- Hx: sore mouth, dysphagia, altered taste perception, or asymptomatic.
- Risks (w/ HIV): CD4 < 200, recent antibiotic or steroid use, malnutrition.
- See oral candidiasis module for thrush in non-HIV populations.
- Pseudomembranous: most common, white plaques on oral mucosa that can be wiped away to leave erythematous base.
- Erythematous: red patches usually on palate or angular cheilitis.
- Differential dx: substernal odynophagia/dysphagia suggests thrush + esophagitis, oral hairy leukoplakia (white non-removable plaques on sides of tongue)
- Usually a clinical diagnosis based upon inspection.
- Gram or KOH stain: mycelia seen.
- Culture: rarely unnecessary, but consider in refractory cases to confirm diagnosis OR to perform fungal culture for species identification and susceptibility testing.
- First episode, preferred:
- Fluconazole resistant: azole resistance risks correlate with chronic or repeated azole exposure, CD4 < 50, chronic abx (TMP-SMX).
Provocative factors (reversible)
TREATMENT REGIMEN DETAILS
Drug Interactions: ART and Azoles (risks)
Severe, may ↑ NVP levels and cause hepatoxicity
Itra. ↓ 35%
Posa. ↓ 50%
Vori. ↓ 50%
Vori. ↓ 40%
Selected Drug Comments
The preferred azole. Usually highly effective but repeated or prolonged use risks emergence of azole resistance.
Average dose:100-200 mg/day. Cheaper than fluconazole, but absorption less predictable. There are more drug interactions and more hepatotoxicity. May also lead to azole resistance.
(Oral tabs 10 mg 5x/d) This is a preferred treatment, but complicated by the frequency of dosing. Delays exposure to azoles, which may decrease risk of resistance. Clinical trials show efficacy comparable to that of fluconazole with uncomplicated cases.
Topical treatment with vaginal tablets (100,000 units) TID dissolved slowly or oral solution (100,000 units/ml) & pastilles (200,000 units) all given 4-5 x daily. This is a preferred treatment, but may be less effective than clotrimazole.
- Daily fluconazole (100mg PO) effective as secondary prophylaxis, but use risks emergence of azole resistance.
- Recurrent: consider dapsone for PCP prophylaxis instead of TMP-SMX.
- Refractory cases: order culture with in vitro susceptibility testing or empirically escalate dose (fluconazole 400-800mg daily) or change to different agent (itraconazole, voriconazole, or posaconazole).
- If pt has thrush with dysphagia or odynophagia: treat empirically for esophagitis with systemic therapy (e.g., azole).
Pathogen Specific Therapy
Basis for recommendation
- Kaplan JE et al: Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep 58:1, 2009 [PMID:19357635]
Comment: Diagnosis: Usually clinical features, but usually can easily show typical organisms with KOH prep; culture is "rarely required."
Treatment: Fluconazole preferred (100 mg/d x 7-14d)
1st infections -- alternative is topical clortrimazole (10 mg troche to dissolve, not swallow, 5x/d 7-14d, nystatin, miconazole. Alternative systemic agent: itraconazole.
Treatment: Esophageal candidiases -- fluconazole (IV or po); itraconazole, IV voriconazole or IV caspofungin.
- Pappas PG et al: Guidelines for treatment of candidiasis. Clin Infect Dis 38:161, 2004 [PMID:14699449]
Comment: IDSA guidelines for treatment of candidiasis. For thrush: clotrimazole 10 mg 5x/d or nystatin 200,000-400,000 units 5x/d or fluconazole 100-200 mg/d x 7-14 d post improvement. Alternatives are itraconazole 200 mg/d or Ampho B>0.3 mg/kg/d IV or caspofungin. For esophagitis it is fluconazole 100-200 mg/d po or IV x 14-21 d post improvement. Alternate is voriconazole 4mg/kg IV or po, Ampho B 0.3-0.7 mg/kg/d or caspofungin.
