How does penicillin shortage affect syphilis treatment. What are the CDC guidelines for managing syphilis during drug shortages. Can alternative antibiotics effectively treat syphilis. How is syphilis diagnosed and managed in different stages. Why are syphilis cases increasing in the US.

The Penicillin Shortage Crisis: Impact on Syphilis Treatment

The United States is currently facing a critical shortage of injectable penicillin, particularly penicillin G benzathine, which is the preferred drug for treating syphilis. This shortage has significant implications for public health, especially given the recent surge in syphilis cases across the country.

The Food and Drug Administration (FDA) reported this shortage, attributing it to increased demand. Pfizer, the sole supplier of this form of penicillin in the U.S., cited the concurrent amoxicillin shortage as a contributing factor, as it led doctors to recommend penicillin as an alternative. The rising number of syphilis cases has likely further exacerbated the demand.

Why is penicillin G benzathine crucial for syphilis treatment?

Penicillin G benzathine is particularly valuable in treating syphilis because:

• It can be used in adults, children, and pregnant individuals
• It effectively treats both the mother and the unborn child in cases of maternal syphilis
• It has fewer side effects compared to alternative antibiotics
• It’s easy to administer, often given in outpatient clinics or urgent care settings

Dr. Jeremy Cauwels, chief physician at Sanford Health, emphasizes the importance of this drug: “The nice part about penicillin G benzathine is that you can give it to a pregnant mother and if she has syphilis, it will also treat the baby.”

Rising Syphilis Cases: A Public Health Concern

The penicillin shortage comes at a particularly concerning time, as syphilis cases in the U.S. have reached a 70-year high. According to the Centers for Disease Control and Prevention (CDC), 2021 saw the highest number of reported cases in seven decades.

What factors are contributing to the increase in syphilis cases?

Several factors may be contributing to the rise in syphilis cases:

1. Decreased funding for public health programs
2. Reduced access to healthcare services
3. Changes in sexual behavior and practices
4. Inadequate sex education and awareness
5. Stigma surrounding sexually transmitted infections (STIs)

This surge in cases, coupled with the penicillin shortage, presents a significant challenge for healthcare providers and public health officials.

CDC Guidelines for Syphilis Treatment During Penicillin Shortages

In light of the current penicillin shortage, the CDC has provided guidelines for managing syphilis treatment. These recommendations aim to ensure that patients receive appropriate care while conserving the limited supply of penicillin G benzathine.

What are the CDC’s recommendations for syphilis treatment during penicillin shortages?

The CDC suggests the following approaches:

• Prioritizing penicillin G benzathine for pregnant individuals and infants with congenital syphilis
• Using alternative antibiotics for non-pregnant adults when appropriate
• Implementing a staged approach to treatment based on disease severity and risk factors
• Enhancing surveillance and follow-up to ensure treatment efficacy

Healthcare providers are advised to consult with infectious disease specialists or local health departments when considering alternative treatments.

Alternative Antibiotics for Syphilis Treatment: Efficacy and Limitations

While penicillin G benzathine remains the gold standard for syphilis treatment, alternative antibiotics can be considered in certain situations. However, these alternatives come with their own set of challenges and limitations.

Which alternative antibiotics can be used to treat syphilis?

Some alternative antibiotics that may be used include:

• Doxycycline
• Tetracycline
• Ceftriaxone
• Azithromycin (in limited cases)

It’s important to note that these alternatives may not be suitable for all patients, particularly pregnant individuals or those with allergies. Additionally, some strains of syphilis have shown resistance to certain antibiotics, particularly azithromycin.

How do alternative antibiotics compare to penicillin in treating syphilis?

While alternative antibiotics can be effective in treating syphilis, they have some limitations compared to penicillin:

• Longer treatment durations may be required
• Higher risk of side effects and drug interactions
• Potential for antibiotic resistance
• Less data on efficacy, especially in pregnant individuals and congenital syphilis

Dr. Cauwels notes that although alternatives exist, “we know [penicillin G benzathine] always works and we know it’s easy to administer.”

Diagnosis and Staging of Syphilis: A Comprehensive Approach

Accurate diagnosis and staging of syphilis are crucial for determining the appropriate treatment regimen. Healthcare providers use a combination of clinical assessment, laboratory tests, and patient history to diagnose and stage syphilis.

What are the stages of syphilis and how are they diagnosed?

Syphilis progresses through several stages, each with distinct characteristics:

1. Primary syphilis: Characterized by a painless chancre at the site of infection
2. Secondary syphilis: Involves a rash and other systemic symptoms
3. Latent syphilis: No visible symptoms, but the infection remains present
4. Tertiary syphilis: Can cause severe organ damage if left untreated

Diagnosis typically involves serological tests, including:

• Nontreponemal tests (e.g., RPR, VDRL)
• Treponemal tests (e.g., FTA-ABS, TP-PA)

In some cases, direct visualization of the Treponema pallidum bacteria through darkfield microscopy may be used for definitive diagnosis.

Managing Syphilis in Special Populations: Pregnant Women and Newborns

Syphilis management in pregnant women and newborns requires special consideration due to the risk of congenital syphilis. The penicillin shortage poses particular challenges for these vulnerable populations.

How is syphilis managed in pregnant women and newborns?

For pregnant women:

• Penicillin G benzathine remains the only recommended treatment
• Treatment should be initiated as soon as possible after diagnosis
• Close monitoring and follow-up are essential to ensure treatment success

For newborns with suspected or confirmed congenital syphilis:

• Immediate treatment with intravenous penicillin G is recommended
• Treatment duration depends on maternal treatment history and infant evaluation results
• Long-term follow-up is crucial to monitor for potential complications

The current penicillin shortage underscores the importance of early prenatal care and syphilis screening to prevent congenital syphilis cases.

Public Health Strategies to Combat Rising Syphilis Rates

Addressing the rising syphilis rates requires a multifaceted approach that combines improved access to healthcare, enhanced surveillance, and targeted prevention efforts.

What public health strategies can help reduce syphilis rates?

Effective strategies to combat rising syphilis rates include:

• Expanding access to STI testing and treatment services
• Implementing comprehensive sex education programs
• Conducting targeted outreach to high-risk populations
• Strengthening partner notification and treatment services
• Enhancing surveillance systems to identify and respond to outbreaks quickly
• Promoting condom use and other safe sex practices
• Addressing social determinants of health that contribute to STI risk

Public health officials emphasize the need for increased funding and resources to support these initiatives, particularly in light of the ongoing penicillin shortage.

The Future of Syphilis Treatment: Research and Innovation

As the healthcare community grapples with the challenges posed by rising syphilis rates and antibiotic shortages, researchers are exploring innovative approaches to syphilis treatment and prevention.

What new developments are on the horizon for syphilis treatment?

Several promising areas of research include:

• Development of long-acting antibiotics for simplified treatment regimens
• Exploration of novel antibiotic compounds effective against Treponema pallidum
• Investigation of immunotherapeutic approaches to enhance the body’s natural defenses against syphilis
• Advancements in rapid, point-of-care diagnostic tests for improved detection and staging
• Research into syphilis vaccines to prevent infection

While these innovations hold promise, it’s important to note that their development and implementation may take years. In the meantime, healthcare providers and public health officials must work together to optimize the use of existing resources and treatment options.

