment of chromoblastomycosis with 5-fluorocytosine. British Journal of Dermatology 90, 4459.[ISI][Medline]
60 . Silber, J. G., Gombert, M. E., Green, K. M. & Shalita, A. R. (1983). Treatment of chromomycosis with ketoconazole and 5-fluorocytosine. American Academy of Dermatology 8, 2368.
61 . Deonarain, M. P., Spooner, R. A. & Epenetos, A. A. (1995). Genetic delivery of enzymes for cancer therapy. Gene Therapy 2, 23544.[ISI][Medline]
62 . Stamm, A. M., Diasio, R. B., Dismukes, W. E., Shadomy, S., Cloud, G. A., Bowles, C. A. et al. (1987). Toxicity of amphotericin B plus flucytosine in 194 patients with cryptococcal meningitis. American Journal of Medicine 83, 23642.[ISI][Medline]
63 . Kauffman, C. A. & Frame, P. T. (1977). Bone marrow toxicity associated with 5-fluorocytosine therapy. Antimicrobial Agents and Chemotherapy 11, 2447.[ISI][Medline]
64 . Schlegel, R. J., Bernier, G. M., Bellanti, J. A., Maybee, D. A., Osborne, G. B., Stewart, J. L. et al. (1970). Severe candidiasis associated with thymic dysplasia, IgA deficiency, and plasma antilymphocyte effects. Pediatrics 45, 92636.[Abstract]
65 . Meyer, R. & Axelrod, J. L. (1974). Fatal aplastic anemia resulting from flucytosine. Journal of the American Medical Association 228, 1573.[ISI][Medline]
66 . Williams, K. M., Duffield, A. M., Christopher, R. K. & Finlayson, P. J. (1981). Identification of minor metabolites of 5-fluorocytosine in man by chemical ionization gas chromatography mass spectrometry. Biomedical Mass Spectrometry 8, 17982.[ISI][Medline]
67 . Diasio, R. B., Lakings, D. E. & Bennett, J. E. (1978). Evidence for conversion of 5-fluorocytosine to 5-fluorouracil in humans: possible factor in 5-fluorocytosine clinical toxicity. Antimicrobial Agents and Chemotherapy 14, 9038.[ISI][Medline]
68 . Finch, R. E., Bending, M. R. & Lant, A. F. (1979). Plasma levels of 5-fluorouracil after oral and intravenous administration in cancer patients. British Journal of Clinical Pharmacology 7, 6137.[ISI][Medline]
69 . Harris, B. E., Manning, B. W., Federle, T. W. & Diasio, R. B. (1986). Conversion of 5-fluorocytosine to 5-fluorouracil by human intestinal microflora. Antimicrobial Agents and Chemotherapy 29, 448.[ISI][Medline]
70 . Malet-Martino, M. C., Martino, R., de Forni, M., Andremont, A., Hartmann, O. & Armand, J. P. (1991). Flucytosine conversion to fluorouracil in humans: does a correlation with gut flora status exist? A report of two cases using fluorine-19 magnetic resonance spectroscopy. Infection 19, 17880.[ISI][Medline]
71 . Vermes, A., van der Sijs, H. & Guchelaar, H.-J. (1999). An accelerated stability study of 5-flucytosine in intravenous solution. Pharmacy World and Science 21, 359.[Medline]
72 . Holt, R. J. (1978). Clinical problems with 5-fluorocytosine. Mykosen 21, 3639.[Medline]
73 . Albengres, E., Le Louët, H. & Tillement, J. P. (1998). Systemic antifungal agents. Drug interactions of clinical significance. Drug Safety 18, 8397.[ISI][Medline]
Received 6 January 2000; returned 31 January 2000; revised 7 February 2000; accepted 13 March 2000