Jennifer Horton, DO

Antifungal medications for intravaginal use have been available in the United States for more than a decade. Women may be inclined to self-diagnose yeast infections with any vaginal discharge or other vulvovaginal symptoms that they deem abnormal. As we saw in the first part of this article, “Abnormal vaginal discharge: Using office diagnostic testing more effectively” (JFP2004; 53[10]:805–814), abnormal discharge is more likely to be bacterial vaginosis or no pathogen at all. Potential delay in diagnosis and treatment of a sexually transmitted disease is also a concern. Increasing resistance of Candida sp. to imidazoles is associated with indiscriminate use of over-the-counter products.

Bacterial vaginosis

The standard treatment for bacterial vaginosis (BV) has been oral metronidazole (Flagyl) 500 mg twice daily for 5 to 7 days. Intravaginal 0.75% metronidazole gel (MetroGel) has been shown to be as effective as oral metronidazole (SOR: A).^1,2

Oral metronidazole can cause nausea and abdominal pain in some patients; vaginal treatment may be preferable for them. A meta-analysis of 52 studies of regimens of oral metronidazole at a dose of 2 g daily of varying duration showed similar initial cure rates of 85%, 87%, 86%, and 87% for 1, 2, 5, and 7 days, respectively (strength of recommendation [SOR]: A).³ Single-dose therapy may improve adherence (SOR: C).

Clindamycin (Cleocin), orally or in vaginal cream, for 5 days is also effective for BV (SOR: A).^4-8 Clindamycin cream is used at a dose of 5 g daily and a concentration of 2%. Lower concentration (1%) has been less effective.⁶ Oral regimens range from 300 mg twice daily to 450 mg 3 times daily. Oral and vaginal preparations have shown equal efficacy in direct comparisons (SOR: A).⁸ A 3-day course of vaginal clindamycin is as effective as a 5-day course (SOR: B).⁹

Several studies have compared clindamycin and metronidazole head to head. They have shown similar cure rates that were not statistically different in the 75% to 90% range (SOR: A).^4,5,10,11 Other antibiotics that have shown in vitro efficacy for treating the spectrum of microbes associated with BV are amoxicillin-clavulanate (Augmentin), imipenem (Primaxin), and cefmetazole (Zefazone) (SOR: C).^8,12 Some Mobiluncus strains show resistance to metronidazole (SOR: C).¹²

Recurrences of BV are common. The initial regimen or an alternative regimen may be used. A longer, 10- to 14-day, course of antibiotic therapy has been recommended by one expert for treating relapses (SOR: C).¹³ Recolonizing the vagina with lactobacilli by eating yogurt or using bacteria-containing suppositories is an approach that deserves further study (SOR: C).¹⁴ Suppressive therapy such as intravaginal metronidazole twice weekly may also be considered as maintenance therapy to prevent recurrences (SOR: C).

BV and pregnancy

A number of studies have been published on screening for BV in pregnancy using Gram stain and on treating positive cases with antibiotics. While studies that used metronidazole for treatment have not shown consistently good results, more recent studies using clindamycin orally or intravaginally have been promising (SOR: B).^7,15 Oral dosing at 300 mg twice daily, at 12 to 22 weeks gestation, has reduced preterm delivery for pregnant women with BV diagnosed by Nugent’s criteria (number needed to treat [NNT]=10).⁷ Likewise, for women with BV treated at 13 to 20 weeks gestation, intravaginal clindamycin therapy for 3 days has reduced the incidence of preterm births (NNT=17).¹⁵

Clindamycin appears to be the treatment of choice for BV in pregnancy (SOR: C) since it is considered safe (category B) throughout pregnancy, and because use of metronidazole in the first trimester is controversial.

Candidiasis

Treating vulvovaginal candidiasis (VVC) with intravaginal imidazoles reduces symptoms with NNT=3 after 1 month (SOR: A) ( Table ).¹⁶ No difference has been seen in outcomes with the various imidazoles or with treatment durations of 1 to 14 days. Intravaginal nystatin also decreases symptoms of VVC, with a NNT of 3 after 1 week compared with placebo (SOR: B).

Data showing that imidazoles are more effective than nystatin are not strong (SOR: B). A Clinical Evidencereview¹⁶ identified 1 trial comparing intravaginal miconazole, clotrimazole, econazole, and nystatin; symptomatic relapse was lower with intravaginal imidazoles than with nystatin. Another trial comparing clotrimazole and nystatin showed no difference in the proportion of women with persistent symptoms after 4 weeks. An open label study¹⁷ comparing econazole, miconazole, and nystatin showed that the imidazoles had more antifungal activity, but there was no difference in clinical outcome assessment.

Oral treatments are popular, most commonly a single dose of fluconazole. Oral itraconazole and ketoconazole have also been used successfully (SOR: A).^18-21 A systematic review of oral vs vaginal azoles showed similar efficacy, but more side effects occurred with oral therapy (SOR: A).²² Gastrointestinal side effects occur in up to 15% of women.²³

TABLE

Antifungal medications used to treat vulvovaginal candidiasis

Treating complicated VVC

About 5% of women diagnosed with VVC will have frequent recurrences, 4 or more per year.²⁴ Current therapies are fungistatic rather than fungicidal, so the yeast are reduced but not eradicated. Hypersensitivity and allergic reactions to topical preparations may be confused with recurrences. Experts recommend that, if wet mount or culture results confirm recurrent vaginitis, topical therapy should be increased from 5 to 7 days up to 10 to 14 days, or that a second oral fluconazole tablet be given 3 days after the first (SOR: C).²⁴ Women with severe cases of VVC also benefit from 2 sequential doses of fluconazole given 3 days apart (SOR: B).²⁵

Suppressive therapy may be used after initial treatment for 6 months or more (SOR: B). Suppressive therapy options include oral fluconazole 150 mg or vaginal clotrimazole 500 mg once a week, oral or intravaginal nystatin twice weekly, and oral itraconazole 200 mg monthly.^24,26

Non-albicans species tend to be more resistant to oral and topical azoles (SOR: B).^27-29 If this species is detected on culture, a long course of suppressive therapy should be attempted (SOR: C).²⁴ If imidazole therapy fails to control symptoms, suspect resistance.

Resistance to azoles may be demonstrated by in vitro susceptibility testing. Cross-resistance to topical and oral (fluconazole) azoles has been documented.³⁰ There have been few studies of alternatives to azoles for treatment of resistant yeast vaginitis. One little-studied alternative is intravaginal boric acid, which may be used as a 14-day course of 600 mg daily in gelatin capsules (SOR: C).³¹ Nystatin and flucytosine (Ancoban) for 7 to 14 days are other alternatives (SOR: C).²⁴

Candida in pregnancy

Commonly used topical imidazoles are classified as category C in pregnancy and have not been associated with increased risk of birth defects.

Trichomoniasis

Current treatment for trichomoniasis is oral metronidazole, given as a 2-g single dose, 250 mg 3 times daily for 7 days or 500 mg twice a day for 7 days. Treatment should also be given to the woman’s partner (SOR: A).³² Intravaginal therapy is not effective, probably due to the parasite’s presence in inaccessible areas such as the vaginal glands and urethra.^33,34 Short-term treatment is comparable with long-term treatment, with similar rates of nausea and vomiting (SOR: A).³² A 1.5-g single-dose treatment has been shown to be equivalent to 2 g (SOR: B).³⁵

The incidence metronidazole-resistant trichomoniasis has been estimated at 5%.³⁶ In such cases, higher-dose therapy may be still be effective. For low to moderate resistance, 2 too 2.5 g daily for 3 to 10 days has been recommended (SOR: B).³⁷ Intravenous high-dose metronidazole, 2 g every 8 hours for 3 days, has been reported to successfully treat highly resistant trichomonas (SOR: C).³⁸ Another case report of 2 women with presumed allergy to metronidazole were successfully treated with incremental dosing of IV metronidazole (SOR: C).³⁹ A small case series of women with metronidazole allergy or resistance treated with paromomycin cream intravaginally showed cure in 6 of 9 cases (SOR: C).⁴⁰ Oral tinidazole has been approved in 2004 for use in the treatment of metronidazole-resistant trichomoniasis (SOR: B).⁴¹

Corresponding author
Linda French, MD, Associate Professor, Department of Family Practice, College of Human Medicine, Michigan State University, B101 Clinical Center, East Lansing, MI 48824. E-mail: Linda.French@ht.msu.edu.

Antifungal medications for intravaginal use have been available in the United States for more than a decade. Women may be inclined to self-diagnose yeast infections with any vaginal discharge or other vulvovaginal symptoms that they deem abnormal. As we saw in the first part of this article, “Abnormal vaginal discharge: Using office diagnostic testing more effectively” (JFP2004; 53[10]:805–814), abnormal discharge is more likely to be bacterial vaginosis or no pathogen at all. Potential delay in diagnosis and treatment of a sexually transmitted disease is also a concern. Increasing resistance of Candida sp. to imidazoles is associated with indiscriminate use of over-the-counter products.

Bacterial vaginosis

The standard treatment for bacterial vaginosis (BV) has been oral metronidazole (Flagyl) 500 mg twice daily for 5 to 7 days. Intravaginal 0.75% metronidazole gel (MetroGel) has been shown to be as effective as oral metronidazole (SOR: A).^1,2

Oral metronidazole can cause nausea and abdominal pain in some patients; vaginal treatment may be preferable for them. A meta-analysis of 52 studies of regimens of oral metronidazole at a dose of 2 g daily of varying duration showed similar initial cure rates of 85%, 87%, 86%, and 87% for 1, 2, 5, and 7 days, respectively (strength of recommendation [SOR]: A).³ Single-dose therapy may improve adherence (SOR: C).

