Drug Treatment of Common STDs: Part I. Herpes, Syphilis, Urethritis, Chlamydia and Gonorrhea - October 1, 1999

Drug Treatment of Common STDs: Part I. Herpes, Syphilis, Urethritis, Chlamydia and Gonorrhea

CAROL WOODWARD, PHARM.D

West Virginia University Hospitals, Morgantown, West Virginia

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

West Virginia University, Morgantown, West Virginia

In 1998, the Centers for Disease Control and Prevention released guidelines for the treatment of sexually transmitted diseases. Several treatment advances have been made since the previous guidelines were published. Part I of this two-part article describes current recommendations for the treatment of genital ulcer diseases, urethritis and cervicitis. Treatment advances include effective single-dose regimens for many sexually transmitted diseases and improved therapies for herpes infections. Two single-dose regimens, 1 g of oral azithromycin and 250 mg of intramuscular ceftriaxone, are effective for the treatment of chancroid. A three-day course of 500 mg of oral ciprofloxacin twice daily may be used to treat chancroid in patients who are not pregnant. Parenteral penicillin continues to be the drug of choice for treatment of all stages of syphilis. Three antiviral medications have been shown to provide clinical benefit in the treatment of genital herpes: acyclovir, valacyclovir and famciclovir. Valacyclovir and famciclovir are not yet recommended for use during pregnancy. Azithromycin in a single oral 1-g dose is now a recommended regimen for the treatment of nongonococcal urethritis. (Am Fam Physician 1999;60:1387-94.)

Several advances have been made in the treatment of sexually transmitted diseases (STDs). These advances have been incorporated into the "1998 Guidelines for the Treatment of Sexually Transmitted Diseases," published by the Centers for Disease Control and Prevention (CDC).¹

See editorial
on page 1335.

Highly effective single-dose oral therapies are now available for most common curable STDs. Single-dose regimens may be used for the treatment of chancroid, nongonococcal urethritis, uncomplicated gonococcal infections, bacterial vaginosis, trichomoniasis, candidal vaginitis and chlamydial infections.

Improved therapies are now available for the treatment of genital herpes and human papillomavirus (HPV) infections. New regimens have been approved for the use of acyclovir (Zovirax) in the treatment of genital herpes. In addition, two new antiviral agents, valacyclovir (Valtrex) and famciclovir (Famvir), have been labeled for the treatment of genital herpes. Patient-applied therapies are now recommended for management of HPV.

A new testing method for the diagnosis of chlamydial infections employs an extremely accurate urine test that can easily be incorporated into screening programs. Hepatitis A and hepatitis B vaccines are now recommended for all sexually active adolescents and young adults.

Treatments for STDs in pregnant women have been improved, producing fewer side effects and reducing the number of premature births. Treatment guidelines for the management of STDs in special patient populations, including pregnant women, were recently published in this journal.²

TABLE 1
Treatment of Diseases Characterized by Genital Ulcers

Regimens

Disease
Agent
Dosage
Cost *

Chancroid Azithromycin (Zithromax) 1 g orally in a single dose $ 20.50 (brand)

Ceftriaxone (Rocephin) 250 mg IM in a single dose 13.00 (brand)

Ciprofloxacin (Cipro) 500 mg orally twice daily for 3 days 24.00 (brand)

Erythromycin base 500 mg orally four times daily for 7 days 6.50 to 9.00 (generic)

Granuloma inguinale

Recommended regimen Trimethoprim/sulfamethoxazole (Bactrim, Septra) Double strength, taken orally twice daily for 21 days 54.00 (brand)
14.00 to 25.00 (generic)

or

Doxycycline (Vibramycin) 100 mg orally twice daily for 21 days 167.00 (brand)

Alternative regimen Ciprofoxacin 750 mg orally twice daily for 21 days 168.00 (brand)

or Erythromycin base 500 mg orally four times daily for 21 days 19.50 to 27.00 (generic)

plus (during pregnancy)

Aminoglycoside (i.e., gentamicin) 1 mg per kg IV three times daily for 21 days 337.00 (brand)
66.00 to 312.00 (generic)

Lymphogranuloma venereum

Recommended regimen Doxycycline 100 mg orally twice daily for 21 days 85.00 (brand)
5.50 to 26.50 (generic)

Alternative regimen (including pregnancy) Erythromycin base 500 mg orally four times daily for 21 days 42.00 (brand)
20.50 to 27.50 (generic)

