What Antibiotics Treat STIs: Chlamydia, Gonorrhea & More

Most bacterial STIs are curable with a short course of antibiotics, but the specific drug depends on which infection you have, where in the body it is, and whether the bacterium has developed resistance to older treatments. Doxycycline has become the workhorse for chlamydia, ceftriaxone remains the backbone of gonorrhea treatment, and penicillin is still the gold standard for syphilis decades after it was introduced. The landscape shifts often enough that what your friend was prescribed a few years ago may no longer be the first choice today.

Chlamydia and the Shift Away From Azithromycin

For years, a single one-gram dose of azithromycin was the go-to chlamydia treatment because it was easy: one pill, done. That convenience made it popular in clinics where follow-up was uncertain. But the evidence has caught up, and doxycycline (100 mg twice daily for seven days) is now the preferred option. A head-to-head trial found zero treatment failures in the doxycycline group, while azithromycin failed in about 3% of participants with urogenital chlamydia.¹ The gap widens further at other body sites. In a study of women with rectal chlamydia, the cure rate for azithromycin was only about 79%, compared with roughly 96% for doxycycline.²

The practical trade-off is obvious: seven days of twice-daily pills versus one dose. If you struggle with adherence, that matters. But the cure-rate difference is large enough that most guidelines now put doxycycline first. Azithromycin still has a role when someone genuinely cannot take doxycycline, or in situations where directly observed single-dose therapy is the only realistic option.

Gonorrhea and the Resistance Problem

Gonorrhea is treated with a single intramuscular injection of ceftriaxone, usually 500 mg (or 1 g in some guidelines for complicated infections). That might sound straightforward, but the story behind it is alarming. Neisseria gonorrhoeae, the bacterium that causes gonorrhea, has burned through almost every antibiotic class ever thrown at it: sulfonamides, penicillins, tetracyclines, fluoroquinolones. Ceftriaxone is essentially the last reliable first-line option for empiric treatment.³

The bacterium achieves this through mutations that affect drug-efflux pumps and the targets antibiotics bind to. Mutations in a gene called mtrR, for example, ramp up a transporter that actively pumps antibiotics out of the bacterial cell before they can do their job.⁴ The first gonococcal strain with high-level ceftriaxone resistance was identified in Japan, and researchers have warned that an era of untreatable gonorrhea could follow.⁵

This is why you get a shot in the clinic rather than a pill to take home. Intramuscular ceftriaxone achieves high, reliable blood levels that oral drugs cannot always match, and the directly observed dose eliminates the risk of someone skipping pills. If you test positive for gonorrhea and are also found to have chlamydia (which happens frequently), you will typically receive the ceftriaxone injection for gonorrhea plus a course of doxycycline for chlamydia.

Syphilis and Penicillin’s Staying Power

Treponema pallidum, the spirochete that causes syphilis, has never developed meaningful resistance to penicillin. This is remarkable given how long the drug has been in use. The standard treatment for early syphilis (primary, secondary, or early latent) is a single intramuscular injection of benzathine penicillin G at 2.4 million units. Late latent syphilis or syphilis of unknown duration calls for three weekly injections of the same dose.⁶

There is no well-established oral substitute that works as reliably. People with documented penicillin allergies present a genuine clinical challenge, especially pregnant individuals, for whom penicillin is the only proven option to prevent congenital syphilis. In those cases, desensitization protocols can be used: the patient receives increasing oral doses of penicillin under medical supervision until they can tolerate a full treatment dose. A program that desensitized pregnant women with syphilis found that all patients tolerated the procedure without adverse reactions.⁷

Neurosyphilis and Ocular Syphilis

When syphilis reaches the central nervous system or the eyes, the stakes and the treatment both escalate. Neurosyphilis requires high-dose intravenous penicillin G, typically 18 to 24 million units per day, administered continuously or in divided doses for 10 to 14 days.⁸ This is a hospital-level treatment, not something handled at a walk-in clinic.

Ocular syphilis, which can cause blurred vision, eye pain, or even blindness, is treated with the same neurosyphilis regimen regardless of the stage of syphilis or when eye symptoms first appear.⁹ The logic is that if syphilis can reach the eyes, it has access to the nervous system, and the standard intramuscular shot does not achieve adequate drug levels in the cerebrospinal fluid. Visual symptoms with a known or suspected syphilis infection should be treated as an urgent matter.

