C albicans and Candida tropicalis usually present with symptoms of itching, sometimes with burning and vulvar dysuria as well. Although C albicans vaginitis classically is accompanied by a white, clumped, cottage cheese-like discharge that is often not particularly copious, vaginal secretions frequently appear normal clinically. Vestibular erythema is usual, and some patients develop more extensive erythema, skinfold fissures, and scale, as well as peripheral satellite pustules, erosions, or collarettes (Fig. 14-3). VVC classically occurs or flares during menses and following sexual activity. Rarely, remarkable, immediate edema occurs with sexual intercourse.

Vaginitis produced by non-albicans yeast, including Candida glabrata, Candida parapsilosis, Candida krusei, and Saccharomyces cerevisiae, comprise about 15% of all yeast infections.⁴ These are overwhelmingly asymptomatic. If symptoms occur, women generally report irritation and burning more than itching. Vaginal secretions in women with non-albicans Candida infections are clinically unremarkable, and redness, fissures, and satellite pustules are absent.

Complicated VVC is defined as severe nonalbicans Candida infection or recurrent VVC. Four or more episodes of documented Candida infections identify recurrent VVC.

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.

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 infection.⁷

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 species.

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 yeast forms.¹²

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.

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 infections.¹⁶

Trichomonas vaginitis produces extreme itching and irritation. Dysuria and lower abdominal pain are common, and most patients experience a copious yellow or green vaginal discharge.

Bright red erythema of the vestibule is usual on physical examination. The vagina is inflamed as well, and although a “strawberry” cervix with discrete, punctate, bright red, and hemorrhagic macules and papules is classic, this appearance is by no means sensitive or specific. A copious, yellow or greenish, vaginal discharge is typical. The vaginal pH is higher than normal, as occurs with most extremely inflammatory vaginal diseases and cervicitis characterized by an absence of lactobacilli.

Trichomonas can occur in men, where it remains a reservoir for infection, but it is generally asymptomatic. A purulent urethral discharge occurs in some patients.

Risk factors include the presence of bacterial vaginosis, poverty, multiple sex partners, and a history of incarceration.¹⁷

In the past few years, the Trichomonas vaginalis virus has been described and reported discovered in 40% of 355 isolates of archived frozen T vaginalis in Birmingham, AL.¹⁸ However, this did not correlate with symptoms, clinical course, or resistance, suggesting that the virus is commensal.

This diagnosis often is made on a wet mount if it is examined immediately under high power. When identified, the trichomonads are obvious and the specificity is 100%. These flagellate organisms are teardrop shaped, and they are extremely active, so their motion is not missed easily, and neutrophils are abundant (Fig. 14-6). However, the absence of trichomonads in no way rules out the diagnosis. As trichomonads cool, they lose their characteristic teardrop shape, becoming round and still, making differentiation from lymphocytes very difficult. The sensitivity of a microscopic examination varies from about 44% to 68%.¹⁹ Therefore, when there is a high index of suspicion, cultures or DNA probes are indicated in the absence of a positive wet mount, with molecular studies being the most sensitive.²⁰ Although less sensitive, a thin prep Papanicolaou test showing the presence of trichomonads generally correlates with the presence of infection, although the accuracy is dependent upon the expertise of the examiner.²¹ There are no specific histologic findings on biopsy.

The differential diagnosis of Trichomonas vaginitis includes all causes of a purulent vaginitis, including desquamative inflammatory vaginitis (DIV) and inflammation associated with an atrophic vaginal epithelium, an intravaginal foreign body, or any erosive vaginal skin disease.

Trichomoniasis is caused by the protozoan T vaginalis. This disease is always sexually transmitted. The vagina is the primary area of involvement, but the organism is sequestered in other areas in both men and women, including the paraurethral ducts, the urethra, and Skene glands. Circumcision reduces infection rate with trichomonads in men, and this disease can be prevented by the use of condoms. Risk factors include the presence of an intrauterine device and older age in women.²²

Trichomoniasis should be treated orally because topical therapies do not eliminate organisms sequestered within the urethra and paraurethral ducts. In addition, sex partners must be treated to prevent immediate reinfection. Oral metronidazole, at a dose of 500 mg twice a day for 1 week is the treatment of choice and is superior to the single 2-g dose, which is also advocated.²³ The widely held belief in the disulfiramlike effect of metronidazole with alcohol consumption is erroneous, based on no scientific or theoretic data considering the mechanism of action of both metronidazole and tinidazole.²⁴ Individual case reports of this can be ascribed to effects of the alcohol or metronidazole alone, so there is no need to avoid alcohol with these medications, in some patients, although this is actually uncommon and poorly documented. Tinidazole is better tolerated with slightly higher cure rates.

