Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

98. Superficial Fungal Infections

Thomas E. R. Brown and Linda D. Dresser


KEY CONCEPTS

 Images Vulvovaginal candidiasis (VVC) is a fungal infection of the vagina that can be classified as uncomplicated or complicated. This classification is useful in determining appropriate pharmacotherapy.

 Images Candida albicans is the major pathogen responsible for VVC. The number of cases of non–C. albicans species appears to be increasing.

 Images Signs and symptoms of VVC are not pathognomonic, and reliable diagnosis must be made with laboratory tests including vaginal pH, saline microscopy, and 10% potassium hydroxide (KOH) microscopy.

 Images C. albicans is the predominant species causing all forms of mucosal candidiasis. Important host and exogenous risk factors have been identified that predispose an individual to the development of mucosal candidiasis. In oropharyngeal and esophageal candidiasis, the key risk factor is impaired host immune system.

 Images A topical antimycotic agent is the first choice for treating oropharyngeal candidiasis. Systemic therapy can be used in patients who are not responding to an adequate trial of topical treatment or are unable to tolerate topical agents and in those at high risk for systemic candidiasis. Fluconazole and itraconazole are the most effective azole antimycotic agents.

 Images For esophageal candidiasis, topical agents are not of proven benefit; fluconazole or itraconazole solution is the first choice.

 Images Optimal antiretroviral therapy is important for the prevention of recurrent and refractory candidiasis in patients with human immunodeficiency virus (HIV) infection.

 Images Primary or secondary prophylaxis of fungal infection is not recommended routinely for HIV-infected patients; use of secondary prophylaxis should be individualized for each patient.

 Images Topical antimycotic agents are first-line treatment for fungal skin infections. Oral therapy is preferred for the treatment of extensive or severe infection and those with tinea capitis or onychomycosis.

 Images Oral antimycotic agents such as terbinafine and itraconazole are first-line treatment for toenail and fingernail onychomycosis.


Superficial mycoses are among the most common infections in the world and the second most common vaginal infections in North America. Mucocutaneous candidiasis can occur in three forms—oropharyngeal, esophageal, and vulvovaginal disease—with oropharyngeal and vulvovaginal disease being the most common. These infections were reported in humans as far back as 1839. Over the past 15 to 20 years, the occurrence rates of some fungal infections have increased dramatically. The prevalence of fungal skin infections varies throughout different parts of the world, from the most common causes of skin infections in the tropics to relatively rare disorders in the United States. This chapter reviews the pharmacotherapy of vulvovaginal candidiasis, oropharyngeal and esophageal candidiasis, and common dermatophyte infections.

VULVOVAGINAL CANDIDIASIS

Images Vulvovaginal candidiasis (VVC) refers to infections in individuals with or without symptoms who have positive vaginal cultures for Candida species. Depending on episodic frequency, VVC can be classified as either sporadic or recurrent.1 This classification is essential to understanding the pathophysiology, as well as the pharmacotherapy, of VVC. Furthermore, VVC may be defined as uncomplicated, which refers to sporadic infections that are susceptible to all forms of antifungal therapy regardless of the duration of treatment, or complicated, in which consideration of factors affecting the host, microorganism, and pharmacotherapy all have an essential role in successful treatment.1 Complicated VVC includes recurrent VVC, severe disease, non–Candida albicans candidiasis, and host factors, including diabetes mellitus, immunosuppression, and pregnancy.1

Epidemiology

Minimal information on the incidence and prevalence of VVC exists. Healthcare workers are not required to report cases of VVC; therefore, estimates are derived from self-reported histories. Epidemiologic data are limited because VVC usually is diagnosed without microscopy and/or cultures, and antifungal nonprescription preparations are available for self-treatment.1 By 25 years of age, approximately 50% of college women will have had at least one episode of VVC.1 It is rare before menarche and increases dramatically at about 20 years of age, with the peak incidence between age 30 and 40 years. It is associated with the initial act of sexual intercourse. As many as 75% of women experience one bout of symptomatic VVC in their lifetime. Between 40% and 50% of women who experience one episode of VVC experience a second episode, and 5% experience recurrent VVC.2,3 Black women appear to be at higher risk than white women of developing VVC (62.8% vs. 55%, respectively).4 The incidence after menopause remains unknown. However, one study of 149 healthy postmenopausal women with vulvar conditions reported significantly more women taking hormone replacement therapy (HRT) were prone to developing VVC than those who were not taking HRT (culture-positive, clinical VVC in 49% on HRT versus 1% on those not on HRT).5

Costs from VVC can be direct (medical visits and self-treatment) and indirect (nonmedical expenses, e.g., time losses from work, costs of travel, and time required in obtaining treatment). There are an estimated 6 million visits to healthcare providers each year, resulting in more than $1 billion spent annually on these medical visits and self-treatment.6

Pathophysiology

Images Candida albicans is the major pathogen responsible for VVC, accounting for 80% to 92% of symptomatic episodes. The remainder are caused by non–C. albicans species, with Candida glabratadominating.7 The number of cases of non–C. albicans candidiasis appears to be increasing, possibly related to the use of nonprescription vaginal antifungal preparations and short-course therapy and/or the increased use of long-term maintenance therapy in preventing recurrent infections.1

Candida species can act as commensal members of the vaginal flora. Asymptomatic colonization with Candida species has been found in 10% to 20% of women of reproductive age.7,8 Candida organisms are dimorphic; blastospores are believed to be responsible for colonization (transmission and spread), whereas germinated Candida forms are associated with tissue invasion and symptomatic infections.9 To colonize the vagina, Candida species must be able to attach to the mucosa. The attachment process is complex. Not only are candidal surface structures important for attachment, but appropriate receptors for attachment must be present in the epithelial tissue. Not all women have the same range of receptors, which may explain variation in colonization.8 Changes in the host’s vaginal environment or response are necessary to induce a symptomatic infection. Unfortunately, in most cases of symptomatic VVC, no precipitating factor can be identified.9

Risk Factors

Several factors predispose a woman to VVC. VVC is not considered to be a sexually transmitted disease, although sexual factors can be important. There is a dramatic increase in the frequency of VVC when women become sexually active. In addition, oral-genital contact can increase the risk.1 However, current guidelines do not recommend the treatment of asymptomatic partners.7 Contraceptive agents, including the diaphragm with spermicide, the contraceptive sponge, and the intrauterine device, increase the risk of VVC. An in vitro adherence demonstrated that four different isolates of Candida species were capable of adhering to the contraceptive vaginal ring.10 Oral contraceptive users demonstrated increased risk of candidiasis; however, these reports were with the higher-dose oral contraceptive pills, and the risk may not be as great with the lower-estrogen-dose oral contraceptives.11

Antibiotic use can increase the risk of VVC, but it is significant in only a small number of women. The mechanism by which antibiotics can increase the risk of VVC is unknown; colonization, however, is a prerequisite.1 A small pilot study of short course antibiotic use of 3 days of antibiotics increased the prevalence of asymptomatic vaginal colonization of Candida and the incidence of symptomatic VVC.12Diet (excess refined carbohydrates), douching, and tight-fitting clothing often are listed as important risk factors; however, no association has been established between these factors and increased risk of VVC.1

Clinical Presentation

Images The clinical presentation of VVC is given in Table 98–1.1,7 These signs and symptoms are not pathognomonic, and a reliable diagnosis cannot be made without laboratory tests. Self-diagnosis has a sensitivity of 35%, a specificity of 89%, and a positive predictive value of 62%.4 More than 50% of women who had self-diagnosed VVC did not have yeast as the causative agent.13 This limits the value of self-diagnosis and the success of self-treatment. The American College of Obstetricians and Gynecologists (ACOG) recommends that whenever possible women requesting treatment for VVC should be examined and evaluated. They only recommend self-diagnosis in compliant women with multiple confirmed prior cases of VVC who report the same symptoms. They further recommend that if these individuals fail to improve on a short course of therapy, they be evaluated for a further diagnosis.14Therefore, in most instances the diagnosis should be based on both clinical presentation and investigations, including vaginal pH, saline microscopy, and 10% potassium hydroxide (KOH) microscopy. The vaginal pH remains normal in VVC, and microscopic investigations should detect blastospores or pseudohyphae. Candida cultures usually are not required in the diagnosis of uncomplicated VVC; however, they are recommended when an individual presents with classic signs and symptoms of VVC, has a normal vaginal pH, but microscopy is inconclusive or recurrence is suspected.7

TABLE 98-1 Clinical Presentation of Vulvovaginal Candidiasis

Images

TREATMENT

Goals of Therapy

The goal of therapy is complete resolution of symptoms in patients who have symptomatic VVC. A test of the cure is not necessary if symptoms resolve.7 Antimycotic agents used in the treatment of VVC do not meet the definition of being fungicidal agents because of their slower killing rate. At the end of therapy, the number of viable organisms drops below the detectable range. However, by 6 weeks after a course of therapy, 25% to 40% of women will have positive yeast cultures and remain asymptomatic.1 Asymptomatic colonization with Candida species does not require therapy.

General Approaches to Treatment

The approach to therapy is to remove or improve any predisposing factors if they can be identified. A pharmacologic antimycotic agent should have limited local and systemic side effects, a high cure rate, and easy administration. Additionally, it would be advantageous to use a therapy that is able to resolve symptoms within 24 hours, that has broad antimycotic activity (to cover increasing rates on non–C. albicansspecies), that prevents recurrence, and that can be used over a shortened period of time, such as 1 to 3 days. Many topical azoles medications (such clotrimazole, miconazole, etc) are available without a prescription, and although this may increase public access to these medications, there is concern that having them available without a prescription may lead to inappropriate use. A study conducted using 10 actors as simulated patients who visited 60 pharmacies found that vaginal antimycotics were more likely to be supplied to appropriate individuals as more information was exchanged, if interactions involved a pharmacist, and if questions regarding specific symptoms were used.15

Patients should be advised to avoid harsh soaps and perfumes that can cause or worsen vulvar irritation. The genital area must be kept clean and dry by avoiding constrictive clothing and frequent or prolonged exposure to hot tub use.3 Douching is not recommended for either prevention or treatment.13 Cool baths can soothe the skin.3 The oral use of lactobacillus remains unclear. A small trial of 55 women being treated for VVC showed that the addition of oral lactobacillus to single dose oral fluconazole augmented the cure rate compared to the use of fluconazole alone.16 A trial of a mixture of oral consumption of bee-honey and yogurt showed some efficacy with mycotic cure rates of 76.9% compared to cure rates with antifungal agents of 91.5%.17 Daily ingestion of 240 mL yogurt containing Lactobacillus acidophilus decreased colonization and symptomatic infections of VVC in women with recurrent infections.18 However, a subsequent study showed that the addition of oral lactobacillus to itraconazole therapy in the treatment of recurrent VVC did not confer any additional benefit. This same trial showed that treatment using classic homeopathy was less effective than the use of itraconazole in recurrent VVC.19

Treatment of VVC will be considered to have positive outcomes if the symptoms of VVC are resolved within 24 to 48 hours and no adverse medication events are experienced. Self-assessment of symptom relief is appropriate for most cases of VVC. If symptoms remain unresolved or recur, then further testing and treatment can be required.

Pharmacologic Treatments

Uncomplicated Vulvovaginal Candidiasis

Cure rates for uncomplicated VVC are between 80% and 95% with topical or oral azoles and between 70% and 90% with nystatin preparations. Table 98–2 lists available topical and oral preparations for the treatment of uncomplicated VVC. There are many topical nonprescription preparations for the treatment of VVC. No significant differences in in vitro activity or clinical efficacy exist between the topical azole agents.1,3,7,14 The selection of a topical azole antimycotic agent should be based primarily on an individual patient’s preference as to product formulation. Some topical products can cause vaginal burning, stinging, or irritation; conversely, the vehicle used in topical creams or gels can provide initial symptomatic relief.1 Of note, most topical preparations can decrease the efficacy of latex condoms and diaphragms.

