Treating Opportunistic Infections Among HIV-Infected Adults and Adolescents Disease Specific Recommendations Mucocutaneous Candidiasis Epidemiology      Oropharyngeal and esophageal candidiasis are common . The majority of infection is caused by Candida albicans. Fluconazole (or azole) resistance is predominantly the consequence of previous exposure to fluconazole (or other azoles), particularly repeated and long-term exposure . In this setting, C. albicans resistance has been accompanied by a gradual emergence of non-albicans Candida species, particularly C. glabrata, as a cause of refractory mucosal candidiasis, particularly in patients with advanced immunosuppression  The occurrence of oropharyngeal or esophageal candidiasis is recognized as an indicator of immune suppression, and these are most often observed in patients with CD4+ T lymphocyte counts <200 cells/µL. In contrast, vulvovaginal candidiasis is common among healthy, adult women and is unrelated to HIV-1 status. Recurrent vulvovaginal candidiasis alone should not be considered a sentinel of HIV-1 infection among women. The introduction of ART has led to a dramatic decline in the prevalence of oropharyngeal candidiasis and a marked diminution in cases of refractory disease.  Clinical Manifestations Oropharyngeal candidiasis is characterized by painless, creamy white, plaque-like lesions of the buccal or oropharyngeal mucosa or tongue surface. Lesions can be easily scraped off with a tongue depressor or other instrument. Less commonly, erythematous patches without white plaques can be seen on the anterior or posterior upper palate or diffusely on the tongue. Angular chelosis is also noted on occasion and may be caused by Candida. Esophageal candidiasis is occasionally asymptomatic but often presents with fever, retrosternal burning pain or discomfort, and odynophagia. Endoscopic examination reveals whitish plaques similar to those observed with oropharyngeal disease that might progress to superficial ulceration of the esophageal mucosa, with central or surface whitish exudates. Vulvovaginitis might be mild to moderate and sporadic, similar in presentation to that in normal hosts, and characterized by a creamy to yellow-white adherent vaginal discharge associated with mucosal burning and itching. In those with more advanced immunosuppression, episodes might be more severe, more frequently recurrent, of longer duration, or refractory to treatment. Diagnosis Diagnosis of oropharyngeal candidiasis is usually clinical and based on the appearance of lesions. The feature that distinguishes these from oral hairy leukoplakia is the ability to scrape off the superficial whitish plaques. If laboratory confirmation is required, a scraping for microscopic examination for yeast forms using a potassium hydroxide (KOH) preparation provides supportive diagnostic information. Cultures of clinical material identify the species of yeast present. The diagnosis of esophageal candidiasis requires endoscopic visualization of lesions with histopathologic demonstration of characteristic Candida yeast forms in tissue and culture confirmation of the presence of Candida species. The diagnosis of vulvovaginal candidiasis is based on the clinical presentation coupled with the demonstration of characteristic yeast forms in vaginal secretions examined microscopically after KOH preparation. Culture confirmation is rarely required but might provide supportive information. Because self-diagnosis of vulvovaginitis is unreliable, microscopic confirmation is required to avoid unnecessary exposure to inappropriate treatments. Treatment Recommendations Although initial episodes of oropharyngeal candidiasis can be adequately treated with topical therapy, including clotrimazole troches or nystatin suspension or pastilles (BII), oral fluconazole is as effective and, in certain studies, superior to topical therapy and is more convenient and generally better tolerated  (AI). Itraconazole oral solution for 7--14 days is as effective as oral fluconazole but less well tolerated (AI). Ketoconazole and itraconazole capsules are less effective than fluconazole because of their more variable absorption and should be considered second line alternatives (DII). Systemic therapy is required for effective treatment of esophageal candidiasis (AII). A 14--21-day course of either fluconazole or itraconazole solution is highly effective (AI). As with oropharyngeal candidiasis, ketoconazole and itraconazole capsules are less effective than fluconazole because of variable absorption (DII). Although caspofungin (AII) and voriconazole (AII) are effective in treating esophageal candidiasis among HIV-1--infected patients, experience is limited and fluconazole remains the preferred agent. Although symptoms of esophageal candidiasis might be mimicked by other pathogens, a diagnostic trial of antifungal therapy is often appropriate before