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The management of superficial candidiasis
SUPPORTED BY AN EDUCATIONAL GRANT FROM PFIZER INC
The management of superficial candidiasis Roderick J. Hay, DM, FRCP, FRCPath London, United Kingdom Superficial Candida infection includes several common conditions, most often related to some underlying local or systemic predisposition. Appropriate identification of the pathogen is important in the management of candidiasis as the result of differences in susceptibility among species and strains of Candida to different antifungal drugs. Treatment options are reviewed for oropharyngeal candidiasis, vaginal candidiasis, cutaneous candidiasis, paronychia and onychomycosis, and chronic mucocutaneous candidiasis. Because of the importance of predisposing conditions for candidiasis, adjunctive measures to abate these may be useful, although they are seldom effective in immunocompromised patients. (J Am Acad Dermatol 1999;40:S35-42.)
Superficial mycoses caused by species of the genus Candida are common in most countries. They include some of the most common mucosal infections, such as thrush, C vaginitis, paronychia, and interdigital candidiasis. Most Candida infections result from some form of local or systemic predisposition. C albicans is the organism most commonly associated with superficial candidiasis. However, other species such as C tropicalis, C parapsilosis, C glabrata, or C guilliermondii may be involved.1 C albicans is a common saprophyte on mucosal surfaces, particularly the mouth, gastrointestinal tract, and vagina. C albicans may also be isolated from the environment, particularly when human contact is frequent (eg, washbasins, cups). Oral colonization may originate early in infancy, although its incidence is increased by a number of factors, including hospitalization, bottle feeding, antibiotic therapy, and immunosuppression. Most individuals with superficial candidiasis have some underlying predisposition (Table I). The major exception is vaginal candidiasis, where it is unusual to uncover any underlying clinical abnormality in affected patients.2 In recent years there has been an increasing concern over the significance and management of From St John’s Institute of Dermatology, Guy’s Hospital, London. No grants or research support was received for preparation of this work. The author has received research support from Novartis and Janssen Pharmaceutical. Reprint requests: R. J. Hay, DM, St John’s Institute of Dermatology, Guy’s Hospital, London SE1 9RT, United Kingdom. Copyright © 1999 by the American Academy of Dermatology, Inc. 0190-9622/99/$8.00 + 0 16/0/98111
Table I. Superficial candidiasis: predisposing factors Infancy, pregnancy, old age, occlusion of epithelial surfaces (eg, by dentures, occlusive dressings) Disorders of immunity and of cells of the immune system Primary (eg, chronic granulomatous disease) Secondary (eg, leukemia, corticosteroid therapy) Chemotherapy Immunosuppressive Antibiotic Endocrine disease (eg, diabetes mellitus, Cushing’s syndrome) Carcinoma Miscellaneous (eg, damaged nail folds, oral lichen planus)
oropharyngeal candidiasis in patients with HIV infections.3,4 In patients with progressive immunodeficiency and AIDS, the prevalence of oral carriage ranges from 43% to 98%.5 Factors that appear to increase oropharyngeal carriage rates in individuals who are HIV positive range from low CD4 counts6 to smoking,7 although the wider use of protease inhibitors in the treatment of HIV has led to a decline in the frequency of clinically apparent candidiasis in the population with AIDS. At present, the extent of this change has not been well documented. The non–albicans Candida species have been detected more frequently in clinical isolates in recent years, particularly from oropharyngeal cultures in patients who are HIVpositive8 and in blood cultures; a new species C dubliniensis has been isolated from oral candidiasis in patients with AIDS.9 The clinical implicaS35
S36 Hay tions of the isolation of this new organism are difficult to evaluate as yet, because it is difficult to separate C dubliniensis from C albicans in many identification systems, although it has a characteristic DNA profile and is distinguishable from C albicans on CHROMagar Candida (CHROMagar, North Massapequa, NY), an agar medium on which different Candida species appear as different colors. In addition, C dubliniensis is often notably resistant to fluconazole. DRUG RESISTANCE
The problem of azole drug resistance has dominated the discussion of candidiasis management in recent years. In the development of early antifungal chemotherapy, the only drug known to be associated with in vitro resistance among strains of C albicans was flucytosine. However, with the wider use of long-term ketoconazole in patients with chronic mucocutaneous candidiasis, a number of reports appeared of azole-resistant isolates of C albicans in patients who were receiving longterm suppressive treatment with the drug. There has subsequently been an upsurge in the numbers of such instances of drug resistance in patients with AIDS.10 At present, it is clear that some species of Candida exist that are intrinsically resistant in vitro to certain azoles. For example, C krusei and C glabrata are generally resistant to fluconazole, and C tropicalis is often resistant to ketoconazole. This resistance is well documented and forms part of the in vitro spectrum of activity of each drug.11 In addition, and mainly in the AIDS population, a proportion of patients with oropharyngeal candidiasis harbor strains of C albicans whose in vitro sensitivity to certain azoles, mainly fluconazole12 and ketoconazole, are higher than would be expected with standardized measures such as the National Committee for Clinical Laboratory Standards assay. These high minimum inhibitory concentrations (MICs), which provide a guide to potential drug resistance, are more than 10 mg/liter and in some cases 100 mg/L, raising the specter of treatment failure because of drug resistance. Indeed, certain patients with oropharyngeal candidiasis, or Candida infections elsewhere, fail to respond to therapy with azoles. Here again the immunosuppressed population bear the brunt of this problem. What is confusing, however, is that Candida isolates from patients whose condition does not respond to azole therapy may be
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apparently sensitive, whereas patients whose condition responds to treatment may have strains that show MIC values consistent with in vitro resistance.13 This is a particular problem when MICs are in the median range (10-60 mg/L). In practice it implies that resistance is a real problem, but the MICs do not necessarily predict treatment failure. Despite attempts to take into consideration extraneous reasons for aberrant test results (such as failure to test multiple oral isolates or perform DNA fingerprinting of strains to ensure that pre- and posttreatment isolates are identical, because oral infection may occur simultaneously with different strains),14 it has not yet been possible to provide a fool-proof way to predict treatment outcome. In a large study of patients with candidemia, it was found that species rather than MIC was a better predictor of treatment failure, with specific non–albicans Candida species being isolated more frequently from patients whose condition does not respond to either fluconazole or amphotericin B.15 A second important issue concerning drug resistance is the occurrence of cross resistance. Once again, this is not predictable and isolates must be tested individually. However, organisms with high MICs to fluconazole, for example, are more likely to have high MICs to itraconazole, although some are fully sensitive in vitro to the latter.16 In addition, it is not clear whether there are intrinsic differences in the facility of Candida strains to develop resistance to different azoles.14,16 At present, the frequency of isolated itraconazole resistance in C albicans is low, whereas fluconazole-resistant isolates may also show itraconazole resistance. It is possible that this reflects an intrinsic difference in the sensitivity of the organism to each drug and that, for example, a higher binding capacity of itraconazole to the target cytochrome P450 may lead to a lower frequency of resistance. Azole resistance has been associated in some cases with decreased intracellular concentrations of the drugs in yeasts, suggesting either decreased permeability or increased extracellular transport.17 One potential difficulty with this argument is that few patients receive itraconazole as a primary therapy for AIDS-related mucosal candidiasis over long periods, and the difference in the frequency of resistance between the 2 drugs may merely reflect exposure rates to each form of therapy. These concerns have to be considered in select-
