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The Treatment of Superficial Ringworm Infections
The Treatment of Superficial Ringworm Infections JOHN S. STRAUSS 1 M.D.*
physician is being constantly bombarded with literature pertaining to new, extremely effective methods for controlling fungus infections. lVlost of these claims of effectiveness are based on in vitro testing methods and do not reflect the effectiveness of the compound or agents in the treatment of the actual clinical disease. The number of compounds that have been described in itself clearly shows that we are still without a highly effective agent for the treatment of this group of diseases. Therapy is still dependent upon a combination of specific antifungal therapeutic agents and nonspecific methods many of which are based upon a knowledge of the underlying pathologic physiology of superficial fungus infections. Therefore, in order to discuss intelligently the treatment of this group of diseases it is necessary first to summarize some of the information concerned with the growth and proliferation of these fungi in the skin.
THE
THE SUPERFICIAL MYCOSES
The superficial fungi have one property in common-they proliferate in the stratunl corneum (outer horny layer) where they live on the products or by-products of keratinization. They never invade the "living" portion of the epidermis and are truly "necrophilic," growing only on dead material. An example of this "necrophilic" property is demonstrated by the ability of the organisms to grow in tissues such as lung or spleen in a test tube; i.e., in dead tissue, while in the normal host the fungi will not invade either the lung or the spleen. Recently insight into the possible mechanisms involved in this phenomenon has been obtained from the experimental studies of Lorincz et al. in which it has been shown that serum contains a factor which inhibits the growth of the superficial dermatophytes. 1 In the human host the organisms are necessarily in a dynamic relation* Assistant Professor of Dermatology, Boston University School of Medicine; Assistant Visiting Physician, Massachusetts Memorial Hospitals, Boston; Consultant in Dermatology, Le1nuel Shattuck I10spital, Jamaica Plain, Massachusetts. 1375
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ship with the processes of keratinization. If this were not so, all of these infections would be self-limited, because keratinization is a continuous process and as new keratin is formed the surface keratinous squamae (scales) fall off. The best example of this dynamic relationship between the host and the parasite is that observed in tinea capitis in which the fungi grow down in the hair at the same rate as the hair grows Up.2 Since by actual measurements it is known that the average scalp hair grows at the rate of approximately 0.35 mm. per day, we can assume that the fungi must grow down at the rate of 0.35 mm. per day; when the fungi cease growing at this rate the infection cannot be maintained in the hair. Within this group of necrophilic fungi there are two main divisions. The most important group is the keratinolytic fungi; these are the organisms which cause ringworm infections. The organisms of this group include those of the genera Microsporum, Trichophyton and Epidermophyton and all of the organisms contain an enzyme which is capable of digesting keratin. Therefore, the organisms directly invade the keratinized portion of the stratum corneum, hair and nails. In addition, these fungi have a group-specific antigen (trichophytin) and the standard trichophytin used in skin testing can be made from a single organism. Of course, with a group-specific antigen cross-reactivity is present; therefore the trichophytin test does not aid in the diagnosis of a specific causative organism. The diseases caused by the fungi in this group include tinea capitis (ringworm of the scalp), tinea corporis (ringworm of the body), tinea cruris (ringworm of the groin), tinea pedis (ringworm of the feet), and tinea unguum (ringworm of the nails). The second group of superficial fungi consists of a few miscellaneous species which do not possess keratinolytic enzymes. These fungi therefore cannot directly invade the keratinous cells and grow in the interspaces between these cells. They therefore are exposed more easily to topical agents and therapeutically are more easily controlled. The most important disease caused by this group of fungi is tinea versicolor. Erythrasma and trichomycosis axillaris also are caused by fungi in this group. Another point that should be emphasized is that the superficial fungi in general cause diseases that are not highly inflammatory. Actually, marked inflammation is incompatible with the continued proliferation of the organisms and there is usually a tendency for markedly inflamed lesions to undergo a spontaneous cure. This is probably due to the fact that the organisms either are thrown off in the marked inflammatory reaction or that the inflammation actually interferes with the synthesis of keratin which is the foodstuff for the fungi that are keratinolytic. PRECIPITATING FACTORS
At present, a rational approach to the treatment of fungus infections is hampered by the failure to understand the precipitating factors concerned in these infections. In tinea; capitis, and to a lesser extent in inter-
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digital infections of the foot, the pathogenesis has been worked out. 2 , 3, 4 However, in the other infections there are many gaps in our knowledge. In general, it can be said that the infectivity of the fungus infections is low and they are not highly contagious. Thus it is possible to infect only a small number of people in experimental studies. There is very little knowledge at the present moment concerning this natural immunity which protects a good percentage of the population. Actually the two known precipitating factors which go together, hand in hand, are heat and moisture. The incidence of fungus infections is much higher in warm climates where skin hydration is increased. Also, many fungus infections tend to localize in the intertriginous areas such as the groin, axillae and interdigital spaces, all areas characterized by increased moisture. In experimental studies the incidence of positive inoculations in the interdigital spaces of the foot was increased when moisture was increased. THE DIFFERENCE BETWEEN IN VITRO AND IN VIVO RESULTS
Because it is impossible experimentally to produce reproducible infections with great regularity, most of the antifungal testing is done with in vitro methods. Unfortunately, the results in the test tube or on the culture plate do not in any way approach the conditions that are encountered in the living host. Of course many of the compounds which have been found to be antifungal by in vitro methods are too toxic to be used in the human host. Many other compounds which are highly effective in vitro are ineffective in vivo. Probably the greatest factor in the difference between the two types of tests is bringing the agent into contact with the organisms in the in vivo tests. In the living host the fungi grow within the keratinized cells and the agents must penetrate to this location in order to be effective. A newer test has been devised using infected scales, a condition approaching the natural infection, but even with this test it is impossible to reproduce the circumstances where the organisms may grow in thick keratinous structures such as the keratinous zone of the hair. 6 It is virtually impossible at present to get active agents to these locations. These remarks apply particularly to the ringworm fungi while, as has already been mentioned, the miscellaneous fungi, i.e., those causing tinea versicolor, erythrasma and trichomycosis axillaris, are more accessible to the action of fungicides. GENERAL PRINCIPLES OF THERAPY
Before discussing the specific regional problems that exist, the general principles of therapy will be outlined. Make the Correct Diagnosis
