Diagnosis and Treatment of Vulvovaginal Candidiasis

CLINICAL ACTIONS:

Vulvovaginal candidiasis (VVC) presents with symptoms of itching, redness and discharge. Recurrent VVC (RVVC) is diagnosed when women have ≥4 episodes of VVC within 12 months.

• Focus on the following when obtaining the history
  • Location | Duration | Relation to menses | Response to prior treatment and self-treatment | Sexual partners | Contraception
  • Note: Self-diagnosis and telephone diagnosis are unreliable
• Physical exam includes examination of vulva and vaginal vault
  • Signs of inflammation | Ulcers | Excoriation
• Diagnosis
  • Blastospores or pseudohyphae on saline or 10% KOH microscopy or
  • Positive culture in the presence of symptoms suggestive of candidiasis

Note: Diagnosis based on history and physical alone are unreliable |  If pH paper, KOH, and microscopy are not available, FDA approved commercial tests are available

Classification

Classify as uncomplicated or complicated

• Uncomplicated
  • Sporadic or infrequent
  • Candida albicans infection (suspected or proven)
  • Non-immunocompromised
  • Mild/ moderate symptoms and findings
• Complicated
  • Recurrent: ≥4 infections in 12 months
  • Severe symptoms and findings
  • Non-Albicans Candida (NAC)
  • Immunocompromised, including
    • Diabetes | Immunosuppression meds | HIV

SYNOPSIS:

VVC is a common clinical condition with most infections due to C. albicans. Uncomplicated infections respond promptly to 1-,3- and 7- day treatment options (see below).  Complicated/recurrent VVC may require longer duration of treatment and higher doses of medication.  NAC subtypes may be resistant to typical treatment.

KEY POINTS:

• Candida albicans is the most common cause of VVC
• NAC
  • Accounts for an increasing number of cases
  • NAC species include
    • glabrata | C. tropicalis | C. krusei | C. parapsilosis | C. guilliermondii
  • Correct identification is important as NACs have resistance/decreased susceptibilities to commonly used treatment

Treatment

Uncomplicated

• One-day therapy
  • Butoconazole 2% sustained-release cream intravaginally 5 g or
  • Fluconazole 150 mg po (Note – only oral agent) or
  • Miconazole 1,200 mg vaginal suppository or
  • Tioconazole 6.5% ointment 5 gram intravaginally
• 3-day therapy
  • Clotrimazole 2% cream 5 g daily intravaginally or
  • Miconazole 200 mg vaginal suppository daily or
  • Miconazole 4% cream 5 g intravaginally daily or
  • Terconazole 0.8% cream 5 gm intravaginally daily  or
  • Terconazole 80 mg vaginal suppository daily
• 7-day therapy
  • Clotrimazole 1% cream 5 g intravaginally daily or
  • Miconazole 2% cream 5 g intravaginally daily or
  • Miconazole 100 mg vaginal suppository
  • Terconazole 0.4% cream 5g intravaginally daily

Complicated 

• Fluconazole “is an effective and convenient treatment”

Recurrence (Candida albicans)

• Intensive therapy for 7–14 days
• Followed by prolonged treatment with fluconazole (first line)
  • Fluconazole 150 mg weekly for 6 months
• Acceptable alternative prolonged therapy (second line) if patient does not want or cannot tolerate fluconazole
  • Clotrimazole 500 mg weekly or
  • Clotrimazole 200 mg twice a week

Severe Infection (erosions, fissures, edema)

• Acute infection
  • Topical intravaginal azoles for 10 to 14 days or
  • Oral fluconazole every 3 days (day 1, 4 and 7)

If NAC confirmed

• Approximately 50% of patients may respond to topical imidazole treatment
• If unresponsive to topical imidazole treatment use
  • Boric acid 600 mg vaginal capsules daily x 14 days (minimum)
  • Note: Boric acid should not be used during pregnancy or lactation
• If unresponsive patient, should be referred to a subspecialist

