Lauren S. Schlesselman
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Explain the underlying pathophysiology of vulvovaginal candidiasis (VVC), oropharyngeal candidiasis (OPC), esophageal candidiasis, and fungal skin infections.
2. Identify symptoms of VVC, OPC, esophageal candidiasis, and fungal skin infections.
3. Identify the desired therapeutic outcomes for patients with uncomplicated and complicated VVC, OPC, esophageal candidiasis, and fungal skin infections.
4. Recommend appropriate lifestyle modifications and pharmacotherapy interventions for patients with VVC, OPC, esophageal candidiasis, and fungal skin infections.
5. Recognize when long-term suppressive therapy is indicated for a patient with VVC.
6. Recognize when topical versus oral treatment is indicated for a patient with OPC, esophageal candidiasis, VVC, and fungal skin infections.
7. Educate patients about the disease state, appropriate lifestyle modifications, and medication therapy required for effective treatment of VVC, OPC, esophageal candidiasis, and fungal skin infections.
KEY CONCEPTS
The predominant pathogen associated with vulvovaginal candidiasis (VVC) is Candida albicans, although a small percentage of cases are caused by C. glabrata, C. tropicalis, C. krusei, and C. parapsilosis.
A variety of factors including antibiotic use, diabetes, and immunosuppression may increase the risk of developing symptomatic VVC. No risk factors are consistently associated with any case of VVC.
Asymptomatic vaginal colonization of C. albicans is not diagnostic of VVC since 10% to 20% of women are asymptomatic carriers of Candida species. Asymptomatic vaginal colonization does not require treatment.
Selection of antifungal agents to treat uncomplicated VVC is influenced by patient preference, including route of administration, duration of therapy, cost, risk of adverse effects, and potential for medication interactions.
Recurrent VVC, defined as four or more infections per year, requires long-term suppressive therapy for 6 months.
The occurrence of oropharyngeal candidiasis (OPC) and esophageal candidiasis is an indicator of immune suppression, often developing in infants, the elderly, and the immunocompromised.
Topical antifungal agents are first-line therapy for OPC, although oral agents may be used for severe or unresponsive cases.
Esophageal candidiasis is a severe extension of OPC that requires oral antifungal therapy.
Since dermatophyte hyphae seldom penetrate into the living layers of the skin, instead remaining in the stratum corneum, most mycotic infections of the skin can be treated with topical antifungals. Infections covering large areas of the body or infections involving nails or hair may require oral therapy.
Onychomycosis, fungal infections involving the nails, requires oral antifungal therapy. Topical agents do not adequately penetrate the nail.
VULVOVAGINAL CANDIDIASIS
Vulvovaginal candidiasis (VVC), whether symptomatic or asymptomatic, refers to infections in women whose vaginal cultures are positive for Candida species.
EPIDEMIOLOGY AND ETIOLOGY
VVC, also known as moniliasis, is a common form of vaginitis, accounting for 20% to 25% of vaginitis cases. Although VVC is uncommon prior to menarche, nearly 50% of women will experience one or more episodes by the age of 25 years.1 A survey of women in the United States found that 6.5% of women over the age of 18 years reported experiencing at least one episode of vaginitis during the previous 2 months.2
According to the treatment guidelines of the Centers for Disease Control and Prevention (CDC),3 VVC can be classified as uncomplicated or complicated. Uncomplicated infections are typically infrequent and cause mild to moderate symptoms. Complicated infections, including recurrent or severe infections, may be caused by azole-resistant fungal organisms. Immunocompromise, including immunosuppression, uncontrolled diabetes, pregnancy, or debilitation, is a risk factor for developing recurrent infection. Recurrent VVC, defined as four or more infections per year, occurs in less than 5% of women.4 Recurrent infection is distinguishable from a persistent infection by the presence of a symptom-free interval between infections.
Candida albicans is the primary pathogen responsible for VVC, accounting for more than 90% of cases.5 A small percentage of cases are caused by nonalbicans species including C. glabrata, C. tropicalis, C. krusei, and C. parapsilosis. In patients with recurrent vaginitis, the causative Candida is twice as likely to be nonalbicans.6 The incidence of nonalbicans VVC is increasing, possibly due to overuse of nonprescription vaginal antifungal products, short-course antifungal treatments, and long-term suppressive therapy with antifungals.7
PATHOPHYSIOLOGY
The normal vaginal environment protects women against vaginal infections. Under the influence of estrogen, vaginal epithelium cornifies to reduce the risk of infection. Vaginal discharge, comprised of exfoliated cells, cervical mucus, and colonized bacteria, cleans the vagina. The volume of discharge varies during pregnancy, during oral contraceptive use, with age, and at mid-menstrual cycle near ovulation. The normal pH of vaginal secretions, near 4, is maintained by Lactobacillus acidophius, diphtheroids, and Staphylococcus epidermidis. The low pH is toxic to many pathogens.
Any alteration in the vaginal environment allows for overgrowth of organisms that are normally suppressed. Increases in the vaginal pH are associated with increased vulvovaginitis. pH changes are caused by stress, changes in hormone level, sexual activity, pregnancy, phases of the menstrual cycle, contraceptive use, presence of foreign bodies or necrotic tissue, use of douches, or the use of antibiotics. An increase in glycogen production, associated with altered estrogen and progesterone levels, can also increase the risk of infection through increased adherence of C. albicans to epithelial cells.
