Candidiasis, Mucocutaneous

para>Vaginal antifungal creams and suppositories can weaken condoms and diaphragms.
Pregnancy Considerations

Vaginal candidiasis is common during pregnancy.
Topical treatment during pregnancy should be extended by several days.
Vaginal yeast infection at birth increases the risk of newborn thrush but is of no overall harm to baby.

EPIDEMIOLOGY

Common in the United States; particularly with immunodeficiency and/or uncontrolled diabetes
Age considerations
- Infants and seniors: thrush and cutaneous infections (infant diaper rash)
- Women of childbearing age: vaginitis
- Prepubertal or postmenopausal: yeast vaginitis
- Predominant sex: female > male

Incidence
Unknown-mucocutaneous candidiasis is common in immunocompetent patients. Complication rates are low.
Prevalence
Candida species are normal flora of oral cavity, pharynx, esophagus, and GI tract that are present in >70% of the U.S. population.

ETIOLOGY AND PATHOPHYSIOLOGY

C. albicans (responsible for 80-92% vulvovaginal and 70-80% oral isolates). Altered cell-mediated immunity against Candida species (either transient or chronic) increases susceptibility to infection.
Genetics
Chronic mucocutaneous candidiasis is a heterogeneous, genetic syndrome with infection of skin, nails, hair, and mucous membranes; typically presents in infancy.

RISK FACTORS

Immunosuppression
Antibacterial therapy (broad-spectrum antibiotics)
Douches, chemical irritants, and concurrent vaginitides alter vaginal pH predisposing to candidal vaginitis.
Denture wear
Birth control pills; intrauterine devices
Hyperglycemia; diabetes
Uncircumcised men at higher risk for balanitis

GENERAL PREVENTION

Use antibiotics and steroids judiciously; rinse mouth after inhaled steroid use (1)[A].
Avoid douching. Treat other vaginal infections.
Minimize perineal moisture (wear cotton underwear; frequent diaper changes).
Clean dentures often; use well-fitting dentures, and remove during sleep.
Optimize glycemic control in diabetics.
Use preventive regimens during cancer treatments (2)[A].
Treat with HAART in HIV-infected patients
Antifungal prophylaxis against oral candidiasis is not recommended in HIV-infected adults unless patients have frequent or severe recurrences (3)[A].

COMMONLY ASSOCIATED CONDITIONS

HIV
Leukopenia
Diabetes mellitus
Cancer and other immunosuppressive conditions

DIAGNOSIS

HISTORY

Infants/children
- Oral: adherent white patches on oral mucosae or on the tongue that do not wipe away easily
- Perineal: erythematous rash with characteristic satellite lesions; painful if skin layer eroded. 40-75% of diaper rashes lasting >3 days are C. albicans (4,5)[A].
- Angular cheilitis: painful fissures in corners of mouth
Adults
- Vulvovaginal lesions; whitish "curd-like" discharge; pruritus; burning
Immunocompromised hosts
- Oral: white, raised, painless, distinct patches; red, slightly raised patches
- Esophagitis: dysphagia, odynophagia, retrosternal pain; usually concomitant thrush
- GI symptoms: abdominal pain
- Balanitis: erythema, erosions, scaling; dysuria
- Folliculitis: follicular pustules
- Interdigital: redness, itchiness at base and webspaces of fingers and/or toes, possible maceration

PHYSICAL EXAM

Infants/children
- Oral: white, raised, distinct patches within the mouth; when wiped off reveals red base
- Perineal: erythematous maculopapular rash with satellite pustules or papules
- Angular cheilitis: tender fissures in mouth corners, often cracked and bleeding
Adults
- Vulvovaginal: thick, whitish, cottage cheese-like discharge; vagina or perineum erythema
Immunocompromised hosts
- Oral: white, raised, nontender, distinct patches; red, slightly raised patches; thick, dark-brownish coating; deep fissures
- Esophagitis: often, oral thrush is visible.
- Balanitis: erythema, linear erosions, scaling
- Folliculitis: follicular pustules
- Interdigital: redness, excoriations at base of fingers and/or toes, often maceration

DIFFERENTIAL DIAGNOSIS

For oral candidiasis
- Leukoplakia; lichen planus; geographic tongue
- Herpes simplex; erythema multiforme
- Pemphigus
Baby formula or breast milk can mimic thrush-easier to remove than thrush (no red base when wiped away)
Hairy leukoplakia: does not rub off; dorsum and lateral margins of tongue
Angular cheilitis from vitamin B or iron deficiency, staphylococcal infection, or edentulous overclosure
Bacterial vaginosis and Trichomonas vaginalis tend to have more odor, itch, and a different discharge.