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ing appropriate treatments for superficial candidiasis. This means, for example, that it is important to adopt appropriate identification schemes for yeasts isolated from superficial sites, particularly the mouth, because the selection of the most effective drug may depend on the identity of the organism isolated. It is also important to obtain specimens that are most appropriate for making an accurate diagnosis. In some cases, such as nail disease associated with the isolation of Candida species, a nail biopsy may be necessary.18 Candida is a common commensal in nails with onycholysis, and its isolation from diseased nails may simply reflect colonization of the undersurface of the nail plate. However, the possibility that the increased frequency of isolation of Candida species from nails in tropical climates is due to genuine infection must be considered.19 MANAGEMENT OF SUPERFICIAL CANDIDA INFECTION
Oropharyngeal candidiasis This is a common condition, particularly in elderly patients, and it may also follow immunosuppression or antibiotic therapy. It is an important infectious complication of AIDS and a marker of progression in HIV infection.20 The infection has solitary or confluent white plaques on the oral mucosa (pseudomembranous candidiasis; Table II). Alternatively, the mucosa may appear glazed and erythematous; on the surface of the tongue this results in the loss of tongue papillae (erythematous candidiasis).22 Signs of infection are therefore sometimes fairly subtle. Esophageal infection often accompanies oral candidiasis in patients with AIDS. Factors to be considered in the treatment selection include the likelihood of relapse after therapy is stopped and the presence of esophageal infection. Treatment with topically applied amphotericin B, nystatin, or miconazole oral gel is effective in many patients, the latter being easiest to use in infants.11 However, immunocompromised patients, including those with AIDS, often do not respond to topical treatment and oral systemic therapies with fluconazole, itraconazole, or ketoconazole are more effective. Most of these medications are well absorbed in patients with AIDS, but ketoconazole and itraconazole may require higher than normal doses (ketoconazole 400 mg daily, normal 200 mg; itraconazole 200 mg daily, normal 100 mg).20 A new oral solution
Hay S37 Table II. Clinical classification of oral candidiasis acute plaque-type Erythematous Chronic plaque-type Erythematous Nodular Atrophic Median rhomboid glossitis21 Angular cheilitis Secondary to existing oral lesions (eg, lichen planus)
of itraconazole in cyclodextrin is available in some countries. It is better absorbed than the conventional capsule preparation and produces faster clinical responses.23,24 The solution is used in doses similar to the capsule formulation, although with seriously immunocompromised patients such as bone marrow transplant recipients, doses of 2.5 mg/kg are usual. In either case, the main objective of treatment in patients with AIDS has been to produce clinical remission, and because relapse is common, retreatment is likely. Although suppressive therapy has been used as a means of preventing relapse or of preventing cryptococcal infection in patients with AIDS, the risk of resistance or clinical tolerance is high. Generally, fluconazole is given for symptomatic oral disease in single courses of 100 mg to 200 mg daily for 5 to 10 days. Ketoconazole and itraconazole use similar strategies. As has been previously discussed, resistance to fluconazole and ketoconazole may develop if these drugs are given continuously in the face of clinically unresponsive infection.25,26 Generally, Candida resistance is mainly seen among certain non-albicans species of Candida such as C krusei and C glabrata, although these are less important in superficial disease than in candidemia. Oral C albicans may also become secondarily resistant to fluconazole and ketoconazole, as has been previously described. Such strains may emerge when azoles are used at low dosages and over long periods, typically in oropharyngeal candidiasis in patients with AIDS.12,27 Risk factors associated with the emergence of azole resistance include low CD4 counts, more than 5 episodes of oropharyngeal candidiasis in the past year, the variety of HIV infection, and the previous use of azoles.27 Of these, the factor independently associated with risk is the prior use of azoles, although some patients with resistant
S38 Hay isolates have not received azole therapy. However, strains with MIC values of more than 8 mg/L (a high value) may still respond to therapy, and MIC values alone may not predict clinical outcome.24 Generally, when patients fail to respond clinically to fluconazole, the dose is usually doubled (eg, from 100 to 200 mg/day) as an initial measure. Only if this fails, is it necessary to check the identity and MIC value of the organism and to change drugs. If itraconazole is used, treatment can involve either the oral solution or the conventional capsule form of the drug. The oral solution is well tolerated by most patients unless they have severe mucositis. A well-tolerated solution formulation of fluconazole is also available. Strategies in the face of treatment failure with either itraconazole or ketoconazole should be the same as with fluconazole (ie, the first step consists of doubling the initial dose of the drug). In nonimmunocompromised patients with dentures, the use of oral antifungal drugs alone may not be sufficient, and hygienic measures such as regular periodic denture cleaning are important. In addition, denture-associated oral candidiasis may require concomitant use of both an antifungal agent such as fluconazole and an antiseptic mouthwash such as chlorhexidine.28 Vaginal candidiasis Vaginal infection with Candida species is common, and although it may be associated with diabetes and the third trimester of pregnancy, most of those patients who are affected have no obvious underlying predisposition. Risk factors associated with vaginal candidiasis in college students have included previous episodes of candidiasis in the past year and the use of oral contraceptives or spermicides.29 However, these factors are not present in every case. The symptoms of vaginal candidiasis are irritation and discomfort associated, in many cases, with a creamy discharge.2 On examination the changes may resemble those seen in oral infections with plaque-type or erythematous lesions. Skin lesions may spread from the vulva to the groin area; the rash is erythematous with a prominent border. Small “satellite” pustules or crusts are often seen outside this border. Some women develop either continuous infections or have regular symptomatic relapses (chronic vaginal candidiasis); the management of these patients presents a major challenge. There is no reliable
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way to distinguish clinically between infections as the result of C albicans and non-albicans Candida species such as C glabrata.30 Vaginal infections respond to intensive topical therapy given for 1 to 5 days with either cream, vaginal tablets, or pessaries.31 Nystatin or a topically applied imidazole such as miconazole is usually successful. Alternatively, oral treatment either with single-dose fluconazole (150 mg) or with fluconazole 100 mg/day for 5 to 7 days or itraconzole 200 mg/day for 3 to 5 days is very effective. If the initial treatment fails, the male partner should be treated as well. Relapse may be a problem in some patients. Some concern exists over the broadscale use of over-the-counter preparations for vaginal symptoms by women who may self-diagnose candidiasis erroneously. It has been suggested that patient education needs to be improved to enable women to distinguish accurately between different causes of infection.32 Recurrent or chronic vaginal candidiasis is a common problem that is very distressing to the patient. However, there is, as yet, no simple remedy. Although there is some evidence to suggest that there are specific and distinct T-lymphocyte populations in the vaginal mucosa in experimental murine infections,33 no evidence exists to show that defects in a specific subpopulation of T cells influence the development of chronic infections in susceptible individuals. In addition, some women experience the development of symptomatic vaginal candidiasis but have scanty yeasts in vaginal smears or culture. These infections may respond to a combination of antifungal medication and either an emollient or oral antihistamines, possibly because of sensitization to low Candida loads. Several different strategies have been developed for managing chronic vaginal candidiasis, although none has been subject to comparative study. These have included the use of continuous or intermittent suppressive treatment with either oral or topical antifungal drugs such as fluconazole, itraconazole, or a topical antifungal agent (eg, terconazole).34,35 However, the long-term results of such studies are not available. It is important that women with recurrent symptoms suggestive of vaginitis be checked clinically and microbiologically for the presence of Candida and other conditions, including bacterial vaginosis and Trichomonas infection, which should include checking the identity of isolates, because non–
