SUGGESTED CITATION: Centers for Disease Control and Prevention. 1998 Guidelines for Treatment of Sexually Transmitted Diseases. MMWR 1998;47(No. RR-1): {inclusive page numbers}.
The material in this report was prepared for publication by: National Center for HIV, STD and TB Prevention, Division of Sexually Transmitted Diseases Prevention
Vaginitis is usually characterized by a vaginal discharge or vulvar itching and irritation; a vaginal odor may be present. The three diseases most frequently associated with vaginal discharge are trichomoniasis (caused by T. vaginalis), BV (caused by a replacement of the normal vaginal flora by an overgrowth of anaerobic microorganisms and Gardnerella vaginalis), and candidiasis (usually caused by Candida albicans). MPC caused by C. trachomatis or N. gonorrhoeae can sometimes cause vaginal discharge. Although vulvovaginal candidiasis usually is not transmitted sexually, it is included in this section because it is often diagnosed in women being evaluated for STDs.
Vaginitis is diagnosed by pH and microscopic examination of fresh samples of the discharge. The pH of the vaginal secretions can be determined by narrow-range pH paper for the elevated pH typical of BV or trichomoniasis (i.e., a pH of greater than 4.5). One way to examine the discharge is to dilute a sample in one to two drops of 0.9% normal saline solution on one slide and 10% potassium hydroxide (KOH) solution on a second slide. An amine odor detected immediately after applying KOH suggests BV. A cover slip is placed on each slide, and they are examined under a microscope at low- and high-dry power. The motile T. vaginalis or the clue cells of BV usually are identified easily in the saline specimen. The yeast or pseudohyphae of Candida species are more easily identified in the KOH specimen. The presence of objective signs of vulvar inflammation in the absence of vaginal pathogens, along with a minimal amount of discharge, suggests the possibility of mechanical, chemical, allergic, or other noninfectious irritation of the vulva. Culture for T. vaginalis is more sensitive than microscopic examination. Laboratory testing fails to identify the cause of vaginitis among a substantial minority of women.
BV is a clinical syndrome resulting from replacement of the normal H2O2-producing Lactobacillus sp. in the vagina with high concentrations of anaerobic bacteria (e.g., Prevotella sp. and Mobiluncus sp.), G. vaginalis, and Mycoplasma hominis. BV is the most prevalent cause of vaginal discharge or malodor; however, half of the women whose illnesses meet the clinical criteria for BV are asymptomatic. The cause of the microbial alteration is not fully understood. Although BV is associated with having multiple sex partners, it is unclear whether BV results from acquisition of a sexually transmitted pathogen. Women who have never been sexually active are rarely affected. Treatment of the male sex partner has not been beneficial in preventing the recurrence of BV.
BV can be diagnosed by the use of clinical or Gram stain criteria. Clinical criteria require three of the following symptoms or signs:
When a Gram stain is used, determining the relative concentration of the bacterial morphotypes characteristic of the altered flora of BV is an acceptable laboratory method for diagnosing BV. Culture of G. vaginalis is not recommended as a diagnostic tool because it is not specific.
The principal goal of therapy for BV is to relieve vaginal symptoms and signs of infection. All women who have symptomatic disease require treatment, regardless of pregnancy status.
BV during pregnancy is associated with adverse pregnancy outcomes. The results of several investigations indicate that treatment of pregnant women who have BV and who are at high risk for preterm delivery (i.e., those who previously delivered a premature infant) might reduce the risk for prematurity. Therefore, high-risk pregnant women who do not have symptoms of BV may be evaluated for treatment.
Although some experts recommend treatment for high-risk pregnant women who have asymptomatic BV, others believe more information is needed before such a recommendation is made. A large, randomized clinical trial is underway to assess treatment for asymptomatic BV in pregnant women; the results of this investigation should clarify the benefits of therapy for BV in women at both low and high risk for preterm delivery.