The first principle of therapy is to lnake the correct diagnosis. While the determination of the factors concerned in making the diagnosis is
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beyond the scope of this paper, it nevertheless Inust be mentioned. Many lesions, particularly those involving the hands and feet, are glibly diagnosed as fungus infections on the basis of mere clinical inspection. The diagnosis is incorrect in a sizeable number of cases and in these misdiagnosed cases antifungal therapy often is contraindicated. Probably the best example of this would be a contact dermatitis which might even be made worse by the use of keratolytics or fungicides. Treatment Should be Consistent with Good Dermatologic l-herapy
While there are special circumstances that cover the use of fungicidal and fungistatic agents, therapy in general follows that consistent with good dermatolog5c practice. In other words, when the lesions are acute and weeping, no irritants should be used and treatment should consist of the use of water compresses for about ten to 15 minutes three to four times a day. This removes the keratinous debris and any crust that may accumulate. As a matter of fact, as has already been pointed out, these highly inflammatory lesions tend to be self-limited. As the lesions become less acute, soaks are not as necessary and ointments and powders can be substituted. However, as directed by good dermatologic therapy, irritants and sensitizers should not be used here. The original Whitfield's ointment contained 12 per cent benzoic acid and 6 per cent salicylic acid; this compound was often an irritant and is therefore usually contraindicated. It is customary now, except under special circumstances, to use only the "half-strength Whitfield's ointment." This latter is now the standard Whitfield's ointment (D.S.P. XV). The formula is as follows: Benzoic acid 6% ~ . .. · 1· ·d 301 In polyethylene glycol oIntment Sa 1ICY IC aCI 10
Prevention of Moisture
As has already been mentioned, moisture is an important factor, particularly in intertriginous infections. Therefore, all efforts to decrease moisture must be made. The specific suggestions will be made in the individual sections. Suffice it to say here that these measures include exposure to the air, wearing of light clothing, and the avoidance of excessive heat and emotional stimuli which cause reflex sweating. Specific Fungistatic and Fungicidal Therapy
The new era of antifungal therapy was ushered in with the discovery by Peck et al. that straight-chain fatty acids are highly fungicidal. 6 Subsequently, it was shown that the activity of the fatty acids increases as the length of the chain increases, with the C-11 compound, undecylenic acid, being the most active agent. 7 The odd-chain fatty acids are those possessing this antifungal activity and these compounds are found in small amounts in the surface lipid film of the human. 8 Actually, these compounds are fungicidal but it is not necessary for an agent to be fungicidal
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because the organism will be thrown off if its growth is just inhibited. Therefore, the advantage of a fungicidal agent as compared to a fungistatic agent is, for the most part, an academic argument. The three fatty acids that have been used for the most part are propionic acid, caprylic acid and undecylenic acid. The last is the most effective and is often prescribed as follows: undecylenic acid 5 per cent; zinc undecylenate 20 per cent; hydrophilic ointment 75 per cent. (Desenex ointment contains 5 per cent undecylenic acid and 20 per cent zinc undecylenate. Desenex powder contains 2 per cent undecylenic acid and 20 per cent zinc undecylenate.) One of the advantages of the fatty acids as a group is that they are a normal product of skin and as such are relatively nontoxic and nonirritating. The advent of the fatty acids has practically eliminated the use of some of the older fungistatic agents such as the mercurials. However, the search for new fungicides and fungistatic agents continues and the salicylanilides and chlorosalicylanilides are often used as is diamthazole dihydrochloride (Asterol). Caution is indicated when the last agent is used as it has caused convulsions in young children. Use of I{eratolytics
Because the organisIlls grow in the superficial keratinized layers of the skin, it is natural to have attempted to desquamate the fungi with keratolytic agents such as phenol, sulfur, resorcinol and salicylic acid. Actually, while these agents are keratolytic they also are fungistatic, and part of their action is due to their specific effect upon the organisms. It is impossible to remove completely the keratin with these agents and they are not usually more effective than the specific fungicidal or fungistatic agents. It must be remembered that these agents applied in sufficiently strong concentrations often act as primary irritants. Areas in which they are most needed, namely those areas which are the sites of the most resistant infections such as the hair, nails, palms and soles, are not particularly affected by these agents. We do not have a good keratolytic agent for infections of hair or nails. In the case of the palms and soles, often the soaking of the hands or feet in water will macerate the keratin a.nd a great amount can be scraped off with a blunt instrument. SPECIFIC REGIONAL THERAPY
RingworDl of the Scalp
In this country the majority of the cases of ringworm of the scalp are caused by Microsporum audouini and Microsporum canis and I will consider in detail the therapy of the disease caused by only these two organisms. Usually Microsporum audouini infections are noninflammatory while those caused by Microsporum canis are inflammatory; otherwise the infections behave the same. If the infection is noninflammatorY,it usually spreads for a period of three to four months; after this, further
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spread is unusual. Of course the inflammatory lesions are self-healing, and even in the usual noninflammatory case a cure is seen in four to six months in 50 to 60 per cent of the cases. Any claims of the effectiveness of therapeutic agents must take into consideration this tendency for a spontaneous cure. It is not my purpose to discuss in detail the pathogenesis of this disease as it is ably discussed elsewhere. 2 , 3 Suffice it to say that the active site of proliferation of the organisms is just above the hair root where the final stages of keratinization take place. This site is relatively inaccessible to topical medication; the agent must not only get down to the bottom of an individual hair follicle but it mu~t penetrate the hair itself. Therefore, it is not surprising that the results to date with the specific fungistatic and fungicidal agents have not really improved on the therapeutic success of Mother Nature herself. Nevertheless, as a routine, parents should use a nonirritating fungicidal agent such as Salundex ointment or Desenex ointment for two reasons: (1) These agents probably keep the spore count down and may control some of the infectivity of the individual case. (2) Mothers feel that something must be done to a child with this disease and these agents at least are unlikely to cause any adverse reactions. Manual epilation is not indicated, as it is ineffective. The fungus-infected hair is weak and will break off above the zone where actual mycotic proliferation takes place so that an infected stub will remain after the hair is plucked. The first line of defense against this disease is nature itself. However, there are a few cases which do not undergo a spontaneous cure, and if, after a period of four to six months there is no evidence of regression of the disease, temporary x-ray epilation is indicated. The rationale behind this type of therapy is that x-ray temporarily interferes with