Department of Clinical Dental Sciences, University of Liverpool, Liverpool L69 3BX, UK
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Abstract |
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Introduction |
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Fluconazole (an orally active triazole agent) is well established as a first-line management option for both localized and systemic C. albicans infections. 7 ,8 Until recently, itraconazole (the other triazole licensed in the UK) was available only as a highly lipophilic capsule formulation with poor and variable absorption, and its use was therefore limited.9,10 A solution formulation with improved absorption, resulting from the combination of itraconazole with the carrier hydroxypropylß-cyclodextrin (HPCD), has recently been developed and is currently undergoing clinical evaluation. 11 ,12 ,13
The aim of this paper is to compare the pharmacokinetics of fluconazole, itraconazole capsules and itraconazole solution, and to evaluate their efficacy, safety and place in the treatment of C. albicans infections. Their use in children, the elderly and patients with impaired immunity will be considered.
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Pharmacokinetics |
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Adults. Fluconazole is water soluble and available in oral capsule, oral solution and saline-based iv solution formulations. All formulations exhibit predictable pharmacokinetics.14 ,15 ,16 When given orally, fluconazole is rapidly absorbed, with peak plasma levels occurring 13 h after dosing. Absorption is unaffected by food or gastric acidity, 17 ,18 and peak plasma concentrations are proportional to dose over a wide range (25400 mg).15 The parent compound is active and has a plasma elimination half-life of around 30 h. Bioavailability is consistently high (approximately 90%) and distribution to body sites and tissues is widespread and rapid. This pharmacokinetic profile of fluconazole allows the convenience of once daily dosing, and the treatment of both localized and systemic C. albicans infections.
Special patient populations. The volume of distribution and clearance of
fluconazole are greater in children than in adults;19 a
relatively high mg/kg dose of fluconazole is therefore necessary in young patients. For those aged
greater than 4 weeks, once daily dosing is appropriate. Neonates (aged 4 weeks) excrete
fluconazole slowly, and less frequent dosing is therefore desirable.
19
,20 The pharmacokinetics of fluconazole in the elderly are
similar to those in non-elderly adults.15 Immune status has
no effect on the pharmacokinetics of fluconazole in either adultsor children.
7
,21
,22
Itraconazole
Adults. Itraconazole is a lipophilic agent and its absorption is therefore poor and variable. 9 ,10 Itraconazole capsules should be taken with food, as their water-solubility (and hence absorption) improves when gastric pH falls. 17 ,18 Absorption is lower when itraconazole capsules are administered together with H2-blockers.23 Owing to its lipophilicity, itraconazole is not found in body fluids, such as cerebrospinal fluid, ocular fluids and saliva, but in many organs and tissues (skin, lung, kidney, liver, fat, spleen, brain, muscle, bone), the drug concentration exceeds the corresponding plasma concentration by a factor of 1.520.10 Clinical trials have demonstrated that itraconazole concentrations remain high in the skin and nails after treatment for dermatomycosis or onychomycosis for up to 2 weeks and 3 months, respectively, after the end of therapy.24,25
A solution formulation of itraconazole has been developed recently to improve its water solubility, and thereby to improve, and minimize variations in, absorption.11 The solution contains itraconazole 10 mg/mL solubilized in 40% (v/v) HPCD, which has a `cage-like' structure with a hydrophobic interior but hydrophilic exterior. Only a few small studies have evaluated the pharmacokinetics of itraconazole solution, but available data suggest an overall improvement in absorption and bioavailability over the capsule formulation.12,26 In healthy volunteers, the bioavailability of itraconazole from solution was 30% greater than from capsules.11
Special patient populations. No published study has examined the pharmacokinetics of either itraconazole formulation in children or the elderly. Variations in the absorption of itraconazole from capsules are particularly marked in patients with impaired immunity, who frequently experience reduced gastric function, hypoacidity and mucositis.9,27 Greater absorption of itraconazole from solution than from capsules was observed in small studies of patients with neutropenia owing to chemotherapy before autologous bone marrow transplantation11 and AIDS;12 wide inter-patient variation, nevertheless, remained.
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Efficacy |
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Fluconazole has excellent in-vitro activity against C. albicans.28 Fluconazole can also be effective against some non-albicans Candidaspecies, including Candida parapsilosis, Candida tropicalis and Candida glabrata, although higher doses may be required.28,29
Fluconazole is effective against C. albicans infections at a wide range of body sites and tissues, irrespective of the patient's immune status. 7 ,30 ,31 Indications in adults include vaginal,32,33 mucosal,31 dermal and systemic 30 ,34 ,35 ,36 candidosis (Table I). Prophylactic administration of fluconazole can be useful in patients considered at risk of fungal infections as a consequence of neutropenia following chemotherapy or radiotherapy. 37 ,38 ,39 ,40 ,41 Experimental evidence42 and clinical case reports43 suggest that prophylaxis with fluconazole may be useful in preventing C. albicans-associated endocarditis.
