Lesson 8. Vaginitis

Vaginitis is common among women of reproductive age and is usually characterized by vaginal discharge, vulvar itching and irritation, and a vaginal odor.[1] The three most common conditions diagnosed among women with vaginal symptoms presenting in the primary care setting are bacterial vaginosis (22 to 50%), trichomoniasis (4 to 35%), and vulvovaginal candidiasis (17 to 39%).[2] In some cases, the etiology of vaginitis may be mixed, and in approximately 30% of symptomatic women, no etiologic agent is identified.[3,4] The development of vaginitis is impacted by the dynamic vaginal ecosystem, which changes with age. The normal vaginal bacterial microbiota is dominated by Lactobacillus species, but a variety of other facultative and strict anaerobic bacteria are also present at much lower levels. Lactobacilli convert glycogen to lactic acid, which helps to maintain a normal acidic vaginal pH of 3.8 to 4.5. Some lactobacilli produce H₂O₂ (hydrogen peroxide), which serves as a host defense mechanism and kills bacteria and viruses. Normal vaginal discharge is clear to white, odorless, and of high viscosity. The following will address the most common causes of vaginitis is addressed in the individual sections in this lesson on Bacterial Vaginosis, Trichomoniasis, and Vulvovaginal Candidiasis.

General Principles of Diagnosis

Vaginitis is primarily a clinical diagnosis, but a complete history, physical examination, and laboratory evaluation are necessary for accurate diagnosis. When evaluating a woman with vaginal symptoms, clinicians should inquire specifically about a woman’s menstrual cycle, sexual history (including sex partners and specific sexual practices), vaginal hygiene practices (such as douching), medication use (including any intravaginal products), and any other underlying medical conditions.[5] The following briefly addresses the general approach for evaluating vaginitis, including clinical evaluation and diagnostic testing options.

Clinical Evaluation

The evaluation of vaginitis requires visual inspection of the vaginal discharge, the vagina, and the cervix, as well as the collection and evaluation of a discharge specimen under the microscope. Visualization of the cervix is important in order to rule out cervicitis as a source of abnormal vaginal discharge. The following characteristics of the vaginal discharge should be noted during examination:

• Color
• Viscosity
• Adherence to vaginal walls
• Presence of odor

Diagnostic Methods for Initial Evaluation of Vaginitis

Most of the diagnostic methods at the initial evaluation of vaginitis are not organism-specific, but can provide valuable information when trying to diagnose the cause of vaginitis[2,3,6]. The following provides a summary of major diagnostic tests used in evaluating women with vaginitis.

• Saline Wet Mount: To perform a saline wet mount, begin by collecting a sample of vaginal fluid from the lateral wall of the vagina using a cotton-tipped swab. Next, place a drop of 0.9% saline on a glass slide. Last, mix the vaginal fluid sample with the saline on the slide. Alternatively, place the vaginal swab into a test tube (with less than 1 mL of saline), gently stir, and then extract a drop from the solution in the tube and place it onto a glass slide. With either method, carefully place a coverslip over the mixed solution on the slide and then immediately examine under a microscope at both low (10x) and high (40x) power. Scan the slide thoroughly for clue cells and for motile trichomonad organisms. Delays of more than 10 minutes in viewing the wet mount significantly reduce the chance of visualizing motile trichomonads. Visualizing large motile organisms (trichomonads) is diagnostic for trichomoniasis and observing greater than 20% clue cells per high-power field is one of the Amsel criteria for a clinical diagnosis of bacterial vaginosis.
• Potassium Hydroxide (KOH) Preparation and Whiff Test: To perform this test, collect a sample of vaginal fluid (using a cotton-tipped swab) from the lateral wall of the vagina, place the sample on a glass slide, and add several drops of a 10% KOH solution to the slide. Soon after applying the KOH, the slide should be brought near the nose to perform the whiff test; the presence of a strong amine “fishy” odor is considered a positive whiff test. A positive whiff test is also one of the Amsel criteria for a clinical diagnosis of bacterial vaginosis. After performing the whiff test, carefully place a coverslip over the preparation on the slide and immediately examine under a microscope at both low (10x) and high (40x) power. The KOH kills most of the cells and bacteria, but does not significantly impact the fungal organisms, thereby making it easier to visualize the presence of yeasts or pseudohyphae. Visualizing fungal organisms in a person who is symptomatic is consistent with a diagnosis of vulvovaginal candidiasis.
• Litmus Testing for pH of Vaginal Fluid: To determine the pH of the vaginal fluid, place a pH litmus paper on the wall of the vagina or directly in pooled vaginal secretions. The normal pH of the vagina is typically between 3.8 and 4.5. A pH greater than 4.5. An elevated vaginal pH occurs in the setting of bacterial vaginosis and trichomoniasis. It should be noted, however, that trichomoniasis may occur in the setting of an elevated or normal vaginal pH.
• Vaginal Gram Stain: Performing an initial Gram stain on a sample from the vagina can provide useful information in women with suspected bacterial vaginosis or vulvovaginal candidiasis. With bacterial vaginosis, the Nugent criteria is an established scoring system used for the microbiological evaluation of bacterial vaginosis on a vaginal Gram stain slide.[7] In addition, clue cells can be visible on the Gram stain. For women with vulvovaginal candidiasis, the Gram stain may show large, gram-positive staining yeasts and hyphae, but a wet mount KOH is preferred.[6,8] Trichomoniasis is not diagnosed on Gram stain of a vaginal specimen.
• Point-of-Care Organism-Specific Tests: In addition to point-of-care diagnostic methods that are not organism-specific (microscopy, pH determination, and the “whiff test”), other point-of-care tests have been developed that are organism-specific and have good sensitivity and specificity.[3]
• Culture: Vaginal cultures can be performed for both T. vaginalis and Candida species. Fungal culture is not usually necessary to make a diagnosis of vulvovaginal candidiasis but may be needed in cases of recurrent vulvovaginal candidiasis or treatment failure with suspected azole resistance. For the diagnosis of T. vaginalis, culture for T. vaginalis is more sensitive than a wet mount, but less sensitive than molecular diagnostic methods, such as nucleic acid amplification testing.[9,10] Vaginal T. vaginalis culture may be needed in cases of persistent trichomoniasis so that antimicrobial resistance testing may be performed on the trichomonas isolate. Vaginal culture for bacterial vaginosis is not recommended due to low sensitivity (less than 50%) and the potential for mistakenly identifying commensal bacteria as pathogens, resulting in inappropriate treatment.[3]
• Nucleic Acid Amplification Tests (NAAT): There are multiple nucleic acid amplification tests (NAATs) that are available and FDA-cleared for the diagnosis of bacterial vaginosis, trichomoniasis, and candida vulvovaginal candidiasis.[10,11,12,13] Most of these NAATs utilize polymerase chain reaction (PCR)-based technology.

Introduction

Bacterial vaginosis (BV) is a condition characterized by alterations in the normal vaginal microbiota, with a loss of protective lactic-acid producing Lactobacillus species in conjunction with increases in the concentration of facultative and strict anaerobic bacteria.[14,15] Bacterial vaginosis can increase the risk of acquiring a number of sexually transmitted infections (STIs), including HIV.[14,16] Further, bacterial vaginosis may contribute to adverse birth outcomes, such as premature birth, low birth weight, and premature rupture of membranes.[17]

Epidemiology

Bacterial vaginosis is the most common cause of vaginal discharge among reproductive-aged women in the United States and worldwide.[2,18,19,20] The estimated prevalence of bacterial vaginosis among reproductive-aged women in the United States has ranged from a low of 17% to a high of 47%, with an overall estimated prevalence of approximately 25 to 30%.[18,20,21] In these studies, many of the women with bacterial vaginosis were asymptomatic. Since bacterial vaginosis is not a reportable infection, data on the prevalence and prevalence trends are limited, with estimates based on published studies. Data on the incidence of bacterial vaginosis are extremely limited. In North America alone, the estimated annual economic burden of treating symptomatic bacterial vaginosis is $1.3 billion, with a global economic burden of $4.8 billion.[20] When taking into account all sequelae associated with bacterial vaginosis, this attributable annual cost in North America increases to approximately $3.7 billion.[20]