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albicans Candida species may respond poorly to treatment. However, resistant C albicans strains are seldom isolated from such patients.36 C glabrata in particular has been associated with vaginitis unresponsive to treatment. This is important to identify, because it is seldom azole sensitive. In C glabrata vaginitis, a variety of approaches may help37; these have included itraconazole or nystatin individually or in combination. Once again, however, the numbers of such cases are low, and there is no published controlled clinical study. In addition, it is important to ensure that women with persistent or relapsing vaginal candidiasis do not have underlying predisposing factors that may encourage chronic infection; for example, recently concurrent treatment with tamoxifen has been associated with chronic vaginal candidiasis.38 Cutaneous candidiasis Candida species invade the skin surface in a number of disease states. However, their management is seldom problematic. In interdigital candidiasis, Candida may cause scaling and maceration between the toes (athlete’s foot). In addition, a superficial erosion on the hand between the fingers within the dorsal web space may also be caused by Candida infection. This type of interdigital erosion is seen much more frequently in warm climates. C intertrigo is the name given to a painful or irritative inflammatory dermatosis confined to body folds to which secondary Candida infections may contribute. Treatment of the Candida infection alone rarely produces a cure, and it is also necessary to take steps to dry the skin and prevent the development of maceration by the use of talcs and powders. This infection is most common in overweight or diabetic individuals, and when attacks recur, it is important to evaluate the patient for diabetes. Secondary infection with Candida may also occur in the diaper area on top of an irritative dermatosis caused by urine. Generally, these forms of candidiasis are secondary infections either on top of an existing medical condition, or, in the case of widespread cutaneous candidiasis, they may appear rarely in infants as primary skin infections. They respond to topical therapies such as azoles, terbinafine cream, or nystatin.39 Only in extensive disease is oral antifungal therapy necessary. Interdigital candidiasis or intertrigo does not always respond to antifungal
Hay S39 therapy, and sometimes regular cleansing with an antiseptic drying agent such as potassium permanganate solution may be more effective. Paronychia and onychomycosis Infection of the nail folds by Candida species is 1 cause of paronychia.40 The periungual skin is raised and painful, and a prominent gap develops between the fold and the nail plate. Pus may be discharged. More rarely, invasion of the nail plate with associated lateral onycholysis occurs. Certain bacteria, such as Staphylococcus aureus, also play a role in the formation of paronychia, and the condition is best regarded as multifactorial, although individuals with much exposure to water and cooking seem to be predisposed. Irritant dermatitis cause by food may provoke inflammation. Patients with abnormal nail folds associated with skin disease, such as hand eczema or contact dermatitis, may also be infected. Considerable confusion persists regarding the frequency of genuine Candida onychomycosis. The problem centers around the ability of Candida species to colonize sites such as the subungual space caused by onycholysis. The presence of yeasts alone is not sufficient grounds to consider that the organism is invasive, and Candida species have not been shown capable of breaking down keratin. Generally, the best described form of Candida onychomycosis is that associated with chronic mucocutaneous candidiasis. It is also uncommonly seen in association with steroid therapy, Cushing’s syndrome, or Raynaud’s disease, where the condition resembles onychomycosis as the result of dermatophytes.1 Candida paronychia requires prolonged topical therapy with frequent applications of polyenes, imidazoles, or nonspecific remedies such as 4% thymol in chloroform or sulphacetamide lotion. Lotions are probably preferable to creams.11 There have been too few studies of either itraconazole or fluconazole to comment on their effectiveness in paronychia. The anti-Candida regimen is followed by general measures such as ensuring adequate drying of the hands. The hands should be kept warm, and poor peripheral circulation should be improved if possible, because patients with recurrent perniosis may experience the development of paronychia. In many patients, particularly in the chronic phases of paronychia, the central role of Candida in prolonging the condition is debatable,
S40 Hay Table III. Classification of CMC Idiopathic CMC (without known associations) Familial CMC associated with endocrinopathy Autosomal recessive CMC with familial endocrinopathy syndrome (hypoparathyroidism or hypoadrenalism) Autosomal dominant CMC with hypothyroidism Familial CMC without endocrinopathy Autosomal dominant Autosomal recessive CMC associated with interstitial keratitis Adult-onset CMC associated with thymoma From Coleman R, Hay RJ. Chronic mucocutaneous candidiasis associated with hypothyroidism: A distinct syndrome? Br J Dermatol 1997;136:24-9. By permission.
and other factors such as irritant or allergic contact dermatitis may play a role. For this reason, in chronic cases, concomitant use of a topical corticosteroid is a logical approach. In proven Candida onychomycosis, ketoconazole or itraconazole offer real hope of success.18 The efficacy of intermittent (pulsed) itraconazole or weekly fluconazole, although logical, has not been established as yet for this indication. It is important, however, to select cases for antifungal treatment carefully on the basis of features associated with genuine Candida nail-plate invasion, such as onycholysis with distal erosion of the nail plate, the presence of yeast and hyphae in nail microscopy, or biopsy specimen and the growth of C albicans. Such cases are not common but may respond well to continuous oral itraconazole therapy.18 In contrast, antifungal treatment of primary or secondary onycholysis complicated by Candida colonization makes no clinical impact. Chronic mucocutaneous candidiasis Chronic Candida infections of the mouth, nails, or other skin surfaces are rare, but in some cases they may persist despite treatment. This condition, known as chronic mucocutaneous candidiasis (CMC), occurs worldwide. It is usually recognized in infancy or childhood, and there are frequently underlying genetic, endocrine, or immunologic features. Autosomal dominant or recessive predisposition and endocrinopathy (such as hypoparathyroidism or hypoadrenalism), and hypothyroidism are all associated conditions (Table III).41-43 Evidence exists, however, that patients may have a variety of immune defects mainly involving defects in T-lymphocyte function,44
