Drug Treatment of Common STDs: Part II. Vaginal Infections, Pelvic Inflammatory Disease and Genital Warts

CAROL WOODWARD, PHARM.D.

West Virginia University Hospitals, Morgantown, West Virginia

MELANIE A. FISHER, M.D., M.SC.

West Virginia University, Morgantown, West Virginia

The Centers for Disease Control and Prevention (CDC) released new guidelines for the treatment of sexually transmitted diseases (STDs) in 1998. Several treatment advances have been made since the previous guidelines were published. Part II of this two-part series on STDs describes recommendations for the treatment of diseases characterized by vaginal discharge, pelvic inflammatory disease, epididymitis, human papillomavirus infection, proctitis, proctocolitis, enteritis and ectoparasitic diseases. Single-dose therapies are recommended for the treatment of several of these diseases. A single 1-g dose of oral azithromycin is as effective as a seven-day course of oral doxycycline, 100 mg twice a day, for the treatment of chlamydial infection. Erythromycin and ofloxacin are alternative agents. Four single-dose therapies are now recommended for the management of uncomplicated gonococcal infections, including 400 mg of cefixime, 500 mg of ciprofloxacin, 125 mg of ceftriaxone or 400 mg of ofloxacin. Advances in the treatment of bacterial vaginosis also have been made. A seven-day course of oral metronidazole is still recommended for the treatment of bacterial vaginosis in pregnant women, but intravaginal clindamycin cream and metronidazole gel are now recommended in nonpregnant women. Single-dose therapy with 150 mg of oral fluconazole is a recommended treatment for vulvovaginal candidiasis. Two new topical treatments, podofilox and imiquimod, are available for patient self-administration to treat human papillomavirus infection. Permethrin cream is now the preferred agent for the treatment of pediculosis pubis and scabies. (Am Fam Physician 1999;60:1716-22.)

This article focuses on vaginal infections, pelvic inflammatory disease and genital warts, with brief mention of proctitis, enteritis and ectoparasitic infections. It should be noted that vaginal candidiasis and bacterial vaginosis are included in the following discussion, although these infections are not sexually transmitted. They are frequently diagnosed at the same time as sexually transmitted diseases (STDs), however, and the treatments often overlap.

Vaginitis

The three diseases that are most commonly associated with vaginitis are bacterial vaginosis, trichomoniasis and candidiasis. Diagnosis is based on pH measurement and microscopic examination of the vaginal discharge. Symptoms of vaginitis include vaginal discharge, vulvar itching, or both, with or without vaginal odor. Vulvovaginal candidiasis is not transmitted sexually but is evaluated at the same time as screening for STDs.

Current evidence for the management of patients with bacterial vaginosis does not support the treatment of male sex partners.

Bacterial Vaginosis
Bacterial vaginosis is the most common cause of vaginal discharge or malodor. It occurs when the normal flora of the vagina that produces Lactobacillus species is replaced with anaerobic bacteria. Bacterial vaginosis occurs more often in women who have multiple sexual partners, but it is not known if it is transmitted sexually. At this time, treatment for male sex partners is not recommended.

All women with symptomatic disease require treatment, including those who are pregnant. Studies have shown that bacterial vaginosis is associated with preterm delivery in pregnant women who are already at high risk for preterm delivery. Bacterial vaginosis is also associated with pelvic inflammatory disease, endometritis and vaginal cuff cellulitis after invasive procedures.

A seven-day course of oral metronidazole (Flagyl) is recommended for the treatment of bacterial vaginosis. In addition, intravaginal clindamycin cream (Cleocin) and metronidazole gel (Metrogel) are recommended treatments in nonpregnant women.¹ Table 1 shows treatment regimens that are approved for use in pregnant women.

Trichomoniasis
Trichomoniasis is a disease associated with vaginal discharge that is caused by the protozoan Trichomonas vaginalis. Trichomoniasis is transmitted sexually, yet men usually remain asymptomatic. Trichomoniasis in women is characterized by a diffuse, malodorous, yellow-green discharge and vulvar irritation. As with bacterial vaginosis, vaginal trichomoniasis may be associated with adverse pregnancy outcomes.