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Itraconazole
Itraconazole has in-vitro activity against a greater range of Candidaspecies than fluconazole.9
Capsule formulation. Itraconazole capsules are effective and indicated for the treatment of a number of localized and systemic fungal infections in adults, irrespective of their immune status (Table II).9 These include vulvovaginal53 and oropharyngeal candidosis. Because of its lipophilicity, itraconazole distributes to the nails, and the capsule formulation is effective in the treatment of onychomycosis.54 Itraconazole capsules can be used as maintenance therapy in patients with AIDS and as prophylaxis before expected neutropenia, but as absorption is often impaired, blood monitoring should be performed and, if necessary, the dose should be increased.
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Solution formulation. Most studies examining the efficacy of itraconazole solution
have been in patients with impaired immunity.
13
,55
,56
,57
,58
,59
,60
,61
Two large comparative studies with fluconazole (Table III) were in
HIV-positive patients with oral (n = 244),57 or oropharyngeal (n = 190)58
candidosis: 14 days of itraconazole solution was at least as effective as fluconazole in effecting a
clinical response (87%). In a further study of 126 immunocompromised patients with
oesophageal candidosis, itraconazole solution and fluconazole led to a clinical response in 94%
and 91% of cases, respectively.60 A comparative study
examining the prophylactic use of itraconazole solution and fluconazole in 445 patients who
were expected to be neutropenic following chemotherapy demonstrated that both agents prevent
fungal infections in most cases (>97%).59
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Management of patients not responding to fluconazole |
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A number of options are available for managing patients who are non-responsive to conventional doses of fluconazole.67 Higher doses of fluconazole have been tried and found to be successful.68,69 In addition, most patients who are non-responsive to fluconazole remain susceptible to wider-spectrum antifungals.
In-vitro testing of isolates can help to identify the fungal species involved and its antifungal sensitivity. An antifungal susceptibility test method (M27) has been proposed by the NCCLS as a result of several collaborative studies.70 During the development process of the susceptibility testing differences were observed in inter-laboratory reproducibility. Recent papers have discussed the technical advances and potential clinical applications of the susceptibility method and the development of interpretive breakpoints aimed to reduce this variability.71,72 Although such sensitivity testing can be a useful guide to clinical outcome, caution should be exercised, as there is no absolute correlation between sensitivity testing to triazoles and clinical outcome.67 Some studies have reported a general correlation between clinical failure and high fluconazole MIC levels, 73 ,74 ,75 whereas others have noted an overlap or poor correlation.76,77 The apparently contradictory literature probably reflects complex clinical differences between patients, for example, in their immune status.
Approximately 70% of fluconazole-resistant isolates (MIC 25 mg/L) remain susceptible
to itraconazole in vitro, although data are limited,78 and itraconazole solution can be effective in treating patients who are
non-responsive to fluconazole treatment.56 In a study of 25
AIDS patients with candidosis (oral or oesophageal) who were non-responsive to other azoles
(fluconazole and/or ketoconazole), itraconazole solution led to clinical cure in over 70% of cases;
the success rate was 50% in those who were non-responsive to itraconazole capsules.56 Among 36 HIV-positive patients who were non-responsive to
fluconazole for oropharyngeal candidosis, 65% responded to itraconazole solution.79 Itraconazole solution is recommended for the treatment of oral and
oesophageal candidosis in AIDS patients who are non-responsive to fluconazole, but a higher
dose (up to 400 mg daily) and a longer treatment period (2 weeks, repeated if necessary) than for
first-line therapy are recommended.80
To date there have been only a few reports of non-responsiveness to itraconazole among patients with C. albicans infections. The relatively low number could reflect the fact that itraconazole has been prescribed to a much lesser extent than fluconazole.62 A recent in-vitro study revealed that some isolates obtained from HIV patients with oral thrush show resistance to itraconazole in vitro, but that none of these resistant strains are susceptible to fluconazole.56 To avoid the emergence of strains that are cross-resistant to a range of antifungals, it may be prudent to reserve itraconazole for use as second-line therapy in patients who fail to respond to fluconazole.