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although aberrant antibody responses (eg, low IgG2 but high IgG3) levels may also be found.45 Severe oral and nail infections, widespread infection, and hyperkeratosis on other surfaces may develop.44 There is some tendency for the condition to improve in adulthood. One of the clinical forms of oral candidiasis (the atrophic form) is seen in patients with CMC who smoke heavily; this may predispose to oral squamous cell carcinoma. Patients with CMC are also susceptible to other skin infections caused by dermatophytes and human papilloma viruses. Treatment of this condition depends critically on antifungal chemotherapy. Attempts have been made to restore T-cell function, usually by the use of transfer factor and latterly with cytokines. Transfer factor has a variable effect on the disease, although it is usually associated with improvements, albeit of a temporary nature; however, improvements in immune functions are not always demonstrable.46 Systemic anti-Candida therapy with fluconazole, itraconazole, or ketoconazole is likely to be necessary and may need to be prolonged and repeated. There is no published experience of the use of intermittent antifungal treatment in patients with CMC. The diagnosis is often made initially by consistent failure of a child with oral candidiasis to respond to topical anti-Candida treatment, and topicals appear to have little role in the management of CMC. In many respects, the treatment is similar to that used in AIDS-associated oropharyngeal candidiasis, and complications such as drug resistance may also occur in patients with CMC. Once a remission has been induced, maintenance therapy should not be used, in view of the risk of drug resistance. Although the tendency to develop oral candidiasis appears to diminish with age in some patients (unless the condition is provoked by antibiotics given for an intercurrent infection), patients with CMC remain susceptible to recurrent Candida infections. However, women with CMC seldom experience the development of recurrent vaginal candidiasis. Attention must be given to investigating new young patients for any endocrine abnormalities. Although their treatment is not likely to lead to improvement in the candidiasis, it may have considerable importance in the maintenance of the child’s health and development. Endocrine screening tests should be repeated even if initially negative, because patients with associated endocrinopathy may experience the development of endocrine disease years
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after the first appearance of candidiasis. Where appropriate, parents should be given genetic counseling (Table III). The possibility of coexisting dermatophytosis should be kept in mind, because it should respond satisfactorily to itraconazole or terbinafine. However, doses are often higher and are given for longer periods than those used for dermatophytosis in other patients (eg, itraconazole 400 mg daily and terbinafine 500 mg daily). DISCUSSION
The management of candidiasis depends on both drug therapy and adjunctive measures, which principally consist of attempts to reverse underlying predispositions. These include cleaning dentures with antiseptic solutions in oropharyngeal candidiasis, drying hands and wearing gloves during wet work to prevent paronychia, and drying interdigital spaces to reduce moisture and the risk of interdigital candidiasis. Such adjunctive measures are seldom effective in superficial Candida infections in immunocompromised patients, where the selection of the appropriate antifungal treatment, usually an oral agent, remains the most important decision. In addition, these measures are not sufficient to prevent recurrences of oral candidiasis in patients with AIDS. For this reason the policy adopted by most clinicians in treating patients with this condition is to use drug therapy to reduce symptoms, although not attempting to suppress the growth of Candida by long-term therapy. The short-term results of triple antiretroviral therapy in patients with HIV have had an impact on the prevalence and course of oropharyngeal candidiasis, and the long-term implications have yet to be defined. A further unsatisfactory situation is the current management of women with chronic or recurrent vaginal candidiasis. Although in some instances treatment failure is caused by an underlying predisposition, the presence of an unusual Candida species, or plain misdiagnosis, a substantial number of women continue to have recurrent episodes of vaginal candidiasis. The design of clinical trials of sufficient power to determine optimal treatment regimens for these patients is long overdue. A number of important challenges remain therefore in the treatment of superficial Candida infections. Although the development of the oral antifungal agents, starting with ketoconazole, has revolutionized the management of infections such as CMC, there is still some way to go.
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S42 Hay 17. Lamb DC, Kelly DE, Manning NJ, Kelly SL. Reduced intracellular accumulation of role antifungal results in resistance in Candida albicans isolate NCPF 3363. FEMS Microbiol Lett 1997;147:189-93. 18. Hay RJ, Baran R, Moore MK, Wilkinson JD. Candida onychomycosis: an evaluation of the role of Candida species in nail disease. Br J Dermatol 1988;118:47-58. 19. Nsanze H, Lestringant GG, Mustafa N, Usmani MA. Aetiology of onychomycosis in Al Ain, United Arab Emirates. Mycoses 1995;38:421-4. 20. Greenspan D, Greenspan JS. Oral mucosal manifestations of AIDS. Dermatol Clin 1987;5:733-7. 21. Cooke BED. Median rhomboid glossitis: candidiasis and not a developmental anomaly. Br J Dermatol 1975;93: 399-405. 22. Samaranayake LP, Yaacob HB. Classification of oral candidiasis. In: Samaranayake LP, MacFarlane TW, editors. Oral candidiasis. London: Wright; 1990. p. 82-101. 23. Prentice AG, Wamock DW, Johnson SA, Taylor PC, Oliver DA. Multiple dose pharmacokinetics of an oral solution of itraconazole in patients receiving chemotherapy for acute myeloid leukemia. J Antimicrob Chemother 1995;36:657-63. 24. Phillips P, Zemcov J, Mahmood W, Montaner JS, Craib K, Clarke AM. Itraconazole cyclodextrin solution for fluconazole-refractory oropharyngeal candidiasis in AIDS: correlation of clinical response with in vitro susceptibility. AIDS 1996;10:1369-76. 25. Drobacheff C, Manteaux A, Millon L, Reboux G, Barale T, Laurent R. Oropharyngeal candidiasis resistant to fluconazole in patients infected by HIV [in French]. Ann Dermatol Venereol 1996;123:85-9. 26. Silverman S Jr, Gallo JW, McKnight ML, Mayer P, deSanz S, Tan MM. Clinical characteristics and management responses in 85 HIV-infected patients with oral candidiasis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;82:402-7. 27. Tumbarello M, Caldarola G, Tacconelli E, Morace G, Posteraro B, Cauda R, et al. Analysis of the risk factors associated with the emergence of azole resistant oral candidiasis in the course of HIV infection. J Antimicrob Chemother 1996;38:691-9. 28. Kulak Y, Arikan A, Delibalta N. Comparison of three different treatment methods for generalized denture stomatitis. J Prosthet Dent 1994;72:283-8. 29. Geiger AM, Foxman B. Risk factors for vulvovaginal candidiasis: a case-control study among university students. Epidemiology 1996;7:182-7. 30. Geiger AM, Foxman B, Sobel JD. Chronic vulvovaginal candidiasis: characteristics of women with Candida albi-
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cans, C glabrata and no candida. Genitourin Med 1995; 71:304-7. Faro S. Vaginitis: diagnosis and management. Int J Fertil Menopausal Stud 1996;41:115-23. Ferris DG, Dekle C, Litaker MS. Women’s use of overthe-counter antifungal medications for gynecologic symptoms. J Fam Pract 1996;42:595-600. Fidel PL Jr, Wolf NA, KuKuruga MA. T lymphocytes in the murine vaginal mucosa are phenotypically distinct from those in the periphery. Infect Immun 1996;64:37939. Sobel JD. Recurrent vulvovaginal candidiasis. N Engl J Med 1986;315:1455-8. Kunzelmann V, Tietz HJ, Rossner D, Czaika V, Hopp M, Schmalreck A, et al. Prerequisites for effective therapy of chronic recurrent vaginal candidiasis [in German]. Mycoses 1996;39(suppl):65-72. Lynch ME, Sobel JD, Fidel PL Jr. Role of antifungal drug resistance in the pathogenesis of recurrent vulvovaginal candidiasis. J Med Vet Mycol 1996;34:337-9. White DJ, Johnson EM, Wamock DW. Management of persistent vulvovaginal candidiasis due to azole-resistant Candida glabrata. Genitourin Med 1993;69:112-4. Sobel JD, Chaim W, Leaman D. Recurrent vulvovaginal candidiasis associated with long-term tamoxifen treatment in postmenopausal women. Obstet Gynecol 1996; 88:704-6. Guidelines/Outcome Committee, American Academy of Dermatology. Guidelines of care for superficial mycotic infections of the skin: mucocutaneous candidiasis. J Am Acad Dermatol 1996;34:110-5. Frain-Bell W. Chronic paronychia: short review of 590 cases. Trans St John’s Hosp Dermatol Soc 1957;38:29-30. Kirkpatrick CH, Rich RB, Bennett JE. Chronic mucocutaneous candidiasis: model building in cellular immunology. Ann Intern Med 1971;74:955-78. Porter SR, Scully C. Candida endocrinopathy syndrome. Oral Surg Oral Med Oral Pathol 1986;61:573-8. Coleman R, Hay RJ. Chronic mucocutaneous candidiasis associated with hypothyroidism: A distinct syndrome? Br J Dermatol 1997;136:24-9. Kirkpatrick CH. Chronic mucocutaneous candidiasis. J Am Acad Dermatol 1994;31:S14-7. Lilic D, Calvert JE, Cant AJ, Abinun M, Spickett GP. Chronic mucocutaneous candidiasis, II: class and subclass of specific antibody responses in vivo and in vitro. Clin Exp Immunol 1996;105:213-9. Masi M, De Vinci C, Baricordi OR. Transfer factor in chronic mucocutaneous candidiasis. Biotherapy 1996;9: 97-103.