endoscopy is undertaken to search for other causes of esophagitis. Uncomplicated vulvovaginal candidiasis is observed in 90% of HIV-1--infected women and responds readily to short-course oral or topical treatment with any of several therapies including single-dose regimens (AII): topical azoles (clotrimazole, butaconazole, miconazole, ticonazole, or terconazole) for 3--7 days; topical nystatin 100,000 units daily for 14 days; itraconazole oral solution 200 mg twice a day for 1 day or 200 mg daily for 3 days; or oral fluconazole 150 mg for 1 dose. Complicated vaginitis (prolonged or refractory episodes) is observed in approximately 10% of patients and requires antimycotic therapy for >7 days (AII). Monitoring and Adverse Events For the majority of patients, response to therapy is rapid, with improvement in signs and symptoms within 48--72 hours. Short courses of topical therapy rarely result in adverse effects, although patients might experience cutaneous hypersensitivity reactions, with rash and pruritis. Patients might experience gastrointestinal upset with oral azole treatment. Patients treated for >7--10 days with azoles might experience hepatotoxicity. If prolonged therapy is anticipated (>21 days), periodic monitoring of liver chemistry studies should be considered. Management of Treatment Failure Treatment failure is generally defined as signs and symptoms of oropharyngeal or esophageal candidiasis that persist for more than 7--14 days of appropriate therapy. Fluconazole-refractory oropharyngeal candidiasis will respond at least transiently to itraconazole solution in approximately two thirds of persons (AII). Amphotericin B oral suspension (1 mL four times daily of the 100 mg/mL suspension) is sometimes effective among patients with oropharyngeal candidiasis who do not respond to itraconazole (CIII); however, this product is not available in the United States. Intravenous amphotericin B is usually effective and can be used among patients with refractory disease (BII). Fluconazole-refractory esophageal candidiasis should be treated with caspofungin (BIII) or intravenous amphotericin B, either conventional or liposomal or lipid complex formulations (BII). Prevention of Recurrence The majority of HIV specialists do not recommend secondary prophylaxis (chronic maintenance therapy) of recurrent oropharyngeal or vulvovaginal candidiasis because of the effectiveness of therapy for acute disease, the low mortality associated with mucosal candidiasis, the potential for resistant Candida organisms to develop, the possibility of drug interactions, and the cost of prophylaxis (DIII). However, if recurrences are frequent or severe, an oral azole, fluconazole (CI), or itraconazole solution (CI) (or for recurrent vulvovaginal candidiasis, daily prophylaxis with any topical azole [CII]) should be considered. Other factors that influence choices related to such therapy include impact of recurrences on the patient's well-being and quality of life, need for prophylaxis for other fungal infections, cost, toxicities, drug interactions, nutritional status, and potential to induce drug resistance among Candida and other fungi. Prolonged use of systemically absorbed azoles, specifically among patients with low CD4+ T lymphocyte counts (i.e., <100 cells/µL) increases the risk for developing azole resistance. Adults or adolescents who have a history of one or more episodes of documented esophageal candidiasis should be considered candidates for secondary prophylaxis. Fluconazole 100--200 mg daily is appropriate (BI). However, potential azole resistance should be considered when long-term azoles are considered. Special Considerations During Pregnancy Pregnancy increases the risk for vaginal colonization with Candida species. Diagnosis of oropharyngeal, esophageal, and vulvovaginal candidiasis is the same as among nonpregnant adults. Fluconazole is teratogenic in high doses in animal studies . Among humans, four cases of an unusual cluster of defects (i.e., craniofacial and skeletal) have been reported after prolonged use at high doses in the first trimester of pregnancy . Teratogenic effects have not been described among animals at doses similar to those used in humans, and anomalies do not appear to be increased among infants born to women receiving single-dose fluconazole treatment in the first trimester.  Itraconazole is teratogenic among rats and mice (i.e., skeletal defects, encephalocele, and macroglossia) at high doses . Similar to fluconazole, no increase in anomalies has been noted among women exposed to treatment doses in the first trimester. Invasive or refractory esophageal Candida infections should be treated the same in pregnancy as in the nonpregnant woman, with the exception that amphotericin B should be substituted for fluconazole or itraconazole (if indicated) in the first trimester if similar efficacy is to be expected (BIII).