Herpes simplex virus

First episode Acyclovir (Zovirax) 400 mg orally three times daily for 7 to 10 days
or 53.00 (brand)
37.50 to 43.00 (generic)

200 mg orally five times daily for 7 to 10 days 45.00 (brand)
32.00 to 37.00 (generic)

Famciclovir (Famvir) 250 mg orally three times daily for 7 to 10 days 70.00 (brand)

Valacyclovir (Valtrex) 1 g orally twice daily for 7 to 10 days 56.00 (brand)

Recurrent episodes Acyclovir 400 mg orally three times daily for 5 days 38.00 (brand)
27.00 to 31.00 (generic)

200 mg orally five times daily for 5 days 32.50 (brand)
23.00 to 26.50 (generic)

800 mg orally twice daily for 5 days 50.00 (brand)
35.00 to 40.00 (generic)

Famciclovir 125 mg orally twice daily for 5 days 28.00 (brand)

Valacyclovir 500 mg orally twice daily for 5 days 31.00 (brand)

Daily suppressive therapy Acyclovir 400 mg orally twice daily 5.00 (brand) **
3.50 to 4.00 (generic)

Famciclovir 250 mg orally twice daily 6.50 (brand)

Valacyclovir 500 mg orally once daily (in patients with < 10 episodes per year) 3.00 (brand)

Valacyclovir 1,000 mg orally once daily (in patients with > 10 episodes per year) 6.00 (brand)

Syphilis

Primary and secondary disease Benzathine penicillin G 2.4 million units IM in a single dose 24.00 (brand)

Penicillin allergy Doxycycline 100 mg orally twice daily for 14 days 111.00 (brand)
6.00 to 25.00 (generic)

Tetracycline 500 mg orally four times daily for 14 days 3.50 to 6.00 (generic)

Early latent disease Benzathine penicillin G 2.4 million units IM in a single dose 24.00 (brand)

Late latent, unknown duration, tertiary disease Benzathine penicillin G 7.2 million units IM total, divided into three weekly doses of 2.4 million units each 71.50 (brand)

Neurosyphilis Aqueous crystalline penicillin G 18 to 24 million units IV daily, divided as 3 to 4 million units every 4 hours for 10 to 14 days 12.00 (generic)

Procaine penicillin plus probenecid 2.4 million units of penicillin daily, plus 500 mg probenecid orally four times daily, both for 10 to 14 days. 277.00 (generic)

IM = intramuscularly; IV = intravenously.
Reprinted 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):1-111.
*--Estimated cost to the pharmacist (rounded to the nearest half dollar) based on average wholesale prices (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.
**--Cost for one day of therapy.

Genital Ulcer Diseases

Before a genital ulcer is treated, an accurate diagnosis with appropriate testing is essential. Concomitant testing for human immunodeficiency virus (HIV) infection should be considered.

Chancroid
The goals of therapy for chancroid are to cure the infection, resolve symptoms and prevent transmission. Four recommended drug regimens for the treatment of chancroid are shown in Table 1. Two are single-dose regimens consisting of either azithromycin (Zithromax) or ceftriaxone (Rocephin). Erythromycin, which continues to be recommended for the treatment of chancroid, requires a seven-day dosing regimen. Ciprofloxacin (Cipro) has been added to the guidelines for the treatment of chancroid. However, ciprofloxacin is contraindicated for use in pregnant and lactating women, and in patients under 18 years of age. All four regimens are effective for treatment of chancroid in patients with or without HIV. Of note, several isolates of chancroid with intermediate resistance to either ciprofloxacin or erythromycin have been reported. Patients should be re-examined within three to seven days after initiation of therapy. Symptomatic improvement should be reported within three days if treatment is successful.

Genital Herpes
Genital herpes is a recurrent, incurable viral disease. Patient counseling should include information about recurrent episodes, asymptomatic viral shedding, perinatal transmission and sexual transmission. Episodic antiviral therapy during outbreaks may shorten the duration of the lesions, and suppressive antiviral therapy may prevent recurrences.

Patients who are HIV-positive and allergic to penicillin require desensitization and penicillin treatment for all stages of syphilis.

