Screening, treatment, and follow-up of syphilis patients: Issues, concerns and efforts to improve current paradigms.

Sir,

Despite an effective treatment being available since the penicillin introduction, syphilis remains an important concern worldwide, also for the limitations encountered with the available serological tests for diagnosis and follow-up.

Recently, confidence in benzathine penicillin G(BPG) for treatment of early syphilis (ES) wavered based on the literature concerning its serological treatment failures and on the remarkable number of patients (immunocompetent and HIV-infected) with late complications despite adequate BPG therapy.[1] Our aim is to renew the discussion of current paradigms for syphilis diagnosis, treatment, and follow-up.

For syphilis screening, we simultaneously used treponemal test (TT) and non-TTs (NTTs).

Regarding therapy, in the last 5 years, we treated 32 patients with early and late syphilis with an enhanced regimen that adds doxycycline (100 mg/twice daily for 20 days) and ceftriaxone (1 g/daily for 10 days intramuscularly) to conventional BPG. Dosages and treatment duration have been decided based on the use of these antibiotics in other spirochetal infections with cerebrospinal fluid (CSF) involvement.[2]

All patients are still in follow-up but to date no side effects, relapses or complications have been reported, and both NTT and TT titers decreased over four-fold within 6 months.

To diagnose syphilis, the Center for Disease Control and Prevention (CDC) guidelines recommend a NTT, rapid plasma reagin or venereal disease research laboratory (VDRL), and to confirm the diagnosis, to test positive sera with a TT, Treponema pallidum particle agglutination assay or immunoenzymatic assay (EIA). To initiate the screening algorithm with a TT is not recommended for the high rate of false positive results with these tests.

Since NTT may give false negative results, and automated EIA tests have low specificity while TTs facilitate the identification of early and late stage infections, we use and propose both a NTT and a TT for screening.

For syphilis treatment, CDC recommends intramuscular administration of BPG 2.4 million units in a single dose for ES (primary, secondary, early latent) patients. A study by Ghanem et al., however, suggests that 5% of ES immunocompetent patients treated with BPG failed therapy.[3] HIV patients have an even higher rate of serological failure, and viable T. pallidum have been isolated from their CSF following standard treatment.[1]

A possible explanation for BPG treatment failure could be attributed to its inability to reach specific body districts that can be invaded by T. pallidum, attaining in the CSF only 1–2% of the serum concentration and not achieving treponemicidal levels in the central nervous system (CNS), eye and inner ear. Furthermore, CSF penetration is hampered by the lack of meningeal inflammation in the earlier syphilis stage when neuroinvasion occurs.[1]

BPG phenotypic resistance in vivo cannot be excluded: Giacani et al. recently found that during primary experimental syphilis, transcription of two T. pallidum sigma factors significantly increases as infection progresses towards the pathogen immune clearance, suggesting that these transcriptional regulators may help T. pallidum to respond to harmful stimuli in the host environment. Given the ability of sigma factors to control numerous genes and cellular functions, the phenotypic changes induced in T. pallidum may also involve its impaired ability to proliferate, making it refractory to the BPG action.[4]

Another hypothesis is that following antibiotic treatment and host immune attack; replicating spirochetes may descend to a state called “L-forms,” that do not have cell walls and consequently, are not affected by antibiotics. These forms might revert to normal replicating bacteria in the absence of antibiotics.[5] The question is: Could other treatment regimens be able to decrease late complications? We implemented, therefore, a regimen that adds doxycycline and ceftriaxone to BPG.

Doxycycline is the most used tetracycline in CNS infections, as neuroborrelliosis, because it is lipophilic, readily absorbed after oral administration and enters the eye and CSF more effectively than other tetracyclines. Doxycycline elimination half-life is long (15–25 h) and median CSF concentration in patients treated orally with 200 mg/daily is 0.6 µg/ml, 4 h after administration.[2]

Ceftriaxone has a half-life in serum (7–8 h) long enough to allow once-daily administration and a CSF penetration higher than BPG. A 1 g daily dose achieves CNS levels well above the minimal inhibitory concentration for T. pallidum (0.0006 μg/ml).[2]

All our patients that received the enhanced treatment are still in follow-up but to date no side-effects, relapses or complications have been reported. In all of them, both NTT and TT titers decreased over fourfold within 6 months. However, we emphasize that the decrease of serological titers and the resolution of cutaneous lesions may be insufficient to predict a therapeutic success since cutaneous lesions may resolve, and antibody titers may decline even without therapy. We are aware that a larger cohort of patients and an appropriately controlled trial with long-term follow-up are required to evaluate the efficacy of this treatment, but our encouraging results prompted us to bring this therapy to the attention of other sexually transmitted diseases centres.

Since Doxycycline is contraindicated in pregnant and lactating women and children younger than 8 years, we currently follow CDC guidelines for these categories.

For syphilis follow-up, CDC recommends a quantitative NTT for monitoring the serological response to treatment. TT titers do not correlate with disease activity and can remain positive for life, regardless of treatment. Therefore, they are considered unreliable for the follow-up. However, NTT titres might become nonreactive over time even without therapy. We think that TT should be added in the follow-up, especially in late latent syphilis, where NTT are often negative. In fact, in our experience, among 7 late latent syphilis patients, only 1 had a positive VDRL test, and TT titers always decreased after therapy.

In conclusion, we emphasize that for syphilis diagnosis the clinical history and the physical examination should be considered together with serology. Along with the laboratory results, the clinical follow-up is mandatory to exclude progression towards late complications after therapy. Finally, we should not resign ourselves to accept suboptimal results in syphilis treatment and look forward to defining an optimal treatment for a disease that is still a great concern for healthcare providers.