the keratinization of the hair and the organisms are deprived of any further keratin on which to grow. This type of therapy is safe provided it is performed by adequately trained dermatologists or radiologists who are familiar with the course of the disease as well as the use of the equipment. The hair falls out in a period of about three weeks and regrowth starts in approximately two months. The regrowth is usually complete by six months. It should be emphasized again that this procedure is not the first line of defense in this disease and is employed only after adequate conservative therapy has been tried. As a matter of fact, if x-ray epilation is given early in the course of the disease before the natural host resistance develops, reinfections are common. Children with thi~ disease are generally not excluded from school. While the disease is communicable, it is not highly contagious. It would be an economic and social hardship to exclude children from school when it takes four to six months to promote a cure. Efforts should be made to prevent bodily contact with infected children. A cap should be worn by the infected child and he should make every effort to see that no one else uses this cap. Another source of infection is from hairs that may be trans-
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ferred to the backs of upholstered seats such as those in movie theaters or in busses. If the infection is one that has come from an animal, such aFt a dog or cat, appropriate measures should be taken to control the infection in the animal host. A special inflammatory lesion that is sometimes seen is a kerion. This is a marked erythematous, eczematous inflammatory lesion which may appear purulent and represents a severe allergic tissue reaction to the fungus organisms. It is seen particularly in M. canis infections (animal type ringworm) but on occasion an M. audouini infection will also develop into a kerion. A kerion signifies the development of an allergic response on the part of the host and at this time the trichophytin test will become positive. Id reactions also may occur at this time. When this severe inflammatory reaction occurs, the follicles collapse and the hair stops growing. Therefore, the development of a kerion signifies the imminent termination of the infection; these lesions are self-healing. Kerions are wild looking and convincing arguments on the part of the physician are required to keep parents from demanding all types of heroic medications. Here is a lesion in which the principles of good general dermatologic care must be employed. It is an acute lesion and therefore compresses three to four times a day are indicated. It is an acute lesion and active medications such as fungicides often will lead to an exacerbation. It is not caused by bacteria, although they may be recovered on culture. However, frank secondary infection is rare, and as a routine antibiotic therapy is not indicated. If the patient or the family is unwilling to accept the use of water soaks, a mild solution such as 1 :20 Burow's solution or physiologic saline should be used for the soaks. Of course x-ray therapy is contraindicated. The parents should be reassured that this event definitely heralds the disappearance of the disease. However, the severe inflammatory reaction may possibly be accompanied by permanent alopecia which is usually, at the most, partial and most commonly minor in extent. In the southern section of the United States an increasing number of cases of tinea capitis due to Trichophyton tonsurans are now being seen. '1'his particular type of infection is much more difficult to diagnose and is a much greater therapeutic problem. While the Microsporum infections characteristically involve only children, Trichophyton tonsurans infections may also involve adults. There is no tendency to spontaneous cure and vigorous therapeutic approaches are necessary. Usually topical antifungal therapy is of no avail and temporary x-ray epilation is necessary. After the x-ray epilation, topical antifungal therapy must be continued but in spite of this the infection often recurs. The care of these patients definitely belongs to those who specialize in dermatology. Tinea Pedis
This, the most common superficial fungus infection, is actually the disease that is most subjected to mismanagement by the patient. Also
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there is a tendency on the part of many physicians to call every lesion seen on the foot and in the interdigital spaces a fungus infection. Most patients readily ascribe the infection to walking barefooted in a shower stall, around a swimming pool or similar types of circumstances. Actually, recent evidence has shown that the exogenous source of fungi is probably minor and that the acute reinfection is probably an endogenous process. 4 , 9,10 The thick, horny material of the soles and of the nails is usually the reservoir from which the fungi disseminate to the test of the foot. Infections of the soles and nails are extremely resistant to treatment and often may exist without the presence of clinical signs. Treatment must be discussed by area involved and acuteness of the lesions. The most common lesion that the physician is called upon to treat is the acute interdigital lesion. The regimen in severe acute cases should· include the following: 1. Rest. It is essential that the patient rest as much as possible and there is much to be gained by actually having the patient keep his shoes and socks off and stay in bed. 2. Exposure to air. The afflicted area should be exposed to air by keeping the toes separated with material such as interdigital pads, lamb's wool or gauze. 3. Soaks. Water soaks should be used for about ten minutes out of every two hours. Longer soaks are contraindicated in that they will aggravate the maceration. Active medication need not be incorporated in the soaks unless the patient is unwilling to accept the use of plain water. 4. Specific antifungal treatment. No specific antifungal measures should be used at this time as they may only irritate the lesions. As the lesions become more chronic and the erythema and maceration disappear, the frequency of the soaks can be decreased and specific antifungal agents such as Desenex powder or ointment can be applied to the interspaces. Contrary to popular opinion, Desenex ointment may be used in the interdigital spaces provided only a thin coat is applied. In the treatment of interdigital infections, systemic antibiotics are necessary only if there is evidence of a bacterial cellulitis. Acute vesicular lesions of the soles should be handled similarly to the acute interdigital infections. Chronic scaling hyperkeratotic lesions of the soles are virtually impossible to treat and are best left alone. Nail infections will be discussed later. The major problem in the treatment of ringworm of the foot is one of r;rophylaxis. Eighty-five per cent of the patients who have an infection in the interdigital spaces will have an infection in either the soles or the nails, and actually in about 50 per cent of the patients there will be an infection in both the soles and the nails; these are the sources of reinfection. 4 Probably the most important factors in reinfection are the presence of moisture and heat, and the prophylactic measures are mainly directed
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toward these factors. Therefore, the patient should be warned to wear a lightweight shoe, preferably a ventilated shoe. Leather soles are preferred over rubber-soled shoes. Socks should be of light-weight cotton, and if the patient must wear shoes for a long period of time he should be advised to bring an extra pair of shoes and socks to work. Nylon socks tend to prevent evaporation of moisture and are contraindicated. When the patient gets home he should be told to remove his shoes and walk around in his stocking feet or open-toed slippers. The infectivity of this type of infection from person to person is low and therefore the patient does not have to be concerned about infecting other members of the family. A medicated powder such as Desenex should be lightly dusted into the socks before they are applied, possibly to keep the spore count down. Most patients find that by following a regimen such as this they are able to prevent recurrences of the infection. Nail Infections