The management of superficial candidiasis Roderick J. Hay, DM, FRCP, FRCPath London, United Kingdom Superficial Candida infection includes several common conditions, most often related to some underlying local or systemic predisposition. Appropriate identification of the pathogen is important in the management of candidiasis as the result of differences in susceptibility among species and strains of Candida to different antifungal drugs. Treatment options are reviewed for oropharyngeal candidiasis, vaginal candidiasis, cutaneous candidiasis, paronychia and onychomycosis, and chronic mucocutaneous candidiasis. Because of the importance of predisposing conditions for candidiasis, adjunctive measures to abate these may be useful, although they are seldom effective in immunocompromised patients. (J Am Acad Dermatol 1999;40:S35-42.)
Superficial mycoses caused by species of the genus Candida are common in most countries. They include some of the most common mucosal infections, such as thrush, C vaginitis, paronychia, and interdigital candidiasis. Most Candida infections result from some form of local or systemic predisposition. C albicans is the organism most commonly associated with superficial candidiasis. However, other species such as C tropicalis, C parapsilosis, C glabrata, or C guilliermondii may be involved.1 C albicans is a common saprophyte on mucosal surfaces, particularly the mouth, gastrointestinal tract, and vagina. C albicans may also be isolated from the environment, particularly when human contact is frequent (eg, washbasins, cups). Oral colonization may originate early in infancy, although its incidence is increased by a number of factors, including hospitalization, bottle feeding, antibiotic therapy, and immunosuppression. Most individuals with superficial candidiasis have some underlying predisposition (Table I). The major exception is vaginal candidiasis, where it is unusual to uncover any underlying clinical abnormality in affected patients.2 In recent years there has been an increasing concern over the significance and management of From St John’s Institute of Dermatology, Guy’s Hospital, London. No grants or research support was received for preparation of this work. The author has received research support from Novartis and Janssen Pharmaceutical. Reprint requests: R. J. Hay, DM, St John’s Institute of Dermatology, Guy’s Hospital, London SE1 9RT, United Kingdom. Copyright © 1999 by the American Academy of Dermatology, Inc. 0190-9622/99/$8.00 + 0 16/0/98111
Table I. Superficial candidiasis: predisposing factors Infancy, pregnancy, old age, occlusion of epithelial surfaces (eg, by dentures, occlusive dressings) Disorders of immunity and of cells of the immune system Primary (eg, chronic granulomatous disease) Secondary (eg, leukemia, corticosteroid therapy) Chemotherapy Immunosuppressive Antibiotic Endocrine disease (eg, diabetes mellitus, Cushing’s syndrome) Carcinoma Miscellaneous (eg, damaged nail folds, oral lichen planus)
oropharyngeal candidiasis in patients with HIV infections.3,4 In patients with progressive immunodeficiency and AIDS, the prevalence of oral carriage ranges from 43% to 98%.5 Factors that appear to increase oropharyngeal carriage rates in individuals who are HIV positive range from low CD4 counts6 to smoking,7 although the wider use of protease inhibitors in the treatment of HIV has led to a decline in the frequency of clinically apparent candidiasis in the population with AIDS. At present, the extent of this change has not been well documented. The non–albicans Candida species have been detected more frequently in clinical isolates in recent years, particularly from oropharyngeal cultures in patients who are HIVpositive8 and in blood cultures; a new species C dubliniensis has been isolated from oral candidiasis in patients with AIDS.9 The clinical implicaS35
S36 Hay tions of the isolation of this new organism are difficult to evaluate as yet, because it is difficult to separate C dubliniensis from C albicans in many identification systems, although it has a characteristic DNA profile and is distinguishable from C albicans on CHROMagar Candida (CHROMagar, North Massapequa, NY), an agar medium on which different Candida species appear as different colors. In addition, C dubliniensis is often notably resistant to fluconazole. DRUG RESISTANCE
The problem of azole drug resistance has dominated the discussion of candidiasis management in recent years. In the development of early antifungal chemotherapy, the only drug known to be associated with in vitro resistance among strains of C albicans was flucytosine. However, with the wider use of long-term ketoconazole in patients with chronic mucocutaneous candidiasis, a number of reports appeared of azole-resistant isolates of C albicans in patients who were receiving longterm suppressive treatment with the drug. There has subsequently been an upsurge in the numbers of such instances of drug resistance in patients with AIDS.10 At present, it is clear that some species of Candida exist that are intrinsically resistant in vitro to certain azoles. For example, C krusei and C glabrata are generally resistant to fluconazole, and C tropicalis is often resistant to ketoconazole. This resistance is well documented and forms part of the in vitro spectrum of activity of each drug.11 In addition, and mainly in the AIDS population, a proportion of patients with oropharyngeal candidiasis harbor strains of C albicans whose in vitro sensitivity to certain azoles, mainly fluconazole12 and ketoconazole, are higher than would be expected with standardized measures such as the National Committee for Clinical Laboratory Standards assay. These high minimum inhibitory concentrations (MICs), which provide a guide to potential drug resistance, are more than 10 mg/liter and in some cases 100 mg/L, raising the specter of treatment failure because of drug resistance. Indeed, certain patients with oropharyngeal candidiasis, or Candida infections elsewhere, fail to respond to therapy with azoles. Here again the immunosuppressed population bear the brunt of this problem. What is confusing, however, is that Candida isolates from patients whose condition does not respond to azole therapy may be
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apparently sensitive, whereas patients whose condition responds to treatment may have strains that show MIC values consistent with in vitro resistance.13 This is a particular problem when MICs are in the median range (10-60 mg/L). In practice it implies that resistance is a real problem, but the MICs do not necessarily predict treatment failure. Despite attempts to take into consideration extraneous reasons for aberrant test results (such as failure to test multiple oral isolates or perform DNA fingerprinting of strains to ensure that pre- and posttreatment isolates are identical, because oral infection may occur simultaneously with different strains),14 it has not yet been possible to provide a fool-proof way to predict treatment outcome. In a large study of patients with candidemia, it was found that species rather than MIC was a better predictor of treatment failure, with specific non–albicans Candida species being isolated more frequently from patients whose condition does not respond to either fluconazole or amphotericin B.15 A second important issue concerning drug resistance is the occurrence of cross resistance. Once again, this is not predictable and isolates must be tested individually. However, organisms with high MICs to fluconazole, for example, are more likely to have high MICs to itraconazole, although some are fully sensitive in vitro to the latter.16 In addition, it is not clear whether there are intrinsic differences in the facility of Candida strains to develop resistance to different azoles.14,16 At present, the frequency of isolated itraconazole resistance in C albicans is low, whereas fluconazole-resistant isolates may also show itraconazole resistance. It is possible that this reflects an intrinsic difference in the sensitivity of the organism to each drug and that, for example, a higher binding capacity of itraconazole to the target cytochrome P450 may lead to a lower frequency of resistance. Azole resistance has been associated in some cases with decreased intracellular concentrations of the drugs in yeasts, suggesting either decreased permeability or increased extracellular transport.17 One potential difficulty with this argument is that few patients receive itraconazole as a primary therapy for AIDS-related mucosal candidiasis over long periods, and the difference in the frequency of resistance between the 2 drugs may merely reflect exposure rates to each form of therapy. These concerns have to be considered in select-
