The diagnosis of a C albicans infection requires identification of the organism on a microscopic examination of vaginal secretions, a positive culture or positive molecular studies. The diagnosis cannot be made by history alone, and erythema, fissures, and satellite pustules or collarettes can be caused by other conditions such as inverse psoriasis. The organism can be identified on a microscopic smear, where a drop of vaginal fluid is placed on the microscope slide, and a drop of KOH is added to dissolve skin cells, leaving the buds, hyphae, and pseudohyphae. However, the ease of this examination is generally underestimated by the nondermatologist; when the index of suspicion is high but a smear is negative or a smear is positive but the patient does not improve as expected, a vaginal culture or molecular studies should be performed.
The identification of non-albicans Candida
on microscopic smear is much more difficult the first time an examiner finds it on wet mount or fungal preparation, since only buds are seen. Only C albicans
and C tropicalis
exhibit hyphae, pseudohyphae, and budding yeasts that are normally seen with the 10× objective (Fig. 14-4
). Non-albicans Candida
infections reveal only small, budding yeasts that can be seen best with the 40× objective (Fig. 14-5
). However, a non-albicans Candida
infection usually exhibits multiple budding yeasts, so nearly every field shows at least one yeast form. This author finds presence of non-albicans Candida
far more easily identified on a wet mount rather than a smear treated with potassium hydroxide. Debris from the lysis of cells by potassium hydroxide obscures the small budding yeasts.
Molecular testing with a screen for vaginal organisms also confirms this diagnosis and often yields the species, but the cost is generally significantly higher. A culture provides the most information, with sensitivity and speciation in the case of non-albicans Candida.
Fig. 14-4. A fungal preparation of Candida albicans of the vagina shows branching hyphae and pseudohyphae.
Fig. 14-5. Non-albicans Candida shows only budding yeast without mycelia. This wet mount exhibits the fairly large round buds of Saccharomyces.
Biopsies of yeast vaginitis are performed only if the diagnosis is not suspected by the clinician, because less expensive and less painful methods of diagnosis are usual. However, a typical tissue sample of acute vaginal candidiasis reveals inflammation consisting primarily of lymphocytes with some plasma cells and neutrophils, as well as stromal edema and spongiosis. Fungal elements are often seen within the most superficial portions of the vaginal epithelium. Less inflammation is seen in chronic candidiasis.
C albicans vaginitis often coexists with, precipitates, and drives eczema. Therefore, C albicans vaginitis should be considered in the differential diagnosis of eczema or any other itchy vulvovaginal disease. Vulvar psoriasis, contact dermatitis, and lichen sclerosus are other pruritic dermatoses that are often misdiagnosed as and often coexist with Candida vulvovaginitis.
Non-albicans Candida infection is nearly always asymptomatic. This rarely produces irritation or burning, so vulvodynia is often mistaken for non-albicans candidiasis. However, documented non-albicans candidiasis is generally coincidental rather than causative, and when the infection clears, symptoms persist.
The most common cause of vulvovaginal yeast infections is C albicans
, representing about 85% of yeast infections.4
Most U.S. providers do not find that non-albicans Candida
infections represent this large proportion of yeast infections, but the fact that non-albicans Candida
is usually asymptomatic leads to underdiagnosis. In Europe, C albicans
accounts for 95% of yeast species.5
The simple presence of C albicans
does not provide a diagnosis of Candida
vaginitis. Nonculture testing for Candida
shows the presence of yeast in more than 60% of premenopausal, nonpregnant women, with cultures positive in about 20% of immunocompetent women and 30% of immunocompromised patients.5
A yeast infection generally is produced by higher numbers of organisms and an inflammatory response to these organisms. Cutaneous vulvar candidiasis is associated with superficial invasion of the epithelium by yeast.