There is no local therapy that is adequate for nail infections. Surgical avulsion is often practical but as commonly done the recurrence rate is high. The primary site of nail involvement is the nail bed and not the nail itself. Therefore, it is necessary to remove all of the nail bed keratin. This is done by vigorous curetting of the nail bed distal to the nail matrix (which is the actual organ which produces the nail). All of the keratinous debris must be removed carefully, including the material in the lateral nail grooves. If the matrix is not touched, the regrowth of the nail will be normal. After this treatment, local fungicides should be used during the period in which the nail regrows. Even with these vigorous methods the cure rate is not exceptional, and only certain cases should be considered for this procedure. I do not routinely treat infected toenails since there is almost always a recurrence after treatment. If an isolated fingernail or a few fingernails are involved, particularly if these nails are acting as sources for reinfection of glabrous skin, these nails should be treated. Often the patient will complain of pain from the thickened toenails, and, if avulsion is not indicated, the nails can be trimmed down with dental burrs. Tinea Cruris
This is an intertriginous infection and should be handled in much the same manner as intertriginous infections of the feet. When there is marked exudation and maceration, treatment consists of rest, aeration and sitz baths along with the use of a bland dusting powder or shake lotion. In the more chronic phases, preparations containing 2 to 3 per cent precipitated sulfur and salicylic acid in an emulsion base can be used. An alcoholic lotion of 2 per cent salicylic acid in 50 per cent ethyl alcohol also is quite effective, but care must be taken to prevent this from coming into contact with the adjacent mucous membranes. Grease type
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ointments should be avoided and the patient should be instructed in the use of loose fitting underwear, frequent powdering and other methods to keep the area dry and cool. Fungus Infections of the Glabrous Skin
This type of ringworm infection is very easy to handle when compared with some of the other infections such as those involving the hair or squamous portions of the soles. Many of the preparations already mentioned, such as the fatty acid compounds or sulfur and salicylic acid ointments, are effective. A thin coat of ointment should be applied two to three times a day. Whitfield's ointment (U.S.P. XV) is also effective in these infections. There is also a group of plaque-like lesions caused by Trichophyton rubrum. These are extremely resistant to therapy and require the use of strong keratolytic agents such as the old full-strength Whitfield's ointment (12 per cent benzoic acid and 6 per cent salicylic acid). Id Reactions (Trichophyton Reactions)
This type of reaction is an acute response on the part of the host to the dissemination of some products of the fungi through the blood stream. It is a true allergic reaction and occurs in association with severe, acute lesions elsewhere on the body. This reaction is often associated with too energetic treatment of an acute lesion. Id reactions usually tend to be disseminate and often are follicular in distribution. T~hey may be erythematous papules, vesicles or scaling lesions. The "id" lesions are sterile while the active original foci elsewhere of course will show fungal elements. Since the id reaction is a specific allergic manifestation, the trichophytin skin test is positive even in weak dilutions. rThe treatment of the id reaction is dependent upon the eradication of the primary focus. Subsequently the id reaction will completely disappear. Specific therapy for the "id" lesions is that described elsewhere for good dermatologic therapy. Miscellaneous Fungus Infections Tinea versicolor is the most common infection in this group. The superficiality of this type of infection has already been pointed out, and a response is rapidly obtained to many topical medications such as fatty acid preparations or sulfur and salicylic acid preparations. Actually, the use of a good scrub brush often will remove many of the lesions; vinegar applications and sodium hyposulfite (20 per cent) applied locally also have been highly effective. Unfortunately the recurrence rate is extremely high with this disease and upon the cessation of treatment the lesions will recur. Erythrasma will respond to the same type of therapy as that advocated for tinea versicolor.
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Trichomycosis axillaris, while having been considered to be a fungus infection, probably should no longer be classified in this group. The disease is caused by a Corynebacterium, and treatment consists either of shaving the hair or using topical antibiotics or antiseptics. The disease often recurs, and the patient should be advised that relapses will likely' be seen. SUMMARY
In general, treatment of the superficial fungus infections of the skin follows the general therapeutic patterns established for the treatment of other cutaneous diseases. Treatment must be correlated with the acuteness of the particular lesion. Acute lesions should not be treated with agents that may be irritating. Moisture and heat are common precipitating factors and the prevention of excessive moisture and heat is important in the treatment of these infections. As the infections become more chronic, the use of specific antifungal agents or keratolytics is indicated. Above all, the primary duty of the physician is to make the correct diagnosis before he undertakes therapy. REFERENCES 1. Lorincz, A. L., Priestley, J. O. and Jacob, P. H.: Evidence for a Humoral Mechanism Which Prevents Growth of Dermatophytes. Presented at the 18th Annual Meeting of the Society for Investigative Dermatology, June 2,1957, New York, N. Y. 2. Kligman, A. M.: Tinea Capitis Due to M. audouini and M. canis. 11. Dynamics of the Host-Parasite Relationship. A.M.A. Arch. Dermat. 71: 313-337 (March) 1955. 3. Kligman, A. M.: The Pathogenesis of Tinea Capitis Due to Microsporum audouini and Micrisporum canis. I. Gross Observations Following the Inoculations of Humans. J. Invest. Dermat. 18: 231-246 (March) 1952. 4. Strauss, J. S. and Kligman, A. M.: An Experimental Study of Tinea Pedis and Onychomycosis of the Foot. A.M.A. Arch. Dermat. 76: 70-79 (July) *1957. 5. Dolan, M. M., Ebelhare, J. S., Kligman, A. M. and Bard, R. C.: A Semi-In Vivo Procedure for Testing Antifungal Agents for Topical Use. J. Invest. Dermat. 28: 359-362 (May) 1957. 6. Peck, S. M., Rosenfeld, H., Leifer, W. and Bierman, W.: Role of Sweat as a Fungicide, with Special Reference to the Use of Constituents of Sweat in the Therapy of Fungous Infections. Arch. Dermat. & Syph. 39: 126-148 (Jan.) 1939. 7. Grunberg, E.: The Fungistatic and Fungicidal Effiects of the Fatty Acids on Species of Trichophyton. Yale J. BioI. & Med. 19: 855-876 (May) 1947. 8. Rothman, S., Smiljanic, A., Shapiro, A. L. and Weitkamp, A. W.: The Spontaneous Cure of Tinea Capitis in Puberty. J. Invest. Dermat. 8: 81-98 (Feb.) 1947. 9. Baer, R. L., Rosenthal, S. A., Litt, J. Z. and Rogachefsky, H.: Experimental Investigations on Mechanism Producing Acute Dermatophytosis of Feet. J.A.M.A. 160: 184-190 (Jan. 21) 1956. 10. Baer, R. L., Rosenthal, S. A., Rogachefsky, Hand Litt, J. Z.: Newer Studies on the Epidemiology of Fungus Infections of the Feet. Am. J. Pub. Health J,.5: 784-790 (June) 1955.
