STD Awareness: Antibiotic-Resistant Syphilis

Treponema pallidum under a microscope. Image: Dr. Edwin P. Ewing, Jr., CDC

The image to your right, with lively yellow splotches against a pale green background, is not a long-lost Jackson Pollack piece, and the dark squiggly lines aren’t strands of paint haphazardly splattered onto a canvas. In fact, those squiggly lines are magnified images of the spiral-shaped bacteria species Treponema pallidum. You might not have heard of T. pallidum, but you’ve probably heard of syphilis, the sexually transmitted disease (STD) that these bacteria cause. While syphilis isn’t as common as other STDs, like chlamydia and HPV, it’s still out there, and occasionally communities experience outbreaks. It’s always best for sexually active people to be screened for STDs and practice safer sex.


The evolution of syphilis strains that are resistant to certain antibiotics underscores the need to use antibiotics properly.


Syphilis can inflict serious long-term damage — in fact, before the introduction of antibiotics, syphilis was the worst STD out there! Known as the Great Pox when it descended upon Europe 500 years ago, it could cause large and painful boils. Eventually, natural selection led to T. pallidum’s evolution into a form with milder symptoms, which benefited the bacteria by enabling its less boil-ridden (and presumably more attractive) human hosts to spread it farther and wider. Nevertheless, the symptoms of syphilis, if present, still include infectious sores, and when the disease goes untreated, it can cause severe, possibly fatal, damage to the nervous system.

Back in the day, there were myriad inadequate “treatments” for syphilis, ranging from straight-up quackery to the use of partially effective but toxic chemicals such as mercury. But a century ago, in 1912, a new arsenic-based chemical called Neosalvarsan was hailed as a “magic bullet.” Unfortunately, this treatment took weeks or even more than a year to administer — and had dangerous side effects. Quack treatments continued to flourish, and it wasn’t until the widespread adoption of penicillin in the 1940s that an effective cure with few side effects was available.

But natural selection endures; in fact, by flooding T. pallidum’s habitat with certain antibiotics, we’ve created an environment that favors the organism’s evolution against us. While not as immediately threatening as antibiotic-resistant gonorrhea, syphilis has been quietly evolving resistance to some of the antibiotics we use to treat it. This underscores the importance of using antibiotics correctly and emphasizing safer-sex practices, such as using latex condoms during vaginal or anal intercourse and during oral contact with a penis.

Penicillin still cures syphilis, and an intramuscular shot of the drug is the recommended treatment in the United States. Second-choice drugs include doxycycline, tetracyclines, and ceftriaxone. However, strains of syphilis that are resistant to another class of antibiotics, called macrolides (including erythromycin and azithromycin), are arising. Even though macrolides are not a top treatment choice, there are many reasons health care providers might prefer them to penicillin: First, some people have penicillin allergies; second, macrolides can be administered orally, which is more comfortable for many patients and more practical in areas without widespread access to clean needles and trained personnel; and third, azithromycin has been shown to cure syphilis in a single dose, allowing clinicians to provide additional pills for patients to give to their sex partners.

Macrolides work by immobilizing a susceptible bacterium’s ribosomes, which are cells’ protein-manufacturing units; this ultimately halts the bacteria’s growth. Strains of syphilis that have evolved resistance to macrolides have mutated ribosomes that, while still functional, are shaped differently. The active molecules in macrolides cannot attach to these misshapen ribosomes, and therefore can’t shut down protein production and bacterial growth. Unfortunately, this results from a single mutation in T. pallidum’s genetic sequence — which means the mutation is more likely to occur spontaneously in other syphilis strains. In fact, we’ve already discovered syphilis strains in which this identical mutation occurred independently.

Erythromycin failures have been documented since the 1970s, and azithromycin failures were noted a decade ago when the San Francisco Department of Public Health noticed a cluster of syphilis cases that weren’t responsive to azithromycin. Investigators found that, among the specimens they collected, azithromycin resistance had grown from 4 percent in 2000–2002 to 77.3 percent in 2006. This increase continued even after the SFDPH ceased use of azithromycin in 2004, and azithromycin-resistant strains of syphilis have been found in the United States, Canada, Europe, and China.

One hypothesis for the origin of azithromycin-resistant syphilis is that using azithromycin for unrelated infections creates an environment that favors the mutant T. pallidum. For instance, macrolides are often prescribed for respiratory tract infections and are used to cure chlamydia. Because the drug remains active in human tissues for so long, a subsequent syphilis infection could be affected by lingering macrolide levels. This is just one more reason why it’s important to use antibiotics properly, and only when there’s good justification.

Although penicillin remains the go-to drug for syphilis, researchers have found mechanisms by which T. pallidum might someday evolve resistance to penicillin. For instance, T. pallidum produces an enzyme that can break down penicillin’s active component — however, when that enzyme interacts with penicillin, further chemicals are released that dampen the enzyme’s effect. But could the organism someday evolve a more effective penicillin-degrading enzyme? Additionally, some researchers propose that T. pallidum could “hide” in the central nervous system and be reached by small, but not lethal, amounts of penicillin that could drive its evolution. Slowly, syphilis strains with significant penicillin resistance might arise. However, this scenario is deemed unlikely; syphilis’ continued susceptibility to penicillin after 70 years of use suggests that penicillin resistance requires a complicated series of mutations. The probability of that happening is deemed low.

You can get tested for syphilis and other STDs at a Planned Parenthood health center. It’s important to catch syphilis in its early stages, as any damage it does to your body is irreversible. Further information can be found on the Centers for Disease Control and Prevention’s website.

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