During the first clinical episode, the goal of systemic antiviral drug therapy is to control the signs and symptoms of genital herpes. Daily suppressive therapy is recommended for use in patients who have six or more recurrences per year. Three antiviral medications have been proved in randomized trials to provide clinical benefit in patients with genital herpes: acyclovir, valacyclovir and famciclovir. Clinical experience with systemic acyclovir in the treatment of genital herpes has been substantial. Topical therapy is less effective than systemic therapy, and its use is not recommended. Two newer antiviral agents are valacyclovir and famciclovir.^3,4 Valacyclovir is a valine ester of acyclovir with enhanced absorption properties when administered orally. Famciclovir, a prodrug of penciclovir, also has high oral bioavailability. The safety of antiviral therapy in pregnant women has not been established, but extensive clinical experience with acyclovir has been reassuring. Severe or first-episode disease that occurs during pregnancy may be treated with acyclovir. However, the routine administration of antiviral agents in pregnant women with uncomplicated or recurrent genital herpes is not recommended.

Syphilis
Syphilis is a systemic disease caused by the sexual transmission of Treponema pallidum. It can present as primary, secondary or tertiary disease. Primary disease presents with one or more painless ulcers or chancres at the inoculation site. Secondary disease manifestations include rash and adenopathy. Cardiac, neurologic, ophthalmic, auditory or gummatous lesions characterize tertiary infections. Latent disease may be detected by serologic testing, without the presence of signs and symptoms. Early latent disease is defined as disease acquired within the preceding year. All other cases of latent syphilis are considered late latent disease or disease of unknown duration.

The recommended treatment regimens have not changed since the 1993 CDC Guidelines. Parenteral penicillin G is still the preferred drug for treating all stages of syphilis, including disease in pregnant women. Table 1 outlines the different penicillin preparations and the proper dosages and durations of therapy, depending on the stage of syphilis at patient presentation. Patients with early disease and penicillin allergy may be desensitized first and then treated with penicillin or treated with another recommended regimen. Patients with HIV infection require treatment with penicillin at all stages of syphilis. Treatment may be associated with the Jarisch-Herxheimer reaction. This reaction is an acute febrile illness that may occur within the first 24 hours of therapy and includes symptoms such as headache and myalgias. Concomitant antipyretic therapy may be beneficial.

Granuloma Inguinale and Lymphogranuloma Venereum
Granuloma inguinale and lymphogranuloma venereum are rare in the United States. Granuloma inguinale presents as a painless, highly vascular ulcer that is caused by Calymmatobacterium granulomatis. Patients with lymphogranuloma venereum present most often with regional lymphadenopathy; it is often a diagnosis of exclusion. The disease is caused by L serogroup strains of Chlamydia trachomatis. The diagnosis is usually made clinically and serologically. Treatment regimens for these diseases are given in Table 1.

TABLE 2
Treatment of Urethritis and Cervicitis *

Regimens

Disease
Agent
Dosage
Cost **

Nongonococcal uretritis

Recommended regimens Azithromycin (Zithromax) 1 g orally (single dose) 20.50 (brand)

Doxycycline (Vibramycin) 100 mg orally twice daily for 7 days 55.50 (brand)
2.50 to 19.00 (generic)

Alternative regimens Erythromycin base
or 500 mg orally four times daily for 7 days 6.50 to 9.00 (generic)

Erythromycin ethylsuccinate
or 800 mg orally four times daily for 7 days 10.00 to 22.00 (generic)

Ofloxacin (Floxin) 300 mg orally twice daily for 7 days 62.50 (brand)

If high-dose erythromycin is not tolerated:

Erythromycin base
or 250 mg orally four times daily for 14 days 8.00 to 24.00 (generic)

Erythromycin ethylsuccinate 400 mg orally four times daily for 14 days 5.00 to 11.00 (generic)

Recurrent / persistent urethritis Metronidazole (Flagyl) 2 g orally in a single dose 11.50 (brand)
1.50 to 3.00 (generic)

plus either

Erythromycin base
or 500 mg orally four times daily for 7 days 6.50 to 9.00 (generic)

Erythromycin ethylsuccinate 800 mg orally four times daily for 7 days 10.00 to 22.00 (generic)

Chlamydial infection

Recommended regimens Azithromycin
or 1 g orally (single dose) 20.50 (brand)

Doxycycline 100 mg orally twice daily for 7 days 55.50 (brand)
2.50 to 19.00 (generic)

Alternative regimens Erythromycin base
or 500 mg orally four times daily for 7 days 6.50 to 9.00 (generic)