Mycoplasma Genitalium

Mycoplasma genitalium is a lesser-known STI that can cause urethritis, cervicitis, and pelvic inflammatory disease. It is trickier to treat than chlamydia because resistance to macrolide antibiotics (like azithromycin) has become common. The current best approach is resistance-guided therapy: a lab test checks whether the bacterium carries mutations that confer macrolide resistance, and the antibiotic choice follows accordingly.

When the bacterium is macrolide-susceptible, a course of doxycycline followed by azithromycin achieves cure rates around 95%. When macrolide resistance is present, doxycycline followed by moxifloxacin (a fluoroquinolone) cures about 92% of cases.¹⁰ Without this tailored approach, clinicians are essentially guessing, and the failure rate climbs. Many clinics still do not routinely test for Mycoplasma genitalium, so if you have persistent urethral or vaginal symptoms after chlamydia and gonorrhea testing comes back negative, it is worth asking about.

Lymphogranuloma Venereum Requires a Longer Course

Lymphogranuloma venereum, or LGV, is caused by specific strains of the same Chlamydia trachomatis species that causes ordinary chlamydia, but it behaves very differently. Instead of staying on mucosal surfaces, LGV strains penetrate into deeper tissue and spread to lymph nodes. This deeper invasion is why the standard seven-day course of doxycycline used for regular chlamydia is not enough. LGV requires 21 days of doxycycline to clear the infection, and studies using repeated testing have shown that the bacterium’s genetic material can remain detectable for up to 16 days after starting treatment.¹¹

LGV has been increasingly recognized as a cause of severe rectal inflammation, particularly among men who have sex with men. Symptoms can mimic inflammatory bowel disease, and misdiagnosis is not uncommon. Whether shorter regimens might work just as well is an active area of research.¹²

When Infections Spread Deeper

Pelvic inflammatory disease (PID) happens when bacteria from the cervix travel upward into the uterus, fallopian tubes, or surrounding tissue. Because PID is often caused by a mix of organisms, including chlamydia, gonorrhea, and other vaginal bacteria, treatment requires broad-spectrum combinations rather than a single drug. A typical inpatient regimen pairs an intravenous cephalosporin with doxycycline, or clindamycin with an aminoglycoside, followed by oral antibiotics to complete about two weeks of therapy.¹³ Outpatient regimens exist for milder cases but follow the same multi-drug logic.

Epididymitis in younger, sexually active men is often caused by the same organisms as other STIs. European guidelines recommend ceftriaxone (now at a 1 g dose) as a single intramuscular injection alongside a course of oral doxycycline when a sexually transmitted cause is suspected. When enteric bacteria are the likely culprit, a fluoroquinolone like ofloxacin or levofloxacin is used instead.¹⁴

STI Treatment During Pregnancy

Pregnancy complicates STI treatment because several commonly used antibiotics carry safety concerns. Doxycycline has long been avoided during pregnancy due to concerns about fetal bone and tooth development, particularly in the second and third trimesters. However, a large cohort study found that first-trimester doxycycline exposure was not associated with an increased risk of major birth defects, with malformation rates of about 7.7% among exposed pregnancies compared to 7.0% among unexposed ones — a difference that was not statistically meaningful. Third-trimester exposure was linked to a higher risk of very low birth weight, though other late-pregnancy outcomes were comparable.¹⁵

In practice, amoxicillin or azithromycin are typically used as chlamydia alternatives during pregnancy. For syphilis, penicillin remains the only acceptable treatment, with desensitization offered to those who are allergic. Gonorrhea is still treated with ceftriaxone, which is considered safe throughout pregnancy. These decisions should always be made with a clinician who knows your full history, but the point is that effective treatment options exist for every major bacterial STI during pregnancy.

Treating Partners to Prevent Reinfection

Curing your own infection does not help much if your partner remains infected and passes it right back to you. This is where expedited partner therapy (EPT) comes in. With EPT, a diagnosed patient receives a prescription or medication pack to give directly to their sexual partner, bypassing the need for the partner to visit a clinic separately. In a community-level trial in Washington State, the share of patients receiving EPT roughly doubled during the intervention period, and chlamydia positivity among young women dropped from about 8.2% to 6.5%, while gonorrhea incidence among women fell dramatically.¹⁶

Modeling research has estimated that delivering EPT to even a fifth of eligible men who have sex with men could reduce cumulative STI incidence by about 27% over a decade.¹⁷ EPT is legal in most U.S. states, though the specific rules vary. It works best for chlamydia and gonorrhea, which can be treated with simple oral regimens. Syphilis, which requires an injection, is not suited to EPT.