The current penicillin shortage and rising syphilis rates underscore the need for continued investment in public health infrastructure, research, and education. By addressing these challenges head-on, we can hope to reverse the trend of increasing syphilis cases and ensure effective treatment for all affected individuals.

Shortage of penicillin limits access to the go-to drug for syphilis

The Food and Drug Administration on Wednesday reported a shortage of an injectable form of penicillin, an antibiotic used to treat syphilis and other bacterial infections like strep throat.

The drug joins a growing list of medications facing supply shortages in the U.S. Liquid amoxicillin, another antibiotic used to treat strep, has been in short supply since October, according to the FDA.

The form of penicillin affected, called penicillin G benzathine, is the preferred drug for syphilis, because it can be used in adults, children and pregnant people. It’s often administered in outpatient clinics or urgent care settings. Dosages for both children and adults are in short supply, according to the FDA.

“The nice part about penicillin G benzathine is that you can give it to a pregnant mother and if she has syphilis, it will also treat the baby,” said Dr. Jeremy Cauwels, the chief physician at Sanford Health, a medical system in Minnesota and North and South Dakota. He said pharmacists in his network have been dealing with a limited supply of penicillin since the winter.

Syphilis cases in the U.S. reached a 70-year high in 2021, the last year for which data is available, according to the Centers for Disease Control and Prevention. The sexually transmitted infection can result in organ damage or death if left untreated.

The FDA attributed the penicillin shortage to increased demand. Pfizer, the sole supplier of that form of penicillin in the U.S., pointed to the amoxicillin shortage as the main issue, because it prompted doctors to recommend penicillin instead. The rise in syphilis cases most likely further accelerated demand, the company said.

The amoxicillin shortage arose during a surge of respiratory virus infections over the fall and winter, when the antibiotic was prescribed for secondary bacterial infections resulting from Covid, flu or respiratory syncytial virus.

Amoxicillin has also been used to treat a rise in severe strep cases dating to the fall. In November, the American Academy of Pediatrics recommended penicillin G benzathine as an alternative to amoxicillin for strep throat patients.

Strep throat case numbers remain elevated. The CDC said last week that unpublished data from its national surveillance program showed a five-year high in emergency department visits for regular strep infections in February and March.

Pfizer said it has been delivering more of its injectable penicillin to the market than ever before but still can’t keep up with demand. The FDA said on its website that supply issues are expected to resolve sometime from October to December.

The American Society of Health-System Pharmacists has reported an additional shortage of another form of penicillin, penicillin G procaine, which doesn’t last as long in the body or cross the placental barrier. But Michael Ganio, the society’s senior director of pharmacy practice and quality, said “benzathine is probably a little bit more of a challenging shortage, because it is the drug of choice. “

Overall, the Covid pandemic seems to have worsened drug supply issues, Cauwels said.

New medication shortages increased by nearly 30% from 2021 to 2022, according to a March report from Democrats on the Senate Homeland Security and Governmental Affairs Committee. The reasons, it said, include a surge in demand for certain drugs, overreliance on foreign suppliers and manufacturers’ moving overseas.

The U.S. is seven months into a shortage of Adderall, a medication for attention-deficit/hyperactivity disorder. Four cancer drugs, including two common forms of chemotherapy, are under shortage as well, according to the FDA.

Injectable medications are more than twice as likely to experience shortages compared to other forms, such as oral or topical drugs, the Senate committee report said.

Cauwels said his health system doesn’t expect to get additional penicillin supply until the fall, although it is likely to have enough until then. Its amoxicillin supply is also limited, he added, but it’s getting a steady allocation based on what it has used in previous years.

He added that although there are alternatives to Pfizer’s penicillin drug for treating syphilis, other antibiotics come with more side effects.

The injectable penicillin became the go-to, he said, because “we know it always works and we know it’s easy to administer.”

Aria Bendix

Aria Bendix is the breaking health reporter for NBC News Digital.

Diagnosis and Management of Syphilis

DAVID L. BROWN, MAJ, MC, USA, AND JENNIFER E. FRANK, CPT, MC, USA

Syphilis is a sexually transmitted disease with varied and often subtle clinical manifestations. Primary syphilis typically presents as a solitary, painless chancre, whereas secondary syphilis can have a wide variety of symptoms, especially fever, lymphadenopathy, rash, and genital or perineal condyloma latum. In latent syphilis, all clinical manifestations subside, and infection is apparent only on serologic testing. Late or tertiary syphilis can manifest years after infection as gummatous disease, cardiovascular disease, or central nervous system involvement. Neurosyphilis can develop in any stage of syphilis. The diagnosis of syphilis may involve dark-field microscopy of skin lesions but most often requires screening with a nontreponemal test and confirmation with a treponemal-specific test. Parenterally administered penicillin G is considered first-line therapy for all stages of syphilis. Alternative regimens for non-pregnant patients with no evidence of central nervous system involvement include doxycycline, tetracycline, ceftriaxone, and azithromycin. In pregnant women and patients with neurosyphilis, penicillin remains the only effective treatment option; if these patients are allergic to penicillin, desensitization is required before treatment is initiated. Once the diagnosis of syphilis is confirmed, quantitative nontreponemal test titers should be obtained. These titers should decline fourfold within six months after treatment of primary or secondary syphilis and within 12 to 24 months after treatment of latent or late syphilis. Serial cerebrospinal fluid examinations are necessary to ensure adequate treatment of neurosyphilis.

Syphilis is a sexually transmitted disease (STD) caused by the spirochete Treponema pallidum. Previously known as the “great imitator,” this disease can have numerous and complex manifestations. Family physicians should understand its presentations, stage-specific diagnostic testing, and appropriate antibiotic treatments, because missed or inappropriately treated syphilis can result in devastating cardiovascular and neurologic disease, as well as congenital syphilis.

Epidemiology

The incidence of syphilis decreased significantly with the introduction of penicillin in the 1940s but rose sharply again with the advent of human immunodeficiency virus (HIV) infection in the 1980s. From 1990 through 2000, primary and secondary syphilis infection rates decreased by 89.2 percent. Despite the overall decreases, outbreaks of syphilis have recently been reported in men who have sex with men. In the United States, syphilis is more prevalent in the South, in urban areas, in men, and in blacks.¹

Stages of Syphilis

Primary syphilis most often manifests as a solitary, painless chancre that develops at the site of infection an average of three weeks after exposure to T. pallidum.

Without treatment, blood-borne spread of T. pallidum over the next several weeks to months results in secondary syphilis, which has numerous clinical manifestations. The most common features are fever, lymphadenopathy, diffuse rash, and genital or perineal condyloma latum.

During the latent stage of syphilis, skin lesions resolve, and patients are asymptomatic. However, serologic tests are positive for T. pallidum.

Tertiary or late syphilis develops years after the initial infection and can involve any organ system. The most dreaded complications are neurosyphilis and involvement of the aortic valve and root.

