Nystatin and amphotericin B in the treatment of denture-related candidiasis

Nystatin and amphotericin B in the treatment of denture-related candidiasis R. I. Nairn,

M.&x, P.D.X.R.C.S.,

DEPARTMENT LONDON,

OF SCHOOL

PROSTHETIC OF

DENTAL

London, England

DENTISTRY,

ROYAL

DEKTAL

HOSPITAL

OF

SURGERY

A double-blind trial of nystatin, amphotericin B, and a placebo was carried out in fifty-two cases of denture-related candidiasis and/or angular cheilitis. The drugs effected a significant clinical cure, but recurrence of the signs was common after withdrawal of the drugs. Concurrent bacteriologic examination showed few cures and the continued presence of Cnndidn albicans during the trial. A specimen from a red palate was examined histologically.

D

enture-related candidiasis is probably a better name for that condition variously known as denture-sore mouth, denture stomatitis,l chronic atrophic candidiasis,’ or oral candidiasis. Its clinical features are familiar, consisting of a diffuse or patchy redness of the palate under a denture and confined to the area covered by the denture. This seldom gives rise to symptoms or discomfort, and the condition is never seen to affect the lower jaw. It is often associated with the angular cheilitis, which is uncomfortable. There have been a number of studies concerned with the etiology and treatment of the disorder. Most of these have emphasized the importance of the fungus Candida albicuns in its causation and have investigated the use of antifungal drugs in treatment.‘, 3-5 Some claim trauma to be a significant factor,6’ 7 and there has recently been some speculation about the etiologic role played by stagnation and denture-borne plaque.1, 7, fi Van ReenenO suggests that gram-positive cocci may play a significant role. The present study aimed to determine the effect of the administration of antifungal drugs on the clinical signs in controlled conditions and, in so doing, to clarify the role of Candida albicans. At the same time, a comparison was made between the two drugs used-nystatin and amphotericin B. The work had the following features: 1. The cases used in the trial were all considered to present the characteristic appearance described. 2. It was a central assumption that the appearance was due primarily to the activity of Candida albicans. 68

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3. It seemed reasonable to suppose that, though an attempt might be made by bacteriologic investigation and smear examination to confirm the presence of Caqtdida akbicum, it would be good evidcncc of its causative role to demonstrate a favorable responseto the administration of a specific anticandidal dru g, compared with a placebo, in circumstances where every care was taken to introduce only minimal alteration to the existing pattern of denture wear. 4. The opportunity was taken to use two drugs, nystatin and amphotericin B, which have been shown to be equally effective against Can&da albicaw. It, has been suggested that amphotericin B is more acceptable to patients because of its more pleasant taste.l” 5. The changes in mucosal appearance were recorded photographically with a standard technique. 6. The nature of the red color has not been satisfactorily explained, and this seemedto warrant consideration. METHOD Sample

Six hundred consecutive patients attending the prosthetic clinic for examination or treatment were screened for the appearance of either angular cheilitis or a diffuse or patchy redness of the palate under the upper denture. Fifty-two such cases were found. Twenty-two patients had a red palate, nine had angular cheilitis only, and twenty-one had both conditions. Recording

On a prepared record sheet a notation was made of any symptoms, the history of denture wearing, whether the dentures were worn at night, and how they were cleaned. Relevant illnesses and current medication were recorded. The palatal surface and the occlusion of the dentures were examined. The mouth was examined, and a notation was made of the nature and distribution of the signs, soft-tissue consistency, form of the corners of t,he mouth, and any other oral signs. Each affected mouth was photographed. These and all subsequent photographs were made on Kodachrome II daylight film with a Minicam ring flash, a 105 mm. lens, a 2 cm. extension tube, an aperture of fll, and closest focus. The palate was photographed with a surface silvered mirror. Bacteriology

A smear was made in each case by firmly scraping one side of the palate. A swab was taken from the other side, ancl a saliva sample was collected. The smears were Gram stained. In their examination the presence of hyphal forms of Candida albicaw was regarded as necessary evidence of pathogenicitg.’ Swab and saliva were cultured on Sabouraud’s medium. If no yeast was grown, they were reported negative. Any yeasts isolated were subcultured on cornmeal agar, and the presence of chlamydospores was required in order to identify Ca,ndidccalbicans. If no chlamydospores were present, a report of “negative” was entered.

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Oral Rurg. .Tuly, 1975

I. Results of clinic improvement when nystatin, amphotericin B, ant1 placebo were given for 1 month and after a further month without, the tlrug Table

Ihi{J

Nystatin Amphotericin Placebo

Table

I

No.

B

of cnscs

(hrrrl

nt 1 mo. 10

1x 15

16

) Recur3xnce

nt d mos. .1;'

6

2

II. The relevant comparisons subjcctctl to the chi-square test Comwnrison

Cure

Nystatin vs. placebo Amphotericin B vs. placebo Nystatin vs. amphotericin H

Table

(

13

Ill.