Pregnancy

• Topical imidazole therapy for “probably” 7 days (CDC)

Note: Oral fluconazole used at high doses for extended periods of time may be associated with a small increase in birth defects | There have been conflicting studies regarding miscarriage and stillbirth | The FDA did not find conclusive evidence for risk of stillbirth or miscarriage with single 150 mg dose (see ‘Related ObG Topics’ below) | The FDA does “advise cautious prescribing of oral fluconazole in pregnancy”

Other treatments

• Data on the efficacy of the following are currently inconclusive
  • Probiotics | Yogurt | Garlic | Tea tree oil | Low carb diet | Depot medroxyprogesterone | Douching

Learn More – Primary Sources:

ACOG Practice Bulletin 215: Vaginitis in Nonpregnant Patients

An Update on the Roles of Non-albicans Candida Species in Vulvovaginitis

Recurrent Vulvovaginitis

BMJ Clinical Evidence: Candidiasis (vulvovaginal)

CDC STI Treatment Guidelines 2021: Vulvovaginal Candidiasis

BMJ: Recurrent vulvovaginal candidiasis

Is Oral Fluconazole Use in Pregnancy Linked to Stillbirths?

BACKGROUND AND PURPOSE:

• Despite recommendations against oral fluconazole during pregnancy, 4% of pregnant women in the US are still using this medication
• There have been studies associating stillbirth risk with higher doses (>300 mg) but not lower doses (see ‘Related ObG Entries’ below)
• Pasternak et al. (JAMA, 2018) evaluated the association between oral fluconazole use and stillbirth

METHODS:

• Nationwide Retrospective Cohort study
  • Women with singleton pregnancies and stillbirths in Sweden (2006-2104)
• Exclusions included pregnancies missing the following information
  • ID | GA | Nonresidence | Fluconazole or any nonfluconazole oral azole antifungal within 28 days of conception
• Primary outcome: Any fluconazole exposure during pregnancy
  • Stillbirth
  • Neonatal death (0-27 days after live birth)
• Secondary analyses based on dose

RESULTS:

• 1,485,316 pregnancies were included
  • Stillbirth analysis included 10,669 exposed and 106,690 unexposed pregnancies
  • Neonatal outcome analysis included 10,640 exposed and 106,387 unexposed pregnancies
• There were no significant differences when comparing exposed to unexposed
  • Stillbirth: 7 vs 3.6 (per 1000); Hazard ratio [HR] 0.76; 95% CI, 0.52-1.10
  • Neonatal death: 2 vs 1.7 (per 1000); Risk ratio [RR] 0.73; 95% CI, 0.42-1.29
• Dose did not alter lack of association

CONCLUSION:

• There was no association between fluconazole use in pregnancy and increased risk of still birth or neonatal death
• The authors do recommend additional studies and data review prior to changing recommendations

Learn More – Primary Sources:

Oral Fluconazole in Pregnancy and Risk of Stillbirth and Neonatal Death

Are Probiotics Useful for the Treatment of Vulvovaginal Candidiasis?

BACKGROUND AND PURPOSE:

• 70-75% of women will experience vulvovaginal candidiasis (VVC)
• It is difficult to adequately research VVC because it is not reportable and often unconfirmed
• VVC is associated with a decrease in lactobacilli and overgrowth of Candida species
• Probiotics, consisting of bacteria or yeast, are live microorganisms that may provide health benefits and are regulated as dietary supplements and foods
• Probiotics used for prevention and treatement of Candida include
  • Lactobacillus fermentum RC-14 | Lactobacillus fermentum B-54 | Lactobacillus rhamnosus GR-1 | Lactobacillus rhamnosus GG and Lactobacillus acidophilus
• Routes of administration include oral, vaginal or combined
• Xie et al. (Cochrane Database Syst Rev, 2017) sought to determine the effectiveness and safety of probiotics for the treatment of VVC in non-pregnant women

METHODS:

• Systematic Review and meta-analysis
• Literature search, utilizing multiple databases, information from pharmaceutical companies and experts in the field
• Included data from randomized controlled trials (RCT) using probiotics, alone or as adjuvant therapy to antifungal drugs
• Probiotics were included from single or multiple species and in any preparation type/dosage/route of administration
• Primary Outcomes
  • Clinical cure rate: Including both ‘short-term clinical cure rate’ (zero to 14 days after treatment) and ‘long-term clinical cure rate’ (one, three and six months after treatment)
  • Mycological cure rate: Including both ‘short-term mycological cure rate’ (zero to 14 days after treatment)’ and ‘long-term mycological cure rate’ (one, three and six months after treatment)
  • Relapse rate: Symptom recurrence confirmed by microscopic examination or vaginal culture at one, three and six months
  • Rate of serious adverse events
• Secondary Outcomes
  • Time to relapse | non-serious events | need for additional treatment | patient satisfaction | cost effectiveness

RESULTS:

• Data was pooled from 10 RCTs, which all used probiotics as adjuvant therapy to antifungal drugs
• Women were between the ages of 16 and 50
• Women did not have recurrent VVC, diabetes or immunosuppressive disorders or using immunosuppressive medications
• Adjuvant probiotics vs conventional antifungal drugs alone
  • Improved the short-term clinical cure rate
    • Risk Ratio (RR) 1.14, 95% CI 1.05 to 1.24; 5 trials, 695 participants
  • Improved the short-term mycological cure rate
    • RR 1.06, 95% CI 1.02 to 1.10; 7 trials, 969 participants
  • Decreased the relapse rate at one month
  • RR 0.34, 95% CI 0.17 to 0.68; 3 trials, 388 participants
• Probiotics did not impact long term clinical cure or mycological cure
• Probiotics were not associated with serious adverse outcomes
• Additional research is needed to assess probiotic impact on first relapse, need for additional treatment, patient satisfaction and cost effectiveness

CONCLUSION:

• The use of probiotics as adjuvant therapy increases rates of clinical and mycological cure while not increasing serious risk
• The authors strongly caution that the primary studies used in this analysis were generally of low and very low quality and further research is still required

Learn More – Primary Sources:

Probiotics for vulvovaginal candidiasis in non-pregnant women.

 

Diagnosing Vaginitis – Why the Office Visit Still Matters

CLINICAL ACTIONS:

A patient presents with vaginal inflammation with discharge, pain and/or itching. Next steps should include

Problem-focused history

• BV
  • Fishy odor | Thin homogeneous discharge (possibly worse after intercourse)
• Candidiasis
  • No odor | White, thick, ‘curdlike’ or ‘cheesy’ discharge | Itching and/or burning
• Trichomoniasis
  • Foul odor | Green or yellow, frothy discharge | Vaginal pain or soreness
• Atrophic vaginitis
  • Thin, clear discharge | Dryness | Dyspareunia | Itching
• Irritant/allergic vaginitis
  • Burning and/or soreness
• Desquamative Inflammatory vaginitis
  • Green or yellow (purulent) discharge | Burning | Dyspareunia

Exam including inspection of the vulva, vagina and cervix

• BV
  • Inflammation not usually present
• Candidiasis
  • Erythema | Edema
• Trichomoniasis
  • Inflammation | Strawberry Cervix
• Atrophic vaginitis
  • Inflammation | Thin/friable mucosa
• Irritant/allergic vaginitis
  • Erythema
• Desquamative Inflammatory vaginitis (DIV)
  • Varying vestibular and vaginal erythema