Clindamycin (Cleocin), orally or in vaginal cream, for 5 days is also effective for BV (SOR: A).^4-8 Clindamycin cream is used at a dose of 5 g daily and a concentration of 2%. Lower concentration (1%) has been less effective.⁶ Oral regimens range from 300 mg twice daily to 450 mg 3 times daily. Oral and vaginal preparations have shown equal efficacy in direct comparisons (SOR: A).⁸ A 3-day course of vaginal clindamycin is as effective as a 5-day course (SOR: B).⁹

Several studies have compared clindamycin and metronidazole head to head. They have shown similar cure rates that were not statistically different in the 75% to 90% range (SOR: A).^4,5,10,11 Other antibiotics that have shown in vitro efficacy for treating the spectrum of microbes associated with BV are amoxicillin-clavulanate (Augmentin), imipenem (Primaxin), and cefmetazole (Zefazone) (SOR: C).^8,12 Some Mobiluncus strains show resistance to metronidazole (SOR: C).¹²

Recurrences of BV are common. The initial regimen or an alternative regimen may be used. A longer, 10- to 14-day, course of antibiotic therapy has been recommended by one expert for treating relapses (SOR: C).¹³ Recolonizing the vagina with lactobacilli by eating yogurt or using bacteria-containing suppositories is an approach that deserves further study (SOR: C).¹⁴ Suppressive therapy such as intravaginal metronidazole twice weekly may also be considered as maintenance therapy to prevent recurrences (SOR: C).

BV and pregnancy

A number of studies have been published on screening for BV in pregnancy using Gram stain and on treating positive cases with antibiotics. While studies that used metronidazole for treatment have not shown consistently good results, more recent studies using clindamycin orally or intravaginally have been promising (SOR: B).^7,15 Oral dosing at 300 mg twice daily, at 12 to 22 weeks gestation, has reduced preterm delivery for pregnant women with BV diagnosed by Nugent’s criteria (number needed to treat [NNT]=10).⁷ Likewise, for women with BV treated at 13 to 20 weeks gestation, intravaginal clindamycin therapy for 3 days has reduced the incidence of preterm births (NNT=17).¹⁵

Clindamycin appears to be the treatment of choice for BV in pregnancy (SOR: C) since it is considered safe (category B) throughout pregnancy, and because use of metronidazole in the first trimester is controversial.

Candidiasis

Treating vulvovaginal candidiasis (VVC) with intravaginal imidazoles reduces symptoms with NNT=3 after 1 month (SOR: A) ( Table ).¹⁶ No difference has been seen in outcomes with the various imidazoles or with treatment durations of 1 to 14 days. Intravaginal nystatin also decreases symptoms of VVC, with a NNT of 3 after 1 week compared with placebo (SOR: B).

Data showing that imidazoles are more effective than nystatin are not strong (SOR: B). A Clinical Evidencereview¹⁶ identified 1 trial comparing intravaginal miconazole, clotrimazole, econazole, and nystatin; symptomatic relapse was lower with intravaginal imidazoles than with nystatin. Another trial comparing clotrimazole and nystatin showed no difference in the proportion of women with persistent symptoms after 4 weeks. An open label study¹⁷ comparing econazole, miconazole, and nystatin showed that the imidazoles had more antifungal activity, but there was no difference in clinical outcome assessment.

Oral treatments are popular, most commonly a single dose of fluconazole. Oral itraconazole and ketoconazole have also been used successfully (SOR: A).^18-21 A systematic review of oral vs vaginal azoles showed similar efficacy, but more side effects occurred with oral therapy (SOR: A).²² Gastrointestinal side effects occur in up to 15% of women.²³

TABLE

Antifungal medications used to treat vulvovaginal candidiasis

Treating complicated VVC

About 5% of women diagnosed with VVC will have frequent recurrences, 4 or more per year.²⁴ Current therapies are fungistatic rather than fungicidal, so the yeast are reduced but not eradicated. Hypersensitivity and allergic reactions to topical preparations may be confused with recurrences. Experts recommend that, if wet mount or culture results confirm recurrent vaginitis, topical therapy should be increased from 5 to 7 days up to 10 to 14 days, or that a second oral fluconazole tablet be given 3 days after the first (SOR: C).²⁴ Women with severe cases of VVC also benefit from 2 sequential doses of fluconazole given 3 days apart (SOR: B).²⁵

Suppressive therapy may be used after initial treatment for 6 months or more (SOR: B). Suppressive therapy options include oral fluconazole 150 mg or vaginal clotrimazole 500 mg once a week, oral or intravaginal nystatin twice weekly, and oral itraconazole 200 mg monthly.^24,26

Non-albicans species tend to be more resistant to oral and topical azoles (SOR: B).^27-29 If this species is detected on culture, a long course of suppressive therapy should be attempted (SOR: C).²⁴ If imidazole therapy fails to control symptoms, suspect resistance.

Resistance to azoles may be demonstrated by in vitro susceptibility testing. Cross-resistance to topical and oral (fluconazole) azoles has been documented.³⁰ There have been few studies of alternatives to azoles for treatment of resistant yeast vaginitis. One little-studied alternative is intravaginal boric acid, which may be used as a 14-day course of 600 mg daily in gelatin capsules (SOR: C).³¹ Nystatin and flucytosine (Ancoban) for 7 to 14 days are other alternatives (SOR: C).²⁴

Candida in pregnancy

Commonly used topical imidazoles are classified as category C in pregnancy and have not been associated with increased risk of birth defects.

Trichomoniasis

Current treatment for trichomoniasis is oral metronidazole, given as a 2-g single dose, 250 mg 3 times daily for 7 days or 500 mg twice a day for 7 days. Treatment should also be given to the woman’s partner (SOR: A).³² Intravaginal therapy is not effective, probably due to the parasite’s presence in inaccessible areas such as the vaginal glands and urethra.^33,34 Short-term treatment is comparable with long-term treatment, with similar rates of nausea and vomiting (SOR: A).³² A 1.5-g single-dose treatment has been shown to be equivalent to 2 g (SOR: B).³⁵

The incidence metronidazole-resistant trichomoniasis has been estimated at 5%.³⁶ In such cases, higher-dose therapy may be still be effective. For low to moderate resistance, 2 too 2.5 g daily for 3 to 10 days has been recommended (SOR: B).³⁷ Intravenous high-dose metronidazole, 2 g every 8 hours for 3 days, has been reported to successfully treat highly resistant trichomonas (SOR: C).³⁸ Another case report of 2 women with presumed allergy to metronidazole were successfully treated with incremental dosing of IV metronidazole (SOR: C).³⁹ A small case series of women with metronidazole allergy or resistance treated with paromomycin cream intravaginally showed cure in 6 of 9 cases (SOR: C).⁴⁰ Oral tinidazole has been approved in 2004 for use in the treatment of metronidazole-resistant trichomoniasis (SOR: B).⁴¹

Corresponding author
Linda French, MD, Associate Professor, Department of Family Practice, College of Human Medicine, Michigan State University, B101 Clinical Center, East Lansing, MI 48824. E-mail: Linda.French@ht.msu.edu.

Antifungal medications for intravaginal use have been available in the United States for more than a decade. Women may be inclined to self-diagnose yeast infections with any vaginal discharge or other vulvovaginal symptoms that they deem abnormal. As we saw in the first part of this article, “Abnormal vaginal discharge: Using office diagnostic testing more effectively” (JFP2004; 53[10]:805–814), abnormal discharge is more likely to be bacterial vaginosis or no pathogen at all. Potential delay in diagnosis and treatment of a sexually transmitted disease is also a concern. Increasing resistance of Candida sp. to imidazoles is associated with indiscriminate use of over-the-counter products.

Bacterial vaginosis

The standard treatment for bacterial vaginosis (BV) has been oral metronidazole (Flagyl) 500 mg twice daily for 5 to 7 days. Intravaginal 0.75% metronidazole gel (MetroGel) has been shown to be as effective as oral metronidazole (SOR: A).^1,2

Oral metronidazole can cause nausea and abdominal pain in some patients; vaginal treatment may be preferable for them. A meta-analysis of 52 studies of regimens of oral metronidazole at a dose of 2 g daily of varying duration showed similar initial cure rates of 85%, 87%, 86%, and 87% for 1, 2, 5, and 7 days, respectively (strength of recommendation [SOR]: A).³ Single-dose therapy may improve adherence (SOR: C).