80 E. Concord Street Boston 18, Massachusetts
physician is being constantly bombarded with literature pertaining to new, extremely effective methods for controlling fungus infections. lVlost of these claims of effectiveness are based on in vitro testing methods and do not reflect the effectiveness of the compound or agents in the treatment of the actual clinical disease. The number of compounds that have been described in itself clearly shows that we are still without a highly effective agent for the treatment of this group of diseases. Therapy is still dependent upon a combination of specific antifungal therapeutic agents and nonspecific methods many of which are based upon a knowledge of the underlying pathologic physiology of superficial fungus infections. Therefore, in order to discuss intelligently the treatment of this group of diseases it is necessary first to summarize some of the information concerned with the growth and proliferation of these fungi in the skin.
THE
THE SUPERFICIAL MYCOSES
The superficial fungi have one property in common-they proliferate in the stratunl corneum (outer horny layer) where they live on the products or by-products of keratinization. They never invade the "living" portion of the epidermis and are truly "necrophilic," growing only on dead material. An example of this "necrophilic" property is demonstrated by the ability of the organisms to grow in tissues such as lung or spleen in a test tube; i.e., in dead tissue, while in the normal host the fungi will not invade either the lung or the spleen. Recently insight into the possible mechanisms involved in this phenomenon has been obtained from the experimental studies of Lorincz et al. in which it has been shown that serum contains a factor which inhibits the growth of the superficial dermatophytes. 1 In the human host the organisms are necessarily in a dynamic relation* Assistant Professor of Dermatology, Boston University School of Medicine; Assistant Visiting Physician, Massachusetts Memorial Hospitals, Boston; Consultant in Dermatology, Le1nuel Shattuck I10spital, Jamaica Plain, Massachusetts. 1375
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ship with the processes of keratinization. If this were not so, all of these infections would be self-limited, because keratinization is a continuous process and as new keratin is formed the surface keratinous squamae (scales) fall off. The best example of this dynamic relationship between the host and the parasite is that observed in tinea capitis in which the fungi grow down in the hair at the same rate as the hair grows Up.2 Since by actual measurements it is known that the average scalp hair grows at the rate of approximately 0.35 mm. per day, we can assume that the fungi must grow down at the rate of 0.35 mm. per day; when the fungi cease growing at this rate the infection cannot be maintained in the hair. Within this group of necrophilic fungi there are two main divisions. The most important group is the keratinolytic fungi; these are the organisms which cause ringworm infections. The organisms of this group include those of the genera Microsporum, Trichophyton and Epidermophyton and all of the organisms contain an enzyme which is capable of digesting keratin. Therefore, the organisms directly invade the keratinized portion of the stratum corneum, hair and nails. In addition, these fungi have a group-specific antigen (trichophytin) and the standard trichophytin used in skin testing can be made from a single organism. Of course, with a group-specific antigen cross-reactivity is present; therefore the trichophytin test does not aid in the diagnosis of a specific causative organism. The diseases caused by the fungi in this group include tinea capitis (ringworm of the scalp), tinea corporis (ringworm of the body), tinea cruris (ringworm of the groin), tinea pedis (ringworm of the feet), and tinea unguum (ringworm of the nails). The second group of superficial fungi consists of a few miscellaneous species which do not possess keratinolytic enzymes. These fungi therefore cannot directly invade the keratinous cells and grow in the interspaces between these cells. They therefore are exposed more easily to topical agents and therapeutically are more easily controlled. The most important disease caused by this group of fungi is tinea versicolor. Erythrasma and trichomycosis axillaris also are caused by fungi in this group. Another point that should be emphasized is that the superficial fungi in general cause diseases that are not highly inflammatory. Actually, marked inflammation is incompatible with the continued proliferation of the organisms and there is usually a tendency for markedly inflamed lesions to undergo a spontaneous cure. This is probably due to the fact that the organisms either are thrown off in the marked inflammatory reaction or that the inflammation actually interferes with the synthesis of keratin which is the foodstuff for the fungi that are keratinolytic. PRECIPITATING FACTORS
At present, a rational approach to the treatment of fungus infections is hampered by the failure to understand the precipitating factors concerned in these infections. In tinea; capitis, and to a lesser extent in inter-
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digital infections of the foot, the pathogenesis has been worked out. 2 , 3, 4 However, in the other infections there are many gaps in our knowledge. In general, it can be said that the infectivity of the fungus infections is low and they are not highly contagious. Thus it is possible to infect only a small number of people in experimental studies. There is very little knowledge at the present moment concerning this natural immunity which protects a good percentage of the population. Actually the two known precipitating factors which go together, hand in hand, are heat and moisture. The incidence of fungus infections is much higher in warm climates where skin hydration is increased. Also, many fungus infections tend to localize in the intertriginous areas such as the groin, axillae and interdigital spaces, all areas characterized by increased moisture. In experimental studies the incidence of positive inoculations in the interdigital spaces of the foot was increased when moisture was increased. THE DIFFERENCE BETWEEN IN VITRO AND IN VIVO RESULTS
Because it is impossible experimentally to produce reproducible infections with great regularity, most of the antifungal testing is done with in vitro methods. Unfortunately, the results in the test tube or on the culture plate do not in any way approach the conditions that are encountered in the living host. Of course many of the compounds which have been found to be antifungal by in vitro methods are too toxic to be used in the human host. Many other compounds which are highly effective in vitro are ineffective in vivo. Probably the greatest factor in the difference between the two types of tests is bringing the agent into contact with the organisms in the in vivo tests. In the living host the fungi grow within the keratinized cells and the agents must penetrate to this location in order to be effective. A newer test has been devised using infected scales, a condition approaching the natural infection, but even with this test it is impossible to reproduce the circumstances where the organisms may grow in thick keratinous structures such as the keratinous zone of the hair. 6 It is virtually impossible at present to get active agents to these locations. These remarks apply particularly to the ringworm fungi while, as has already been mentioned, the miscellaneous fungi, i.e., those causing tinea versicolor, erythrasma and trichomycosis axillaris, are more accessible to the action of fungicides. GENERAL PRINCIPLES OF THERAPY
Before discussing the specific regional problems that exist, the general principles of therapy will be outlined. Make the Correct Diagnosis