Diagnosis

DARK-FIELD MICROSCOPY

Dark-field microscopy is the most specific technique for diagnosing syphilis when an active chancre or condyloma latum is present.² However, its accuracy is limited by the experience of the operator performing the test, the number of live treponemes in the lesion, and the presence of non-pathologic treponemes in oral or anal lesions.³

In preparation for dark-field microscopy, the lesion is cleansed and then abraded gently with a gauze pad. Once a serous exudate appears, it is collected on a glass slide and examined under a microscope equipped with a dark-field condenser.²T. pallidum is identified by its characteristic corkscrew appearance.⁴ Given the inherent difficulties of dark-field microscopy, negative examinations on three different days are necessary before a lesion may be considered negative for T. pallidum.⁴

NONTREPONEMAL TESTS

Syphilitic infection leads to the production of non-specific antibodies that react to cardiolipin. This reaction is the basis of traditional nontreponemal tests such as the VDRL test and rapid plasma reagin test.

With nontreponemal tests, false-positive reactions can occur because of pregnancy, autoimmune disorders, and infections.^5,6 In addition, these tests may show a “prozone” phenomenon in which large amounts of antibody block the antibody-antigen reaction, causing a false-negative test in the undiluted sample.²

Qualitative nontreponemal tests are widely used for syphilis screening. However, their usefulness is limited by decreased sensitivity in early primary syphilis and during late syphilis, when up to one third of untreated patients may be nonreactive.³

After adequate treatment of syphilis, nontreponemal tests eventually become nonreactive. However, even with sufficient treatment, patients sometimes have a persistent low-level positive nontreponemal test (referred to as a serofast reaction).

Titers are not interchangeable between different test types. Hence, the same nontreponemal test should be used for follow-up evaluations.

TREPONEMAL-SPECIFIC TESTS

Treponemal-specific tests detect antibodies to antigenic components of T. pallidum. These tests are used primarily to confirm the diagnosis of syphilis in patients with a reactive nontreponemal test. However, the enzyme immunoassay (EIA) test for antitreponemal IgG also may be used for screening.⁷ Treponemal-specific tests include the EIA for anti-treponemal IgG, the T. pallidum hemagglutination (TPHA) test, the microhemagglutination test with T. pallidum antigen, the fluorescent treponemal antibody-absorption test (FTA-abs), and the enzyme-linked immunosorbent assay.

Treponemal tests have sensitivities and specificities equal to or higher than those for nontreponemal tests.^2,5 However, treponemal-specific tests are more difficult and expensive to perform, which limits their usefulness as screening tests. In addition, false-positive results can occur, especially when the FTA-abs test is used in patients with systemic lupus erythematosus or Lyme disease.^2,8

Unlike nontreponemal tests, which show a decline in titers or become nonreactive with effective treatment, treponemal-specific tests usually remain reactive for life. Therefore, treponemal-specific test titers are not useful for assessing treatment efficacy.

Stage-Specific Diagnosis and Treatment

TREATMENT GUIDELINES

Guidelines from the Centers for Disease Control and Prevention (CDC) recommend parenterally administered penicillin G for the treatment of all stages of syphilis (Figure 1).⁹ [Evidence level C, consensus/expert guidelines] Alternative regimens may be used in patients who are allergic to penicillin. However, pregnant women and patients with neuro-syphilis require treatment with penicillin even if they are allergic to the drug. In these patients, desensitization is necessary before penicillin therapy is initiated.

The treatment of syphilis is similar in HIV-positive and HIV-negative patients. However, HIV-positive patients require more frequent follow-up because of an increased risk of treatment failure. In addition, a higher index of suspicion for central nervous system (CNS) involvement must be maintained.⁹

Treatment of syphilis in any stage should take into account the risks of acquiring other STDs. HIV testing should be considered in the initial evaluation of all patients with syphilitic infection.⁹Screening for hepatitis B and C, gonorrhea, and chlamydial infection also should be considered.

After appropriate treatment has been administered, patients should be followed with quantitative nontrepone-mal test titers to establish treatment response. Typically, nontreponemal test titers should become at least four times lower within six months after treatment of primary or secondary syphilis, and within 12 to 24 months after treatment of latent or late infection. ¹⁰ [Evidence level B, cohort study]

PRIMARY SYPHILIS

Primary syphilis is most often associated with a single, painless chancre, although it can manifest in other ways (i.e., multiple chancres, painful papules or ulcers, or no lesions).⁴ The chancre is most commonly found on the external genitalia and develops 10 to 90 days (average: 21 days) after infection.¹¹ Associated regional lymphadenopathy is common. The chancre usually resolves spontaneously in one to four months.

Lesions that can be confused with the chancre of primary syphilis include herpes simplex virus infection, chancroid, fixed drug eruption, lymphogranuloma venereum, granuloma inguinale (donovanosis), traumatic ulcer, furuncle (boil), and aphthous ulcer.¹² A selected differential diagnosis is provided in Table 1.^12,13

Disorder or disease	Characteristics of genital lesion	Etiology
Primary syphilis: chancre	Solitary, painless ulcer with indurated border	Treponema pallidum
Secondary syphilis: condyloma latum	Slightly raised or flat, round or oval papules covered by gray exudate	T. pallidum
Genital herpes	Cluster of shallow, small, painful ulcers on a red base	Herpes simplex virus
Chancroid	Painful ulcer with sharp, undermined borders	Haemophilus ducreyi
Venereal warts	Soft, usually painless skin-colored or red papules	Human papillomavirus
Lymphogranuloma venereum: primary stage	Painless papule, shallow erosion, or ulcer; may be multiple or single	Chlamydia trachomatis

Primary syphilis is diagnosed by dark-field microscopy of a suspected lesion or by serologic testing (Table 2).^2,9 Either technique can have a false-negative result early in the course of the disease. Thus, if clinical suspicion is high, treatment for syphilis should be initiated.

Stage	Clinical manifestations	Diagnosis (sensitivity)	Treatment
Primary syphilis	Chancre	Dark-field microscopy of skin lesion (80%) Nontreponemal tests (78% to 86%) Treponemal-specific tests (76% to 84%)	Penicillin G benzathine, 2.4 million units IM (single dose) Alternatives in nonpregnant patients with penicillin allergy: doxycycline (Vibramycin), 100 mg orally twice daily for 2 weeks; tetracycline, 500 mg orally four times daily for 2 weeks; ceftriaxone (Rocephin), 1 g once daily IM or IV for 8 to 10 days; or azithromycin (Zithromax), 2 g orally (single dose)
Secondary syphilis	Skin and mucous membranes: diffuse rash, condyloma latum, other lesions Renal system: glomerulonephritis, nephrotic syndrome Liver: hepatitis Central nervous system: headache, meningismus, cranial neuropathy, iritis and uveitis Constitutional symptoms: fever, malaise, generalized lymphadenopathy, arthralgias, weight loss, others	Dark-field microscopy of skin lesion (80%) Nontreponemal tests (100%) Treponemal-specific tests (100%)	Same treatments as for primary syphilis
Latent syphilis	None	Nontreponemal tests (95% to 100%) Treponemal-specific tests (97% to 100%)	Early latent syphilis: same treatments as for primary and secondary syphilis Late latent syphilis: penicillin G benzathine, 2. 4 million units IM once weekly for 3 weeks Alternatives in nonpregnant patients with penicillin allergy: doxycycline, 100 mg orally twice daily for 4 weeks; or tetracycline, 500 mg orally four times daily for 4 weeks
Tertiary (late) syphilis	Gummatous disease, cardiovascular disease	Nontreponemal tests (71% to 73%) Treponemal-specific tests (94% to 96%)	Same treatment as for late latent syphilis
Neurosyphilis	Seizures, ataxia, aphasia, paresis, hyperreflexia, personality changes, cognitive disturbance, visual changes, hearing loss, neuropathy, loss of bowel or bladder function, others	Cerebrospinal fluid examination	Aqueous crystalline penicillin G, 3 to 4 million units IV every 4 hours for 10 to 14 days; or penicillin G procaine, 2.4 million units IM once daily, plus probenecid, 500 mg orally four times daily, with both drugs given for 10 to 14 days