TABLE 98-2 Treatment for Uncomplicated Vulvovaginal Candidiasis

Images

Oral azoles (such as fluconazole or itraconazole) have been used in the treatment of VVC. Patients may prefer oral therapy because of its convenience.20 Oral and topical therapies are therapeutically equivalent.1 A Cochrane review of 19 trials analyzing 22 oral versus topical antifungal comparisons concluded that there were no differences between the routes in short-term mycologic cure rates. There was a significant difference between long-term cure rates in favor of long-term followup; however, the authors stated that the clinical significance of this finding is uncertain.21

In the treatment of uncomplicated VVC, the duration of therapy is not critical. Cure rates with different lengths of treatment have not demonstrated that one duration of therapy is significantly better.20,21,22Shorter-duration therapies (e.g., clotrimazole 1-day therapy) consist of higher concentrations of azoles that maintain the local therapeutic effect for up to 72 hours and allow for resolution of signs and symptoms.23 A review of 14 trials that examined 1-day treatments showed less than 7% difference in short-term cure rates or improvement between any two treatments in any two studies and no significant differences in short- or long-term clinical cure rates among 1-day regimens.22 Table 98–2 lists the therapeutic options for the treatment of uncomplicated VVC.


Clinical Controversy…

Self-diagnosis of vulvovaginal candidiasis (VVC) is unreliable; however, the availability of nonprescription antifungal agents encourages self-diagnosis and self-treatment for the majority of women. Therefore, women who self-treat should be monitored to ensure that the infection clears within a few days, or they need to see a physician for an accurate diagnosis.

Complicated Vulvovaginal Candidiasis

Complicated VVC occurs in patients who are immunocompromised or have uncontrolled diabetes mellitus.1 These individuals need a more aggressive treatment plan.14 Current recommendations are to lengthen therapy to 10 to 14 days regardless of the route of administration.14 Therapeutic options include those listed in Table 98–2; however, regimens should be continued for 10 to 14 days. A study of oral fluconazole therapy in women with complicated VVC demonstrated that cure rates increased from 67% with single-dose therapy to 80% when the 150 mg dose of fluconazole was repeated 72 hours after the initial dose.24

VVC during pregnancy can be considered complicated because consideration of host factors such as hormonal changes that can affect normal flora are essential in selecting therapeutic regimens. Topical agents are considered to be safe throughout pregnancy. A systematic review of 10 trials demonstrated that imidazole topical agents (such as fluconazole) were more effective than nystatin. Two of the trials showed that treatment for 7 days was more effective than treatments of 4 days or less.25 Oral agents are contraindicated in pregnancy because of the concern for fetal complications. A prospective assessment of pregnancy outcomes in 226 women exposed to fluconazole in the first trimester did not indicate increased risk of congenital abnormalities or other adverse outcomes.26 The median dose of fluconazole was 200 mg, with 46.5% of the cohort receiving a single dose of fluconazole 150 mg.27 However, the ACOG recommends avoiding oral therapy, as larger doses of fluconazole have been linked to birth defects.27Instead, the ACOG recommends a topical imidazole therapy for 7 days.14

Recurrent Vulvovaginal Candidiasis

Recurrent vulvovaginal candidiasis (RVVC) is defined as having more than four episodes of VVC within a 12-month period.1,7 Fewer than 5% of women develop RVVC, and its pathogenesis is poorly understood. A proper diagnosis should be obtained to rule out other infections or nonmycotic contact dermatitis. RVVC is best treated in two stages: an initial intensive stage followed by prolonged antifungal therapy to achieve mycologic remission. This was demonstrated in a randomized controlled trial in which women were assigned to receive 150 mg fluconazole daily for 10 days followed by 6 months of either fluconazole 150 mg weekly or placebo. Ninety percent of women receiving both active treatments were symptom free for the 6 months following initial treatment (during the weekly fluconazole therapy), and there were 50% fewer symptomatic episodes in the 6 months following weekly suppressive therapy.28 The Infectious Diseases Society of America stated that there is good evidence from more than one properly randomized controlled trial to recommend 10 to 14 days of induction therapy with a topical or oral azole, followed by 150 mg of fluconazole once weekly for 6 months for recurring Candida VVC.29

Antifungal-Resistant Vulvovaginal Candidiasis

Resistance to azole antimycotics should be considered in individuals who have persistently positive yeast cultures and fail to respond to therapy despite adherence to prescribed regimens.1 These infections can be treated with boric acid or 5-flucytosine.30,31 Boric acid is administered as a 600 mg intravaginal capsule daily for 14 days of induction therapy, followed by a maintenance regimen of one capsule intravaginally twice weekly. Boric acid should not be administered orally, as it is toxic. 5-Flucytosine cream is administered vaginally, 1,000 mg inserted nightly for 7 days. The prevalence of C. glabrata is higher in those with diabetes. In a study of 111 consecutive diabetic patients with VVC, 68% had isolates for C. glabrata compared with 28.8% for C. albicans. Those with C. glabrata had significantly higher mycological cure rates with 600 mg of boric acid suppositories for 14 days compared with a single dose of fluconazole 150 mg.32

OROPHARYNGEAL AND ESOPHAGEAL CANDIDIASIS

Oropharyngeal candidiasis (OPC), or thrush, is a common and localized infection of the oral mucosa caused by the yeast Candida. Candida albicans, a common oral commensal organism, is the most frequent infecting species. OPC is also referred to as candidiasis (or the more correct but less commonly used term candidosis). The infection may extend into the esophagus, causing esophageal candidiasis.

Microbiology and Epidemiology

Candida is a commensal fungus found in the oral cavity in up to 65% of healthy individuals with higher prevalence in healthy children and young adults.33,34 Candida carriage increases under immunocompromised conditions and also among hospitalized patients.34 Even in the era of highly active antiretroviral therapy (HAART) up to 80% of human immunodeficiency virus (HIV)-infected persons may demonstrate oral yeast colonization.35 The organism is capable of transition to a pathogen causing symptomatic mucosal infections in association with predisposing host factors.34 Candida albicans is the predominant colonizing Candida species (70% to 80%), but any of the non–C. albicans species can be colonizers. Colonization rates are influenced by the severity and nature of the underlying medical illness and the duration of hospitalization, as well as age (highest in infants younger than 18 months of age and in adults older than 60 years of age). A variety of host and exogenous factors (Table 98–3) can lead to the transformation of asymptomatic colonization to symptomatic disease, such as oropharyngeal and esophageal candidiasis. C. albicans is the most common species causing all forms of mucosal candidiasis in humans. Less frequently, non–C. albicans species can be pathogenic and cause disease. These include C. glabrata, Candida tropicalis, Candida krusei, and Candida parapsilosis.35,36 Candida krusei, although relatively uncommon, generally is recovered from mucosal surfaces of neutropenic patients with hematologic malignancies.36 Another species, Candida dubliniensis, has been identified in both HIV-infected and noninfected patients, and may cause ~15% of infections previously ascribed to C. albicans.36 In patients with cancer, non–C. albicans species account for almost half of all Candidainfections.

TABLE 98-3 Risk Factors for the Development of Oropharyngeal and/or Esophageal Candidiasis

Images

Oropharyngeal candidiasis is the most common opportunistic infection in patients with HIV disease, and it may be the first clinical manifestation of the HIV infection in the majority of untreated patients. OPC occurs in 50% to 90% of HIV-infected patients at some point during the progressive course of the disease to acquired immunodeficiency syndrome (AIDS),33,35,36 although significant reductions in the incidence have been observed after the introduction of highly active antiretroviral therapy. The absolute CD4 T-cell count has been suggested to be the primary risk factor for development of OPC with the greatest risk at CD4 T-cell levels <200 cells/mm3 (<0.2 × 109/L). Also, the HIV viral load has been identified as a predictor of OPC development; OPC is thought to increase with HIV viral loads >10,000 copies/mL (>10 × 106/L). This finding correlates with the observation that initiation of antiretroviral therapy and subsequent increase in CD4 T-cell counts does not fully account for the decrease in OPC incidence.35 Regardless of the CD4 T-cell count, or HIV viral load OPC is predictive for the development of AIDS-related illnesses if left untreated.33,36

In non-HIV diseases, such as cancer, the incidence of OPC varies depending on the type of malignant neoplastic disease, level of immune suppression, and type and duration of treatment, but it is less common than in HIV-infected patients. OPC was initially reported in ~25% of patients with solid tumors and up to 60% in those with hematologic malignancies or bone marrow transplant recipients.37 Current rates of OPC have decreased significantly in these patients because of widespread use of antifungal prophylaxis. Incidence in other patient populations predisposed to OPC such as the hospitalized patient administered broad-spectrum antibiotics or denture and other oral appliance users is not well quantified, however, do represent at-risk individuals where the clinical pharmacist has an important patient-care role.34,37

OPC can predispose patients to develop more invasive disease, including esophageal candidiasis.37 The esophagus is the second most common site of GI candidiasis. The prevalence of esophageal candidiasis has increased mainly because of the number of individuals with AIDS, as well as the increased numbers of other severely immunocompromised patients, especially those with hematologic malignancies.36Esophageal candidiasis is the first opportunistic infection in 3% to 10% of HIV-infected patients and is the second most common AIDS-defining disease after Pneumocystis jiroveci pneumonia.36 The mean incidence of esophageal candidiasis among HIV-infected patients is less than OPC and ranges from 15% to 20%.36 The risk of esophageal candidiasis is increased in HIV-infected patients when the CD4 T-cell count has dropped below 100 to 200 cells/mm3 (0.1 × 109 to 0.2 × 109/L), as well as in those with OPC.37,38 However, the absence of OPC does not necessarily exclude the possibility of esophageal disease. Like OPC, the presence of esophageal candidiasis can help predict HIV disease progression and prognosis.37 The incidence of esophageal candidiasis in non-HIV-infected immunocompromised patients is not well established. Candida albicans is the most common cause of esophageal candidiasis, accounting for ~80% of cases, with the rest being caused by non–C. albicans species.35

The introduction of HAART appears to have resulted in a significant decline in the incidence of OPC and esophageal candidiasis.35,36 In addition, the widespread use of the azole agents for treatment and prophylaxis has led to a decline in the prevalence of mucosal candidiasis while leading to the emergence of refractory infections that are more challenging to treat.

Pathogenesis and Host Defenses

The pathogenesis of OPC is most clearly elucidated in the setting of HIV infection. There appear to be several levels of immune defense against the development of OPC in HIV-infected persons, and they involve both systemic and local immunity. The primary line of host defense against C. albicans is cell-mediated immunity (CMI) at the mucosal surfaces, which is mediated by CD4 T cells.33 The efficacy of the CD4 T cells is reduced when the number of cells drops below a protective threshold, and protection against infection becomes dependent on secondary or local immune mechanisms.33,35 When the number of CD4 T cells drops too low, recruitment of these cells to the oral cavity is impaired. The CD4 T-cell count has been considered as the hallmark predictor for development of OPC. However, HIV viral load may have a stronger association with OPC than CD4 cell number.35,39 The possibility that HIV plays a strong role in susceptibility to infection is supported clinically by the observation that OPC is more common in HIV-infected persons than in those with similar immunosuppression, such as lymphoma and bone marrow transplant. When the primary line of defense fails, the secondary host defenses become crucial. These include the CD8 T cells, salivary cytokines, and other innate immune cells, such as the neutrophils, macrophages, and epithelial cells (with anti-Candida activity). Deficiencies or dysfunction in any of these can result in increased susceptibility to OPC. The problem with the CD8 T cells is caused more by a dysfunction of the microenvironment, specifically, reduction in the E-cadherin adhesion molecule that promotes migration of the cells through mucosal tissues.36 The role of humoral immunity by antibodies as a protective mechanism is unclear and controversial. The changeover of the role of Candida species from commensal to pathogenic in the human host usually occurs when breakdown in these host defenses occurs. The pathogenesis of OPC is still not completely understood. It is important to develop a better understanding of the pathogenesis and role of host defenses, including the mechanism of CD8 T-cell activity, reduced adhesion molecules, and whether other cofactors, such as HIV viral load, HAART, and injection drug use, play a role. Immunotherapeutic modalities can then be developed to eliminate the susceptibility factors and significantly reduce OPC in the at-risk populations.