The bacterial flora that characterizes BV has been recovered from the endometria and salpinges of women who have PID. BV has been associated with endometritis, PID, and vaginal cuff cellulitis after invasive procedures such as endometrial biopsy, hysterectomy, hysterosalpingography, placement of an intrauterine device, cesarean section, and uterine curettage. The results of one randomized controlled trial indicated that treatment of BV with metronidazole substantially reduced postabortion PID. On the basis of these data, consideration should be given to treatment of women who have symptomatic or asymptomatic BV before surgical abortion procedures are performed. However, more information is needed before recommending whether patients who have asymptomatic BV should be treated before other invasive procedures are performed.
Recommended Regimens for Nonpregnant Women
For treatment of pregnant women, see Bacterial Vaginosis, Special Considerations, Pregnancy.
Metronidazole 500 mg orally twice a day for 7 days,
OR
Clindamycin cream 2%, one full applicator (5 g) intravaginally at bedtime for 7 days,
OR
Metronidazole gel 0.75%, one full applicator (5 g) intravaginally twice a day for 5 days.
NOTE: Patients should be advised to avoid consuming alcohol during treatment with metronidazole and for 24 hours thereafter. Clindamycin cream is oil-based and might weaken latex condoms and diaphragms. Refer to condom product labeling for additional information.
Alternative Regimens
Metronidazole 2 g orally in a single dose,
OR
Clindamycin 300 mg orally twice a day for 7 days.
Metronidazole 2-g single-dose therapy is an alternative regimen because of its lower efficacy for BV. Oral metronidazole (500 mg twice a day) is efficacious for the treatment of BV, resulting in relief of symptoms and improvement in clinical course and flora disturbances. Based on efficacy data from four randomized controlled trials, overall cure rates 4 weeks after completion of treatment did not differ significantly between the 7-day regimen of oral metronidazole and the clindamycin vaginal cream (78% vs. 82%, respectively). Similarly, the results of another randomized controlled trial indicated that cure rates 7-10 days after completion of treatment did not differ significantly between the 7-day regimen of oral metronidazole and the metronidazole vaginal gel (84% vs. 75%, respectively). FDA has approved Flagyl ER (TM) (750 mg) once daily for 7 days for treatment of BV. However, data concerning clinical equivalency with other regimens have not been published.
Some health-care providers remain concerned about the possible teratogenicity of metronidazole, which has been suggested by experiments using extremely high and prolonged doses in animals. However, a recent meta-analysis does not indicate teratogenicity in humans. Some health-care providers prefer the intravaginal route because of a lack of systemic side effects (e.g., mild-to-moderate gastrointestinal disturbance and unpleasant taste). Mean peak serum concentrations of metronidazole after intravaginal administration are less than 2% the levels of standard 500-mg oral doses, and the mean bioavailability of clindamycin cream is approximately 4%.
Follow-up visits are unnecessary if symptoms resolve. Recurrence of BV is not unusual. Because treatment of BV in high-risk pregnant women who are asymptomatic might prevent adverse pregnancy outcomes, a follow-up evaluation, at 1 month after completion of treatment, should be considered to evaluate whether therapy was successful. The alternative BV treatment regimens may be used to treat recurrent disease. No long-term maintenance regimen with any therapeutic agent is recommended.
The results of clinical trials indicate that a woman's response to therapy and the likelihood of relapse or recurrence are not affected by treatment of her sex partner(s). Therefore, routine treatment of sex partners is not recommended.
Clindamycin cream is preferred in case of allergy or intolerance to metronidazole. Metronidazole gel can be considered for patients who do not tolerate systemic metronidazole, but patients allergic to oral metronidazole should not be administered metronidazole vaginally.
BV has been associated with adverse pregnancy outcomes (e.g., premature rupture of the membranes, preterm labor, and preterm birth), and the organisms found in increased concentration in BV also are frequently present in postpartum or postcesarean endometritis. Because treatment of BV in high-risk pregnant women (i.e., those who have previously delivered a premature infant) who are asymptomatic might reduce preterm delivery, such women may be screened, and those with BV can be treated. The screening and treatment should be conducted at the earliest part of the second trimester of pregnancy. The recommended regimen is metronidazole 250 mg orally three times a day for 7 days. The alternative regimens are a) metronidazole 2 g orally in a single dose or b) clindamycin 300 mg orally twice a day for 7 days.