- 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 [PMID:21069679]
Comment: No significant difference between fluconazole, ketoconazole, itraconazole, clotrimazole or posa conazole for clinical response. Fluconazole and itraconazole were superior to clotrimazole for micologic cure. Gentian violet and ketoconazole are superior to nystatin.
- Delgado AC et al: Clinical and microbiological assessment of patients with a long-term diagnosis of human immunodeficiency virus infection and Candida oral colonization. Clin Microbiol Infect 15:364, 2009 [PMID:19431223]
Comment: Candida colonization and thrush correlated with low CD4 cell count (only). C. albicans accounted for 85%.
- Hamza OJ 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 47:1270, 2008 [PMID:18840077]
Comment: Prospective study in 220 HIV-infected patients that showed single dose fluconazole 750 mg x 1 was as effective as 150 mg once-daily x 14d. Clinical cure rate 95% vs. 96% mycologic cure rates 85% vs. 76% (favoring single dose but p NS).
- Skiest DJ et al: Posaconazole for the treatment of azole-refractory oropharyngeal and esophageal candidiasis in subjects with HIV infection. Clin Infect Dis 44:607, 2007 [PMID:17243069]
Comment: Posaconazole proved safe and effective in 132/176 (75%) of AIDS patients with azole refractory thrush.
- Vazquez JA et al: A multicenter randomized trial evaluating posaconazole versus fluconazole for the treatment of oropharyngeal candidiasis in subjects with HIV/AIDS. Clin Infect Dis 42:1179, 2006 [PMID:16575739]
Comment: Comparative trial of posaconazole vs. fluconazole for thrush in patients with AIDS and thrush or Candida esophagitis . Among 350 patients, cure rates were similar -- 92% for posaconazole and 93% for fluconazole . Sustained mycologic success was somewhat better with posaconazole (41% vs. 26%) and clinical relapse.
- Hospenthal DR, Murray CK, Rinaldi MG: The role of antifungal susceptibility testing in the therapy of candidiasis. Diagn Microbiol Infect Dis 48:153, 2004 [PMID:15023422]
Comment: Review of topic with the conclusion that variations in azole activity makes susceptibility testing a clinically useful tool. They recommend testing of candida from blood cultures, deep infections and recurrent mucosal infections.
- Pinheiro A et al: Dental and oral lesions in HIV infected patients: a study in Brazil. Int Dent J 54:131, 2004 [PMID:15218892]
Comment: Review of 161 patients-thrush in 29%, oral hairy leukoplakia in 9%,KS in 3%, ulcers in 3%, HSV 1%, periodontal disease 4%.
- Vazquez JA et al: Evolution of antifungal susceptibility among Candida species isolates recovered from human immunodeficiency virus-infected women receiving fluconazole prophylaxis. Clin Infect Dis 33:1069, 2001 [PMID:11528582]
Comment: CPCRA study of 91 women receiving placebo vs. prophylactic fluconazole showed significant reduction in rates of thrush or vaginitis 34 vs 12% and low rates of fluconazole resistant Candida albicans (2% vs 1%), but higher rates of non-albicans species with the azole (25% vs 12%).
- Walmsley S et al: Oropharyngeal candidiasis in patients with human immunodeficiency virus: correlation of clinical outcome with in vitro resistance, serum azole levels, and immunosuppression. Clin Infect Dis 32:1554, 2001 [PMID:11340526]
Comment: Good correlation between IN VITRO SENSITIVITY TEST RESULTS and in vivo response to azoles in patients with thrush. Isolates from 61% of patients with refractory thrush had resistant or "susceptible dose dependent" strains compared to 86% with susceptible strains among responders.
- Magaldi S et al: In vitro susceptibility of 137 Candida sp. isolates from HIV positive patients to several antifungal drugs. Mycopathologia 149:63, 2001 [PMID:11265163]
Comment: The authors tested 137 Candida isolates from HIV infected patients: 10% were resistant to fluconazole, 45% of these were from fluconazole treated patients. 93% were cross-resistant to itraconazole.