Erythromycin ethylsuccinate
or 800 mg orally four times daily for 7 days 10.00 to 22.00 (generic)

Ofloxacin 300 mg orally twice daily for 7 days 62.50 (brand)

Gonococcal infection

Uncomplicated infections of the cervix, urethra and rectum Cefixime (Suprax)
or 400 mg orally in a single dose 7.50 (brand)

Ceftriaxone (Rocephin)
or 125 mg IM in a single dose 14.00 per 250-mg vial (brand)

Ciprofloxacin (Cipro)
or 500 mg orally in a single dose 4.00 (brand)

Ofloxacin
plus 400 mg orally in a single dose 5.00 (brand)

Azithromycin
or 1 g orally in a single dose 20.50 (brand

Doxycycline 100 mg orally twice daily for 7 days 55.50 (brand)
2.50 to 19.00 (generic)

Recurrent episodes Ceftriaxone
or 125 mg IM in a single dose 14.00 per 250-mg vial (brand)

Ciprofloxacin
or 500 mg orally in a single dose 4.00 (brand)

Ofloxacin
plus 400 mg orally in a single dose 5.00 (brand)

Azithromycin 1 g orally in a single dose 20.50 (brand)

Doxycycline 100 mg orally twice daily for 7 days 55.50 (brand)
2.50 to 19.00 (generic)

IM = intramuscularly.
Reprinted 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):1-111.
*--Mucopurulent cervicitis should be treated according to the guidelines for chlamydial and gonococcal infections.
**--Estimated cost to the pharmacist (rounded to the nearest half dollar) based on average wholesale prices (for lowest dosage levels and treatment periods) in Red book. Montvale, N.J.: Medical Economics Data, 1999. Cost to the patient will be higher, depending on prescription filling fee.

Diseases Characterized by Urethritis and Cervicitis

Urethritis
Urethritis is an infection characterized by mucopurulent or purulent discharge and burning during urination. Neisseria gonorrhoeae and C. trachomatis are the most common bacterial pathogens associated with urethritis. Empiric treatment is recommended in high-risk patients and those unlikely to return for follow-up. Treatment guidelines are outlined in Table 2.

Several regimens for the management of patients with nongonococcal urethritis are outlined in Table 2. Oral azithromycin is recommended as single-dose therapy.^5-7 Improved compliance and the ability to observe therapy are advantages associated with single-dose regimens.

Mucopurulent Cervicitis
Mucopurulent cervicitis is often asymptomatic. It may be detected by the presence of purulent or mucopurulent endocervical exudate. Some women with this condition have an abnormal vaginal discharge and report vaginal bleeding after sexual intercourse. C. trachomatis or N. gonorrhoeae usually cause mucopurulent cervicitis, but in many cases neither organism can be isolated. Patients with positive cultures or nucleic acid amplification tests for the presence of C. trachomatis or N. gonorrhoeae always require treatment. Empiric therapy is recommended when the likelihood of infection with either organism is high or when patients are unlikely to return for treatment. Recommended treatment regimens are outlined in Table 2.

Uncomplicated Chlamydial and Gonoccocal Infections

Azithromycin may be a cost-effective treatment for Chlamydia because it provides single-dose, observed therapy.

Chlamydial Infection
Chlamydial genital infections are common among adolescents and young adults who are sexually active. C. trachomatis infection may be associated with pelvic inflammatory disease (PID), ectopic pregnancy and infertility. Since chlamydial infection is often asymptomatic and the sequelae can be serious, routine screening for disease during annual examinations is recommended. Single-dose therapy with azithromycin is as effective as a seven-day course of doxycycline (Vibramycin). Doxycycline is less expensive, but azithromycin may be cost-beneficial because it provides single-dose, directly observed therapy. Erythromycin and ofloxacin (Floxin) also may be used to treat C. trachomatis. Erythromycin is less efficacious than azithromycin and doxycycline, and its adverse gastrointestinal effects may decrease patient compliance. Ofloxacin is as effective as the recommended regimens but offers no dosing or cost advantages. Doxycycline and ofloxacin are contraindicated in pregnant women. In addition, the safety and efficacy of azithromycin in pregnant women has not been established; therefore, a seven-day course of either erythromycin or amoxicillin is recommended in this group. Since neither regimen is considered highly effective, cultures should be repeated in three weeks.

