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Syphilis
Questions & Answers - 2010 Treatment Guidelines

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Congenital

Question 1: For congenital syphilis evaluation if a lab is not doing rapid plasma reagin (RPR) or venereal disease research laboratory (VDRL) testing, which specific test is recommended, immunoglobulin G (IgG), or immunoglobulin M (IGM)?

Answer: The 2010 STD Treatment Guidelines (page 36) are clear that a quantitative nontreponemal serologic test (RPR or VDRL) should be performed on infant serum and that commercially-available immunoglobulin tests are not recommended. If a lab is not doing RPR or VDRL, then the serum should be sent to another lab where one of these tests can be performed.

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Exposure Periods

Question 2: The guidelines state that individuals exposed to early syphilis should be treated if the exposure occurred within 90 days prior to the diagnosis of the infected person. This is incorrect. The partner should be treated for any exposure to the infected patient that occurred within 90 days from the date when the partner is seen by the clinician. The date of diagnosis of the infected patient should not enter into the equation. The guidelines offer the wrong starting point from which to count back.

Answer: The 2010 STD Treatment Guidelines (page 27) are correct. The date of diagnosis of the index case is the proper date from which to calculate the 90-day period. For example, suppose an index case was diagnosed with early syphilis on January 1. According to the Guidelines, all partners who had sexual contact with the index case for the previous 90 days should be evaluated and treated (that is, October 1 through December 31). Suppose a partner had sex with the index patient on October 10. This person should be treated empirically because he is within the 90 window described by the Guidelines. Now imagine that it takes until January 15 to track down the partner and get him evaluated by a clinician. Using the questioner's timeframe of, "90 days from when the partner is seen by the clinician," places the October 10 date of sexual contact outside the empiric treatment window. In this case the Guidelines offer a more comprehensive empiric partner treatment strategy.

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Neurosyphilis

Question 3: How often does neurosyphilis occur with a negative rapid plasma reagin (RPR) (serum), negative cerebrospinal fluid nontreponemal (CSF VDRL) test, but positive CSF treponemal fluorescent treponemal antibody (FTA) test? This case involves a patient with high suspicion of of neurosyphilis, without known treatment in the past, and with a high protein white blood count in CSF.

Answer: True numbers are not available to answer this question with any specificity. That said, it is at worst an extremely rare event. Active CSF neurologic disease should be correlated with an active immune response, with the production of a nontreponemal response in the serum. It is true that a negative CSF nontreponemal (CSF-VDRL) test does not rule out CSF involvement. It is highly specific for, but insensitive for neurosyphilis. The laboratory diagnosis of neurosyphilis, therefore, depends on a combination of reactive serologic and CSF test results, CSF cell counts, CSF protein, and clinical findings. The CSF FTA-ABS is less specific for neurosyphilis than the CSF-VDRL, but is highly sensitive. A negative CSF FTA-ABS would make neurosyphilis highly unlikely, but a positive CSF FTA-ABS may represent a biological false positive. One should rule out a prozone reaction of the serum nontreponemal test and, if ruled out, pursue other considerations for CSF results described.

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Question 4: Why is a lumbar puncture (LP) not useful in latent syphilis, or syphilis of unknown duration?

Answer: It is questionable whether early detection and treatment of asymptomatic neurosyphilis in the penicillin era improves long-term outcomes. Screening for signs and symptoms of neurologic or ophthalmic involvement, evidence of active tertiary syphilis, or serologic failure, are adequate indications for cerebrospinal fluid (CSF) evaluation.

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Partners

Question 5: If treating a male for suspected syphilis, do we treat any partners at the same time, or await their tests?

Answer: In general, partners of persons with syphilis should be evaluated and treated empirically, according to the criteria specified in the 2010 STD Treatment Guidelines (page 28). However, the Guidelines do not specify how to manage partners of persons with "suspected syphilis." It may first be necessary to confirm the diagnosis of syphilis in the index case (positive darkfield exam, positive serologic test) before notifying and treating partners.

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Screening

Question 6: Why would CDC recommend a reverse serologic screening for syphilis, and what are the implications on treatment?

Answer: Reverse serologic screening (that is, screening with a treponemal test, and confirming with a nontreponemal test) has been introduced in recent years by commercial and other high-throughput laboratories because the treponemal screening tests can be automated and performed more rapidly. However, this approach has led to relatively high rates of "discordant" sera (treponemal-positive/nontreponemal-negative) which may represent false-positive treponemal test results. CDC continues to recommend that nontreponemal tests be used to screen for syphilis and that treponemal testing be used to confirm syphilis as the cause of nontreponemal reactivity, as stated in a recent MMWR publication on this subject [MMWR 2011; 60(05):133–137].

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Staging

Question 7: Absent a clear history of recent chancre, how strictly should we document one year (365 days) for seroconversion or recent partners to differentiate early versus late latent syphilis, since treatment regimens for these conditions differ?

Answer: The 2010 STD Treatment Guidelines (page 30) state that early latent syphilis can be diagnosed if, during the year preceding evaluation, a patient had, "1) a documented seroconversion or fourfold or greater increase in titer of a nontreponemal test; 2) unequivocal symptoms of primary or secondary syphilis; or 3) a sex partner documented to have primary, secondary, or early latent syphilis. Also, persons with reactive nontreponemal and treponemal tests whose only possible exposure occurred during the previous 12 months can be considered to have early latent syphilis. All other cases of latent syphilis should be considered late latent syphilis or syphilis of unknown duration.”

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Testing

Question 8: Does rapid plasma reagin (RPR) or the Treponema pallidum particle agglutation (TP-PA) show positive first?

