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  • Writer's pictureP.K. Peterson

Unlike Smallpox, the Great Pox (Syphilis) Isn’t Going Away

“He who knows syphilis knows medicine.”

- Sir William Osler, Canadian physician, Father of Modern Medicine


“Doxy PEP is moving STI [sexually transmitted infections] prevention efforts into the 21st century.”

- Jonathan Mermin, director, CDC National Center for HIV, Viral Hepatitis, STD, and TB Prevention



Along with other sexually transmitted infections (STIs), syphilis cases began skyrocketing in 2021. Fortunately, new treatment approaches for syphilis also surfaced. In this Germ Gems post, I provide an overview of syphilis, including its interesting history, and highlight several recent advances in the management of the disease.

What is syphilis? Syphilis is a multisystem chronic bacterial infection caused by the spirochete Treponema pallidum. It is a sexually transmitted disease that is easily cured if caught early. It is also one of the oldest diseases known to man.


Researchers have long disputed the origin of syphilis. Some argue that the disease was carried from the New World to Europe after Columbus’s voyages in the late 1400s (the “Columbian hypothesis”). Others claim that syphilis existed in Europe before Columbus returned from the New World (the “Pre-Columbian hypothesis”). In 2020, researchers extracted the DNA from the remains of medieval Europeans and determined that syphilis potentially existed in Europe prior to Columbus’ voyages.


Syphilis was first reported in Europe in 1494 in a war between France and Naples. France’s King Charles VIII’s army invaded Italy and was routed not by the Italian army but by a mysterious new disease spread through sex. French soldiers disseminated the disease across Europe and then it moved into Africa and Asia.


The French referred to it as “the Italian Disease.” The Italians called it “the French Disease.” And the Arabs called it “the Christian disease.” People in the 15th century generally referred to it as “the great pox” due to its painful and repulsive symptoms. (The French differentiated smallpox, “la petite verole,” from the great pox, “la grosse verole,” based on the size of the lesions.) In 1530, the Italian physician and poet Girolamo Fracastoro wrote “Syphilis sive morbus Galicus,” a poem about a shepherd named Syphilis who was afflicted with the dreaded disease. Fracastoro thus coined the term “syphilis” for the disease.


Clinical picture. Few infectious diseases are as fascinating as syphilis. It is often referred to as “The Great Masquerader,” “The Great Imitator,” or “The Great Pretender,” as its symptoms and signs can look like many other diseases.


Syphilis is spread from person-to-person during sex by direct contact with a syphilitic sore, known as a chancre. These sores appear on, in, or around the penis, vagina, anus, rectum, lips, or mouth. Symptoms usually appear within 21 days of contact.

The disease typically follows a progression of stages that can last for weeks, months, or even years. The four stages of syphilis that unfold over time are: primary stage (chancres are most notable); secondary stage (a variety of skin rashes, including on the palms and soles, along with fever, swollen lymph nodes, weight loss, and fatigue); latent or hidden stage(T. pallidum can lay dormant for months to years before becoming manifest); and tertiary syphilis, a rare but potentially fatal form of disease. In untreated patients, tertiary syphilis can effect multiple organs, including the:

  • brain;

  • nerves;

  • eyes;

  • heart;

  • blood vessels;

  • liver;

  • bones;

  • joints.

When syphilis involves the brain (neurosyphilis), it can cause psychiatric disorders including depression, mania, psychosis, personality changes, delirium, and dementia. At the turn of the 19th century, neurosyphilis was a major cause of admissions to “insane asylums.” (This was before the advent of penicillin therapy.)


Epidemiology. After reaching a historic low in 2020, syphilis case reports began to increase. During 2021, there were 176,713 new cases of syphilis. Gay, bisexual, and other men who have sex with men (MSM) are experiencing extreme effects of syphilis. They account for 36% of all primary and secondary syphilis cases in 2021; they also account for 47% of male cases.


In the U.S., case rates are also mounting among heterosexual men and women. Congenital syphilis, occurring when a pregnant woman passes T. pallidum to her fetus, is also increasing dramatically. More than 2,800 cases of congenital syphilis were reported in 2021.


Treatment. Penicillin revolutionized the management of syphilis. The first syphilitic patient was treated with this antibiotic in 1943. To this day, penicillin remains the mainstay for treating syphilis.


The recommended treatment for adults and adolescents with primary, secondary, or early latent syphilis is benzathine penicillin G—2.4 million units administered intramuscularly in a single dose. Different penicillin regimens are used for late latent and tertiary syphilis.


In addition to treating patients with an established diagnosis of syphilis, other groups of people should be routinely tested for the disease because the latent form of syphilis does not manifest clinically. These groups include: pregnant women; sexually active MSM; those living with HIV and are sexually active; and those taking Pre-exposure prophylaxis (PrEP) for HIV. If found positive, the person should be treated with penicillin.


Due to an increased demand for benzathine penicillin G, on April 26, 2023, the U.S. Food and Drug Administrations announced that there was a supply shortage of this antibiotic. This was alarming as benzathine penicillin G plays a pivotal role in the treatment of syphilis. But a subsequent report on October 16, 2023 showing that a single dose of benzathine penicillin G cures early syphilis even in patients with HIV was encouraging as it’s hoped this may help take the pressure off the chronic shortage of this “miracle drug.”


Prevention. Due to a vaccination campaign, smallpox was eradicated in 1980. There is, however, no vaccine to prevent the great pox. Moreover, smallpox is a viral infection spread through air, while the great pox is a bacterial infection spread through unprotected sex—a manner of transmission that’s proved difficult, if not impossible, to adequately control.


As the Centers for Diseases Control and Prevention (CDC) points out, in the absence of a vaccine, “The only way to completely avoid syphilis is to not have vaginal, anal, or oral sex. Another option is to be in a long-term mutually monogamous relationship with a partner who does not have syphilis.”

A third option is to practice safe or protected sex. Research has shown that when used correctly, condoms (“protected sex”) can reduce the risk of acquiring syphilis.


On October 2, 2023, the CDC proposed a new policy aimed at dramatically reducing STIs in those having unprotected sex. Studies had shown that a single dose of doxycycline—a tetracycline-related antibiotic—significantly reduced the risk of acquiring syphilis, chlamydia, and gonorrhea in gay and bisexual MSM, as well as in transgender women after having unprotected sex. Based on these studies, the CDC recommended that this old and safe antibiotic be taken no later than 72 hours after unprotected sex (the so-called “doxy PEP” regimen).


Sex is not going away. And neither is syphilis—at least not in the near future. Thus in addition to promoting condom use (safe sex), for those who engage in high risk (unprotected) sex, get on the doxy PEP bandwagon. It could save you from the scourge of the great pox—syphilis.

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Main Page images courtesy of Shuxian Hu, MD. Dr. Hu is a scientist in the Neuroimmunology Research Laboratory at the University of Minnesota.

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