Candida Vulvovaginitis

1. See also
   1. Vaginitis
2. Epidemiology
   1. Candida Vulvovaginitis accounts for 45% of Vaginitis
   2. Candida is cultured in 20-50% asymptomatic women
   3. Vaginitis often self diagnosed incorrectly
3. Etiology
   1. Acute: Candida albicans (90%)
      1. Normal commensal organism in vagina
      2. Infection when Corynebacterium suppressed
   2. Recurrent Vulvovaginal Candidiasis (4 or more episodes in a year)
      1. Candida glabrata (increasing Incidence, now 15%)
      2. Candida tropicalis
      3. Candida parapsilosis
      4. Candida krusei (responds to Topical Antifungals, but not to Fluconazole)
      5. Saccharomyces cerevisiae
4. Risk Factors
   1. Immunosuppression
      1. Diabetes Mellitus (esp. Uncontrolled)
      2. Depressed cell mediated Immunity (e.g. HIV or AIDS)
   2. Medications
      1. Corticosteroids
      2. Immunosuppressant Medications
      3. Broad spectrum antibiotics
      4. Oral Contraceptives
         1. Increases frequency of Candida carrier state
         2. Does not increase symptomatic Vulvovaginitis
   3. Heat and moisture retaining clothing (e.g. nylon)
   4. Pregnancy (and other hyperestrogenic states)
   5. Premenstrual phase of the Menstrual Cycle
   6. Obesity
5. Symptoms
   1. Asymptomatic in 20-50% of women
   2. Intense vaginal or Vulvar Pruritus (50% of cases)
   3. Vulvar Burning, soreness, or irritation
   4. Thick white curd-like or "cottage cheese" discharge
   5. No odor
   6. Dyspareunia
   7. Dysuria (33% of cases)
6. Signs
   1. Adherent white cottage-cheese discharge in vagina
      1. Sensitivity: 50%
      2. Specificity: 90%
   2. Vulvar erythema and edema (24% of cases)
7. Labs: Initial
   1. KOH Preparation (10%)
      1. Test Sensitivity: 50%
      2. Pseudohyphae or budding yeast forms
      3. 
   2. Vaginal pH <4.5 (Normal acidity)
   3. Absent Amine odor
   4. White Blood Cells not increased
   5. Wet-Prep is not sensitive or specific for yeast
      1. Bornstein (2001) Infect Dis Obstet Gynecol 9:105-11 [PubMed]
   6. Candida on Pap Smear
      1. Specific but very low Test Sensitivity
8. Labs: Complicated cases
   1. Indications: Complicated Vulvovaginal Candidiasis
      1. Recurrent candida Vaginitis (4 or more episodes in a year) OR
      2. Severe candida infections OR
      3. Immunocompromised patients (AIDS, poorly controlled Diabetes Mellitus)
   2. Fungal Culture positive
      1. Fungal Culture is rarely performed in typical cases (fungal PCR preferred)
      2. Fungal Culture may be helpful in complicated cases
         1. Confirm asymptomatic carrier of vaginal Candida
         2. Identify cause of recurrent Vaginitis (e.g. Candida Glabrata)
   3. DNA probe or PCR for candida
      1. Consider in cases refractory to standard therapy
9. Differential Diagnosis (Consider for refractory cases)
   1. Other Vaginitis cause
      1. Bacterial Vaginosis
      2. TrichomonasVaginitis
   2. Infectious Cervicitis (Sexually Transmitted Infection)
   3. Allergic Vaginitis or Vulvitis
   4. Vulvodynia
   5. Herpes Simplex Virus
      1. HSV presents with unilateral painful lesions
      2. Contrast with bilateral, symmetric involvement in Candida Vulvovaginitis
10. Management: OTC Local First-Line Agents
    1. Precautions
       1. In pregnancy, limit to topical azole preparations (Miconazole, Clotrimazole) used for 7 days (lower concentrations)
    2. Miconazole (Monistat)
       1. Miconazole (Monistat-7) 2% cream PV qhs for 7 days
       2. Miconazole (Monistat-3) 4% cream, 5 g PV qhs for 3 days