Low-risk pregnant women (i.e., women who previously have not had a premature delivery) who have symptomatic BV should be treated to relieve symptoms. The recommended regimen is metronidazole 250 mg orally three times a day for 7 days. The alternative regimens are a) metronidazole 2 g orally in a single dose; b) clindamycin 300 mg orally twice a day for 7 days; or c) metronidazole gel, 0.75%, one full applicator (5 g) intravaginally, twice a day for 5 days. Some experts prefer the use of systemic therapy for low-risk pregnant women to treat possible subclinical upper genital tract infections.
Lower doses of medication are recommended for pregnant women to minimize exposure to the fetus. Data are limited concerning the use of metronidazole vaginal gel during pregnancy. The use of clindamycin vaginal cream during pregnancy is not recommended, because two randomized trials indicated an increase in the number of preterm deliveries among pregnant women who were treated with this medication.
Patients who have BV and also are infected with HIV should receive the same treatment regimen as those who are HIV-negative.
Trichomoniasis is caused by the protozoan T. vaginalis. Most men who are infected with T. vaginalis do not have symptoms of infection, although a minority of men have NGU. Many women do have symptoms of infection. Of these women, T. vaginalis characteristically causes a diffuse, malodorous, yellow-green discharge with vulvar irritation; many women have fewer symptoms. Vaginal trichomoniasis might be associated with adverse pregnancy outcomes, particularly premature rupture of the membranes and preterm delivery.
Recommended Regimen
Metronidazole 2 g orally in a single dose.
Alternative Regimen *
Metronidazole 500 mg twice a day for 7 days.
Metronidazole is the only oral medication available in the United States for the treatment of trichomoniasis. In randomized clinical trials, the recommended metronidazole regimens have resulted in cure rates of approximately 90%-95%; ensuring treatment of sex partners might increase the cure rate. Treatment of patients and sex partners results in relief of symptoms, microbiologic cure, and reduction of transmission. Metronidazole gel is approved for treatment of BV, but, like other topically applied antimicrobials that are unlikely to achieve therapeutic levels in the urethra or perivaginal glands, it is considerably less efficacious for treatment of trichomoniasis than oral preparations of metronidazole and is not recommended for use. Several other topically applied antimicrobials have been used for treatment of trichomoniasis, but it is unlikely that these preparations will have greater efficacy than metronidazole gel.
Follow-up is unnecessary for men and women who become asymptomatic after treatment or who are initially asymptomatic. Infections with strains of T. vaginalis that have diminished susceptibility to metronidazole can occur; however, most of these organisms respond to higher doses of metronidazole. If treatment failure occurs with either regimen, the patient should be re-treated with metronidazole 500 mg twice a day for 7 days. If treatment failure occurs repeatedly, the patient should be treated with a single 2-g dose of metronidazole once a day for 3-5 days.
Patients with culture-documented infection who do not respond to the regimens described in this report and in whom reinfection has been excluded should be managed in consultation with an expert; consultation is available from CDC. Evaluation of such cases should include determination of the susceptibility of T. vaginalis to metronidazole.
Sex partners should be treated. Patients should be instructed to avoid sex until they and their sex partners are cured. In the absence of a microbiologic test of cure, this means when therapy has been completed and patient and partner(s) are asymptomatic.
Effective alternatives to therapy with metronidazole are not available. Patients who are allergic to metronidazole can be managed by desensitization (26).
Patients can be treated with 2 g of metronidazole in a single dose.
Patients who have trichomoniasis and also are infected with HIV should receive the same treatment regimen as those who are HIV-negative.
