Category Archives: Candidiasis

Candidiasis

– Christian Hoffmann –

Candidiasis is an infection with yeast-forming fungi. Of the 150 Candida species known to date, only approximately 20 cause disease. By far the most frequent species is C. albicans. Other species such as C. tropicalis, C. glabrata and C. krusei are rare, but may respond less readily to treatment with azoles. Although it is commonly assumed that azole resistance is a problem particularly with albicans strains, this has not been the case to date (Sanglard 2002).

Candidiasis is an important indicator of immunodeficiency and should be seen as a reason to consider starting ART, even with a good immune status. Esophageal candidiasis and even oral thrush often occur following other OIs. Fever, which is not a classic symptom of candidiasis, is a particular indication to be on the alert. If immune status is good, it must be remembered that there are also other reasons for thrush – alcoholism and steroid treatment are only two of many possibilities. In addition to candidiasis of the oropharynx and esophagus, vaginitis is a frequent problem in women (also occurring in healthy individuals). Candidemia occurs only rarely in HIV-infected patients, even with severe immunodeficiency.

Signs and symptoms

The oropharynx is usually affected, with taste disturbances and sometimes, a burning sensation on the tongue. White, non-adherent plaques on the buccal mucosa, tonsillar ring and tongue confirm the diagnosis. Involvement of the tongue alone is rare. Occasionally, there may be atrophic candidiasis, which presents only with an erythematous mucosa.

Candida esophagitis usually occurs with oropharyngeal involvement, but in about one third of cases there is no oral thrush. It often presents with dysphagia (“drinking is ok, but food can’t go down”) and retrosternal pain. Some patients complain of nausea, although vomiting occurs only rarely.

Diagnosis

Diagnosis in the oropharynx can be made based on the clinical appearance. A swab is not usually required. Characterization by culture or even determination of drug susceptibility (beware laboratory uncertainty!) is only advised if one treatment attempt with fluconazole or itraconazole has failed. Oral candidiasis is not to be confused with oral hairy leukoplakia (OHL). In contrast to candidiasis, the whitish, hairy plaques of OHL, on the sides of the tongue, cannot be scraped off. OHL is not caused by fungi but by EBV, and is an important disease marker for HIV, even if it is harmless and does not require treatment.

Candida esophagitis can also initially be diagnosed clinically. Dysphagia, retrosternal pain and oral candidiasis make the diagnosis very probable. Empiric fluconazole therapy reduces costs (Wilcox 1996). Upper GI endoscopy is only required if complaints persist. To distinguish fluconazole-resistant esophageal candidiasis from herpes or CMV esophagitis, samples of lesions should always be taken. In contrast, determination of serum antibodies or antigen is always unnecessary.

Treatment

With relatively good immune status and presentation for the first time, treatment with topical antimycotics such as nystatin, amphomoronal or miconazole can be attempted. However, systemic treatment is usually necessary. This is more effective and prevents relapses for longer (Pons 1997).

Fluconazole is the treatment of choice, and one week of oral treatment is usually sufficient (Sangeorzan 1994). According to a recently published trial, shorter treatment duration with higher dosages seems to be an option. In this large randomized study, a single dose of 750 mg of fluconazole was safe, well tolerated, and as effective as the standard 14-day fluconazole therapy (Hamza 2008).

If symptoms persist for more than a week, then a swab should be taken and the daily fluconazole dose may be increased up to 800 mg for the second attempt.  Itraconazole should only be used if the second treatment attempt fails and non-albicans strains have been found. It will be effective in approximately two thirds of cases (Saag 1997). Although itraconazole suspension is as effective as fluconazole (Graybill 1998), we do not primarily use it as plasma levels are unreliable and there are problems with numerous interactions.

Several new and promising antimycotics have been developed in recent years. However, these should only be used in clear cases of fluconazole resistance. There is insufficient evidence on the superiority of these drugs in the treatment of non-resistant candidiasis (Pienaar 2006). Voriconazole is expected to be as effective as fluconazole, but is possibly not tolerated as well (Ruhnke 1997, Ally 2001). This may be also true for posaconazole (Vasquez 2006). Like amphotericin B, these new azoles should only be used for treatment of multi-azole resistant mycoses. The new antimycotic class of echinocandins has also good efficacy, among them drugs such as caspofungin, micafungin or anidulafungin (Keating 2001, Villanueva 2001, Arathoon 2002, de Wet 2004, Reboli 2007). These drugs which can only be administered intravenously, showed similar efficacy and tolerability to intravenous fluconazole for treatment of candida esophagitis in randomized studies (Villaneuva 2001, de Wet 2004, Reboli 2007). Antiretroviral therapy should be initiated when such mycoses occur, particularly with multiresistant strains, as these usually disappear with sufficient immune reconstitution (Ruhnke 2000).

