Penicillin is the gold-standard treatment for one major STD: syphilis. It has been the first-line drug for every stage of syphilis since the 1940s, and no other antibiotic has replaced it. For other common STDs like chlamydia and gonorrhea, penicillin is either ineffective or no longer used due to widespread resistance.
Penicillin and Syphilis
A specific long-acting form of penicillin, called benzathine penicillin G, is the only recommended treatment for syphilis. It’s given as an injection, not a pill, because the drug needs to stay in your system at a steady level for weeks to kill the bacteria that cause syphilis. For early-stage syphilis (primary and secondary), a single injection is the standard course. Later stages require multiple injections spaced over several weeks.
What makes syphilis unusual among bacterial infections is that the bacterium responsible has never developed meaningful resistance to penicillin, even after more than 80 years of use. This is remarkably rare. Penicillin remains so effective that pregnant women with syphilis who are allergic to it are put through a desensitization process so they can still receive penicillin, rather than being switched to an alternative. No other antibiotic is considered reliable enough to protect a developing baby from congenital syphilis.
What About Gonorrhea?
Penicillin was introduced for gonorrhea treatment in the mid-1940s, and initially it worked well. At that time, nearly all gonorrhea strains were fully susceptible to extremely low concentrations of the drug. But by the late 1960s, many strains required 100 times the original concentration to be killed. The bacteria had evolved reduced permeability in their cell walls, making it harder for penicillin to get inside.
The final blow came in 1976, when strains producing an enzyme that directly breaks down penicillin were reported in the United States and the United Kingdom. Within a year, the World Health Organization had identified these resistant strains in 16 additional countries. The resistance genes sat on small pieces of DNA that could transfer between bacteria, helping the resistance spread rapidly. By the late 1970s, penicillin was no longer a reliable option for gonorrhea, and other drug classes took its place. Today, gonorrhea is typically treated with a different type of injectable antibiotic.
Penicillin Does Not Treat Chlamydia
Chlamydia is caused by a type of bacterium that behaves very differently from syphilis or gonorrhea. It lives and reproduces inside your cells rather than outside them, which makes penicillin-class drugs a poor fit. Animal and lab studies have shown that chlamydia can persist even after exposure to penicillin-type antibiotics, essentially going dormant rather than being eliminated. The standard treatment for chlamydia is doxycycline, a completely different class of antibiotic, taken orally twice a day for seven days.
If You’re Allergic to Penicillin
For syphilis patients who aren’t pregnant and report a penicillin allergy, alternative antibiotics exist but come with caveats. Doxycycline taken twice daily for 14 days is one option. Tetracycline four times daily for 14 days is another. A third possibility is a daily injection of ceftriaxone for 10 days, though the ideal dosing schedule for that drug hasn’t been firmly established. The CDC notes that the evidence supporting all of these alternatives is limited compared to penicillin.
If you have a penicillin allergy but can’t reliably complete a 14-day course of pills, or if follow-up appointments may be difficult, the recommended path is penicillin desensitization. This is a supervised process in which you’re given gradually increasing doses of penicillin until your body tolerates a full therapeutic dose. It’s considered essential for pregnant patients, for whom no alternative is considered safe enough to prevent transmission to the baby.
One antibiotic that might seem like an obvious substitute, azithromycin, should not be used for syphilis. The syphilis bacterium has developed genetic mutations that confer resistance to azithromycin, and treatment failures have been documented across multiple regions of the United States.
A Temporary Treatment After Injection
Something that catches many syphilis patients off guard is a reaction that occurs hours after their penicillin injection. Known as the Jarisch-Herxheimer reaction, it happens when large numbers of syphilis bacteria are killed at once, triggering a temporary inflammatory response. Symptoms can include fever, chills, muscle aches, headache, nausea, flushing, a worsening rash, and a rapid heartbeat. In a study of adults treated for early syphilis, 86% of those who experienced this reaction saw symptoms begin within 12 hours of the injection, with a typical onset around 5 hours. It resolves on its own and is not an allergic reaction to penicillin, though it can feel alarming if you aren’t expecting it.
Current Supply Shortage
There is an ongoing shortage of benzathine penicillin G in the United States. Only one FDA-approved formulation exists domestically (sold as Bicillin L-A), and its manufacturer, a Pfizer subsidiary, has pushed its next expected delivery to October 2026, with full supply recovery not anticipated until the fourth quarter of 2027. To bridge the gap, the FDA has authorized temporary importation of an alternative formulation from outside the U.S.
Because of the shortage, the CDC recommends that available supply be prioritized for pregnant patients, where the stakes of untreated syphilis are highest. If you’re being treated for syphilis and encounter difficulty getting the injection, your provider may need to use one of the oral alternatives or help you locate a facility with available stock.