Vulvovaginal candidiasis (VVC) is caused by C. albicans or, occasionally, by other Candida sp., Torulopsis sp., or other yeasts. An estimated 75% of women will have at least one episode of VVC, and 40%-45% will have two or more episodes. A small percentage of women (i.e., probably less than 5%) experience recurrent VVC (RVVC). Typical symptoms of VVC include pruritus and vaginal discharge. Other symptoms may include vaginal soreness, vulvar burning, dyspareunia, and external dysuria. None of these symptoms is specific for VVC.
A diagnosis of Candida vaginitis is suggested clinically by pruritus and erythema in the vulvovaginal area; a white discharge may occur. The diagnosis can be made in a woman who has signs and symptoms of vaginitis, and when either a) a wet preparation or Gram stain of vaginal discharge demonstrates yeasts or pseudohyphae or b) a culture or other test yields a positive result for a yeast species. Candida vaginitis is associated with a normal vaginal pH (less than or equal to 4.5). Use of 10% KOH in wet preparations improves the visualization of yeast and mycelia by disrupting cellular material that might obscure the yeast or pseudohyphae. Identifying Candida by culture in the absence of symptoms should not lead to treatment, because approximately 10%-20% of women usually harbor Candida sp. and other yeasts in the vagina. VVC can occur concomitantly with STDs or frequently following antibacterial vaginal or systemic therapy.
Topical formulations effectively treat VVC. The topically applied azole drugs are more effective than nystatin. Treatment with azoles results in relief of symptoms and negative cultures among 80%-90% of patients who complete therapy.
Recommended Regimens
Intravaginal agents:
Butoconazole 2% cream 5 g intravaginally for 3 days, ** ***
OR
Clotrimazole 1% cream 5 g intravaginally for 7-14 days, ** ***
OR
Clotrimazole 100 mg vaginal tablet for 7 days, **
OR
Clotrimazole 100 mg vaginal tablet, two tablets for 3 days, **
OR
Clotrimazole 500 mg vaginal tablet, one tablet in a single application, **
OR
Miconazole 2% cream 5 g intravaginally for 7 days, ** ***
OR
Miconazole 200 mg vaginal suppository, one suppository for 3 days, ** ***
OR
Miconazole 100 mg vaginal suppository, one suppository for 7 days ** ***
OR
Nystatin 100,000-unit vaginal tablet, one tablet for 14 days,
OR
Tioconazole 6.5% ointment 5 g intravaginally in a single application ** ***
OR
Terconazole 0.4% cream 5 g intravaginally for 7 days, **
OR
Terconazole 0.8% cream 5 g intravaginally for 3 days, **
OR
Terconazole 80 mg vaginal suppository, one suppository for 3 days. **
Oral agent:
Fluconazole 150 mg oral tablet, one tablet in single dose.
Preparations for intravaginal administration of butaconazole, clotrimazole, miconazole, and tioconazole are available OTC, and women with VVC can choose one of those preparations. The duration for treatment with these preparations may be 1, 3, or 7 days. Self-medication with OTC preparations should be advised only for women who have been diagnosed previously with VVC and who have a recurrence of the same symptoms. Any woman whose symptoms persist after using an OTC preparation or who has a recurrence of symptoms within 2 months should seek medical care.
A new classification of VVC may facilitate antifungal selection as well as duration of therapy. Uncomplicated VVC (i.e., mild-to-moderate, sporadic, nonrecurrent disease in a normal host with normally susceptible C. albicans) responds to all the aforementioned azoles, even those that are short-term (less than 7 days) and single-dose therapies. In contrast, complicated VVC (i.e., severe local or recurrent VVC in an abnormal host {e.g., VVC in a patient who has uncontrolled diabetes, or infection caused by a less susceptible fungal pathogen such as Candida glabrata}) requires a longer duration of therapy (i.e, 10-14 days) with either topical or oral azoles. Additional studies confirming this approach are in progress.