RISK FACTORS
Although no risk factors are consistently associated with conversion to symptomatic infection, a variety of factors may increase the risk of developing symptomatic VVC in certain women (Table 83–1).
TREATMENT
The goals of treatment of VVC are as follows:
• Relief of symptoms
• Eradication of infection
• Re-establishment of normal vaginal flora
• Prevention of recurrence in complicated infections
Clinical Presentation and Diagnosis of VVC
Patients with VVC may present with vulvar and/or vaginal symptoms. Symptoms often develop the week before menses and resolve with the onset of menses.
Symptoms include:
• Itching
• Soreness
• Burning
• Irritation
• External dysuria
• Dyspareunia
Signs include:
• Nonodorous discharge (may vary from watery to curd-like)
• Yellow or yellowish-green discharge
• Erythema and edema of the labia and vulva
• Fissures
• Pustulopapular lesions
• Normal cervix
Diagnostic Testing
• Microscopic investigation for the presence of blastospores or pseudohyphae; saline wet mount has a sensitivity of 40% to 50%, while a KOH preparation has a sensitivity of 50% to 70%.7 Asymptomatic vaginal colonization of Candida albicans is not diagnostic of VVC since 10% to 20% of women are asymptomatic carriers of Candida species. Asymptomatic vaginal colonization does not require treatment; therefore the presence alone of Candida should not determine care.
• Vaginal pH less than or equal to 4.5; pH should remain normal in cases of fungal infection, while an elevated pH suggests bacterial infection.
• Candida cultures should be obtained only if signs and microscopy are inconclusive or in cases of recurrent VVC.
Table 83–1 Possible Risk Factors Associated With VVC
Patient Encounter 1
A 28-year-old woman with a history of diabetes presents to your clinic complaining of what she calls “itching in my private areas.” After questioning her, you determine that she has vaginal burning and itching, accompanied by a curd-like discharge. On examination, she has erythema of the labia and a nonodorous discharge.
What information is suggestive of vulvovaginal candidiasis (VVC)?
What additional information do you need to know before creating a treatment plan for this patient?
Nonpharmacologic Treatments
In combination with pharmacologic treatment, the practitioner should recommend basic nonpharmacologic approaches to treatment and prevention of VVC:
• Keep the genital area clean and dry.
• Avoid prolonged use of hot tubs.
• Avoid constrictive clothing.
• Wear underwear made of breathable materials, such as cotton.
• To reduce vulvar irritation, avoid soaps and perfumes in the genital area.
• Although study results are conflicting, the daily consumption of active L. acidophilus may reduce recurrence. One study found that the daily ingestion of 8 ounces of yogurt produced a threefold reduction in the incidence of infection,8 while other studies found no difference in infection rates in women who ingested yogurt.9,10
Pharmacologic Treatment of Uncomplicated VVC
Most cases of uncomplicated VVC will resolve with a single course of antifungal therapy. Treatment with an oral or vaginal antifungal agent, either prescription or nonprescription, is appropriate for most uncomplicated cases. Nonprescription azole antifungal products are available as one-night, three-night, and seven-night regimens in a variety of formulations, including cream, suppository, and vaginal tablets (Table 83–2). Oral fluconazole offers the option of treatment with one dose administered without regard to time of day. Some practitioners opt to retreat with a second dose of fluconazole 3 days later. Due to the risk of severe hepatotoxicity, the use of oral ketoconazole should be reserved for severe fungal infections resistant to other antifungal options.
Table 83–2 Treatment Options for Uncomplicated VVC
1-Day Therapies
Butoconazole 2% sustained-release cream, 5 g intravaginally as a single application
Fluconazole 150 mg, one tablet orally as a single dose
Tioconazole 6.5% ointment, 5 g intravaginally as a single application
3-Day Therapies
Butoconazole 2% cream, 5 g intravaginally daily for 3 nights
Clotrimazole 100-mg vaginal tablet, two tablets daily for 3 nights
Miconazole 200-mg vaginal suppository, one suppository daily for 3 nights
Terconazole 0.8% cream, 5 g intravaginally daily for 3 nights
Terconazole 80-mg vaginal suppository, one suppository daily for 3 nights
7- to 14-Day Therapies
Boric acid 600-mg vaginal suppository, one suppository intravaginally twice daily for 14 days
Clotrimazole 1% cream, 5 g intravaginally daily for 7–14 nights
Clotrimazole 100-mg vaginal tablet, one tablet daily for 7 nights
Miconazole 2% cream, 5 g intravaginally daily for 7 nights
Miconazole 100-mg vaginal suppository, one suppository daily for 7 nights
Nystatin 100,000-unit vaginal tablet, one tablet daily for 14 nights
Terconazole 0.4% cream, 5 g intravaginally daily for 7 nights
To avoid inappropriate use of nonprescription products, the practitioner should only recommend them to women who have previously been diagnosed with VVC. Estimates of how accurately women self-diagnose VVC are difficult to assess. One study found that only one-third of women accurately diagnosed an episode of vaginitis.11 Women with a previous clinically based diagnosis of VVC are no more accurate at self-diagnosing than women without prior clinical diagnosis.11
Inability to resolve an infection may indicate a mixed infection, infection due to a nonalbicans strain, or an infection that is not fungal. Difficulty treating VVC can also be indicative of serious underlying conditions, such as diabetes or HIV infection. For these reasons, if infection does not resolve easily with a single course of antifungal therapy or if symptoms return within 2 months, practitioners should check cultures and further evaluate the patient’s health status or refer the patient to a physician.