Significant differences exist in the virulence among Candida species in mucosal candidiasis. One virulence factor is the ability of the organism to adapt and survive in response to changes in the host environment.35 The genes required for virulence are regulated in response to the environmental signals indigenous to the host environment (e.g., temperature, pH, osmotic pressure, iron and calcium ion concentrations, oxygenation, and carbon and nitrogen availability). The ability of C. albicans to undergo reversible morphologic transition between the budding pseudohyphal and the more invasive hyphal growth forms is also a determinant of virulence, and genes are recognized to play a role.33 Other virulence factors are the adhesive ability of C. albicans to epithelial cells and proteins and its ability to invade host cells by means of phospholipase and proteinase enzymes. This may be one of the factors leading to OPC in non–HIV-infected individuals. Other components of the pathogenesis in the absence of HIV that have been postulated are the ability of the Candida species to adhere to buccal epithelial cells. A close correlation between adhesion of Candida species and their ability to cause infection has been demonstrated in animal model studies.40 This is hypothesized to be a key element in the development of OPC in patients with altered microflora, including those receiving broad-spectrum antimicrobial therapy.

Risk Factors

Images Several host and exogenous factors contribute to the ability of Candida species to cause infection (see Table 98–3). Local and systemic factors, as well as characteristics of the organism itself, can increase the susceptibility of an individual to Candida infections.33 Endocrine disorders besides diabetes mellitus, such as hypothyroidism, hypoparathyroidism, and hypoadrenalism, also can predispose patients to Candida species overgrowth. Patients with primary immune deficiencies such as lymphocytic abnormalities, phagocytic dysfunction, immunoglobulin A (IgA) deficiency, viral-induced immune paralysis, and severe congenital immunodeficiencies are also at risk for oropharyngeal candidiasis as well as disseminated candidiasis. Oral mucosal disease, such as lichen planus, can be preexistent causes of candidiasis. Smoking has been suggested as a predisposing risk factor. In many cases, multiple concurrent predisposing factors to candidiasis can exist, for example, xerostomia with mucositis and a break in the epithelial surface or immunosuppression, such as might occur in a leukemic patient receiving radiation and chemotherapy. The severity and extent of Candida infections increase with the number and severity of predisposing risk factors.34

Clinical Presentation and Diagnosis

Oropharyngeal candidiasis can manifest in several major forms (Table 98–4).33,34 The clinical signs and symptoms of OPC and the locations of the lesions can be quite diverse (Table 98–5). A presumptive diagnosis of OPC usually is made by the characteristic appearance on the oral mucosa, with resolution of signs and symptoms after antifungal therapy. Pseudomembranous candidiasis, commonly known as oral thrush, is the classic and most common form seen in immunosuppressed and immunocompetent hosts. Erythematous and hyperplastic candidiasis and angular cheilitis occur less commonly in the HIV-infected population. Dysphagia, odynophagia, and retrosternal chest pain are common complaints of esophageal candidiasis, which is usually, but not always, accompanied by the presence of OPC. Clinical symptomatology, along with a therapeutic trial of antifungal, can provide a reliable presumptive diagnosis of esophageal candidiasis. If antifungal therapy does not lead to resolution, more invasive tests such as upper GI endoscopy can be undertaken.

TABLE 98-4 Clinical Classification of Oropharyngeal Candidiasis

Images

TABLE 98-5 Clinical Presentation of Oropharyngeal and Esophageal Candidiasis

Images

TREATMENT

Desired Outcomes

The primary desired outcome in the management of OPC is a clinical cure, that is, elimination of clinical signs and symptoms. Even when the patient is relatively asymptomatic, it is important to treat the initial episode of OPC to avoid progression to more extensive disease. In the most severe cases, the patient’s quality of life can be impaired; this can result in decreased fluid and nutritional intake. Lack of appropriate treatment of OPC can lead to more extensive oral disease, especially in patients who are immunocompromised. The most serious complication of untreated OPC is extension of the infection to esophageal candidiasis. Because esophageal candidiasis is more debilitating, the patient’s quality of life is more affected. It is important to initiate appropriate antifungal therapy for both OPC and esophageal candidiasis. Preventing or minimizing the number of future recurrences of both types of candidiasis is an equally important outcome. The approach depends largely on the underlying predisposing conditions. Mycologic cure is not a necessary treatment outcome because it may not be feasible or realistic, given that Candida species exist commonly as part of the normal mouth flora.

Minimizing toxicities and drug–drug interactions of systemic antifungal agents, as well as maximizing adherence by ensuring that the patient understands the importance of therapy and the directions to take the medication appropriately, are important secondary outcomes of therapy.

General Approach to Treatment

The management of OPC should be individualized for each patient, taking into consideration the underlying immune status, other concurrent mucosal and medical diseases, concomitant medications, and exogenous infectious sources. In HIV-infected patients with inadequately controlled disease, antifungal treatment produces only a transient clinical response, and the relapse rates are higher than in other patient populations. These patients usually require frequent courses of antifungal treatment. Therefore, in patients with HIV disease, treatment with effective HAART is paramount because this would provide the best prophylaxis against recolonization and recurrence of symptoms.34,35,41

Whenever feasible, it is desirable to minimize all predisposing factors, such as administration of corticosteroids, chemotherapeutic agents, and antimicrobials, as well as institute proper oral hygiene and resolve concurrent conditions, such as denture stomatitis. Selection of an appropriate antifungal agent for treatment of candidiasis requires consideration of several factors, including the patient’s drug adherence, adequate saliva for dissolution of solid topical medications, risk of caries from sucrose- or dextrose-containing preparations, potential drug interactions, coexisting medical conditions (e.g., liver disease), location and severity of the infection, and the need for long-term maintenance therapy. Another factor that could affect drug selection is overuse of fluconazole, leading to the emergence of fluconazole-resistant species of C. albicans, and in some cases to all azoles, and other intrinsically more resistant species, such as C. kruseiC. glabrata, and C. tropicalis.

Images Topical antimycotic therapies should be the first choice for milder forms of infections.41 The efficacy of antimycotic agents for OPC varies in different patient populations. Until the polyene antimycotic agents became available in the 1950s, gentian violet, an aniline dye, was used to treat OPC. Problems with gentian violet include fungal resistance, skin irritation, and especially the unaesthetic staining of the oral mucosa. In resource limited areas gentian violet remains a therapeutic option. A study of different concentrations of gentian violet demonstrated that a 0.00165% solution does not stain the oral mucosa and has potent antifungal activity.42 Topical agents, such as nystatin and clotrimazole, have been the standard of treatment for uncomplicated OPC and generally are effective for treatment in otherwise healthy adults and infants with no underlying immunodeficiencies. Topical agents are available in an assortment of formulations, including oral rinses (suspension), troches, powder, vaginal tablets, creams and most recently as a mucoadhesive tablet37,41,43 (Table 98–6).

TABLE 98-6 Therapeutic Options for Mucosal Candidiasis

Images

Images

Topical agents require frequent applications because of the short contact time with the oral mucosa; the ideal contact time is 20 to 30 minutes. Sufficient saliva is needed to dissolve clotrimazole troches, and this can be problematic for patients with xerostomia. Also, the rough surface of the tablet can become irritating to the oral soft tissue. Troches also contain dextrose, which has cariogenic potential. Nystatin suspension might be a better choice for patients with xerostomia, but it is difficult to maintain adequate contact time with the oral mucosa. Some patients complain of the unpleasant taste of nystatin, which can cause nausea and vomiting; this is especially problematic in cancer patients experiencing chemotherapy-induced nausea. The high sucrose content of nystatin suspension is cariogenic in dentate patients, and it should be used with caution in diabetic patients.34,37 Miconazole 50 mg mucoadhesive tablets are the first buccal adherent miconazole product approved for the local treatment of OPC in adults and adolescents older than age 16 years.44 This product offers the advantage of a once-daily formulation that is tasteless, odorless, and sugar free.43 Topical creams, such as clotrimazole, ketoconazole, miconazole, and nystatin (usually mixed with a steroid), are more appropriate for application three times daily to the corners of the mouth in treating angular cheilitis, the inflammation, drying, and cracking of the corners of the mouth.41

Systemic therapy is necessary in patients with OPC that is refractory to topical treatment, those who cannot tolerate topical agents, moderate-to-severe disease, and those at high risk for disseminated systemic or invasive candidiasis. Effective treatment of esophageal candidiasis generally requires the use of systemic antifungal agents. However, these agents have the disadvantage of producing more side effects (see Table 98–6) and drug–drug interactions (see Chap. 99). Fluconazole is inexpensive and generally well tolerated, and its absorption is unaffected by food or gastric acidity. Ketoconazole requires gastric acidity for absorption, which can be problematic in AIDS patients with achlorhydria; hence, it is best given with an acidic beverage. Ketoconazole is not recommended today with the availability of more effective triazoles. Itraconazole capsules also have the same absorption problem and are no longer recommended. In contrast, itraconazole solution has enhanced absorption and is best taken in a fasting state; in addition, the solution provides the benefit of both topical effects to the oral mucosa and systemic effects and is beneficial to patients with mucositis or swallowing problems. Whenever possible, it is generally beneficial to limit the use of systemic azole agents to prevent unnecessary drug exposure and to minimize the potential for occurrence of drug-resistant candidiasis, particularly from fluconazole resistance.

When patients become unresponsive to topical agents or fluconazole and itraconazole, alternative agents are available.37,38,41,45,46 These include amphotericin B and newer triazoles (voriconazole and posaconazole) and echinocandins (caspofungin, micafungin, and anidulafungin) (see discussion below).


Clinical Controversy…

The optimal strategy for the management of recurrent oral mucosal candidiasis is unclear. Specific criteria for use of secondary prophylaxis are not well defined, and a wide range of approaches can be seen in clinical practice.

Oropharyngeal Candidiasis: Human Immuodeficiency Virus–Infected Patients

It is appropriate to start therapy with topical agents for initial or recurrent episodes of OPC, provided that clinical symptoms are not severe and that there is minimal risk of esophageal involvement.36,41Clinical responses with the resolution of signs and symptoms generally occur within 5 to 7 days of initiating treatment. Clotrimazole appears to be the most effective topical agent and demonstrates comparable clinical response rates with both fluconazole and itraconazole.36,41 However, topical therapy is associated with more frequent relapses than with fluconazole.38,41 This may be of limited clinical significance in patients receiving effective HAART because of their decreased susceptibility to opportunistic infection. In practice, nystatin suspension is still used frequently in initial episodes of OPC, although it is the least effective agent and is associated with frequent treatment failures and early relapses, especially in patients with advanced HIV disease or neutropenia.34,37 The safety and efficacy of miconazole mucoadhesive tablets (MMT) for the treatment of OPC in HIV infected patients were studied in a randomized, double-blind, multicenter trial. Clotrimazole troches 10 mg five times daily was the comparator arm in this noninferiority study. The authors concluded that the clinical cure rate of MMT 50 mg once daily was noninferior to clotrimazole treated patients in both the intention to treat (61% vs. 65% respectively) and per protocol (68% vs. 74% respectively) populations at the test of cure visit. Safety and tolerability was also similar between treatment groups.44

Systemic oral azoles should be reserved for use in the more severe episodes of OPC unresponsive to topical agents or in patients with concurrent esophageal involvement.37,41 In clinical practice, fluconazole usually is the systemic azole agent of choice because of its proven efficacy, favorable absorption, safety, and drug-interaction profiles, and it is relatively inexpensive. Fluconazole is superior to ketoconazole and itraconazole capsules.37,41 Current guidelines suggest a fluconazole regimen of 100 to 200 mg/day for 7 to 14 days.41 There is evidence from one study showing a single dose of fluconazole 750 mg orally is as effective as fluconazole 150 mg orally for 14 days, which warrants further evaluation, given the potential advantages of adherence and cost-effectiveness.45 Itraconazole oral solution with an improved absorption profile compared with the capsule formulation is as effective as fluconazole, with comparable clinical and mycologic response and relapse rates.37,41 However, it carries a higher risk of drug interactions because it is a potent inhibitor of the cytochrome P450 enzymes, and it is associated with more nausea than fluconazole. Posaconazole is an extended-spectrum triazole with potent in vitro activity against both C. albicans and non–C. albicans species. It is equivalent to fluconazole in terms of efficacy, safety, and tolerability.46 Posaconazole has joined itraconazole solution and voriconazole as the azole alternatives to fluconazole in the management of moderate-to-severe OPC.40 Other agents that are effective are amphotericin B and the echinocandins (caspofungin, micafungin, and anidulafungin). They are better reserved for refractory OPC, however, because of their greater toxicity. They are also more expensive and are less convenient to use.