Alternative Regimens
Several trials have demonstrated that oral azole agents (e.g., ketoconazole and itraconazole) might be as effective as topical agents. The ease of administering oral agents is an advantage over topical therapies. However, the potential for toxicity associated with using a systemic drug, particularly ketoconazole, must be considered.
Patients should be instructed to return for follow-up visits only if symptoms persist or recur.
VVC usually is not acquired through sexual intercourse; treatment of sex partners is not recommended but may be considered for women who have recurrent infection. A minority of male sex partners may have balanitis, which is characterized by erythematous areas on the glans in conjunction with pruritus or irritation. These sex partners might benefit from treatment with topical antifungal agents to relieve symptoms.
Topical agents usually are free of systemic side effects, although local burning or irritation may occur. Oral agents occasionally cause nausea, abdominal pain, and headaches. Therapy with the oral azoles has been associated rarely with abnormal elevations of liver enzymes. Hepatotoxicity secondary to ketoconazole therapy occurs in an estimated one of every 10,000-15,000 exposed persons. Clinically important interactions might occur when these oral agents are administered with other drugs, including astemizole, calcium channel antagonists, cisapride, coumadin, cyclosporin A, oral hypoglycemic agents, phenytoin, protease inhibitors, tacrolimus, terfenadine, theophylline, trimetrexate, and rifampin.
VVC often occurs during pregnancy. Only topical azole therapies should be used to treat pregnant women. Of those treatments that have been investigated for use during pregnancy, the most effective are butoconazole, clotrimazole, miconazole, and terconazole. Many experts recommend 7 days of therapy during pregnancy.
Prospective controlled studies are in progress to confirm an alleged increase in incidence of VVC in HIV-infected women. No confirmed evidence has indicated a differential response to conventional antifungal therapy among HIV-positive women who have VVC. As such, women who have acute VVC and also are infected with HIV should receive the same treatment regimens as those who are HIV-negative.
RVVC, which usually is defined as four or more episodes of symptomatic VVC annually, affects a small percentage of women (i.e., probably less than 5%). The pathogenesis of RVVC is poorly understood. Risk factors for RVVC include uncontrolled diabetes mellitus, immunosuppression, and corticosteroid use. In some women who have RVVC, episodes occur after repeated courses of topical or systemic antibacterials. However, this association is not apparent in the majority of women. Most women who have RVVC have no apparent predisposing conditions. Clinical trials addressing the management of RVVC have involved continuing therapy between episodes.
The optimal treatment for RVVC has not been established; however, an initial intensive regimen continued for approximately 10-14 days, followed immediately by a maintenance regimen for at least 6 months, is recommended. Maintenance ketoconazole 100 mg orally, once a day for less than or equal to 6 months, reduces the frequency of RVVC episodes. Investigations are evaluating a weekly fluconazole regimen, the results of which will be compared with once-monthly oral and topical antimycotic regimens that have only moderate protective efficacy. All cases of RVVC should be confirmed by culture before maintenance therapy is initiated.
Although patients with RVVC should be evaluated for predisposing conditions, routinely performing HIV testing for women with RVVC who do not have HIV risk factors is unnecessary.
Patients who are receiving treatment for RVVC should receive regular follow-up evaluations to monitor the effectiveness of therapy and the occurrence of side effects.
Treatment of sex partners may be considered for partners who have symptomatic balanitis or penile dermatitis. However, routine treatment of sex partners usually is unnecessary.
Information is insufficient to determine the optimal management of RVVC among HIV-infected women. Until such information becomes available, management should be the same as for HIV-negative women who have RVVC.
* FDA has approved Flagyl 375 (TM) mg twice a day for 7 days for treatment of trichomoniasis on the basis of pharmacokinetic equivalency of this regimen with metronidazole 250 mg three times a day for 7 days. No clinical data are available, however, to demonstrate clinical equivalency of the two regimens.
** These creams and suppositories are oil-based and might weaken latex condoms and diaphragms. Refer to condom product labeling for additional information.
*** Over-the-counter (OTC) preparations.