Authors:
Dr. C.K.W. Chow
Resident, University of Illinois at Chicago, Hospital for Sick Children, Graduate, Faculty of Dentistry, University of Toronto

Dr. D.W. Matear
Senior Advisor Health Policy and Regulation,
Health Authority Abu Dhabi

Correspondence:
Dr. C.K.W. Chow
Director of Clinics office
Faculty of Dentistry,
University of Toronto,
124 Edward Street,
Toronto, Ontario,
Canada M5G 1G6
Tel: (312) 421-6022
Fax: (416) 979-4936
email: Clara.chow@utoronto.ca

Dr. D.W. Matear
Senior Advisor
Health Policy and Regulation
Health Authority Abu Dhabi
PO Box 5674
Abu Dhabi
United Arab Emirates
Tel.: +971 2 419 3612
Fax.: +971 2 444 4728
Cell: +971 50 721 6443
E-mail: dmatear@gahs.ae

Introduction

Chronic atrophic candidiasis is a very common condition in complete denture wearers and it affects up to 72% of institutionalized denture wearers.^1,2,3 The etiology of this infection is multifactorial and includes tissue trauma from ill-fitting dentures, lack of denture cleanliness, dietary factors, xerostomia, continuous wear without removal and a compromised immune system.² The inflammation is causally associated with Candida albicans. The severity of infection can be classified as Newton Type I (localised erythematous), Type II (diffuse erythematous) and Type III (hyperplastic granular), with degree of inflammation greatest in Type III patients.⁴ It is a major problem especially in the geriatric institutionalized population, because many of these patients are immunocompromised and suffer from cognitive and physical problems. Consequently their compliance with conventional therapy is reduced. Conventional therapies to treat denture stomatitis include applying topical antifungal agent or using tissue conditioners to improve the fit of the denture.³ A common topical treatment employs Nystatin. Topical agents provide effective treatment, but are frequently associated with poor patient compliance in some geriatric patients due to difficulty in administration. Hence, incorporating antifungal agents into tissue conditioners has been studied as a possible method of drug delivery.⁵ The major advantage of this type of treatment is that it involves a single application of medication by the dentist thus does not depend on patient compliance.

Douglas and Walker⁶ investigated this method of drug delivery and demonstrated an inhibitory effect of Tempo and Coe-Comfort incorporating Nystatin. Thomas and Nutt⁷ showed that Viscogel combined with nystatin powder was successful in inhibiting Candida. Carter's in vitro study⁸ showed that a ketaconazole-Viscogel combination inhibited Candida growth. However, previous studies⁹ have not been consistent or explicit with respect to methodology and quantification of the drug dose and resulting antifungal activity and there were few clinical studies on this method of drug delivery. The antifungal agents used in these previous studies were mainly nystatin, ketaconazole and miconazole.¹⁰ The development of systemic triazole antifungal drugs, fluconazole and itraconazole, have provided potentially important additional agents for treatment of this type of infection.

In the preceding in vitro study⁵, it was found that itraconazole oral solution in Coe Soft temporary reline material resulted in the best fungicidal activity when compared to combinations of nystatin or fluconazole in either Visco-gel or FITT at the same wt/wt concentration. The best concentration was 5%wt/wt and the peak fungicidal activity was reached after 3 days. Subsequently, minimal fungicidal activity was found at 9 days suggesting that the combination should be changed before this time for maximum effectiveness. The design of the current clinical study was based on these previous findings. The objectives were to diagnose patients with oral candidiasis, to treat them by mixing itraconazole into tissue conditioner, and to measure the clinical and microbiological effectiveness of this treatment.

Methods

The present investigation involved identifying complete denture wearers with oral palatal candidiasis. These patients were identified by severity using the Newton Classification. Infections were confirmed by microbiological swabs and rinse techniques. After explaining the procedure and obtaining consent, the patient's medical history was reviewed to identify any possible contraindications to itraconazole.

A baseline survey consisting of questions about pre-treatment soreness, dryness, discomfort and the stability and retention of the dentures was completed and the area of erythema was illustrated in a diagram. Baseline swabs (along the left, middle and right surfaces of the palate), rinses and intra-oral photographs were taken. The clinical severity of erythema was assessed based on a rating system listed in Table 1. The patients were assigned to treatment and control group based on their age and gender. In the control group, 2 patients received Coe Soft tissue conditioner treatment only, and 3 patients did not receive any treatment at all. In the treatment group, antifungal-tissue conditioner mixtures were placed as temporary relines for patients with complete upper denture. Five patients received 1%wt/wt itraconazole oral solution in Coe Soft (ratio of antifungal agent in soft lining is described in Table 2). Two other patients had their denture relined with 3%wt/wt itraconazole powder and another two patients received 5%wt/wt itraconazole powder in Coe Soft. Each denture was trimmed and fitted. Patients were given oral hygiene instructions and to keep the denture in a moist area and not to soak the denture in commercial denture cleaners as to avoid leakage or interaction with the medication. The patients were asked to return on days 3, 6, and 9 for reassessment of the condition by swabs, rinses, clinical observation and intra-oral photographs.