Oropharyngeal Candidiasis: Non-Human Immunodeficiency Virus–Infected Patients

This patient population includes patients with hematologic malignancy (e.g., leukemias) or blood and bone marrow transplantation (BMT) with a long duration of neutropenia and chronic graft-versus-host disease, patients with solid tumors, patients with solid-organ transplants who are receiving immunosuppressive therapy, and patients with diabetes mellitus, as well as patients on prolonged courses of antibiotics or corticosteroids and the debilitated elderly. Factors to consider in deciding whether to use topical or systemic antifungal therapy include the severity and extent of mucosal involvement (oropharyngeal vs. esophageal), predisposing risk factors, and risk for dissemination. Patients who develop neutropenia (e.g., leukemic and BMT patients) are usually at high risk for disseminated and invasive fungal disease, and treatment of oral candidiasis is more aggressive. Patients with cell-mediated immune deficits but normal or near-normal granulocyte function and number (e.g., solid tumors, solid-organ transplants, or diabetic patients) are at low risk for dissemination of infection.

Specific antifungal therapy can be unnecessary for asymptomatic patients at relatively low risk for disseminated candidiasis, such as those who are not granulocytopenic or who are expected to have a short duration of granulocytopenia.41 Many of these infections will clear spontaneously after recovery of the granulocytes or discontinuation of antibiotic and/or immunosuppressive therapy. However, antifungal therapy usually is required for patients who have persistent infection or significant symptoms, usually pain, or who are granulocytopenic with a relatively high risk of fungal dissemination. Topical agents first can be given a therapeutic trial depending on the severity of infection and the degree of immunosuppression. Although both nystatin and clotrimazole can be effective in treating OPC, nystatin suspension does not effectively reduce the incidence of either oropharyngeal or systemic Candidainfections in immunocompromised patients receiving chemotherapy or radiation; its use often is associated with treatment failures and early relapses.41 Clotrimazole appears to be more effective in reducing colonization and treating acute episodes in cancer patients who are immunocompromised. Miconazole mucoadhesive tablets were evaluated in patients with head and neck cancer and found to be superior in terms of achieving a complete response to therapy when compared to miconazole oral gel.47 MMT has not been studied against clotrimazole in this patient population specifically but is approved for use in adults with OPC.

Systemic azole agents are used for treating OPC in patients who have failed or who are unable to take topical therapy.37,41,46 The preceding discussion on the relative efficacy of fluconazole, itraconazole, and ketoconazole in HIV-infected patients can be extrapolated to the non-HIV-infected population. Oral fluconazole 100 to 200 mg daily is used more commonly because of more extensive experience with its use, and it is more effective and has a more favorable absorption and side-effect profile compared with other available azoles.41 If the oral route is not feasible for reasons such as severe chemotherapy-induced mucositis, fluconazole can be administered IV. In patients unresponsive to azoles, IV amphotericin B in relatively low doses of 0.1 to 0.3 mg/kg/day can be tried.41 Because of the higher risk for dissemination in patients who are severely neutropenic (<0.1 × 109 neutrophils/L) or clinically unstable (hypotensive or febrile), some clinicians prefer to initiate therapy with IV amphotericin B at 0.6 mg/kg/day, with therapy continued until the neutropenia has resolved.41 The echinocandins caspofungin, micafungin, and anidulafungin have all been studied for the treatment of OPC and found to be effective, thus offering another option in the patient with refractory disease.41

Topical therapy with clotrimazole or nystatin for 7 days is usually adequate for treating mucocutaneous candidiasis in most solid-organ transplant patients.37 Use of topical therapy will reduce the number of systemic drugs that these patients receive and hence minimize the risk of drug–drug interactions. Failure to respond to topical agents warrants the use of fluconazole. Low-dose amphotericin B solution as “swish and swallow” (100 mg/mL, 1 mL four times daily) for 7 to 10 days is reserved for the unusual cases of treatment failure.

Patients who develop OPC because of prolonged antibiotic use or aerosolized corticosteroids use can be managed successfully by discontinuation of the offending agent, and the infection usually will resolve. If there is a strong desire to treat because of discomfort or need to hasten symptom resolution or an inability to stop the offending agent, therapy with a topical agent, either miconazole MT, clotrimazole or nystatin, is effective in most cases. The advantage of systemic azoles is the convenience of less frequent dosing. Symptoms usually improve in 3 or 4 days. Infants should be given smaller amounts more frequently (e.g., nystatin 100,000 units every 2 to 3 hours) to ensure better contact time. For denture-related OPC, or candidal stomatitis, effective therapy requires treatment of both the mouth and the dentures to avoid relapse. The dentures must be brushed vigorously and disinfected every night by soaking in antiseptic solution, such as chlorhexidine gluconate 0.25% or a product such as Polident or Efferdent.37,41Topical antifungal therapy of the oral cavity is required. Consistent proper oral hygiene and care of the dentures can help prevent relapse.

Esophageal Candidiasis: Human Immunodifiency Virus–Infected Patients

Images Treatment of esophageal candidiasis has not been as well studied as OPC. Because of the significant morbidity of esophageal candidiasis and the absence of evidence supporting the efficacy of topical antifungals, treatment requires systemic antifungal agents.32,35 Fluconazole is superior to ketoconazole and itraconazole capsules with respect to endoscopic cure and clinical response and usually produces a more rapid onset of action and resolution of symptoms. Fluconazole is as effective as itraconazole solution, with reported response rates of >80% to 90%.38,41 However, itraconazole solution causes more nausea and drug interactions because of inhibition of the cytochrome P450 enzymes. Amphotericin B, voriconazole, posaconazole, and the echinocandins are also effective in esophageal candidiasis, but they are generally reserved for patients with advanced or inadequately controlled HIV disease where the candidiasis tends to recur or becomes refractory to azole therapy.4851

Esophageal Candidiasis: Non–Human Immunodifiency Virus–Infected Patients

As in the case of HIV-infected patients, treatment of esophageal candidiasis requires systemic therapy. Patients can be started on fluconazole 200 to 400 mg/day for 14 to 21 days.41 Higher fluconazole doses (up to 400 mg/day) have been suggested for patients with severe symptoms or those who are neutropenic.52 Other agents currently recommended if fluconazole is not an option are an echinocandin or amphotericin B at 0.3 to 0.7 mg/kg. Itraconazole solution, posaconazole, and voriconazole are effective alternatives that may be considered for those not responding adequately to fluconazole. An echinocandin or IV amphotericin B may be selected over fluconazole for initial therapy in neutropenic patients who present with severe symptoms or who are at high risk for dissemination of Candida species, such as those receiving other aggressive immunosuppressive therapy (e.g., corticosteroids, total-body irradiation, or antithymocyte globulin) and who have documented evidence of esophageal candidiasis or who have failed an initial empirical trial of oral nonabsorbable agents or systemic azoles.41 Therapy should be continued at least until the neutropenia resolves. For patients whose symptoms have resolved and who are afebrile and clinically stable, therapy should be discontinued, and the patients should be monitored closely for infection recurrence. In high-risk patients, particularly those with persistent fever and neutropenia, the potential presence of clinically occult, diffuse GI or disseminated candidiasis should be considered. The echinocandins and newer azole agents (voriconazole and posaconazole) offer less toxic alternatives or oral agents and are preferred in patients who are intolerant of amphotericin B deoxycholate or who have preexisting renal impairment.37,52,53 There are limited data on the clinical efficacy of anidulafungin compared with fluconazole, 95% versus 89% cure rates, respectively, in the non-HIV-infected patients.53

Antifungal-Refractory Oral Mucosal Candidiasis

Treatment failure is generally defined as persistence of signs and symptoms of OPC or esophageal candidiasis after an appropriate trial of antifungal therapy.36 Treatment of refractory oral mucosal candidiasis is frequently unsatisfactory, and clinical response is usually short-lived, with rapid and periodic recurrences. The key risk factors for occurrence of refractory candidiasis are advanced stage of AIDS with low CD4 cell counts (<50 cells/mm3[<0.05 × 109/L]) and repeated or prolonged courses of various systemic antifungal agents, in particular systemic azoles.37,41 Frequent or prolonged use of fluconazole can be associated with fluconazole-refractory candidiasis because of selection of more resistant non–C. albicans species. An important initial management strategy is to assess and optimize the antiretroviral therapy of the patient with refractory OPC to help improve the immune function. With the widespread use of HAART, fluconazole-refractory OPC is now less commonly encountered. It is also important to identify and rectify potentially correctable causes of clinical failures of mucosal candidiasis, such as poor drug adherence, adequate dosing, reduced drug absorption associated with hypochlorhydria, and drug–drug interactions.

There have been few controlled studies that assess the effectiveness of antifungal agents. Doubling of the fluconazole dosage to 400 or 800 mg/day can be effective in some patients with infection caused by Candida species of intermediate resistance, although the response may be only transient.38 Fluconazole oral suspension can be beneficial in some patients because of increased salivary concentrations obtained when the suspension is taken with the swish and swallow technique.41 Patients with fluconazole-refractory mucosal candidiasis can be treated with itraconazole oral suspension because it can be effective in 64% to 80% of patients; however, the benefit is short-lived if chronic suppressive therapy is not maintained.36,41 Posaconazole suspension has been reported to be successful in ~74% of patients with refractory oral or esophageal candidiasis; voriconazole may also be efficacious in these patients. Amphotericin B oral suspension is another alternative for azole-refractory patients.38,41 It has broad-spectrum activity against many fungal species and low likelihood of Candida species resistance. There are limited data and experience on its use in immunosuppressed patients, and results from small studies have yielded mixed results.54 Amphotericin B suspension is no longer available commercially in the United States, but it can be prepared extemporaneously by the pharmacy.54


Clinical Controversy…

Several antifungal agents, in both the triazole and echinocandin class, are available for the treatment of oral mucosal candidiasis. Although they have demonstrated efficacy, their place in therapy remains to be defined. It is not established which specific agent should be used next after failing fluconazole or itraconazole, and current guidelines suggest an echinocandin or amphotericin. Factors to consider in the selection can include the underlying clinical condition, the risk for drug, and side effect profiles.