Primary syphilis is treated with 2. 4 million units of penicillin G benzathine delivered intramuscularly in a single dose. In nonpregnant patients who are allergic to penicillin, alternative regimens include doxycycline (Vibramycin), in a dosage of 100 mg taken orally twice daily for two weeks, or tetracycline, in a dosage of 500 mg taken orally four times daily for two weeks. Limited evidence indicates that ceftriaxone (Rocephin), in a dosage of 1 g delivered intramuscularly or intravenously once daily for eight to 10 days, or azithromycin (Zithromax), in a single 2-g dose taken orally, may be effective for the treatment of primary syphilis, although close follow-up is warranted to assess treatment efficacy.⁹

At six and 12 months after treatment, patients with primary syphilis should be reexamined and undergo repeat serologic testing. Treatment failure is defined as recurrent or persistent symptoms or a sustained fourfold increase in nontreponemal test titers despite appropriate treatment. Patients with treatment failure should be tested for HIV infection and evaluated for neurosyphilis with a cerebrospinal fluid (CSF) examination. ⁹

SECONDARY SYPHILIS

Secondary syphilis develops several weeks to months after the chancre appears.⁴ The skin is most often affected. Patients may present with macular, maculopapular, or even pustular lesions, beginning on the trunk and proximal extremities. The rash of secondary syphilis may involve all skin surfaces, including the palms and soles. Condyloma latum also is associated with secondary syphilis. Involving mainly warm, moist areas such as the perineum and perianal skin, this soft, verrucous plaque is painless but highly infectious.

Other organs and systems that can be affected in secondary syphilis include the renal system (glomerulonephritis, nephrotic syndrome), the liver (hepatitis), the CNS (headache, meningitis, cranial neuropathy, iritis, and uveitis), and the musculoskeletal system (arthritis, osteitis, periostitis).⁴ Patients also may have constitutional symptoms such as fever, malaise, generalized lymphadenopathy, arthralgias, and weight loss.

The diagnosis of secondary syphilis is confirmed by nontreponemal and treponemal-specific tests. Treatment employs the same antibiotic regimens used for primary syphilis. Follow-up is the same as that for primary syphilis (Figure 2).⁹

LATENT SYPHILIS

It is important to distinguish between early and late latent syphilis, because relapse to secondary syphilis and recurrent infectivity are possible during the early latent stage. Early latent syphilis encompasses the first year after infection. This stage can be established only in patients who have seroconverted within the past year, who have had symptoms of primary or secondary syphilis within the past year, or who have had a sexual partner with primary, secondary, or early latent syphilis within the past year. Patients who do not meet any of these criteria should be presumed to have late latent syphilis.

CNS involvement may be asymptomatic. Therefore, the possibility of neurosyphilis should be considered in patients with early or late latent syphilis.

Early latent syphilis is treated in the same way as primary and secondary syphilis. Late latent syphilis is treated with 2.4 million units of penicillin G benzathine administered intramuscularly once a week for three weeks. Alternative regimens in nonpregnant patients with penicillin allergy include doxycycline, in a dosage of 100 mg taken orally twice daily for four weeks, or tetracycline, in a dosage of 500 mg taken orally four times daily for four weeks.⁹

After treatment of early or late latent syphilis, quantitative nontreponemal titers should be measured at six, 12, and 24 months. Neurosyphilis should be strongly considered in patients who show a fourfold increase in titers, patients who have an initially high titer (1:32 or greater) that fails to decline at least fourfold, patients who have HIV infection, and patients who develop signs or symptoms of neurosyphilis.⁹

TERTIARY SYPHILIS

Tertiary or late syphilis is classified into gummatous syphilis, cardiovascular syphilis, and neurosyphilis. Gummas are granulomatous-like lesions; they are clinically significant because they cause local destruction.⁴ These lesions may affect any organ system but most commonly occur in the skin, mucous membranes, and bones.

Cardiovascular syphilis results from destruction of the elastic tissue of the aorta, which leads to aortitis and the formation of aneurysms that rarely rupture. The ascending aorta is most often affected, with the potential complications of aortic valve insufficiency and coronary artery stenosis. A diagnostic clue is the presence of linear calcifications of the aorta on a chest radiograph. Approximately 11 percent of untreated patients progress to cardiovascular syphilis.¹⁴

Antibiotic therapy for gummatous and cardiovascular syphilis is the same as that for late latent syphilis, provided no evidence of neurologic involvement is present. Consensus is lacking on the appropriate follow-up in patients who have tertiary syphilis with no CNS involvement. Clinical response to treatment varies and depends on the type and location of gummatous or cardiovascular lesions.⁹

NEUROSYPHILIS AT ANY STAGE OF SYPHILIS

Neurologic involvement occurs in up to 10 percent of patients with untreated syphilis.¹⁴ Neurosyphilis should be considered in patients with signs or symptoms of neurologic involvement at any stage of T. pallidum infection and in all patients with late latent or tertiary syphilis, although asymptomatic neurosyphilis is the most common presentation.⁴ Neurologic involvement also should be suspected in patients who previously have been treated for neurosyphilis, patients who have not responded to treatment for primary, secondary, or latent syphilis, and patients who have HIV infection or other conditions that compromise immune status.

Lumbar puncture is required to establish the diagnosis of neurosyphilis. The CSF should be tested for white blood cell count and protein level, and for reactivity on a VDRL test. ^5,15 Although a positive CSF VDRL test result is specific for neurosyphilis, a negative result does not exclude the possibility of this infection, because sensitivity is less than 100 percent. A CSF white blood cell count greater than 10 per mm³(10 × 10⁶per L) or a CSF protein level greater than 50 mg per dL (0.50 g per L) indicates possible neurosyphilis.

Treponemal-specific testing (e.g., TPHA) is helpful only when the result is negative (i.e., it rules out neurosyphilis). Because IgG can cross the blood-brain barrier, a positive test may falsely imply CNS involvement.⁵ TPHA testing to compare serum and CSF values (TPHA index) may prove beneficial in establishing the diagnosis of neurosyphilis. Testing for spirochete DNA via poly-merase chain reaction methods is an evolving technique that may be helpful because it detects organisms, rather than antibodies, in the CSF.¹⁶

In late neurosyphilis, both vascular lesions (meningo-vascular neurosyphilis) and neuronal degeneration (parenchymatous neurosyphilis) are possible. ⁴ The clinical manifestations of neurosyphilis include seizures, ataxia, aphasia, paresis, hyperreflexia, personality and cognitive changes, visual changes, hearing loss, neuropathy, and loss of bowel and bladder functions.