Due to the numerous treatment options available, a variety of factors can influence product selection, with patient preference playing a significant role. To improve adherence with therapy, the practitioner should discuss with the patient what options are available and what her preferences are.
Adherence rates are greater with oral treatment than with vaginal therapy. This may be due to the ease of administration, short duration, and flexibility on time of administration. Vaginal creams provide rapid relief of itching and burning. The practitioner may wish to advise a patient to apply a vaginal cream externally to reduce itching and burning if using an oral agent. The need to clean the vaginal applicator for reuse is unappealing for some women. Many nonprescription vaginal products are now packaged with sufficient disposable applicators to prevent the need for reuse with subsequent doses. Available regimens range from 1 to 7 days for topical preparations and fluconazole. Cure rates are similar among different durations of therapy.12 Most OTC products cost $10 to $20 per course of therapy. The cost of prescription products can vary based on whether or not the patient has insurance coverage as well as the type of coverage the patient has. If the patient does not have prescription coverage, nonprescription products may prove less expensive than even one or two fluconazole tablets.
Risk of Adverse Effects and Interactions
Systemic adverse effects associated with vaginal azoles are less frequent than with oral products. Common adverse effects associated with fluconazole include headache, diarrhea, nausea, dizziness, abdominal pain, and taste alterations. With topical products, local discomfort such as burning, itching, stinging, and redness may occur, particularly with the first application. Fifteen percent of patients experience GI side effects with orally administered antifungal agents.13 Oral ketoconazole is associated with hepatic toxicity at a rate of 1 in 15,000.14
Oral azoles are associated with significant interactions, particularly due to cytochrome P450 isoenzymes. Medications that interact with azoles include warfarin, phenytoin, theophylline, rifampin, cyclosporine, and zidovudine. For patients receiving only a few doses, these interactions do not pose a significant risk. These interactions may pose a risk for patients receiving long-term suppressive therapy for recurrent infections.
TREATMENT OF RECURRENT VVC
The goal of treating recurrent VVC is control of the infection, rather than cure. First, any acute episodes are treated, followed by maintenance therapy. For the treatment of acute episodes, intravaginal or oral azoles can be utilized. Although acute episodes of recurrent VVC will respond to azole therapy, some patients may require prolonged therapy in order to achieve remission. To achieve remission, a second dose of oral fluconazole 150 mg repeated 3 days after the first dose or 14 days of topical azole therapy can be used. The practitioner should consider that nonalbicans infections are more common in recurrent VVC; therefore, fluconazole and itraconazole resistance may make these agents less effective.
After achieving remission, recurrent VVC requires long-term suppressive therapy for 6 months (Table 83–3). To improve adherence to long-term suppressive therapy, oral therapy, typically with fluconazole, is preferred. Fluconazole 150 mg weekly for 6 months will prevent recurrence of infection in 90% of women.15 Cessation of suppressive therapy is associated with resurgence of symptomatic infection in 50% of women.16
TREATMENT OF NONALBICANS INFECTIONS
Treatment response rates are lower for nonalbicans infections. Although an optimal regimen is unknown, use of intravaginal azole therapy for 7 to 14 days is recommended. Terconazole may prove more effective than other azoles in the treatment of nonalbicans infections since C. glabrata and C. tropicalis are more susceptible to terconazole.17 For second-line therapy, boric acid 600 mg in a gelatin capsule administered vaginally twice daily for 2 weeks followed by once daily during menstruation is effective.18 Local irritation often limits the use of boric acid. Topical 4% flucytosine is also effective but use should be limited due to the potential for resistance.
Table 83–3 Treatment Options for Maintenance Therapy
Daily
Boric acid 600 mg in gelatin capsule vaginally daily during menses (5 days)
Itraconazole 100 mg orally once daily
Ketoconazole 100 mg orally once daily
Weekly
Clotrimazole 500 mg vaginal suppository once weekly
Fluconazole 100 or 150 mg orally once weekly
Terconazole 0.8% cream 5 g vaginally once weekly
Monthly
Fluconazole 150 mg orally once monthly
Itraconazole 400 mg orally once monthly
VVC DURING PREGNANCY
During pregnancy, VVC may prove difficult to treat due to elevated estrogen levels, accompanied by concern about harm to the fetus. Response rates are lower and recurrences are frequent during pregnancy. Vaginal antifungals remain the preferred treatment during pregnancy, although therapy should continue for 1 to 2 weeks to ensure effectiveness.16 Most topical antifungals are classified as risk category C, while clotrimazole is classified as risk category B. The primary reason for the risk category C classification is the lack of studies, rather than increased risk. Fluconazole is also classified as risk category C. Despite oral fluconazole’s classification, studies have not demonstrated an increased risk to the fetus when the pregnant mother was exposed to fluconazole,19,20 although case studies have reported congenital limb deformities.21
Cultural Awareness During Treatment of VVC
As with all gynecological issues, the practitioner is faced with cultural perceptions of female genitalia. In particular, practitioners are treating an increased number of patients who have undergone female genital mutilation. More than 100 million women and girls worldwide have undergone such procedures for cultural and religious reasons.22 Female genital mutilation, formerly known as female circumcision, describes the intentional alteration or injury of female genitalia. Some authorities suggest using the term “genital cutting” when dealing with patients to avoid appearing judgmental.23 Regardless of the terminology used, many immigrants are aware of common cultural views in the United States pertaining to female genital mutilation. Women who have undergone this procedure suffer acute and chronic complications. Within the scope of this chapter, the practitioner may find patients with female genital mutilation suffer from recurrent VVC due to inadequate drainage of vaginal fluids. Regardless of what the practitioner’s opinion is about female genital mutilation, the practitioner must be sensitive to the patient’s feeling and cultural values.