The first principle of therapy is to lnake the correct diagnosis. While the determination of the factors concerned in making the diagnosis is
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beyond the scope of this paper, it nevertheless Inust be mentioned. Many lesions, particularly those involving the hands and feet, are glibly diagnosed as fungus infections on the basis of mere clinical inspection. The diagnosis is incorrect in a sizeable number of cases and in these misdiagnosed cases antifungal therapy often is contraindicated. Probably the best example of this would be a contact dermatitis which might even be made worse by the use of keratolytics or fungicides. Treatment Should be Consistent with Good Dermatologic l-herapy
While there are special circumstances that cover the use of fungicidal and fungistatic agents, therapy in general follows that consistent with good dermatolog5c practice. In other words, when the lesions are acute and weeping, no irritants should be used and treatment should consist of the use of water compresses for about ten to 15 minutes three to four times a day. This removes the keratinous debris and any crust that may accumulate. As a matter of fact, as has already been pointed out, these highly inflammatory lesions tend to be self-limited. As the lesions become less acute, soaks are not as necessary and ointments and powders can be substituted. However, as directed by good dermatologic therapy, irritants and sensitizers should not be used here. The original Whitfield's ointment contained 12 per cent benzoic acid and 6 per cent salicylic acid; this compound was often an irritant and is therefore usually contraindicated. It is customary now, except under special circumstances, to use only the "half-strength Whitfield's ointment." This latter is now the standard Whitfield's ointment (D.S.P. XV). The formula is as follows: Benzoic acid 6% ~ . .. · 1· ·d 301 In polyethylene glycol oIntment Sa 1ICY IC aCI 10
Prevention of Moisture
As has already been mentioned, moisture is an important factor, particularly in intertriginous infections. Therefore, all efforts to decrease moisture must be made. The specific suggestions will be made in the individual sections. Suffice it to say here that these measures include exposure to the air, wearing of light clothing, and the avoidance of excessive heat and emotional stimuli which cause reflex sweating. Specific Fungistatic and Fungicidal Therapy
The new era of antifungal therapy was ushered in with the discovery by Peck et al. that straight-chain fatty acids are highly fungicidal. 6 Subsequently, it was shown that the activity of the fatty acids increases as the length of the chain increases, with the C-11 compound, undecylenic acid, being the most active agent. 7 The odd-chain fatty acids are those possessing this antifungal activity and these compounds are found in small amounts in the surface lipid film of the human. 8 Actually, these compounds are fungicidal but it is not necessary for an agent to be fungicidal
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because the organism will be thrown off if its growth is just inhibited. Therefore, the advantage of a fungicidal agent as compared to a fungistatic agent is, for the most part, an academic argument. The three fatty acids that have been used for the most part are propionic acid, caprylic acid and undecylenic acid. The last is the most effective and is often prescribed as follows: undecylenic acid 5 per cent; zinc undecylenate 20 per cent; hydrophilic ointment 75 per cent. (Desenex ointment contains 5 per cent undecylenic acid and 20 per cent zinc undecylenate. Desenex powder contains 2 per cent undecylenic acid and 20 per cent zinc undecylenate.) One of the advantages of the fatty acids as a group is that they are a normal product of skin and as such are relatively nontoxic and nonirritating. The advent of the fatty acids has practically eliminated the use of some of the older fungistatic agents such as the mercurials. However, the search for new fungicides and fungistatic agents continues and the salicylanilides and chlorosalicylanilides are often used as is diamthazole dihydrochloride (Asterol). Caution is indicated when the last agent is used as it has caused convulsions in young children. Use of I{eratolytics
Because the organisIlls grow in the superficial keratinized layers of the skin, it is natural to have attempted to desquamate the fungi with keratolytic agents such as phenol, sulfur, resorcinol and salicylic acid. Actually, while these agents are keratolytic they also are fungistatic, and part of their action is due to their specific effect upon the organisms. It is impossible to remove completely the keratin with these agents and they are not usually more effective than the specific fungicidal or fungistatic agents. It must be remembered that these agents applied in sufficiently strong concentrations often act as primary irritants. Areas in which they are most needed, namely those areas which are the sites of the most resistant infections such as the hair, nails, palms and soles, are not particularly affected by these agents. We do not have a good keratolytic agent for infections of hair or nails. In the case of the palms and soles, often the soaking of the hands or feet in water will macerate the keratin a.nd a great amount can be scraped off with a blunt instrument. SPECIFIC REGIONAL THERAPY
RingworDl of the Scalp
In this country the majority of the cases of ringworm of the scalp are caused by Microsporum audouini and Microsporum canis and I will consider in detail the therapy of the disease caused by only these two organisms. Usually Microsporum audouini infections are noninflammatory while those caused by Microsporum canis are inflammatory; otherwise the infections behave the same. If the infection is noninflammatorY,it usually spreads for a period of three to four months; after this, further
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spread is unusual. Of course the inflammatory lesions are self-healing, and even in the usual noninflammatory case a cure is seen in four to six months in 50 to 60 per cent of the cases. Any claims of the effectiveness of therapeutic agents must take into consideration this tendency for a spontaneous cure. It is not my purpose to discuss in detail the pathogenesis of this disease as it is ably discussed elsewhere. 2 , 3 Suffice it to say that the active site of proliferation of the organisms is just above the hair root where the final stages of keratinization take place. This site is relatively inaccessible to topical medication; the agent must not only get down to the bottom of an individual hair follicle but it mu~t penetrate the hair itself. Therefore, it is not surprising that the results to date with the specific fungistatic and fungicidal agents have not really improved on the therapeutic success of Mother Nature herself. Nevertheless, as a routine, parents should use a nonirritating fungicidal agent such as Salundex ointment or Desenex ointment for two reasons: (1) These agents probably keep the spore count down and may control some of the infectivity of the individual case. (2) Mothers feel that something must be done to a child with this disease and these agents at least are unlikely to cause any adverse reactions. Manual epilation is not indicated, as it is ineffective. The fungus-infected hair is weak and will break off above the zone where actual mycotic proliferation takes place so that an infected stub will remain after the hair is plucked. The first line of defense against this disease is nature itself. However, there are a few cases which do not undergo a spontaneous cure, and if, after a period of four to six months there is no evidence of regression of the disease, temporary x-ray epilation is indicated. The rationale behind this type of therapy is that x-ray temporarily interferes with the keratinization of the hair and the organisms are deprived of any further keratin on which to grow. This type of therapy is safe provided it is performed by adequately trained dermatologists or radiologists who are familiar with the course of the disease as well as the use of the equipment. The hair falls out in a period of about three weeks and regrowth starts in approximately two months. The regrowth is usually complete by six months. It should be emphasized again that this procedure is not the first line of defense in this disease and is employed only after adequate conservative therapy has been tried. As a matter of fact, if x-ray epilation is given early in the course of the disease before the natural host resistance develops, reinfections are common. Children with thi~ disease are generally not excluded from school. While the disease is communicable, it is not highly contagious. It would be an economic and social hardship to exclude children from school when it takes four to six months to promote a cure. Efforts should be made to prevent bodily contact with infected children. A cap should be worn by the infected child and he should make every effort to see that no one else uses this cap. Another source of infection is from hairs that may be trans-