Although treatment failure is discussed as an increasing issue, this is actually uncommon, with most “resistant” trichomonas due to reinfection. A large survey recently did not find prospective studies that confirm high levels of drug resistance, and very little in the way of high level in vitro resistance, although clinical resistance was widely reported.²⁵

Old studies showed that resistance to metronidazole is present in 4%-10% of cases and to tinidazole in 1% of patients.¹⁷ Often, high-dose therapy overcomes this resistance, and first-line therapy consists of high-dose metronidazole or tinidazole.^26,27 Other therapies include combination therapies, including high-dose tinidazole with intravaginal paromomycin cream, intravaginal boric acid, and intravaginal metronidazole/miconazole.²⁷

An occasional patient is allergic to metronidazole, and if alternative therapies are not useful, desensitization can be used.

Women with bacterial vaginosis report an increased volume of vaginal secretions and an unpleasant fishy odor, especially after contact with alkaline semen during intercourse. In spite of the increased volume of theoretically irritating alkaline secretions, itching and burning are generally absent or mild, and there is no vaginal or introital redness. This lack of clinical inflammation and the lack of inflammatory cells on wet mount are the reason for the term “vaginosis” rather than “vaginitis.” Complications of symptomatic bacterial vaginosis include an increased risk of preterm labor and acquisition of sexually transmitted diseases including HIV, gonorrhea, chlamydia, and trichomonas, as well as pelvic inflammatory disease.³⁰ Herpes simplex virus 1 and 2 and human papillomavirus infection rates are higher as well.³¹

The diagnosis of bacterial vaginosis is very easy and does not require laboratory testing beyond that provided by a microscope. A very quick, high-power scan of a wet mount shows clue cells and loss of lactobacilli, and the diagnosis is confirmed by a positive whiff test. For a formal diagnosis, the vaginal fluid should show at least three of the following Amsel criteria; a profuse, milky vaginal discharge; a vaginal pH >5 due to loss of lactobacilli; the presence of a fishy odor when secretions are exposed to 10% or 20% potassium hydroxide (positive whiff test); and the presence of clue cells on microscopic examination of vaginal smears (Fig. 14-7). Clue cells are squamous epithelial cells covered by coccobacilli that give the cytoplasm a ground-glass appearance and obscure the crisp margins of the cell, leaving ragged borders. Bacterial vaginosis is also characterized by no increase in white blood cells.

For practical purposes, a vaginal pH > 5 and the milky nature of the vaginal discharge are nonspecific, and the diagnosis should not be made without the presence of clue cells and the absence of lactobacilli. The diagnosis can be suggested but not be made by molecular studies that show the presence of vaginal microbiota associated with bacterial vaginosis. In addition, bacterial vaginosis exists on a spectrum, from a few to very many clue cells, etc.

Vaginal biopsies are not performed for this disease, but they are presumably normal. Poor hygiene producing odor and a heavy but normal physiologic discharge can mimic bacterial vaginosis, but the relatively high pH and characteristic microscopic findings are diagnostic.

Trichomonas can produce a heavy discharge and pH >5, as can DIV, but these conditions exhibit an increase in white blood cells on wet mount, no clue cells, and a negative whiff test.

Bacterial vaginosis is produced by shift in the proportion of organisms often present as part of the normal vaginal flora, a polybacterial dysbiosis. The usual predominance of lactobacilli is replaced by Gardnerella vaginalis, Prevotella species, Mobiluncus species, Atopobium vaginae, among others.²⁹ The characteristic odor of bacterial vaginosis is produced by the release of bacterial amines following exposure to an alkaline substance such as potassium hydroxide or semen.

Although bacterial vaginosis occurs primarily in women who are sexually active, the role of sexual activity is not clear, and this does not appear to be a sexually transmitted disease. Women who have never been sexually active are rarely affected.³² However, multiple male sex partners, female partners, and sexual relationships with more than one person are risk factors.³³ A new sex partner and lack of condom use are risk factors,²⁹ as is regular douching,³⁴ and perhaps alcohol consumption.³⁵ Male circumcision decreases the risk of BV in female partners.³⁶