Genital Ulcer Disease - Antibiotic Therapy

ANTIMICROBIAL THERAPY

               During the course of some evaluations, there are instances in which no apparent diagnosis can be assigned to the patient with genital ulcer disease. It is at this point when a decision must be made to reinstitute the evaluative process; empirically treat the ulcerative illness while repeating necessary diagnostic testing; or begin empiric treatment for most, if not all, pathogens. Many STD’s have similar epidemiologic links, and it is prudent to consider co-infection at all phases of the investigation.

               There is no consensus regarding the empiric therapy of undiagnosed genital ulcer disease. Hperes simplex virus is generally omitted initially, given its distinct clinical course, but many suggest the administration of an antiviral agent following failed bacterial antibiotic treatment. Oftentimes therapeutic options for syphilis remain outside of the recommendations since serologic tests are simple, reliable, and available. The simplest course of therapy would be azithromycin 1 gram orally which will treat chancroid and lymphogranuloma venereum, and begin the first of 3 administrations weekly for granuloma inguinale. An alternative regimen would be doxycycline 100 mg BID for 3 weeks coupled with a single dose of ceftriaxone 250 mg IM, which would cover the most difficult to diagnose genital ulcer disease pathogens as well as syphilis. Occasionally, multiple empiric courses of therapy are prescribed, along with several repetitive investigations without significant improvement. Noninfectious disease processes should be considered if the infectious diseases evaluations remain negative and the patient demonstrates no clinical improvement (Table 1).

Table 1: Differential Diagnosis Of Genital Ulcer Disease

Infectious Causes	Non-infectious Causes
Chancroid Genital herpes Granuloma inguinale Lymphogranuloma venereum Syphilis	Bechet’s disease Erythema multiforme Fixed drug eruption Squamous cell carcinoma  Trauma

               Epidemiologic treatments are therapies rendered to those sex partners of diagnosed patients with genital ulcer disease. These “epi-treats” play an integral role in the management of genital ulcers and serve to interrupt future transmission emanating from that newly exposed/infected person, possibly even before signs and symptoms appear in that individual.

Chancroid: Appropriate therapy will cure the infection as well as prevent transmission (Table 2). Clinical symptoms will diminish and eventually disappear over time. Complete resolution of all signs and symptoms is the expected outcome. Patients should notice symptomatic improvement within three days, and certainly by seven days. Larger size of the ulcer(s) may prolong the recovery period. The inguinal adenopathy resolves more slowly than the genital ulcers and may require drainage, which may be repetitive and possibly may include an open surgical intervention rather than needle aspiration. If allowed to remain fluctuant, a suppurative lymph node may spontaneously rupture and convert into a chronic draining sinus. Sexual partners should be treated, whether symptomatic or not. HIV testing is essential. Failure of the infection to resolve might suggest consideration for the correctness of the diagnosis, for the presence of co-infection with another STD, for poor adherence to the prescribed therapy, for resistance to the prescribed therapy, or for underlying HIV infection modifying the disease course.

Genital Herpes: Primary herpes simplex virus infection is treated with antiviral agents  (Table 2). Suppressive antiviral therapy following the primary episode reduces the frequency of recurrences by 70%-80%. Acyclovir 400 mg po BID, famciclovir 250 mg po BID, and valacyclovir 500 mg or 1 gm po daily have proven effective. The need for continuous suppression wanes over time, as recurrences often decrease in number and intensity. Treatment choices for recurrent genital herpes include acyclovir 400 mg po TID x 5 days, 800 mg po BID x 5 days, or 800 mg po TID x 2 days; famciclovir 125 mg po BID x 5 days or 1000 mg po BID x 1 day; and valacyclovir 500 mg po BID x 3 days or 1 gm daily x 5 days. On occasion, intravenous acyclovir (5-10 mg/kg IV q 8 hours) may be necessary for those individuals with severe herpes simplex virus disease, for those unable to tolerate enteral therapy, for those with complications resulting in hospitalization (dissemination, pneumonitis, hepatitis), or for those who have central nervous system complications such as meningitis or encephalitis. The intravenous form of acyclovir is continued for 2 to 7 days or until the patient is clinically improved, followed by an oral antiviral agent to complete at least 10 days of treatment.