Risk factors for VVC, in addition to virulence factors of the yeast organisms, include immunosuppression by virtue of illness or medications, poorly controlled diabetes mellitus, sexual activity, oral sex, spermicides, condoms, and high estrogen states to include high estrogen oral contraceptives, pregnancy, and estrogen replacement. The oral sodium-glucose cotransporter-2 (SGLT-2) inhibitors for diabetes, empagliflozin (Jardiance), canagliflozin (Invokana), dapagliflozin (Farxiga), and ertugliflozin (Steglatro) have been associated with an increase in genital candidiasis in both men and women, because these medications produce glycosuria. Antibiotics increase both colonization and infection with yeast, but the reason is not clear.6
It does not appear that the cause is elimination of lactobacilli, since candidiasis occurs primarily in the presence of lactobacilli. Women with abundant lactobacilli have a four times higher likelihood of a Candida
Recently, the role of the vaginal biofilm produced by Candida
has become recognized as a factor in virulence of the yeast, and protection of the yeast leading to poor responses to antifungal therapy, unrelated to specific drug resistance.8
There are multiple effective, inexpensive, well-known, and safe options, both oral and topical, for treating C albicans
vaginitis. These include over-the-counter and prescription medications, both off-label and approved for candidiasis by the Food and Drug Administration (FDA). These medications are roughly equal in effectiveness for C albicans
and differ by price, convenience, patient preference, and tolerability. Both the Centers for Disease Control and Prevention (CDC)9
and the Vulvovaginal Yeast App developed by the International Society for the Study of Vulvovaginal Disease ($4.99 at the App store) are convenient and detailed sources for the treatment of uncomplicated and complicated vulvovaginal yeast infections. The latter discusses management for each of the major non-albicans Candida
Topical antifungal medications are available over the counter. Miconazole and clotrimazole are topical agents available over the counter as creams or tablets, ranging from a one dose formulation up to 7-day dosing. Tioconazole is available over the counter as a one dose cream or ointment. Butoconazole (1- and 3-day vaginal cream) and terconazole (3- and 7-day cream and 3-day suppositories) are topical agents available by prescription. The topical creams, especially those that are 1-day or 3-day formulations, may be irritating for those women who are especially inflamed, so either nystatin ointment or oral therapy is preferred in those patients. Nystatin ointment is no longer available as vaginal tablets, so the ointment can be inserted, 100 000 units once or twice a day for 1-2 weeks. Or, nystatin vaginal suppositories can be compounded. With these topical preparations, the creams and ointments can be applied to the involved vulvar skin as well twice a day until the patient is comfortable.
Oral therapy has the advantage of avoiding irritation from the alcohols, preservatives, and stabilizers in topical creams, and it also has the benefit of treating both the vulva and vagina simultaneously, although many providers add a topical agent when there is marked vulvar involvement. Until recently, fluconazole was the only oral medication with FDA approval for vaginal candidiasis, although is itraconazole is known to be effective, as is ketoconazole. However, ketoconazole is no longer used for this condition, since it has specifically been withdrawn by the FDA for the indication of superficial fungal infections because of the risk of idiosyncratic hepatotoxicity, and the fact that fluconazole is equally effective but safer. The dose for an uncomplicated vulvovaginal C albicans
infection is 150 mg once, although a repeat in 3 days is commonly prescribed. When larger numbers of tablets are prescribed, such as for suppression for frequently recurrent infection, the 200 mg size generally is inexplicably less expensive per tablet. The most common side
effects of fluconazole are headache, occurring in about 13% of patients (as compared with 7% of those receiving placebo), and nausea, occurring in 7% of patients. Itraconazole is another oral azole that has similar efficacy to one fluconazole tablet in uncomplicated vaginal candidiasis at a dose of two 100-mg capsules twice in 1 day, but it does not have indication approval for vulvovaginal candidiasis.10
The average patient with C albicans vaginitis experiences resolution of symptoms within 2 or 3 days. Patients who have had severe vulvovaginal candidiasis can require longer time for their symptoms to resolve.
Patients who do not clear with these standard therapies most often do not have resistant candidiasis
but rather have symptoms that are not due to yeast. In immunocompetent patients, symptoms of C albicans
that do not clear are most often associated with vulvodynia or dermatoses such as lichen simplex chronicus or lichen sclerosus. Despite the frequent use of empiric anticandidal therapy and long-term suppressive use of fluconazole, resistant C albicans
is not a common clinical issue in the usual outpatient setting.5
However, some patients have complicated vaginal candidiasis, defined as three or more episodes of vaginal yeast per year, an unusually severe episode of vulvovaginal yeast with vulvar redness, fissures, and erosions, candidiasis in an immunosuppressed patient, or a non-albicans Candida
infection. These patients generally require therapy beyond the standard discussed above, and the reader is again referred to the CDC site regarding complicated yeast therapy, and in more detail on the Vulvovaginal Yeast App. Patients who simply experience frequent C albicans
infections generally experience suppression of yeast with weekly fluconazole 150 mg, rarely requiring twice weekly dosing. Again, the use of fluconazole 200 mg rather than 150 mg is less expensive. Also, because fluconazole is only FDA approved as a one-time dose for uncomplicated candidiasis, the use of the 200 mg preparation avoids the issue of pre-authorization for off-label use of multiple doses. When symptoms persist despite weekly dosing, cultures should be performed to ensure that persistence of yeast is the cause of the patients’ symptoms. When cultures are positive despite twice-weekly dosing of fluconazole, both cultures and sensitivities should be obtained. Whereas ongoing weekly fluconazole generally suppresses candidiasis, it is not curative, and discontinuation usually results in recurrence of yeast.11
For patients whom fluconazole is not an option, either because of allergy, side effects, or potential medication reactions, a topical medication to clear the infection, when inserted two or three times a week is usually equally efficacious.
In vitro sensitivities do not correlate directly to clinical responses to antifungal therapy and should not be obtained routinely in clinical practice, but only for those patients with C albicans who do not respond to aggressive routine therapy. The pH of the vagina is different than that used during laboratory testing, which is one reason that clinical response may not mirror that expected from in vitro sensitivities. However, if the in vitro testing shows resistance to a medication, that medication will not be useful.