Clindamycin (Cleocin), orally or in vaginal cream, for 5 days is also effective for BV (SOR: A).^4-8 Clindamycin cream is used at a dose of 5 g daily and a concentration of 2%. Lower concentration (1%) has been less effective.⁶ Oral regimens range from 300 mg twice daily to 450 mg 3 times daily. Oral and vaginal preparations have shown equal efficacy in direct comparisons (SOR: A).⁸ A 3-day course of vaginal clindamycin is as effective as a 5-day course (SOR: B).⁹

Several studies have compared clindamycin and metronidazole head to head. They have shown similar cure rates that were not statistically different in the 75% to 90% range (SOR: A).^4,5,10,11 Other antibiotics that have shown in vitro efficacy for treating the spectrum of microbes associated with BV are amoxicillin-clavulanate (Augmentin), imipenem (Primaxin), and cefmetazole (Zefazone) (SOR: C).^8,12 Some Mobiluncus strains show resistance to metronidazole (SOR: C).¹²

Recurrences of BV are common. The initial regimen or an alternative regimen may be used. A longer, 10- to 14-day, course of antibiotic therapy has been recommended by one expert for treating relapses (SOR: C).¹³ Recolonizing the vagina with lactobacilli by eating yogurt or using bacteria-containing suppositories is an approach that deserves further study (SOR: C).¹⁴ Suppressive therapy such as intravaginal metronidazole twice weekly may also be considered as maintenance therapy to prevent recurrences (SOR: C).

BV and pregnancy

A number of studies have been published on screening for BV in pregnancy using Gram stain and on treating positive cases with antibiotics. While studies that used metronidazole for treatment have not shown consistently good results, more recent studies using clindamycin orally or intravaginally have been promising (SOR: B).^7,15 Oral dosing at 300 mg twice daily, at 12 to 22 weeks gestation, has reduced preterm delivery for pregnant women with BV diagnosed by Nugent’s criteria (number needed to treat [NNT]=10).⁷ Likewise, for women with BV treated at 13 to 20 weeks gestation, intravaginal clindamycin therapy for 3 days has reduced the incidence of preterm births (NNT=17).¹⁵

Clindamycin appears to be the treatment of choice for BV in pregnancy (SOR: C) since it is considered safe (category B) throughout pregnancy, and because use of metronidazole in the first trimester is controversial.

Candidiasis

Treating vulvovaginal candidiasis (VVC) with intravaginal imidazoles reduces symptoms with NNT=3 after 1 month (SOR: A) ( Table ).¹⁶ No difference has been seen in outcomes with the various imidazoles or with treatment durations of 1 to 14 days. Intravaginal nystatin also decreases symptoms of VVC, with a NNT of 3 after 1 week compared with placebo (SOR: B).

Data showing that imidazoles are more effective than nystatin are not strong (SOR: B). A Clinical Evidencereview¹⁶ identified 1 trial comparing intravaginal miconazole, clotrimazole, econazole, and nystatin; symptomatic relapse was lower with intravaginal imidazoles than with nystatin. Another trial comparing clotrimazole and nystatin showed no difference in the proportion of women with persistent symptoms after 4 weeks. An open label study¹⁷ comparing econazole, miconazole, and nystatin showed that the imidazoles had more antifungal activity, but there was no difference in clinical outcome assessment.

Oral treatments are popular, most commonly a single dose of fluconazole. Oral itraconazole and ketoconazole have also been used successfully (SOR: A).^18-21 A systematic review of oral vs vaginal azoles showed similar efficacy, but more side effects occurred with oral therapy (SOR: A).²² Gastrointestinal side effects occur in up to 15% of women.²³

TABLE

Antifungal medications used to treat vulvovaginal candidiasis

Treating complicated VVC

About 5% of women diagnosed with VVC will have frequent recurrences, 4 or more per year.²⁴ Current therapies are fungistatic rather than fungicidal, so the yeast are reduced but not eradicated. Hypersensitivity and allergic reactions to topical preparations may be confused with recurrences. Experts recommend that, if wet mount or culture results confirm recurrent vaginitis, topical therapy should be increased from 5 to 7 days up to 10 to 14 days, or that a second oral fluconazole tablet be given 3 days after the first (SOR: C).²⁴ Women with severe cases of VVC also benefit from 2 sequential doses of fluconazole given 3 days apart (SOR: B).²⁵

Suppressive therapy may be used after initial treatment for 6 months or more (SOR: B). Suppressive therapy options include oral fluconazole 150 mg or vaginal clotrimazole 500 mg once a week, oral or intravaginal nystatin twice weekly, and oral itraconazole 200 mg monthly.^24,26

Non-albicans species tend to be more resistant to oral and topical azoles (SOR: B).^27-29 If this species is detected on culture, a long course of suppressive therapy should be attempted (SOR: C).²⁴ If imidazole therapy fails to control symptoms, suspect resistance.

Resistance to azoles may be demonstrated by in vitro susceptibility testing. Cross-resistance to topical and oral (fluconazole) azoles has been documented.³⁰ There have been few studies of alternatives to azoles for treatment of resistant yeast vaginitis. One little-studied alternative is intravaginal boric acid, which may be used as a 14-day course of 600 mg daily in gelatin capsules (SOR: C).³¹ Nystatin and flucytosine (Ancoban) for 7 to 14 days are other alternatives (SOR: C).²⁴

Candida in pregnancy

Commonly used topical imidazoles are classified as category C in pregnancy and have not been associated with increased risk of birth defects.

Trichomoniasis

Current treatment for trichomoniasis is oral metronidazole, given as a 2-g single dose, 250 mg 3 times daily for 7 days or 500 mg twice a day for 7 days. Treatment should also be given to the woman’s partner (SOR: A).³² Intravaginal therapy is not effective, probably due to the parasite’s presence in inaccessible areas such as the vaginal glands and urethra.^33,34 Short-term treatment is comparable with long-term treatment, with similar rates of nausea and vomiting (SOR: A).³² A 1.5-g single-dose treatment has been shown to be equivalent to 2 g (SOR: B).³⁵

The incidence metronidazole-resistant trichomoniasis has been estimated at 5%.³⁶ In such cases, higher-dose therapy may be still be effective. For low to moderate resistance, 2 too 2.5 g daily for 3 to 10 days has been recommended (SOR: B).³⁷ Intravenous high-dose metronidazole, 2 g every 8 hours for 3 days, has been reported to successfully treat highly resistant trichomonas (SOR: C).³⁸ Another case report of 2 women with presumed allergy to metronidazole were successfully treated with incremental dosing of IV metronidazole (SOR: C).³⁹ A small case series of women with metronidazole allergy or resistance treated with paromomycin cream intravaginally showed cure in 6 of 9 cases (SOR: C).⁴⁰ Oral tinidazole has been approved in 2004 for use in the treatment of metronidazole-resistant trichomoniasis (SOR: B).⁴¹

Corresponding author
Linda French, MD, Associate Professor, Department of Family Practice, College of Human Medicine, Michigan State University, B101 Clinical Center, East Lansing, MI 48824. E-mail: Linda.French@ht.msu.edu.

In primary care practice, abnormal vaginal discharge is a common complaint. Signs and symptoms of vaginitis—the most common gynecologic diagnosis in primary care¹ —are not specific for any single underlying cause.² Officebased diagnostic testing, which is underused,³ must be employed to ensure accurate diagnosis and effective treatment. (An article on treatment by the same authors will appear in next month’s issue of The journal of family practice.)

In a primary-care study,⁴ vulvovaginal symptoms including vaginal discharge were due to vulvovaginal candidiasis (VVC) in 27% of patients, bacterial vaginosis (BV) in 21%, trichomoniasis in 8%, Chlamydia trachomatis in 2%, Neisseria gonorrhea (GC) in 1%, and no infection in 34%. Several pathogens may coexist.² VVC, BV, and trichomoniasis account for at least 90% of infectious vaginitis.⁵ This review will therefore focus heavily on these causes of vaginal discharge among women of reproductive age, including pregnant women.

Cervicitis and physiologic cervical discharge

Some women may interpret a physiologic increase in cervical mucous production as abnormal. It occurs cyclically prior to ovulation, is typically transparent and colorless, and may be more pronounced in women with an everted cervix.

Chlamydial infection

In the clinical examination of the cervix, 3 characteristics have been associated with chlamydial infection: yellow endocervical discharge, easily induced cervical bleeding, and opaque cervical discharge.⁶ All 3 findings are statistically significant and independently associated with chlamydial infection (odds ratios 2.8, 2.3, and 2.9, respectively). In the primary care study cited above, purulent cervical discharge was found in 6% of women, most commonly testing positive for Chlamydia, less often for GC.⁴

Trichomonas vaginalis may cause cervicitis as well as vaginitis. Mycoplasma genitalium has been proposed as an additional possible pathogen. It was identified in 7% of more than 700 women with mucopurulent cervical discharge seen in a STD clinic with otherwise negative cultures.⁷ With cervical discharge that appears to be purulent, testing is warranted as a minimum for Chlamydia and GC (SOR: B). Screening of asymptomatic women less than 26 years of age for Chlamydia is recommended by the US Preventive Services Task Force (SOR: A).

Bacterial Vaginosis

Bacterial vaginosis (BV) is neither an inflammatory condition nor an STD, but is a shift in vaginal flora from the normal condition in which lactobacilli predominate, to a polymicrobial flora in which gram-positive anaerobes predominate. In addition to annoying vaginal symptoms, BV is associated with increased risks of more serious conditions such as pelvic inflammatory disease (PID), postoperative infections, and pregnancyrelated complications including prematurity. It also increases the likelihood of acquiring HIV in women exposed to the virus.^8,9

Two principal factors put women at risk for acquiring BV: douching and exposure to a new sexual partner, both of which are thought to disrupt the vaginal ecosystem.¹⁰

Relative benefits of diagnostic tests

A gold standard test has not been established for BV. In about 50% of asymptomatic women, culture results are positive for flora such as Gardnerella vaginalis.⁵ While Amsel’s criteria are often used as a reference and generally suffice for the evaluation of symptomatic women, the best candidate for a gold standard test is probably Gram stain assessment using Nugent’s criteria (described in this section).¹¹ Lack of leukocytes in the vaginal fluid supports a diagnosis of BV. A finding of white blood cells in excess of the number of vaginal epithelial cells suggests an inflammatory process (SOR: C).¹²

Amsel’s criteria with wet mount. The diagnostic approach most commonly used in the office is Amsel’s criteria—homogenous discharge, positive whiff-amine test, pH >4.5, and clue cells found on wet-mount microscopy (see How to perform a wet mount ).¹³ Three of 4 criteria deemed positive is considered diagnostic. If Gram stain is used as the reference standard, then Amsel’s criteria have 70% sensitivity and 94% specificity for diagnosing BV.¹⁴ An analysis of the individual criteria follows. The positive and negative predictive values of each compared with the whole group as reference standard is displayed in Table 1 .

