a University of Glasgow Dental School, Level 2, 378 Sauchiehall Street, Glasgow G2 3JZ; b Public Health Laboratory Service Mycology Reference Laboratory, Bristol, UK
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Abstract |
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Introduction |
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Itraconazole has been effective in the management of oral candidosis among immunocompromised patients. The new cyclodextrin solution of itraconazole has been used successfully in AIDS patients unresponsive to itraconazole capsules4 and has been shown to result in higher serum concentrations than capsules in such patients,5 but the kinetics have been less fully studied among the immunocompetent. Until now, no clinical trials of either formulation of itraconazole have been undertaken in the management of oral candidosis in immunocompetent hosts. The present study compared the liquid and capsule preparations of itraconazole in treatment of denture stomatitis and correlated clinical outcome with serum and salivary concentrations of the drug.
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Patients and methods |
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The 40 patients were randomized to receive either cyclodextrin solution of itraconazole (Sporanox Liquid, Janssen-Cilag Ltd, High Wycombe, UK) at a dose of 100 mg bd for 15 days or itraconazole capsules (Sporanox, Janssen-Cilag Ltd) at the same dosage, also for 15 days. There were no significant differences in the age or sex distribution between those receiving the two preparations. The clinician examining the patients was blinded to the treatment code. Patients were instructed to take itraconazole capsules after food and itraconazole solution 1 h before food. Patients receiving itraconazole solution were asked to remove their dentures and briefly swill the solution around their mouth before swallowing.
All patients were reviewed after 15 days, on completion of their course of antifungal medication and those who had failed to complete the course were excluded. Erythema of the palatal mucosa was assessed objectively by means of an electro-optical instrument called an erythema meter.7 The instrument is based on the principle that when white light is reflected off a cutaneous or mucosal surface, haemoglobin in the vasculature selectively absorbs green light but has little effect on red. An erythema meter index, defined as the ratio of red to green reflected light, can be determined. The difference between the erythema index measured before and after treatment is related to reduced vasodilation following a reduction in the degree of inflammation. An oral rinse and imprint cultures were collected and inoculated on to plates of Sabouraud's dextrose agar (Life Technologies, Paisley, UK) and CHROMagar Candida agar (Life Technologies). All plates were incubated at 37°C for 48 h. One colony of each morphological type on CHROMagar Candida was plated for purity, identified and stored at 70°C. The proportion of each morphological type was also recorded for each patient. Four further colonies from the Sabouraud plates were selected at random from the specimens available. Each isolate was formally identified and stored at 70°C for further investigation. Candida albicans was identified on the basis of germ-tube production. A sucrose assimilation test was performed on germ-tube-positive yeasts to distinguish C. albicans from Candida stellatoidea. Germ-tube-negative yeasts were identified by the API 32C test (bioMerieux SA, MarcylEtoile, France). A blood sample (10 mL) was collected into a plain bottle and at least 1 mL of whole saliva was collected into a sterile universal container to enable measurement of itraconazole concentrations in serum and saliva. The time intervals between last dose and specimen collection are given in the Table. Itraconazole concentrations were measured by reverse-phase high-performance liquid chromatography with a lower limit of detection of 0.01 mg/L and coefficients of variation of 2.27.8% over the concentration range 0.021.6 mg/L.8 The standard curve was linear from 0.01 to 10 mg/L.
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Statistical analysis
Data were analysed with the Minitab statistical program, Release 11 for Windows. Two-sample t-tests were used for both within-group and between-group comparisons. A 2 test was used to compare the frequency of zero and non-zero salivary itraconazole concentrations in each treatment group. P < 0.05 was considered significant.
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Results |
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The relationship between the serum itraconazole concentration and the mean reduction in erythema meter index for patients in both treatment groups on review following completion of treatment is shown in Figure 1. There was a significant (P = 0.033), moderately positive relationship (95% confidence interval 0.030.61) between the serum itraconazole concentration and the mean reduction in erythema meter index recorded following treatment for patients in both the treatment groups. The sample correlation coefficients were 0.370 for the cyclodextrin group and 0.302 for the itraconazole capsule group, revealing that, on completion of treatment, the reductions in palatal inflammation related to the serum itraconazole concentrations were very similar for both forms of itraconazole. However, given the low correlation coefficients between the serum itraconazole concentrations and mean reduction in erythema meter index, this result should be considered with some caution.
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Baseline C. albicans isolates tested had an MIC50 of 0.125 mg/L and an MIC90 of 0.25 mg/L. However, C. glabrata isolates had an MIC50 of 2 mg/L and an MIC90 of 4 mg/L.
