REVIEW ARTICLE

Drugs 44 (I): 9·35, 1992 0012.6667/92/0007-OC1J9{$ I 3.50/0 © Adis International Limited. All rights reserved. DRUl170

Systemically Administered Antifungal Agents

A Review of Their Clinical Pharmacology and Therapeutic Applications Caron A. Lyman and Thomas J. Walsh

Infectious Diseases Section, Pediatric Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

Contents 10

10 10

13 14 15 16 17 17 17 18 18 18 18 19 19 21 22 23 25 25 25 25 26 26 26 26 26 27 27 27 28 28 28 28

Summary I. Amphotericin B 1.1 Mechanism of Action 1.2 Pharmacokinetics 1.3 Tolerability 1.4 Indications 1.5 Lipid Formulations 2. Flucytosine 2.1 Mechanism of Action 2.2 Pharmacokinetics 2.3 Tolerability 2.4 Indications 3. Azoles 3.1 Mechanism of Action 3.2 Imidazoles 3.2.1 Ketoconazole 3.3 Triazoles 3.3.1 Itraconazole 3.3.2 Fluconazole 3.3.3 Saperconazole 3.4 Other Azoles 3.4.1 SCH 39304 3.4.2 ICI 195739 3.4.3 SDZ 89·485 3.4.4 BAY·R·3783 4. Other Investigational Compounds 4.1 Echinocandins 4.1.1 LY-121019 (Cilofungin) 4.1.2 L-693989 4.2 Polyoxins and Nikkomycins 4.3 Allylamines 4.4 Pradimicins and Benanomicins 4.5 Faerifungin 4.6 Azasterols 5. Future Considerations

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Summary

Systemic antifungal agents express great diversity in their pharmacokinetic profiles, mechanisms of action, and toxicities. Understanding the diverse pharmacokinetic properties of systemic antifungals is critical to their appropriate application. Amphotericin B, drug of choice for most invasive mycoses, has unique pharmacokinetic properties, binding initially to serum lipoproteins and redistributing from blood to tissues. Dosing recommendations are based on the specific infection and the status of the host. Lipid formulations of amphotericin B may be able to attenuate some of its toxicities. flucytosine is a water-soluble, fluorinated pyrimidine that possesses excellent bioavailability. It is administered only in combination with amphotericin B because of frequent development of secondary drug resistance, and is associated with dosedependent bone marrow suppression. The antifungal azoles are relatively well tolerated, have broad spectrum antifungal activity, and are fungistatic in vitro. Ketonconazole and itraconazole are highly bound to plasma proteins, are extensively metabolised by the liver, and are relatively insoluble in aqueous solution. By comparison, fluconazole is only weakly bound to serum proteins, is relatively stable to metabolic conversion, and is water soluble. fluconazole penetrates the cerebrospinal fluid well and is approved for primary and suppressive therapy of cryptococcal meningitis in AIDS patients. The echinocandins have a narrow spectrum of antifungal activity, being effective only against Candida spp.

The incidence of systemic mycoses continues to rise steadily. This increase is due in part to improved recognition and diagnosis of fungal infections, but also to the prolonged survival of patients with global defects in their host defence mechanisms, including patients with neoplastic diseases, organ transplant recipients, diabetics, and patients with AIDS. These patient populations are susceptible to an ever growing list of opportunistic fungi. Fungi, like the human host, are eukaryotic organisms, and thus the number of suitable targets for therapeutic attack are limited. Nonetheless, considerable progress in treating systemic fungal infections has been achieved through better application of established antifungal agents and the development of promising new investigational agents. This ever expanding battery of antifungal agents exhibits a wide variety of pharmacokinetic profiles, mechanisms of action and toxicities (see table I). Understanding these parameters is critical for the appropriate use and continued development of these agents.