Women who exhibit severe vulvar candidiasis with extensive redness and fissuring should receive a topical vulvar antifungal therapy as well as vaginal therapy. Nystatin ointment applied three or four times a day is arguably the most soothing preparation. These patients may require longer than usual standard therapy.
Patients who are immunosuppressed, especially those with HIV disease, are more likely to require longer antifungal therapy, chronic suppression, and more likely to experience resistant Candida
infection. Therefore, immunosuppressed patients who remain symptomatic following therapy lasting 2 weeks rather than 1 week should be re-evaluated with cultures and sensitivities. The standard next step when oral or topical azoles are not sufficient is the use of vaginal boric acid 600-mg capsules inserted once or twice a day for 2 or more weeks. These are poisonous if swallowed. A recently approved oral anticandidal therapy unrelated to fluconazole is ibrexafungerp; in vitro
studies suggest that it may prove useful for resistant C albicans
in immunosuppressed patients, as well as nonalbicans
The role of lactobacilli (probiotics) in the treatment is controversial with no definitive data at this time.13
Unfortunately, most non-albicans Candida
infections are clinically resistant to usual therapies, especially those caused by C glabrata
, C krusei
, and S cerevisiae
, despite in vitro
sensitivities that may indicate sensitivity to these medications. These yeast forms sometimes are extraordinarily difficult to eradicate (Table 14-1
). Although an azole can be tried first for these non-albicans Candida
infections (except C krusei
, which is always resistant to azoles), patients should be advised that their infection likely will not clear. The occurrence of resistant non-albicans Candida
organisms is related to characteristics of the organism rather than the presence of immunosuppression in the host.
TABLE 14-1 Therapies for Recalcitrant Non-albicans Candida Vaginal Infections
Boric acid vaginal capsules
600 mg inserted bid ×2-4 wk
Primary medication used for azole-resistant infection; inexpensive, usually effective
Sometimes irritating, poisonous if ingested orally
Nystatin vaginal suppositories or ointment
Insert bid ×1 mo
1% solution painted in the office weekly, or
0.5 cc onto tampon inserted for 3-4 h twice a day up to 12 d
Often effective medication
Can produce erosive contact dermatitis, stains skin, clothing, bathroom fixtures, exam tables
Flucytosine fourteen 500-mg capsules dissolved in 45 g of hydrophilic cream base
6.4 g inserted hs × 1-2 wk
Well tolerated, effective
Amphotericin suppositories 50 mg
Insert hs for 2-4 wk
Expensive, can be irritating
Amphotericin/flucytosine vaginal suppositories
Expensive, can be irritating
a All are often ineffective, and often several in sequence or together must be used for the best chance of success.
b All except nystatin are unavailable commercially and must be compounded, and nystatin suppositories must be compounded.
First-line treatment for non-albicans Candida
infections resistant to azole therapy is boric acid capsules, which are prescribed by instructing a pharmacist to place 600 mg of boric acid in a gelatin capsule.14
This capsule is inserted in the vagina daily for 2 weeks. Boric acid capsules are irritating in some patients, particularly those who are already irritated by their infection. Most women experience significant improvement but not necessarily cure, with symptoms recurring off therapy, requiring maintenance therapy with boric acid. Nystatin vaginal tablets or ointment are sometimes more beneficial than azoles.
Also used is intravaginal flucytosine. Fourteen 500-mg capsules of flucytosine are dissolved in 45 g of a hydrophilic cream base, and a 6.4-g vaginal applicator filled with cream is inserted in the vagina daily for a week. This can be extremely expensive but the price fluctuates. Resistance occurs quickly.
Compounded 50 mg amphotericin vaginal suppositories inserted nightly represent still another alternative, but there are no data on the effectiveness of intravaginal amphotericin. There are several recipes for these suppositories, and these are generally available from any compounding pharmacy.
Gentian violet is a traditional potent fungicidal substance that is rarely used for practical reasons. This is an extreme irritant in some patients, occasionally producing even blisters and erosions. It is also extremely messy and causes permanent purple staining of clothes, furniture, and bathroom fixtures. One regimen consists of a weekly application of a 1% solution painted onto the vaginal walls with a saturated gauze swab in the office. However, to avoid the occasional blistering reaction to the 1% concentration of gentian violet, I use a 0.25% solution for the first treatment, followed by 0.5% a few days later, and then 0.75% solution before graduating to a full 1.0% solution. Medication is applied weekly in the office for 4-6 weeks. Far less burdensome for the provider’s office, is the use of tampons as a delivery system. Gentian violet 1%, 0.5 cc, is applied to a tampon, which is inserted and left in place for 3-4 hours once or twice a day for up to 12 days.
Combinations of therapies may logically be useful, but there are no confirmatory data. Also, there are few data on these alternative therapies even singly for complicated yeast infections.15
In addition, ibrexafungerp, as noted above, is a novel oral triterpenoid antifungal therapy, the first of a new class of anticandidal agents to received FDA approval in decades. This medication shows promise against C glabrata in vitro
, but it remains to be seen if this translates into a useful medication in vaginal non-albicans Candida