Penicillin is the only drug that has proved effective in the treatment of neurosyphilis. The CDC endorses two regimens.⁹ The first is aqueous crystalline penicillin G, in a dosage of 3 to 4 million units administered intravenously every four hours for 10 to 14 days. The second regimen consists of penicillin G procaine, in a dosage of 2.4 million units administered intramuscularly once daily, plus probenecid, in a dosage of 500 mg orally four times daily, with both drugs given for 10 to 14 days.

Follow-up of patients treated for neurosyphilis depends on the initial CSF findings.⁹ If pleocytosis was present, the CSF should be reexamined every six months until the white blood cell count is normal. Retreatment should be considered if the CSF white blood cell count does not decline after six months or completely normalize after two years. ⁹ [Evidence level C, consensus/expert guidelines]

The CSF also can be reexamined to look for serial decreases in antibodies on the VDRL test or serial decreases in protein levels, although the management of persistent abnormalities is not well established. It is expected that CSF parameters will normalize within two years. Failure to normalize may warrant retreatment. Most treatment failures occur in immunocompromised patients.

Syphilis of the nervous system in patients treated for syphilis in the past

In pre-revolutionary Russia, every tenth patient with syphilis after 7-15 years developed late neurosyphilis (progressive paralysis, dorsal tabes, meningovascular syphilis) [1]. According to other authors (1913), among untreated patients with early syphilis, 25% subsequently developed progressive paralysis, 11% had spinal tachycardia, and 3% had cerebral syphilis, and among those who were vigorously treated using methods used at that time, progressive palsy developed in 3. 2%, tasco dorsalis in 2.7%, and cerebral syphilis in 7.6% of cases [2].

In the period after the Great Patriotic War, the number of registered patients with the main forms of late neurosyphilis sharply decreased, and the clinical picture underwent a certain evolution towards mitigation of its manifestations, which can be explained by the introduction of penicillin into the arsenal of antisyphilitic drugs.

In the 60-70s of the last century, mesenchymal forms of early neurosyphilis prevailed, and among them – asymptomatic meningitis, detected only in the study of cerebrospinal fluid. The subsequent gradual elimination of lumbar puncture as a mandatory procedure in patients with secondary recurrent, especially latent, syphilis significantly reduced the incidence of asymptomatic syphilitic meningitis, and its prevalence is currently unknown [3]. There are data in the literature of the 60-80s of the last century on this subject. So, G.V. Robustov, who by the middle of the last century had vast material on neurosyphilis, pointed out that in primary (seropositive) syphilis, the incidence of asymptomatic meningitis is 15%, in secondary syphilis – from 20 to 40% [4]. In later guidelines, the total data of various authors vary significantly: in primary syphilis, the frequency of asymptomatic meningitis is 8–31.8%, in secondary syphilis 20–73.1%, and in latent early syphilis 50–57.5% [5].

Some modern authors indicate that without treatment, neurosyphilis develops in 4-9%, with ineffective treatment – in 5% of patients. A number of authors note syphilis of the nervous system, including in patients who received full-fledged specific treatment [3]. According to E.Sh. Taktamysheva (1999), 24% of patients with neurosyphilis who were under observation had previously been treated for various forms of syphilis. Of these, 69.2% received adequate treatment with penicillin preparations. The author explains this by undiagnosed asymptomatic meningitis, already present in the early stages of syphilis [6].

Identification of asymptomatic specific meningitis in patients with early forms of syphilis makes it possible to classify such cases as more severe, requiring more significant therapeutic efforts for sanitation. According to the literature [7], there were sectional cases when patients with pathology in the CSF who did not have clinical neurological manifestations during life showed phenomena of specific infiltration of the pia mater of the brain and spinal cord. This was observed even with a negative RV in the cerebrospinal fluid.

Of great importance is the identification of cases of unknown, untreated or poorly treated syphilis, on the basis of which progressive paralysis and dorsal tabes are formed [1]. Neurosyphilis against the background of unspecified syphilis develops in 45.5% of cases [6].

If the patient has not been examined for cerebrospinal fluid, then it is impossible to decide whether he has damage to the nervous system in the absence of complaints and it is impossible to establish the presence of asymptomatic neurosyphilis. Accordingly, its treatment will be inadequate, not providing the antibiotic concentration necessary for sanitation of the cerebrospinal fluid.

In the past, syphilidologists were well aware of the importance of identifying asymptomatic meningitis. It is of interest to trace when this understanding was lost. In the “Instructions for the treatment and prevention of syphilis” (1976) [8] on p. 7 we read: “The study of cerebrospinal fluid is recommended to be carried out before treatment necessarily in patients with secondary fresh and recurrent, early and late latent, tertiary, congenital, seroresistant syphilis, in cases of clinical or serological relapse (regardless of the stage of the disease in which the previous treatment was performed), as well as if a specific lesion of the nervous system and internal organs is suspected. It is desirable to conduct a study of cerebrospinal fluid in patients with primary syphilis before starting treatment.

The same “Instruction” also provides a justification for the need to detect asymptomatic meningitis: “The practical feasibility of detecting it before starting treatment is determined by the need to increase the dose of antibiotics by 20% and add pyrogenic drugs. ”

A small comment on this quote. One cannot but agree that the detection of asymptomatic meningitis should lead to changes in the method of treatment, however, a simple increase in the course dose by 20% (and why by 20%?) does not change the fact that intramuscular administration of low doses of penicillin (and in those at times, a single dose of penicillin was only 50 thousand units) does not provide sanitation of the cerebrospinal fluid. Now we know that penicillin must be administered in high doses intravenously to sanitize the cerebrospinal fluid, but we have completely lost the desire to detect asymptomatic syphilitic meningitis.

The following “Instruction for the treatment and prevention of syphilis” was issued in 1988 [9]. This is where a completely modern (i.e., repeated in subsequent instructions of 1993 and 1999) recommendation is given for conducting a cerebrospinal fluid examination. Briefly stated: “The study of cerebrospinal fluid for diagnostic purposes is carried out in patients with clinical symptoms of damage to the nervous system, as well as in latent and late forms of syphilis. ” These are the 12 years between 1976 and 1988, when the tradition of the urgent need to detect asymptomatic meningitis in almost all forms of syphilis was lost. These were the years of well-being with the incidence of neurosyphilis, the gradual oblivion of this pathology and the reign of calmness of dermatovenereologists in this regard. Calmness even beyond the instructions: indeed, who in our time does punctures “with latent and late forms of syphilis”? The question will not be completely idle, but are punctures always performed on “patients with clinical symptoms of damage to the nervous system”?

The epidemic of the 1990-2000s returned us to the problem of neurosyphilis and made the question of the frequency and causes of neurosyphilis in patients previously treated for syphilis relevant.

Purpose of the study: based on the study of the anamnesis of patients with NS previously treated for syphilis, to establish possible factors predisposing to the onset of NS.

Material and methods

Analysis of archival case histories of 71 patients with NS, registered in the Moscow region in 2007-2008.