1. Amphotericin B Amphotericin B, the first commercially available systemic antifungal drug, remains the cornerstone for therapy in critically ill patients with sys-

temic fungal infections. It was first isolated in the 1950s from Streptomyces nodosus, an actinomycete cultured from the soil of the Orinoco Valley in Venezuela (Gold et al. 1955). It is a polyene macrolide that consists of seven conjugated double bonds, an internal ester, a free carboxyl group and a glycoside side chain with a primary amino group (fig. 1). Amphotericin B is amphoteric, forming soluble salts in both basic and acidic environments. It is not orally or ~ntramuscularly absorbed, and is virtually insoluble in water. The intravenous infusion is commercially formulated as a deoxycholate micellar suspension consisting of amphotericin 50mg and deoxycholate 41mg. 1.1 Mechanism of Action The primary mechanism of action of the polyenes in general, and amphotericin B in particular, is due to binding to ergosterol, the principal sterol present in the cell membrane of sensitive fungi (Kerridge 1986). This binding alters membrane permeability, causing leakage of sodium, potassium and hydrogen ions, eventually leading to cell death (Palacios & Serrano 1978). However, for amphotericin B to gain access to ergosterol, it must first pass through the rigid cell wall of the fungus,

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Pharmacology of Systemic Antifungal Agents

Table I. Tolerability and drug interaction profile of antifungal agents

Drug

Adverse effect

Drug interactions

Nephrotoxicity; fever, chills; phlebitis; hypokalaemia; anaemia; GI disturbance Reduced azotaemia

Azotaemia with aminoglycosides; cyclosporin; pulmonary toxicity with granulocyte transfuSion

Bone marrow suppression; hepatotoxicity; GI disturbance

Minimal

Polyenes

Amphotericin B (deoxycholate)

(lipid formulations) Fluorinated pyrimidines

Flucytosine Azoles Imidazo/es

Miconazole

Ketoconazole

Triazo/es Itraconazole Fluconazole

Saperconazole SCH 39304 ICI195739 SDZ 89·485

Headache; pruritus; thrombophlebitis; hepatotoxicity; autoinduction of hepatic degrading enzymes GI disturbance; hepatotoxicity

GI disturbance; rare hepatotoxicity GI disturbance; rare hepatotoxicity; rare Stevens·Johnson syndrome GI disturbance; rare hepatotoxicity Oncogenic (withdrawn from further testing) Unknown Unknown

Drugs that induce hepatic microsomal enzymes e.g. rifampicin, cyclosporin; antacids, H2·receptor blockers Rifampicin; phenytoin; ?cyclosporin Phenytoin; warfarin; ?cyclosporin Similar to itraconazole Unknown Unknown Unknown

Echinocandins

L Y·121019 (cilofungin) L·693989

Metabolic acidosis (withdrawn from further testing) Unknown

Unknown

Unknown Unknown

Unknown Unknown

Unknown Unknown Unknown 10·fold less than amphotericin B

Unknown Unknown Unknown ?similar to amphotericin B

, Chitin synthetase inhibitors

Polyoxins Nikkomycins Other investigational drugs

Allylamines Pradimicins Benanomicins Faerifungin Abbreviation: GI = gastrointestinal.

which is composed primarily of chitin and 1,3-13glucans. How this is accomplished, and the role these compounds play in amphotericin B resistance has not been elucidated (Gale 1986). Amphotericin B also binds to a lesser extent to

other sterols, such as cholesterol, which accounts for much of the toxicity associated with its usage (Medoff & Kobayashi 1980). The basis of the clinical usefulness of amphotericin B is its more avid binding to ergosterol-containing membranes

Drugs 44 (1) 1992

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OH

OH

Polyene: binds to ergosterol. alters membrane permeability causing cation leakage: ? oxidative membrane damage

Amphotericin B

Fluorinated pyrimidine: disruption 01 protein synthesIs: inhibition 01 thymldylate synthetase

Flucytosine

Echlnocandin: inhibition 01 1.3-.81llucan synthetase disrupting lungal cell wall biosynthesis

LY121019 (cilolungln)

HNYr

r

~ JJ

HOOC

r') I'I'n 'NH-C~I H N

HO~Il-

CH J

0

H

H

OH

OH

H

H

Nikkomycln: Inhibition 01 chitin synthetase disrupting lungal cell wall biosynthesis

Nikkomycln Z

Allylamine: inhibition 01 squalene epoxidase

Terbinafine ~H, CONH-CK-COOH CH,

. OH

0

OH

0 ~

oHO

o 0 HO~ HO

BMY 28567

Fig.

