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Data from refs. 2,14.

Data from refs. 2,14.

Topical cidofovir, a nucleotide analog, has been successfully used in immunocompromised patients with acyclovir-resistant HSV infections (22). In a trial of cidofovir gel, 10 of 20 AIDS patients had reduction in lesions by at least 50%, compared to no healing by placebo (22). Because of renal toxicity with intravenous cidofovir, topical cidofovir is preferred for treatment of genital herpes. Trifluridine, a nucleoside analog, is used frequently for the treatment of ophthalmic HSV infections. A series of 26 patients with HIV who had mucucutaneous HSV infections unresponsive to acyclovir demonstrated complete healing in 7 and partial healing in 14 patients using trifluridine (23).

Immunocompromised patients may have prolonged and severe recurrent genital herpes. Dissemination requires treatment with 5-10 mg/kg of acyclovir intravenously (see Table 2). HSV is a common clinical presentation of HIV infection and most HSV-infected persons with HIV will respond to acyclovir (18). Most patients with HIV and HSV infection will benefit from chronic suppressive therapy (14). As mentioned previously, acyclovir resistance is rare but is more common in the immunocompromised host.

Pregnant women with genital HSV may transmit the virus to their babies. The risk of transmission of neonatal herpes from an infected mother is higher (50%) for women who have acquired primary HSV infection near the time of delivery than for those mothers with new HSV-2 but previous HSV-1 infection (20%) (2,14). The lowest risk of transmission to the neonate is from mothers with recurrent herpes or HSV acquired during the first half of pregnancy (3%) (2). Therefore, prevention of neonatal herpes should focus on prevention of acquisition of genital HSV infection during late pregnancy. Susceptible women (HSV-2 or HSV-1 seronegative with seropositive partners) should be counseled to avoid unprotected genital and oral sexual contact during late pregnancy. At the onset of labor, all women should be examined and questioned regarding genital herpes and those with no clinical evidence of lesions can be delivered vagi-nally (2). Although routine treatment of recurrent HSV in pregnant women is not currently recommended, the first clinical episode of genital herpes during pregnancy may be treated with oral acyclovir (2).

Syphilis

Syphilis is a systemic infection with periods of active clinical disease and periods of latency. The primary stage develops approx 3 wk from exposure and is characterized by a chancre (painless lesion) and bilateral nontender regional adenopathy (24). The ulcerative lesion with well-circumscribed borders can be found at genital, perirectal, perianal, or nongenital sites (24). Untreated, the chancre heals in a few weeks. Secondary syphilis represents multiplication and dissemination of treponemes throughout the body. Occurring up to 6 mo after the initial chancre, this stage is characterized by low-grade fever, malaise, sore throat, headache, adenopathy, and cutaneous or mucosal rash. Mucous patches in the oral cavity or genital tract, alopecia, hepatitis, or rarely nephrotic syndrome may develop (24).

Persons with no clinical syndrome but positive serologic tests are said to have latent syphilis. Early latency occurs during the first year of infection and late latency occurs more than 1 yr from initial chancre. In 25% of untreated syphilis cases, latency can be interrupted by a second clinical relapse or recrudescence (24). Tertiary (late) syphilis develops in one-third of untreated patients 10-25 yr after the initial infection (25). Treponemes invade the central nervous system (CNS), cardiovascular system, eyes, skin, and other internal organs. Gummas, which are locally, destructive lesions involving the liver, skin, bones, and other organs, can develop (24). Transmission of syphilis to sexual contacts does not occur during this stage; however, sexual partners and infants born to mothers with any stage of syphilis should be evaluated according to the Centers for Disease Control (CDC) guidelines (2).

The incidence of syphilis in the United States has fluctuated, with peak rates occurring recently during the late 1980s. Syphilis incidence is currently at its lowest since 1941, 2.6 per 100,000 population in 1999 (26). Syphilis remains more common in non-Hispanic blacks and is concentrated in the southern United States (26). Historically, syphilis has been associated with the use of illicit drugs (particularly crack cocaine) and exchange of sex for drugs (24,26,27).

It is well recognized that syphilis facilitates transmission of HIV, and all patients with syphilis should be tested for HIV infection (2,3). Nearly all cases of syphilis are acquired by direct sexual contact with lesions from an individual with primary or secondary syphilis. However, syphilis can be transmitted congenitally and less commonly by the bloodborne route (blood transfusion/needle sharing), nonsexual personal contact, and accidental direct inoculation (25).