Gonococcal Infection
Men with a gonococcal infection experience symptoms that require treatment, but women often are asymptomatic until complications of the infection, such as PID, occur. For this reason, screening is recommended in high-risk patients. Co-infection with C. trachomatis often occurs in patients with gonococcal infections. The cost of doxycycline therapy for C. trachomatis is less expensive than testing for the organism, so empiric treatment of co-infection is becoming routine. Also, dual therapy with doxycycline and azithromycin may decrease the development of antimicrobial-resistant N. gonorrhoeae, because most gonococci are susceptible to both drugs. Quinolone-resistant N. gonorrhoeae has been reported in the United States and is becoming more widespread in Asia. At this time, fluoroquinolone regimens can be used with confidence, but continued monitoring of emerging resistance will be important.

Table 2 outlines therapy for gonococcal infections. Four single-dose regimens are now available for treatment of uncomplicated gonococcal infections of the cervix, urethra and rectum. They include cefixime (Suprax), ceftriaxone, ciprofloxacin and ofloxacin. Cefixime, ciprofloxacin and ofloxacin are given orally, while ceftriaxone is administered intramuscularly. Gonococcal infections of the pharynx are more difficult to eradicate but, with the exception of cefixime, the recommended therapy is the same as for urogenital and anorectal infections, and should include concomitant treatment for chlamydial infection.

This is Part I of a two-part article on drug treatment of common sexually transmitted diseases. Part II, "Vaginal Infections, Pelvic Inflammatory Disease and Genital Warts," will appear in the next issue of AFP.

The Authors

CAROL WOODWARD, PHARM.D.
is assistant director of pharmaceutical services at West Virginia University Hospitals and clinical assistant professor at the West Virginia University School of Pharmacy, both in Morgantown. Dr. Woodward received her doctor of pharmacy degree from the University of North Carolina at Chapel Hill. She completed a residency in pharmacy at West Virginia University Hospitals, Inc.

MELANIE ANN FISHER, M.D., M.SC.
is associate professor of medicine in the Department of Medicine, Infectious Diseases Section, at the West Virginia University School of Medicine, Robert C. Byrd Health Sciences Center, Morgantown. She received her medical degree from the Pennsylvania State University College of Medicine, Hershey, and completed an internship and a residency in internal medicine at West Virginia University Medical Center. She has also completed a clinical and research fellowship in infectious diseases at the University of Pennsylvania School of Medicine, Philadelphia, and earned a master of science degree in epidemiology at the Harvard School of Public Health, Boston.

Address correspondence to Carol Woodward, Pharm.D., Department of Pharmaceutical Services, Morgantown, WV, 26506-8045. Reprints are not available from the authors.

REFERENCES

Centers for Disease Control and Prevention. 1998 guidelines for the treatment of sexually transmitted diseases. MMWR Morb Mortal Wkly Rep 1998; 47(RR-1):1-111.

Rose VL. CDC releases the 1998 guidelines for the treatment of sexually transmitted diseases. Am Fam Physician 1998;57:2003-4,2007-8.

Fife KH, Barbarash RA, Rudolph T, Degregorio B, Roth R. Valaciclovir versus acyclovir in the treatment of first-episode genital herpes infection. Results of an international, multicenter, double-blind, randomized clinical trial. The Valaciclovir International Herpes Simplex Virus Study Group. Sex Transm Dis 1997;24:481-6.

Mertz GJ, Loveless MD, Levin MJ, Kraus SJ, Fowler SL, Goade D, et al. Oral famciclovir for suppression of recurrent genital herpes simplex virus infection in women. A multicenter, double-blind, placebo-controlled trial. Collaborative Famciclovir Genital Herpes Research Group. Arch Intern Med 1997; 157:343-9.

Lauharanta J, Saarinen K, Mustonen M, Happonen HP. Single-dose oral azithromycin versus seven-day doxycycline in the treatment of non-gonococcal urethritis in males. J Antimicrob Chemother 1993;31(Suppl E):177-83.

Lister PJ, Balechandran T, Ridgway GL, Robinson AJ. Comparison of azithromycin and doxycycline in the treatment of non-gonococcal urethritis in men. J Antimicrob Chemother 1993;31(Suppl E):185-92.

Stamm WE, Hicks CB, Martin DH, Leone P, Hook EW 3d, Cooper RH, et al. Azithromycin for empirical treatment of the nongonococcal urethritis syndrome in men. A randomized double-blind study. JAMA 1995;274:545-9.

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