Factors Associated with Increased Prevalence

Increased bacterial vaginosis prevalence is associated with a greater number of male sex partners, sex with a female partner, douching, and herpes simplex virus type 2 (HSV-2) infection (Figure 1).[18,19,22,23,24] A reduced risk is associated with consistent condom use, male partners who are circumcised, and oral contraceptive pills.[25,26] Increasing evidence suggests that sexual activity is integral to the development of incident bacterial vaginosis in most persons, as it correlates with the frequency of sexual activity, younger age at sexual debut, participating in anal and oral sex, and use of vaginal sex toys.[21,27,28,29,30,31] A recent study showing a significant reduction in recurrent bacterial vaginosis when regular male sex partners are treated with twice-daily oral metronidazole and topical clindamycin (applied to the penis glans and upper shaft), each for 7 days, has further strengthened the belief that sexual transmission of bacterial vaginosis–associated bacteria plays a key role in women developing bacterial vaginosis.[32,33] The role of sexual activity in bacterial vaginosis is also supported by indirect evidence, including (1) the absence of BV in women prior to sexual debut, (2) concordant vaginal flora among women in same-sex partnerships, and (3) elevated rates of bacterial vaginosis-associated bacterial colonization (as measured with penile swabs) among men engaging in extramarital sexual relationships, as compared with men who are monogamous.[30,34,35,36,37]

Pathogenesis and Microbiology

Current understanding of the pathogenesis of bacterial vaginosis suggests loss of normal Lactobacillus species in the vagina by multiple facultative and strict anaerobic bacteria, which subsequently leads to vaginal dysbiosis and a proinflammatory state.[14,16,38] To date, however, the exact etiology of bacterial vaginosis has not been determined, despite extensive research. The following summarizes current step-by-step conceptual models for the pathogenesis of bacterial vaginosis.[14,16,39]

• In the baseline state in a healthy vaginal microbiome, protective Lactobacillus species are dominant, and they produce lactic acid from glycogen, a process that maintains a low vaginal pH; this acidic pH environment inhibits the growth of other bacterial species that are normally present in the vagina at very low levels.
• The process of vaginal dysbiosis usually begins with the colonization of the vagina by a virulent strain of Gardnerella species, typically following sexual exposure; the proliferation of this organism displaces vaginal lactobacilli and creates a biofilm scaffolding conducive to recruiting Prevotella bivia (and other BV-associated bacteria).[40,41]
• Gardnerella species and P. bivia engage in a synergistic relationship in which proteolysis by Gardnerella species produces amino acids that enhance the growth of P. bivia. In turn, ammonia produced by P. bivia enhances the growth of Gardnerella species.
• Sialidase, produced by both P. bivia and Gardnerella species, promotes the breakdown of the mucin layer of the vaginal epithelium and increases adherence of other strict anaerobes, including Fannyhesseae vaginae, Sneathia species, Megasphaera type I, and others which join the BV biofilm on the upper layers.
• Fannyhesseae vaginae stimulates a strong host immune response from vaginal epithelial cells, leading to localized cytokine and beta-defensin production.
• Gradually, the healthy normal dominant vaginal lactobacilli are replaced by Gardnerella species, F. vaginae, bacterial vaginosis-associated bacteria-2 (BVAB-2), Sneathia species, Megasphaera type I, and other BV-associated bacteria.
• In the final phase of this transition to bacterial vaginosis, mucus degradation occurs, the vaginal pH is elevated, and multiple harmful compounds are produced (biogenic amines, toxic metabolites, and proinflammatory cytokines)—all resulting in a final state of vaginal dysbiosis and inflammation, which may progress to cause vaginal symptoms and adverse outcomes associated with this infection.[16]

Clinical Manifestations

Among women with bacterial vaginosis, approximately 50 to 75% are asymptomatic.[18,42] If symptomatic, most women with bacterial vaginosis will describe vaginal malodor and vaginal discharge.[43] The odor is often described as an unpleasant “fishy smell” that may become more prominent after sexual intercourse and around the time of menstruation; the discharge is typically off-white, thin, and homogeneous.[3,38,44] Symptoms may remit spontaneously. Bacterial vaginosis does not typically cause pruritus, burning, dysuria, dyspareunia, vaginal inflammation, or vulvar swelling.[44] Qualitative studies have shown that bacterial vaginosis can negatively impact self-esteem, sexual relationships, and quality of life.[21,28,45]

Obstetrical and Gynecologic Complications

Bacterial vaginosis has been linked to several obstetric complications, including late miscarriage, premature rupture of membranes, premature delivery, and low birth weight at delivery.[17,46,47,48] Bacterial vaginosis has also been associated with gynecologic complications, particularly an increased risk of post-operation infections after gynecological procedures.[49,50] There are some data to suggest bacterial vaginosis may cause additional gynecologic complications, including endometritis, pelvic inflammatory disease, and infertility, but prospective, longitudinal studies are needed to conclusively determine if bacterial vaginosis clearly causes these complications.[51,52]

Impact on Acquisition and Transmission of STIs

Longitudinal studies have also shown that bacterial vaginosis confers a substantially increased risk of acquiring multiple bacterial and viral STIs, including chlamydia, gonorrhea, trichomonas, Mycoplasma genitalium, herpes simplex virus type 2, human papillomavirus, and HIV.[53,54,55,56,57,58] Investigators have shown that disruptions of vaginal microbiota with bacterial vaginosis result in high concentrations of specific vaginal bacteria that increase the risk of HIV acquisition in women.[59] The increased risk for HIV acquisition from bacterial vaginosis is thought to occur from the altered bacterial microflora environment, causing genital inflammation, impaired vaginal wound healing, and disruptions in the integrity of the mucosal barrier.[60] Additional studies have also shown that bacterial vaginosis increases genital HIV-1 shedding in women and enhances the risk of female-to-male HIV-1 transmission.[61]

Diagnostic Approach

Gram staining of a vaginal specimen with Nugent scoring has traditionally been considered the gold standard for diagnosing bacterial vaginosis, but it is primarily used only in research settings. In the clinical setting, point-of-care testing, such as the Amsel criteria and OSOM BVBlue test, are the most frequently used tests for diagnosing bacterial vaginosis. In addition, in recent years, molecular assays have emerged to play an increasingly important role in the diagnosis of bacterial vaginosis. Specimens for molecular testing should only be obtained from symptomatic women.[62,63] Making a diagnosis of bacterial vaginosis with vaginal culture or by examining a Papanicolaou smear (Pap test) is not recommended due to low sensitivity and specificity.[64,65,66]

Amsel Criteria

Bacterial vaginosis is most commonly diagnosed clinically using the Amsel criteria.[67] Compared with the traditional gold standard (vaginal fluid Gram stain with Nugent scoring), the Amsel criteria have a sensitivity in the range of 37 to 70% and specificity of 94 to 99%.[12] In the Amsel criteria, The presence of three of the following four criteria provides sufficient evidence for a clinical diagnosis of bacterial vaginosis:[43,68]

• Vaginal pH greater than 4.5, which is the most sensitive but least specific sign
• Positive amine, “whiff” or “fishy odor” test (liberation of biologic amines with or without the addition of 10% KOH)
• Homogeneous, nonviscous, milky-white discharge adherent to the vaginal walls
• The presence of “clue cells” (bacterial clumping that obscures the borders of vaginal epithelial cells) (Figure 2) in at least 20% of vaginal epithelial cells per high-power field viewed on saline microscopy

Vaginal Gram Stain with Nugent Scoring

The traditional gold standard for diagnosing bacterial vaginosis is a vaginal Gram stain with Nugent score determination, which is based on the relative concentration of Lactobacillus, Bacteroides, Gardnerella, and Mobiluncus species (Figure 3).[7,63] A normal Gram stain should show Lactobacillus species only or Lactobacillus species with only a few Gardnerella morphotypes; a Nugent score of 0 to 3 is considered normal and is consistent with a Lactobacillus-predominant vaginal microbiota, a score of 4 to 6 indicates intermediate microbiota (emergence of G. vaginalis), and 7 to 10 is consistent with bacterial vaginosis.[7,63] Although this test is traditionally considered the gold standard, it is not used often in clinical practice because it is time-consuming, requires training and expertise for interpretation, and results are not typically available during a clinic visit.[12]

Point-of-Care Assays

In addition to the point-of-care methods used to determine the Amsel criteria, several assays have been developed as point-of-care tests for the diagnosis of bacterial vaginosis.