Trichomoniasis is treated with oral metronidazole (Flagyl). Topical metronidazole is not recommended. Table 1 shows treatment regimens in pregnant and nonpregnant women.

Vulvovaginal Candidiasis
Symptoms of vulvovaginal candidiasis include pruritis, vaginal discharge and, sometimes, vaginal soreness, vulvar burning, dyspareunia and external dysuria. Vulvovaginal candidiasis can occur concomitantly with an STD or following antimicrobial therapy.

Several topical agents are still recommended for the treatment of vulvovaginal candidiasis and are first-line therapies in pregnant women. An oral agent, fluconazole (Diflucan), has now been labeled for use in the treatment of vulvovaginal candidiasis.^2,3 Systemic effects, side effects and drug interactions must be considered when oral agents are used. Table 1 lists recommended therapies for the treatment of vulvovaginal candidiasis.

TABLE 1 Diseases Characterized By Vaginal Discharge Disease Recommended regimens Agent Dosage Cost* Bacterial vaginosis Recommended regimens in nonpregnant women Metronidazole (Flagyl) 500 mg orally twice daily for 7 days $ 6.50 to 9.00 (generic) Clindamycin cream (Cleocin) 2%, one full applicator intravaginally at bedtime for 7 days 40.00 (brand/40 g) Metronidazole gel (Metrogel) 0.75%, one full applicator intravaginally twice daily for 5 days 35.00 (brand/20 g) Alternative regimens in nonpregnant Metronidazole 2 g orally in a single dose 11.50 (brand) 1.50 to 3.00 (generic) Clindamycin 300 mg orally twice daily for 7 days 46.00 (brand) Recommended regimens in pregnant women (second trimester) Metronidazole 500 mg orally twice daily for 7 days 6.50 to 9.00 (generic) Metronidazole 2 g orally in a single dose 11.50 (brand) 1.50 to 3.00 (generic) Clindamycin 300 mg orally twice daily for 7 days 46.00 (brand) Trichomoniasis Recommended regimen Metronidazole 2 g orally in a single dose 11.50 (brand) 1.50 to 3.00 (generic) Alternative regimen Metronidazole 500 mg orally twice daily for 7 days 6.50 to 9.00 (generic) Recommended regimen in pregnant women (second trimester) Metronidazole 2 g orally in a single dose 11.50 (brand) 1.50 to 3.00 (generic) Vulvovaginal candidiasis Recommended intravaginal agents Butoconazole (Femstat) 2% cream, 5 g intravaginally for 3 days 14.00 (brand/15 g) Clotrimazole (Lotrimin) 1% cream, 5 g intravaginally for 7 to 14 days 6.00 to 9.00 (brand) Clotrimazole 100-mg vaginal tablet daily for 7 days 10.50 (generic) Clotrimazole 100-mg vaginal tablet, two tablets daily or 3 days 4.50 (generic) Clotrimazole (Mycelex-G) 500-mg vaginal tablet, one tablet in a single application 15.00 (brand) Miconazole (Monistat) 2% cream, 5 g intravaginally for 7 days 15.00 (brand) Miconazole 200-mg vaginal suppository, one daily for 3 days 30.00 (brand) Miconazole 100-mg vaginal suppository, one daily for 7 days 12.00 (brand) Nystatin (Mycolog II) 100,000-unit vaginal tablet, one daily for 14 days 17.50 to 29.50 (brand) Tioconazole (Vagistate-1) 6.5% ointment, 5 g intravaginally in a single application 14.50 (brand/4.6 g) Terconazole (Terazole) 0.4% cream, 5 g intravaginally for 7 days 29.00 (brand/45 g) Terconazole 0.8% cream, 5 g intravaginally for 3 days 29.00 (brand/20 g) Terconazole 80-mg vaginal suppository, one daily for 3 days 29.00 (brand) Recommended oral agent Fluconazole (Diflucan) 150-mg tablet taken orally in a single dose 11.50 (brand) *--Cost per single dose/single application/one container. Estimated cost to the pharmacist based on average wholesale prices rounded to the nearest half dollar (for one day of treatment at the lowest dosage level) in Red book. Montvale, N.J.: Medical Economics Data, 1999. Cost to the patient will be higher, depending on prescription filling fee. Adapted from Centers for Disease Control and Prevention. 1998 Guidelines for the treatment of sexually transmitted diseases. MMWR Morb Mortal Wkly Rep 1998;47(RR-1).