Homogenous discharge. A thin, homogenous, grayish discharge is traditionally associated with BV. However, it is not specific to BV, being found commonly also in women with culture results positive for VVC or no diagnosis of vaginitis.^2,15 It is the criterion least likely to be consistent with the whole group, seen in about half of women BVpositive and over one third of women BV-negative using Amsel’s criteria as the reference standard. ¹⁵

Whiff test. The whiff test is performed by adding drops of 10% potassium hydroxide solution to the vaginal fluid. A positive result is a “fishy” amine odor. In a study¹⁶ of 100 women complaining of malodorous discharge, a positive whiff test was predictive of positive culture results for anaerobic flora such as Bacteroides sp. with sensitivity 67%, specificity 94%, and a positive predictive value of 95%. The whiff test was not positive in any of the 5 cases with positive culture results for G vaginalis in the absence of anaerobes. There were also 12 cases positive for anaerobes without G vaginalis.

pH >4.5. Since the abnormal flora of BV is consistently associated with a vaginal pH >4.5, a normal pH excludes a diagnosis of BV.^17,18 The determination of pH in the narrow range around 4.5 is not accurate using standard nitrazine paper. Narrower-range test paper is available and more accurate. Examples include pH paper for 4.5 to 5.5 (Micro Essential Laboratory), FemExam pH and Amines Test Card (Litmus Concepts), pHem-ALERT: pH paper on a stick (Imagyn Gynecology). Cervical mucous, semen, and blood are alkaline and can interfere with pH testing. Estrogen production is also necessary to maintain an acidic environment. A pH of 3.8 to 4.5 is consistent with normal vaginal flora in premenopausal women with normal estrogen production.¹⁷

Clue cells. Clue cells are vaginal epithelial cells coated with coccobacilli giving an appearance as if coated with ground black pepper. Clue cells on wet mount preparation is considered the most accurate of Amsel’s diagnostic criteria for BV.¹⁹ On the other hand, office evaluation of the wet mount is considered by some authors to be unreliable due to dependence on the clinician’s microscopy skills and lack of a durable record of the patient sample.

Gram stain a more objective test. A Gram stain evaluation using Nugent’s criteria has been adopted as the gold standard test for research purposes, including studies of prematurity. The Gram-stained vaginal specimen is scored from 0 to 10 based on semi-quantitative assessment of 3 classes of morphotypes ( Table 2 ): large gram-positive rods (Lactobacilli), small gram-negative rods (Gardnerella and Bacteroides spp.), and small curved gram-variable rods (Mobiluncus spp.).¹¹

Diagnosis of BV is typically made when the Nugent score is 7 or more, which appears qualitatively as dominant morphotypes other than Lactobacilli. Gram staining is more objective and reproducible compared with wet-mount examination, with a sensitivity of 93% and specificity of 70% if Amsel’s criteria are used as the gold standard.¹⁴ It is useful for the evaluation of asymptomatic women. It also provides a durable record of the patient specimen. Compared with Gram stain, Amsel’s criteria tend to underdiagnose cases. We can expect that if screening for BV in pregnancy becomes a recommendation, Gram staining in a clinical laboratory will be the recommended method of diagnosis.

Other diagnostic tests for BV. DNA testing for Gardnerella is accurate for detection, but it is not synonymous with a diagnosis of BV, as described.²⁰ DNA testing is further described under “Differential Diagnosis.” Gram staining is more reliable than gas-liquid chromatography²¹ and an assay for proline aminopeptidase (a metabolic product of some of the bacteria associated with BV).²² Latex agglutination testing for vaginal lactoferrin is a nonspecific marker for leukocytes, and thus inflammation. It is of little clinical utility in the diagnosis of vaginal discharge.²³

TABLE 1
Predictive values of Amsel’s criteria (using 3 of 4 positive as diagnostic reference standard)

TABLE 2
How to use Nugent’s Gram stain criteria to diagnose bacterial vaginosis

Vulvovaginal Candidiasis

Candidiasis is the second most commonly diagnosed vaginitis in the United States. Some experts estimate that 75% of women will have a yeast infection at some point in life and 5% will have recurrent infections.²⁴ However, 10% to 30% of asymptomatic women with normal flora have positive culture results for Candida.^25-29 The proportion of symptomatic women with positive culture results is 20% to 40%.^4,30,31 Complications of VVC are rare,³² though vulvar vestibulitis³³ and chorioamnionitis in pregnancy³² have been reported.

Risk factors. Symptomatic yeast vaginitis has been associated with condom and diaphragm use, recent antibiotic use, receptive oral sex, oral contraceptive use, spermicide use, diabetes, and immunosuppression including AIDS.^31,34-37 The associations with antibiotic use and oral contraceptives are not consistent.^30,38 Although pregnancy has been postulated as a risk factor for symptomatic VVC, prevalence of yeast on culture in pregnant women is similar to that of nonpregnant women.³⁰

Suggestive symptoms. Among women with a culture result positive for Candida, the most common symptom is pruritus or burning.²⁸ Abnormal discharge is a complaint for most symptomatic women with VVC confirmed by culture.² In addition, women may complain of a thick, odorless, cottage cheese–like discharge.³⁹ A thick, curdled-appearing discharge points to a diagnosis of Candida because it is rarely present with BV or trichomoniasis. In one study,²⁸ a thick curdled discharge had a positive predictive value of 84% for diagnosis of VVC by culture (SOR: B). However, a thin discharge does not rule out VVC; in another study, clinicians described discharge as thin in about half of women ultimately diagnosed with VVC by culture in another study (SOR: B).² On exam, vulvar and vaginal erythema are often present but are not specific findings. The accuracy of the clinical exam for VVC is poor compared with culture (SOR: A).^2,30

Pathogens. Candida albicans is present in 80% to 90% of patients with VVC.^5,40 remainder have non-albicans species, including C glabrata and others.²⁸ An increase to almost 20% of non-Candida species in a vaginitis clinic by the mid-1990’s may be related to increased use of imidazoles available over-the-counter.^40,41 Wet mount results are typically negative in the presence of non-Candida VVC.²⁸

Diagnosis of VVC

The gold standard test for diagnosis of VVC is culture. The potassium hydroxide (KOH) wet mount is only 40% to 75% sensitive.^28,29,42,43 False-positive results are also observed with variable frequency.⁴⁴ The pH of the discharge is usually not more than 5.0 with Candida albicans, but may be higher with non-albicans species such as C glabrata.⁴⁵ Culture is recommended for patients with recurrent or persistent symptoms and a negative wet mount result (SOR: B).^5,28,46 Rapid slide latex agglutination testing is not better than microscopy (SOR: B).⁴²

Trichomoniasis

Trichomonas, a motile protozoan with 4 flagella, causes the third most common form of vaginitis in the United States and is more common in some developing countries. Trichomoniasis accounts for no more than 10% of all cases of vaginitis, and it appears to be decreasing since the introduction of metronidazole.^47,48 It is classified as an STD, although transmission is possible by other means if the organism is protected from desiccation—for example, in dirty washcloths or towels and contaminated water. Nonsexual transmission is thought to be uncommon.

Trichomoniasis is associated with GC and Chlamydia infections, and, like them, has been associated with seroconversion to HIV-positive status.⁴⁹ Trichomonads are identified in 30% to 80% of male sexual partners of infected women. In men, trichomoniasis most often is an asymptomatic carrier state.⁵⁰ However, it is the cause of about 10% of cases of nongonococcal urethritis in men.⁵¹

Clinical presentations. Women with trichomoniasis have variable presentations ranging from an asymptomatic carrier state to a malodorous, purulent discharge with vulvovaginal erythema. Punctate hemorrhagic cervical lesions are considered pathognomonic of trichomoniasis, but are seen in only about 2% of cases (SOR: B).⁵²

Diagnosis. Culture for trichomoniasis is the gold standard. Several culture media have been used, most commonly the Diamond medium. Recently introduced is a transport and culture medium for detection of Trichomonas (InPouch TV), which performs as well as Diamond medium (SOR: A).^53-55 A DNA probe is also available and accurate (SOR: A).

Motile trichomonads are seen on wet preparation in only 50% to 80% of culture-positive cases (SOR: B).^50,54,56 Polymorphonuclear leukocytes can be dominant on wet mount, making visualization of trichomonads more difficult. The pH of the vaginal fluid is usually basic.

Trichomonas reported with cervical cytology

Trichomonas may also be reported on Pap smears. A meta-analysis⁵⁷ comparing the pooled sensitivities and specificities of wet mounts and cytology demonstrated low sensitivities of 68% and 58%, respectively, and high specificities, 99.9% and 97%, respectively (SOR: A).