• OSOM BVBlue Test: The OSOM BVBlue test detects elevated vaginal fluid sialidase, an enzyme that is produced in increased quantities by certain bacterial microorganisms (i.e., G. vaginalis) that are involved in bacterial vaginosis.[69,70] This test is a Clinical Laboratory Improvement Amendments (CLIA)-waived, point-of-care test that provides results in about 10 minutes.[12] The test is easy to perform and requires six steps: (1) obtain a vaginal swab sample using the kit swab (either through self-collected or clinician-collected specimens), (2) insert the collection swab into the kit testing vial that contains liquid, (3) wait 10 minutes with the swab in the vial, (4) add one drop of the developer solution to the testing vessel, (5) stir the swab in the vial to mix the test solution with the vial solution, and (6) immediately read the test and interpret based on the color change. Compared with a Nugent score, this test has a sensitivity in the range of 88 to 92% and a specific range of 92-95%.[69,70]
• Affirm VPIII: This molecular assay uses a DNA hybridization probe that can detect high concentrations of G. vaginalis (greater than 5 × 10⁵ colony-forming units of G. vaginalis per mL of vaginal fluid); this assay can also detect T. vaginalis and C. albicans. The test requires approximately 30 minutes to obtain results. When the Affirm VPIII assay is used alone to diagnose bacterial vaginosis, it has a low sensitivity and specificity when compared with a Gram stain and Nugent scoring. If, however, this test is used in conjunction with a vaginal pH measurement and the presence of amine odor, the test performance improves, with a sensitivity of 97% and specificity of 81%.[12]
• FemExam Test Card: The FemExam Test Card measures vaginal pH, proline aminopeptidase, and trimethylamine (a metabolic by-product of G. vaginalis).[71] When compared with a Gram stain and Nugent score, this test has a sensitivity of 91% and specificity of 61%.[63] This test has primarily been used in resource-limited settings, and although it has been reported to be beneficial compared with syndromic management, it is not a preferred diagnosis method for bacterial vaginosis.[62,71]

Nucleic Acid Amplification Tests

Although multiple nucleic acid amplification tests (NAATs) are commercially available for diagnosing bacterial vaginosis in symptomatic women, only three of these are cleared by the United States Food and Drug Administration (FDA): BD MAX Vaginal Panel, Aptima BV, and GeneXpert Xpress MVP.[12,63] These tests are currently intended only for use in women with vaginitis symptoms, and can be run using a self-obtained or clinician-collected vaginal swab specimens, with results available within 24 hours.[12,62]

• BD MAX Vaginal Panel: The BD MAX Vaginal Panel is a multiplex, real-time PCR assay used to evaluate women with vaginitis symptoms. This assay can detect major Lactobacillus species that are present in a healthy vaginal microbiota (L. crispatus, L. gasseri, and L. jensenii) and prominent bacterial vaginosis-associated bacteria (G. vaginalis, A. vaginae, BVAB-2, and Megasphaera type 1).[63,72] In addition, the BD MAX Vaginal Panel can detect organisms responsible for causing trichomoniasis and vulvovaginal candidiasis.[72] This assay bases the diagnosis of bacterial vaginosis on the relative concentrations of the healthy Lactobacillus species and the bacterial vaginosis-causing organisms, with a final determination based on a proprietary algorithm.[63] For the diagnosis of bacterial vaginosis, this test has a reported sensitivity with clinician-collected specimens of 90.5% and specificity of 85.8%; similar results were seen with self-obtained specimens (Figure 4).[72]
• Aptima BV Test: The Aptima BV test can be used in symptomatic women to detect certain Lactobacillus species (L. crispatus, L. gasseri, and L. jensenii) and bacterial vaginosis-associated bacteria (G. vaginalis and A. vaginae). This test has a reported sensitivity with clinician-collected specimens of 95.0% and specificity of 89.6%; similar results were seen with self-obtained specimens (Figure 5).[73]
• Gene Xpert Xpress MVP: The Xpert Xpress MVP is a Clinical Laboratory Improvement Amendments (CLIA)-waived, on-demand diagnostic PCR test which detects DNA targets from anaerobic bacteria associated with BV (F. vaginae, BVAB-2, Megasphaera type 1), Candida species, and T. vaginalis. For bacterial vaginosis, as compared to the BD MAX Vaginal Panel, the MVP test demonstrated high positive and negative percent agreement for both clinic and self-collected specimens (93.6-99% and 92.1%-99.8%, respectively).[74]

Screening Recommendations

In general, screening for bacterial vaginosis in asymptomatic women is not recommended. Screening and treatment of women with bacterial vaginosis prior to a surgical abortion or hysterectomy can be considered due to decreased rates of postsurgical infections in women pretreated with metronidazole; cost-comparison studies have found that adding metronidazole to standard surgical prophylaxis is more cost-effective than a screen-and-treat approach.[75,76,77,78] Despite a link between bacterial vaginosis and preterm birth, several studies have concluded that treatment of bacterial vaginosis does not reduce the likelihood of preterm birth.[79,80,83] For pregnant women who do not have vaginal symptoms, routine screening for bacterial vaginosis is not recommended, including women at low risk or high risk for preterm delivery.[63]

Treatment

Treatment of Bacterial Vaginosis in Nonpregnant Women

Women who have vaginal symptoms consistent with bacterial vaginosis should receive treatment.[63] The recommended regimens include metronidazole 500 mg orally twice daily for 7 days; metronidazole 0.75% gel, 5 grams intravaginally once a day for 5 days; or clindamycin 2% cream, 5 grams intravaginally at bedtime for 7 days (see Table 1 below).[63] Accumulating reports have refuted prior warnings that metronidazole (or tinidazole) causes a disulfiram-like reaction in persons who ingest alcohol while taking these antibiotics.[84,85] Accordingly, experts now consider it unnecessary for persons to refrain from ingesting alcohol when they are taking metronidazole or tinidazole.[63,85] Secnidazole is a newer nitroimidazole that has been FDA-approved as a 2-gram single-dose packet for the treatment of bacterial vaginosis for females who are 12 years of age and older.[86,87] Although the use of probiotics that target vaginal repletion of Lactobacillus species is an attractive concept for treatment and for prevention of recurrences of bacterial vaginosis, this strategy is not recommended at this time.[63,88,89,90]

Management of Sex Partners

Current CDC guidelines do not recommend routine testing or treatment of male or female sex partners of women diagnosed with bacterial vaginosis.[63]

• Management of Male Sex Partners: The current recommendation for the management of male sex partners of women diagnosed with bacterial vaginosis is likely to change based on a recently published trial from Australia that showed a significant benefit in reducing recurrent bacterial vaginosis when treating male partners with oral metronidazole and clindamycin cream (applied to the penis glans and upper shaft).[33,37] In this trial, investigators enrolled premenopausal women diagnosed with bacterial vaginosis who were in a monogamous relationship with a male partner and randomized the male sex partners to receive treatment for bacterial vaginosis or placebo.[32] A total of 164 heterosexual couples were enrolled.[32] Women with bacterial vaginosis were treated with a first-line regimen and male partners randomized to treatment received oral metronidazole 400 mg twice daily for 7 days and topical 2% clindamycin cream applied to the glans penis and upper shaft for 7 days.[32] The primary outcome measure was recurrent bacterial vaginosis within 12 weeks of receiving treatment. Among the 137 couples who completed the trial, recurrent bacterial vaginosis occurred in 24 of 69 (35%) of women in the partner-treatment group, compared with 43 of 68 (63%) of women in the partner-placebo group (P<0.001).[32] Of note, the trial was stopped early because of the superiority of the primary outcome in the male partner treatment group.[32] Experts have noted that findings from this study support the role of sexual transmission of bacterial vaginosis-associated bacteria, likely leading to a new approach that involves routinely treating male sex partners of women diagnosed with bacterial vaginosis.[33]
• Management of Female Sex Partners: Data for the treatment of female partners of women diagnosed with bacterial vaginosis are limited. Because female sex partners are often concurrent with bacterial vaginosis status, the option of screening and treatment of female sex partners could be considered, but this approach has not been studied rigorously in clinical trials.[91]

Post-Treatment Follow-Up

Follow-up after treatment of bacterial vaginosis is only necessary if symptoms persist or recur.[63]

Special Considerations

The following situations require unique consideration when treating bacterial vaginosis.