Pelvic Inflammatory Disease

Parenteral therapy for pelvic inflammatory disease should be considered in women who are pregnant, immunodeficient or intolerant of oral therapy, as well as in those who have a tubo-ovarian abscess or severe illness.

Pelvic inflammatory disease is an infection of the upper female genital tract caused by Neisseria gonorrhoeae, Chlamydia trachomatis, or both, although it may also be caused by micro-organisms that are part of the normal vaginal flora. Disease can manifest as any combination of endometritis, salpingitis, tubo-ovarian abscess and pelvic peritonitis. The clinical diagnosis of pelvic inflammatory disease is complicated; therefore, the CDC guidelines should be checked for more information about diagnosis.

Treatment is usually empiric, and antimicrobial therapy should cover N. gonorrhoeae, C. trachomatis, anaerobes, gram-negative facultative bacteria and streptococci. Parenteral therapy is required in several types of patients, including those who are pregnant, those who do not respond to or are unable to tolerate oral antimicrobial therapy, those with severe illness such as nausea, vomiting or high fever, those with tubo-ovarian abscess and patients who are immunodeficient. Sexual partners of patients with pelvic inflammatory disease should be evaluated and treated; empiric treatment is recommended for gonorrhea and Chlamydia. Recommended antimicrobial regimens are listed in Table 2.

TABLE 2 Treatment of Pelvic Inflammatory Disease Recommended regimens Agent Dosage Cost* Parenteral regimens Cefotetan (Cefotan) or 2 g IV every 12 hours $ 46.50 (brand) Cefoxitin (Mefoxin) plus 2 g IV every 6 hours 85.50 (brand) Doxycycline (Vibramycin) 100 mg IV or orally every 12 hours 33.50 (generic) Alternative parenteral regimen Clindamycin (Cleocin) plus 900 mg IV every 8 hours 29.00 (brand) Gentamicin IV or IM, 2 mg per kg loading dose, followed by 1.5 mg per kg every 8 hours 3.00 to 15.00 (generic) Oral regimens Ofloxacin (Floxin) plus 400 mg orally twice daily for 14 days 131.00 (brand) Metronidazole (Flagyl) 500 mg orally twice daily for 14 days 79.00 (brand) 8.50 to 13.00 (generic) Alternative regimen† Ceftriaxone (Rocephin) or 250 mg IM in a single dose 13.50 (brand) Cefoxitin plus 2 g IM 21.50 (brand) Probenecid 1 g orally in a single dose given once concurrently with cefoxitin 0.50 to 20.00 (generic) IV = intravenously; IM = intramuscularly. Adapted from Centers for Disease Control and Prevention. 1998 Guidelines for treatment of sexually transmitted diseases. MMWR Morb Mortal Weekly Rep 1998;47(RR-1). *--Estimated cost to the pharmacist based on average wholesale prices rounded to the nearest half dollar (for one day of treatment at the lowest dosage level) in Red book. Montvale, N.J.: Medical Economics Data, 1999. Cost to the patient will be higher, depending on prescription filling fee. †--These patients should also receive presumptive therapy for Chlamydia infection with doxycycline in a dosage of 100 mg twice daily for 7 days. Please refer to CDC Guidelines for alternative regimens appropriate for pregnant women. 1998 Guidelines for treatment of sexually transmitted diseases. MMWR Morb Mortal Weekly Rep 1998;47(RR-1).

Epididymitis

Recommendations for treatment of epididymitis that is caused by sexually transmitted organisms remain the same as in previous guidelines. Ofloxacin (Floxin) is recommended for treatment of epididymitis caused by enteric organisms or occurring in patients who are allergic to cephalosporins or tetracyclines (Table 3).