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ing appropriate treatments for superficial candidiasis. This means, for example, that it is important to adopt appropriate identification schemes for yeasts isolated from superficial sites, particularly the mouth, because the selection of the most effective drug may depend on the identity of the organism isolated. It is also important to obtain specimens that are most appropriate for making an accurate diagnosis. In some cases, such as nail disease associated with the isolation of Candida species, a nail biopsy may be necessary.18 Candida is a common commensal in nails with onycholysis, and its isolation from diseased nails may simply reflect colonization of the undersurface of the nail plate. However, the possibility that the increased frequency of isolation of Candida species from nails in tropical climates is due to genuine infection must be considered.19 MANAGEMENT OF SUPERFICIAL CANDIDA INFECTION
Oropharyngeal candidiasis This is a common condition, particularly in elderly patients, and it may also follow immunosuppression or antibiotic therapy. It is an important infectious complication of AIDS and a marker of progression in HIV infection.20 The infection has solitary or confluent white plaques on the oral mucosa (pseudomembranous candidiasis; Table II). Alternatively, the mucosa may appear glazed and erythematous; on the surface of the tongue this results in the loss of tongue papillae (erythematous candidiasis).22 Signs of infection are therefore sometimes fairly subtle. Esophageal infection often accompanies oral candidiasis in patients with AIDS. Factors to be considered in the treatment selection include the likelihood of relapse after therapy is stopped and the presence of esophageal infection. Treatment with topically applied amphotericin B, nystatin, or miconazole oral gel is effective in many patients, the latter being easiest to use in infants.11 However, immunocompromised patients, including those with AIDS, often do not respond to topical treatment and oral systemic therapies with fluconazole, itraconazole, or ketoconazole are more effective. Most of these medications are well absorbed in patients with AIDS, but ketoconazole and itraconazole may require higher than normal doses (ketoconazole 400 mg daily, normal 200 mg; itraconazole 200 mg daily, normal 100 mg).20 A new oral solution
Hay S37 Table II. Clinical classification of oral candidiasis acute plaque-type Erythematous Chronic plaque-type Erythematous Nodular Atrophic Median rhomboid glossitis21 Angular cheilitis Secondary to existing oral lesions (eg, lichen planus)
of itraconazole in cyclodextrin is available in some countries. It is better absorbed than the conventional capsule preparation and produces faster clinical responses.23,24 The solution is used in doses similar to the capsule formulation, although with seriously immunocompromised patients such as bone marrow transplant recipients, doses of 2.5 mg/kg are usual. In either case, the main objective of treatment in patients with AIDS has been to produce clinical remission, and because relapse is common, retreatment is likely. Although suppressive therapy has been used as a means of preventing relapse or of preventing cryptococcal infection in patients with AIDS, the risk of resistance or clinical tolerance is high. Generally, fluconazole is given for symptomatic oral disease in single courses of 100 mg to 200 mg daily for 5 to 10 days. Ketoconazole and itraconazole use similar strategies. As has been previously discussed, resistance to fluconazole and ketoconazole may develop if these drugs are given continuously in the face of clinically unresponsive infection.25,26 Generally, Candida resistance is mainly seen among certain non-albicans species of Candida such as C krusei and C glabrata, although these are less important in superficial disease than in candidemia. Oral C albicans may also become secondarily resistant to fluconazole and ketoconazole, as has been previously described. Such strains may emerge when azoles are used at low dosages and over long periods, typically in oropharyngeal candidiasis in patients with AIDS.12,27 Risk factors associated with the emergence of azole resistance include low CD4 counts, more than 5 episodes of oropharyngeal candidiasis in the past year, the variety of HIV infection, and the previous use of azoles.27 Of these, the factor independently associated with risk is the prior use of azoles, although some patients with resistant
S38 Hay isolates have not received azole therapy. However, strains with MIC values of more than 8 mg/L (a high value) may still respond to therapy, and MIC values alone may not predict clinical outcome.24 Generally, when patients fail to respond clinically to fluconazole, the dose is usually doubled (eg, from 100 to 200 mg/day) as an initial measure. Only if this fails, is it necessary to check the identity and MIC value of the organism and to change drugs. If itraconazole is used, treatment can involve either the oral solution or the conventional capsule form of the drug. The oral solution is well tolerated by most patients unless they have severe mucositis. A well-tolerated solution formulation of fluconazole is also available. Strategies in the face of treatment failure with either itraconazole or ketoconazole should be the same as with fluconazole (ie, the first step consists of doubling the initial dose of the drug). In nonimmunocompromised patients with dentures, the use of oral antifungal drugs alone may not be sufficient, and hygienic measures such as regular periodic denture cleaning are important. In addition, denture-associated oral candidiasis may require concomitant use of both an antifungal agent such as fluconazole and an antiseptic mouthwash such as chlorhexidine.28 Vaginal candidiasis Vaginal infection with Candida species is common, and although it may be associated with diabetes and the third trimester of pregnancy, most of those patients who are affected have no obvious underlying predisposition. Risk factors associated with vaginal candidiasis in college students have included previous episodes of candidiasis in the past year and the use of oral contraceptives or spermicides.29 However, these factors are not present in every case. The symptoms of vaginal candidiasis are irritation and discomfort associated, in many cases, with a creamy discharge.2 On examination the changes may resemble those seen in oral infections with plaque-type or erythematous lesions. Skin lesions may spread from the vulva to the groin area; the rash is erythematous with a prominent border. Small “satellite” pustules or crusts are often seen outside this border. Some women develop either continuous infections or have regular symptomatic relapses (chronic vaginal candidiasis); the management of these patients presents a major challenge. There is no reliable