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Discussion |
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The serum itraconazole concentrations in those patients who were mycologically cured on completion of treatment were compared with the concentrations found in those patients from whom yeasts could still be isolated. The patients were grouped according to their mycological response, irrespective of treatment group, as it was now apparent that both formulations of itraconazole had similar efficacy in the treatment of denture stomatitis. Considerable overlap was found between the serum itraconazole concentrations of the mycologically cured and non-cured patients. However, patients who were free of yeasts on completion of treatment did have slightly higher serum concentrations of itraconazole, although this proved not to be statistically significant (P = 0.28). Nevertheless, it is interesting to note that the majority of mycologically cured patients in this clinical trial had serum itraconazole concentrations of greater than 0.6 mg/L whereas most of the mycologically non-cured patients had serum itraconazole concentrations of 0.5 mg/L or less. In contrast to this, Cartledge et al.5 found higher serum drug concentrations and better clinical response rates with the cyclodextrin solution of itraconazole than with itraconazole capsules in AIDS patients. The bioavailability of itraconazole capsules in immunocompromised patient groups is variable and known to be lower than in non-immunocompromised individuals, largely resulting from low gastric acidity or chemotherapy-induced gastro-intestinal toxicity associated with patients in the former group.10 Cartledge et al.5 also suggested that a serum itraconazole concentration of less than 1.0 mg/L on day 7 was predictive of therapeutic failure. Therapeutic success was achieved with much lower serum itraconazole concentrations in the denture stomatitis patients. This may reflect the immunocompetent status of the patients enrolled in this study or the multifactorial aetiology of denture stomatitis.
C. albicans species isolated from trial participants at baseline all proved to be susceptible to itraconazole. The MICs (0.060.5 mg/L) related well to the serum itraconazole concentrations discussed above. However, MICs of itraconazole for C. glabrata isolates tended to be suscep-tible dependent on dose or resistant. There was no correlation between itraconazole sensitivity and clinical outcome.
Patients in the cyclodextrin group had significantly higher (P < 0.001) concentrations of itraconazole in their saliva compared with patients in the itraconazole capsule group, the majority of whom had no itraconazole detectable in their saliva at all. Only two patients in the capsule group had unusually high salivary itraconazole concentrations. These results were so aberrant that they may be attributed to laboratory or sampling error. The detection of itraconazole in the saliva of patients treated with the cyclodextrin formulation suggests an additional topical effect of cyclodextrin which would provide an obvious advantage of this preparation in the treatment of oropharyngeal candidosis. However, in this study, despite the significantly higher salivary itraconazole concentrations achieved with the cyclodextrin solution of itraconazole, the advantage of a topical effect was not apparent, as both formulations were equally effective in the management of denture stomatitis in terms of mycological response and reduction in erythema.
There was no relationship between the serum and saliva itraconazole concentrations of the group on the cyclodextrin preparation (P = 0.704). This implies that the presence of itraconazole in the saliva following administration of the cyclodextrin solution is due to persistence of the drug following direct contact with the buccal mucosa, to which itraconazole adheres and is subsequently released,10 rather than systemic absorption followed by secretion of itraconazole into saliva. This is confirmed by the fact that no active metabolite has been found in saliva.10
In conclusion, the absorption of itraconazole with the liquid preparation was no greater than with the capsules, but itraconazole was more likely to be found in the saliva on treatment with the liquid preparation. Itraconazole cyclodextrin solution and itraconazole capsules were equally effective in the treatment of denture stomatitis.
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Acknowledgments |
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Notes |
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References |
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2 . Budtz-Jörgensen, E. (1974). The significance of Candida albicans in denture stomatitis. Scandinavian Journal of Dental Research 82, 15190.[ISI][Medline]
3 . Budtz-Jörgensen, E. (1990). Candida-associated denture stomatitis and angular cheilitis. In Oral Candidosis, (Samaranayake, L. P. & MacFarlane, T. W., Ed.), pp. 15683. Wright, London.
4 . Cartledge, J. D., Midgeley, J., Youle, M. & Gazzard, B. G. (1994). Itraconazole cyclodextrin solution: effective treatment for HIV-related candidosis unresponsive to other azole therapy. Journal of Antimicrobial Chemotherapy 33, 10713.[ISI][Medline]
5 . Cartledge, J. D., Midgeley, J. & Gazzard, B. G. (1997). Itraconazole solution: higher serum drug concentrations and better clinical response rates than the capsule formulation in acquired immunodeficiency syndrome patients with candidosis. Journal of Clinical Pathology 50, 47780.[Abstract]
6 . British Medical Association and Royal Pharmaceutical Society of Great Britain. (1996). Section 5.2Antifungal Drugs. British National Formulary 32, 2626.
7 . Cross, L. J., Bagg, J. & Moseley, H. (1998). Evaluation of an optical instrument for objective assessment of oral mucosal erythema. Journal of Oral Rehabilitation 25, 496501.[ISI][Medline]
8 . Warnock, D. W., Turner, A. & Burke, J. (1988). Comparison of high performance liquid chromatographic and microbiological methods for determination of itraconazole. Journal of Antimicrobial Chemotherapy 21, 93100.[Abstract]
9 . Rex, J. H., Pfaller, M. A., Galgiani, J. N., Bartlett, M. S., Espinel-Ingroff, A., Ghannoum M. A. et al. (1997). Development of interpretive breakpoints for antifungal susceptibility testing: conceptual framework and analysis of in vitroin vivo correlation data for fluconazole, itraconazole and candida infections. Clinical Infectious Diseases 24, 23547.[ISI][Medline]
10 . Janssen-Cilag Ltd. (1996). Sporanox liquid. In Sporanox (Itraconazole) in Systemic Fungal Infection. Product Monograph, pp. 7586. Janssen-Cilag Ltd, Buckinghamshire, UK
Received 25 August 1998; returned 3 April 1999; revised 10 June 1999; accepted 19 September 1999