OUTCOME EVALUATION
Patients should notice relief of itching and discomfort within 1 to 2 days. The volume of discharge should also begin to decrease within a few days. The entire course of therapy should be continued even if symptoms have resolved. If the condition does not resolve or worsens, the patient should be referred to a physician for aggressive therapy. If the condition recurs within 4 weeks or more than four times per year, the patient should be further evaluated or referred to a physician for evaluation of possible non-Candida infections, resistant organism, or other complicating factors, along with assessment of need for long-term suppressive therapy.
Patient Care and Monitoring of VVC
1. Assess the patient’s symptoms to determine if self-treatment with OTC antifungal therapy is appropriate or whether the patient should be evaluated by a practitioner or physician. OTC preparations should only be recommended for patients who have previously been diagnosed with VVC. Patients who experience more than four episodes per year should be referred to a physician for culturing and initiation of maintenance therapy.
2. Review any available diagnostic data, including cultures and potassium hydroxide (KOH) preps.
3. Obtain a thorough history of prescription, nonprescription, and natural drug product use. Is the patient taking any medications, such as steroids, antibiotics, or immunosuppressants, that may contribute to VVC? Is the patient taking any medications that may interfere with treatment?
4. If the patient has had VVC previously, determine what treatments were helpful to the patient in the past.
5. Educate the patient on lifestyle modifications that may prevent recurrence, including decreased consumption of sucrose and refined carbohydrates, increased consumption of yogurt containing live cultures, and wearing cotton underwear.
6. Develop a plan to assess effectiveness of antifungal therapy.
7. Determine if long-term suppressive therapy is necessary.
8. Evaluate the patient for the presence of adverse drug reactions, drug allergies, and drug interactions.
9. Stress the importance of adherence with the antifungal regimen, including lifestyle modifications.
10. Provide patient education pertaining to VVC and antifungal therapy.
• Causes of VVC
• How to administer vaginal antifungal creams
• Adverse effects of vaginal antifungal creams and suppositories on latex condoms and diaphragms
• Potential adverse effects that may occur with antifungal therapy
• Medications that may interact with antifungal therapy
• Preventing the spread of infection
• Warning signs to report to a physician (recurrent or difficult-to-cure infections, infections with malodorous discharge)
OROPHARYNGEAL AND ESOPHAGEAL CANDIDIASIS
Oropharyngeal candidiasis (OPC) is a common fungal infection, usually associated with immune suppression. If left untreated, it will progress to more serious oral disease. Esophageal candidiasis, representing a serious progression of OPC, is associated with increased morbidity.
EPIDEMIOLOGY AND ETIOLOGY
The occurrence of oropharyngeal and esophageal candidiasis is an indicator of immune suppression, often developing in infants, the elderly, and the immunocompromised. One-third to one-half of geriatric inpatients develop OPC. Denture stomatitis is present in 24% to 60% of denture wearers,24 more commonly in women than men. Oral candidiasis is the most commonly reported adverse drug event among patients receiving inhaled corticosteroids.25The prevalence of esophageal candidiasis is 37% among patients treated with inhaled corticosteroids.26 The incidence is highest among patients receiving high doses of corticosteroids or those with diabetes.
The prevalence of HIV infection plays a significant role in the incidence of OPC and esophageal candidiasis. In the 1980s, the incidence of OPC increased fivefold, in association with the spread of HIV infections.27 Although HIV infection remains a risk factor for candidiasis, the introduction of highly active antiretroviral therapy precipitated a decline in the incidence of both infections by 50% to 60%.28
OPC remains the most common opportunistic infection in patients with HIV. Eighty to ninety percent of HIV-positive patients develop OPC.29 For 70% of these patients, it is the first manifestation of HIV infection.30 The incidence of oropharyngeal infection increases with decreasing CD4 lymphocyte counts, with an incidence of 60% in patients with a CD4 count less than 200 cells/mm3.
Although esophageal candidiasis represents the first manifestation of HIV infection in less than 10% of cases, it is the second most common AIDS-defining disease.31 As with OPC, the incidence of esophageal candidiasis increases with decreasing CD4 counts.
C. albicans accounts for 80% of cases of OPC and esophageal candidiasis. Over the last 20 years, an increasing incidence of C. albicans resistance has been accompanied by an increased incidence of nonalbicans species infections, including C. glabrata, C. tropicalis, C. krusei, and C. parapsi-losis. In patients with cancer, nonalbicans Candida species account for almost half of all cases.29
PATHOPHYSIOLOGY
Similar to VVC, the development of OPC occurs when the normal environment is altered. Candida organisms frequently colonize the oropharynx and mucous membranes. These organisms do not become pathogenic until the environmental balance is disturbed. This occurs in the setting of broad-spectrum antibiotic use, tissue damage (due to chemotherapy, catheter tubing, trauma), or immune deficiency.
