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Amphotericin B in the treatment of oral monilial infections
AMPHOTERICIN MONILIAL
TREATMENT
OF ORAL
INFECTIONS
Austin H. Kutscher, Robert E. Herlands, New York, N. Y. Divisions
of
Coluwlbia
University
A
B IN THE
Stowdology
D.D.S., Edward V. Zegarelli, D.D.N., ll.S., D.D.S., und Herbert F. Silvers, D.D.S.,
und
Ecstomtiue
Dentistry,
Sicl~ool
of
Dcnttcl
chtlaOral
Swgcry,
the various oral lesions with which Candida albicans has been implicated, either as a primary infectious agent or as a secondary invader, are denture stomatitis, angular stomatitis, and frank moniliasis which occurs more often in very young persons or in debilitated older patients. An increase in the frequency of oral monilial infections has been evident since the advent of the antibiotics. Fortunately, because of the availability of new, simpler, and more efficient laboratory procedures (for example, the Pagano-Levin medium), the general practitioner is in a better position today to establish the presence of C. albicans organisms in pathogenic numbers, so that the diagnosis of oral moni.liasis is more easily established. Reports describing the efficacy of various antifungal agents, such as Mycostatin, in treating monilial lesions have been published.l, 2 More recently, a new antifungal antibiotic, amphotericin B, which has a therapeutic spectrum much the same as that of Mycostatin, has been introduced.2, 3 Amphotericin B is produced by a hitherto unidentified species of streptomyces. Its chemical structure is as yet not known. The pure antibiotic is highly stable and has been tested successfully for antifungal action against a large number of pathogenic and nonpathogenic fungi. No resistant strains of Candida albicans have thus far been encountered. Amphotcricin B, as a topical agent for oral use, posssesses a distinct advantage (from the patient’s point of view-) in that it has an innocuous taste when compared to the disagreeable taste of Mycostatin. This report will detail the results obtained when amphotericin B was used in the treatment of patients with oral lesions in which C’. nlbicnns played a role either as a primary etiological agent or as a secondary invader. The
MONG
Formulations of amphotericin Squibb Institute for Medical
B in Or-abase, Orahesive, Research, New Brunswick, 31
and Plastibase N. J.
were
supplied
by
This aerics includctl I wrtity-one patients with tlc~llnre stomatitis, four with anglilar stomatiiis. fi\-cL with oi~rl moniliilsis ot’ unl~nown etiology or association, and tlirc~ with antil)iotk indiic*c~tl stonintitis. Amphotericin I( was ~~dministc~rc~d in it L’ per ~111 c*oncentration, either in an adhesive pastch t O~~al~usc~, containing gelatin, pectin, and c~arbosymethylcellulose in a mineral oil- ~~~l~c~thyl~~c hse) 01’ in 311 adhesive powder formulation (Orahcsiv(l, containin y only q>latin, lx&iii, ant1 ~arbox?-mcthylcellulosc J. Thcsc medications wer(~ al~plic~cl II>- 1tic patient to the affected areas after meals and also before rc%iring----81 I~71st foul. tiinc3 dail>-. A4pprosimately 250 mg. of the medication was al)plktl as ;I thin filnl of pastch or sl)rayecl onto the affected arCas with a So. 1 l!) Ik~\7ill)iss atomizer. In the treatment of dentllrc stomatitis, either the l);istcj or the ~~~~lcr was npplkd to the tlcntnre in the manner cust~omarily usctl for tllcl application of dcnturc adhesive powders and p&es. Thus, :lpl,roxirnatc,l?. 1,000 my. 01 medication, including approximately 20 lllg. of the active i+g~lil illnpllot C‘riCitl 13,was applied to a given lesion during the course of ii siiigL.1~~ da!-. I+‘or tlic: IlY’ilt tll~‘llt3 of angular stoma.titis, 2 per cent amphotericin K in an oint,mcnt basc~OCmineral oil and polyethylene (l’lastihlst~) Wns pwsci~ilwtl ;Itld six il~l~)li(‘ilt ions lN’1’(la>- IV(‘t’(’ I’c’(~Ilt’stc’cI. .\t ttlcc Olltsc~t of tllcsC stntlics Sc~\~c~l’;ll I)illiPtlls \v(‘t’(’ 1I’c~:ltOtlwith 1 I)(‘r’ P?llt I’otxiulutioli 0T amphotcricin 13. Sllril!