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (lab, imaging)

10% KOH slide preparation: mycelia (hyphae) or pseudo-mycelia (pseudohyphae) yeast forms; few WBC
Associated with normal vaginal pH (<4.5)
Barium swallow: cobblestone appearance, fistulas, or dilatation (denervation)

Diagnostic Procedures/Other

If 1st-line treatment fails, obtain samples for culture
Esophagitis may require endoscopy with biopsy (if suspicious for cancer).
HIV seropositive patients with thrush and dysphagia relieved by antifungal have Candida esophagitis.

Test Interpretation
Biopsy: epithelial parakeratosis with polymorphonuclear leukocytes in superficial layers; periodic acid-Schiff staining reveals presence of candidal hyphae.

TREATMENT

GENERAL MEASURES

Screen for immunodeficiency.

MEDICATION

First Line

Vaginal (choose 1)
- Miconazole (Monistat) 2% cream: one applicator or 200 mg (one suppository), intravaginally qhs for 7 days
- Clotrimazole (Gyne-Lotrimin, Mycelex): intravaginal tablets (100 mg qhs for 7 days; 200 mg qhs for 3 days; 500 mg daily for 1 day) or 2% cream (one applicator qhs for 3 days)
- Fluconazole 150 mg PO single dose
Oropharyngeal
- Mild disease
  - Clotrimazole (Mycelex): oral 10 mg troche; 20 minutes 5 times daily for 7 to 14 days
  - Nystatin suspension: 100,000 U/mL swish and swallow 400,000 to 600,000 U 4 times per day
  - Nystatin pastilles: 200,000 U each, QID daily for 7 to 14 days (6)[B],(7)[A]
  - Denture wearers
    - Nystatin ointment: 100,000 U/g under denture and corners of mouth for 3 weeks
    - Remove dentures at night; clean 2 weekly with diluted (1:20) bleach.
- Moderate to severe disease
  - Fluconazole: 200 mg load then 100 to 200 mg (>14 days of age: 6 mg/kg 1 dose, then 3 mg/kg q24h 7-14 days [max 100 mg/day])
Esophagitis
- Fluconazole: PO 400 mg load then 200 to 400 mg/day for 14 to 21 days or IV 400 mg (6 mg/kg) daily if oral therapy not tolerated

Pregnancy Considerations

2% Miconazole cream, intravaginally, for 7 days in uncomplicated candidiasis. Systemic amphotericin B for invasive candidiasis in pregnancy.

Second Line

Vaginal
- Terconazole (Terazol): 0.4% cream (one applicator qhs for 7 days of induction therapy); 0.8% cream/80-mg suppositories (one applicator or one suppository qhs for 3 days)
- For recurrent cases (≥4 symptomatic episodes in 1 year): induction therapy with 10 to 14 days of topical or oral azole, then, fluconazole, 150 mg once per week for 6 months (6)[A]
  - In HIV patients: concerns with this regimen include emergence of drug resistance (8)[A].
Oropharyngeal
- Miconazole oral gel (20 mg/mL): QID, swish and swallow
- Itraconazole (Sporanox) suspension: 200 mg (20 mL) daily; swish-swallow for 7 to 14 days
- Posaconazole (Noxafil) oral suspension: 400 mg BID for 3 days, then 400 mg daily for up to 28 days
- Amphotericin B (Fungizone) oral suspension (100 mg/mL): 1 mL QID daily, swish and swallow; use between meals
Esophagitis
- Amphotericin B (variable dosing) IV dose of 0.3 to 0.7 mg/kg daily; or an echinocandin should be used for patients who cannot tolerate oral therapy.
- For refractory disease:
  - Itraconazole (Sporanox) oral solution: 200 mg daily
  - Posaconazole (Noxafil) oral suspension: 400 mg BID
  - Voriconazole (Vfend) 100 to 200 mg q12h PO or IV for 14 to 21 days (6)[A]
Continue treatments for 2 days after infection gone:
- Contraindications
  - Ketoconazole, itraconazole, or nystatin (if swallowed): severe hepatotoxicity
  - Amphotericin B: can cause nephrotoxicity
- Precautions
  - Miconazole: can potentiate the effect of warfarin but drug of choice in pregnancy
  - Fluconazole: renal excretion: rare; hepatotoxicity: resistance frequent
  - Itraconazole: doubling the dosage results in ~3-fold increase in itraconazole plasma concentrations.
Possible interactions (rarely seen with creams, lotions, or suppositories)
- Fluconazole
  - Rifampin: decreased fluconazole concentrations
  - Tolbutamide: decreased concentrations
  - Warfarin, phenytoin, cyclosporine: altered metabolism; check levels.
- Itraconazole: potent CYP 3A4 inhibitor. Carefully assess all coadministered medications.