CHI

NHCH,

OH

Pr.dlmlcln: ? forms complexes with mannose-contalnlng components 01 lungal membrane

1. Chemical structures and mechanisms of action of non-azole antifungal agents.

Pharmacology of Systemic Antifungal Agents

than to cholesterol-containing membranes, as has been demonstrated by spectrophotometry (VertutCroquin et al. 1983). Another proposed mechanism of chemotherapeutic effect is the oxidation-dependent, amphotericin B-induced stimulation of cells of macrophages (Sokol-Anderson et al. 1986; Wilson et al. 1991). This immunomodulation is augmented by oxidative metabolites such as hydrogen peroxide and may be due to auto-oxidation of the drug with formation of free radicals, or to an increase in membrane permeability, especially to monovalent cations (Brajtburg et al. 1990). Thus, in addition to its effect on fungi, its effect on host cells may contribute to its antifungal properties. 1.2 Pharmacokinetics Several studies have contributed to our knowledge about the pharmacokinetics of amphotericin B (Atkinson & Bennett 1978; Benson & Nahata 1989; Craven et al. 1979; Starke et al. 1987). Following intravenous administration, amphotericin B is highly protein bound (91 to 95%), primarily to lipoproteins, erythrocytes and cholesterol in the plasma, and then redistributes from the blood into tissues (Christiansen et al. 1985). It is thought to follow a three compartment model of distribution, with an overall apparent volume of distribution of 4 L/kg (Atkinson & Bennett 1978). Peak serum concentrations following intravenous administration may be related to dose, frequency and rate of infusion (Gallis et al. 1990; Walsh & Pizzo 1988). In adults, an intravenous infusion of 0.6 mg/kg yields peak serum concentrations of approximately I to 3 mg/L. These concentrations rapidly decline to achieve a prolonged plateau phase of 0.2 to 0.5 mgjL. Administration of twice the daily dose on alternate days results in slightly higher peak concentrations with no difference in minimum values (Bindschadler & Bennett 1969). Powderly et al. (1987) demonstrated a direct relationship between dose and serum concentration. They found peak concentrations of 1.2 and 2.4 mg/L 1 hour after infusion, and trough concentrations of 0.5 and 1.1 mg/L 23 hours postinfusion, following 3 days' administration of 0.5 and 1 mg/kg, respectively.

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Increased rates of infusion (i.e. over 45 minutes) results in higher peak serum concentrations, but does not affect values measured 18 to 42 hours postinfusion (Fields 1971). Concentrations of amphotericin B in peritoneal, pleural and synovial fluids are usually less than half those in the serum (Polak 1979), while cerebrospinal fluid (CSF) concentrations range from undetectable (Bindschadler & Bennett 1969) to no more than 4% of serum concentrations (Vtz et al. 1975). Amphotericin B follows a biphasic pattern of elimination from serum, with an initial half-life of 24 to 48 hours, followed by a long elimination halflife (tl12) of up to 15 days (Atkinson & Bennett 1978), probably because of the extremely slow release of the drug from peripheral tissues. Detectable levels of the drug have been demonstrated in bile for up to 12 days and in urine for 27 to 35 days following administration (Craven & Drutz 1979). Amphotericin B can be detected in tissues such as liver and kidney for as long as 12 months after therapy has been terminated, supporting the theory that tissue accumulation accounts for the majority of drug disposition (Reynolds et al. 1963). Since only 5 to 10% of amphotericin B is excreted in urine and bile, no modification of the dosage is necessary in patients with renal or hepatic failure not attributable to the drug (Daneshmend & Warnock 1983). Haemodialysis usually does not alter blood concentrations of amphotericin B, except in hyperlipidaemic patients where concentrations are decreased apparently due to binding of the amphotericin B-lipoprotein complex to the dialysis membrane (Walsh & Pizzo 1988). The pharmacokinetic profile of amphotericin B is somewhat different in children than in adults. Starke et al. (1987) reported a smaller «4 L/kg) volume of distribution, and a larger (>0.026 L/h/ kg) clearance than what is usually found in adults. The peak serum concentrations were significantly lower (approximately one-half) than those obtained in adults receiving equivalent doses. Benson and Nahata (1989) reported a strong inverse correlation between patient age and total clearance of amphotericin B, suggesting that lower dosages may