il
CONTROL
PROCEDL~RES
For additional control purposes, a suitable placebo formulation was used prior to amphotericin R therapy in five patients with dcnturc stomatitis and in bwo pat&k with oral moniliasis of undrtcrmined origin. A placebo preparat,ion containing only Plastibase was used in two patients with angular stomatitis. KESUI,TS
Response to Placebo l’hempy.-As reported previous1.v in studies of patients with various scutc and chronic lesions of the oral mucous membranes,’ the intraoral application of placebo-protectant preparations per se (Orabase or Orahcsive without amphoteriain K) has been fount1 to afford some relief of existent symptoms. In these casts, t,hcbperiod of relief’ has paralleled the timrl during which the vehicle remained in position, but as the vehicle dissolved ot disappeared the symptomatolopy rctnrned. Thus, the temporary subjective improvement was undoubtedly due to the protectant properties of the placebo preparations. Furthermore, usually no considerable alteration in the objective
Volume Number
17 I
AMPHOTERICIN
B FOR
ORAL
MOSILIAL
INFECTIONS
33
clinical picture of the lesion was noted. Parallel effects have been noted following the use of placebo-protectant formulations in nine additional patients who had lesions similar to those discussed in this report but who were not treated subsequently with amphotericin B. Of course, most patients with denture stomatitis are not bothered by any disturbing symptoms associated with their lesions. Admittedly, a few cases of denture stomatitis did improve objectively on vehicle “therapy” alone, but this was thought to be due to the increased stability of the dent.ure resulting from the use of the adhesive material. Response to Amphotericin B Therapy.-Amphotericin B was found to have either marked suppressant or curative effects on all monilial lesions studied. The term suppressant has been used to indicat.e a decrease or disappearance of the clinically observable inflammation. With discontinuation of therapy, however, a recurrence was usually noted or anticipated, since the basic etiological factor remained essentially unaffected. The term curative has been used to indicate healing of the entire lesion; in such cases recurrences, without further provocation, mere not noted or anticipated. Action in Specific Disease Xtates.Denture stomatitis: Twenty-one patients with denture stomatitis were t,rcatcd with amphotericin B in an adhesive base. ApplicaGons were continued for periods of 1 to 2 weeks. In many cases therapy was instituted after one of the three previously noted procedures (placebo-protectant therapy, adjustment of vertical dimension, or treatment with other antifungal agents) had been used without notable success. Moderate improvement was noted in nineteen patients and slight improvement in two patients. Maximum improvement was usually attained within 1 week, and no additional improvement appeared to occur thereafter in spite of continued therapy. Follow-up observations in this group indicated that frequent recurrences of denture stomatitis occurred after amphotericin B therapy had been disconCnued. These recurrences reflect the fact that most such monilial infections of the mouth are secondary to some other local or systemic predisposing factor. So long as the latter are not eliminated, recurrences should be expected, It is to be noted that each recurrence which was treated again responded favorably and in a similar fashion when amphotericin B therapy was reinstituted. It should be emphasized that when dentures require adjustment or refitting the use of drugs should be viewed merely as adjunctive or suppressant therapy, and not as conclusive or definitive treatment, and that technical improvement of tho denture should bc sought. itngu7ar stomatitis: Four patients with angular stomatitis were treated with 2 per cent amphotericin B in Plastibasc. ,pplication of the antibiotic was continued for a period of at least 1 week. Marked improvement of the angular stomatitis was noted in three cases, and slight improvement was seen in one patient. It was noted that maximum improvement was usually attained in 1 week
I)ISCUSSION
(‘liniVi%l data folio\\-iiig lhc (/Ix/. administration of amphotericin K, as rcportcd by other invcsti&ors, indicate that this agent, since it is not absorbed from the gast.roint,est.inal tract. is a ramarkably safe compound, eren in dosages greatI\- in excess of the minimal amounts utilized in topical oral therapy. As wc pointed out carli(~r, r~currcnecs of monilial lesions were often O~Jserved following discontinuation of amphotcricin R therapy. Athough our study intentionally disregarded other local and systemic predisposing factors, such as hypovitaminosis, local itsritation, clonn~~~ of the bite, etc., such fact,ors obviousl> must, be dealt with in a positive Eashion if curntive results arc IO be obtained. SUMMARY
~1mphotericin 13 was administered to thirty-three patients with lesions of crlbicans was implicated, either as :I 111~ oral nlu~ons membranes in which (1. st~<*(>tldi~r*y invader. These lesions included primary etiological factor or as a denture stomatitis, angular stomatitis, oral moniliasis of unknown etiology 01 association, and antibiotic-induced stomatitis. Amphotericin I3 was found to have marked suppressant, or curative effects on all lesions studied.