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ferred to the backs of upholstered seats such as those in movie theaters or in busses. If the infection is one that has come from an animal, such aFt a dog or cat, appropriate measures should be taken to control the infection in the animal host. A special inflammatory lesion that is sometimes seen is a kerion. This is a marked erythematous, eczematous inflammatory lesion which may appear purulent and represents a severe allergic tissue reaction to the fungus organisms. It is seen particularly in M. canis infections (animal type ringworm) but on occasion an M. audouini infection will also develop into a kerion. A kerion signifies the development of an allergic response on the part of the host and at this time the trichophytin test will become positive. Id reactions also may occur at this time. When this severe inflammatory reaction occurs, the follicles collapse and the hair stops growing. Therefore, the development of a kerion signifies the imminent termination of the infection; these lesions are self-healing. Kerions are wild looking and convincing arguments on the part of the physician are required to keep parents from demanding all types of heroic medications. Here is a lesion in which the principles of good general dermatologic care must be employed. It is an acute lesion and therefore compresses three to four times a day are indicated. It is an acute lesion and active medications such as fungicides often will lead to an exacerbation. It is not caused by bacteria, although they may be recovered on culture. However, frank secondary infection is rare, and as a routine antibiotic therapy is not indicated. If the patient or the family is unwilling to accept the use of water soaks, a mild solution such as 1 :20 Burow's solution or physiologic saline should be used for the soaks. Of course x-ray therapy is contraindicated. The parents should be reassured that this event definitely heralds the disappearance of the disease. However, the severe inflammatory reaction may possibly be accompanied by permanent alopecia which is usually, at the most, partial and most commonly minor in extent. In the southern section of the United States an increasing number of cases of tinea capitis due to Trichophyton tonsurans are now being seen. '1'his particular type of infection is much more difficult to diagnose and is a much greater therapeutic problem. While the Microsporum infections characteristically involve only children, Trichophyton tonsurans infections may also involve adults. There is no tendency to spontaneous cure and vigorous therapeutic approaches are necessary. Usually topical antifungal therapy is of no avail and temporary x-ray epilation is necessary. After the x-ray epilation, topical antifungal therapy must be continued but in spite of this the infection often recurs. The care of these patients definitely belongs to those who specialize in dermatology. Tinea Pedis
This, the most common superficial fungus infection, is actually the disease that is most subjected to mismanagement by the patient. Also
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there is a tendency on the part of many physicians to call every lesion seen on the foot and in the interdigital spaces a fungus infection. Most patients readily ascribe the infection to walking barefooted in a shower stall, around a swimming pool or similar types of circumstances. Actually, recent evidence has shown that the exogenous source of fungi is probably minor and that the acute reinfection is probably an endogenous process. 4 , 9,10 The thick, horny material of the soles and of the nails is usually the reservoir from which the fungi disseminate to the test of the foot. Infections of the soles and nails are extremely resistant to treatment and often may exist without the presence of clinical signs. Treatment must be discussed by area involved and acuteness of the lesions. The most common lesion that the physician is called upon to treat is the acute interdigital lesion. The regimen in severe acute cases should· include the following: 1. Rest. It is essential that the patient rest as much as possible and there is much to be gained by actually having the patient keep his shoes and socks off and stay in bed. 2. Exposure to air. The afflicted area should be exposed to air by keeping the toes separated with material such as interdigital pads, lamb's wool or gauze. 3. Soaks. Water soaks should be used for about ten minutes out of every two hours. Longer soaks are contraindicated in that they will aggravate the maceration. Active medication need not be incorporated in the soaks unless the patient is unwilling to accept the use of plain water. 4. Specific antifungal treatment. No specific antifungal measures should be used at this time as they may only irritate the lesions. As the lesions become more chronic and the erythema and maceration disappear, the frequency of the soaks can be decreased and specific antifungal agents such as Desenex powder or ointment can be applied to the interspaces. Contrary to popular opinion, Desenex ointment may be used in the interdigital spaces provided only a thin coat is applied. In the treatment of interdigital infections, systemic antibiotics are necessary only if there is evidence of a bacterial cellulitis. Acute vesicular lesions of the soles should be handled similarly to the acute interdigital infections. Chronic scaling hyperkeratotic lesions of the soles are virtually impossible to treat and are best left alone. Nail infections will be discussed later. The major problem in the treatment of ringworm of the foot is one of r;rophylaxis. Eighty-five per cent of the patients who have an infection in the interdigital spaces will have an infection in either the soles or the nails, and actually in about 50 per cent of the patients there will be an infection in both the soles and the nails; these are the sources of reinfection. 4 Probably the most important factors in reinfection are the presence of moisture and heat, and the prophylactic measures are mainly directed
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toward these factors. Therefore, the patient should be warned to wear a lightweight shoe, preferably a ventilated shoe. Leather soles are preferred over rubber-soled shoes. Socks should be of light-weight cotton, and if the patient must wear shoes for a long period of time he should be advised to bring an extra pair of shoes and socks to work. Nylon socks tend to prevent evaporation of moisture and are contraindicated. When the patient gets home he should be told to remove his shoes and walk around in his stocking feet or open-toed slippers. The infectivity of this type of infection from person to person is low and therefore the patient does not have to be concerned about infecting other members of the family. A medicated powder such as Desenex should be lightly dusted into the socks before they are applied, possibly to keep the spore count down. Most patients find that by following a regimen such as this they are able to prevent recurrences of the infection. Nail Infections