• Metronidazole (or Tinidazole) Allergy or Intolerance: For women who are allergic or intolerant to metronidazole (or tinidazole), the preferred option is to treat with clindamycin cream using one full applicator (5 grams) intravaginally at bedtime for 7 days.[63]
• Treatment of Symptomatic Bacterial Vaginosis in Pregnancy: All pregnant women who have symptomatic bacterial vaginosis should receive treatment since symptomatic bacterial vaginosis is clearly associated with adverse pregnancy outcomes.[63] Further, treating symptomatic bacterial vaginosis in pregnancy reduces symptoms and may reduce certain adverse obstetrical outcomes, such as late miscarriage. Any of the recommended bacterial vaginosis treatments for nonpregnant women (oral metronidazole, metronidazole gel, and clindamycin cream), as well as certain alternative regimens (oral clindamycin and clindamycin ovules), can be used to treat symptomatic bacterial vaginosis during pregnancy. Metronidazole crosses the placenta and is excreted in breast milk, but it has not been linked to teratogenic effects.[92,93,94] Tinidazole is not recommended during pregnancy due to evidence of fetal harm in animal studies. There are insufficient data in pregnancy to recommend using secnidazole in pregnant women with bacterial vaginosis.[95,96,97] Several additional preparations should not be used during pregnancy, including metronidazole 1.3% vaginal gel, the 750-mg vaginal metronidazole tablets, and the Clindesse brand of 2% clindamycin vaginal cream, which is a high-dose single-application treatment for bacterial vaginosis. For breastfeeding mothers with symptomatic bacterial vaginosis, oral metronidazole can be used.[63]
• Management of Asymptomatic Bacterial Vaginosis in Pregnancy: Since routine screening for bacterial vaginosis is not recommended for pregnant women who do not have vaginal symptoms, the need to address the treatment of asymptomatic bacterial vaginosis during pregnancy should not routinely arise. Available data suggest no benefit for the treatment of asymptomatic bacterial vaginosis in pregnant women who are considered at low risk for preterm delivery.[98] For pregnant women at high risk for preterm delivery, the impact of treating asymptomatic bacterial vaginosis is not clear, and available data are conflicting: four studies showed benefit with treatment, two showed no benefit, and one showed harm.[63]
• Treatment in Women with HIV: Women with HIV experience higher prevalence and longer persistence of bacterial vaginosis compared to women without HIV.[99] The treatment of bacterial vaginosis in women with HIV should be the same as for women without HIV.[63]

Treatment of Recurrent Bacterial Vaginosis

Bacterial vaginosis recurs in approximately 30% of women within the first 3 months following treatment and in up to 50% of women after 6 to 12 months.[100,101] Very little is known about antimicrobial resistance with pathogens that cause bacterial vaginosis, although clinical experience suggests that treatment failure from true antimicrobial resistance is uncommon.[28,102]

• Single Recurrence: Women with a single recurrence can be treated with either the same recommended regimen or a different recommended regimen.[63,103]
• Multiple Recurrences: For women who experience multiple recurrences of bacterial vaginosis after completing treatment with a recommended regimen, a different approach from the initial treatment should be utilized.[102] Suggested interventions include switching the route of therapy (from oral to vaginal or vice versa) or switching the class of drug.[102,104] Based on available data, the following alternative regimens are suggested as options for these women.[63]
  • Metronidazole gel (0.75%) vaginal suppository twice-weekly for at least 3 months.[101]
  • Metronidazole 750 mg vaginal suppository twice-weekly for at least 3 months.[105]
  • Metronidazole 500 mg orally twice daily (or tinidazole 500 mg orally twice daily) for 7 days, followed by intravaginal boric acid 600 mg daily for 21 days, followed by suppressive therapy with intravaginal metronidazole gel (0.75%) twice-weekly for 4 to 6 months.[106]
  • Metronidazole 2 grams orally once per month plus fluconazole 150 mg orally once per month given over a 12-month timeframe has also been evaluated as periodic presumptive therapy; this approach resulted in fewer episodes of bacterial vaginosis in one study when compared to placebo.[107]
  • Astodrimer 1% gel (a dendrimer-based microbicide) at a dose of 5 grams vaginally every other day for 16 weeks.[108]
• Treatment of Male Sex Partners: Although not yet recommended as an approach in CDC guidelines, new data have shown that treatment of male sex partners with oral metronidazole and topical clindamycin cream (applied to penis glans and upper shaft) markedly reduces the incidence of recurrent bacterial vaginosis in women.[32] Thus, treatment of male sex partners should now be considered for the prevention and management of recurrent bacterial vaginosis in women.[33]

Counseling and Education

Patient counseling and education about bacterial vaginosis should cover the nature of the disease and transmission issues.

Nature of the Disease

• Asymptomatic bacterial vaginosis is common, and screening of asymptomatic women is not generally recommended.
• Bacterial vaginosis is caused by a shift in the normal vaginal flora microbiota from lactobacillus predominance to a predominance of facultative and strict anaerobic bacteria.
• The hallmark of symptomatic bacterial vaginosis is vaginal malodor and discharge.
• Bacterial vaginosis is associated with multiple obstetric and gynecologic complications, including preterm birth and pelvic inflammatory disease, and it is associated with an increased risk of acquisition of HIV and other STIs.

Transmission Issues

• Sexual activity is significantly implicated in the pathogenesis of incident bacterial vaginosis; sexual transmission of bacterial vaginosis-associated bacteria is highly likely.
• The pathogenesis of recurrent and persistent bacterial vaginosis may be different from incident bacterial vaginosis.
• There is a high concordance for the presence or absence of bacterial vaginosis in partnerships involving women who have sex with women.
• Bacterial vaginosis increases a woman’s risk of acquiring sexually transmitted infections (STIs), including chlamydia, gonorrhea, genital herpes, and HIV.
• Women with HIV and bacterial vaginosis have a higher likelihood of transmitting HIV to their sex partners.

Introduction

Trichomoniasis is caused by the protozoan parasite Trichomonas vaginalis and is the most common curable STI worldwide. Clinical manifestations associated with trichomoniasis include asymptomatic infection, acute infection, and chronic vaginitis.[109,110] Trichomoniasis in pregnancy has been associated with obstetrical and gynecologic adverse outcomes.[111,112] A meta-analysis of 17 published studies found that women with T. vaginalis were at a two-fold higher risk for developing cervical cancer.[113] In addition to these clinical complications, trichomoniasis also confers a two- to three-fold risk of acquiring HIV.[114,115,116]

Epidemiology

An estimated 3.7 million people have trichomoniasis in the United States, with approximately 1.1 million new cases occurring each year.[117,118,119] The prevalence of T. vaginalis infection among women of reproductive age in the United States is estimated at 2.1%, but rates are at least four times higher among non-Hispanic Black women.[120] In contrast to chlamydia and gonorrhea, which have the highest rates in women younger than age 25 years, the prevalence of T. vaginalis is lower in women younger than 20 years of age than in women 20 to 50 years of age (Figure 6).[121] Prevalence rates are significantly higher in women with vaginal symptoms: in one study of women attending sexually transmitted diseases (STD) clinics, the trichomonas prevalence was 26.2% among symptomatic women compared to 6.5% among asymptomatic women.[122] Although men are not routinely tested for trichomoniasis, studies have reported rates from 3 to 17% in men attending STI clinics and as high as 72% among men who have female sex partners diagnosed with trichomoniasis.[123,124,125] Men who have sex with men appear to be at low risk of acquiring trichomoniasis.[126] Transmission of T. vaginalis between women who have sex with women has been documented to occur at a substantial rate.[127,128]

Pathogenesis and Microbiology

The etiologic agent in trichomoniasis is T. vaginalis, which is a single-celled flagellated anaerobic protozoan parasite. It is the only known protozoan parasite that infects the genital tract. Trichomonas vaginalis has four anterior flagella and one flagellum embedded in an undulating membrane (Figure 7).[110] The flagella are responsible for the jerky motility of this organism that is seen under a microscope. After attaching to vaginal epithelial cells, this globular, pear-shaped organism transforms into a thin, flat, ameboid shape.[129] Trichomoniasis is almost always sexually transmitted. Trichomonas vaginalis may persist for months to years in epithelial crypts and periglandular areas of the genital tract.[110] Distinguishing persistent, subclinical infection from remote sexual acquisition is not always possible.

Factors Associated with Increased Prevalence

Investigators have identified multiple factors associated with trichomoniasis, including current or past incarceration, two or more sex partners in the prior year, a diagnosis of bacterial vaginosis, education less than completion of high school, and living below the national poverty level.[130,131,132,133]​​

Clinical Manifestations

Genitourinary Infection in Women

Vaginitis due to acute infection with T. vaginalis can have a characteristic “frothy” gray or yellow-green vaginal discharge and pruritus, but many women are asymptomatic. On pelvic examination, the presence of cervical punctate hemorrhages, often referred to as a “strawberry cervix,” strongly suggests a diagnosis of trichomoniasis, but this occurs in fewer than 5% of women with trichomoniasis (Figure 8).[110] Chronic infection may be associated with minimal vaginal discharge, mild pruritus, and/or dyspareunia.[110,134] Infection with T. vaginalis has also been associated with an increased risk of infertility, PID, and cervical cancer.[113,135,136]

Trichomoniasis in Pregnancy

Infection with T. vaginalis in pregnant women is associated with both obstetrical and gynecologic adverse outcomes, including premature rupture of membranes and preterm labor; trichomoniasis in pregnancy increases the risk of preterm birth by about 30%.[111,112,137,138] Neonatal trichomoniasis is unusual but can occur.[139,140]

Trichomoniasis in Persons with HIV

Among women with HIV, more than half are coinfected with T. vaginalis, and they have been shown to have an increased risk for pelvic inflammatory disease and for shedding of HIV in the genital tract.[141,142,143,144] Antiretroviral therapy appears to lessen the potentiating effects of trichomoniasis infections on HIV transmission risk.[144] Infection with HIV does not make a woman more likely to have persistent or recurrent trichomoniasis.[145]

Trichomoniasis in Men

Trichomonas vaginalis may cause up to 11 to 13% of nongonococcal urethritis (NGU) in men, but urethral infection in men is frequently asymptomatic.[146] Men with T. vaginalis infection may also rarely present with prostatitis or epididymitis.[147] Infection with T. vaginalis in men may also contribute to impaired sperm motility.