Table 83–4 Risk Factors for OPC and Esophageal Candidiasis
RISK FACTORS
Risk factors for OPC can be found in Table 83–4.
CLINICAL PRESENTATION AND DIAGNOSIS
See text boxes for clinical presentations and diagnosis of OPC and esophageal candidiasis.
TREATMENT
Along with selecting an effective treatment, selection of an appropriate antifungal agent requires consideration of location and severity of infection, medication adherence, potential drug interactions, concomitant medical conditions, and presence of sucrose or dextrose. Topical agents require frequent dosing and prolonged contact time with oral mucosa. Rough surfaces of tablets and troches may irritate sensitive mucosa. Patients with xerostomia may have inadequate saliva to dissolve troches. Topical agents containing sucrose or dextrose may increase the risk of caries or cause elevated blood sugar in patients with diabetes. Along with being expensive, oral azoles exhibit an increased risk of toxicity and drug interactions due to cytochrome P450.
Since oropharyngeal and esophageal candidiasis are signs of immunocompromise, the immune status of the patient should be considered in the therapeutic care plan. For HIV-infected patients, this should also include an evaluation of the patient’s antiretroviral therapy since fungal infections may represent deterioration in immune status.
Clinical Presentation and Diagnosis of OPC
OPC is often a presumptive diagnosis based on signs and symptoms, along with the resolution of them after treatment with antifungal agents.
Symptoms
• Sore, painful mouth and tongue
• Burning tongue
• Dysphagia
• Metallic taste
Signs
Signs vary depending on the type of OPC:
• Diffuse erythema on the surface of buccal mucosa, throat, tongue, and gums.
• White patches on tongue, gums, or buccal mucosa; removal of patches reveals erythematous and bloody tissue; ability to remove patches distinguishes OPC from oral hairy leukoplakia.
• Angular cheilitis presents with small cracking lesions, erythema, and soreness at the corners of the mouth; associated with vitamin and iron deficiency.
• Denture stomatitis presents with flat, red lesions on mucosa beneath dentures; signs of chronic erythema and edema on mucosa.
• Hyperplastic OPC presents with discrete, transparent raised lesions on the inner mucosa of the cheek; typically found in men who smoke.
• Pseudomembranous OPC presents with yellow-white plaques that may be small and discrete or confluent; most common form found in HIV patients.
Diagnostic Testing
Diagnosis is primarily based on identification of characteristic lesions. Although rarely necessary, diagnostic testing is possible if a definitive diagnosis is required.
• Cytology, although presence of Candida is not diagnostic since colonization is common.
• Culture to identify species of yeast or presence of resistance.
• Biopsy.
For low-risk patients, topical agents are first-line therapy for OPC, although systemic agents may be used for severe or unresponsive cases. For patients with severe OPC, oral fluconazole remains the agent of choice. Oral fluconazole administered for 2 weeks exhibits a mycological cure rate of 48% and a clinical cure rate of 84% in HIV patients.32 Response occurs within 5 days in patients receiving 100 to 200 mg daily.16 Doses as low as 50 mg are effective, but clinical response is slow and potentially leads to resistance. Two weeks of oral itraconazole solution is as effective as fluconazole but is less well tolerated. Due to variable absorption, risk of toxicity, and potential for drug interactions, ketoconazole and itraconazole capsules are considered second-line alternatives to fluconazole.
Clinical Presentation and Diagnosis of Esophageal Candidiasis
Symptoms
• Fever
• Odynophagia
• Dysphagia
• Retrosternal pain
Signs
• Fever
• Hyperemic or edematous white plaques
• Ulceration of esophagus
• Increased mucosal friability
• Narrowing of lumen
Diagnostic Testing
Unlike OPC, diagnosis of esophageal candidiasis is not based solely on clinical presentation, instead requiring endoscopic visualization of lesions and culture confirmation. Due to the invasive nature of these procedures, most practitioners opt to treat the infection presumptively, reserving endoscopic evaluation for patients who fail therapy.
• Cytology and culture to identify species of yeast or presence of resistance
• Barium esophagogram
• Endoscopy revealing whitish plaques with progression to superficial ulceration of the esophageal mucosa
• Mucosal biopsy
Patient Encounter 2
A 35-year-old woman presents to your clinic complaining of “burning and soreness in my mouth” along with a metallic taste and “this funny white stuff.” On initial examination, she has white patches on her tongue, gums, and buccal mucosa. These patches are easily removed, revealing erythematous tissue underneath.
This is the woman’s first visit to your clinic, therefore no medical history is available in her chart.
What additional information do you need to know before creating a treatment plan for this patient?
What underlying medical conditions might make her susceptible to fungal infections?
How is the treatment care plan altered if the patient has a history of frequent and severe OPC? If the patient is HIV-positive? If the patient is neutropenic?