Treponema pallidum, the etiologic agent of syphilis, is a spirochete that can be visualized by dark-field microscopy and silver staining (25). Dark-field examination or DFA tests of lesions or tissue are the methods used to make a definitive diagnosis of syphilis (2). A presumptive diagnosis can be made using two types of serologic tests: the nontreponemal, which includes the VDRL (Venereal Disease Research Laboratory) and the RPR (rapid plasma reagin), and treponemal, which includes the FTA-ABS (fluorescent treponemal antibody absorption) and the MHA-TP (micro-hemagglutination assay for T. pallidum antibody) (27). Positive nontreponemal tests require confirmation with treponemal antibody tests. The nontreponemal tests are sensitive but not specific (~70% sensitive in primary and late disease and 99% sensitive in secondary) (25). Therefore, a negative test result does not exclude the diagnosis of early syphilis.

False positive nontreponemal tests for syphilis are common in individuals with autoimmune diseases, viral infections (particularly Epstein-Barr and hepatitis viruses), protozoal infections, and mycoplasmal infections, as well as in the elderly, pregnant women, and intravenous drug users (27). About 1-2% of patients with secondary syphilis will exhibit a prozone reaction (excess anticardiolipin antibody present in undiluted serum) which results in a false-negative result with RPR testing (27).

The nontreponemal tests are quantitative and correlate well with disease activity. Sequential serologic tests should be performed by the same testing method (VDRL or RPR) and in the same laboratory if possible. Failure of a nontreponemal titer to decrease fourfold (two dilutions, e.g., from 1:16 to 1:4) within 6 mo after therapy for primary or secondary syphilis identifies persons at risk for treatment failure (2). It is expected that a nontreponemal test will become nonreactive; however, some patients are serofast and their nontreponemal antibodies persist at a low titer for the remainder of their lives (2). Treponemal tests often remain reactive for the remainder of life regardless of disease activity and should not be used to assess clinical response (2). The new multiplex PCR should be commercially available soon and appears to be more sensitive for the detection of T. pallidum than dark-field microscopy (91% vs 81%) (8).

Penicillin G is the drug of choice for treatment of patients with all stages of syphilis (Table 3) (2). Second-line therapies include tetracycline or erthromycin (2). Although penicillin treatment for syphilis is the standard of care, no adequately conducted comparative trials have been performed and even less data are available regarding nonpenicillin regimens. Ceftriaxone has been used but the optimal dose and duration of therapy is not established and most agree that single-dose ceftriaxone is not effective for treating syphilis (2). There have been preliminary studies of azithromycin for treatment of patients with primary and secondary syphilis but it is not currently recommended (28).

Physicians treating patients with syphilis should be aware of the Jarisch-Herx-heimer reaction, which is a febrile reaction with chills, fevers, arthralgias, headache, and an increase in prominence of lesions. This is believed to be due to a release of tre-ponemal constituents that occurs 4-6 h posttreatment and subsides within 24 h (24). Reassurance and aspirin or ibuprofen appear to alleviate the symptoms.

Follow-up is necessary to ensure that treatment of syphilis has been successful. The CDC recommends reevaluation of the patient clinically and serologically at 6 and 12 mo. Treatment failure is suspected in patients with primary or secondary syphilis who have nontreponemal antibody titers that have not decreased by two dilutions (fourfold) at 6 mo after therapy or who have persistent signs or symptoms. These patients should be retreated and evaluated for reexposure, HIV, or neurosyphilis (2). Unless reinfection is certain, a lumbar puncture should be performed in treatment failure (2).

There is a high probability that an infectious syphilitic individual will infect his or her partner during sexual activity (50%) (25). Persons who have been exposed within 90 d of the index case's diagnosis should receive presumptive treatment. Patients who were exposed >90 d prior to diagnosis should be evaluated and if serologic tests are not available immediately and follow-up is uncertain, presumptive treatment should be given (2).

There has been much debate on the optimal management of syphilis in HIV-infected patients. Although there are anecdotal reports of increased risk of treatment failure and increased incidence of neurosyphilis in HIV-positive patients, no randomized studies have proven this. In one multicenter, randomized, double-blind trial (541 patients), few clinical differences according to HIV status were noted (29). The serologic response of HIV patients was poorer, but there were few clinically defined failures in either group (29). CDC recommendations suggest treating HIV-positive patients with the same regimens as HIV-negative patients, but encourage closer follow-up. Clinical and serologic evaluation at 3, 6, 9, 12, and 24 mo is important in HIV patients (2). Some experts give additional treatment for primary and secondary syphilis in the HIV population, but it is not officially recommended. The CDC recommends that HIV-infected patients with either late latent syphilis or syphilis of unknown duration have a cerebrospinal fluid (CSF) examination before treatment (2).

All pregnant women with syphilis should receive penicillin appropriate to their stage of disease (Table 3). Owing to potential side effects in the fetus and erratic transplacen-tal transfer, no antimicrobial agent other than penicillin is recommended, even in penicillin-allergic patients (2,27). The CDC recommends skin testing and desensitization in penicillin-allergic pregnant women with syphilis (2). A manifestation of Jarisch-Herx-

Stage

Drug

Dose

Duration Comments

Primary/secondary

Benzathine penicillin G

2.4 million units i.m.

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