There is evidence to suggest that voriconazole, a newly developed triazole agent, may be
useful in the management of C. albicans infections in patients who are non-responsive
to fluconazole.81 In an in-vitro study of 105 isolates from
the oral cavities of patients with HIV infection, voriconazole showed good activity against both
fluconazole-susceptible and -resistant isolates (MIC 25 mg/L), although the voriconazole
MIC was higher with the latter (0.39 versus 0.19 mg/L).81
Of six patients with C. albicans showing in-vitroresistance to fluconazole but
not to voriconazole (MIC
0.39 mg/L), all had a clinical response to voriconazole. Although
these data are promising, further studies are necessary to determine the clinical usefulness of
voriconazole relative to fluconazole and itraconazole.
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Safety |
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Fluconazole is generally well tolerated over a wide dose range. 7 ,82 ,83 ,84 Clinical experience is extensive, with over 16 million patient-days of treatment with fluconazole since its introduction in the UK, and 300 million patient-days world-wide. The incidence of side effects is low, and symptoms are generally mild and do not require discontinuation from therapy.7 The most common side effects are associated with the gastrointestinal tract (nausea, abdominal discomfort, vomiting, diarrhoea). Others include headache and rashes, but these are rarely encountered (incidence of <2%). Tolerability is high even in special patient groups including children and severely ill patients with AIDS or cancer.7,85
Although not licensed, high doses of fluconazole (up to 800 mg/day) are well tolerated in the treatment of immunocompromised patients with severe systemic mycoses.86,87 Doses of up to 1600 mg fluconazole have been shown to be well tolerated in studies of AIDS patients with histoplasmosis88 and cryptococcal meningitis.83,87
In rare cases, particularly in patients with serious underlying diseases such as AIDS and cancer, abnormalities of hepatic, renal, haematological and other biochemical function tests have been observed, but the clinical significance and relationship of these to treatment is uncertain.7 Very rarely, post-mortem examinations of patients who died with severe underlying disease and had received multiple-dose fluconazole therapy have revealed hepatic necrosis: an assessment of the riskbenefit ratio of continued fluconazole administration for patients in whom a significant rise in liver enzymes occurs is, therefore, recommended. 89 ,90
Itraconazole
Like fluconazole, the most frequently reported side effects associated with itraconazole are gastrointestinal (abdominal pain, nausea and vomiting, dyspepsia).9 Other side effects include dizziness, pruritus and headache. Owing to a risk of transient increases in hepatic enzymes, itraconazole capsules are not suitable for the routine treatment of infections in patients with raised liver enzymes, a history of liver disease, or who have experienced liver toxicity with other drugs. In instances when prolonged (>1 month) treatment is given, liver enzyme monitoring should be undertaken.
Only limited safety data are available for itraconazole solution. Comparative studies of itraconazole solution and fluconazole indicated similar types and incidences of side effects, but higher withdrawal frequencies with itraconazole solution (Table III).57 ,58 ,59 ,60 In HIV-positive patients with oral or oropharyngeal candidosis, treatment discontinuations as a result of adverse events occurred in only one of 60 patients treated with fluconazole, but in seven of 119 patients who received itraconazole oral solution.58 Similar types (nausea, vomiting, diarrhoea and rash) and frequencies of adverse events were also seen following itraconazole solution or fluconazole prophylaxis in 445 neutropenic patients, but 18% of patients who received itraconazole solution therapy were withdrawn prematurely, compared with only 4% on fluconazole.59
With the improved absorption of the oral solution formulation of itraconazole, it is possible that the maximum-tolerated dose may be lower than that of the capsule formulation, and it should be borne in mind that at high doses, ß-cyclodextrins can cause depletion of membrane components, thereby affecting the gastric mucosa with long-term exposure.91 In murine toxicity studies, HPCD has been found to induce liver enlargement.92
Experience with itraconazole solution at more than 400 mg/day is limited: no published study has established the maximum limit for the new formulation. A small clinical study demonstrated that 600 mg/day may be near the upper limit of itraconazole capsules: patients started to experience side effects such as adrenal insufficiency, hypertension and gynaecomastia at this level.93
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Other considerations |
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Fluconazole is available in oral capsule, pleasant-tasting solution and saline-based iv formulations; all are well tolerated. There is anecdotal evidence of patients refusing itraconazole solution, especially once any symptoms of oral thrush diminish and taste sensation is restored:66 this suggests an unpleasant taste.
Cost
An important advantage of fluconazole over itraconazole is its cost. A weekly supply of the UK-recommended daily dose of 200 mg itraconazole solution for the treatment of oral candidosis in AIDS patients costs £52.28. This compares with the UK-recommended od 50 mg fluconazole regimen, which costs £16.61 per week.
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Conclusions |
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Acknowledgments |
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Notes |
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References |
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Received 11 October 1998; returned 25 February 1999; revised 21 April 1999; accepted 27 July 1999