Bacteriologic

~2 = 3.88 (Sig. 5%) x2 = 8.80 (Sig. 1%) x” = 0.80 (N.R.)

x2 = 0.42 (N.S.) x2 = 2.26 (N.S.) x2 = 0.91 (N.S.)

culture of saliva samples and swabs in parallel with

Table I No. of cases Ihg Nystntin Amphotericin Placebo

Drug

(+ VE R

mltures) 10 16 10

(‘urefl (- BE

nt

1 mo. cultures)

4 1 2

Eecurrence (+ VE

at d mos. cultures) 2 1 2

therapy

Each patient was given a bottle of tablets. These contained either nystatin, 500,000 units, amphotericin B (Fungilin lozenges, 10 mg.), or a heat-denatured fungilin lozenge. The sequence of bottles had been randomly arranged. The patients were instructed to suck four tablets a day (at approximately 4-hour intervals) with the dentures out. Sufficient tablets were provided for 1 month. The patients were told not to make any other alteration in their denture-wearing habits. Sequence

of examination

The patients were seen at 2 weeks, and 1 month, and then at 2 months, that is, 1 month after ceasing to use the tablets. At each visit the mouth was photographed, and a smear, a swab, and a saliva sample were taken. Assessment

At the completion of the trial, the photographs were collected and set up in sequencefor each patient. They were scored for severity of signs (0, +, +t, +++) at each examination by comparison within the whole set. Rarely there was an alteration in skin color (processing variation perhaps) and an adjustment was necessary in the decision about the condition of the mouth. A results sheet was filled in without reference to the original clinical record. Subsequently the bacteriologic results were entered.

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Fig. 1. A patient with palatal inflammation before drug administration (B), and after a further month without the drug (C).

wndidiasis

71

(A), after 1 month

RESULTSAND DISCUSSION Drug therapy

The results of administering nystatin, amphotericin B, or a placebo will be considered in relation to the signs as judged in the photographic series and also in relation to the bacteriologic findings. The results are given for 1 month’s drug administration. Although a substantial improvement occurred in 2 weeks, further improvement was evident in the additional 2 weeks. Clinical signs. The results for all cases together appear in Table I, and in Table II are set out the figures when the relevant comparisons are subjected to the chi-square text. It is apparent that both nystatin and amphotericin B are equally effective in producing a clinical cure after 1 month’s administration. The placebo is not effective, so that the cure is due not to taking out the dentures and sucking on the tablets but to the pharmacologic effect. Recurrence is common after a month without the drug, and it is not influenced by which drug has been previously administered. (See Figs. 1 and 2 for two representative sequences in treatment). Further breakdown of the results revealed no important differences in response between males and females or between red palate and angular cheilitis. There was a slight indication that red palate might be more difficult to get rid of with drug therapy alone, but the numbers in such subgroups were too small for statistical analysis to be valid. It was an incidental finding that deep folds of

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Nairn

Fig. 2. A patient month (B), and after

with angular cheilitis before administration a further month without the drug (C).

of

the

drug

(A),

Surg. 1975

after

1

the corners of the mouth do not reduce the efficiency of either drug in leading to rapid healing of angular cheilitis. Of the fourteen patients with angular cheilitis and deep folds who were given an active drug, thirteen were cured in 1 month. Bacterioloyic fi&inga. These are set out in Table II and represent the results of culture of swabs and saliva specimens. Microscopic examination of smears was nearly always negative and had to be discarded as a criteria of infection. A positive culture from either the swab or the saliva was entered as a positive result. The results demonstrate quite clearly that a clinical cure was not accompanied by a bacteriologic cure. It seems reasonable to assume that nystatin and amphotericin B suppress the population of (‘rr?~Jid(~ nlbictr?ls (and perhaps the pathogenicity) sufficiently to lead to the remission of signs. The fungi are still present, however, perhaps on the denture, and, on removal of the drug, reassert themselves. These results support the belief that, Calzdida nlbicans is the principle direct cause of red palate am1 angular cheilitis in denture wearers, because the administration of an antifungal drug in the absence of any other measures produced a high and significant rate of clinical curt. It must be said further that such drug administration alone is insufficient in the treatment of the condition. AS other workers have suggested, the tlentures should be left out at night, thoroughly cleaned, and kept in a disinfecting solution overnight. This will help to reduce the likelihood of recurrence. Taste

It is usually said that patients intensely dislike the taste of nystatin, and amphotericin B has often been prescribed for the treatment of oral candidiasis because of its more acceptable taste. In this trial the patients were asked to

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Fig. J. A, Longitudinal section of palatal specimen. The denture border and line of demarcation of red and normal palate is marked by arrow. The affected area is to be left. (Periodic acid-Schiff stain. Magnification, x12.5.)

Fig. 3, of area N.

cont’d.