       3. Miconazole Vag tabs 100mg PV qhs for 7 days
       4. Miconazole (Monistat-3) 200mg PV qhs for 3 days
       5. Miconazole 1200 mg vaginal tab PV qhs, 1 dose
    3. Clotrimazole (Gyn-Lotrimin, Mycelex G)
       1. Clotrimazole 1% cream qhs for 7 days
       2. Clotrimazole 2% cream qhs for 3 days
       3. Clotrimazole 200 mg vaginal tab PV qhs for 3 days
       4. Clotrimazole 100 mg vaginal tab PV qhs for 7 days
       5. Clotrimazole 500 mg vaginal tab PV qhs, 1 dose
    4. Terconazole (Newer, binds better to Candida)
       1. Vagistat-1 6.5% ointment, 5 g intravaginally once
          1. Highly effective and less irritating than creams
11. Management: Prescription Local First-Line Agents
    1. Butoconazole (Femstat)
       1. Mycelex-3 5g of 2% Cream PV QHS for 3 days
       2. Gynezole-1 (sustained release, bioadhesive) 5 g of 2% cream once intravaginally
    2. Terconazole (Newer, binds better to Candida)
       1. Terazol 80 mg vaginal suppository PV for 3 days
       2. Terazol-3 (0.8%) 5 g vaginal cream for 3 days
       3. Terazol-7 (0.4%) 5 g vaginal cream qhs for 7 days
    3. Nystatin
       1. Nystatin vaginal tablet (100,000 unit) PV daily for 14 days
       2. Nystatin ointment (100,000 units/g)
          1. Ointments are less irritating than creams
12. Management: Oral Agents
    1. Fluconazole 150 mg PO for 1 dose
       1. As effective as Clotrimazole PV
       2. Do not use in pregnancy
          1. Evidence of Miscarriage risk, with even 1-2 doses
          2. Mølgaard-Nielsen (2016) JAMA 315(1):58-67 +PMID:26746458 [PubMed]
       3. Consider repeat scheduled treatment for persistent symptoms
          1. Consider prescribing Fluconazole 150 mg every 3 days for up to 3 doses for persistent Vaginitis symptoms
       4. Symptom improvement delayed for 24 hours with Fluconazole
          1. Consider concurrently treating with Nystatin ointment (100,000 units) for the first several days (least irritating)
       5. Higher mycologic cure rates in the short term (NNT 30) and long term (NNT 19) compared with intravaginal agents
       6. References
          1. (1994) Med Lett Drugs Ther 36(631): 1-2 [PubMed]
          2. Denison (2020) Cochrane Database Syst Rev (8): CD002845 [PubMed]
    2. Brexafemme (Ibrexafungerp)
       1. Dosing: 150 mg tablet with two tablets (300 mg) taken in 2 doses at 12 hours apart (total course: 600 mg)
          1. Reduce dose to 150 mg every 12 hours for 2 doses if taking strong CYP3A4 inhibitors (e.g. Ketoconazole, Clarithromycin)
       2. Consider in recurrent candida Yeast Vaginitis refractory to repeat Fluconazole dosing
       3. Cost is nearly 50 fold higher than generic Fluconazole (approxmately $500 for 2 doses)
       4. Marketed as fungicidal against yeast (in contrast to fungistatic azoles such as Fluconazole, Clotrimazole)
          1. However, in practice, first-line azoles are 80-90% effective for definitive resolution
       5. Contraindicated in pregnancy
          1. Use reliable Contraception during treatment and for 4 days after last dose
       6. Adverse effects include Nausea, Abdominal Pain and Diarrhea
       7. References
          1. (2021) Presc Lett 28(9): 49-50
          2. Woolfolk (2022) Am Fam Physician 106(3): 324-6 [PubMed]
13. Management: Recurrent or resistant Treatment
    1. Precautions
       1. Avoid treating asymptomatic carriers (may be normal flora in some patients)
       2. Consider risk factors above
       3. Consider Fungal Culture and exam timing before and after treatment