Diagnostic Methods

Diagnostic testing for trichomoniasis should be performed in women seeking evaluation of vaginal discharge.[147] In clinical practice, wet mount preparation has been the most commonly used method for diagnosing trichomoniasis, primarily because of the low cost, convenience, and point-of-care diagnosis.[9,10] This approach, however, has a sensitivity (44 to 68%) that is significantly lower than with newer molecular NAATs.[13] Papanicolaou testing is not considered an appropriate diagnostic tool for trichomoniasis; if T. vaginalis infection is identified on routine Papanicolaou testing, a standard trichomonas diagnostic test should be used to verify infection. The following summarizes the major methods used to diagnose trichomoniasis.

Wet Mount Preparation

In the clinical setting, the diagnosis of trichomoniasis can be made by microscopic visualization of motile trichomonads on a vaginal wet mount slide (Figure 9).[9,148] Although the wet mount method is inexpensive and relatively simple to perform, it has a sensitivity of only 44 to 68%, and it is operator-dependent.[9] Once a vaginal fluid sample is collected, it should be stored in saline (for a maximum of one hour) until the operator is ready to perform microscopy.[149] Once the specimen has been placed on the slide, microscopic evaluation is recommended as soon as possible and always within 10 minutes, since the trichomonads will become increasingly sluggish on the wet mount, and motility is required for positive identification.[9,148,149]

Culture

Obtaining a culture using modified Diamond’s medium was the previous gold standard for diagnosis of trichomoniasis prior to the availability of highly sensitive NAATs. Culture is a more sensitive diagnostic tool than wet mount alone, but results are not immediately available. Specialized culture systems (i.e., InPouch System [Biomed Diagnostics]) are available to allow for transport of cultures when shipping to an off-site laboratory. Culture may be used for diagnosing T. vaginalis in both men and women. Culture in men may be performed on samples of urethral secretions, urine sediment, or semen, but testing in women requires sampling of vaginal secretions, as the sensitivity is low in urine culture.[147] Trichomonas vaginalis culture is categorized by the Clinical Laboratory Improvement Amendments (CLIA) as moderately complex as it is time-consuming and requires incubation.[13] If T. vaginalis is isolated in culture, drug susceptibility testing can be performed, particularly in cases of persistent infection.

Nucleic Acid Amplification Testing (NAAT)

Several NAAT-based methods are available for the diagnosis of T. vaginalis, including transcription-mediated amplification and polymerase chain reaction (PCR). There are no data to suggest T. vaginalis causes oral or anorectal infection, and therefore use of NAAT to detect T. vaginalis oral or anorectal infection is not recommended.[147,150,151]

• Aptima Trichomonas vaginalis Assay (Becton Dickinson [BD]): This assay uses transcription-mediated amplification for the detection of T. vaginalis RNA.[146,152] This test is FDA-cleared for detectingT. vaginalis in symptomatic and asymptomatic women.[147] The test can be performed on clinician-collected vaginal swabs, clinician-collected endocervical swabs, female urine specimens, or liquid endocervical Pap smear specimens collected in PreservCyt Solution.[146,153] The Aptima Trichomonas vaginalis assay has a sensitivity of 95.3 to 100% and specificity of 95.2 to 100%, which are considerably higher than wet mount or culture (Figure 10).[146,154,155,156] The Aptima Trichomonas vaginalis assay is not FDA-cleared for use in men, but it may be used to test urine or urethral swabs from men if the assay is internally validated in accordance with CLIA regulations.[147]
• Probe Tec TV Qx Amplified DNA Assay (Becton Dickinson [BD]): This assay uses Strand Displacement Amplification technology and is FDA-cleared for detection of T. vaginalis from vaginal swabs (clinician-collected or self-collected), endocervical swabs (clinician-collected), and female urine specimens.[147] This assay can be used to detect T. vaginalis in symptomatic and asymptomatic females. The Probe Tec TV Qx Amplified DNA assay has a sensitivity of 98.3% and specificity of 99.6% for detecting T. vaginalis.[157]
• GeneXpert TV (Cepheid): This PCR-based NAAT is FDA-cleared for the detection of T. vaginalis genomic DNA using self-collected or clinician-collected vaginal specimens, female urine specimens, clinician-collected endocervical swab specimens, and male urine specimens.[147,158] With this assay, the results are available within 63 minutes; for samples that have a clear positive result after 45 PCR cycles have been completed, the Early Assay Termination function will provide the positive result earlier, typically within 40 minutes.[158] The GeneXpert TV has a sensitivity of 99.5 to 100% and a specificity of 99.4 to 99.9%.[72]
• Gene Xpert Xpress MVP (Cepheid): The Xpert Xpress MVP is a CLIA-waived on-demand diagnostic PCR test that detects DNA targets from T. vaginalis as well as Candida species and anaerobic bacteria associated with BV (F. vaginae, BVAB-2, Megasphaera type 1.[74]
• Max CTGCTV2 Assay (Becton Dickinson): This test is an FDA-cleared PCR assay for detecting Chlamydia trachomatis, Neisseria gonorrhoeae, and T. vaginalis from vaginal specimens (self-collected or clinician-collected), female urine specimens, and male urine specimens.[147,159] The Max CTGCTV2 Assay has a sensitivity of 96.2-100% and a specificity of 99.1-100% for detecting T. vaginalis.[72]
• Cobas TV/MG (Roche Diagnostics): This PCR-based NAAT is FDA-cleared for the detection of T. vaginalis and M. genitalium using vaginal specimens (self-collected or clinician-collected), clinician-collected endocervical swab specimens, female urine specimens, male urine specimens, and clinician-collected meatal specimens.[160] This assay is FDA-cleared for both symptomatic and asymptomatic patients. The Cobas TV/MG has a sensitivity and specificity greater than 99.5%.[160,161]
• Alinity m STI Assay (Abbott): The Alinity m STI assay is an in vitro reverse transcription-polymerase chain reaction (RT-PCR) assay that is FDA-cleared for the detection of four common STIs: C. trachomatis, N. gonorrhoeae, T. vaginalis, and M. genitalium. This assay may be used on clinician or self-collected vaginal swab specimens, endocervical swab specimens, gynecological specimens collected in ThinPrep PreservCyt solution, and female and male urine specimens from asymptomatic and symptomatic individuals.[162] In a recent study, the overall percent agreements of the Alinity m STI assay in comparison with the Aptima and cobas assays for the four organisms tested were: C. trachomatis (99.5% [97.2%, 99.9%]), N. gonorrhoeae (99.5% [97.2%, 99.9%]), T. vaginalis (98.4% [95.5%, 99.5%]), and M. genitalium (86.4% (66.7%, 95.3).[163]

Point-of-Care Testing

There are multiple point-of-care tests available for diagnosing trichomoniasis in women.[164]

• Osom Trichomonas Rapid Test (Sekisui Diagnostics): This is an antigen-detection point-of-care test for use with clinician-collected vaginal samples. The test requires about 10 to 15 minutes for test results to become available; this test has a sensitivity of 82 to 95% and a specificity of 97 to 100%.[165,166] The Osom Trichomonas Rapid Test is not FDA-cleared for use in men.
• Solana Trichomonas Assay (Quidel): This point-of-care test uses isothermal Helicase-Dependent Amplification technology to detect T. vaginalis DNA from asymptomatic and symptomatic female urine specimens or clinician-collected vaginal specimens, with a sensitivity greater than 92% for urine specimens and greater than 98% for vaginal samples.[167] Results are available within 40 minutes. This test is not FDA-cleared for use in men.
• Sexual Health Click Test (Visby Medical): This point-of-care, CLIA-waived PCR test is a single-use, disposable test that can detect chlamydia, gonorrhea, and trichomonas using self-collected vaginal swabs.[168] The compact test device provides results within 30 minutes. In an analysis of self-collected vaginal swabs obtained in 1,449 women, this test had a sensitivity of 99.2% and specificity of 96.9% for detection of T. vaginalis.[168]