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way to distinguish clinically between infections as the result of C albicans and non-albicans Candida species such as C glabrata.30 Vaginal infections respond to intensive topical therapy given for 1 to 5 days with either cream, vaginal tablets, or pessaries.31 Nystatin or a topically applied imidazole such as miconazole is usually successful. Alternatively, oral treatment either with single-dose fluconazole (150 mg) or with fluconazole 100 mg/day for 5 to 7 days or itraconzole 200 mg/day for 3 to 5 days is very effective. If the initial treatment fails, the male partner should be treated as well. Relapse may be a problem in some patients. Some concern exists over the broadscale use of over-the-counter preparations for vaginal symptoms by women who may self-diagnose candidiasis erroneously. It has been suggested that patient education needs to be improved to enable women to distinguish accurately between different causes of infection.32 Recurrent or chronic vaginal candidiasis is a common problem that is very distressing to the patient. However, there is, as yet, no simple remedy. Although there is some evidence to suggest that there are specific and distinct T-lymphocyte populations in the vaginal mucosa in experimental murine infections,33 no evidence exists to show that defects in a specific subpopulation of T cells influence the development of chronic infections in susceptible individuals. In addition, some women experience the development of symptomatic vaginal candidiasis but have scanty yeasts in vaginal smears or culture. These infections may respond to a combination of antifungal medication and either an emollient or oral antihistamines, possibly because of sensitization to low Candida loads. Several different strategies have been developed for managing chronic vaginal candidiasis, although none has been subject to comparative study. These have included the use of continuous or intermittent suppressive treatment with either oral or topical antifungal drugs such as fluconazole, itraconazole, or a topical antifungal agent (eg, terconazole).34,35 However, the long-term results of such studies are not available. It is important that women with recurrent symptoms suggestive of vaginitis be checked clinically and microbiologically for the presence of Candida and other conditions, including bacterial vaginosis and Trichomonas infection, which should include checking the identity of isolates, because non–
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albicans Candida species may respond poorly to treatment. However, resistant C albicans strains are seldom isolated from such patients.36 C glabrata in particular has been associated with vaginitis unresponsive to treatment. This is important to identify, because it is seldom azole sensitive. In C glabrata vaginitis, a variety of approaches may help37; these have included itraconazole or nystatin individually or in combination. Once again, however, the numbers of such cases are low, and there is no published controlled clinical study. In addition, it is important to ensure that women with persistent or relapsing vaginal candidiasis do not have underlying predisposing factors that may encourage chronic infection; for example, recently concurrent treatment with tamoxifen has been associated with chronic vaginal candidiasis.38 Cutaneous candidiasis Candida species invade the skin surface in a number of disease states. However, their management is seldom problematic. In interdigital candidiasis, Candida may cause scaling and maceration between the toes (athlete’s foot). In addition, a superficial erosion on the hand between the fingers within the dorsal web space may also be caused by Candida infection. This type of interdigital erosion is seen much more frequently in warm climates. C intertrigo is the name given to a painful or irritative inflammatory dermatosis confined to body folds to which secondary Candida infections may contribute. Treatment of the Candida infection alone rarely produces a cure, and it is also necessary to take steps to dry the skin and prevent the development of maceration by the use of talcs and powders. This infection is most common in overweight or diabetic individuals, and when attacks recur, it is important to evaluate the patient for diabetes. Secondary infection with Candida may also occur in the diaper area on top of an irritative dermatosis caused by urine. Generally, these forms of candidiasis are secondary infections either on top of an existing medical condition, or, in the case of widespread cutaneous candidiasis, they may appear rarely in infants as primary skin infections. They respond to topical therapies such as azoles, terbinafine cream, or nystatin.39 Only in extensive disease is oral antifungal therapy necessary. Interdigital candidiasis or intertrigo does not always respond to antifungal
Hay S39 therapy, and sometimes regular cleansing with an antiseptic drying agent such as potassium permanganate solution may be more effective. Paronychia and onychomycosis Infection of the nail folds by Candida species is 1 cause of paronychia.40 The periungual skin is raised and painful, and a prominent gap develops between the fold and the nail plate. Pus may be discharged. More rarely, invasion of the nail plate with associated lateral onycholysis occurs. Certain bacteria, such as Staphylococcus aureus, also play a role in the formation of paronychia, and the condition is best regarded as multifactorial, although individuals with much exposure to water and cooking seem to be predisposed. Irritant dermatitis cause by food may provoke inflammation. Patients with abnormal nail folds associated with skin disease, such as hand eczema or contact dermatitis, may also be infected. Considerable confusion persists regarding the frequency of genuine Candida onychomycosis. The problem centers around the ability of Candida species to colonize sites such as the subungual space caused by onycholysis. The presence of yeasts alone is not sufficient grounds to consider that the organism is invasive, and Candida species have not been shown capable of breaking down keratin. Generally, the best described form of Candida onychomycosis is that associated with chronic mucocutaneous candidiasis. It is also uncommonly seen in association with steroid therapy, Cushing’s syndrome, or Raynaud’s disease, where the condition resembles onychomycosis as the result of dermatophytes.1 Candida paronychia requires prolonged topical therapy with frequent applications of polyenes, imidazoles, or nonspecific remedies such as 4% thymol in chloroform or sulphacetamide lotion. Lotions are probably preferable to creams.11 There have been too few studies of either itraconazole or fluconazole to comment on their effectiveness in paronychia. The anti-Candida regimen is followed by general measures such as ensuring adequate drying of the hands. The hands should be kept warm, and poor peripheral circulation should be improved if possible, because patients with recurrent perniosis may experience the development of paronychia. In many patients, particularly in the chronic phases of paronychia, the central role of Candida in prolonging the condition is debatable,
S40 Hay Table III. Classification of CMC Idiopathic CMC (without known associations) Familial CMC associated with endocrinopathy Autosomal recessive CMC with familial endocrinopathy syndrome (hypoparathyroidism or hypoadrenalism) Autosomal dominant CMC with hypothyroidism Familial CMC without endocrinopathy Autosomal dominant Autosomal recessive CMC associated with interstitial keratitis Adult-onset CMC associated with thymoma From Coleman R, Hay RJ. Chronic mucocutaneous candidiasis associated with hypothyroidism: A distinct syndrome? Br J Dermatol 1997;136:24-9. By permission.