However, since cytology carries a 3% false-positive rate, its results are not diagnostic of trichomoniasis in low-risk, asymptomatic women.^50,57 Treatment may be prescribed empirically based on positive cytology results. However, if an asymptomatic woman were concerned about whether she really has an STD, a positive wet prep would confirm the diagnosis. A negative wet prep should be followed up with culture to reliably rule out disease (SOR: B).

Trichomoniasis in pregnancy

Screening for asymptomatic trichomoniasis in pregnancy has not been recommended. In fact, some evidence suggests that treatment of trichomoniasis in pregnancy is associated with poorer pregnancy outcomes including lower birth weight and more prematurity (SOR: B).^58,59

Aerobic vaginitis

Aerobic vaginitis is a term proposed to describe purulent vaginal discharge with predominance of abnormal aerobic flora.⁶⁰ Aerobic vaginitis, which may be severe, has been reported as the cause of 5% of cases in a series from a specialty vaginitis clinic.⁶¹ The usual predominant microorganisms are group B streptococci, Escherichia coli, and Staphylococcus aureus. It is likely that less severe cases of aerobic vaginitis are not recognized in the primary care setting and are treated as BV or resolve spontaneously (SOR: C). The case series referred to above also reported good therapeutic response to 2% topical clindamycin (SOR: C).⁶¹

Noninfectious Vaginitis

Noninfectious causes of vaginal discharge include physiologic, irritant and allergic, cytolytic vaginitis, desquamative inflammatory vaginitis, collagen vascular disease, and idiopathic vaginitis.

Irritant and allergic vaginitis may result from sensitivities to topical medications, the active or base ingredients of spermicidal products, douching solutions, and the latex of condoms or diaphragms. If a woman with persistent symptoms has been using such intravaginal products, she should stop (SOR: C).

Cytolytic vaginitis is characterized by overgrowth of lactobacilli and cytolysis of squamous cells, including presence of cytoplasmic fragments and intact cells with naked nuclei.⁶² The cause is uncertain but may include a reaction to intravaginal medications or other products such as tampons. It can be found in up to 5% of women with symptoms and signs of vaginitis.^62,63 Symptoms often mimic VVC and may include a white, cheesy discharge. Vaginal pH ranges from 3.5 to 5.5. Recurrences during luteal phase of the menstrual cycle have been described.⁶⁴ Intravaginal antifungals should be discontinued. Baking soda sitz baths or douches are often used, but clinical trial data to support this practice are lacking (SOR: C).

Noninfectious desquamative inflammatory vaginitis (DIV) has also been described.⁶⁵ DIV is an uncommon vaginitis characterized by profuse purulent discharge with epithelial cell exfoliation. It may occur at any time during the reproductive years or after menopause. There is probably a heterogeneous group of causes of DIV. Some cases may correspond to a disorder within the spectrum of lichen planus.⁶⁶ Treatment is usually difficult, though there may be some response to local or systemic corticosteroid therapy (SOR: C).⁶⁵

Differential diagnosis

A comparison of physical examination findings an diagnostic test results for various etiologies of vaginitis is summarized in Table 3 . An algorithmic approach to the differential diagnosis of abnormal vaginal discharge is presented in the Figure . Diagnosis is complicated in that signs and symptoms do little to help differentiate among BV, VVC, and trichomoniasis. A study² of 22 genitourinary symptoms and signs showed that none differentiated among the 3 infections. This lack of clear-cut differences in symptoms also makes self-diagnosis and telephone triage inaccurate.^67,68

A DNA probe testing system (Affirm VP III Microbial ID Test) for differential diagnosis is available but expensive. It identifies Gardnerella, Trichomonas, and Candida albicans with a sensitivity of 90% to 95%.^54,66 The analyzer costs approximately $10,000 and would typically be purchased by a laboratory. Individual test kits cost about $27.

TABLE 3
Comparative findings among causes of vaginitis

FIGURE
Sequence of office tests to evaluate abnormal vaginal discharge

Corresponding author
Linda French, MD, Associate Professor, Department of Family Practice, College of Human Medicine, Michigan State University, B101 Clinical Center, East Lansing, MI 48824. E-mail: Linda.French@ht.msu.edu.

In primary care practice, abnormal vaginal discharge is a common complaint. Signs and symptoms of vaginitis—the most common gynecologic diagnosis in primary care¹ —are not specific for any single underlying cause.² Officebased diagnostic testing, which is underused,³ must be employed to ensure accurate diagnosis and effective treatment. (An article on treatment by the same authors will appear in next month’s issue of The journal of family practice.)

In a primary-care study,⁴ vulvovaginal symptoms including vaginal discharge were due to vulvovaginal candidiasis (VVC) in 27% of patients, bacterial vaginosis (BV) in 21%, trichomoniasis in 8%, Chlamydia trachomatis in 2%, Neisseria gonorrhea (GC) in 1%, and no infection in 34%. Several pathogens may coexist.² VVC, BV, and trichomoniasis account for at least 90% of infectious vaginitis.⁵ This review will therefore focus heavily on these causes of vaginal discharge among women of reproductive age, including pregnant women.

Cervicitis and physiologic cervical discharge

Some women may interpret a physiologic increase in cervical mucous production as abnormal. It occurs cyclically prior to ovulation, is typically transparent and colorless, and may be more pronounced in women with an everted cervix.

Chlamydial infection

In the clinical examination of the cervix, 3 characteristics have been associated with chlamydial infection: yellow endocervical discharge, easily induced cervical bleeding, and opaque cervical discharge.⁶ All 3 findings are statistically significant and independently associated with chlamydial infection (odds ratios 2.8, 2.3, and 2.9, respectively). In the primary care study cited above, purulent cervical discharge was found in 6% of women, most commonly testing positive for Chlamydia, less often for GC.⁴

Trichomonas vaginalis may cause cervicitis as well as vaginitis. Mycoplasma genitalium has been proposed as an additional possible pathogen. It was identified in 7% of more than 700 women with mucopurulent cervical discharge seen in a STD clinic with otherwise negative cultures.⁷ With cervical discharge that appears to be purulent, testing is warranted as a minimum for Chlamydia and GC (SOR: B). Screening of asymptomatic women less than 26 years of age for Chlamydia is recommended by the US Preventive Services Task Force (SOR: A).

Bacterial Vaginosis

Bacterial vaginosis (BV) is neither an inflammatory condition nor an STD, but is a shift in vaginal flora from the normal condition in which lactobacilli predominate, to a polymicrobial flora in which gram-positive anaerobes predominate. In addition to annoying vaginal symptoms, BV is associated with increased risks of more serious conditions such as pelvic inflammatory disease (PID), postoperative infections, and pregnancyrelated complications including prematurity. It also increases the likelihood of acquiring HIV in women exposed to the virus.^8,9

Two principal factors put women at risk for acquiring BV: douching and exposure to a new sexual partner, both of which are thought to disrupt the vaginal ecosystem.¹⁰

Relative benefits of diagnostic tests

A gold standard test has not been established for BV. In about 50% of asymptomatic women, culture results are positive for flora such as Gardnerella vaginalis.⁵ While Amsel’s criteria are often used as a reference and generally suffice for the evaluation of symptomatic women, the best candidate for a gold standard test is probably Gram stain assessment using Nugent’s criteria (described in this section).¹¹ Lack of leukocytes in the vaginal fluid supports a diagnosis of BV. A finding of white blood cells in excess of the number of vaginal epithelial cells suggests an inflammatory process (SOR: C).¹²

Amsel’s criteria with wet mount. The diagnostic approach most commonly used in the office is Amsel’s criteria—homogenous discharge, positive whiff-amine test, pH >4.5, and clue cells found on wet-mount microscopy (see How to perform a wet mount ).¹³ Three of 4 criteria deemed positive is considered diagnostic. If Gram stain is used as the reference standard, then Amsel’s criteria have 70% sensitivity and 94% specificity for diagnosing BV.¹⁴ An analysis of the individual criteria follows. The positive and negative predictive values of each compared with the whole group as reference standard is displayed in Table 1 .

Homogenous discharge. A thin, homogenous, grayish discharge is traditionally associated with BV. However, it is not specific to BV, being found commonly also in women with culture results positive for VVC or no diagnosis of vaginitis.^2,15 It is the criterion least likely to be consistent with the whole group, seen in about half of women BVpositive and over one third of women BV-negative using Amsel’s criteria as the reference standard. ¹⁵

Whiff test. The whiff test is performed by adding drops of 10% potassium hydroxide solution to the vaginal fluid. A positive result is a “fishy” amine odor. In a study¹⁶ of 100 women complaining of malodorous discharge, a positive whiff test was predictive of positive culture results for anaerobic flora such as Bacteroides sp. with sensitivity 67%, specificity 94%, and a positive predictive value of 95%. The whiff test was not positive in any of the 5 cases with positive culture results for G vaginalis in the absence of anaerobes. There were also 12 cases positive for anaerobes without G vaginalis.

pH >4.5. Since the abnormal flora of BV is consistently associated with a vaginal pH >4.5, a normal pH excludes a diagnosis of BV.^17,18 The determination of pH in the narrow range around 4.5 is not accurate using standard nitrazine paper. Narrower-range test paper is available and more accurate. Examples include pH paper for 4.5 to 5.5 (Micro Essential Laboratory), FemExam pH and Amines Test Card (Litmus Concepts), pHem-ALERT: pH paper on a stick (Imagyn Gynecology). Cervical mucous, semen, and blood are alkaline and can interfere with pH testing. Estrogen production is also necessary to maintain an acidic environment. A pH of 3.8 to 4.5 is consistent with normal vaginal flora in premenopausal women with normal estrogen production.¹⁷

Clue cells. Clue cells are vaginal epithelial cells coated with coccobacilli giving an appearance as if coated with ground black pepper. Clue cells on wet mount preparation is considered the most accurate of Amsel’s diagnostic criteria for BV.¹⁹ On the other hand, office evaluation of the wet mount is considered by some authors to be unreliable due to dependence on the clinician’s microscopy skills and lack of a durable record of the patient sample.

