Review of Current Evidence and Comparison of Guidelines for ...

Introduction
EUR/03/5045931
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Ever since syphilis was first described its treatment has caused controversy. Despite Frascatoro’s
claim the first effective cure for syphilis (Treponema pallidum subsp pallidum) was penicillin,
which became available in the 1940s. Internationally there is now a broad consensus about the
most effective therapies for syphilis. However, differences still remain around many details of
treatment and the evidence base is not complete. In an attempt to rationalize treatment strategies,
guidelines are regularly produced by different countries, regions and by the WHO worldwide.
European guidelines were recently elaborated as a consensus document based on the Austrian,
Dutch, German, Russian Federation and United Kingdom national guidelines; they were
approved by the European branch of the International Union against Sexually Transmitted
Infections (IUSTI) and the Regional Office for Europe of the World Health Organization (2).
The purpose of this paper is to compare the most recent European (2), United Kingdom (3,4),
and Russian Federation (6) guidelines, to include the CDC guidelines (5) and to highlight
differences in recommended treatments between them. The paper outlines the evidence and
current thought that supports these differences, by consolidating information summarised in the
guidelines and the many excellent review articles addressing the management of syphilis. The
background section presents an overview of why differences in treatment recommendations
exist. The body of the paper compares recommended treatments for different stages of disease
and clinical contexts. Recommendations from the different guidelines have been presented
together in tabular form to facilitate comparison, and the appendices refer to the full texts of the
guidelines discussed.
While precise definitions of the different stages of syphilis infection are somewhat arbitrary and
have always varied, a detailed discussion of this is beyond the remit of this paper. Where the
different guidelines use different definitions for stage of infection these are noted but the
treatment of each stage of syphilis is presented as defined by the individual guidelines. For
information on the diagnostic criteria for each stage of disease the reader should refer to the
original guidelines.
Background
In his 1993 review article (which reviews the evidence base for the recommendations for the
management of syphilis presented in the US Centers for Disease Control (CDC) Sexually
Transmitted Disease Guidelines), Robert Rolfs concludes, “the evidence upon which
recommendations for syphilis therapy are based remains inadequate for such a complicated
disease. It is surprising that treatment has been as successful as it has, given the poor data and
simplistic approach followed for the last 40 years” (7). This lack of evidence stems from a
number of factors, which together have led to a paucity of good clinical trials.
Firstly, there is incomplete understanding of the natural history and pathogenesis of the disease,
which is compounded by the inability to culture the organism in vitro. This makes treatment
outcomes difficult to measure, necessitates long-term serological follow up and constrains the
interpretation of uncontrolled studies. Secondly, the diagnostic criteria for different stages of
disease are complex, and to some extent arbitrary, creating difficulties for both the application of
study inclusion criteria, and for the conduct of satisfactory meta-analyses. Thirdly, a significant
decline in many countries, in the occurrence of syphilis since the advent of penicillin (8) has
made recruitment of sufficient cases to adequately power single centre trials very difficult. In