Treatment/prophylaxis of candidiasis  (daily doses)

Acute therapy

Duration: 5-10 days

In mild cases

Topical

e.g. amphotericin B 1 lozenge qid or

nystatin suspension 1 ml qid

Treatment of choice

Fluconazole

Fluconazole 1 x 1 cap at 100 mg for oral candidiasis

Fluconazole 1 x 1 cap at 200 mg for esophageal candidiasis (twice the dose on the first day in each case)

Alternative

Itraconazole

Itraconazole 1-2 cap. at 100 mg bid or

Itraconazole suspension 10-20 ml bid (1 ml = 10 mg)

Prophylaxis

Not recommended

Prophylaxis

No survival benefit has been demonstrated for any Candida prophylaxis to date (McKinsey 1999, Rex 2000, Goldmann 2005). In probably the largest randomized study on this theme, a reduction in oral candidiasis episodes as well as in invasive candidiasis was observed on long-term prophylaxis (Goldman 2005). The hypothesis that long-term prophylaxis will lead to the selection of resistant non-albicans strains (Vazquez 2001) was not confirmed in this study. Azole resistant infections were not seen more frequently in the long-term therapy group. Nonetheless, every immunocompromised patient should be screened for oral thrush at every visit.

References

Ally R, Schurmann D, Kreisel W, et al. A randomized, double-blind, double-dummy, multicenter trial of voriconazole and fluconazole in the treatment of esophageal candidiasis in immunocompromised patients. Clin Infect Dis 2001, 33:1447-54.

Arathoon EG, Gotuzzo E, Noriega LM, et al. Randomized, double-blind, multicenter study of caspofungin versus amphotericin B for treatment of oropharyngeal and esophageal candidiases. Antimicrob Agents Chemother 2002, 46:451-7.

de Wet N, Llanos-Cuentas A, Suleiman J, et al. A randomized, double-blind, parallel-group, dose-response study of micafungin compared with fluconazole for the treatment of esophageal candidiasis in HIV-positive patients. Clin Infect Dis 2004, 39:842-9.

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 Study 40. Clin Infect Dis 2005, 41:1473-80.

Graybill JR, Vazquez J, Darouiche RO, et al. Randomized trial of itraconazole oral solution for oropharyngeal candidiasis in HIV/AIDS patients. Am J Med 1998, 104:33-9.

Hamza OJ, Matee MI, Brüggemann RJ, 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, 47:1270-6.

Keating GM, Jarvis B. Caspofungin. Drugs 2001, 61:1121-9; discussion 1130-1.

McKinsey DS, Wheat LJ, Cloud GA, et al. Itraconazole prophylaxis for fungal infections in patients with advanced HIV infection: randomized, placebo-controlled, double-blind study. Clin Infect Dis 1999, 28:1049-56.

Pienaar ED, Young T, Holmes H. Interventions for the prevention and management of oropharyngeal candidiasis associated with HIV infection in adults and children. Cochrane Database Syst Rev 2006, 3:CD003940. Review.

Pons V, Greenspan D, Lozada-Nur F, et al. Oropharyngeal candidiasis in patients with AIDS: randomized comparison of fluconazole versus nystatin oral suspensions. Clin Infect Dis 1997, 24:1204-7.

Reboli AC, Rotstein C, Pappas PG, et al. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med 2007;356:2472-82.

Rex JH, Walsh TJ, Sobel JD, et al. Practice guidelines for the treatment of candidiasis. Clin Infect Dis 2000, 30:662-78.

Ruhnke M, Adler A, Muller FM. Clearance of a fluconazole-resistant Candida albicans strain after switching antifungal therapy and initiation of triple therapy for HIV infection. Clin Microbiol Infect 2000, 6:220-3.

Ruhnke M, Schmidt-Westhausen A, Trautmann M. In vitro activities of voriconazole (UK-109,496) against fluconazole-susceptible and -resistant Candida albicans isolates from oral cavities of patients with HIV infection. Antimicrob Agents Chemother 1997, 41:575-7.

Saag MS, Fessel WJ, Kaufman CA, et al. Treatment of fluconazole-refractory oropharyngeal candidiasis with itraconazole oral solution in HIV-positive patients. AIDS Res Hum Retroviruses 1999, 15:1413-7.

Sangeorzan JA, Bradley SF, He X, et al. Epidemiology of oral candidiasis in HIV-infected patients: colonization, infection, treatment, and emergence of fluconazole resistance. Am J Med 1994, 97:339-46.

Sanglard D, Odds FC. Resistance of Candida species to antifungal agents: molecular mechanisms and clinical consequences. Lancet Infect Dis 2002, 2:73-85.

Vazquez JA, Peng G, Sobel JD, et al. Evolution of antifungal susceptibility among Candida species isolates recovered from HIV-infected women receiving fluconazole prophylaxis. Clin Infect Dis 2001, 33:1069-75.

Vazquez JA, Skiest DJ, Nieto L, A multicenter randomized trial evaluating posaconazole versus fluconazole for the treatment of oropharyngeal candidiasis in subjects with HIV/AIDS. Clin Infect Dis 2006, 42:1179-86.

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, 33:1529-35.

Walsh TJ, Gonzalez CE, Piscitelli S, et al. Correlation between in vitro and in vivo antifungal activities in experimental fluconazole-resistant oropharyngeal and esophageal candidiasis. J Clin Microbiol 2000, 38:2369-73.

Wilcox CM, Alexander LN, Clark WS, Thompson SE 3rd. Fluconazole compared with endoscopy for HIV-infected patients with esophageal symptoms. Gastroenterology 1996, 110:1803-9.

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Filed under 11. Opportunistic Infections, Candidiasis, Part 3 - AIDS