H, Higher

magnification

(xl 15) of area A. C, Highrr

magnification

(x115)

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Oral July,

Surg. 1975

describe the taste of the tablets they had been given. Of those given nystatin, eight thought it unpleasant and five considered it pleasant, five considered amphotericin B unpleasant and thirteen described it as pleasant, and the placebo was considered unpleasant by one patient and pleasant by eleven. Although this n-ould suggest that nystatin is by no means universally found repellent, amphotericin B is to be preferred. It is equally effective. The side effects reported in its use refer to parenteral administration in vast dosage in t,he t,rcatment of systemic candidiasis. Palatal

appearance

In a patient showing a clear line of demarcation between the red palate under the denture and unaffected tissue beyond the posterior border of the denture, a specimen was removed from the sagittal plane to include tissue on both sides of the line. Photomicrographs of a histologic section of the specimen are shown in Fig. 3. The affected area shows considerable thinning of the epithelium within intense cellular infiltration of the subepithelial tissue. There is noticeable engorge of the blood vessels of the corium. It is likely that the inflammatory response beneath the thin epithelium produces the characteristic red appearance SO different from oral inflammation due to other causes. CONCLUSION

The local administration of nystatin and amphotericin B to patients with the red palate of denture-related candidiasis or with angular eheilitis will, in most cases, lead to remission of the signs. In this trial the drugs were given without any change in the dentures or the habits of denture wearing. Tested against a placebo, the drugs were significantly effective. This must be accepted as evidence that Caltdida albicans is a principal direct cause of the conditions. The culture of specimens of saliva and swabs from the affected areas showed the continued presence of Calzdida a1bica.m in spite of the clinical improvement. This suggests that the lesions are the result of excessive candida activity and that a reduction in the Candida population and pathogenicity is sufficient to produce healing. This is not surprising, considering that Candida are a normal part of the oral flora. The dentures may play an important part as a site for the growth of Candida, and reinfection from this source may explain the high incidence of recurrence when the drug was discontinued. Treatment, therefore, must be directed not only at the use of an antifungal agent but also at keeping the mouth and dentures clean. The red palate, diffuse or patchy, which is the sign of denture-associated oral candidiasis, is quite unlike the signs of traumatic damage of the oral tissues from rough or ill-fitting dentures. The curious fiery red quality is probably a result of the considerable thinning (and, therefore, transparency) of the palatal epithelium with a subepithelial inflammation notable for its chronic nature and vascular engorgement. SUMMARY

A double-blind trial of nystatin, amphotericin B, and a placebo was carried out in fifty-two cases of denture-related candidiasis and/or angular cheilitis. The

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drugs effected a significant clinical cure, but recurrence of the signs was common after withdrawal of the drugs. Concurrent bacteriologic examination showctl few cures and the continued presence of Cnwdidct crlbicmas during the trial. A spccimen from a red palate was examined histologically. I would like to thank the staff of the Department of Pathology of the Royal Dental Hospital for their work in the bacteriologic examination and in the preparation of the histologic material and photomicrographs. E. R. Squibb & Company supplied the drugs and arranged their random distribution. REFERENCES

1. C&won, R. A.: Denture Sore Mouth and Angular Cheilitis, Rr. Dent. J. 115: 441.449, 1963. 2. Lehner, T.: In Symposium on Denture Sore Mouth, Dent. Practit. 16: 142-146, 1965. :i. Lyon, D. G., and Chick, A. 0.: Denture Sore Mouth and Angular Cheilitis: A Preliminary Investigation Into Their Possible Association With Candida Infection, Dent. Practit. 7: 212-217. 1957. on Denture Sore Mouth, Dent. Practit. 16: 135138, 1965. 4. Neil], h. J.: In Symposium 5. Phillips, H. I.: Treatment of Denture Stomatitis With Polynoxylin, Br. Dent. J. 128: 1970. 6. Nyquist, 78-80, G.: Study of Denture Sore Mouth, Acta Odontal. Scan& 10: Supp. 9, pp. 11-154, 1952. 7. Budzt-Jorgenson, E., and Bertram, V.: Denture Stomatitis. I. The Etiology in Relation to Trauma and Infection, Acta Odontal. Stand. 28: 71, 1970. 8. Davenport, .J. C.: The Oral Distribution of Cantlitla in Denture Stomatitis, Br. Dent. .J. 129: 151, 1970. 9. Van Reenen, J. F.: Microbiologic Studies on Denture Stomatitis, J. Prosthet. Dent. 30: 493.505, 1973. 10. Kutscher, A. H., and others: Amphotericin B in the Treatment of Oral Monilinl Infections, ORAL SURG. 17: 31-35, 1964. 11. Cawson, R. A.: Yeasts and Mycelial Phases of Candida in Oral Infection, J. Dent. Res. 43: 951-952 (Supp.) 1964. Reprint requests to : Dr. R. I. Nairn Department of Prosthetic Dentistry Royal Dental Hospital of London School of Dental Surgery Leicester Square London, WC2, England