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be needed in patients older than 9 years of age to achieve optimal efficacy and minimise dose-related toxicity (Benson & Nahata 1989). 1.3 Tolerability The formidable effectiveness of amphotericin B is tempered by the variety and frequency of adverse effects (table I). Understanding the toxicity of this an~ifungal agent, as well as strategies to prevent or manage it, has been a major area of research in recent years. Despite the preferential binding of amphotericin B to ergosterol over cholesterol, its interaction with and disruption of mammalian cells is postulated as the primary cause of many of the toxicities associated with this compound (Medoff & Kobayashi 1980). The most significant adverse effect of amphotericin B is nephrotoxicity. The clinical and laboratory manifestations may include a decrease in glomerular filtration rate and renal blood flow, presence of casts in the urine, hypokalaemia, hypomagnesaemia, renal tubular acidosis and nephrocalcinosis (Burgess & Birchall 1972; Maddux & Barriere 1980; Sabra & Branch 1990). The exact mechanisms involved in amphotericin B-induced azotaemia have not been clearly delineated. It has been established that the drug can cause changes in tubular cell permeability to ions both in vivo and in vitro (Bolard et al. 1980; Cheng et a1. 1982). Thus, one possible explanation for amphotericin B-induced azotaemia is tubuloglomerular feedback, a mechanism whereby increased delivery and reabsorption of chloride ions in the distal tubule initiates a decrease in the glomerular filtration rate of that nephron (Branch 1988; Heidemann et a1. 1983). Tubuloglomerular feedback is amplified by sodium deprivation and suppressed by previous sodium loading. Burgess and Birchall (1972) suggested other possible mechanisms for amphotericin B nephrotoxicity, including renal arteriolar spasm, calcium deposition during periods of ischaemia, and direct tubular or renal cellular toxicity. More recent studies implicate roles for prostaglandins and tumour necrosis factor a in mediating amphotericin B-induced azotaemia (Wasan et a1. 1990). The actual

mechanism may be some combination of these events. Irreversible renal dysfunction has been reported but it is rare, and may be related to total dose or individual susceptibility to toxicity. Generally, renal azotaemia is reversible, and renal function may return to normal following cessation of therapy. However, return to pretreatment levels may take several months in some cases (Butler et a1. 1964). Amphotericin B-induced azotaemia may be reduced or prevented by various manoeuvres. In laboratory and clinical studies, sodium loading has been effective in attenuating the decrease in glomerular filtration rate (Feely et a1. 1981; Heidemann et a1. 1983; Ohnishi et a1. 1989). Normal saline (1 L/day) administered with amphotericin B 40 mgfday to leukaemic patients reduced the incidence of renal dysfunction (Branch 1988). Patients with cancer who are concomitantly receiving antibiotics with a high sodium content, such as carbenacillin, experience less severe nephrotoxicity than patients receiving amphotericin B plus antibiotics with a lower sodium content (Branch et a1. 1987). However, sodium loading requires close monitoring of patients to avoid hypernatraemia, hyperchloraemia, metabolic acidosis and pulmonary oedema. Furthermore, sodium loading will not ameliorate, and may indeed aggravate hypokalaemia. Hypokalaemia, which occurs in the majority of patients receiving amphotericin B, may require parenteral administration of 5 to 15 mmol/L of supplemental potassium per hour. Amphotericin B-induced hypokalaemia appears to be a result of increased renal tubular cell membrane permeability to potassium due to direct toxic effects, or it may be caused by enhanced excretion via activation of sodium/potassium exchange (Butler 1966; Warda & Barriere 1985). Magnesium wasting may also occur in association with amphotericin B therapy (Barton et a1. 1984). Such hypomagnesaemia may be more profound in cancer patients who develop a divalent cation-losing nephropathy associated with the antineoplastic drug cisplatin (Walsh & Pizzo 1988). Anaemia is another common side effect of am-