- Fichtenbaum CJ et al: Refractory mucosal candidiasis in advanced human immunodeficiency virus infection. Clin Infect Dis 30:749, 2000 [PMID:10816143]
Comment: ACTG 816: Observational study of 842 patients with mean CD4 count of 14 and candidiasis, primarily thrush, who failed a 14 day course of fluconazole. Risk factors = low CD4 count, extensive prior use of fluconazole and TMP-SMX prophylaxis. Cultures showed C. albicans in 97% and in vitroFLUCONAZOLE RESISTANCE in 19%.
- Sorensen HT et al: Risk of malformations and other outcomes in children exposed to fluconazole in utero. Br J Clin Pharmacol 48:234, 1999 [PMID:10417502]
Comment: Report from Denmark showing rate of malformations was 4/121 (3.3% women given fluconazole compared to 5.2% in 697 controls.
- Fichtenbaum CJ, Powderly WG: Refractory mucosal candidiasis in patients with human immunodeficiency virus infection. Clin Infect Dis 26:556, 1998 [PMID:9524822]
Comment: FLUCONAZOLE-RESISTANT CANDIDA infection usually associated with extensive prior exposure to azoles and CD4 <50/mm3.
- Heald AE et al: Oropharyngeal yeast flora and fluconazole resistance in HIV-infected patients receiving long-term continuous versus intermittent fluconazole therapy. AIDS 10:263, 1996 [PMID:8882665]
Comment: CHRONIC ADMINISTRATION OF FLUCONAZOLE for >6 months associated with reduced carriage of C. albicans in the mouth and reduced recurrences of thrush.
- Mastroiacovo P et al: Prospective assessment of pregnancy outcomes after first-trimester exposure to fluconazole. Am J Obstet Gynecol 175:1645, 1996 [PMID:8987954]
Comment: Review of 226 women exposed to fluconazole in first trimester vs. 452 controls. There were 22 miscarriages, 1 stillbirth and 7 congenital anomalies in the fluconazole group; this was not different from controls. The conclusion was that fluconazole is safe when given to pregnant women.
- Powderly WG et al: A randomized trial comparing fluconazole with clotrimazole troches for the prevention of fungal infections in patients with advanced human immunodeficiency virus infection. NIAID AIDS Clinical Trials Group. N Engl J Med 332:700, 1995 [PMID:7854376]
Comment: FLUCONAZOLE PROPHYLAXIS prevents infections with C. neoformans and Candida spp. Concerns are cost, azole resistance and lack of a survival benefit.
- Pons V, Greenspan D, Debruin M: Therapy for oropharyngeal candidiasis in HIV-infected patients: a randomized, prospective multicenter study of oral fluconazole versus clotrimazole troches. The Multicenter Study Group. J Acquir Immune Defic Syndr 6:1311, 1993 [PMID:8254467]
Comment: TOPICAL THERAPY WITH CLOTRIMAZOLE as effective as fluconazole for initial treatment of thrush.
- Vazquez JA et al: Safety and efficacy of posaconazole in the long-term treatment of azole-refractory oropharyngeal and esophageal candidiasis in patients with HIV infection. HIV Clin Trials 8:86, 2007 Mar-Apr [PMID:17507324]
Comment: Non-comparative trial of posaconazole (400 mg bid) in 100 patients with azole-refractory thrush or candida esophagitis . The response rate was 86%.
- Brito GN et al: In vitro antifungal susceptibility of Candida spp. oral isolates from HIV-positive patients and control individuals. Braz Oral Res 25:28, 2011 Jan-Feb [PMID:21271179]
Comment: Thrush isolates -- C. albicans (59), C. tropicals (9), C. glambrata (1), C. guilliermondii. Sensitivities of these isolates from AIDS-patients with thrush were similar to clinical isolates of Candida from other sites.
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