Results

Over the past 2 years (2007-2008), 71 patients were diagnosed with neurosyphilis in the Moscow region. In 23 (32.4%) of them, other forms of syphilis have already been registered in previous years. The ratio of untreated to previously treated patients who developed neurosyphilis was 2:1. In the 1990s, during the syphilis epidemic, this ratio was 3:1 [6].

Of these 23 cases, 22 cases of NS were analyzed, in which patients had previously received treatment for syphilis. One case is not considered, since the patient avoided treatment for 6 years due to newly diagnosed secondary syphilis of the skin and mucous membranes.

Among the selected patients there were 13 men and 9 women aged 24 to 56 years (20-29 years old – 5 men and 2 women, 30-39 years old – 2 men and 2 women, over 40 years old – 6 men and 5 women) .

Initially, syphilis was detected in these patients under various circumstances: 4 were in neurological departments, 3 of them had acute cerebrovascular accident, one had a convulsive syndrome. Another patient diagnosed with acute cerebrovascular accident was in intensive care when he was found to have positive serological tests for syphilis. 3 patients were identified in the trauma departments, 1 in the therapeutic department, 1 in the endocrinology department, and 2 in the gynecology department. Outpatient network specialists identified 2 patients, both of them by an ophthalmologist. Under other circumstances (getting a job, periodic medical examinations, applied themselves or the circumstances of detection are unknown), 8 patients were identified.

At that time, these patients were predominantly diagnosed with early forms of syphilis. Thus, the diagnosis of “latent early syphilis” was made in 13 patients, “secondary syphilis of the skin and mucous membranes” – 5, “primary syphilis” – 2. In some cases, especially when diagnosing latent early syphilis in patients with neurological symptoms in combination with positive seroreactions, one can doubt the correctness of the diagnosis and suspect NS. It should only be noted that at that time a liquorological study was not carried out and there is no reason to assert anything confidently. The only exception is one 55-year-old patient, who underwent spinal puncture, revealed pathology in the cerebrospinal fluid (colorless, transparent, cytosis 2 cells/mm ³ , protein 0.6 g/l, Nonne-Apelt reaction – negative, Pandey reaction – positive, RV negative, ELISA (IgM + IgG) positive, ELISA IgM negative, RMP positive ++, RPHA positive ++), however, despite everything, he was diagnosed with early latent syphilis and treated with intramuscular injections of water-soluble penicillin (in high doses – 1 million IU 6 times a day).

In 2 people who arrived from other regions of the Russian Federation, it was not possible to clarify the initial diagnosis, there were only anamnestic information about syphilis transferred in the past; these patients were unable to indicate exactly the treatment they received (one remembers injections, the other some pills). Both patients subsequently developed progressive paralysis. The remaining 20 patients received a variety of treatments when they were initially diagnosed with syphilis.

One patient with primary syphilis was treated with extencillin, and after treatment, persistent negative nontreponemal tests were observed. Late meningovascular syphilis developed 13 years after this treatment. In this case, re-infection cannot be ruled out. At the same time, it was mentioned above that approximately 15% of patients with primary syphilis are diagnosed with asymptomatic meningitis, which could serve as the basis for the onset of overt neurosyphilis. Another patient with primary syphilis was treated with bicillin-5. He also had persistent negative non-treponemal tests after treatment, but 3 years later, early meningovascular syphilis was registered.

Of 5 patients with secondary syphilis of the skin and mucous membranes treated with bicillin-3, procaine-penicillin, extencillin, penicillin intramuscularly and ceftriaxone, 2 developed late meningovascular syphilis (after bicillin-3, the exact number per course is unknown) – after 8 years and procaine-penicillin – 24. 0 million units – after 5 years) and asymptomatic neurosyphilis was detected in 3 patients (6 years after treatment with penicillin at a course dose of 80 million units, 1 year after treatment with ceftriaxone – 20 g, 3 years after treatment extencillin – 7.2 million units). Among the listed drugs, the only one that provides a treponemicidal concentration of the antibiotic in the cerebrospinal fluid when administered intramuscularly is at least 1.0 per injection is ceftriaxone [10]. Theoretically, when using this technique, the sanitation of the cerebrospinal fluid should have occurred, but this did not happen. True, the patient was later diagnosed not with manifest, but with latent neurosyphilis. But such an observation draws attention to itself and necessitates certain conclusions regarding the thoroughness of monitoring patients treated with ceftriaxone.

Patients with early latent syphilis (n=5) were treated with intramuscular penicillin. Four of them subsequently developed manifest forms of neurosyphilis — early meningovascular in one after 3 years and late meningovascular in 3 after 2, 3 and 4 years, respectively. Most likely, the nervous system was involved in these patients, but asymptomatic meningitis was not established, and intramuscular treatment with penicillin was insufficient for them. Another patient treated with penicillin developed asymptomatic neurosyphilis. He underwent a liquorological study after 7 years of treatment for delayed negative serological reactions, during which 2 courses of additional treatment (bicillin-3 and soluble penicillin administered intramuscularly) were carried out. In all patients of this group, during the period of clinical and serological control, seroresistance or delayed negativity of nontreponemal tests were observed. They received additional courses of treatment with procaine-penicillin – 24.0 million units, ceftriaxone – 20 g, penicillin intramuscularly – 80 million units.

Another 3 patients with a diagnosis of “early latent syphilis” were prescribed durant penicillin – retarpen or extencillin – 7.2 million units per course. After 2, 4 and 6 years, respectively, they were diagnosed with asymptomatic neurosyphilis. During the period of clinical and serological control, all of them received 1–2 courses of additional treatment with procaine-penicillin (24.0 million units per course) and ceftriaxone (20 g per course) due to seroresistance or delayed negativity of nontreponemal tests.

Procaine-penicillin as the first course of treatment for latent early syphilis was received by 3 patients. During the follow-up, there was no trend towards negative non-treponemal tests, despite the fact that 2 of them received additional treatment with ceftriaxone (10 and 20 g per course). After 1, 2 and 3 years, a CSF examination revealed asymptomatic neurosyphilis.

In one patient, the symptoms of eye damage were not taken into account, a diagnosis of early latent syphilis was made and treatment with ceftriaxone 14 g per course was prescribed. CSF examination after 2 years revealed a pathology corresponding to meningovascular syphilis.

These cases confirm the earlier observation about the results of treatment with ceftriaxone in terms of CSF sanitation.

One patient with a diagnosis of “early latent syphilis” received doxycycline treatment – for a course of 6.3 g. Seror resistance was observed, additional treatment with procaine-penicillin (24.0 million units per course) did not lead to negative serological reactions. 4 years after the discovery of syphilis, cerebrospinal fluid was taken from her and asymptomatic neurosyphilis was detected. In this case, there was an unreasonable replacement of the drug of choice – penicillin – with the reserve drug – doxycycline. The 20-day treatment with procaine-penicillin, which was later transferred without complications, allows us to consider this replacement unreasonable.

Thus, out of 22 detected cases of neurosyphilis in persons previously treated for other forms of syphilis, 11 were diagnosed with asymptomatic specific meningitis, 9 with meningovascular syphilis, and 2 with progressive paralysis.

It is of interest to compare the initial diagnosis and treatment methods with the later diagnosed form of neurosyphilis (Table 1). It can be seen from the presented data that the relationship between the compared parameters cannot be identified.