For non–HIV-infected patients who have suppressed immune systems, the practitioner must consider the patient’s risk of dissemination. Patients with cell-mediated immune deficiency but near-normal granulocyte function, such as patients with diabetes, solid organ transplant, or solid tumors, are at low-risk for dissemination. The risk of dissemination is higher for patients who develop neutropenia, including patients with leukemia or bone marrow transplant. These patients should be treated aggressively to prevent invasive fungal infection.
For the treatment of OPC in HIV-infected individuals, initial episodes can be adequately controlled with topical agents, such as clotrimazole troches, so long as symptoms are not severe and no esophageal involvement is suspected.28 Topical nystatin is the least effective agent, especially in severely immunocompromised patients.33 Topical clotrimazole appears to be the most effective topical antifungal, exhibiting clinical responses equivalent to oral fluconazole and itraconazole solution, but mycological cure rates are lower and relapse rates higher with clotrimazole.31
Representing a severe extension of OPC, esophageal candidiasis requires systemic antifungal therapy. The significant morbidity associated with esophageal candidiasis warrants aggressive treatment. The diagnosis of esophageal candidiasis requires endoscopic evaluation, but rather than employing invasive procedures, patients can be treated with an appropriate course of antifungal based on clinical presentation. If patients do not respond, endoscopy should be considered.
Two to three weeks of fluconazole or itraconazole solution are highly effective and demonstrate similar clinical response rates.34 Oral doses of 100 to 200 mg are effective in immunocompetent patients but doses up to 400 mg are recommended for immunocompromised patients. Due to variable absorption, ketoconazole and itraconazole capsules should be considered second-line therapy. In severe cases, oral azoles may prove ineffective, warranting the use of IV amphotericin B for 10 days. Although echinocandins and voriconazole are effective in treatment of esophageal candidiasis, experience remains limited.
Fluconazole-Resistant Infections
Twenty percent of HIV-infected patients develop fluconazole resistant C. albicans isolates after repeated exposure to fluconazole.35 To treat fluconazole-resistant OPC, daily itraconazole for 2 to 4 weeks may be used. Oral itraconazole solution exhibits a mycological cure rate of 88% and a clinical cure rate of 97% in immunocompromised patients.36 Fluconazole-resistant esophageal candidiasis should be treated with IV amphotericin B or caspofungin.
Recurrent Infections
If immunocompromised patients experience frequent or severe recurrences, particularly of esophageal candidiasis, chronic maintenance therapy with fluconazole 100 to 200 mg daily should be considered. In patients with infrequent or mild cases, secondary prophylaxis is not recommended. The rationale for not giving prophylaxis includes availability of effective treatments for acute episodes, risk of developing resistant organisms, potential for drug interactions, and the cost of therapy.
Patient Care and Monitoring of OPC
1. Assess the patient’s symptoms to determine if symptoms are consistent with OPC or esophageal candidiasis. All patients with suspected OPC or esophageal candidiasis should be referred to a practitioner or physician since no antifungal products appropriate for oral use are available without a prescription.
2. Review any available diagnostic data, including cultures.
3. Obtain a thorough history of prescription, nonprescription, and natural drug product use. Is the patient taking any medications that may contribute to candidiasis? Is the patient taking any medications that may interfere with treatment?
4. If the patient has had OPC or esophageal candidiasis previously, determine what treatments were helpful to the patient in the past.
5. If the patient has had OPC or esophageal candidiasis previously, determine if the patient has risk factors for recurrent infection.
6. Develop a plan to assess effectiveness of antifungal therapy.
7. Determine if long-term suppressive therapy is necessary.
8. Evaluate the patient for the presence of adverse drug reactions, drug allergies, or drug interactions.
9. Stress the importance of adherence with the antifungal regimen.
10. Provide patient education pertaining to OPC or esophageal candidiasis and antifungal therapy.
• Causes of OPC or esophageal candidiasis
• Risk factors for developing candidiasis
• How to administer topical antifungal agents, including cleaning the oral cavity prior to administration, shaking suspensions prior to use, administering after meals, how to dissolve troches, and how to swish suspensions
• Importance of completing the course of therapy
• Potential adverse effects that may occur with antifungal therapy
• Medications that may interact with antifungal therapy
• Warning signs to report to a physician (recurrent or difficult-to-cure infections, or worsening symptoms)
OUTCOME EVALUATION
• Patients should notice symptomatic relief within 2 to 3 days of initiating therapy. Complete resolution typically occurs within 7 to 10 days. The entire course of therapy should be continued even if symptoms have resolved. If the condition does not resolve or worsens, the patient should be referred to a specialist for aggressive therapy.
• Short courses of oral azoles are associated with GI upset, while courses lasting longer than 7 to 10 days are associated with increased risk of hepatotoxicity. In patients receiving prolonged therapy lasting more than 3 weeks, periodic monitoring of liver function tests should be considered.
• Immunocompetent patients generally do not require reassessment after treatment. Patients with neutropenia exhibit an increased risk of dissemination of infection, and therefore should be monitored for signs of systemic fungal infection. Due to an increased risk of recurrence, HIV-positive patients should routinely be evaluated for recurrence at each visit.
MYCOTIC INFECTIONS OF THE SKIN, HAIR, AND NAILS
Tinea infections are superficial fungal infections in which the pathogen remains within the keratinous layers of the skin or nails (Table 83–5). Typically these infections are named for the affected body part, such as tinea pedis (feet), tinea cruris (groin), and tinea corporis (body). Tinea infections are commonly referred to as ringworm due to the characteristic circular lesions. In actuality, tinea lesions can vary from rings to scales and single or multiple lesions.