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Pharmacology of Systemic Antifungal Agents

photericin B therapy. It is characterised as a normochromic and normocytic process that is probably mediated by suppression of erythrocyte and erythropoietin synthesis (MacGregor et al. 1978; Maddux & Barriere 1980). The anaemia is exacerbated by deterioration of renal function due to a decrease in red blood cell production (Sarosi 1990). Maximal decreases in haemoglobin usually reach a nadir of betwen 18 and 35% below baseline, with levels usually returning to normal within several months of discontinuing therapy. Fever, chills and rigors, which are frequently associated with amphotericin B therapy, may be mediated by tumour necrosis factor and interleukin1, cytokines that are released from human peripheral monocytes in response to the drug (Gelfand et al. 1988). These acute reactions may possibly be blunted by corticosteroids, paracetamol (acetaminophen), aspirin or pethidine (meperidine) [Burks et al. 1980; Koldin & Medoff 1983]: corticosteroids should be utilised only in low dosages, such as 0.5 to 1 mg/kg of hydrocortisone; pethidine in low doses (0.2 to 0.5 mg/kg) appears to attenuate development of rigors; paracetamol may decrease fever but appears to have little effect on rigors; and aspirin should be avoided in thrombocytopenic patients. Thrombophlebitis is a common local side effect associated with amphotericin B infusion. Slow infusion of the drug, rotation of the infusion site, addition of a small dose of heparin to the infusion, application of hot packs, use of inline filters and avoidance of amphotericin B concentrations in excess of 0.1 giL have all been recommended to minimise this reaction (Graybill 1988; Maddux & Barriere 1980). Infusion of amphotericin B through a central venous line avoids these complications. Nausea, vomiting, anorexia, headache, myalgias and arthralgias are other infusion-related reactions that have been reported during the initiation of amphotericin B therapy. A number of important drug interactions with amphotericin B have been described. The renal toxicity caused by aminoglycosides and cyclosporin are often enhanced by amphotericin B (Kennedy et al. 1983). Acute pulmonary reactions

(hypoxaemia, acute dyspnoea and radiographic evidence of pulmonary infiltrates) have been associated with simultaneous transfusion of granulocytes and infusion of amphotericin B (Wright et al. 1981). While some investigators have disputed the causality of amphotericin B to such reactions (Dana et al. 1981), a rational approach may be to separate the infusions of amphotericin B and granulocytes by the longest time period possible. In addition, concentrations of amphotericin B of > 5 mg/L have been shown to have deleterious effects on normal neutrophil function in vitro (Roilides et al. 1990). 1.4 Indications 1.4.1 Treatment of Proven Infection Amphotericin B is still the drug of choice for treating most deeply invasive mycoses, including both endemic mycoses and opportunistic mycoses. Among the opportunistic mycoses, amphotericin B is the preferred treatment for most patients with invasive candidiasis, invasive aspergillosis, and zygomycosis. It remains the preferred therapy for patients with life-threatening infections due to Cryptococcus neoformans and the endemic fungi. The practical questions of daily dosage, total dosage and duration remain relatively anectdotal and seldom have been studied in a prospective manner. Current recommendations are based upon the type of infection and the status of the host. As will be discussed later, some of the newer antifungal agents are proving to be less toxic, useful alternatives with some fungal infections in nonimmunosuppressed patients. 1.4.2 Empirical Antifungal Therapy Disseminated fungal infections in granulocytopenic patients are difficult to detect and carry a high mortality (Horn et al. 1985). In a randomised prospective clinical trial, it was shown that persistently febrile granulocytopenic patients had significantly fewer invasive fungal infections when they received empirical amphotericin B therapy (Pizzo et al. 1982). These findings were confirmed in a larger trial that demonstrated decreased at-