Answer: The 2010 STD Treatment Guidelines do not address which test (RPR or TP-PA test) becomes positive first. However, a recent MMWR publication on serologic tests for syphilis [MMWR 2011;60(05)133–137] emphasizes that, "CDC continues to recommend that nontreponemal tests be used to screen for syphilis and that treponemal testing be used to confirm syphilis as the cause of nontreponemal reactivity."

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Question 9: How does CDC recommend management of patients with immunoglobulin G (IgG) treponema test positive, negative rapid plasma reagin (RPR) and positive second treponemal test? What does CDC recommend if the patient is a pregnant woman?

Answer: A positive IgG treponemal specific antibody test with a negative nontreponemal test (RPR, TRUST) will identify both persons with previous treatment and persons with untreated or incompletely treated syphilis. False-positive results can occur, particularly among populations with a low prevalence of syphilis. Persons with a positive treponemal screening test should have a standard nontreponemal test with titer to guide patient management decisions. If the nontreponemal test is negative, then a different treponemal test should be performed to confirm the results of the initial test. If a second treponemal test is positive, persons with a history of previous treatment will require no further management, while those without a history of treatment for syphilis should be offered stage-appropriate therapy. Unless history or results of a physical examination suggest a recent infection, previously untreated patients are unlikely to be infectious and should be treated for late latent syphilis, even though they do not meet the surveillance case definition. These recommendations would also apply to pregnant women. Discrepant treponemal specific antibody tests with a negative nontreponemal test (RPR/TRUST) and no signs of primary syphilis are likely to represent a biologic false positive. It is reasonable to offer repeat testing with a nontreponemal test (RPR/TRUST) within 2–4 weeks. If this test is negative, no treatment and no further testing are indicated.

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Treatment

Question 10: Does CDC recommend only one round of treatment for syphilis, regardless of how long the patient has been infected or what stage is diagnosed?

Answer: Single dose therapy with benzathine penicillin is recommended for persons with primary, secondary, or early latent syphilis. For patients with latent syphilis of unknown duration, therapy with three weekly injections of benzathine penicillin G is recommended.

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Question 11: For treatment of late latent syphilis, how long is one week? That is, if a patient returns for penicillin dose two or dose three after six, eight, nine, or ten days, is it necessary to restart the series?

Answer: Benzathine penicillin is slowly absorbed, and as a result has a long half-life. Intervals of 10–14 days between doses of benzathine penicillin might be acceptable before restarting the sequence of injections.

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Treatment Alternatives

Question 12: What alternative antibiotics can be used for the treatment of syphilis, besides penicillin G or doxycycline?

Answer: Penicillin is the preferred therapy for syphilis. The 2010 STD Treatment Guidelines (pages 30–31) state that data to support the use of alternatives to penicillin are limited. In nonpregnant, penicillin-allergic patients, doxycycline or tetracycline may be used. There are some data to suggest that ceftriaxone (1 g. injections daily for 10–14 days) may be effective for early syphilis. Studies have also shown that azithromycin 2 g. single oral dose is effective for treating early syphilis, but azithromycin must be used with caution, and only when treatment with penicillin or doxycycline are not feasible, due to chromosomal mutations which confer resistance to azithromycin.

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Question 13: Why is azithromycin 2 g. not recommended as an alternative therapy for primary, secondary, and early latent syphilis in men who have sex with men (MSM)?

Answer: Azithromycin treatment failures were first recognized in San Francisco in 2002. Subsequent investigation identified eight cases occurring from 2002–2003, all of whom were MSM [see MMWR 2004; 53(09)197-8]. Further investigation revealed 52 cases of azithromycin-resistant syphilis which occurred between 2000–2004, all of whom were MSM [see Clin Infect Dis. 2006;42(3):337-45]. For this reason CDC cautions against use of azithromycin for treating syphilis among MSM, since it is possible that azithromycin-resistant strains may be more common within this population.

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Syphilis and HIV

Question 14: Do we need to perform lumbar puncture (LP) for everyone presenting with HIV and a headache from primary syphilis?

Answer: The 2010 STD Treatment Guidelines (page 27) state that, "clinical signs of neurosyphilis" warrant further investigation. These clinical signs include cranial nerve dysfunction, meningitis, stroke, acute or chronic altered mental status, loss of vibration sense, and auditory or ophthalmic abnormalities. Most experts would probably not consider a lone symptom of headache, in the absence of other objective findings, to warrant a lumbar puncture (LP) in patients with early syphilis, but this is not specifically addressed in the Guidelines.

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Question 15: In late latent syphilis in HIV positive patients, should we still give benzathine penicillin 2.4 mil units weekly for three weeks?

Answer: Recommended therapy for HIV-infected patients with syphilis of all stages is the same as for persons without HIV infection. Thus, persons with HIV and syphilis of unknown duration should receive three injections of benzathine penicillin, spaced at one-week intervals.

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Question 16: Currently we treat HIV positive persons who also have syphilis with bicillin 2.4 mil units weekly for three weeks. Do we now only need to provide one injection?

Answer: There remains a lot of misunderstanding about the treatment of syphilis. The duration of syphilis treatment in patients with HIV has been studied. Studies conducted over a decade ago by the CDC show that there is no benefit in treating HIV infected individuals with higher doses of penicillin, nor are there proven benefits for treating with longer durations. In HIV infected patients, you need to treat them with exactly the same regimen that is recommended for patients who have syphilis but not HIV. There may be a slight increased risk of serologic treatment failures so it is suggested that patients be followed clinically and serologically more closely.

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