Clinical Presentation and Diagnosis of Mycotic Infections
Symptoms and Signs
• See Table 83–5
Diagnostic Testing
• KOH prep
• Wood’s ultraviolet lamp
• Microscopic examination
• Fungal cultures
• Periodic acid-Schiff (PAS) staining of nail
Treatment of Skin and Hair Infections
The goals of treatment include:
• Providing symptomatic relief
• Resolution of infection
• Preventing spread of infection
EPIDEMIOLOGY AND ETIOLOGY
Tinea infections are second only to acne in frequency of reported skin disease.37 The common tinea infections are tinea pedis, tinea corporis, and tinea cruris. Tinea pedis, the most prevalent cutaneous fungal infection, afflicts more than 25 million people annually in the United States.
Fungal skin infections are primarily caused by dermatophytes such as Trichophyton, Microsporum, and Epidermophyton. T. rubrum accounts for more than 75% of all cases in the United States.38 To a lesser extent, Candida and other fungal species cause skin infections. With tinea infections, the causative dermatophyte typically invades the stratum corneum without penetration into the living tissues, leading to a localized infection.
PATHOPHYSIOLOGY
The primary mode of transmission of tinea infections is direct contact with other persons or surface reservoirs. Upon contact, the dermatophytes attach to the keratinized cells, leading to thickening of the cells. Although infection remains localized, bacterial superinfections may develop.
The pathophysiology of onychomycosis depends on the clinical type. With the most common form of onychomycosis, distal lateral subungual, the fungus spreads from the plantar skin. The fungus invades the underside of the nail through the distal lateral nail bed, leading to inflammation of the area. In cases of white superficial onychomycosis, the fungus invades the surface of the nail plate directly and the nail bed and hyponychium are infected secondarily. Proximal subungual onychomycosis infections begin in the cuticle and the proximal nail fold, then penetrate the dorsum of the nail plate.
RISK FACTORS
• Prolonged exposure to sweaty clothing
• Excessive skin folds
• Sedentary lifestyle
• Warm, humid climate
• Use of public pools
• Walking barefoot in public areas
• Skin trauma
• Poor nutrition
• Diabetes mellitus
• Immunocompromise
• Impaired circulation
Table 83–5 Signs, Symptoms, and Risk Factors of Superficial Fungal Infections
Nonpharmacologic Therapy
• Since fungi thrive in warm, moist environments, the practitioner should encourage patients to wear loose-fitting clothing and socks, preferably garments made of cotton or other fabrics that wick moisture away from the body. Avoid clothing made with synthetic fibers or wool.
• Clean the infected area daily with soap and water.
• The infected area should be dried completely prior to dressing, paying particular attention to skin folds.
• To allow circulation of air, the infected area should not be bandaged.
• For foot infections, cotton socks are recommended, although these should be changed two to three times a day to reduce moisture.
• To prevent spreading of the infection towels, clothing, and footwear should not be shared with other persons.
• Wear protective footwear in public showers and pool areas.
Table 83–6 Available Topical Antifungal Agents
Table 83–7 Dosing of Systemic Therapy for Tinea Infections
Pharmacologic Therapy of Tinea Infections
Since dermatophyte hyphae seldom penetrate into the living layers of the skin, instead remaining in the stratum corneum, most infections can be treated with topical antifungals. Infections covering large areas of the body or infections involving nails or hair may require systemic therapy. Treatment is typically initiated based on symptoms, rather than on microscopic evaluation. For infections accompanied by inflammation, combination therapy with a topical steroid can be considered (Tables 83–6 and 83–7). Patients with chronic infections or infections that do not respond to topical therapy are also candidates for systemic therapy.
For the treatment of tinea pedia, corporis, and cruris, topical agents can be utilized unless the infection is refractory. Typically, tinea pedis requires treatment one to two times daily for 4 weeks, while tinea corporis and tinea cruris require treatment one to two times daily for 2 weeks. When applying treatment, the medication should be applied at least 1 inch beyond the affected area. Treatment of any infection should continue at least 1 week after resolution of symptoms. Many practitioners opt to initiate therapy with nonprescription clotrimazole or terbinafine, reserving prescription topical agents, such as naftifine, ciclopirox, and butenafine, for second-line therapy or refractory cases. For refractory cases or widespread lesions, systemic therapy can be prescribed.
When recommending topical therapy, the selection of vehicle is based on the type of lesion and location of the infection. Solutions are recommended for hairy areas and oozing lesions, while creams are better for moderately scaling and nonoozing lesions. For hyperkeratotic lesions, ointments can be considered. The selected formulation should be applied to the affected area that is cleaned and dried. The medication should be rubbed into the infected area for improved penetration. Since most patients do not rub in sprays and powders, penetration of the epidermis is minimal, making them less effective than other formulations. Sprays and powders should be considered as adjuvant therapy with a cream or lotion or as prophylactic therapy to prevent recurrence.