Drugs 44 (1) 1992

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tributable mortality and fewer infections due to fungi (EORTC 1989). This approach provides early therapy for occult fungal infections and systemic prophylaxis for patients at high risk of invasive mycoses. As mentioned, the recommended dose of amphotericin B varies according to the specific fungus involved and the immune status of the patient. Persistently febrile granulocytopenic patients at the National Cancer Institute receive an initial test dose of Img (0.5mg in children < 30kg) followed later by a dose of 0.5 mg/kg infused over 2 to 3 hours. Empirical therapy is continued until the patient recovers from their granulocytopenia (Walsh & Pizzo 1988). Fungaemia in a granulocytopenic adult patient is usually treated with a total dose of 15 mg/kg over 2 to 4 weeks, while fungaemia in a nongranulocytopenic adult patient is treated with a total dose of approximately 7 mg/kg over 2 weeks. Dosage and duration are increased for invasive candidiasis with tissue proven infection. Treatment of hepatosplenic candidiasis often requires several months of therapy. Treatment of invasive aspergillosis is discussed in greater length elsewhere (Walsh 1990). 1.5 Lipid Formulations The major limiting factor in amphotericin B therapy is its toxicity, and therefore a number of strategies have been explored for reducing toxic effects. One such strategy has been to examine vehicles other than deoxycholate. Liposomes, defined as phospholipid bilayers of one or more closed concentric structures, have been used as vehicles for amphotericin B with encouraging results. It has been proposed that they may act as a 'donor', carrying the amphotericin B to the ergosterol-containing 'target' in the fungal cell membrane (Juliano et al. 1987). However, not all lipid formulations of amphotericin Bare liposomes. A number of these compounds are currently under investigation, including amphotericin B lipid complex (ABLC), a small unilamellar vesicle (SUY) and amphotericin B colloidal dispersion (ABCD). The lipid composition, molar ratio of lipid and liposomal size all

playa role in toxicity and fungicidal activity (Szoka et al. 1987). Each lipid formulation of amphotericin B confers distinct pharmacokinetic properties. They distribute to organs rich in reticuloendothelial cells leading to higher levels in liver, spleen and lung and lower levels in kidneys, as compared with deoxycholate amphotericin B (Gondal et al. 1989; Lopez-Berestein et al. 1984). In mice and rats, 5 mg/kg of a SUY preparation of amphotericin B resulted in peak plasma concentrations of87 and 118 mg/L, and t'l2 of 3 to 36 and 7 to 56 hours, respectively (Proffitt et al. 1991). A single dose of 1.5 mg/kg of ABCD in healthy human volunteers resulted in a mean t'/2 of 235 hours, and a plasma concentration of 0.10 mg/L at 168 hours (Sanders et al. 1991). In a comparative study in rats, ABCD resulted in decreased plasma concentrations, increased t'/2 and increased volume of distribution as compared with deoxycholate amphotericin B (Fielding et al. 1991). Given their distinctive properties, the pharmacology of each of the lipid formulations needs to be closely examined as part of their overall evaluation. The most significant contribution of lipid formulations of amphotericin B appears to be reduced toxicity to mammalian cells. They are rapidly taken up by the reticuloendothelial system, thereby reducing protein binding (Barwicz et al. 1991). This distribution also results in a reduction in the amount of drug taken up by renal tissue, resulting in decreased renal toxicity. When amphotericin B was incorporated into liposomes composed of dimiristoylphosphatidylcholine and dimiristoylphosphatidylglycerol, there was selective toxicity for fungal cells but not for red blood cells (Mehta et al. 1984). Limited clinical studies have shown remarkably little toxicity with administration of higher doses of the liposome formulations of the drug (Lopez-Berestein et al. 1985). Some data suggest that amphotericin B incorporated into liposomes has enhanced and prolonged activity as compared with equivalent concentrations of deoxycholate amphotericin B (Meunier 1989). In a rabbit model of primary pulmonary aspergillosis, a unilamellar liposomal

