For neurosyphilis, due to the poor penetration of benzylpenicillin into the central nervous system, those affected are recommended to be given large doses of intravenous penicillin for a minimum of 10 days. If a person is allergic, ceftriaxone may be used or penicillin desensitization attempted. Other late presentations may be treated with once-weekly intramuscular benzylpenicillin for three weeks. If allergic, as in the case of early disease, doxycycline or tetracycline may be used, albeit for a longer duration. Treatment at this stage limits further progression but has only slight effect on damage which has already occurred.

One of the potential side effects of treatment is the Jarisch-Herxheimer reaction. It frequently starts within one hour and lasts for 24 hours, with symptoms of fever, muscle pains, headache, and a fast heart rate. It is caused by cytokines released by the immune system in response to lipoproteins released from rupturing syphilis bacteria.

The Jarisch-Herxheimer reaction, which is the response to the body after endotoxins are released by the death of harmful organisms in the human body, starts usually during the first day of antibiotic treatment. The reaction increases the person's body temperature, decreases the overall blood pressure (both systolic and diastolic levels), and results in leukopenia and rigors in the body. This reaction can occur during any treatment of spirochete diseases.

It is important to realize that syphilis can recur. An individual who has had the disease once, even if it has been treated, does not prevent the person from experiencing recurrence of syphilis. Individuals can be re-infected, and because syphilis sores can be hidden, it may not be obvious that the individual is infected with syphilis. In these cases, it is vital to become tested and treated immediately to reduce spread of the infection.

In the case of rape, the person can be treated prophylacticly with antibiotics.

An option for treating partners of patients (index cases) diagnosed with chlamydia or gonorrhea is patient-delivered partner therapy, which is the clinical practice of treating the sex partners of index cases by providing prescriptions or medications to the patient to take to his/her partner without the health care provider first examining the partner.

The most popular treatment forms for any type of syphilis uses penicillin, which has been an effective treatment used since the 1940s.

Other forms also include Benzathine penicillin, which is usually used for primary and secondary syphilis (it has no resistance to penicillin however). Benzathine penicillin is used for long acting form, and if conditions worsen, penicillin G is used for late syphilis.

Penicillin is used to treat neurosyphilis; however, early diagnosis and treatment is critical. Two examples of penicillin therapies include:

- Aqueous penicillin G 3–4 million units every four hours for 10 to 14 days.

- One daily intramuscular injection and oral probenecid four times daily, both for 10 to 14 days.

Follow-up blood tests are generally performed at 3, 6, 12, 24, and 36 months to make sure the infection is gone. Lumbar punctures for CSF fluid analysis are generally performed every 6 months.

Neurosyphilis was almost at the point being unheard of in the United States after penicillin therapy was introduced. However, concurrent infection of "T. pallidum" with human immunodeficiency virus (HIV) has been found to affect the course of syphilis. Syphilis can lie dormant for 10 to 20 years before progressing to neurosyphilis, but HIV may accelerate the rate of the progress. Also, infection with HIV has been found to cause penicillin therapy to fail more often. Therefore, neurosyphilis has once again been prevalent in societies with high HIV rates and limited access to penicillin. Blood testing for syphilis was once required in order to obtain a marriage license in most U.S. states, but that requirement has been discontinued by all 50 states over recent years, also contributing to the spread of the disease.

The CDC recommendation for chancroid is a single oral dose (1 gram) of azithromycin, or a single IM dose of ceftriaxone, or oral erythromycin for seven days.

Abscesses are drained.

"H. ducreyi" is resistant to sulfonamides, tetracyclines, penicillins, chloramphenicol, ciprofloxacin, ofloxacin, trimethoprim and aminoglycosides. Recently, several erythromycin resistant isolates have been reported.

Treatment failure is possible with HIV co-infection and extended therapy is sometimes required.

Researchers had hoped that nonoxynol-9, a vaginal microbicide would help decrease STI risk. Trials, however, have found it ineffective and it may put women at a higher risk of HIV infection.

Prognosis is excellent with proper treatment. Treating sexual contacts of affected individual helps break cycle of infection.

If a pregnant mother is identified as being infected with syphilis, treatment can effectively prevent congenital syphilis from developing in the fetus, especially if he or she is treated before the sixteenth week of pregnancy. The fetus is at greatest risk of contracting syphilis when the mother is in the early stages of infection, but the disease can be passed at any point during pregnancy, even during delivery (if the child had not already contracted it). A woman in the secondary stage of syphilis decreases her fetus's risk of developing congenital syphilis by 98% if she receives treatment before the last month of pregnancy. An afflicted child can be treated using antibiotics much like an adult; however, any developmental symptoms are likely to be permanent.

Kassowitz’s law is an empirical observation used in context of congenital syphilis stating that the greater the duration between the infection of the mother and conception, the better is the outcome for the infant. Features of a better outcome include less chance of stillbirth and of developing congenital syphilis.

The Centers for Disease Control and Prevention recommends treating symptomatic or babies born to infected mother with unknown treatment status with procaine penicillin G, 50,000 U/kg dose IM a day in a single dose for 10 days. Treatment for these babies can vary on a case by case basis. Treatment cannot reverse any deformities, brain, or permanent tissue damage that has already occurred.