          1. Baseline
          2. Two weeks (after treatment regimen above)
          3. Three months
          4. Six months (when stopping prophylaxis)
    2. Any of above intravaginal meds (e.g. Clotrimazole) for 14-21 days
       1. Consider maintenance after initial daily regimen (see below)
       2. Consider Terconazole (see above)
          1. More effective against other candida species
    3. Fluconazole (Diflucan)
       1. Less effective for non-albicans Candida (e.g. Candida Glabrata)
       2. Dose 1: 150 mg orally
       3. Dose 2: 150 mg PO at 72 hours after first dose
       4. Consider a 3rd dose at 72 hours after second
       5. Consider, repeat dosing once weekly for up to 6 months (See below for maintenance protocol)
       6. Sobel (2001) Am J Obstet Gynecol 185:363-9 [PubMed]
    4. Other options (many with increased toxicity and risk)
       1. Itraconazole (Sporanox) 200 mg PO qd for 3 days
       2. Gentian Violet vaginal staining 1-2x (Office charge)
       3. Boric Acid 600 mg vaginal tab bid for 14 days
          1. Use is controversial, but may be considered in refractory non-albicans candidal infection (e.g. Candida Glabrata)
          2. Sobel (2003) Am J Obstet Gynecol 189(5): 1297-1300 [PubMed]
       4. Flucytosine (Ancobon) cream applied to affected area
       5. Ketoconazole (Nizoral) 200 mg orally twice daily for 5-14 days
          1. Avoid oral Ketoconazole due to hepatotoxicity
14. Management: Prophylaxis or Maintenance Protocol
    1. Indication
       1. Three to Four or more vaginal yeast infections per year
    2. Topical Antifungal Protocol
       1. Repeat application once or twice weekly for 6 months
       2. Consider using monthly at time of Menses
       3. Clotrimazole 500 mg vaginal tab weekly to montly
       4. Miconazole 100 mg vaginal tab qhs twice weekly
    3. Fluconazole Protocol
       1. Initial treatment: Fluconazole (Diflucan) 150 mg orally every 3 days for 3 doses
       2. Maintenance
          1. Fluconazole (Diflucan) 150 mg orally each week
          2. Monitor liver enzymes (consider every 1-2 months)
       3. Efficacy
          1. Suppression while on treatment: 90%
          2. Following treatment: Infection recurs in 60%
       4. References
          1. Sobel (2004) N Engl J Med 351:876-83 [PubMed]
    4. Oteseconazole (Vivjoa)
       1. No evidence of benefit over other less expensive, less risky Antifungal options above
       2. Expensive ($2700 per course)
       3. Teratogenic for up to 2 years after use in animal studies
          1. Do NOT Use in any woman of child bearing potential
          2. Limit to post-menopausal women or who are permanently infertile
       4. References
          1. (2022) Presc Lett 29(9): 53
15. Prevention
    1. Control predisposing condition (e.g. Diabetes Mellitus)
    2. Reduce predisposing medications (e.g. Corticosteroid)
    3. Avoid moisture-retaining products near vagina
       1. Nylon underwear
       2. Panty-liners
       3. Vaginal Lubricants or Spermicides
    4. Lactobacillus (Probiotic) is not effective
       1. Does not prevent post-antibiotic Vaginitis
       2. Pirotta (2004) BMJ 329:548-51 [PubMed]
16. References
    1. Desai (1996) Am Fam Physician 54(4):1337-40 [PubMed]
    2. Hainer (2011) Am Fam Physician 83(7): 807-15 [PubMed]
    3. Nyirjesy (2001) Am Fam Physician 63(4):697-702 [PubMed]
    4. Paladine (2018) Am Fam Physician 97(5): 321-9 [PubMed]
    5. Sobel (1998) Am J Obstet Gynecol 178:203-11 [PubMed]
    6. Tobin (1995) Am Fam Physician 51(7):1715-20 [PubMed]