Gram stain a more objective test. A Gram stain evaluation using Nugent’s criteria has been adopted as the gold standard test for research purposes, including studies of prematurity. The Gram-stained vaginal specimen is scored from 0 to 10 based on semi-quantitative assessment of 3 classes of morphotypes ( Table 2 ): large gram-positive rods (Lactobacilli), small gram-negative rods (Gardnerella and Bacteroides spp.), and small curved gram-variable rods (Mobiluncus spp.).¹¹

Diagnosis of BV is typically made when the Nugent score is 7 or more, which appears qualitatively as dominant morphotypes other than Lactobacilli. Gram staining is more objective and reproducible compared with wet-mount examination, with a sensitivity of 93% and specificity of 70% if Amsel’s criteria are used as the gold standard.¹⁴ It is useful for the evaluation of asymptomatic women. It also provides a durable record of the patient specimen. Compared with Gram stain, Amsel’s criteria tend to underdiagnose cases. We can expect that if screening for BV in pregnancy becomes a recommendation, Gram staining in a clinical laboratory will be the recommended method of diagnosis.

Other diagnostic tests for BV. DNA testing for Gardnerella is accurate for detection, but it is not synonymous with a diagnosis of BV, as described.²⁰ DNA testing is further described under “Differential Diagnosis.” Gram staining is more reliable than gas-liquid chromatography²¹ and an assay for proline aminopeptidase (a metabolic product of some of the bacteria associated with BV).²² Latex agglutination testing for vaginal lactoferrin is a nonspecific marker for leukocytes, and thus inflammation. It is of little clinical utility in the diagnosis of vaginal discharge.²³

TABLE 1
Predictive values of Amsel’s criteria (using 3 of 4 positive as diagnostic reference standard)

TABLE 2
How to use Nugent’s Gram stain criteria to diagnose bacterial vaginosis

Vulvovaginal Candidiasis

Candidiasis is the second most commonly diagnosed vaginitis in the United States. Some experts estimate that 75% of women will have a yeast infection at some point in life and 5% will have recurrent infections.²⁴ However, 10% to 30% of asymptomatic women with normal flora have positive culture results for Candida.^25-29 The proportion of symptomatic women with positive culture results is 20% to 40%.^4,30,31 Complications of VVC are rare,³² though vulvar vestibulitis³³ and chorioamnionitis in pregnancy³² have been reported.

Risk factors. Symptomatic yeast vaginitis has been associated with condom and diaphragm use, recent antibiotic use, receptive oral sex, oral contraceptive use, spermicide use, diabetes, and immunosuppression including AIDS.^31,34-37 The associations with antibiotic use and oral contraceptives are not consistent.^30,38 Although pregnancy has been postulated as a risk factor for symptomatic VVC, prevalence of yeast on culture in pregnant women is similar to that of nonpregnant women.³⁰

Suggestive symptoms. Among women with a culture result positive for Candida, the most common symptom is pruritus or burning.²⁸ Abnormal discharge is a complaint for most symptomatic women with VVC confirmed by culture.² In addition, women may complain of a thick, odorless, cottage cheese–like discharge.³⁹ A thick, curdled-appearing discharge points to a diagnosis of Candida because it is rarely present with BV or trichomoniasis. In one study,²⁸ a thick curdled discharge had a positive predictive value of 84% for diagnosis of VVC by culture (SOR: B). However, a thin discharge does not rule out VVC; in another study, clinicians described discharge as thin in about half of women ultimately diagnosed with VVC by culture in another study (SOR: B).² On exam, vulvar and vaginal erythema are often present but are not specific findings. The accuracy of the clinical exam for VVC is poor compared with culture (SOR: A).^2,30

Pathogens. Candida albicans is present in 80% to 90% of patients with VVC.^5,40 remainder have non-albicans species, including C glabrata and others.²⁸ An increase to almost 20% of non-Candida species in a vaginitis clinic by the mid-1990’s may be related to increased use of imidazoles available over-the-counter.^40,41 Wet mount results are typically negative in the presence of non-Candida VVC.²⁸

Diagnosis of VVC

The gold standard test for diagnosis of VVC is culture. The potassium hydroxide (KOH) wet mount is only 40% to 75% sensitive.^28,29,42,43 False-positive results are also observed with variable frequency.⁴⁴ The pH of the discharge is usually not more than 5.0 with Candida albicans, but may be higher with non-albicans species such as C glabrata.⁴⁵ Culture is recommended for patients with recurrent or persistent symptoms and a negative wet mount result (SOR: B).^5,28,46 Rapid slide latex agglutination testing is not better than microscopy (SOR: B).⁴²

Trichomoniasis

Trichomonas, a motile protozoan with 4 flagella, causes the third most common form of vaginitis in the United States and is more common in some developing countries. Trichomoniasis accounts for no more than 10% of all cases of vaginitis, and it appears to be decreasing since the introduction of metronidazole.^47,48 It is classified as an STD, although transmission is possible by other means if the organism is protected from desiccation—for example, in dirty washcloths or towels and contaminated water. Nonsexual transmission is thought to be uncommon.

Trichomoniasis is associated with GC and Chlamydia infections, and, like them, has been associated with seroconversion to HIV-positive status.⁴⁹ Trichomonads are identified in 30% to 80% of male sexual partners of infected women. In men, trichomoniasis most often is an asymptomatic carrier state.⁵⁰ However, it is the cause of about 10% of cases of nongonococcal urethritis in men.⁵¹

Clinical presentations. Women with trichomoniasis have variable presentations ranging from an asymptomatic carrier state to a malodorous, purulent discharge with vulvovaginal erythema. Punctate hemorrhagic cervical lesions are considered pathognomonic of trichomoniasis, but are seen in only about 2% of cases (SOR: B).⁵²

Diagnosis. Culture for trichomoniasis is the gold standard. Several culture media have been used, most commonly the Diamond medium. Recently introduced is a transport and culture medium for detection of Trichomonas (InPouch TV), which performs as well as Diamond medium (SOR: A).^53-55 A DNA probe is also available and accurate (SOR: A).

Motile trichomonads are seen on wet preparation in only 50% to 80% of culture-positive cases (SOR: B).^50,54,56 Polymorphonuclear leukocytes can be dominant on wet mount, making visualization of trichomonads more difficult. The pH of the vaginal fluid is usually basic.

Trichomonas reported with cervical cytology

Trichomonas may also be reported on Pap smears. A meta-analysis⁵⁷ comparing the pooled sensitivities and specificities of wet mounts and cytology demonstrated low sensitivities of 68% and 58%, respectively, and high specificities, 99.9% and 97%, respectively (SOR: A).

However, since cytology carries a 3% false-positive rate, its results are not diagnostic of trichomoniasis in low-risk, asymptomatic women.^50,57 Treatment may be prescribed empirically based on positive cytology results. However, if an asymptomatic woman were concerned about whether she really has an STD, a positive wet prep would confirm the diagnosis. A negative wet prep should be followed up with culture to reliably rule out disease (SOR: B).

Trichomoniasis in pregnancy

Screening for asymptomatic trichomoniasis in pregnancy has not been recommended. In fact, some evidence suggests that treatment of trichomoniasis in pregnancy is associated with poorer pregnancy outcomes including lower birth weight and more prematurity (SOR: B).^58,59

Aerobic vaginitis

Aerobic vaginitis is a term proposed to describe purulent vaginal discharge with predominance of abnormal aerobic flora.⁶⁰ Aerobic vaginitis, which may be severe, has been reported as the cause of 5% of cases in a series from a specialty vaginitis clinic.⁶¹ The usual predominant microorganisms are group B streptococci, Escherichia coli, and Staphylococcus aureus. It is likely that less severe cases of aerobic vaginitis are not recognized in the primary care setting and are treated as BV or resolve spontaneously (SOR: C). The case series referred to above also reported good therapeutic response to 2% topical clindamycin (SOR: C).⁶¹

Noninfectious Vaginitis

Noninfectious causes of vaginal discharge include physiologic, irritant and allergic, cytolytic vaginitis, desquamative inflammatory vaginitis, collagen vascular disease, and idiopathic vaginitis.

Irritant and allergic vaginitis may result from sensitivities to topical medications, the active or base ingredients of spermicidal products, douching solutions, and the latex of condoms or diaphragms. If a woman with persistent symptoms has been using such intravaginal products, she should stop (SOR: C).