Until recently, IV amphotericin B deoxycholate has been the alternative for patients with endoscopically proven disease who have failed fluconazole or itraconazole therapy. Patients with severe disease unresponsive to other agents require IV amphotericin B 0.3 to 0.7 mg/kg/day for 7 to 10 days to achieve clinical response; higher dose or longer treatment duration can be needed in more severe disease.38,41After response, suppressive therapy with amphotericin B is required to increase disease-free intervals. Patients who fail to respond to amphotericin B and require >1 mg/kg/day might be candidates for liposomal amphotericin B preparations because of renal and/or bone marrow toxicities, although at a markedly higher cost. Flucytosine usually is not used as monotherapy because of rapid development of resistance but can be used in combination with an azole or amphotericin B.38 Less toxic agents that are also effective are voriconazole and the echinocandins.52,53 Voriconazole, a triazole antifungal available in both oral and IV preparations, appears to be as effective as fluconazole for esophageal candidiasis, and it has shown success in treatment of fluconazole-refractory disease.51 However, voriconazole has more side effects and multiple pharmacokinetic drug interactions compared to fluconazole.51 Caspofungin is the first of the echinocandins to be approved for esophageal candidiasis; more recently, micafungin and anidulafungin have been approved for this indication. All three echinocandins have similar efficacy and tolerability profile as fluconazole, although higher relapse has been reported with caspofungin and anidulafungin compared with fluconazole.41,53 Because the echinocandins require IV administration and are expensive, they are primarily used in patients who are refractory to the triazoles or have serious triazole-related adverse effects. As a class, the echinocandins have a favorable adverse effect profile. They are less toxic than amphotericin B (see Table 98–6) and have less impact on the cytochrome P450 enzymes than either itraconazole or voriconazole. Immunomodulation with adjunctive granulocyte-macrophage colony-stimulating factor and interferon have been used for refractory oral candidiasis in very limited numbers of patients.41

Antifungal Prophylaxis

Images Ensuring that the HIV-infected patient is receiving appropriate antiretroviral therapy to enhance the immune system is perhaps the most important measure in preventing future episodes of mucosal candidiasis (oropharyngeal, esophageal, and vulvovaginal).41 Initial success of treatment often is followed by symptomatic recurrences, especially in patients with advanced or poorly controlled HIV disease. Long-term suppressive therapy with fluconazole is effective in preventing recurrences or new infections of OPC in AIDS and in patients with cancer.41 However, the indications for antifungal prophylaxis and the best long-term management strategy still have not been well established. Fluconazole does not provide complete protection, and breakthrough infections can occur.38 The reduced risk of recurrence of OPC also has not been demonstrated to improve survival. In addition, chronic exposure to azole therapy is a concern in that it might lead to the development of refractory disease or emergence of azole resistance.41However, in a randomized trial of continuous versus episodic fluconazole therapy, continuous therapy did not result in a higher rate of refractory OPC or esophageal disease.53 Currently, HIV specialists do not recommend primary or secondary prophylaxis for OPC.38 The rationale includes effectiveness of therapy for acute episodes of OPC, low incidence of serious invasive fungal disease, low mortality associated with mucosal candidiasis, potential for drug interactions, potential for emergence of drug resistance, and the prohibitive long-term cost of prophylaxis.

Images The decision to use secondary prophylaxis should be individualized for each patient. Secondary prophylaxis can be considered in patients with multiple recurrent episodes of symptomatic OPC or when the disease is sufficiently severe and affecting the quality of life.38 Patients with a history of one or more episodes of documented esophageal candidiasis and a CD4 T-cell count still <200 cells/mm3 (<0.2 × 109/L) despite being on HAART are candidates for secondary prophylaxis. Oral fluconazole 100 mg daily is the usual regimen recommended for OPC and esophageal candidiasis,38,41 although 200 mg three times weekly also appears to be effective.55 Once-weekly oral fluconazole (200 mg) is also effective for preventing OPC recurrences in those with less-advanced AIDS.38 Itraconazole solution 200 mg daily orally is an alternative as suppressive therapy for OPC.41

Patients with malignant neoplastic diseases who are receiving irradiation, cytotoxic, and/or immunosuppressive therapy are at high risk for fungal infections in addition to bacterial and viral infections. Prophylaxis of Candidainfection is controversial, and the results of studies have been conflicting and difficult to evaluate. In the hematopoietic stem cell transplant (HSCT) population, fluconazole prophylaxis is recommended prior to engraftment. Cross-resistance to other azoles may occur among Candida species; this should be a treatment consideration in a patient who develops a breakthrough fungal infection. Micafungin is an alternative to fluconazole prophylaxis of candidiasis.56 The value of antifungal prophylaxis in these patients needs to be considered in the broader context of not only reducing colonization and the risk of superficial candidiasis but also, more importantly, reducing the risk for invasive candidiasis and improving survival. Management of these infections in this patient population is discussed further in Chapter 100.

Evaluation of Therapeutic Outcomes

Efficacy end points for oropharyngeal and esophageal candidiasis include rapid relief of symptoms and prevention of complications without early relapse after completion of the course of therapy.38,41Sterilization of the oral cavity is not a feasible end point because mycologic eradication is rarely achievable, especially in HIV-positive patients. Symptomatic relief of presenting signs and symptoms (see Table 98–5) generally occurs within 48 to 72 hours of starting therapy, with complete resolution by 7 to 10 days. Patients should be advised about the time course and told to return for reassessment when signs and symptoms recur. It is usually unnecessary for the patient to be reassessed soon after finishing the treatment course. However, HIV patients should be questioned and examined for the occurrence of mucosal candidiasis as part of their regular followup. The frequency of monitoring can be more often in neutropenic patients because of concern for dissemination of candidiasis. During the period of neutropenia, temperature should be monitored daily, as well as signs of dissemination.

Efficacy of the antifungal agent is partly influenced by patient adherence to the medication regimen. Patients must be counseled on proper administration and dosing, in particular for topical agents (Table 98–7).52 Safety end points include monitoring for occurrence of the relevant drug side effects and drug interactions (see Table 98–6). Mild GI intolerance can occur with topical therapy, but serious adverse effects are rare. It is still prudent to monitor for hypersensitivity reactions, especially rash and pruritus, that might occur with any medication. GI intolerance is more associated with the oral azoles. Hepatotoxicity can occur when azole therapy is prolonged beyond 7 to 10 days or high doses are used. Periodic monitoring of liver enzymes (alanine transaminase and aspartate amino-transferase) should be considered, especially if prolonged therapy (longer than 21 days) is anticipated. Patients who are receiving IV amphotericin B require daily monitoring by a pharmacist.

TABLE 98-7 Patient Counseling Tips for Managing Oropharyngeal Candidiasis

Images

MYCOTIC INFECTIONS OF THE SKIN, HAIR, AND NAILS

Superficial mycotic infections of the skin are referred to as dermatophytoses. They are common infections that usually are caused by dermatophytes classified by genera: TrichophytonEpidermophyton, and Microsporum.57,58Dermatophytes have the ability to penetrate keratinous structures of the body. These infections affect both male and female genders and all races. Reservoirs of mycotic infections include humans, animals, and soil.58,59 Individuals can develop an infection if they come in contact with a reservoir in addition to having a conducive environment for mycotic growth (i.e., moist conditions).60 Risk factors for the development of an infection include prolonged exposure to sweat, maceration, intertriginous folds, sharing personal belongings such as combs, close living quarters (dormitories, barracks).59,60

Mycotic infections of the skin have a classic appearance that consists of a central clearing surrounded by an advancing red, scaly, elevated border.60 Infections of the nail can appear chalky and dull yellow or white and become brittle and crumbly.

Diagnosis usually is based on patient history, as well as the physical examination.61 Diagnostic tests include direct microscopic examination of a specimen after the addition of KOH or fungal cultures. The KOH test is quick, inexpensive, and easy to perform, whereas cultures are more expensive and take longer to obtain results. Diagnostic tests are recommended when systemic therapy is likely to be prescribed.61

Images A general approach to treatment of superficial mycotic infections includes keeping the infected area dry and clean and limiting exposure to the infected reservoir. Topical agents generally are considered to be first-line therapy for infections of the skin. Oral therapy is preferred when the infection is extensive or severe or when treating tinea capitis or onychomycosis.6264 Table 98–8 lists specific treatments for each mycotic infection. Superficial mycotic infections are categorized by the pattern and site of infection.59 The most commonly occurring infections in North America are detailed in the following sections.

TABLE 98-8 Treatment of Mycoses of the Skin, Hair, and Nails

Images

Tinea Pedis

Tinea pedis is the most common dermatophytoses (affecting ~70% of adults). It is better known as “athlete’s foot” and occurs in hot weather, with exposure to surface reservoirs (locker room floors), and with use of occlusive footwear.60 Treatment with topical therapy for 2 to 4 weeks often is adequate for mild infections; however, severe infections or involvement of the nails require oral therapy60 (see Table 98–8). Recurrence of infection occurs in up to 70% of individuals. Prolonged treatment with either topical or systemic therapy may be required.59,62

Tinea Manuum

Tinea manuum usually involves the palmar surface of the hands, is unilateral, and can involve the feet. Treatment of this infection is similar to tinea pedis (see Table 98–8). Emollients that contain lactic acid also can be useful.60

Tinea Cruris

Tinea cruris is an infection of the proximal thighs and buttocks.63 It is referred to as “jock itch” and is more common in males. The scrotum and penis often are spared from infection. Treatment with topical therapy is recommended and should continue for 1 to 2 weeks after symptom resolution. Severe infections can require oral therapy (see Table 98–8). Relief of pruritus and burning can be facilitated by the use of short-term (2 or 3 days) topical steroids (2.5% hydrocortisone).60

Tinea Corporis

Tinea corporis is an infection of the glabrous skin of the trunk and extremities.63 Therapy is similar to that for tinea pedis, tinea manuum, and tinea cruris (see Table 98–8).

Tinea Capitis

Tinea capitis is a mycotic infection involving the scalp, hair follicles, and adjacent skin that primarily affects children.64,65 Treatment should consist of oral therapy, as well as the cleaning of combs and brushes, which can be contaminated (see Table 98–8). Daily shampooing is recommended for removal of scales. Some children and adults can be asymptomatic carriers, thereby facilitating spread of the infection.64 Family members who culture positive for Trichophyton tonsurans should be treated with an antifungal shampoo (e.g., ketoconazole, selenium sulfide, or povidone-iodine).64

Tinea Barbae

Tinea barbae affects the hairs and follicles of beards and mustaches.64 Treatment is similar to that for tinea capitis (see Table 98–8). Removal of the beard or mustache is recommended.60

Pityriasis Versicolor

Hyper- and hypopigmented scaly patches characterize pityriasis versicolor, which is also known as tinea versicolor. It is caused by yeasts of the Malassezia genus which with the exception of Malassezia pachydermatis, are all lipophilic. The seborrheic areas (scalp, face, back and front of the trunk) of the human body are always colonized by one or more Malassezia spp., such as M. globosaM. sympodialisM. sloffiae, and M. restricta are the most common colonizers; M. globosa and M. furfur are most frequent clinical infection isolates. The lesions are found on the trunk, face and extremities.59 It is more common in adults and in areas with tropical ambient temperatures. Topical treatment usually is adequate unless there is extensive involvement, recurrent infections, or failure of topical therapy.66 A study of 100 subjects treated with either ketoconazole 2% shampoo or selenium sulfide 2.5% shampoo showed that ketoconazole was significantly more effective that selenium sulfide (89% vs. 35% cure rate).66Recurrence of infection after cessation of treatment may be as high as 60% in the first year and 80% the second year. Suppressive maintenance therapy either orally or topically may be used in these cases.58

Onychomycosis (Tinea Unguium)

Onychomycosis is a fungal infection of the nail apparatus and is the most common single cause of nail dystrophy, affecting up to 8% of the general population and accounting for up to 50% of all nail problems.6669 Onychomycosis more commonly affects the toenails (2% to 14% of adults), ~4 to 19 times more frequently than fingernails, with prevalence increasing with age.69 This can be because of the slower growth of toenails (three times slower than fingernails), making it easier for fungi to establish infection. Onychomycosis has a significant impact on quality of life, both functional and psychosocial. In addition, the affected nails can disrupt the integrity of the surrounding skin, potentially increasing the risk of secondary bacterial infections.69