TABLE 3 Treatment of Epididymitis Cause Recommended regimen Dosage Cost* Gonococcal or chlamydial infection Ceftriaxone (Rocephin) plus 250 mg IM in a single dose $ 13.50 (brand) Doxycycline (Vibramycin) 100 mg orally twice daily for 10 days 79.50 (brand) 3.50 to 27.00 (generic) Enteric organisms Ofloxacin (Floxin) 300 mg twice daily for 10 days 89.00 (brand) IM = intramuscularly. Adapted from Centers for Disease Control and Prevention. 1998 Guidelines for treatment of sexually transmitted diseases. MMWR Morb Mortal Weekly Rep 1998;47(RR-1). *--Estimated cost to the pharmacist based on average wholesale prices rounded to the nearest half dollar (for lowest dosage level and treatment period) in Red book. Montvale, N.J.: Medical Economics Data, 1999. Cost to the patient will be higher, depending on prescription filling fee.

Human Papillomavirus Infection

Human papillomavirus infection manifests as genital warts and is associated with cervical dysplasia. There are over 20 types of human papillomavirus, and not all types exhibit visible warts. Papanicolaou smears often identify associated cellular changes.

Two new treatments, podofilox and imiquimod, are available for patient-administered treatment of genital warts.

The goal of treatment is to eliminate visible genital warts. No evidence indicates that treatment affects the natural course of human papillomavirus infection or decreases its rate of sexual transmission. Two new treatments are available for patients' self-administration: podofilox (Condylox) and imiquimod (Aldara).⁴ Recommendations for provider-administered therapies still exist and are outlined in Table 4. Several factors should be considered when choosing a mode of therapy, such as wart size, wart number, anatomic site of wart, patient preference, cost of therapy, convenience, adverse effects and provider experience. Even with the patient-applied therapies, it is recommended that the health care provider apply the initial treatment to demonstrate the proper application technique.

TABLE 4 Treatment of Human Papillomavirus Infection Recommended regimen Wart location Agent Dosage Appropriate therapy External genital area Podofilox (Condylox) 0.5% solution or gel (patient-applied) Twice daily for three days, wait four days, then repeat as necessary for four cycles Imiquimod (Aldara) 5% cream (patient-applied) Daily at bedtime three times weekly for up to 16 weeks Cryotherapy Physician-applied Repeat every 1 to 2 weeks Podophyllum resin 10 to 25% (physician-applied) Weekly Trichloroacetic acid or bichloroacetic acid 80 to 90% (physician-applied) Weekly Surgical removal Alternative treatments Intralesional interferon Laser surgery Vaginal Cryotherapy With liquid nitrogen Repeat every 1 to 2 weeks Trichloroacetic acid or bichloroacetic acid 80 to 90% Weekly Podophyllum 10 to 25% Weekly Urethral meatus Cryotherapy With liquid nitrogen Repeat every 1 to 2 weeks Podophyllum 10 to 25% Weekly Anal area Cryotherapy With liquid nitrogen Repeat every 1 to 2 weeks Trichloroacetic acid or bichloroacetic acid 80 to 90% Weekly Surgical removal Oral Cryotherapy With liquid nitrogen Repeat every 1 to 2 weeks Surgical removal Adapted from Centers for Disease Control and Prevention. 1998 Guidelines for treatment of sexually transmitted diseases. MMWR 1998;47(RR-1).

Proctitis, Proctocolitis, Enteritis and Ectoparasitic Infections

Mucopurulent proctitis and proctocolitis may be empirically treated as STDs (Table 5) while definitive diagnostic studies are performed. Permethrin cream (Nix) is the preferred agent for treatment of pediculosis pubis and scabies. Lindane (Kwell) and sulfur topical therapies are recommended as alternative regimens. See Table 5 for detailed treatment recommendations.