Due to the severity of infection and inflammation, tinea capitis does not adequately respond to topical agents. Oral agents for 6 to 8 weeks are recommended for eradication of tinea capitis. Griseofulvin has long been considered the treatment of choice due to its ability to achieve high levels within the stratum corneum. Itraconazole has also demonstrated effectiveness. Due to its lipophilicity, itraconazole achieves high levels in the skin. These levels are maintained for 4 weeks after medication is discontinued. Some practitioners recommend adjunct therapy with the oral agent to decrease dissemination, including ketoconazole or selenium sulfide shampoos.
TREATMENT OF ONYCHOMYCOSIS
Onychomycosis is a chronic infection that rarely remits spontaneously. Adequate treatment is essential to prevent spread to other sites, secondary bacterial infections, cellulitis, or gangrene. Due to the chronic nature and impenetrability of nails, topical agents have low efficacy rates for treating onychomycosis. Oral agents that can penetrate the nail matrix and nail base, such as itraconazole and terbinafine, are more effective than ciclopirox lacquer. Itraconazole and terbinafine demonstrate mycological cure rates of 62%39 and 76%,40 respectively, while ciclopirox has a cure rate of 29% to 36%.41
Itraconazole can be administered continuously (200 mg orally daily) or as pulse therapy (200 mg orally twice daily for 1 week per month). Terbinafine is administered orally 250 mg per day as continuous therapy. Whether administered continuously or as pulse therapy, oral treatment for toenail infections should continue for at least 3 months, while treatment for fingernail infections should continue for at least 2 months. Terbinafine is an inhibitor of CYP450 2D6 isozyme. When administered with other medications metabolized via this isozyme, the other medication should be started at a low dose if it has a narrow therapeutic range. Griseofulvin is also effective for the treatment of onychomycosis, but therapy must be continued for 4 months for fingernail infections or 6 months for toenail infections. For patients with liver disease or who are unable to use oral agents, ciclopirox nail lacquer remains a reasonable alternative, although it requires 48 weeks of therapy.
The FDA has released warnings pertaining to itraconazole and terbinafine as there is a small but real risk of developing congestive heart failure with itraconazole therapy due to its negative inotropic effects. Itraconazole should not be administered to patients with ventricular dysfunction such as congestive heart failure. The FDA also released warnings that itraconazole and terbinafine are associated with serious hepatic toxicity, including liver failure and death. Liver failure associated with these medications has occurred in patients with no pre-existing living disease or serious underlying medical conditions. Treatment with itraconazole or terbinafine for prolonged periods requires laboratory monitoring of liver function tests before initiation of therapy and at monthly intervals thereafter.
Cultural Awareness When Treating Mycotic Infections
Awareness of cultural beliefs related to feet and hands is essential when treating patients with fungal infections. In Arab countries, showing the bottom of the foot is a grave insult. The foot is considered the dirtiest part of the body. As such, patients from these countries may be hesitant to show their feet to the practitioner. In other countries, the open palm “high five” gesture is considered insulting. When treating patients with infections on the hand, the practitioner should refrain from making this gesture while discussing the patient’s hand infection.
OUTCOME EVALUATION
For infections of the skin, patients should notice relief of symptoms, including pruritus, scales, and inflammation, within 1 to 2 weeks. Therapy should be continued at least 1 week after complete resolution of symptoms. If the condition worsens or does not resolve within 4 weeks, the patient should be treated with oral therapy.
For onychomycosis, relief of symptoms is slow. The infected nail will need months to grow out. The practitioner should advise the patient not to become frustrated by the slow resolution. Despite the slow progress, the antifungal agent is curing the infection. The practitioner should also advise the patient that even after the infection is cured, the nail may not look “normal.”
Patient Care and Monitoring of Mycotic Infections
1. Assess the patient’s symptoms to determine if self-treatment with OTC antifungal therapy is appropriate or whether the patient should be evaluated by a practitioner. Exclusions for self-treatment include infection of nails or hair, unsuccessful initial treatment, worsening condition, signs of secondary bacterial or systemic infection, large infected areas, or chronic medical conditions such as diabetes, immunosuppression, or impaired circulation.
2. Review any available diagnostic data, including cultures and KOH preps.
3. Obtain a thorough history of prescription, nonprescription, and natural drug product use.
4. If the patient has had a mycotic infection previously, determine what treatments were helpful to the patient in the past.
5. Educate the patient on lifestyle modifications that will prevent recurrence, which includes keeping the area dry, wearing shower shoes, washing clothing in hot water, using drying powders, avoiding sharing of towels or clothing, and wearing loose-fitting clothing.
6. Develop a plan to assess effectiveness of antifungal therapy.
7. Determine if long-term prophylactic therapy is necessary to prevent recurrence.
8. Evaluate the patient for the presence of adverse drug reactions, drug allergies, and drug interactions.
9. Stress the importance of adherence with the antifungal regimen.
10. Provide the patient education pertaining to mycotic infections and antifungal therapy.
• Causes of mycotic infections of the skin, hair, or nails
• Different types of OTC antifungal products, such as creams, sprays, shampoos, ointments, gel, lotions, solutions, and powders
• How to apply various OTC antifungal products
• How long therapy should be continued
• How to avoid spread of infection
• How to avoid recurrent infection
• Potential adverse effects that may occur with antifungal therapy
• Dietary modifications that are necessary with oral agents
• Medications that may interact with antifungal therapy, particularly with oral agents used for nail infections
• Warning signs to report to a physician (recurrent or difficult-to-cure infections, infections with malodorous discharge or bleeding)
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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