ISSUES FOR REFERRAL

Patients without obvious reasons for recurrent superficial candidal infections should be evaluated for concurrent immunodeficiency.
GI candidiasis

ADDITIONAL THERAPIES

For infants with thrush: Boil pacifiers and bottle nipples; assess mother's breasts/nipples for concurrent candida infection.
For denture-related candidiasis: disinfect dentures (using soak solution of benzoic acid, 0.12% chlorhexidine gluconate, 1:20 NaOCl or alkalize proteases), and treat orally

COMPLEMENTARY & ALTERNATIVE MEDICINE

Probiotics: Lactobacillus and Bifidobacterium may inhibit Candida spp.

INPATIENT CONSIDERATIONS

Nursing
Proper oral hygiene. Protocols for brushing, denture care, and oral cavity moistening reduce oral candidiasis.

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Patient Monitoring
Immunocompromised persons benefit from regular evaluation and screening.

DIET

Active-culture yogurt or other live lactobacillus may decrease colonization; indeterminate evidence.

PATIENT EDUCATION

Advise patients at risk for recurrence about overgrowth with antibacterial therapy.
"Azole" medications are pregnancy category C.

PROGNOSIS

Benign prognosis in immunocompetent patients
For immunosuppressed persons, Candida may become an AIDS-defining illness with significant morbidity.

COMPLICATIONS

In HIV patients, moderate immunosuppression (e.g., CD4 200 to 500 cells/mm3) may be associated with chronic candidiasis. With more severe immunosuppression (e.g., CD4 <100 cells/mm3), esophagitis or systemic infection are possible.

REFERENCES

11 Yang IA, Clarke MS, Sim EH, et al. Inhaled corticosteroids for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012;(7):CD002991.22 Glenny AM, Gibson F, Auld E, et al. The development of evidence-based guidelines on mouth care for children, teenagers and young adults treated for cancer. Eur J Cancer. 2010;46(8):1399-1412.33 Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. Accessed June 10, 2015.44 Coughlin CC, Eichenfield LF, Frieden IJ. Diaper dermatitis: clinical characteristics and differential diagnosis. Pediatr Dermatol. 2014;31(Suppl 1):19-24.55 Williams DW, Jordan RP, Wei XQ, et al. Interactions of Candida albicans with host epithelial surfaces. J Oral Microbiol. 2013;5.66 Pappas PG, Kauffman CA, Andes D, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;48(5):503-535.77 Martins N, Ferreira IC, Barros L, et al. Candidiasis: predisposing factors, prevention, diagnosis and alternative treatment. Mycopathologia. 2014;177(5-6):223-240.88 Ray A, Ray S, George AT, et al. Interventions for prevention and treatment of vulvovaginal candidiasis in women with HIV infection. Cochrane Database Syst Rev. 2011;(8):CD008739.

ADDITIONAL READING

Kumar S, Bansal A, Chakrabarti A, et al. Evaluation of efficacy of probiotics in prevention of candida colonization in a PICU-a randomized controlled trial. Crit Care Med. 2013; 41(2):565-572.
Nyirjesy P, Sobel JD. Genital mycotic infections in patients with diabetes. Postgrad Med. 2013;125(3):33-46.
Terai H, Shimahara M. Tongue pain: burning mouth syndrome vs Candida-associated lesion. Oral Dis. 2007;13(4):440-442.

CODES

ICD10

B37.9 Candidiasis, unspecified
B37.0 Candidal stomatitis
B37.49 Other urogenital candidiasis
B37.3 Candidiasis of vulva and vagina
B37.81 Candidal esophagitis
B37.89 Other sites of candidiasis
B37.2 Candidiasis of skin and nail

ICD9

112.9 Candidiasis of unspecified site
112.0 Candidiasis of mouth
112.2 Candidiasis of other urogenital sites
112.1 Candidiasis of vulva and vagina
112.89 Other candidiasis of other specified sites
112.3 Candidiasis of skin and nails

SNOMED

29147005 Mucocutaneous candidiasis (disorder)
79740000 Candidiasis of mouth (disorder)
84679006 Gastrointestinal candidiasis (disorder)
111904009 candidiasis of urogenital site (disorder)
72605008 Candidal vulvovaginitis (disorder)
187014000 Candidiasis of skin and nails

CLINICAL PEARLS

Candidiasis is generally a clinical diagnosis. KOH preparations are a simple confirmatory test in the office setting. Culture and biopsy are rarely needed to identify resistant strains.
Person-to-person transmission is rare.
If tongue pain continues after treatment, consider burning mouth syndrome. Obtain a biopsy if there is concern for oral cancer.
Oral antifungal medications are hepatically metabolized and may have serious side effects.

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