Volumt 17 Number I
AMPHOTERICIN
B FOR
ORAL
JIOSILIAT,
INFECTIOSS
35
Inasmuch as the lesions investigated are frequently dependent upon predisposing systemic factors, such as hypovitaminosis, or local exciting factors, such as closed-bite or trauma, the satisfactory management of these lesions demands the eradication of all influences predisposing to the disturbance. REFERENCES 1. Wright,
E. T., Graham, J. H., and Sternberg, T. H.: Treatment of Moniliasis With Nystatin, J. A. M. A. 163: 92, 1957. 2. Kozinn, P. J., Taschdjian, C. L., Dragutsky, D., and Minsky, A.: Treatment of Cutaneous Candidiasis in Infancy and Childhood With Nystatin and Amphotericin. In Welch, H., and Marti-Ibtiez, F. (editors) : Antibiotics Annual, 195657, New York, 1957, Medical Encyclopedia, Inc. 3. Gold, W., Stout, H. A., Pagano, J. F., and Donovick, R.: Amphotericins A and B, Antifungal Antibiotics Produced by a Streptomyceto. I. In Vitro Studies. In Welch, H., and Marti-Ibtiez, F. (editors) : Antibiotics Annual, 1955-56, New York, 1956, Medical Encyclopedia, Inc., p. 576. 4. Kutscher, A. H., Zegarelli, E. V., Beube, F. E., Stern, I. B., Tuoti, F., Herlands, R. E., Berman, C. L., and Mercadante, J. L.: A New Oral Adhesive-Protectant-Vehicle, J. Periodont. 31: 59, 1959.
630 WEST 168~~ ST.
TREATMENT
OF ORAL
INFECTIONS
Austin H. Kutscher, Robert E. Herlands, New York, N. Y. Divisions
of
Coluwlbia
University
A
B IN THE
Stowdology
D.D.S., Edward V. Zegarelli, D.D.N., ll.S., D.D.S., und Herbert F. Silvers, D.D.S.,
und
Ecstomtiue
Dentistry,
Sicl~ool
of
Dcnttcl
chtlaOral
Swgcry,
the various oral lesions with which Candida albicans has been implicated, either as a primary infectious agent or as a secondary invader, are denture stomatitis, angular stomatitis, and frank moniliasis which occurs more often in very young persons or in debilitated older patients. An increase in the frequency of oral monilial infections has been evident since the advent of the antibiotics. Fortunately, because of the availability of new, simpler, and more efficient laboratory procedures (for example, the Pagano-Levin medium), the general practitioner is in a better position today to establish the presence of C. albicans organisms in pathogenic numbers, so that the diagnosis of oral moni.liasis is more easily established. Reports describing the efficacy of various antifungal agents, such as Mycostatin, in treating monilial lesions have been published.l, 2 More recently, a new antifungal antibiotic, amphotericin B, which has a therapeutic spectrum much the same as that of Mycostatin, has been introduced.2, 3 Amphotericin B is produced by a hitherto unidentified species of streptomyces. Its chemical structure is as yet not known. The pure antibiotic is highly stable and has been tested successfully for antifungal action against a large number of pathogenic and nonpathogenic fungi. No resistant strains of Candida albicans have thus far been encountered. Amphotcricin B, as a topical agent for oral use, posssesses a distinct advantage (from the patient’s point of view-) in that it has an innocuous taste when compared to the disagreeable taste of Mycostatin. This report will detail the results obtained when amphotericin B was used in the treatment of patients with oral lesions in which C’. nlbicnns played a role either as a primary etiological agent or as a secondary invader. The
MONG
Formulations of amphotericin Squibb Institute for Medical
B in Or-abase, Orahesive, Research, New Brunswick, 31
and Plastibase N. J.