Screening Recommendations

Routine urogenital screening for trichomoniasis may be considered for (1) women receiving care in high trichomonas prevalence settings (STI clinics or correctional facilities), and 2) asymptomatic women at high risk of acquiring T. vaginalis (e.g., women with multiple sex partners, persons who exchange sex for money or drugs, or a history of STIs or incarceration).[147,169] Screening for trichomoniasis is recommended in all sexually active women with HIV (when they enter care and then annually thereafter).[147,169] Screening for T. vaginalis of the pharynx or rectum is not recommended, primarily because these infections are extremely uncommon, and the cost-effectiveness of screening at these sites has not been established.[147] Screening for trichomoniasis is not currently recommended for men.[169]

Treatment

Treatment of Trichomoniasis

All women diagnosed with trichomoniasis, regardless of HIV or pregnancy status, should receive treatment with metronidazole 500 mg twice daily for 7 days.[147] All men diagnosed with trichomoniasis, regardless of HIV status, should receive treatment with a single dose of 2 grams of oral metronidazole.[147] These recommendations are based on two studies conducted on women, most of whom were symptomatic, that demonstrated oral metronidazole given for 7 days was more effective at curing infection than a single 2-gram oral dose.[170,171] Tinidazole, given as a 2-gram oral dose, is the alternative for both women and men, but it should be avoided in pregnant women.[147] Experts now consider it unnecessary for persons to refrain from ingesting alcohol when they are taking metronidazole or tinidazole.[147] After the publication of the 2021 CDC STI guidelines, a single 2-gram oral dose of secnidazole, which has a longer half-life than both metronidazole and tinidazole, has been evaluated and FDA-approved for T. vaginalis treatment in females and males who are 12 years of age and older.[172,173,174] Metronidazole gel (intravaginal) is not effective for the treatment of trichomoniasis and is not recommended. Persons who are allergic to metronidazole should be referred to an allergy specialist; if this is not possible, additional options are limited but would include intravaginal paromomycin cream or intravaginal boric acid.[147,175,176,177]

Treatment of Persistent or Recurrent Trichomoniasis

The most likely reasons for persistent or recurrent trichomoniasis are reinfection from an untreated partner or lack of adherence with treatment, but in some individuals, antimicrobial-resistant T. vaginalis infection can occur. Rates of metronidazole resistance have ranged from 4 to 10%, and the rates of tinidazole resistance have been approximately 1%.[178,179] These resistance rate data are old and contemporary resistance data are needed, including resistance data with secnidazole. Tinidazole retains activity against many metronidazole-refractory strains. The following summarizes the approach to treatment in persons with persistent or recurrent trichomoniasis.[147]

• Treatment Failure with Reexposure: For women and men who received standard treatment for trichomoniasis and have treatment failure due to reexposure from an untreated partner, retreatment should consist of the same regimen they initially received.[147]
• Treatment Failure without Reexposure: For men who have treatment failure after receiving an initial single-dose therapy of metronidazole 2 grams orally (and reexposure has not occurred), the recommended retreatment is metronidazole 500 mg orally twice daily for 7 days.[147] For women who have failed the initial regimen of metronidazole 500 mg twice daily for 7 days and have not been reexposed, repeat treatment should be given with a 7-day regimen of either metronidazole 2 grams given once per day or tinidazole 2 grams once per day.[147] Tinidazole or secnidazole should not be used in pregnant women.
• Treatment Failure after Second-Line Treatment without Reexposure: If an individual experiences persistent infection after receiving treatment with a second-line regimen (and reexposure to a partner with trichomoniasis has not occurred), the clinician should request a special kit from the Centers for Disease Control and Prevention for 5-nitroimidazole drug-resistance testing (Trichomonas Susceptibility Testing).[147,180]
• Treatment of 5-Nitroimidazole-Resistant Trichomonas: If drug-resistance testing reveals nitroimidazole resistance and treatment with a 7-day regimen of either metronidazole 2 grams given once per day or tinidazole 2 grams once per day has been unsuccessful, then the next option is oral tinidazole 2 grams daily plus intravaginal tinidazole 500 mg twice daily for 14 days.[147,181] If this option fails, then consider using high-dose oral tinidazole (1 gram 3 times daily) plus intravaginal paromomycin (4 grams of 6.25% intravaginal paromomycin cream nightly) for 14 days.[147,177] A 14-day course of oral secnidazole 2 grams in combination with intravaginal boric acid 600 mg twice daily has also recently been used to successfully treat a case of persistent 5-nitroimidazole-resistant trichomoniasis.[182] Note that oral tinidazole or secnidazole should not be used in pregnant women. Intravaginal boric acid 600 mg twice daily for 60 days has been successfully used to treat trichomoniasis in women allergic to nitroimidazole and thus could be considered as an option for women with treatment-refractory nitroimidazole-resistant trichomoniasis.[147,176,183]

Management of Sex Partners

All persons diagnosed with trichomoniasis should refer all sex partners in the prior 60 days for evaluation, comprehensive STI testing, HIV testing, and presumptive treatment of trichomoniasis. All current sex partners should be referred for presumptive trichomoniasis therapy.[147] For persons diagnosed with trichomoniasis, expedited partner management (where a clinician provides presumptive antibiotic therapy and educational materials to a patient’s partner) may be considered in states where it is legally permitted (see the CDC United States Map for the Legal Status of Expedited Partner Therapy). Expedited partner management is permissible in most states.

Resumption of Sexual Activity

Persons diagnosed with trichomoniasis should be instructed to avoid sex until they and their sex partners have been treated and until they no longer have any symptoms of trichomoniasis. This usually takes about 7 days after completion of treatment.[147]

Post-Treatment Follow-Up

All sexually active women who are diagnosed and treated for T. vaginalis infection (including pregnant women and women with HIV) should be retested 3 months after initial treatment to evaluate the possibility of reinfection. Retesting in men is not routinely recommended.[147]

Treatment of Special Populations

• Treatment of Women During Pregnancy: Pregnant women with symptomatic trichomoniasis, in any trimester, should receive treatment with metronidazole 500 mg orally twice daily for 7 days.[147] Treatment of asymptomatic trichomoniasis in pregnancy, however, has not been shown to reduce preterm birth.[184] Both metronidazole and tinidazole are secreted in breast milk. Some clinicians advise deferring breastfeeding by 12-24 hours after taking a dose of metronidazole.[147,185] Tinidazole is not recommended during pregnancy due to limited animal studies suggesting fetal risk; women who are breastfeeding should wait 72 hours after taking tinidazole before breastfeeding.[147] Secnidazole is not currently recommended for use in pregnancy or during breastfeeding due to limited data.
• Treatment of Women with HIV: Women with HIV who are diagnosed with trichomoniasis should receive a 7-day treatment course of metronidazole 500 mg twice daily.[147,186] In women with HIV, the longer course of oral metronidazole therapy (500 mg twice daily for 7 days) has been shown to have higher cure rates than a 2 g single-dose of metronidazole (Figure 11).[141,186,187,188]

Patient Counseling and Education

Patient counseling and education should cover the nature of the disease, transmission issues, and risk reduction.

Nature of the Disease

• Trichomoniasis can be asymptomatic in men and women, and it may persist silently for years.
• Untreated trichomoniasis is associated with adverse pregnancy outcomes such as premature rupture of membranes, preterm delivery, and low birth weight infants.
• Infection with T. vaginalis in women has been associated with an increased risk of cervical cancer.
• Douching may worsen vaginal discharge in patients with trichomoniasis.

Transmission Issues

• Trichomoniasis is almost always sexually transmitted.
• Current and recent sex partners should undergo evaluation and receive empiric treatment for trichomoniasis.
• Persons diagnosed with trichomoniasis should abstain from intercourse until they and their sex partners are cured (about 7 days).
• Trichomoniasis has been associated with increased susceptibility to HIV acquisition and transmission.