Some vertically transmitted infections, such as toxoplasmosis and syphilis, can be effectively treated with antibiotics if the mother is diagnosed early in her pregnancy. Many viral vertically transmitted infections have no effective treatment, but some, notably rubella and varicella-zoster, can be prevented by vaccinating the mother prior to pregnancy.

If the mother has active herpes simplex (as may be suggested by a pap test), delivery by Caesarean section can prevent the newborn from contact, and consequent infection, with this virus.

IgG antibody may play crucial role in prevention of intrauterine infections and extensive research is going on for developing IgG-based therapies for treatment and vaccination.

The disease can be treated with penicillin, tetracycline (not to be used in pregnant women), azithromycin or chloramphenicol, and can be prevented through contact tracing by public health officials. A single intramuscular injection of long-acting penicillin is effective against endemic treponematoses including pinta, yaws, and bejel

The treatment of TORCH syndrome is mainly supportive and depends on the symptoms present; medication is an option for herpes and cytomegalovirus infections.

Intravenously administered penicillin is the treatment of choice. Associated pain can be treated with opiates, valproate, or carbamazepine. Those with tabes dorsalis may also require physical therapy to deal with muscle wasting and weakness. Preventive treatment for those who come into sexual contact with an individual with syphilis is important.

It is treatable with penicillin or other antibiotics, resulting in a complete recovery.

TORCH syndrome can be prevented by treating an infected pregnant person, thereby preventing the infection from affecting the fetus.

Each type of vertically transmitted infection has a different prognosis. The stage of the pregnancy at the time of infection also can change the effect on the newborn.

Left untreated, tabes dorsalis can lead to paralysis, dementia, and blindness. Existing nerve damage cannot be reversed.

Death from congenital syphilis is usually due to bleeding into the lungs.

Since each case is different, the following are possible treatments that patients might receive in the management of myelitis.

- Intravenous steroids

High-dose intravenous methyl-prednisolone for 3–5 days is considered as a standard of care for patients suspected to have acute myelitis, unless there are compelling reasons otherwise. The decision to offer continued steroids or add a new treatment is often based on the clinical course and MRI appearance at the end of 5 days of steroids.

- Plasma exchange (PLEX)

Patients with moderate to aggressive forms of disease who don’t show much improvement after being treated with intravenous and oral steroids will be treated with PLEX. Retrospective studies of patients with TM treated with IV steroids followed by PLEX showed a positive outcome. It also has been shown to be effective with other autoimmune or inflammatory central nervous system disorders. Particular benefit has been shown with patients who are in the acute or subacute stage of the myelitis showing active inflammation on MRI. However, because of the risks implied by the lumbar puncture procedure, this intervention is determined by the treating physician on a case-by-case basis.

- Immunosuppressants/Immunomodulatory agents

Myelitis with no definite cause seldom recurs, but for others, myelitis may be a manifestation of other diseases that are mentioned above. In these cases, ongoing treatment with medications that modulate or suppress the immune system may be necessary. Sometimes there is no specific treatment. Either way, aggressive rehabilitation and long-term symptom management are an integral part of the healthcare plan.

Bejel, or endemic syphilis, is a chronic skin and tissue disease caused by infection by the "endemicum" subspecies of the spirochete "Treponema pallidum".

Bejel is also known by a variety of other names, including belesh, dichuchwa, endemic syphilis, nonvenereal syphilis, frenga, njovera, skerljevo, siti, or treponematosis-bejel type.

Prophylaxis and treatment with an anti-inflammatory agent may stop progression of the reaction. Oral aspirin or ibuprofen every four hours for a day or 60 mg of prednisone orally or intravenously has been used as an adjunctive treatment . However, steroids are generally of no benefit. Patients must be closely monitored for the potential complications (collapse and shock) and may require IV fluids to maintain adequate blood pressure. If available, meptazinol, an opioid analgesic of the mixed agonist/antagonist type, should be administered to reduce the severity of the reaction. Anti TNF-a may also be effective.

A chancre ( ) is a painless ulceration (sore) most commonly formed during the primary stage of syphilis. This infectious lesion forms approximately 21 days after the initial exposure to "Treponema pallidum", the gram-negative spirochaete bacterium yielding syphilis. Chancres transmit the sexually transmissible disease of syphilis through direct physical contact. These ulcers usually form on or around the anus, mouth, penis, and vagina. Chancres may diminish between four and eight weeks without the application of medication.

Chancres, as well as being painless ulcerations formed during the primary stage of syphilis, are associated with the African trypanosomiasis sleeping sickness, surrounding the area of the tsetse fly bite.

Neurosyphilis is an infection of the brain or spinal cord caused by the spirochete "Treponema pallidum". It usually occurs in people who have had chronic, untreated syphilis, usually about 10 to 20 years after first infection and develops in about 25%–40% of persons who are not treated. The United States' Centers for Disease Control and Prevention (CDC) advises that neurosyphilis can occur at any stage of a syphilis infection.

Treponematosis is a term used to collectively or individually describe any of the diseases caused by the bacterial species "Treponema". There are four subspecies described which cause the following diseases:

- Syphilis ("Treponema pallidum pallidum")

- Yaws ("Treponema pallidum pertenue")

- Bejel ("Treponema pallidum endemicum")

- Pinta ("Treponema carateum")