Source: Johnson, Taylor, and Heid 1989

Results

Patient Demographics

Repeated measures ANOVA was performed to find adjusted mean percentage reduction of colonies over time. ANCOVA test was done to find the mean percentage reduction adjusted for baseline levels of fungi. Statistical tests were performed but due to the limited number of patients in this pilot study, the significance of the statistical tests done were restricted by the power of the tests and could not be truly indicative of the difference between groups.

Clinical Observations

There was a decrease in clinical scores for all treatment group cases (Fig. 1,2). For the oral solution treatment group, the clinical severity of erythema for all patients declined up to day 6. There was regression of erythema on day 9 in some patients. For the powder treatment group, all patients had decreased severity of erythema. This reduction was maintained up to day 9 for the patients on 5%wt/wt itraconazole powder combination. The control groups' severity in erythema either remained unchanged or progressed to a higher level (Fig. 3).

Figure 1 Treatment Group-1%wt/wt Oral Solution Clinical Score Results

There was a decrease in clinical severity after day 3 and 6. For patients D and E, their clinical score returned to higher levels at day 9.

Figure 2 Treatment Group-Powder Clinical Score

There was a decline in clinical score in all cases treated with itraconazole powder.

Figure 3 Control Group Clinical Score

Patients indicated with red bars are control group patients that received temporary relines only (patients F and G). Patients with green bars are control patients that did not receive any treatment. (patients H, I and J).

Microbiological Findings

Peak fungicidal activity was reached after 3 days. The mean reduction in colonies/cm² for the oral solution was 84% for swabs and 67% for rinses for the treatment group on day 3 as compared to baseline figures (Table 4,5). The average reduction on day 3 for the powder form was 46% for swabs and 60% for rinses (Table 4,5). For both drug forms, there was regrowth of cultures after 6 days in some patients, which suggests that mixtures should be replaced after peak activity is reached at 3 days for maximum effectiveness (Fig. 4,5). The powder form had less regrowth of cultures after 6 days as compared to the oral solution group. After 6 days, the fungicidal activity of the powder seemed to be unpredictable. Moreover, on the average there was still a 5-20% reduction in Day 9 rinse results for the treatment groups. There was a definite treatment effect when the fungicidal activities of the treatment and control groups were compared. The results of the control group are illustrated in Fig. 6.

Table 4  Average Reduction in Colonies/CM2 for Swab vs. Baseline

Table 5  Average Reduction in Colonies/CM2 for Rinse vs. Baseline

Figure 4 Treatment Group Oral Solution Swab and Rinse Results

There was a decline in colonies and this decline peaked at day 3. Colony counts either remained the same or returned to higher levels thereafter.

Figure 5 Treatment Group-Powder, Swab and Rinse Results

Patients K and L received 3%wt/wt itraconazole; whilst patients M and N received 5%wt/wt itraconazole mixed into Coe Soft tissue conditioner. There was a reduction in colonies in both powder and rinse results.

Figure 6 Control Group Swab and Rinse Results

The colonies result of the control group either remained the same or increased during the course of study. Patients F and G received reline with Coe Soft only; whilst patients H, I and J did not receive any tissue conditioning relines.

The 1% oral solution had superior fungicidal activity than itraconazole 3% powder and 5% powder and the control reline groups at 3 days. The forementioned groups are all significantly different than the control group as listed in Table 3. Similarly, there was significant reduction in colonies after 3 days for rinses compared to baseline figures (p<0.05). 1% wt/wt oral solution and 3% wt/wt and 5% wt/wt powder had comparable fungicidal effects (Table 4,5).

Patient Satisfaction and Complaints

80% of patients (n=4) on the oral solution experienced bitterness. Patients treated with the powder form did not notice any bitterness. No adverse reaction or nausea was found. Most patients found that the denture was a better fit and some felt that they were getting more saliva.

Recall Analysis

All patients were re-evaluated at 4 months post-treatment to document the condition of their oral candidiasis. It was found that patients with initial presentation of Type I candidiasis did not have reactivation of infection regardless of the type of treatment received. On the other hand, patients with Type II or Type III infection had reactivation of disease (Table 8). Moreover, all patients in the treatment group did not feel any discomfort, nausea, vomiting or adverse reaction due to itraconazole at any time during this study up to the end of the re-evaluation period. All control group patients had the same or more severe presentation of infection at time of re-evaluation versus baseline (Table 8).