In 15 patients, there were significant data on the presence of seroresistance or delayed negativity of non-treponemal tests. One of them developed an acute cerebrovascular accident during the period of clinical and serological observation, in the rest, due to seroresistance, the cerebrospinal fluid was examined at the initiative of a venereologist. In 11 patients, neurological symptoms were absent and, as indicated above, asymptomatic meningitis was registered, and 3 were diagnosed with “early” or “late meningovascular syphilis” during additional examination.

In tab. Figure 2 shows the timing of the diagnosis of neurosyphilis from the start of observation and the forms of neurosyphilis found in patients previously treated for syphilis.

Thus, the terms of ascertaining neurosyphilis – both manifest and asymptomatic – cover a large time period – from 1 to 13 years after treatment for early forms of syphilis. It draws attention to the fact that the detection of asymptomatic NS, i.e. cerebrospinal fluid examination, in some cases, was delayed, and this worsens the prospects for sanitation of cerebrospinal fluid. Late asymptomatic neurosyphilis, diagnosed several years after treatment of an early stage of syphilis, was considered a precursor of progressive paralysis, the so-called pre-paralytic neurosyphilis [11], which should be taken into account when determining the timing of lumbar puncture, in particular, for patients with seroresistant.

There is another problem in diagnosing neurosyphilis in previously treated patients for syphilis. This is the problem of registering neurosyphilis. According to the requirements of modern statistical accounting, in cases of an early diagnosis of syphilis established in the past, neurosyphilis diagnosed in the future is not registered as a new disease, and, therefore, is not included in the statistics. This leads to incomplete registration of neurosyphilis and a distorted idea of ​​the incidence of neurosyphilis, since about 1/3 of patients are “lost” (at present, the ratio of treated in the past and untreated patients is 1:2).

Conclusion

Based on the study of case histories of patients with neurosyphilis registered in 2007-2008. in the Moscow region and who had a history of treated early syphilis, it was found that neurosyphilis, both overt and asymptomatic, was diagnosed within 1 to 13 years after initial treatment. Neurosyphilis developed mainly in patients with seroresistant and delayed negative seroreactions after treatment for various forms of early syphilis, including primary.

In comparison with publications 10 years ago, the ratio of the number of patients with neurosyphilis registered for the first time in their lives to the number of those treated in the past has changed from 3:1 to 2:1. This indicates an increase in the proportion of patients treated for early forms of syphilis among patients with neurosyphilis, and, consequently, the relevance of the problems discussed.

Draws attention to the fact that the diagnosis of early latent syphilis was established in some patients in neurological hospitals in the presence of neurological symptoms. This gives reason to doubt the correctness of the diagnosis of early latent syphilis.

It should be noted that asymptomatic meningitis in a number of patients was detected 4-10 years after treatment for early syphilis. Since the timing of the detection of this pathology depends mainly on the activity of the doctor, and late therapy (after 3 years) may not provide cerebrospinal fluid sanitation, it is necessary to take into account all of the above when conducting clinical and serological monitoring of patients, especially those treated for latent syphilis and especially with seroresistant and delayed negativity seroreactions. It is necessary to take adequate measures for the examination and treatment of such patients in a timely manner (before the expiration of 3 years).

As a cause of the development of neurosyphilis in patients treated with penicillin preparations in accordance with the standards, the presence of previously undiagnosed asymptomatic meningitis can be assumed. It is noteworthy that among these methods there was one that could provide a treponemicidal concentration of the antibiotic in the cerebrospinal fluid, namely the use of ceftriaxone. This method treated 2 patients for early syphilis and 9 received ceftriaxone as adjunctive therapy due to seroresistance. The development of neurosyphilis in them in the future indicates that the sanitation of the cerebrospinal fluid did not occur and, therefore, one should not place excessive hopes on ceftriaxone as a means of preventing neurosyphilis. Our data serve as a signal of the need to carefully monitor the effectiveness of ceftriaxone treatment and to accumulate convincing material on this issue. This is relevant right now, as ceftriaxone is increasingly being used in the outpatient practice of treating syphilis. The choice of this drug is explained by two quite understandable reasons – the absence of procaine-penicillin in the pharmacy network and the preference for outpatient treatment over inpatient treatment – both by patients and doctors.

Terminals

1. The problem of studying the factors contributing to the occurrence of neurosyphilis in patients who have received treatment for early forms of syphilis in the past is relevant, since the proportion of such patients is large – every third patient with neurosyphilis. It is necessary to carefully study the anamnesis both in relation to treatment and clinical and serological control.

2. To reduce the number of cases of neurosyphilis in treated patients, it is necessary to introduce into practice a diagnostic liquorological examination of patients with early forms of syphilis with a disease duration of 6 months or more. This will help identify asymptomatic meningitis, which is the basis for the development of neurosyphilis, and the appropriate correction of treatment.

3. If positive serological tests are detected in patients with neurological symptoms, a diagnostic liquorological examination should become an indispensable rule. This will improve the quality of both diagnosis and treatment of patients. In the absence of a CSF examination, these patients may be misdiagnosed as latent (usually early or unspecified) syphilis instead of neurosyphilis.

4. It is necessary to conduct a study of cerebrospinal fluid in all patients with seroresistant and delayed negative seroreactions no later than 2-3 years after treatment for early syphilis.

5. The problem of registering neurosyphilis in patients previously treated for syphilis should be solved by entering this position as a separate line in the state statistical form No. 34.

90,000 disease or condition? — St. Petersburg State Budgetary Institution of Health “Dermatovenerological Dispensary No. 4”