and other factors such as irritant or allergic contact dermatitis may play a role. For this reason, in chronic cases, concomitant use of a topical corticosteroid is a logical approach. In proven Candida onychomycosis, ketoconazole or itraconazole offer real hope of success.18 The efficacy of intermittent (pulsed) itraconazole or weekly fluconazole, although logical, has not been established as yet for this indication. It is important, however, to select cases for antifungal treatment carefully on the basis of features associated with genuine Candida nail-plate invasion, such as onycholysis with distal erosion of the nail plate, the presence of yeast and hyphae in nail microscopy, or biopsy specimen and the growth of C albicans. Such cases are not common but may respond well to continuous oral itraconazole therapy.18 In contrast, antifungal treatment of primary or secondary onycholysis complicated by Candida colonization makes no clinical impact. Chronic mucocutaneous candidiasis Chronic Candida infections of the mouth, nails, or other skin surfaces are rare, but in some cases they may persist despite treatment. This condition, known as chronic mucocutaneous candidiasis (CMC), occurs worldwide. It is usually recognized in infancy or childhood, and there are frequently underlying genetic, endocrine, or immunologic features. Autosomal dominant or recessive predisposition and endocrinopathy (such as hypoparathyroidism or hypoadrenalism), and hypothyroidism are all associated conditions (Table III).41-43 Evidence exists, however, that patients may have a variety of immune defects mainly involving defects in T-lymphocyte function,44
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although aberrant antibody responses (eg, low IgG2 but high IgG3) levels may also be found.45 Severe oral and nail infections, widespread infection, and hyperkeratosis on other surfaces may develop.44 There is some tendency for the condition to improve in adulthood. One of the clinical forms of oral candidiasis (the atrophic form) is seen in patients with CMC who smoke heavily; this may predispose to oral squamous cell carcinoma. Patients with CMC are also susceptible to other skin infections caused by dermatophytes and human papilloma viruses. Treatment of this condition depends critically on antifungal chemotherapy. Attempts have been made to restore T-cell function, usually by the use of transfer factor and latterly with cytokines. Transfer factor has a variable effect on the disease, although it is usually associated with improvements, albeit of a temporary nature; however, improvements in immune functions are not always demonstrable.46 Systemic anti-Candida therapy with fluconazole, itraconazole, or ketoconazole is likely to be necessary and may need to be prolonged and repeated. There is no published experience of the use of intermittent antifungal treatment in patients with CMC. The diagnosis is often made initially by consistent failure of a child with oral candidiasis to respond to topical anti-Candida treatment, and topicals appear to have little role in the management of CMC. In many respects, the treatment is similar to that used in AIDS-associated oropharyngeal candidiasis, and complications such as drug resistance may also occur in patients with CMC. Once a remission has been induced, maintenance therapy should not be used, in view of the risk of drug resistance. Although the tendency to develop oral candidiasis appears to diminish with age in some patients (unless the condition is provoked by antibiotics given for an intercurrent infection), patients with CMC remain susceptible to recurrent Candida infections. However, women with CMC seldom experience the development of recurrent vaginal candidiasis. Attention must be given to investigating new young patients for any endocrine abnormalities. Although their treatment is not likely to lead to improvement in the candidiasis, it may have considerable importance in the maintenance of the child’s health and development. Endocrine screening tests should be repeated even if initially negative, because patients with associated endocrinopathy may experience the development of endocrine disease years
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after the first appearance of candidiasis. Where appropriate, parents should be given genetic counseling (Table III). The possibility of coexisting dermatophytosis should be kept in mind, because it should respond satisfactorily to itraconazole or terbinafine. However, doses are often higher and are given for longer periods than those used for dermatophytosis in other patients (eg, itraconazole 400 mg daily and terbinafine 500 mg daily). DISCUSSION
The management of candidiasis depends on both drug therapy and adjunctive measures, which principally consist of attempts to reverse underlying predispositions. These include cleaning dentures with antiseptic solutions in oropharyngeal candidiasis, drying hands and wearing gloves during wet work to prevent paronychia, and drying interdigital spaces to reduce moisture and the risk of interdigital candidiasis. Such adjunctive measures are seldom effective in superficial Candida infections in immunocompromised patients, where the selection of the appropriate antifungal treatment, usually an oral agent, remains the most important decision. In addition, these measures are not sufficient to prevent recurrences of oral candidiasis in patients with AIDS. For this reason the policy adopted by most clinicians in treating patients with this condition is to use drug therapy to reduce symptoms, although not attempting to suppress the growth of Candida by long-term therapy. The short-term results of triple antiretroviral therapy in patients with HIV have had an impact on the prevalence and course of oropharyngeal candidiasis, and the long-term implications have yet to be defined. A further unsatisfactory situation is the current management of women with chronic or recurrent vaginal candidiasis. Although in some instances treatment failure is caused by an underlying predisposition, the presence of an unusual Candida species, or plain misdiagnosis, a substantial number of women continue to have recurrent episodes of vaginal candidiasis. The design of clinical trials of sufficient power to determine optimal treatment regimens for these patients is long overdue. A number of important challenges remain therefore in the treatment of superficial Candida infections. Although the development of the oral antifungal agents, starting with ketoconazole, has revolutionized the management of infections such as CMC, there is still some way to go.
Hay S41 REFERENCES 1. Odds FC. Candida and candidiasis. London: Bailliere Tindall; 1988. 2. Sobel JD. Vulvovaginal candidiasis: what we do and do not know. Ann Intern Med 1984;101:390-2. 3. Torssander J, Morfeldt-Manson L, Biberfeld G, Karlsson A, Putkonen PO, Wasserman J. Oral Candida albicans in HIV infection. Scand J Dis 1987;19:291-5. 4. Lin RY, Goodhart P. The role of oral candidiasis in survival and hospitalization patterns: analysis of an inner city hospital immunodeficiency virus/acquired immune deficiency syndrome registry. Am J Med Sci 1993;306: 345-53. 5. Powderly WG, Robinson K, Keath EJ. Molecular epidemiology of recurrent oral andidiasis in human immunodeficiency virus-positive patients: evidence for two patterns of recurrence. J Infect Dis 1993;168:463-6. 6. Alcabes P, Schoenbaum EE, Klein RS. Correlates of the rate of decline of CD4+ lymphocytes among injection drug users infected with the human immunodeficiency virus. Am J Epidemiol 1993;137:989-1000. 7. Conley LJ, Bush TJ, Buchbinder SP, Penley KA, Judson FN, Holmberg SD. The association between cigarette smoking and selected HIV-related medical conditions. AIDS 1996;10:1121-6. 8. Dronda F, Alonso-Sanz M, Laguna F, Chaves F, Martinez-Suarez JV, Rodriguez-Tudela JL, et al. Mixed oropharyngeal candidiasis due to Candida albicans and non-albicans Candida strains in HIV-infected patients. Eur J Clin Microbiol Infect Dis 1996;15:446-52. 9. Sullivan DJ, Henman MC, Moran GP, O’Neill LC, Bennett DE, Shanley DB, et al. Molecular genetic approaches to identification, epidemiology and taxonomy of non-albicans Candida species. J Med Microbiol 1996;44:399-408. 10. Pfaller MA, Rhine-Chalberg J, Redding SW, Smith J, Farinacci G, Fothergill AW, et al. Variations in fluconazole susceptibility and electrophorectic karyotype among oral isolates of Candida albicans from patients with AIDS and oral candidiasis. J Clin Microbiol 1994;32:59-64. 11. Hay RJ. Antifungal therapy of yeast infections. J Am Acad Dermatol 1994;31:S6-9. 12. Maenza JR, Merz WG, Romagnoli MJ, Keruly JC, Moore RD, Gallant JE. Infection due to fluconazoleresistant Candida in patients with AIDS: prevalence and microbiology. Clin Infect Dis 1997;24:28-34. 13. Revankar SG, Kirkpatrick WR, McAtee RK, Dib OP, Fothergill AW, Redding SW, et al. Detection and significance of fluconazole resistance in oropharyngeal candidiasis in human immunodeficiency virus-infected patients. J Infect Dis 1996;174:821-7. 14. Le Guennec R, Reynes J, Mallie M, Pujol C, Janbon F, Bastide JM. Fluconazole- and itraconazole-resistant Candida albicans strains from AIDS patients: multilocus enzyme electrophoresis analysis and antifungal susceptibilities. J Clin Microbiol 1995;33:2732-7. 15. Rex JH, Pfaller MA, Barry AL, Nelson PW, Webb CD. Antifungal susceptibility testing of isolates from a randomized multicenter trial of fluconazole versus amphotericin B as treatment of non-neutropenic patients with candidemia. Antimicrob Agents Chemother 1995;39:40-4. 16. Johnson EM, Davey KG, Szekely A, Warnock DW. Itraconazole susceptibilities of fluconazole susceptible and resistant isolates of five Candida species. J Antimicrob Chemother 1995;36:787-93.
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