Onychomycosis is due to infection by dermatophytes (tinea unguium), yeasts and nondermatophyte fungi.70 Dermatophytes are the most frequent causes of onychomycosis (~90% in toenail and ~50% in fingernail infections).71The dermatophytes responsible for causing >90% of cases of onychomycosis are Trichophyton rubrum (71%) and Trichophyton mentagrophytes (20%).64,65 Less common fungi causing onychomycosis are the nondermatophytic molds (2.3% to 11%) and yeasts (5.6%). Candida albicans is the most commonly isolated yeast and typically affects fingernails rather than toenails.66,72 Risk factors for dermatophytic onychomycosis are increasing age (especially older than 40 years), family history and genetic factors, immunodeficiency (e.g., HIV, renal transplant, immunosuppressive therapy, and defective polymorphonuclear chemotaxis), diabetes mellitus, psoriasis, peripheral vascular disease, smoking, prevalence of tinea pedis, frequent nail trauma, and sporting activities such as swimming.72,73These risk factors also appear to apply to recurrence of onychomycosis. Mold onychomycosis does not seem to be associated with systemic or local predisposing factors, but there is a risk of systemic dissemination in immunosuppressed patients.72 Candida onychomycosis seems to always occur in immunosuppressed patients.72

Onychomycosis can present in four or five different major clinical forms, of which lateral distal subungual onychomycosis (DSO) is the most common type.66,72,74 In DSO, the nail plate, the nail bed, and, in advanced cases, the matrix are all affected, and T. rubrum is the most common etiologic cause. The worst case of onychomycosis is progression of the infection to total dystrophic onychomycosis, characterized by almost complete destruction of the nail plate. White superficial onychomycosis (WSO) is usually caused by T. mentagrophytes, where the infection is localized to the surface of the nail plate. In proximal subungual onychomycosis (PSO), the fungi (usually T. rubrum) invade the nail through the proximal nail fold and spread to the nail plate and matrix. Although PSO is relatively uncommon in the general population, it occurs most frequently in severely immunocompromised patients and is often considered a marker for AIDS.72,74 Because of the multifactorial etiology of onychomycosis, it is important to differentiate onychomycosis from other causes of nail dystrophies so that the patient receives appropriate therapy and is not subjected to prolonged treatment with unnecessary drugs. Besides clinical history and physical examination, proper diagnosis of onychomycosis can include the combination of direct microscopy of scrapings from the appropriate nail area to look for fungal hyphae and fungal cultures, and, if necessary, histologic examination.68,75,76 Table 98–9 provides a differential diagnosis for fungal nail diseases.77

TABLE 98-9 Differential Diagnosis of Fungal Nail Infections

Images

TREATMENT

General Approach

Onychomycosis merits proper assessment and treatment consideration because it is a debilitating disease and can exert a negative impact on quality of life (e.g., cosmetic and psychosocial effects, pain, discomfort, and decreased ambulation).68,70,72,78 It is reasonable to not treat persons with minimal toenail involvement and no associated symptoms.77 Although definitive data are lacking regarding the risk of progression of untreated disease, it can lead to complications such as cellulitis or reduced mobility, which can further compromise peripheral circulation in those with diabetes or peripheral vascular disease; additionally, infected nails can serve as a source of transmission of fungi to other areas of the body, as well as to other people, such as close household contacts, or in communal bathing places.69,70,72,78,79Treatment decisions should be made on an individual basis. The primary end point of treatment is eradication of the organism, with secondary end points being clinical cure and improvement.69 Assessment of clinical success (cure or improvement) requires followup for several months after the end of treatment because of the slow growth rate of nails, especially toenails (1 mm/month).68,72 Successful eradication of the fungus does not always result in normalization of the nails because they can have been dystrophic prior to infection. This can cause patient dissatisfaction, especially if this is not explained before starting treatment.74 There are several factors that must be taken into account on a patient-by-patient basis to ensure appropriate treatment decisions (Table 98–10). The impact of patient adherence on the success of treatment cannot be overemphasized. Patients need to be educated about their disease, expectations of treatment, and prevention of recurrence, and various strategies have been suggested to improve treatment success.76

TABLE 98-10 Factors That May Impact Treatment Decisions and Outcomes

Images

In general, onychomycosis of the toenail is more difficult to treat than fingernails, requires longer treatment duration, and is associated with a higher recurrence. The treatment options for onychomycosis include oral and topical therapies, mechanical or chemical nail avulsion, or a combination of these. Mechanical or chemical nail avulsion is used primarily as adjunct to oral therapy in patients with total dystrophic onychomycosis, in whom there is severe onycholysis and extensive nail thickening or longitudinal spikes. This is to enhance penetration of the antifungal agent to the entire nail plate and unit.68,70,76,79

Topical Therapy

Images Conventional topical antifungal products are available as creams, ointments, powders, and solutions. Because these formulations do not penetrate through the nail plate to the nail bed, they are most appropriately used when the nail plate has been removed.70,79 Even then cure rates are still low and variable and are influenced by patient adherence.70,72,79 Nail lacquer represents the latest advance in topical formulation. The volatile vehicle, used to deliver the drug, evaporates and leaves an occlusive film with a high drug concentration on the nail surface.72,79 There are only two marketed nail lacquers, amorolfine 5% and ciclopirox 8% solution (Penlac), the latter being the only one approved in the United States for the treatment of mild-to-moderate onychomycosis caused by T. rubrum without lunula involvement.72,78,79 Ciclopirox, a hydroxypyridine, has a broad spectrum of antifungal activity (dermatophytes, Candida species, and some molds) and requires treatment for 1 year. Although ciclopirox was significantly better than vehicle alone, the mycologic cure rate was only 32% with ciclopirox versus 10% for vehicle alone after 48 weeks of treatment; the overall treatment cure (mycologic cure with 0% to 10% involvement of the target nail) was 9% versus 0.9% for drug and vehicle, respectively.72,79 However, higher mycologic cure rates of 45% to 65% have been reported in a variety of open-label trials involving 6 to 12 months of treatment.72 Amorolfine appears to produce higher mycologic and treatment cure rates than ciclopirox.70,78 Most experts consider topical therapy a feasible option when the infection is superficial involving the nail plate without matrix involvement, such as WSO, involves a partial area of the nail plate not exceeding 50% (owing to difficulty of applying treatment to the margin of the nail), is limited to a few (three or four) nails, is in the very early stages of DSO when infection is still confined to the distal edge of the nail, or when systemic therapy is contraindicated.68,72,78 Combining topical therapy with debridement of the affected nail (thus diminishing the amount of nail requiring treatment) may increase the likelihood of successful treatment, although there is no strong supporting evidence.77 Topical therapy is not associated with systemic adverse effects or drug interactions. Any adverse effect will be localized to the application site, such as mild erythema in the adjacent skin area.


Clinical Controversy…

Treatment of onychomycosis is associated with a high failure rate of 20% to 50%. There appears to be a sound pharmacologic rationale behind the use of combination therapy, which has been used to improve overall efficacy. However, the best combination of agents for use in treating onychomycosis is unclear, and there is no consensus on when to use such agents.

Systemic Therapy

Oral antifungal therapy is considered to be more effective than topical for treating onychomycosis. Terbinafine and itraconazole (capsule), the current first-line agents for treatment, have yielded higher efficacy rates using shorter treatment periods (generally 3 months or shorter) for toenail and fingernail onychomycosis compared with the traditional agents, such as griseofulvin and ketoconazole, which are rarely used nowadays. Terbinafine, an allylamine, exerts fungicidal activity and demonstrates the greatest in vitro activity against dermatophytes compared with the other oral antifungals; it has good activity against nondermatophyte molds and only marginal activity against Candidaspecies.68,79 Like other azoles, itraconazole is fungistatic, has a broad antifungal spectrum, and is very active against dermatophytes, nondermatophytes, and Candida species.68,79 Both agents have lipophilic and keratinophilic properties, which explains their excellent penetration (appearing in the nail plate within days of treatment initiation) and accumulation in the nails, achieving concentrations far exceeding the minimal inhibitory concentration (MIC) of most dermatophytes. Nail terbinafine concentrations are detected within 1 week of starting therapy, whereas itraconazole can be detected 1 (fingernails) to 2 weeks (toenails) after starting therapy.72 Both drugs are slowly eliminated from the nail, with effective drug concentrations persisting in nails for 30 to 36 weeks after completion of treatment with terbinafine and for 27 weeks with itraconazole.74 The persistence of drug in the nails explains in part the long-term protection against relapses after the end of treatment and also permits use of intermittent (pulse) dosing.

The treatment of toenail onychomycosis requires a 12-week course, whereas a 6-week course is adequate for fingernail onychomycosis with either drug.69,74 In general, cure rates of 80% to 90% for fingernail infection and 70% to 80% for toenail infection can be expected.68 Terbinafine is licensed for daily dosing (see Table 98–8).69,74,80 Various terbinafine pulse regimens have been evaluated;73 in some trials, pulse dosing was less effective than continuous dosing, and it did not provide clear safety advantages.75,76 One trial demonstrated similar efficacy of pulse terbinafine compared with continuous therapy and better outcomes compared with pulse itraconazole treatment.81Itraconazole pulse therapy is the preferred method over continuous dosing for fingernail infections, and it is licensed as twice-daily dosing for a 1-week cycle per month for 2 consecutive months (i.e., two pulses), or as daily therapy for 6 weeks (see Table 98–8).74,80 Although itraconazole pulse therapy is not approved by the U.S. Food and Drug Administration (FDA), three or four pulses are effective for toenail infections; otherwise, half the dose is taken daily for 3 months (see Table 98–8).74,80 In addition to lower drug cost, the potential advantages of itraconazole pulse therapy compared with continuous therapy are a lower risk of adverse drug effects and improved patient adherence.

Terbinafine is generally considered by most experts as the first-line agent for onychomycosis; itraconazole is the alternative. Direct comparative trials generally have shown that terbinafine is more effective than itraconazole either by continuous or pulse dosing.68,78,79 Mycologic cure rates for terbinafine range from 77% to 100% depending on the study.72,82,83 In a cumulative meta-analysis of randomized, controlled trials, mycologic cure rates for terbinafine, itraconazole pulse, itraconazole continuous, fluconazole, and griseofulvin were 76% ± 3%, 63% ± 7%, 59% ± 5%, 60% ± 6%, and 48% ± 5%, respectively.84 An earlier meta-analysis and systematic review also reported that continuous terbinafine was the most effective therapy for toenail onychomycosis.84,85,86 In addition, terbinafine was reported to achieve high cure rates in high-risk immunosuppressed patients, such as diabetics and organ transplant recipients, comparable to the immunocompetent population, with no significant adverse effects or drug interactions. It also appears to be effective in HIV patients and nondermatophyte infections.80,87 A pharmacoeconomic analysis of oral and topical (ciclopirox) therapies showed that from a managed-care perspective, terbinafine was the most cost-effective therapy in terms of highest success rate, lowest relapse rate, and highest number of disease-free days for both fingernail and toenail infections.88 An analysis that looked only at oral therapy estimated that the cost per cure with the use of terbinafine (based on cure rates from clinical trials) ranged from $2,439 to $7,944, depending on disease severity.89 Compared with the amount of money a patient would consider reasonable to spend on treatment, the current charges for a course of systemic therapy are considerably higher.89,90