were
supplied
by
This aerics includctl I wrtity-one patients with tlc~llnre stomatitis, four with anglilar stomatiiis. fi\-cL with oi~rl moniliilsis ot’ unl~nown etiology or association, and tlirc~ with antil)iotk indiic*c~tl stonintitis. Amphotericin I( was ~~dministc~rc~d in it L’ per ~111 c*oncentration, either in an adhesive pastch t O~~al~usc~, containing gelatin, pectin, and c~arbosymethylcellulose in a mineral oil- ~~~l~c~thyl~~c hse) 01’ in 311 adhesive powder formulation (Orahcsiv(l, containin y only q>latin, lx&iii, ant1 ~arbox?-mcthylcellulosc J. Thcsc medications wer(~ al~plic~cl II>- 1tic patient to the affected areas after meals and also before rc%iring----81 I~71st foul. tiinc3 dail>-. A4pprosimately 250 mg. of the medication was al)plktl as ;I thin filnl of pastch or sl)rayecl onto the affected arCas with a So. 1 l!) Ik~\7ill)iss atomizer. In the treatment of dentllrc stomatitis, either the l);istcj or the ~~~~lcr was npplkd to the tlcntnre in the manner cust~omarily usctl for tllcl application of dcnturc adhesive powders and p&es. Thus, :lpl,roxirnatc,l?. 1,000 my. 01 medication, including approximately 20 lllg. of the active i+g~lil illnpllot C‘riCitl 13,was applied to a given lesion during the course of ii siiigL.1~~ da!-. I+‘or tlic: IlY’ilt tll~‘llt3 of angular stoma.titis, 2 per cent amphotericin K in an oint,mcnt basc~OCmineral oil and polyethylene (l’lastihlst~) Wns pwsci~ilwtl ;Itld six il~l~)li(‘ilt ions lN’1’(la>- IV(‘t’(’ I’c’(~Ilt’stc’cI. .\t ttlcc Olltsc~t of tllcsC stntlics Sc~\~c~l’;ll I)illiPtlls \v(‘t’(’ 1I’c~:ltOtlwith 1 I)(‘r’ P?llt I’otxiulutioli 0T amphotcricin 13. Sllril!
il
CONTROL
PROCEDL~RES
For additional control purposes, a suitable placebo formulation was used prior to amphotericin R therapy in five patients with dcnturc stomatitis and in bwo pat&k with oral moniliasis of undrtcrmined origin. A placebo preparat,ion containing only Plastibase was used in two patients with angular stomatitis. KESUI,TS
Response to Placebo l’hempy.-As reported previous1.v in studies of patients with various scutc and chronic lesions of the oral mucous membranes,’ the intraoral application of placebo-protectant preparations per se (Orabase or Orahcsive without amphoteriain K) has been fount1 to afford some relief of existent symptoms. In these casts, t,hcbperiod of relief’ has paralleled the timrl during which the vehicle remained in position, but as the vehicle dissolved ot disappeared the symptomatolopy rctnrned. Thus, the temporary subjective improvement was undoubtedly due to the protectant properties of the placebo preparations. Furthermore, usually no considerable alteration in the objective
Volume Number
17 I
AMPHOTERICIN
B FOR
ORAL
MOSILIAL
INFECTIONS
33
clinical picture of the lesion was noted. Parallel effects have been noted following the use of placebo-protectant formulations in nine additional patients who had lesions similar to those discussed in this report but who were not treated subsequently with amphotericin B. Of course, most patients with denture stomatitis are not bothered by any disturbing symptoms associated with their lesions. Admittedly, a few cases of denture stomatitis did improve objectively on vehicle “therapy” alone, but this was thought to be due to the increased stability of the dent.ure resulting from the use of the adhesive material. Response to Amphotericin B Therapy.-Amphotericin B was found to have either marked suppressant or curative effects on all monilial lesions studied. The term suppressant has been used to indicat.e a decrease or disappearance of the clinically observable inflammation. With discontinuation of therapy, however, a recurrence was usually noted or anticipated, since the basic etiological factor remained essentially unaffected. The term curative has been used to indicate healing of the entire lesion; in such cases recurrences, without further provocation, mere not noted or anticipated. Action in Specific Disease Xtates.Denture stomatitis: Twenty-one patients with denture stomatitis were t,rcatcd with amphotericin B in an adhesive base. ApplicaGons were continued for periods of 1 to 2 