Remaining Questions in Syphilis Treatment
By Carol A. Kemper, MD, FACP
Clinical Associate Professor of Medicine, Stanford University, Division of Infectious Diseases, Santa Clara Valley
SOURCE: Tuddenham S, Ghanem KG. Management of adult syphilis: Key questions to inform the 2021 Centers for Disease Control and Prevention Sexually Transmitted Infection Treatment Guidelines. Clin Infect Dis 2022;74:S127-S133.
Eight leading experts on sexually transmitted diseases (STDs) convened to discuss key questions in the management of syphilis in adults with and without HIV infection based on a systematic review of the literature. More than 3,000 articles were screened, and the discussion focused on 95 relevant publications and three main topics, as follows:
• Therapeutic management of early syphilis, including treatment options when penicillin is not an option. No difference in serologic response or clinical outcome has been demonstrated in patients receiving one vs. three doses of benzathine penicillin G (BP) to treat early syphilis (as demonstrated by several smaller prospective clinical studies and one larger retrospective study), including patients with well-controlled HIV infection. One larger prospective study, referenced in the 2015 CDC guidelines, which has since been published, showed no difference between one and three doses of BP, although a subanalysis favored three doses.
In patients with HIV infection and higher RPR titers (≥ 1:32) treated for early syphilis, 98.4% achieved serologic response by eight months (≥ four-fold drop in titer). Only one HIV-positive patient later showed evidence of clinically asymptomatic neurosyphilis. Another anticipated Phase IV study of one vs. three doses of BP for early syphilis, begun in 2018, has not been published.
Data also support the effectiveness of doxycycline or other tetracyclines to treat early syphilis or latent syphilis when BP is unavailable or is contraindicated. On the other hand, macrolides no longer are recommended, based on observed resistance and treatment failures in the United States.
A 10-day course of intramuscular ceftriaxone also is an effective alternative, based on one randomized trial, although the data are more limited in support of 3 g of amoxicillin plus probenecid. These data provide a good explanation for the not infrequent occurrence of patients with low or serofast RPR titers who declaim a history of syphilis, who likely have received inadvertent effective treatment.
• Managing patients with serologic non-response or failure to respond to appropriate therapy. It is apparent many patients treated for syphilis never serorevert (become non-reactive) and another portion appear to have responded inadequately. Generally, treatment failure has been defined as a lack of a ≥ four-fold drop in RPR titer by six to 12 months of treatment for early syphilis and by 12-24 months of treatment for latent syphilis.
What is a “serologic non-responder,” do they require cerebrospinal fluid (CSF) investigation or additional treatment, and, if so, when? Remember that earlier syphilis stage and higher baseline titers often increase the likelihood of serological cure and seroreversion, whereas older age and female gender are associated with a greater likelihood of a serofast response. In other words, it is likely the longer a patient has been infected, the less likely those (often lower) RPR titers will serorevert in response to therapy.
Differences in the definitions of “treatment failure,” “serological non-response,” and “serofast” complicate any literature assessment. Experts attempted to provide some standardization for these terms and recommended future publications stick to this: Serofast is defined as a “failure to achieve a ≥ four-fold drop in nontreponemal antibody titer after stage-appropriate therapy.” (Presumably, the authors also intended to convey this was a stable, persistent titer over some period.) In such patients, two studies showed no further benefit in the serologic response when serofast patients received additional doses of BP, although clinical outcomes were not examined, and there were no data on the long-term clinical outcome when serofast patients receive additional treatment.
The authors of one study suggested there was no difference in the proportion of asymptomatic patients with neurosyphilis who were serofast and those who achieved a four-fold decline in titers. Another study of patients with HIV infection who were serofast at 12 months found that five of 12 exhibited asymptomatic neurosyphilis.
• Treating neurosyphilis, including ocular syphilis. In neurosyphilis, serologic and clinical response predicts normalization of cerebrospinal fluid parameters in both non-HIV-infected patients and those with well controlled HIV infection who receive appropriate treatment. Therefore, follow-up lumbar punctures in these two groups is not necessary to confirm therapeutic response.
The most common manifestations of ocular syphilis are panuveitis and posterior uveitis. Previously, researchers have recommended all such patients undergo CSF analysis, perhaps in part to confirm the diagnosis. The experts agreed clinicians reasonably can assume patients with ocular and otic syphilis are likely to exhibit neurosyphilis on CSF analysis and can treat as such without first obtaining a lumbar puncture.
At least 10% to 60% of patients with ocular syphilis in one study showed CSF abnormalities, and 50% returned a positive venereal disease research laboratory test. Unfortunately, despite appropriate IV penicillin therapy, visual outcomes will depend on the duration and severity of symptoms at presentation. There were no good data on alternative treatments for ocular syphilis, nor on steroid use. Discussion regarding antibacterial post-exposure prophylaxis for syphilis was deferred to the recently published clinical STD prevention guideline. Discussion regarding the utility of the reverse paradigm testing algorithm for diagnosis of syphilis will be published in the soon-to-be released Laboratory guidelines.
The only additional comment made by the convention was an observation that some clinical laboratories are reporting RPR titers as simply “> 1:32” without providing an endpoint. To provide appropriate treatment recommendations, a nontreponemal antibody endpoint is necessary, and laboratories should provide one.
Eight leading experts on sexually transmitted diseases convened to discuss key questions in the management of syphilis in adults with and without HIV infection based on a systematic review of the literature. More than 3,000 articles were screened, and the discussion focused on 95 relevant publications and three main topics.
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