Both terbinafine and itraconazole generally are well tolerated. The more common adverse effects reported with terbinafine are GI (e.g., diarrhea, dyspepsia, nausea, and abdominal pain), dermatologic (e.g., rash, urticaria, and pruritus), and headache; less common adverse effects are taste disturbances, fatigue, inability to concentrate, and asymptomatic liver enzyme abnormalities.74,78,80 Terbinafine can cause transient decrease in absolute lymphocyte counts; hence, monitoring of complete blood counts can be useful, especially in immunocompromised patients.80 Although uncommon, severe adverse effects have been reported with terbinafine, including erythema multiforme, Stevens-Johnson’s syndrome, toxic epidermal necrolysis, pancytopenia, lupus erythematosus, psoriasis, hair loss, and hepatotoxicity. Although the incidence of severe hepatotoxicity is considered rare, the FDA issued a public health advisory in 2001 regarding the association of terbinafine tablets with 16 possible cases of liver failure, including 2 liver transplants and 11 deaths.91 Terbinafine thus is not recommended for patients with chronic or active liver disease, although hepatotoxicity can occur in patients with no preexisting liver disease or serious underlying medical condition. Prior to initiating terbinafine treatment, it is recommended to obtain appropriate nail specimens for laboratory testing to confirm the diagnosis of onychomycosis. Liver function parameters (serum transaminases) should be assessed at baseline and periodically during treatment with terbinafine.80,91

The common adverse effects of itraconazole are similar to those of terbinafine, such as GI disturbance, dermatologic disorders, and headache; less common adverse effects include dizziness, fatigue, fever, decreased libido, and asymptomatic liver enzyme abnormalities (1% to 5% with continuous dosing and ~2% with pulse dosing).74,78,92 Although still considered rare, 24 serious cases of liver failure, including transplantation and death, have been reported with the use of itraconazole, resulting in an FDA public health advisory warning.91 Some of these patients did not have preexisting liver disease or serious underlying medical conditions, and some developed within the first week of treatment. Itraconazole should be avoided in patients with elevated liver enzymes or active liver disease or in those who have experienced other drug-induced liver toxicity. Liver function parameters (serum transaminases) should be assessed prior to and periodically during treatment. However, some experts have suggested that frequent monitoring is not as necessary if pulse therapy is used because symptomatic hepatotoxicity has not been reported with pulse therapy.92 In addition, there is an FDA warning on the risk of developing congestive heart failure (CHF) associated with the use of itraconazole, possibly related to its potential negative inotropic effect.69,82 Therefore, itraconazole should not be used in patients with evidence of ventricular dysfunction, such as CHF. Symptomatic assessment for the development of CHF also should be included as part of therapy monitoring. Before a patient is subjected to several months of itraconazole treatment, it is important to confirm the diagnosis of onychomycosis.

In contrast to the azoles, terbinafine does not inhibit the cytochrome P450 (CYP)3A4 isoenzymes, but it is a potent inhibitor of the CYP2D6 isoenzymes, which are responsible for metabolism of tricyclic antidepressants and other psychotropic drugs.69,74,80 The most significant drug interactions with terbinafine are decreased clearance of 33% by cimetidine and increased clearance of 100% by rifampin. Other drug interactions of variable clinical significance are tricyclic antidepressants, cyclosporine, caffeine, theophylline, and terfenadine. Itraconazole and its major metabolite can inhibit the CYP3A4 isoenzymes and result in numerous clinically significant drug interactions where coadministration with several drugs are contraindicated (e.g., alprazolam, midazolam, triazolam, pimozide, lovastatin, simvastatin, cisapride, and terfenadine).68,74,80

Fluconazole is also active against dermatophytes, Candida species, and some nondermatophytes;74,78 however, it does not have current FDA-approved indication for treatment of onychomycosis. The overall mycologic cure rate of fluconazole is 48%, which is lowest compared with all other oral agents.84 The most effective dose and treatment duration have not been clearly established, with a variety of dosing regimens used, ranging from 50 mg daily to 300 mg once weekly for 6 to 12 months (see Table 98–8).74,80 The advantages of fluconazole include a relatively good safety profile and fewer drug interactions compared with itraconazole.74,80

These three oral antifungal agents have superseded the use of griseofulvin and ketoconazole as treatments of choice for onychomycosis.68,78,79 Griseofulvin has a narrow antifungal spectrum, low clinical efficacy, especially for toenail infections, high relapse rates, and the need for prolonged treatment duration (up to 12 to 18 months for toenails). Use of ketoconazole is also associated with high relapse rates, and the prolonged treatment duration carries an increased risk of hepatotoxicity.

Treatment Response and Recurrence

Treatment failures and recurrence rates of infection following initial cure are high, ranging from 20% to 50%.69,77 Recurrence could be either a relapse (original infection not completely cured) or reinfection (new infection after achieving a cure of the original). Factors associated with poor response to systemic therapy include a compromised immune system (AIDS), reduced blood flow (diabetes, peripheral vascular disease, vasculitis, connective tissue disease, and CHF), coexisting nail disease (psoriasis), nail factors (slow growth, thick nails, and severe disease), drug-resistant organisms because of extensive prior drug exposure, and reduced bioavailability (absorption problems, poor compliance, and drug interactions).74,77 To improve treatment outcomes and reduce recurrence, patients should be counseled on the importance of proper foot hygiene, for example, wearing breathable footwear and 100% cotton socks with frequent changes, keeping the nails short and clean, keeping the feet dry, protecting the feet in shared bathing areas, treating tinea pedis, and controlling other predisposing medical conditions.77

The use of combination therapy (topical–oral or oral–oral agents) can improve cure rates and shorten treatment duration, as this approach provides complementary mechanisms of attack.77,78 Studies in Europe have reported favorable results achieved with itraconazole or terbinafine combined with amorolfine.77,78 To date, no specific combination has been approved or endorsed for use. Other novel approaches include giving supplemental therapy and use of boosted therapy.77,78 The efficacy and role of either approach remain to be defined.


Clinical Controversy…

There is controversy regarding the cost–benefit ratio of treating onychomycosis. People commonly receive treatment without a proper diagnosis of onychomycosis. These patients are not accounted for in any pharmacoeconomic analysis as such this inappropriate treatment will markedly increase the cost per cure. Also relevant to decision making are the risks of treatment and the effects of treatment on quality of life. A study translating these considerations into an amount of money a patient would consider reasonable to spend on treatment found the current costs of a course of therapy are much greater than this sum.84

ABBREVIATIONS

Images

REFERENCES

    1. Sobel JD, Faro S, Force R, et al. Vulvovaginal candidiasis: Epidemiologic, diagnostic and therapeutic considerations. Am J Obstet Gynecol 1998;178:203–211.

    2. Center for Disease Control and Prevention. Vaginal Discharge-STD Treatment Guidelines. 2006, www.cdc.gov/std/treatment/2006/vaginaldischarge.htm.

    3. Haefner HK. Current evaluation and management of vulvovaginitis. Clin Obstet Gynecol 1999;42:184–195.

    4. Foxman B, Barlow R, D’arcy H, et al. Candida vaginitis self-reported incidence and associated costs. Sex Transm Dis 2000;27:230–235.

    5. Fischer G, Bradford J. Vulvovaginal candidiasis in postmenopausal women: The role of hormone replacement therapy. J Low Genit Tract Dis 2011;15:263–237.

    6. Lipsky MS, Waters T, Sharp LK. Impact of vaginal antifungal products on utilization of health care services: Evidence from physician visits. J Am Board Fam Pract 2000;13:178182.

    7. Clinical Effectiveness Group. National guideline for the management of vulvovaginal candidiasis. Sex Transm Infect 1999;75(suppl 1):S19–S20.

    8. Larsen B. Vaginal flora in health and disease. Clin Obstet Gynecol 1993;36:107–121.

    9. Sobel JD. Clinical vulvovaginitis. Clin Obstet Gynecol 1993;36:153–165.

   10. Camacho DP, Consolaro ME, Patussi EV, Donatti L, Gasparetto A, Svidzinski TL. Vaginal yeast adherence to the combined contraceptive vaginal ring (CCVR). Contraception 2007;76:439–443.

   11. Barbone F, Austin H, Louv WC, Alexander WJ. A follow-up study of the methods of contraception, sexual activity, and rates of trichomoniasis, candidiasis, and bacterial vaginosis. Am J Obstet Gynecol 1990;163:510–514.

   12. Xu J, Schwartz K, Bartoces M, Monsur J, Severson RK, Sobel JD. J Am Board Fam Med 2008;21:261–268.

   13. Ferris DG, Dekle C, Litaker MS. Women’s use of over-the-counter antifungal pharmaceutical products for gynecologic symptoms. J Fam Pract 1996;42:595–600.

   14. ACOG practice bulletin: Clinical management guidelines for obstetrician-gynecologists. Obstet Gynecol 2006;107: 1195–1206.

   15. Watson MC, Bond CM, Grimshaw J, Johnston M. Factors predicting the guideline compliant supply (or non-supply) of non-prescription medicines in the community pharmacy setting. Qual Saf Health Care 2006;15:53–57.

   16. Martinez RC, Franceschini Sa, Patta MC, et al. Improved treatment of vulvaovaginal candidiasis with fluconazole plus probiotic Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14. Lett Appl Microbiol 2009;48:269–274.

   17. Abdelmonem AW, Rasheed SM, Mohamed AS. Bee-honey and yogurt: a novel mixture for treating patients with vulvovaginal candidiasis during pregnancy. Arch Gynecol Obstet 2012;8: Epub ahead of print.

   18. Hilton E, Isenberg HD, Alperstein P, et al. Ingestion of yogurt containing Lactobacillus acidophilus as prophylaxis for candidal vaginitis. Ann Intern Med 1992;116:353–357.

   19. Witt A, Kaufmann U, Bitschnau M, et al. Monthly itraconazole versus classic homeopathy for the treatment of recurrent vulvovaginal candidiasis: a randomized trial. Br J Obstet Gynecol 2009;116:1499–1505.

   20. Tooley PJ. Patient and doctor preferences in the treatment of vaginal candidiasis. Practitioner 1985;229:655–662.

   21. Nurbhai M, Grimshaw J, Watson M, Bond CM, Mollison JA, Ludbrook A. Oral versus intravaginal imidazole and triazole antifungal treatment of uncomplicated vulvovaginal candidiasis (thrush). Cochrane Database Syst Rev 2007;4:CD002845, DOI:10.1002/14651858.CD002845.pub2.

   22. Edelman DA, Grant S. One-day therapy for vaginal candidiasis a review. J Reprod Med 1999;44:543–547.

   23. Mendling W, Plempel M. Vaginal secretion levels after 6 days, 3 days and 1 day of treatment with 100-, 200-, 500-mg vaginal tablets of clotrimazole and their therapeutic efficacy. Chemotherapy 1982;28(suppl 1):43–47.

   24. Sobel JD, Kapernick PS, Zervos M, et al. Treatment of complicated candida vaginitis: Comparison of single and sequential doses of fluconazole. Am J Obstet Gynecol 2001;185:363–369.

   25. Young G, Jewell D. Topical treatment for vaginal candidiasis (thrush) in pregnancy. Cochrane Database Syst Rev 2001;4:CD000225, DOI:10.1002/14651858.CD000225.

   26. Mastroiacovo P, Mazzone T, Botto L, et al. Prospective assessment of pregnancy outcomes after first-trimester exposure to fluconazole. Am J Obstet Gynecol 1996;175:1645–1650.

   27. Pursley TJ, Blomquist IK, Abraham J, Andersen HF, Bartley JA. Fluconazole-induced congenital anomalies in three infants. Clin Infect Dis 1996;22:336–340.

   28. Sobel JD, Wiesenfeld HC, Martens M, et al. Maintenance fluconazole therapy for recurrent vulvovaginal candidiasis. N Engl J Med 2004;351:363–369.

   29. Pappas PG, Kauffman CA, Andes DA, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the infectious diseases society of America. Clin Infect Dis 2009;48:503–535.

   30. Sobel JD, Chiam W, Nagappan V, Leaman D. Treatment of vaginitis caused by Candida glabrata: Use of topical boric acid and flucytosine. Am J Obstet Gynecol 2003;189:1297–1300.

   31. Sobel JD, Chaim W. Treatment of Torulopsis glabrata vaginitis: Retrospective review of boric acid therapy. Clin Infect Dis 1996;22:336–340.