Table 8 Re-Evaluation at 4 Months Post-Treatment

Numbers indicate the number of patients along with the status of their candidiasis condition as compared to the end of their treatment period 4 months prior.

Discussion

Treatment Versus Control
Two patients received relines only and two other patients received no treatment so to investigate whether clinical improvement was due to tissue conditioner or antifungal agents or a combination of both. Some patients in the control reline group also had reduction in candidal growth in swab sample only (Table 4). This suggests that tissue conditioning by itself also helped in the treatment of oral candidiasis. The control group without reline exhibited a growth in candidal colonies, whereas all treatment groups (relined with antifungal mixture) had average reduction in colonies ranging from 6-84% for swabs and 5-67% for rinses (Tables 4,5). In terms of clinical presentation, treatment groups had decreased severity score compared to control groups, which had scores that either increased or remained the same. These results suggest that treatment with either 1% wt/wt oral solution or itraconazole powder (3 or 5%wt/wt) improve the clinical outcome of candidal infection.

Drug Concentration and Form

In May 2001, Janssen-ortho, the manufacturer of itraconazole revised its safety information from continued research, monitoring and re-evaluation. Erythromycin has been added to the list of drug interactions since it causes increase of itraconzole levels in the blood. Caution should be used when co-administering itraconazole with calcium channel blockers. Finally, practiotioners should weigh risk and benefit of using itraconazole in patients with risk factors for congestive heart failure. Physicians were advised not to use itraconazole to treat fungal nail or skin infections for patients who had a history of heart failure.¹² Itraconazole is metabolized by the liver and its mechanism of action is by inhibiting cytochrome p450-dependent ergosterol synthesis. Recommended dosage of these antifungal agents as suggested by the Martindale Pharmacopoeia and the Compendium of Pharmaceuticals and Specialities is 200mg/day for a minimum of 3 weeks^13,14 The equivalence of 200mg in itraconazole in this study is 2%wt/wt per day. In this study 1, 3 and 5%wt/wt concentrations were used. However the dosage is applied only once initially with the reline of the denture, hence the dosages were well below recommended dosage suggested by the pharmacopoeias. Since itraconazole was used with minimal dosage topically in a short duration, liver function tests were not performed.

There was similar reduction in clinical scores for different treatment groups (ie. itraconazole 1%wt/wt oral solution, 3% wt/wt powder and 5%wt/wt powder). In most cases, there was a 1 to 2 grades decline in the clinical score severity from pre-treatment to post-treatment. From the 3 day swab and rinse results, 1%wt/wt oral solution had the highest reduction in colonies (84% swab; 67% rinse) followed by 3%wt/wt powder (53% swab; 53% rinse) and 5%wt/wt powder (39% swab and 66% rinse).

After 3 days of treatment, the best combination seems to be itraconazole oral solution and Coe Soft tissue conditioner in 1%wt/wt concentration. However, due to the objectionable taste of the oral solution to some subjects, it might be more desirable to use itraconazole powder forms. The powder form provided comparable fungicidal activity and this activity was more prolonged than the oral solution. Furthermore, it has no taste, which may improve patient acceptability.

All patients in the study did not report of any nausea or other side effects. The pharmacokinetics of itraconazole oral solution is different from its powder form. The peak of the oral solution is at 3 days whereas the fungicidal activity of the powder is more prolonged (Figure 4, 5). This result is quite close to the t1/2 of itraconazole (39.7 ± 13 hours).^13,14 Clinical reduction was evident in all patients in the treatment groups, which provided a gross measure of improvement and treatment effectiveness.

Microbiological Changes

Microbiological changes in this study was recorded by swab and rinse techniques which were deemed acceptable in quantifying the morbidity of the candidal infection.¹⁵
As evident in the results, the combination of tissue conditioner and antifungal agents provides additional reduction in candidal activity. The decrease of candida colonies ranged from 17.1 to 96.9% in the treatment group after 3 days whereas there was growth of 33.7 to 117.7% in colonies in the control without reline group in the same period. The results were similar in the rinse group (Table 5). There was dramatic fungicidal activity in the treatment group with reduction of 39-84% after 3 days of swab results. Hence, the treatment groups were significantly different from control group without relines. The microbiologic results indicate there was a peak to this fungicidal effect at 3 days. For both drug forms, there was either a plateau after this peak or there was slight regrowth of candidal colonies. Itraconazole oral solution was significantly better than the powder at 3 days in swab samples but had comparable reduction in colonies as compared with the powder in rinse results. This finding could be due to the fact that oral solution is a drug form that diffuses better than the powder form. However, the powder seemed to have a more prolonged effect after the peak as compared with the oral solution (Fig. 5).