Cytolytic vaginitis is characterized by overgrowth of lactobacilli and cytolysis of squamous cells, including presence of cytoplasmic fragments and intact cells with naked nuclei.⁶² The cause is uncertain but may include a reaction to intravaginal medications or other products such as tampons. It can be found in up to 5% of women with symptoms and signs of vaginitis.^62,63 Symptoms often mimic VVC and may include a white, cheesy discharge. Vaginal pH ranges from 3.5 to 5.5. Recurrences during luteal phase of the menstrual cycle have been described.⁶⁴ Intravaginal antifungals should be discontinued. Baking soda sitz baths or douches are often used, but clinical trial data to support this practice are lacking (SOR: C).

Noninfectious desquamative inflammatory vaginitis (DIV) has also been described.⁶⁵ DIV is an uncommon vaginitis characterized by profuse purulent discharge with epithelial cell exfoliation. It may occur at any time during the reproductive years or after menopause. There is probably a heterogeneous group of causes of DIV. Some cases may correspond to a disorder within the spectrum of lichen planus.⁶⁶ Treatment is usually difficult, though there may be some response to local or systemic corticosteroid therapy (SOR: C).⁶⁵

Differential diagnosis

A comparison of physical examination findings an diagnostic test results for various etiologies of vaginitis is summarized in Table 3 . An algorithmic approach to the differential diagnosis of abnormal vaginal discharge is presented in the Figure . Diagnosis is complicated in that signs and symptoms do little to help differentiate among BV, VVC, and trichomoniasis. A study² of 22 genitourinary symptoms and signs showed that none differentiated among the 3 infections. This lack of clear-cut differences in symptoms also makes self-diagnosis and telephone triage inaccurate.^67,68

A DNA probe testing system (Affirm VP III Microbial ID Test) for differential diagnosis is available but expensive. It identifies Gardnerella, Trichomonas, and Candida albicans with a sensitivity of 90% to 95%.^54,66 The analyzer costs approximately $10,000 and would typically be purchased by a laboratory. Individual test kits cost about $27.

TABLE 3
Comparative findings among causes of vaginitis

FIGURE
Sequence of office tests to evaluate abnormal vaginal discharge

Corresponding author
Linda French, MD, Associate Professor, Department of Family Practice, College of Human Medicine, Michigan State University, B101 Clinical Center, East Lansing, MI 48824. E-mail: Linda.French@ht.msu.edu.

In primary care practice, abnormal vaginal discharge is a common complaint. Signs and symptoms of vaginitis—the most common gynecologic diagnosis in primary care¹ —are not specific for any single underlying cause.² Officebased diagnostic testing, which is underused,³ must be employed to ensure accurate diagnosis and effective treatment. (An article on treatment by the same authors will appear in next month’s issue of The journal of family practice.)

In a primary-care study,⁴ vulvovaginal symptoms including vaginal discharge were due to vulvovaginal candidiasis (VVC) in 27% of patients, bacterial vaginosis (BV) in 21%, trichomoniasis in 8%, Chlamydia trachomatis in 2%, Neisseria gonorrhea (GC) in 1%, and no infection in 34%. Several pathogens may coexist.² VVC, BV, and trichomoniasis account for at least 90% of infectious vaginitis.⁵ This review will therefore focus heavily on these causes of vaginal discharge among women of reproductive age, including pregnant women.

Cervicitis and physiologic cervical discharge

Some women may interpret a physiologic increase in cervical mucous production as abnormal. It occurs cyclically prior to ovulation, is typically transparent and colorless, and may be more pronounced in women with an everted cervix.

Chlamydial infection

In the clinical examination of the cervix, 3 characteristics have been associated with chlamydial infection: yellow endocervical discharge, easily induced cervical bleeding, and opaque cervical discharge.⁶ All 3 findings are statistically significant and independently associated with chlamydial infection (odds ratios 2.8, 2.3, and 2.9, respectively). In the primary care study cited above, purulent cervical discharge was found in 6% of women, most commonly testing positive for Chlamydia, less often for GC.⁴

Trichomonas vaginalis may cause cervicitis as well as vaginitis. Mycoplasma genitalium has been proposed as an additional possible pathogen. It was identified in 7% of more than 700 women with mucopurulent cervical discharge seen in a STD clinic with otherwise negative cultures.⁷ With cervical discharge that appears to be purulent, testing is warranted as a minimum for Chlamydia and GC (SOR: B). Screening of asymptomatic women less than 26 years of age for Chlamydia is recommended by the US Preventive Services Task Force (SOR: A).

Bacterial Vaginosis

Bacterial vaginosis (BV) is neither an inflammatory condition nor an STD, but is a shift in vaginal flora from the normal condition in which lactobacilli predominate, to a polymicrobial flora in which gram-positive anaerobes predominate. In addition to annoying vaginal symptoms, BV is associated with increased risks of more serious conditions such as pelvic inflammatory disease (PID), postoperative infections, and pregnancyrelated complications including prematurity. It also increases the likelihood of acquiring HIV in women exposed to the virus.^8,9

Two principal factors put women at risk for acquiring BV: douching and exposure to a new sexual partner, both of which are thought to disrupt the vaginal ecosystem.¹⁰

Relative benefits of diagnostic tests

A gold standard test has not been established for BV. In about 50% of asymptomatic women, culture results are positive for flora such as Gardnerella vaginalis.⁵ While Amsel’s criteria are often used as a reference and generally suffice for the evaluation of symptomatic women, the best candidate for a gold standard test is probably Gram stain assessment using Nugent’s criteria (described in this section).¹¹ Lack of leukocytes in the vaginal fluid supports a diagnosis of BV. A finding of white blood cells in excess of the number of vaginal epithelial cells suggests an inflammatory process (SOR: C).¹²

Amsel’s criteria with wet mount. The diagnostic approach most commonly used in the office is Amsel’s criteria—homogenous discharge, positive whiff-amine test, pH >4.5, and clue cells found on wet-mount microscopy (see How to perform a wet mount ).¹³ Three of 4 criteria deemed positive is considered diagnostic. If Gram stain is used as the reference standard, then Amsel’s criteria have 70% sensitivity and 94% specificity for diagnosing BV.¹⁴ An analysis of the individual criteria follows. The positive and negative predictive values of each compared with the whole group as reference standard is displayed in Table 1 .

Homogenous discharge. A thin, homogenous, grayish discharge is traditionally associated with BV. However, it is not specific to BV, being found commonly also in women with culture results positive for VVC or no diagnosis of vaginitis.^2,15 It is the criterion least likely to be consistent with the whole group, seen in about half of women BVpositive and over one third of women BV-negative using Amsel’s criteria as the reference standard. ¹⁵

Whiff test. The whiff test is performed by adding drops of 10% potassium hydroxide solution to the vaginal fluid. A positive result is a “fishy” amine odor. In a study¹⁶ of 100 women complaining of malodorous discharge, a positive whiff test was predictive of positive culture results for anaerobic flora such as Bacteroides sp. with sensitivity 67%, specificity 94%, and a positive predictive value of 95%. The whiff test was not positive in any of the 5 cases with positive culture results for G vaginalis in the absence of anaerobes. There were also 12 cases positive for anaerobes without G vaginalis.

pH >4.5. Since the abnormal flora of BV is consistently associated with a vaginal pH >4.5, a normal pH excludes a diagnosis of BV.^17,18 The determination of pH in the narrow range around 4.5 is not accurate using standard nitrazine paper. Narrower-range test paper is available and more accurate. Examples include pH paper for 4.5 to 5.5 (Micro Essential Laboratory), FemExam pH and Amines Test Card (Litmus Concepts), pHem-ALERT: pH paper on a stick (Imagyn Gynecology). Cervical mucous, semen, and blood are alkaline and can interfere with pH testing. Estrogen production is also necessary to maintain an acidic environment. A pH of 3.8 to 4.5 is consistent with normal vaginal flora in premenopausal women with normal estrogen production.¹⁷

Clue cells. Clue cells are vaginal epithelial cells coated with coccobacilli giving an appearance as if coated with ground black pepper. Clue cells on wet mount preparation is considered the most accurate of Amsel’s diagnostic criteria for BV.¹⁹ On the other hand, office evaluation of the wet mount is considered by some authors to be unreliable due to dependence on the clinician’s microscopy skills and lack of a durable record of the patient sample.

Gram stain a more objective test. A Gram stain evaluation using Nugent’s criteria has been adopted as the gold standard test for research purposes, including studies of prematurity. The Gram-stained vaginal specimen is scored from 0 to 10 based on semi-quantitative assessment of 3 classes of morphotypes ( Table 2 ): large gram-positive rods (Lactobacilli), small gram-negative rods (Gardnerella and Bacteroides spp.), and small curved gram-variable rods (Mobiluncus spp.).¹¹

Diagnosis of BV is typically made when the Nugent score is 7 or more, which appears qualitatively as dominant morphotypes other than Lactobacilli. Gram staining is more objective and reproducible compared with wet-mount examination, with a sensitivity of 93% and specificity of 70% if Amsel’s criteria are used as the gold standard.¹⁴ It is useful for the evaluation of asymptomatic women. It also provides a durable record of the patient specimen. Compared with Gram stain, Amsel’s criteria tend to underdiagnose cases. We can expect that if screening for BV in pregnancy becomes a recommendation, Gram staining in a clinical laboratory will be the recommended method of diagnosis.