TABLE 5 Treatment of Proctitis, Proctocolitis, Enteritis and Ectoparasitic Diseases Recommended regimens Condition Agent Dosage Cost* Proctitis, proctocolitis and enteritis Ceftriaxone (Rocephin) plus 125 mg IM in a single dose $ 14.00 (brand) Doxycycline (Vibramycin) 100 mg orally twice daily for 7 days 55.00 (brand) 2.50 to 19.00 (generic) Pediculosis pubis Permethrin cream (Nix) 1% cream: apply to affected area and wash off after 10 minutes 9.00 (brand/2 oz) Lindane (Kwell) 1% shampoo: apply for 4 minutes, then wash (not recommended for use in pregnant or lactating women, or in children under 2 years of age) 3.00 to 7.00 (generic/2 oz) Pyrethrins with piperonyl butoxide Apply for 10 minutes and wash† Scabies Permethrin cream 1% cream: apply to body from the neck down and wash off after 8 to14 hours; re-evaluate in one week 9.00 (brand/2 oz) Alternative regimens Lindane 1% lotion or cream: apply to body from the neck down and wash off after 8 hours; re-evaluate in one week (not recommended for use in pregnant or lactating women, or in children under 2 years of age) 6.00 to 14.00 (generic/2 oz) Sulfur 6% precipitated in ointment: apply to all areas nightly for 3 nights† IM = intramuscularly. Adapted from Centers for Disease Control and Prevention. 1998 Guidelines for treatment of sexually transmitted diseases. MMWR 1998;47(RR-1). *--Estimated cost to the pharmacist based on average wholesale prices rounded to the nearest half dollar (for lowest dosage level and treatment period or per container) in Red book. Montvale, N.J.: Medical Economics Data, 1999. Cost to the patient will be higher, depending on prescription filling fee. †--These preparations must be compounded by a pharmacist.

Additional information about evaluation, diagnosis and treatment of sexually transmitted diseases may be found in "Guidelines for the Treatment of Sexually Transmitted Diseases" published in 1998 by the CDC, along with specific information regarding special patient populations. Table 6 lists side effects of drug classes commonly used to treat STDs.

TABLE 6 Side Effects Associated with Drugs Commonly Used to Treat Sexually Transmitted Diseases Drug Side effects Cephalosporins Pain at injection site, diarrhea, allergic reactions, Clostridium difficile colitis, hypoprothrombinemia, platelet dysfunction, eosinophilia, positive Coombs' test, serum sickness, cholelithiasis (associated with use of ceftriaxone [Rocephin]) and, rarely, hemolytic anemia, interstitial nephritis, hepatic dysfunction, convulsions (associated with renal failure), neutropenia, thrombocytopenia and confusion Fluoroquinolones Gastrointestinal intolerance, headache, insomnia, dizziness, allergic reactions, photosensitivity, elevated liver enzymes and, rarely, papilledema, nystagmus, C. difficile colitis, marrow suppression, anaphylaxis and central nervous system stimulation Penicillins Rash, serum sickness, positive Coombs' test and, rarely, neutropenia, thrombocytopenia, elevated liver function tests, increased blood urea nitrogen and creatinine levels, headache, confusion and seizures Macrolide antibiotics Diarrhea, nausea, abdominal pain, rash, cholestatic hepatitis and, rarely, C. difficile colitis and hemolytic anemia Tetracyclines Gastrointestinal intolerance, stained teeth (in children), hepatotoxicity, photosensitivity, pain with injection and, rarely, allergic reactions, visual disturbances, hemolytic anemia and C. difficile colitis Information from Handbook of antimicrobial therapy. New Rochelle, N.Y.: Medical Letter, 1998-99:123-37.

This is Part II of a two-part article on drug treatment of sexually transmitted diseases. Part I, "Herpes, Syphilis, Urethritis, Chlamydia and Gonorrhea," appeared in the October 1 issue (Am Fam Physician 1999; 60:1387-94).

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REFERENCES

1. Ferris DG, Litaker MS, Woodward L, Mathis D, Hendrich J. Treatment of bacterial vaginosis: a comparison of oral metronidazole, metronidazole vaginal gel, and clindamycin vaginal cream. J Fam Pract 1995;41:443-9.
2. O-Prasertsawat P, Bourlert A. Comparative study of fluconazole and clotrimazole for the treatment of vulvovaginal candidiasis. Sex Transm Dis 1995;22: 228-30.
3. Sobel JD, Brooker D, Stein GE, Thomason JL, Wermeling DP, Bradley B, et al. Single oral dose fluconazole compared with conventional clotrimazole topical therapy of Candida vaginitis. Fluconazole Vaginitis Study Group. Am J Obstet Gynecol 1995; 172(4 pt 1):1263-8.
4. Syed TA, Ahmadpour OA, Ahmad SA, Ahmad SH. Management of female genital warts with an analog of imiquimod 2% in cream: a randomized, double-blind, placebo-controlled study. J Dermatol 1998;25:429-33.

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