Patient Satisfaction

Most patients were satisfied with the treatment and there was clinical reduction in symptoms and complaints by the patients on both oral solution and powder treatment groups as shown in Table 6. However, 80% of oral solution subjects complained of bitterness with the medication. These patients reported bitterness mostly on chewing but found that the bitter taste was generally tolerable. Most patients noticed the taste within one day of wear and it usually lasted up to 3 days and the bitterness decreased thereafter. Hence, the possibility of improving the flavour of the oral solution should be investigated for future studies.

Workability of Materials

It is difficult to recommend patients to receive relines every 3 days, as chair side preparation is time consuming. Itraconazole oral solution mixed with Coe Soft was easier to measure than the powder since it can be measured with a graduated cylinder instead of weighing out the amount of powder. In addition, it was more difficult to ensure that the powder was incorporated evenly. We were unable to incorporate higher concentrations of oral solution clinically due to how the antifungal agent was supplied. Oral solution was also sticky due to its sodium saccharin component. The major advantage of mixing antifungal agent in tissue conditioner for drug delivery is that patient compliance ceases to become an issue. In this study, complete upper dentures were relined. Further study should be performed in relining metal and acrylic RPDs.

Cost Versus Benefit

The cost of this type of treatment is cheaper than conventional therapy due to the fact that there is only a one time application with minimal amounts of antifungal agent. The cost of this therapy is listed on Table 7. Moreover, it is more time consuming for the dentist due to the need for chair time. Mixing antifungal agents with tissue conditioners is an alternative technique of drug delivery and gives an option to the practitioner when he or she is dealing with a patient with manual dexterity and cognitive problems.

Observations at Re-evaluation

Reactivation of disease that was improved by previous treatment with itraconzole solution or powder in Coe Soft in Type II and Type III patients at re-evaluation suggests that patients with more severe infections should be monitored and given additional treatment as necessary (Table 8). It also suggests that a single application of itraconazole with tissue conditioner is efficacious in acute incidences of candidal infection but should be followed by subsequent applications in chronic conditions. At re-evaluation, all control patients had the same or more severe infection, which signifies that intervention is needed to decrease the severity of Candidiasis. The fact that there was no report of discomfort or adverse reactions as of the re-evaluation date indicates that there was no long-term sequalae to this type of drug therapy.

This study was compromised by the statistical limitations due to difficulty in getting patients for this trial. Further study should include an increase in number of subjects and tests of other combinations.

Conclusion

Treating Candidiasis by mixing itraconazole into tissue conditioner was shown to be clinically effective in the population treated. In this clinical pilot study, the antifungal activity over time of itraconazole oral solution was similar to that tested in the previous in vitro study. The peak was achieved at 3 days and there was a decline in fungicidal activity thereafter. We were unable to incorporate oral solution in the tissue conditioner that was at any percentages higher than 1%wt/wt clinically. The itraconazole powder at 3%wt/wt and 5%wt/wt had similar fungicidal activity as the oral solution but had a more prolonged effectiveness and there was no complains of bitterness. There were no reports of any adverse reactions from the antifungal agents at the concentration used. This was a preliminary study with a limited amount of patients involved hence a larger based study is necessary to contrast this method of drug delivery with conventional therapy with topical agents. Moreover, the results of this pilot study give evidence that mixing antifungal agents into tissue conditioners is a clinically effective method of drug delivery. Based on these results, a possible protocol for candidiasis patients with poor manual dexterity and cognitive impairment may be to give 1%wt/wt oral solution mixed into tissue conditioner to reline dentures of patients with oral candidiasis and to replace it after 3 days for sustained clinical effectiveness. The rationale for this recommendation is that 1%wt/wt oral solution provided the best microbiological outcome of the treatment groups tested and was easy to mix. However, in patients where the bitterness of the oral solution is objectionable, one should consider the use of 3%wt/wt powder since it provided comparable antifungal activity as the 1%wt/wt oral solution. In addition, it had a more prolonged antifungal effect. However, further study of varying concentrations of this antifungal agent is needed to derive a clinical protocol for patients with poor compliance.

Acknowledgement:

We would like to acknowledge the help of all those individuals involved with this project, especially the invaluable assistance of Dr. Herenia Lawrence for statistical analysis, Helen Grad Pharmacy Dept., Faculty of Dentistry, Toronto for supplies and pharmacological advice; laboratory and dental clinic staff at Baycrest Centre for Geriatric Care, Toronto for supplies and patient recruitment; Dr. Edward Fillery, Microbiology Dept., Faculty of Dentistry, Toronto for microbiological advice. This research was supported by Dentistry Canada Fund and MRC grant.

References