Other diagnostic tests for BV. DNA testing for Gardnerella is accurate for detection, but it is not synonymous with a diagnosis of BV, as described.²⁰ DNA testing is further described under “Differential Diagnosis.” Gram staining is more reliable than gas-liquid chromatography²¹ and an assay for proline aminopeptidase (a metabolic product of some of the bacteria associated with BV).²² Latex agglutination testing for vaginal lactoferrin is a nonspecific marker for leukocytes, and thus inflammation. It is of little clinical utility in the diagnosis of vaginal discharge.²³

TABLE 1
Predictive values of Amsel’s criteria (using 3 of 4 positive as diagnostic reference standard)

TABLE 2
How to use Nugent’s Gram stain criteria to diagnose bacterial vaginosis

Vulvovaginal Candidiasis

Candidiasis is the second most commonly diagnosed vaginitis in the United States. Some experts estimate that 75% of women will have a yeast infection at some point in life and 5% will have recurrent infections.²⁴ However, 10% to 30% of asymptomatic women with normal flora have positive culture results for Candida.^25-29 The proportion of symptomatic women with positive culture results is 20% to 40%.^4,30,31 Complications of VVC are rare,³² though vulvar vestibulitis³³ and chorioamnionitis in pregnancy³² have been reported.

Risk factors. Symptomatic yeast vaginitis has been associated with condom and diaphragm use, recent antibiotic use, receptive oral sex, oral contraceptive use, spermicide use, diabetes, and immunosuppression including AIDS.^31,34-37 The associations with antibiotic use and oral contraceptives are not consistent.^30,38 Although pregnancy has been postulated as a risk factor for symptomatic VVC, prevalence of yeast on culture in pregnant women is similar to that of nonpregnant women.³⁰

Suggestive symptoms. Among women with a culture result positive for Candida, the most common symptom is pruritus or burning.²⁸ Abnormal discharge is a complaint for most symptomatic women with VVC confirmed by culture.² In addition, women may complain of a thick, odorless, cottage cheese–like discharge.³⁹ A thick, curdled-appearing discharge points to a diagnosis of Candida because it is rarely present with BV or trichomoniasis. In one study,²⁸ a thick curdled discharge had a positive predictive value of 84% for diagnosis of VVC by culture (SOR: B). However, a thin discharge does not rule out VVC; in another study, clinicians described discharge as thin in about half of women ultimately diagnosed with VVC by culture in another study (SOR: B).² On exam, vulvar and vaginal erythema are often present but are not specific findings. The accuracy of the clinical exam for VVC is poor compared with culture (SOR: A).^2,30

Pathogens. Candida albicans is present in 80% to 90% of patients with VVC.^5,40 remainder have non-albicans species, including C glabrata and others.²⁸ An increase to almost 20% of non-Candida species in a vaginitis clinic by the mid-1990’s may be related to increased use of imidazoles available over-the-counter.^40,41 Wet mount results are typically negative in the presence of non-Candida VVC.²⁸

Diagnosis of VVC

The gold standard test for diagnosis of VVC is culture. The potassium hydroxide (KOH) wet mount is only 40% to 75% sensitive.^28,29,42,43 False-positive results are also observed with variable frequency.⁴⁴ The pH of the discharge is usually not more than 5.0 with Candida albicans, but may be higher with non-albicans species such as C glabrata.⁴⁵ Culture is recommended for patients with recurrent or persistent symptoms and a negative wet mount result (SOR: B).^5,28,46 Rapid slide latex agglutination testing is not better than microscopy (SOR: B).⁴²

Trichomoniasis

Trichomonas, a motile protozoan with 4 flagella, causes the third most common form of vaginitis in the United States and is more common in some developing countries. Trichomoniasis accounts for no more than 10% of all cases of vaginitis, and it appears to be decreasing since the introduction of metronidazole.^47,48 It is classified as an STD, although transmission is possible by other means if the organism is protected from desiccation—for example, in dirty washcloths or towels and contaminated water. Nonsexual transmission is thought to be uncommon.

Trichomoniasis is associated with GC and Chlamydia infections, and, like them, has been associated with seroconversion to HIV-positive status.⁴⁹ Trichomonads are identified in 30% to 80% of male sexual partners of infected women. In men, trichomoniasis most often is an asymptomatic carrier state.⁵⁰ However, it is the cause of about 10% of cases of nongonococcal urethritis in men.⁵¹

Clinical presentations. Women with trichomoniasis have variable presentations ranging from an asymptomatic carrier state to a malodorous, purulent discharge with vulvovaginal erythema. Punctate hemorrhagic cervical lesions are considered pathognomonic of trichomoniasis, but are seen in only about 2% of cases (SOR: B).⁵²

Diagnosis. Culture for trichomoniasis is the gold standard. Several culture media have been used, most commonly the Diamond medium. Recently introduced is a transport and culture medium for detection of Trichomonas (InPouch TV), which performs as well as Diamond medium (SOR: A).^53-55 A DNA probe is also available and accurate (SOR: A).

Motile trichomonads are seen on wet preparation in only 50% to 80% of culture-positive cases (SOR: B).^50,54,56 Polymorphonuclear leukocytes can be dominant on wet mount, making visualization of trichomonads more difficult. The pH of the vaginal fluid is usually basic.

Trichomonas reported with cervical cytology

Trichomonas may also be reported on Pap smears. A meta-analysis⁵⁷ comparing the pooled sensitivities and specificities of wet mounts and cytology demonstrated low sensitivities of 68% and 58%, respectively, and high specificities, 99.9% and 97%, respectively (SOR: A).

However, since cytology carries a 3% false-positive rate, its results are not diagnostic of trichomoniasis in low-risk, asymptomatic women.^50,57 Treatment may be prescribed empirically based on positive cytology results. However, if an asymptomatic woman were concerned about whether she really has an STD, a positive wet prep would confirm the diagnosis. A negative wet prep should be followed up with culture to reliably rule out disease (SOR: B).

Trichomoniasis in pregnancy

Screening for asymptomatic trichomoniasis in pregnancy has not been recommended. In fact, some evidence suggests that treatment of trichomoniasis in pregnancy is associated with poorer pregnancy outcomes including lower birth weight and more prematurity (SOR: B).^58,59

Aerobic vaginitis

Aerobic vaginitis is a term proposed to describe purulent vaginal discharge with predominance of abnormal aerobic flora.⁶⁰ Aerobic vaginitis, which may be severe, has been reported as the cause of 5% of cases in a series from a specialty vaginitis clinic.⁶¹ The usual predominant microorganisms are group B streptococci, Escherichia coli, and Staphylococcus aureus. It is likely that less severe cases of aerobic vaginitis are not recognized in the primary care setting and are treated as BV or resolve spontaneously (SOR: C). The case series referred to above also reported good therapeutic response to 2% topical clindamycin (SOR: C).⁶¹

Noninfectious Vaginitis

Noninfectious causes of vaginal discharge include physiologic, irritant and allergic, cytolytic vaginitis, desquamative inflammatory vaginitis, collagen vascular disease, and idiopathic vaginitis.

Irritant and allergic vaginitis may result from sensitivities to topical medications, the active or base ingredients of spermicidal products, douching solutions, and the latex of condoms or diaphragms. If a woman with persistent symptoms has been using such intravaginal products, she should stop (SOR: C).

Cytolytic vaginitis is characterized by overgrowth of lactobacilli and cytolysis of squamous cells, including presence of cytoplasmic fragments and intact cells with naked nuclei.⁶² The cause is uncertain but may include a reaction to intravaginal medications or other products such as tampons. It can be found in up to 5% of women with symptoms and signs of vaginitis.^62,63 Symptoms often mimic VVC and may include a white, cheesy discharge. Vaginal pH ranges from 3.5 to 5.5. Recurrences during luteal phase of the menstrual cycle have been described.⁶⁴ Intravaginal antifungals should be discontinued. Baking soda sitz baths or douches are often used, but clinical trial data to support this practice are lacking (SOR: C).

Noninfectious desquamative inflammatory vaginitis (DIV) has also been described.⁶⁵ DIV is an uncommon vaginitis characterized by profuse purulent discharge with epithelial cell exfoliation. It may occur at any time during the reproductive years or after menopause. There is probably a heterogeneous group of causes of DIV. Some cases may correspond to a disorder within the spectrum of lichen planus.⁶⁶ Treatment is usually difficult, though there may be some response to local or systemic corticosteroid therapy (SOR: C).⁶⁵

Differential diagnosis

A comparison of physical examination findings an diagnostic test results for various etiologies of vaginitis is summarized in Table 3 . An algorithmic approach to the differential diagnosis of abnormal vaginal discharge is presented in the Figure . Diagnosis is complicated in that signs and symptoms do little to help differentiate among BV, VVC, and trichomoniasis. A study² of 22 genitourinary symptoms and signs showed that none differentiated among the 3 infections. This lack of clear-cut differences in symptoms also makes self-diagnosis and telephone triage inaccurate.^67,68

A DNA probe testing system (Affirm VP III Microbial ID Test) for differential diagnosis is available but expensive. It identifies Gardnerella, Trichomonas, and Candida albicans with a sensitivity of 90% to 95%.^54,66 The analyzer costs approximately $10,000 and would typically be purchased by a laboratory. Individual test kits cost about $27.

TABLE 3
Comparative findings among causes of vaginitis

FIGURE
Sequence of office tests to evaluate abnormal vaginal discharge

Corresponding author
Linda French, MD, Associate Professor, Department of Family Practice, College of Human Medicine, Michigan State University, B101 Clinical Center, East Lansing, MI 48824. E-mail: Linda.French@ht.msu.edu.