Risk Reduction

• Individualize risk-reduction plans with each patient.
• Prevention strategies include abstinence, mutual monogamy with an uninfected partner, consistent condom use, and limiting the number of sex partners.
• Douching should be avoided since it increases the risk for trichomoniasis.
• Male circumcision reduces the risk of trichomoniasis.[189,190]

Introduction

Vulvovaginal candidiasis is caused by an abnormal proliferation of one or more Candida species in the vaginal tract. Vulvovaginal candidiasis is commonly referred to as a “yeast” infection. Globally, about 138 million women have vulvovaginal candidiasis on an annual basis.[191,192] Although vulvovaginal candidiasis is not a sexually transmitted infection, it frequently causes clinical manifestations that overlap with other sexually transmitted infections and vaginal conditions.

Epidemiology

An estimated 70 to 75% of women will experience at least one episode of vulvovaginal candidiasis in their lifetime, 40 to 50% will experience a second episode, and approximately 5 to 10% will develop recurrent vulvovaginal candidiasis (defined as three or more symptomatic episodes in one year).[192,193,194] Overall, candidiasis is responsible for about 15 to 30% of all cases of vaginitis.[195] Candidiasis is the second most common cause of vaginal infections after bacterial vaginosis, though information on the incidence of vulvovaginal candidiasis is incomplete since vulvovaginal candidiasis is not reportable.[196] Women with HIV have more frequent episodes of vulvovaginal candidiasis than women without HIV.[197,198] In addition, with more advanced HIV disease, vulvovaginal candidiasis is often more severe and may recur more frequently.

Pathogenesis and Microbiology

Candida species are normal flora of the vagina and are not considered a sexually transmitted pathogen. Indeed, an estimated 20% of healthy women who have no vulvovaginal symptoms will have Candida species isolated from their vagina.[192] Disruption in the host vaginal environment, however, can cause Candida organisms to transition from a commensal to a pathogenic role.[193] Yeast blastospores are typically responsible for asymptomatic colonization, whereas mycelia (pseudohyphae or hyphae forms) cause symptomatic vaginitis through overgrowth and adherence to vaginal epithelial cells (Figure 12).[192] Destruction of host tissue by Candida species is mediated by hydrolytic enzymes that promote adhesion and host tissue penetration, as well as other virulence factors, such as biofilm formation and phenotypic switching.[193] In the United States, Candida albicans strains are responsible for 85 to 95% of cases of vulvovaginal candidiasis, with the remainder due to non-albicans Candida isolates, most commonly C. glabrata.[192] Fluconazole resistance is most often associated with significant prior azole exposure.[199,200]

Factors Associated with Vulvovaginal Candidiasis

Although most women with vulvovaginal candidiasis do not have specific risk factors associated with vulvovaginal candidiasis, those with frequent, complicated, and/or severe vulvovaginal candidiasis have a number of factors that have been identified, including host factors (uncontrolled diabetes, corticosteroids, repeated courses of antibiotics, pregnancy, HIV, hormone replacement therapy), behavioral factors (sexual practices, use of oral contraceptives, intrauterine devices, condoms, and spermicide), and genetic predisposition.[192,193,194]

Classification of Vulvovaginal Candidiasis

On the basis of clinical presentation, host immunity, and pathogen factors, vulvovaginal candidiasis is classified as either uncomplicated or complicated (Table 3).[198,201,202] Among all women who develop vulvovaginal candidiasis, approximately 10 to 20% will have complicated vulvovaginal candidiasis. Distinguishing uncomplicated from complicated vulvovaginal candidiasis is important, as it influences treatment decisions in most instances. The management of complicated vulvovaginal candidiasis requires unique diagnostic and treatment considerations.[198]

Clinical Manifestations

Vulvovaginal candidiasis characteristically manifests with multiple vaginal symptoms that may include pruritus, vaginal soreness, dyspareunia, external vulvar burning, external dysuria, and, in some, abnormal vaginal discharge.[2,192,195] When vaginal discharge is present, it is typically described as odorless, thick, white, and clumpy (“cottage-cheese-like”) (Figure 13), but it may be thin or watery.[192] Vulvar and labial erythema, fissures, and satellite papular lesions may also be present.[192] Symptoms associated with vulvovaginal candidiasis tend to flare prior to the onset of menses.

Diagnostic Methods

The clinical symptoms of vulvovaginal candidiasis overlap with other causes of vaginitis, so diagnostic evaluation is recommended. Most women with symptomatic vulvovaginal candidiasis can be readily diagnosed based on a microscopic examination of vaginal secretions. A vaginal Gram stain is not recommended for the diagnosis of vulvovaginal candidiasis.

• Vaginal pH: The vaginal pH is typically normal (less than 4.5) in the setting of vulvovaginal candidiasis. If the pH is abnormally high (greater than 4.5), it suggests an alternative diagnosis of bacterial vaginosis, trichomoniasis, or a mixed vaginal infection.
• Wet Mount with Potassium Hydroxide (KOH) and/or Saline: Visualization under microscopy of pseudohyphae (mycelia) and/or budding yeast (conidia) on 10% KOH wet prep examination or saline wet mount can confirm the diagnosis of candidiasis (Figure 14). Use of the 10% KOH preparation dissolves many of the host cells and thus improves sensitivity when compared with the saline wet mount.[192] Microscopy is also useful in differentiating candidiasis from bacterial vaginosis and T. vaginalis. Most women with vulvovaginal candidiasis do not have abundant white blood cells visualized on microscopy. Large numbers of white blood cells indicate a mixed infection or a diagnosis other than vulvovaginal candidiasis.
• Culture: For those with negative wet mounts but existing signs or symptoms worrisome for vulvovaginal candidiasis, fungal culture for Candida species should be considered. Identifying Candida species by vaginal fungal culture in the absence of symptoms or signs is not an indication for treatment because approximately 10 to 20% of healthy women harbor Candida species in the vagina.[192] In women with complicated vulvovaginal candidiasis, however, fungal cultures are indicated to confirm the diagnosis and to detect non-albicans species; this is particularly important for identifying C. glabrata since this organism only forms blastospores and is easily missed on microscopy.[198] In addition, fungal cultures (with resistance testing) should be performed in women with recurrent vulvovaginal candidiasis who have persistent symptoms while receiving maintenance antifungal therapy.[198,200] Because non-albicans species are present in about 10 to 20% of women with recurrent vulvovaginal candidiasis, some experts would obtain vaginal fungal cultures prior to initiating suppressive therapy for vulvovaginal candidiasis.
• Nucleic Acid Amplification Tests: There are now multiple FDA-approved NAAT tests for diagnosing vulvovaginal candidiasis in symptomatic women.
  • BD Max Vaginal Panel (Beckton Dickinson): Candida results reported from the BD Max Vaginal Panel include Candida species group (C. albicans, C. tropicalis, C. parapsilosis, C. dubliniensis) and C. glabrata-C. krusei. Test sensitivity is 90.9%, and specificity is 94.1% for the Candida species group. Sensitivity for C. glabrata was 75.9%, and specificity was 99.7%.
  • Aptima CV/TV Assay (Hologic): Candida results reported from this assay include Candida species group (C. albicans, C. tropicalis, C. parapsilosis, C. dubliniensis) and C. glabrata. The sensitivity and specificity of this assay are 91.7% and 94.9% for the Candida species group and 84.7% and 99.1% for C. glabrata, respectively.
  • Gene Xpert Xpress MVP (Cepheid): The Xpert Xpress MVP is a CLIA-waived on-demand diagnostic PCR test that detects DNA targets Candida species as well as T. aginalis and anaerobic bacteria associated with BV (F. vaginae, BVAB-2, and Megasphaera type 1). Results related to Candida report Candida spp. group (C. albicans, C. tropicalis, C. parapsilosis, C. dubliniensis) and C. glabrata-C. krusei.

Treatment of Uncomplicated Vulvovaginal Candidiasis

Treatment Options

There are multiple recommended short-course, over-the-counter, and prescription formulations for intravaginal antifungal treatments for women with uncomplicated vulvovaginal candidiasis.[198] For women who prefer oral therapy, 150 mg of fluconazole in a single dose is an option.[198] In addition, ibrexafungerp, a novel oral glucan synthase inhibitor, was FDA-approved in June 2021 for the treatment of uncomplicated candidal vulvovaginitis; ibrexafungerp is dosed 300 mg orally twice daily for one day (this medication is not currently available in the United States due to problems with production).[203,204] The short-course topical formulations are effective in treating uncomplicated vulvovaginal candidiasis, and topical azole drugs are more effective than topical nystatin. An estimated 80 to 90% of women with vulvovaginal candidiasis who complete treatment with an azole have relief in symptoms and negative fungal cultures. Of note, the topical intravaginal azole creams and suppositories are oil-based and may potentially weaken latex condoms and diaphragms.[198] Thus, women receiving treatment with a topical antifungal intravaginal cream should abstain from sex during treatment or use a form of birth control that does not rely on a condom or diaphragm.