Doxycycline as Post-Exposure Prevention

One of the more significant recent developments in STI prevention is doxy-PEP: taking a 200 mg dose of doxycycline within 72 hours after condomless sex to prevent bacterial STIs. A landmark trial among men who have sex with men and transgender women found that doxy-PEP reduced the combined incidence of chlamydia, gonorrhea, and syphilis by about two-thirds compared to standard care.¹⁸ The effect was strongest against chlamydia and syphilis. A subsequent meta-analysis confirmed the syphilis and chlamydia benefits but found the effect on gonorrhea was not statistically significant, likely because gonorrhea has higher baseline resistance to tetracycline-class drugs.¹⁹

Real-world data from an urban STD clinic in Philadelphia showed similar results. Participants taking doxy-PEP had a roughly 60% reduction in any incident STI and an even larger drop in chlamydia specifically.²⁰ The main concern is that widespread doxycycline use could accelerate resistance, not just in STI-causing bacteria but in other organisms that are incidentally exposed. For now, doxy-PEP is primarily recommended for men who have sex with men and transgender women with a recent history of bacterial STIs — the population in which the evidence is clearest. Data in cisgender women are more limited, and at least one trial in that group showed less benefit.

What Antibiotics Do to the Microbiome

Any antibiotic you take for an STI does not limit its effects to the target bacterium. Research tracking changes in the vaginal microbiome found that azithromycin, while effective at eradicating its targets (Mycoplasma genitalium and Chlamydia trachomatis), had minimal impact on the overall vaginal bacterial community. Metronidazole, by contrast, significantly disrupted microbial diversity, though in about half of patients the overall community type did not shift.²¹

Doxycycline, taken for a week, can cause GI side effects like nausea and sometimes triggers vaginal yeast infections. These are usually temporary. If you are on a longer course, like the three weeks needed for LGV, probiotics and eating with food can reduce stomach upset. None of these side effects change the recommendation to complete your full course — an untreated or under-treated STI causes more harm than a few days of disrupted gut flora.

New Drugs on the Horizon

Given gonorrhea’s resistance trajectory, new antibiotics are urgently needed. Two drugs have recently reached the market for urogenital gonorrhea: gepotidacin and zoliflodacin. Gepotidacin works differently from existing antibiotics by targeting two bacterial enzymes simultaneously (DNA gyrase and topoisomerase IV), which makes it harder for the bacterium to develop resistance through a single mutation.²² Both drugs are oral, which is a significant practical advantage over the injectable ceftriaxone.

Lab testing has shown no evidence of antagonism when these new drugs are combined with each other or with ciprofloxacin, raising the possibility of future combination regimens that could further slow resistance.²³ These are early days — the drugs are approved for uncomplicated urogenital gonorrhea, not for pharyngeal or rectal infections where treatment is harder. But having more than one viable antibiotic class in the toolkit is something the STI field has not had for gonorrhea in a long time, and it changes the calculus around how to deploy these treatments strategically.

When Standard Antibiotics Are Not an Option

Drug allergies, pregnancy, and coinfections can all force clinicians off the standard script. The penicillin allergy situation with syphilis, as noted earlier, is the most consequential because no good alternative exists. For chlamydia, people who cannot tolerate doxycycline (most commonly due to severe photosensitivity or esophageal irritation) can use azithromycin, accepting its slightly lower cure rate, or sometimes levofloxacin. For gonorrhea, true cephalosporin allergy is rare but serious; alternatives like gentamicin plus azithromycin have been studied, though they are not as well validated.

Drug interactions also matter. Doxycycline’s absorption drops if taken with calcium supplements, antacids, or iron, so timing matters during a treatment course. Metronidazole, sometimes used as part of PID regimens or for trichomoniasis (a parasitic STI that antibiotics also treat), interacts with alcohol and can cause nausea and flushing if the two are combined. These are manageable issues, but they are worth knowing about before you start a course of treatment rather than discovering them mid-way through.