weeks. In many cases therapy was instituted after one of the three previously noted procedures (placebo-protectant therapy, adjustment of vertical dimension, or treatment with other antifungal agents) had been used without notable success. Moderate improvement was noted in nineteen patients and slight improvement in two patients. Maximum improvement was usually attained within 1 week, and no additional improvement appeared to occur thereafter in spite of continued therapy. Follow-up observations in this group indicated that frequent recurrences of denture stomatitis occurred after amphotericin B therapy had been disconCnued. These recurrences reflect the fact that most such monilial infections of the mouth are secondary to some other local or systemic predisposing factor. So long as the latter are not eliminated, recurrences should be expected, It is to be noted that each recurrence which was treated again responded favorably and in a similar fashion when amphotericin B therapy was reinstituted. It should be emphasized that when dentures require adjustment or refitting the use of drugs should be viewed merely as adjunctive or suppressant therapy, and not as conclusive or definitive treatment, and that technical improvement of tho denture should bc sought. itngu7ar stomatitis: Four patients with angular stomatitis were treated with 2 per cent amphotericin B in Plastibasc. ,pplication of the antibiotic was continued for a period of at least 1 week. Marked improvement of the angular stomatitis was noted in three cases, and slight improvement was seen in one patient. It was noted that maximum improvement was usually attained in 1 week
I)ISCUSSION
(‘liniVi%l data folio\\-iiig lhc (/Ix/. administration of amphotericin K, as rcportcd by other invcsti&ors, indicate that this agent, since it is not absorbed from the gast.roint,est.inal tract. is a ramarkably safe compound, eren in dosages greatI\- in excess of the minimal amounts utilized in topical oral therapy. As wc pointed out carli(~r, r~currcnecs of monilial lesions were often O~Jserved following discontinuation of amphotcricin R therapy. Athough our study intentionally disregarded other local and systemic predisposing factors, such as hypovitaminosis, local itsritation, clonn~~~ of the bite, etc., such fact,ors obviousl> must, be dealt with in a positive Eashion if curntive results arc IO be obtained. SUMMARY
~1mphotericin 13 was administered to thirty-three patients with lesions of crlbicans was implicated, either as :I 111~ oral nlu~ons membranes in which (1. st~<*(>tldi~r*y invader. These lesions included primary etiological factor or as a denture stomatitis, angular stomatitis, oral moniliasis of unknown etiology 01 association, and antibiotic-induced stomatitis. Amphotericin I3 was found to have marked suppressant, or curative effects on all lesions studied.
Volumt 17 Number I
AMPHOTERICIN
B FOR
ORAL
JIOSILIAT,
INFECTIOSS
35
Inasmuch as the lesions investigated are frequently dependent upon predisposing systemic factors, such as hypovitaminosis, or local exciting factors, such as closed-bite or trauma, the satisfactory management of these lesions demands the eradication of all influences predisposing to the disturbance. REFERENCES 1. Wright,
E. T., Graham, J. H., and Sternberg, T. H.: Treatment of Moniliasis With Nystatin, J. A. M. A. 163: 92, 1957. 2. Kozinn, P. J., Taschdjian, C. L., Dragutsky, D., and Minsky, A.: Treatment of Cutaneous Candidiasis in Infancy and Childhood With Nystatin and Amphotericin. In Welch, H., and Marti-Ibtiez, F. (editors) : Antibiotics Annual, 195657, New York, 1957, Medical Encyclopedia, Inc. 3. Gold, W., Stout, H. A., Pagano, J. F., and Donovick, R.: Amphotericins A and B, Antifungal Antibiotics Produced by a Streptomyceto. I. In Vitro Studies. In Welch, H., and Marti-Ibtiez, F. (editors) : Antibiotics Annual, 1955-56, New York, 1956, Medical Encyclopedia, Inc., p. 576. 4. Kutscher, A. H., Zegarelli, E. V., Beube, F. E., Stern, I. B., Tuoti, F., Herlands, R. E., Berman, C. L., and Mercadante, J. L.: A New Oral Adhesive-Protectant-Vehicle, J. Periodont. 31: 59, 1959.
630 WEST 168~~ ST.