Management of Sex Partners

Since vulvovaginal candidiasis is not sexually transmitted, there is no treatment necessary for asymptomatic sex partners of women with uncomplicated vulvovaginal candidiasis. Balanitis caused by Candida species is an uncommon finding in men and may be due to factors other than penile-vaginal sex, including age over 40, diabetes mellitus, or uncircumcised status.[205] Men with Candida balanitis should be treated with 7 days of topical antifungal therapy, or a single 150-mg dose of oral fluconazole.[205,206]

Post-Treatment Follow-Up

Follow-up after treatment of uncomplicated vulvovaginal candidiasis is not necessary. Women should seek reevaluation if symptoms persist or recur, since this could indicate complicated disease.

Treatment of Complicated Vulvovaginal Candidiasis

Treatment of Severe Vulvovaginal Candidiasis

Severe disease, which can involve significant skin breakdown, fissuring, and edema, requires treatment with 7 to 14 days of topical azole therapy or two doses of oral fluconazole 150 mg given 72 hours apart.[198]

Treatment of Recurrent Vulvovaginal Candidiasis

Recurrent vulvovaginal candidiasis—defined as three or more episodes within one year—occurs in fewer than 5% of women with vulvovaginal candidiasis.[191] Among women with recurrent disease, approximately 10 to 20% will have non-albicans species, including C. glabrata, isolated from vaginal cultures. Although most women with recurrent vulvovaginal candidiasis have no predisposing or underlying conditions, some will have a risk factor, such as frequent antibiotic use, diabetes mellitus, or immunosuppression. If culture results show C. albicans, the recommended approach is to use a longer 7- to 14-day initial course of therapy to achieve clinical remission, followed by a 6-month maintenance regimen.[198] The goal of the intensive initial therapy is to achieve mycologic remission before initiating maintenance therapy.

• Fluconazole: The preferred oral initial therapy consists of fluconazole given as a 100 mg, 150 mg, or 200 mg oral dose every third day (days 1, 4, and 7) for a total of 3 doses. The preferred maintenance therapy consists of oral fluconazole (100, 150, or 200 mg) given weekly for 6 months; maintenance therapy has been demonstrated to reduce episodes of vulvovaginal candidiasis, but symptoms recur in about 30 to 50% of women once maintenance therapy is stopped.
• Topical Intravaginal Imidazole Therapy: The use of topical therapy for 7 to 14 days is an option for the initial course. Typically, this is followed by oral fluconazole maintenance therapy. For women who cannot take oral fluconazole maintenance therapy, topical azole therapy given intermittently can be used as an alternative.
• Oteseconazole: In 2022, oral oteseconazole was FDA-approved for the treatment of recurrent candidiasis in women who are not of reproductive potential. This approval occurred following several randomized, controlled trials that showed high efficacy of oteseconazole in reducing the incidence of recurrent vulvovaginal infections.[207,208] The recommended dosing for oral oteseconazole is 600 mg orally on day 1, then 450 mg on day 2, then beginning on day 14, weekly 150 mg oral dosing for 11 weeks. Alternatively, oteseconazole can be started following an initial course of oral fluconazole. With this approach, oral fluconazole is given as a 150 mg dose every 72 hours for three doses (given on days 1, 4, and 7), and then on days 14-20, oteseconazole is given as 150-mg oral daily dosing for 6 days, followed by weekly 150 mg dosing beginning on day 28 and continued for 11 weeks.
• Ibrexafungerp: In 2022, ibrexafungerp was FDA-approved for the treatment of recurrent candidiasis. Ibrexafungerp is dosed orally 300 mg twice daily for six months following administration of fluconazole 150 mg orally every 72 hours for three doses.[209] This medication was recalled in September 2023 due to possible cross-contamination with a non-antibacterial drug, and it has not been available since the recall.

Treatment of Non-albicans Vulvovaginal Candidiasis

There are limited data on the treatment of non-albicans vulvovaginal candidiasis, and the optimal treatment approach is not known.[210] Strategies usually employ treatment of non-albicans vulvovaginal candidiasis with a 7- to 14-day course of a non-fluconazole azole, either oral or topical.[198] If this approach fails, intravaginal boric acid (600 mg in a gelatin capsule inserted nightly for 3 weeks) is a reasonable option, with expected high clinical and mycologic response rates.[198,210,211] If all of these measures fail, consultation with a specialist is advised.

Treatment of Immunocompromised Women

Women with diabetes, underlying immunodeficiency, or immunosuppressive therapy (e.g. chronic corticosteroids) should receive longer courses of antifungal therapy—typically a course lasting 7 to 14 days.[198]

Treatment of Women with HIV

Women with HIV and vulvovaginal candidiasis (complicated or uncomplicated) should receive the same treatment as women without HIV.[198] If topical therapies are chosen, it is especially important to counsel women with HIV that the available creams and suppositories are oil-based and might weaken latex condoms. With more advanced HIV disease, vulvovaginal candidiasis is often more severe and may recur more frequently, but primary prophylactic fluconazole therapy is not recommended in these women.[198,212]

Treatment of Women During Pregnancy

The recommended treatment of vulvovaginal candidiasis in pregnant women is a 7-day course of a topical (intravaginal) azole cream.[198] Oral fluconazole should not be used in pregnancy due to several reports that suggested a possible association of oral fluconazole with spontaneous abortion and possible teratogenicity.[213,214] Both oteseconazole and ibrexafungerp are contraindicated for use during pregnancy.[215]

Management of Sex Partners

Insufficient data exist regarding the treatment of sex partners of women who have complicated vulvovaginal candidiasis. Accordingly, there are no recommendations for or against treating male sex partners in this setting.[198]

Counseling and Education

Patient counseling and education about vulvovaginal candidiasis should cover the nature of the disease, transmission issues, and risk reduction.

Nature of the Disease

• Asymptomatic colonization with Candida species is common and does not require treatment.
• Symptomatic vulvovaginal candidiasis is caused by a disruption of the normal vaginal microbiota by various factors, including pregnancy, diabetes, hormonal contraception, sexual activity, and immunosuppressive conditions.
• Women with symptomatic vulvovaginal candidiasis should be treated with antifungal therapy.
• Women with complicated vulvovaginal candidiasis typically require longer courses of antifungal therapy.

Transmission Issues

• Vulvovaginal candidiasis is not considered a sexually transmitted infection, although there are some cases of male sex partners developing Candida balanitis as a result of penile-vaginal sex.

Risk Reduction

• Avoid douching.
• Avoid unnecessary antibiotic use.
• Avoid repeated courses of self-administered, over-the-counter antifungal therapy in settings where no laboratory diagnosis has been confirmed.
• Complete the full course of any prescribed therapy.
• Optimize the management of other concurrent illnesses, such as diabetes mellitus and HIV.

• The three most common conditions diagnosed among women with vaginal symptoms presenting in the primary care setting are bacterial vaginosis, vulvovaginal candidiasis, and trichomoniasis.
• The normal vagina has abundant and dominant Lactobacillus species and a pH that is less than 3.8 to 4.5.
• Vaginitis is primarily a clinical diagnosis, but a wide variety of diagnostic tests are available, including point-of-care tests, culture, molecular detection methods (PCR, NAAT), and indirect testing for enzymatic activity.
• Women with symptomatic bacterial vaginosis typically present with a homogenous, white or gray vaginal discharge that often has a “fishy” odor. Bacterial vaginosis has been linked to several obstetrical and gynecologic complications.
• The preferred treatments for bacterial vaginosis are oral metronidazole (500 mg twice daily for 7 days), 0.75% metronidazole gel (5 grams applied intravaginally once daily for 5 days), or intravaginal 2% clindamycin cream (5 grams applied intravaginally at bedtime for 7 days).
• Women with symptomatic trichomoniasis usually have a characteristic “frothy” gray or yellow-green vaginal discharge and pruritus. Trichomoniasis increases the risk of premature rupture of membranes and preterm labor.
• The preferred treatment for trichomoniasis in women is a 7-day course of oral metronidazole (500 mg twice daily); for men, the preferred treatment is a single 2-gram dose of oral metronidazole.
• Vulvovaginal candidiasis characteristically presents with symptoms of pruritus, vaginal soreness, dyspareunia, vulvar burning, external dysuria, and abnormal vaginal discharge.
• Vulvovaginal candidiasis is classified as either uncomplicated or complicated based on clinical presentation, host immunity, and pathogen factors.
• Uncomplicated vulvovaginal candidiasis can be treated with a wide array of short-course topical antifungal agents or a single 150 mg dose of oral fluconazole.