               Sexual partners of individuals with herpes simplex virus genital disease should be evaluated and treated if appropriate. HIV serologic testing should be offered. Rarely, herpes simplex virus infection resistant to traditional first line agents have been isolated. Clinical failure despite appropriate therapy should suggest a search for an alternative diagnosis or consideration of a drug resistant species of herpes simplex virus.

Granuloma Inguinale:  The CDC recommends doxycycline for treatment of donovanosis (Table 2). The other alternatives listed have been used successfully around the globe as well. Some experts recommend the addition of gentamicin (1 mg/kg IV q 8 hours) if there is no improvement documented in the beginning of therapy. Treatment is continued for at least three weeks and until all the lesions have completely healed. If there has been little or no improvement following the first two weeks of therapy, then an alternative choice of treatment should be selected. Of note is the fact that once therapy has been given for seven days, Donovan bodies are no longer visible in clinical specimens. Those individuals who have had sexual contact with an index patient having granuloma inguinale within 60 days before the onset of the patient’s symptoms should be examined and offered therapy, even though the value of empiric therapy remains unproven.

Lymphogranuloma Venereum: The CDC recommends doxycycline for the treatment of lymphogranuloma venereum (Table 2). Appropriate therapy cures the infection and halts ongoing tissue damage, but regression of the fibrosis and/or scarring previously documented is seldom seen. There is some support for the use of azithromycin 1 gm orally given weekly for 3 weeks, even though there is limited clinical data published. Sex partners who have had contact with lymphogranuloma venereum patients within the 60 days before the onset of the patient’s symptoms should be evaluated for cervical or urethral chlamydia infection, and treated with a standard chlamydia regimen.

Syphilis:  Treatment for primary syphilis is penicillin G, administered intramuscularly (Table 2). Other therapy options exist and have been successfully administered in various situations. There is growing evidence for the use of doxycycline in the treatment of early syphilis. Azithromycin has recently fallen out of favor with the failure of therapy for the treatment of early syphilis in men who have sex with men in San Francisco during 2002-2003. An HIV test is part of the evaluation of the patient with syphilis at any stage, and in high incidence areas, it should be repeated in 3 months. Following therapy for primary syphilis, patients should have an evaluation and repeat VDRL/RPR testing at 6 and 12 months. Failure of these nontreponemal tests to demonstrate a four-fold decrease after 6 months indicates either treatment failure or re-infection, and these patients warrant retreatment. However, since re-infection cannot be reliably distinguished from a therapeutic failure (possibly unrecognized CNS infection), CSF examination should be performed. Patients with HIV disease generally require the same dosage of penicillin G, though some experts would recommend a weekly dose for 3 consecutive weeks. HIV infected individuals should be evaluated clinically and serologically for treatment failure at 3, 6, 9, 12 and 24 months.

  Table 2:  Treatment of New Onset Genital Ulcer Disease

Condition	Organism	Treatment
Chancroid	Haemophilus ducreyi	Azithromycin 1 gm  po once                       OR Ceftriaxone 250mg  IM once                         OR Ciprofloxacin 500 mg   po BID x 3 days                         OR Erythromycin base 500 mg po TID x 7 days
Genital herpes	Herpes simplex	Acyclovir 400 mg  po TID x 7-10 days                         OR Acyclovir 200 mg  po 5X per day for 7-10 days                         OR Famciclovir 250 mg  po TID x 3 days                         OR Valacyclovir 1 gm po BID x 7-10 days
Granuloma inguinale1 (donovanosis)	Klebsiella granulomatis	Doxycycline* 100 mg  po BID x 3 weeks                       OR Azithromycin 1 gm  po weekly x 3 weeks                       OR Ciprofloxacin 750 mg  po BID x 3 weeks                        OR Erythromycin base 500 mg po QID x 3 weeks                        OR TMP-SMX DS po BID x 3 weeks
Lymphogranuloma venereum	Chlamydia trachomatis serovars L1 L2 L3	Doxycycline* 100 mg  po BID x 21days days                         OR Erythromycin base 500 mg po QID x 21 days
Syphilis primary stage	Treponema pallidum	Benzathine PCN G*  2.4 million U IM once daily                          OR Doxycycline 100 mg  po BID x 14 days                          OR Tetracycline 500 mg  po QID x 14 days                          OR Ceftriaxone 1 gm  IM or IV for 8-10 days                           OR Azithromycin 2 gm po once2

*Preferred regimen
¹ All regimens are for at least three weeks and until all lesions are completely healed.
² Less preferred regimen due to recent failures on the United States West Coast.