There is no local therapy that is adequate for nail infections. Surgical avulsion is often practical but as commonly done the recurrence rate is high. The primary site of nail involvement is the nail bed and not the nail itself. Therefore, it is necessary to remove all of the nail bed keratin. This is done by vigorous curetting of the nail bed distal to the nail matrix (which is the actual organ which produces the nail). All of the keratinous debris must be removed carefully, including the material in the lateral nail grooves. If the matrix is not touched, the regrowth of the nail will be normal. After this treatment, local fungicides should be used during the period in which the nail regrows. Even with these vigorous methods the cure rate is not exceptional, and only certain cases should be considered for this procedure. I do not routinely treat infected toenails since there is almost always a recurrence after treatment. If an isolated fingernail or a few fingernails are involved, particularly if these nails are acting as sources for reinfection of glabrous skin, these nails should be treated. Often the patient will complain of pain from the thickened toenails, and, if avulsion is not indicated, the nails can be trimmed down with dental burrs. Tinea Cruris
This is an intertriginous infection and should be handled in much the same manner as intertriginous infections of the feet. When there is marked exudation and maceration, treatment consists of rest, aeration and sitz baths along with the use of a bland dusting powder or shake lotion. In the more chronic phases, preparations containing 2 to 3 per cent precipitated sulfur and salicylic acid in an emulsion base can be used. An alcoholic lotion of 2 per cent salicylic acid in 50 per cent ethyl alcohol also is quite effective, but care must be taken to prevent this from coming into contact with the adjacent mucous membranes. Grease type
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ointments should be avoided and the patient should be instructed in the use of loose fitting underwear, frequent powdering and other methods to keep the area dry and cool. Fungus Infections of the Glabrous Skin
This type of ringworm infection is very easy to handle when compared with some of the other infections such as those involving the hair or squamous portions of the soles. Many of the preparations already mentioned, such as the fatty acid compounds or sulfur and salicylic acid ointments, are effective. A thin coat of ointment should be applied two to three times a day. Whitfield's ointment (U.S.P. XV) is also effective in these infections. There is also a group of plaque-like lesions caused by Trichophyton rubrum. These are extremely resistant to therapy and require the use of strong keratolytic agents such as the old full-strength Whitfield's ointment (12 per cent benzoic acid and 6 per cent salicylic acid). Id Reactions (Trichophyton Reactions)
This type of reaction is an acute response on the part of the host to the dissemination of some products of the fungi through the blood stream. It is a true allergic reaction and occurs in association with severe, acute lesions elsewhere on the body. This reaction is often associated with too energetic treatment of an acute lesion. Id reactions usually tend to be disseminate and often are follicular in distribution. T~hey may be erythematous papules, vesicles or scaling lesions. The "id" lesions are sterile while the active original foci elsewhere of course will show fungal elements. Since the id reaction is a specific allergic manifestation, the trichophytin skin test is positive even in weak dilutions. rThe treatment of the id reaction is dependent upon the eradication of the primary focus. Subsequently the id reaction will completely disappear. Specific therapy for the "id" lesions is that described elsewhere for good dermatologic therapy. Miscellaneous Fungus Infections Tinea versicolor is the most common infection in this group. The superficiality of this type of infection has already been pointed out, and a response is rapidly obtained to many topical medications such as fatty acid preparations or sulfur and salicylic acid preparations. Actually, the use of a good scrub brush often will remove many of the lesions; vinegar applications and sodium hyposulfite (20 per cent) applied locally also have been highly effective. Unfortunately the recurrence rate is extremely high with this disease and upon the cessation of treatment the lesions will recur. Erythrasma will respond to the same type of therapy as that advocated for tinea versicolor.
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Trichomycosis axillaris, while having been considered to be a fungus infection, probably should no longer be classified in this group. The disease is caused by a Corynebacterium, and treatment consists either of shaving the hair or using topical antibiotics or antiseptics. The disease often recurs, and the patient should be advised that relapses will likely' be seen. SUMMARY
In general, treatment of the superficial fungus infections of the skin follows the general therapeutic patterns established for the treatment of other cutaneous diseases. Treatment must be correlated with the acuteness of the particular lesion. Acute lesions should not be treated with agents that may be irritating. Moisture and heat are common precipitating factors and the prevention of excessive moisture and heat is important in the treatment of these infections. As the infections become more chronic, the use of specific antifungal agents or keratolytics is indicated. Above all, the primary duty of the physician is to make the correct diagnosis before he undertakes therapy. REFERENCES 1. Lorincz, A. L., Priestley, J. O. and Jacob, P. H.: Evidence for a Humoral Mechanism Which Prevents Growth of Dermatophytes. Presented at the 18th Annual Meeting of the Society for Investigative Dermatology, June 2,1957, New York, N. Y. 2. Kligman, A. M.: Tinea Capitis Due to M. audouini and M. canis. 11. Dynamics of the Host-Parasite Relationship. A.M.A. Arch. Dermat. 71: 313-337 (March) 1955. 3. Kligman, A. M.: The Pathogenesis of Tinea Capitis Due to Microsporum audouini and Micrisporum canis. I. Gross Observations Following the Inoculations of Humans. J. Invest. Dermat. 18: 231-246 (March) 1952. 4. Strauss, J. S. and Kligman, A. M.: An Experimental Study of Tinea Pedis and Onychomycosis of the Foot. A.M.A. Arch. Dermat. 76: 70-79 (July) *1957. 5. Dolan, M. M., Ebelhare, J. S., Kligman, A. M. and Bard, R. C.: A Semi-In Vivo Procedure for Testing Antifungal Agents for Topical Use. J. Invest. Dermat. 28: 359-362 (May) 1957. 6. Peck, S. M., Rosenfeld, H., Leifer, W. and Bierman, W.: Role of Sweat as a Fungicide, with Special Reference to the Use of Constituents of Sweat in the Therapy of Fungous Infections. Arch. Dermat. & Syph. 39: 126-148 (Jan.) 1939. 7. Grunberg, E.: The Fungistatic and Fungicidal Effiects of the Fatty Acids on Species of Trichophyton. Yale J. BioI. & Med. 19: 855-876 (May) 1947. 8. Rothman, S., Smiljanic, A., Shapiro, A. L. and Weitkamp, A. W.: The Spontaneous Cure of Tinea Capitis in Puberty. J. Invest. Dermat. 8: 81-98 (Feb.) 1947. 9. Baer, R. L., Rosenthal, S. A., Litt, J. Z. and Rogachefsky, H.: Experimental Investigations on Mechanism Producing Acute Dermatophytosis of Feet. J.A.M.A. 160: 184-190 (Jan. 21) 1956. 10. Baer, R. L., Rosenthal, S. A., Rogachefsky, Hand Litt, J. Z.: Newer Studies on the Epidemiology of Fungus Infections of the Feet. Am. J. Pub. Health J,.5: 784-790 (June) 1955.
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