   32. Ray D, Goswami R, Banerjee U, Dadhawl V, et al. Prevalence of Candida glabrata and its response to boric acid vaginal suppositories in comparison with oral fluconazole in patients with diabetes and vulvovaginal candidiasis. Diabetes Care 2007;30:312–317.

   33. Leigh JE, Shetty K, Fidel Jr PL. Oral opportunistic infections in HIV-positive individuals: Review and role of mucosal immunity. AIDS Patient Care STDS 2004;18:443–456.

   34. Farah CS, Lynch N, McCullough MJ. Oral fungal infections: An update for the general practitioner. Aust Dent J 2010;55(1 suppl):48–54.

   35. Thompson III GR, Patel PK, Kirkpatrick WR, et al. Oropharyngeal candidiasis in the era of antiretroviral therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010;109:488–495.

   36. Delgado ACD, de Jesus PR, Aoki FH, et al. Clinical and microbiological assessment of patients with long-term diagnosis of human immunodeficiency virus infection and Candida oral colonization. Clin Microbiol Infect 2009;15:364–371.

   37. Laudenbach JM, Epstein JB. Treatment strategies for oropharyngeal candidiasis. Expert Opin Pharmaocother 2009;10(9):1413–1421.

   38. Benson CA, Kaplan JE, Masur H, et al. Treating opportunistic infections among HIV-infected adults and adolescents: Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. Clin Infect Dis 2004;40:S131–S235.

   39. Mercante DE, Leigh JE, Lilly EA, et al. Assessment of the association between HIV viral load and CD4 cell count on the occurrence of oropharyngeal candidiasis in HIV-infected patients. J Acquir Immune Defic Syndr 2006;42:578–583.

   40. Soysa NS, Samaranayake LP, Ellepola ANB. Antimicrobials as a contributory factor in oral candidosis: A brief overview. Oral Dis 2008;14:138–143.

   41. Pappas PG, Kauffman CA, Andes D, et al. Guidelines for management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 2009;48: 503–535.

   42. Jurevic RJ, Traboulsi RS, Mukherjee PK, et al. Identification of gentian violet concentration that does not stain oral mucosa, possesses anti-candidal activity and is well tolerated. Eur J Clin Microbiol Infect Dis 2011;30(5):629–633.

   43. Lalla RV, Bensadoun RJ. Miconazole mucoadhesive tablet for oropharyngeal candidiasis. Expert Rev Anti Infect Ther 2011;9(1):13.

   44. Vazquez JA, Patton LL, Epstein JB et al. Randomized, comparative, double-blind, double-dummy, multicenter trial of miconazole buccal tablet and clotrimazole troches for the treatment of oropharyngeal candidiasis: Study of Miconazole Lauriad® Efficacy and Safety (SMiLES). HIV Clin Trials 2010;11(4):186–196.

   45. Hamza OJM, Matee MIN, Bruggemann RJM, et al. Single-dose fluconazole versus standard 2-week therapy for oropharyngeal candidiasis in HIV-infected patients: A randomized, double-blind, double-dummy trial. Clin Infect Dis 2008;47:1270–1276.

   46. Vasquez JA, Skiest DJ, Nieto L, et al. A multicenter randomized trial evaluating posaconazole versus fluconazole for the treatment of oropharyngeal candidiasis in subjects with HIV/AIDS. Clin Infect Dis 2006;42: 1179–1186.

   47. Bensadoun RJ, Daoud J, El Gueddari B et al. Comparison of the efficacy and safety of miconazole 50 mg mucoadhesive buccal tablets with miconazole 500 mg gel in the treatment of oropharyngeal candidiasis: a prospective, randomized, single-blind, multicenter, comparative, phase III trial in patients treated with radiotherapy for head and neck cancer. Cancer 2008;112(1):204–211.

   48. Villanueva A, Arathoon EG, Gotuzzo E, et al. A randomized double-blind study of caspofungin versus amphotericin for the treatment of candidal esophagitis. Clin Infect Dis 2001;33:1529–1535.

   49. Arathoon EG, Gotuzzo E, Noriega LM, et al. Randomized, double-blind, multicenter study of caspofungin versus amphotericin B for treatment of oropharyngeal and esophageal candidiasis. Antimicrob Agents Chemother 2002;46:451–457.

   50. Villanueva A, Gotuzzo E, Arathoon EG, et al. A randomized, double-blind study of caspofungin versus fluconazole for the treatment of esophageal candidiasis. Am J Med 2002;113:294–299.

   51. Deresinski SC, Stevens DA. Caspofungin. Clin Infect Dis 2003;36:1445–1457.

   52. Akpan A, Morgan R. Oral candidiasis. Postgrad Med J 2002;78:455–459.

   53. Morris MI, Villmann. Echinocandins in the management of invasive fungal infections, part 1. Am J Health Syst Pharm 2006;63:1693–1703.

   54. Grim SA, Smith KM, Romanelli F, Ofotokun I. Treatment of azole-resistant oropharyngeal candidiasis with topical amphotericin B. Ann Pharmacother 2002;36:1383–1386.

   55. Goldman M, Cloud GA, Wade KD, et al. A randomized study of the use of fluconazole in continuous versus episodic therapy in patients with advanced HIV infection and a history of oropharyngeal candidiasis: AIDS clinical trials group study 323/mycoses study group 40. Clin Infect Dis 2005;41:1473–1480.

   56. Marr KA, Bow E, Chiller T, et al. Fungal infection prevention after hematopoietic cell transplantation. Bone Marrow Transplant 2009;44:483–487.

   57. Nowak MA, Brodell RT. Rapid diagnosis of superficial fungal infections. Postgrad Med 1999;2:179–180.

   58. Schwartz RA. Superficial fungal infections. Lancet 2004;364:1173–1182.

   59. Mendez-Tovar LJ. Pathogenesis of dermatophytosis and tinea versicolor. Clin Dermatol 2010;28:185–189.

   60. Goldstein AO, Smith KM, Ives TJ, Goldstein B. Mycotic infections. Effective management of conditions involving the skin, hair, and nails. Geriatrics 2000;55:40–52.

   61. Drake LA, Dinehart SM, Farmer ER, et al. Guidelines of care for superficial mycotic infections of the skin: Tinea corporis, tinea cruris, tinea faciei, tinea manuum, and tinea pedis. J Am Acad Dermatol 1996;34:282–286.

   62. Gupta AK, Chow M, Daniel CR, Aly R. Treatments of tinea pedis. Dermatol Clin 2003;21:431–462.

   63. Gupta AK, Chaudhry M Elewski B. Tinea corporis, tinea cruris, tinea nigra, and piedra. Dermatol Clin 2003;21: 395–400.

   64. Drake LA, Dinehart SM, Farmer ER, et al. Guidelines of care for superficial mycotic infections of the skin: Tinea capitis and tinea barbae. J Am Acad Dermatol 1996;34:290–294.

   65. Higgins EM, Fuller LC, Smith CH. Guidelines for the management of tinea capitis. Br J Dermatol 2000;143:53–58.

   66. Ansarun H, Ghaffarpour G. Comparison of effectiveness between ketoconazole 2% and selenium sulfide 2% shampoos in the treatment of tinea versicolor. Iranian J Derm 2005;8:21–25.

   67. Effendy I, Lecha M, Feuilhade de Chauvin M, et al. Epidemiology and clinical classification of onychomycosis. J Eur Acad Dermatol Venereol 2005;19(supp1 1):8–12.

   68. Roberts DT, Taylor WD, Boyle J. Guidelines for treatment of onychomycosis. Br J Dermatol 2003;148:402–410.

   69. Nunley KS, Cornelius L. Current management of onychomycosis. J Hand Surg 2008;33A:1211–1214.

   70. Welsh O, Vera-Cabrera L, Welsh E. Onychomycosis. Clin Dermatol 2010;28:151–159.

   71. Kaur R, Kashyap B, Bhalla P. Onychomycosis—Epidemiology, diagnosis and management. Indian J Med Microbiol 2008;26(2):108–116.

   72. Baran R, Kaoukhov A. Topical antifungal drugs for the treatment of onychomycosis: An overview of current strategies for monotherapy and combination therapy. J Eur Acad Dermatol Venereol 2005;19:21–29.

   73. Tosti A, Hay R, Arenas-Guzman R. Patients at risk of onychomycosis—Risk factor identification and active prevention. J Eur Acad Dermatol Venereol 2005;19(suppl 1): 13–16.

   74. Iorizzo M, Piraccini BM, Rech G, Tosti A. Treatment of onychomycosis with oral antifungal agents. Expert Opin Drug Deliv 2005;2:435–440.

   75. Feuilhade de Chauvin M. New diagnostic techniques. J Eur Acad Dermatol Venereol 2005;19(suppl 1):20–24.

   76. Gupta AK, Tu LQ. Onychomycosis therapies: Strategies to improve efficacy. Dermatol Clin 2006;24:381–386.

   77. de Berker D. Fungal nail disease. N Engl J Med 2009;360: 2108–2116.

   78. Lecha M, Effendy I, Feuilhade de Chauvin M, et al. Treatment options—Development of consensus guidelines. J Eur Acad Dermatol Venereol 2005;19(suppl 1):25–33.

   79. Gupta AK, Tu LQ. Therapies for onychomycosis: A review. Dermatol Clin 2006;24:375–379.

   80. Gupta AK, Ryder JE, Skinner AR. Treatment of onychomycosis: Pros and cons of antifungal agents. J Cutan Med Surg 2004;8:25–30.

   81. Gupta AK, Lynch LE, Kogan N, et al. The use of intermittent terbinafine for the treatment of dermatophyte toenail onychomycosis. J Eur Acad Dermatol Venereol 2009;23:256–262.

   82. Sigurgeirsson B, Elewski EE, Rich PA, et al. Intermittent versus continuous terbinafine in the treatment of toenail onychomycosis: A randomized, double-blind, comparison. J Dermatol Treat 2006;17:38–44.

   83. Warshaw EM, Fett DD, Bloomfield HE, et al. Pulse verus continuous terbinafine for onychomycosis: A randomized, double-blind, controlled trial. J Am Acad Dermatol 2005;53: 578–584.

   84. Gupta AK, Ryder JE, Johnson AM. Cumulative meta-analysis of systemic antifungal agents for the treatment of onychomycosis. Br J Dermatol 2004;150:537–544.

   85. Haugh M, Helou S, Boissel JP, Cribier BJ. Terbinafine in fungal infections of the nails: A meta-analysis of randomized clinical trials. Br J Dermatol 2002;147:118–121.

   86. Crawford F, Young P, Godfrey C, et al. Oral treatments for toenail onychomycosis: A systematic review. Arch Dermatol 2002;138:811–816.

   87. Cribier BJ, Bakshi R. Terbinafine in the treatment of onychomycosis: A review of its efficacy in high-risk populations and in patients with nondermatophyte infections. Br J Dermatol 2004;150:414–420.

   88. Casciano J, Amaya K, Doyle J, et al. Economic analysis of oral and topical therapies for onychomycosis of the toenails and fingernails. Manag Care 2003;12:47–54.

   89. Schram SE, Warshaw EM. Costs of pulse versus continuous terbinafine for onychomycosis. J Am Acad Dermatol 2007;56:525–527.

   90. Cham PM, Chen SC, Grill JP, et al. Reliability of self-reported willingness-to-pay and annual income in patients treated for toenail onychomycosis. Br J Dermatol 2007;156:922–928.

   91. Food and Drug Administration. FDA issues health advisory regarding the safety of Sporanox products and Lamisil tablets to treat finger nail infections. 2001, www.fda.gov/cder/drug/advisory/sporanox-lamisil/advisory.htm.

   92. Gupta AK, Chwetzoff, Del Rosso J, Baran R. Hepatic safety of itraconazole. J Cutan Med Surg 2002;6:210–213.