Appropriate laboratory testing

• Collection of and microscopic examination of a 10% KOH and saline prep (wet mount), pH testing and ‘whiff test’ constitute the office-based clinical testing of samples
• Culture (if necessary)
  • Yeast: Obtain if recurrent candidiasis or possible non-albicans Candida (suspect if blastospores ‘only’ or persistent treatment after treatment) | Negative microscopy with signs and/or symptoms of candidiasis
  • Trichomoniasis: ACOG recommends culture with a negative wet mount in the following circumstances
    • Persistent symptoms following treatment | high vaginal pH and WBCs on microscopy | Pap suspicious for T. vaginalis | patient desire for screening
    •  Note: CDC considers NAAT screening more sensitive for T. vaginalis then culture (previous gold standard) or wet mount
  • Mucopurulent cervicitis: Test (DNA or cultures) for gonorrhea or chlamydia
  • HSV: If any vulvar fissure/lesion suggestive of herpes simplex virus, perform viral culture or PCR assay for HSV DNA by swabbing the lesion
    • Type-specific HSV serologic assays might be useful in the following scenarios: 1) recurrent genital symptoms or atypical symptoms with negative HSV PCR or culture; 2) clinical diagnosis of genital herpes without laboratory confirmation (CDC STD Guidelines)

Perform “Whiff Test” with 10% KOH and Microscopy with Saline

• Positive whiff test
  • Negative (-) for WBC: Treat for bacterial vaginosis (BV)
  • Positive (+) for WBC: Review signs/symptoms for trichomoniasis or mixed bacterial vaginosis or cervicitis
• Negative whiff test
  • negative (-) for WBC: Noninfectious

Determine Vaginal pH

• If pH is normal (<4.7) consider the following
  • Infectious: Vulvovaginal candidiasis | Genital herpes
  • Noninfectious: Physiologic leukorrhea | Vulvodynia | Dermatitis/dermatoses

If pH is Elevated (>4.7) Consider the Following

• Infectious
  • Bacterial vaginosis | Trichomoniasis | Cervicitis
• Noninfectious
  • Blood | Semen | Atrophic vaginitis | Lichen planus | Desquamative inflammatory vaginitis (DIV)

SYNOPSIS:

Vaginitis is a general term for disorders of the vagina, but does not indicate the underlying cause.  Vaginitis may result from infection, inflammation, or may reflect changes in the normal vaginal microbiome.  The disorder is termed vulvovaginosis when the vulva is involved. When patients present with symptoms of itching/burning/irritation/dyspareunia/discharge consider a broad range of possibilities including but not limited to the triad of bacterial vaginosis (BV), trichomoniasis and vulvovaginal candidiasis.  Office based tests such as those above also have a low sensitivity. Accurate diagnosis may require a combination of a careful history, vulvar or vaginal biopsy and appropriate culture.

KEY POINTS:

• Self-diagnosis and treatment, while convenient, may be unreliable and results in frequent misuse of OTC products
• FDA approved commercial tests for BV
  • ACOG acknowledges that direct DNA probe assays for G vaginalis or chromogenic point-of-care assays for sialidase activity have acceptable performance vs Amsel criteria and Nugent scoring
  • However, because these tests only pick up one organism (i.e., G vaginalis) “the diagnostic utility of a test that identifies only a single organism (eg G vaginalis) is still being investigated and is not currently supported”
• No microscope
  • Vaginal pH testing narrows the differential diagnosis of vaginitis for BV and trichomoniasis
  • Candidiasis: History | Exam | Culture
  • Obtain vaginal secretions slide for future Gram stain if possible
• Incidental findings on Pap test
  • Not diagnostic
  • BV on Pap
    • Symptomatic: pH, amine test, and wet mount
    • Asymptomatic: Do not treat
  • Trichomoniasis on Pap
    • High false-positive rate (8% standard and 4% liquid-based)
    • Wet mount for confirmation
    • If wet mount negative, NAAT or culture
    • If diagnostic tests not available, can consider metronidazole, but high rate of unnecessary treatment

Learn More – Primary Sources:

ACOG Practice Bulletin 215: Vaginitis in Nonpregnant Patients 

Vaginitis: Diagnosis and Treatment

Advances in Diagnosing Vaginitis: Development of a New Algorithm