Pharmacology of Systemic Antifungal Agents

preparation significantly prolonged survival and reduced the rate of tissue damage as compared to deoxycholate amphotericin B (Francis et al. 1990). In addition, several patients refractory to standard amphotericin B treatment have shown improvement to 'cure' with liposomal formulations of the drug (Sculier et al. 1988). While these results are very encouraging, there is great variability among the various preparations of liposomal amphotericin B. Large multicentre controlled studies in humans is necessary to determine the true efficacy of the drug and the role it should play in antifungal therapy. Recently, lipid formulations of other polyenes have been developed. Nystatin, for example, has been incorporated successfully into liposomes, a formulation which would allow the drug to be given systemically (Mehta et al. I 987a). Preliminary results from a murine model are encouraging concerning its toxicity and therapeutic effectiveness (Mehta et al I 987b).

2. Flucytosine Flucytosine (5-fluorocytosine, 5-FC), a fluorine analogue of cytosine (fig. 1), was first synthesised in the 1950s as a potential antineoplastic agent (Duschinsky et al. 1957). It was not effective against tumours but was found to have in vitro and in vivo antifungal activity (Berger & Duschinsky 1962; Grunberg et al. 1964). Flucytosine has seen increasing usage as an adjunct to amphotericin B therapy. This combination was originally proposed because ofthe observation that amphotericin B potentiated the uptake of flucytosine by increasing fungal cell membrane permeability (Medoff et al. 1972). 2.1 Mechanism of Action Two mechanisms of action have been reported for flucytosine. These are the disruption of protein synthesis by inhibition of DNA synthesis, and alteration of the amino acid pool by inhibition of RNA synthesis. These occur via a 2-step process: initially, flucytosine is taken up into susceptible cells

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by cytosine permease (Polak & Scholer 1973). Intracellularly, flucytosine is converted by cytosine deaminase to 5-fluorouracil, which replaces uracil in the pyrimidine pool and thus disrupts protein synthesis. In addition, 5-fluorouracil may then be converted through several steps to 5-fluorodeoxyuridine monophosphate, a competitive inhibitor of thymidylate synthetase (Diasio et al. 1978). 5-Fluorouracil cannot be directly used as an antifungal agent because it is not taken up by fungal cells and it is highly toxic to mammalian cells (Polak & Grenson 1973). Many fungi are resistant or develop resistance to flucytosine. Resistant fungi may have a deficiency in one of the enzymes necessary for conversion to the active molecule, they may have decreased permeability to the drug, or they may synthesise constituents that compete with flucytosine and its metabolites (Armstrong & Schmitt 1990). Flucytosine treatment is not thought to induce resistance but rather selects for resistant strains in a given population (Armstrong & Schmitt 1990). The selection of resistant strains of Candida spp. most frequently occurs when the compound is used alone. 2.2 Pharmacokinetics Flucytosine is a low molecular weight, watersoluble compound. Absorption of orally administered flucytosine from the gastrointestinal tract is rapid and nearly complete, providing excellent bioavailability (Cutler et al. 1978). There is negligible protein binding in serum and the drug has excellent penetration with a volume of distribution that approximates that of total body water (Schonebeck et al. 1973). Administration of 150 mg/kg/day results in peak serum concentrations of 50 to 80 mg/ L within 1 to 2 hours in adults with normal renal function. CSF concentrations are approximately 74% of corresponding serum concentrations, accounting for its usefulness in central nervous system mycoses (Utz et al. 1975). However, the compound accumulates in patients with impaired renal function, resulting in potentially toxic sc

Systemically administered antifungal agents. A review of their clinical pharmacology and therapeutic applications.

Systemic antifungal agents express great diversity in their pharmacokinetic profiles, mechanisms of action, and toxicities. Understanding the diverse ...
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