For almost 60 years, penicillin has been the drug of choice in the treatment of syphilis. In the history of chemotherapy for infectious diseases, this phenomenon is unique in its own way, since during this period the range of drugs used to treat other sexually transmitted infections (STIs) has changed significantly. Against the background of penicillin, other antibiotics are periodically used to treat syphilis: tetracyclines, macrolides, cephalosporins, which form a group of reserve drugs.
In addition to the evolution of clinical manifestations, the main criterion for the effectiveness of treatment are serological reactions – complement fixation (CFR) and microprecipitation (PM). Under the influence of specific therapy, eradication of pale treponema from the patient’s body occurs, which leads to clinical recovery and, accordingly, a negative antibody response, i.e. negativation of the complex of serological reactions (RSK + RM). However, regardless of the methods used to treat syphilis, there always remains a certain proportion of patients (according to various sources, 2–10%) in whom complete negative serological reactions do not occur.
Why do some patients, despite the complete treatment, do not experience complete negative DSC? Are they dangerous in an epidemic sense? How likely is the recurrence of the disease? Is additional treatment required in these cases? Unfortunately, there are no answers to these questions so far. This happens for many reasons, but the main one, apparently, is that the subject of discussion itself is not formulated clearly enough. The seropositivity that persists in patients after the treatment of syphilis is called seroresistance, but there is no consensus on the timing of this phenomenon. Discrepancies in terms of formalization of the concept of seroresistance are partly caused by the fact that it was assessed by the degree of positivity of seroreactions (from + to 4+), i.e. quite subjective way. In international practice, to assess the effectiveness of treatment, a semi-quantitative method for assessing the negativity of seroreactions is adopted: if within a year after the end of treatment, the antibody titer in the RM decreases by 4 times or more, then the treatment is recognized as unconditionally effective and the patient is monitored.
Recently, interest in this issue has begun to increase again, due to a number of circumstances. First, the analysis of the results of treatment of patients with syphilis with benzathine penicillin, which began to be used in Russia since 1993, begins. It is very important that this assessment be carried out by researchers from the same positions, otherwise the comparison of the results obtained becomes impossible. Since evidence-based medicine has not yet received sufficient development in our country, the role of such multicenter studies is high; it is on their basis that future treatment regimens for syphilis are being developed.
On the other hand, during the years of the epidemic, hundreds of thousands of people who recovered from syphilis became seropositive. It is very important to understand whether the positive results of serological tests are associated with delayed negativity or with the development of sustained seropositivity i.e. seroresistance? In addition to the psycho-emotional trauma associated with the need to recognize the past infection and constant explanations for the reasons for positive reactions, these people may really need additional or preventive treatment.
At present, two definitions are used to designate positive serological reactions (meaning only reactions of the standard complex) in patients after full-fledged treatment: seroresistant syphilis and seroresistant syphilis. Do both of these definitions correspond to the nature of the described phenomena and are they not synonymous?
According to leading experts (N.M. Ovchinnikov, T.V. Vasiliev, I.I. Ilyin, etc.), the definition of “seroresistant syphilis” is incorrect, since it presupposes that the patient has syphilis with positive CSR. It would be more correct to speak of seroresistance in patients treated for syphilis, or, more precisely, “persistently positive serological reactions in patients treated for syphilis.” In essence, by establishing the diagnosis of seroresistant syphilis in persons with positive TSR, we agree that the infectious process caused by pale treponema continues, although this is not always true.
The concept of “seroresistant syphilis” is largely nosological and implies the independent existence of a separate form of the disease with constantly positive serological reactions. Developing this position, one should further recognize the existence of special strains of pale treponema resistant to therapy, the persistence of which causes a similar serological form of the disease. In this case, the same seroresistance would be observed in other sexual partners, which almost never happens.
Studies of the variability of pale treponema are very difficult due to the impossibility of its cultivation. Clinical experience indicates the need to increase the administered doses of penicillin, which proves a gradual increase in the resistance of pale treponema to penicillin. If in schemes
of 1955 an aqueous solution of penicillin was administered in all forms of syphilis, 50,000 IU every 3 hours (daily dose of 400,000 IU), then after 50 years, penicillin is administered already at 1,000,000 IU every 6 hours (daily dose of 4,000 000 units). At present, it has been possible to fix a strain of pale treponema that is not sensitive to erythromycin, while seroresistance is observed regardless of the type of treatment.
Seror resistance is not an independent disease (nosology), it reflects the state of the relationship between the pathogen and the specific organism of the patient, therefore it is more correct to characterize this phenomenon as seroresistance after treatment. Scientific studies have shown that sometimes for various reasons (late treatment, the introduction of low doses of drugs, interrupted treatment), the complete destruction of treponema does not occur and some of them turn into peculiar forms, the so-called cysts, or L-forms. Being resistant to antibiotics, they are able to persist in the patient’s body for an indefinitely long time. Being a weak antigenic stimulus, modified forms of treponema contribute to the formation and maintenance of unstable, fluctuating positive serological reactions.
M.V.Milich proposed to distinguish between true, relative and pseudo-resistance. Relative seroresistance develops in patients who have received specific treatment, in whose body pale treponemas continue to persist in the form of avirulent cysts or polymembrane phagosomes. Most often, relative seroresistance develops after treatment of late latent, late congenital, secondary recurrent and early latent syphilis (with a statute of limitations of more than 6 months), i. e. in cases where pale treponema is a long time in the patient’s body without treatment. The appointment of additional treatment in these cases, the effect does not.
True seroresistance was defined as the result of a progressive course of syphilis, when for some reason microbiological sterilization of the organism did not occur after the treatment. True seroresistance usually develops in primary, secondary and early latent (lasting no more than 5-6 months) syphilis. With true seroresistance, the appointment of additional treatment usually leads to negative seroreactions.
Pseudo-resistance was proposed to consider such a condition when, despite positive serological reactions after treatment, the pathogen is no longer present in the body. The concept of pseudo-resistance is not widely used due to the fact that it is almost impossible to differentiate it from true resistance.
The concepts of relative and true seroresistance have not found wide application and distribution in practical work, since both terms mean the presence of a pathogen in the body in an unknown form of existence.
To date, two points of view on the immune basis of seroresistance have been established. It is generally accepted that, for various reasons, pale treponemas continue to persist in the patient’s body after treatment. This position is fundamental, and the very form of existence of treponemas does not matter (M.P. Frishman, 1984; N.M. Ovchinnikov et al., 1987; E.V. Sokolovsky, 1995; Luger a. Petzoldt, 1979).
According to other authors, seroresistance in syphilis is associated with the formation of so-called anti-idiotypic antibodies, i.e. secondary antibodies formed in response to the appearance of antitreponemal antibodies (T.M. Bakhmetyeva et al., 1988; S.I. Danilov, 1996). With this variant of seroresistance, the causative agent of infection is absent in the body, therefore, additional treatment does not make sense.
Thus, establishing the causes of seroresistance is a rather difficult task, which is of practical importance in deciding whether to prescribe additional treatment. Its performance depends on the identification of specific markers of persistent infection. One of them is antitreponemal immunoglobulin class M (IgM). As early as 10–14 days after infection, IgM to the main species-specific protein antigens of treponema appear in the patient’s blood. Antitreponemal IgG appear no earlier than the 4th week after infection and can subsequently remain in the blood for decades. After a full treatment of early acquired syphilis, antitreponemal IgM disappear after 3–12 months, and after treatment of late syphilis, after 12–24 months. The detection of antitreponemal IgM y in individuals with persistently positive serological reactions is very valuable, as it allows you to determine the activity of the infectious process and determine the tactics of further treatment. In one of the observations (T.V. Vasiliev, 1984) studied IgM in the RIF-abs reaction in 100 patients with seroresistant. In 90 of them, the reaction was positive with a titer of at least 1:100, which indicated the incomplete elimination of pale treponema from the body of patients. After additional specific treatment, IgM-RIF-abs were negative in 50% of patients; in the remaining patients, the antibody titer decreased to 1:13.
In our studies (I.A. Chimitova, V.A. Akovbyan et al., 1999) we found positive results for IgM in enzyme immunoassay (ELISA) in 42.9% of patients with seroresistant, doubtful results occurred in another 9.5%. After additional treatment, 66% of these patients were negative for IgM by ELISA.
Thus, the presence of antitreponemal IgM in some patients with seroresistant is an indicator of the presence of a pathogen in the body, indicates the activity of the infectious process and may serve as an indication for additional specific treatment.
Additional specific treatment for seroresistance is recommended with water-soluble penicillin at high doses. Recently, the 3rd generation cephalosporin ceftriaxone has been increasingly used. Possessing high treponemicidal activity and penetrating ability, ceftriaxone proved to be effective in seroresistance: complete negative reactions of the standard complex occurred in 45. 7% of patients within 6 to 24 months (I. A. Chimitova, 2000).
What should be understood by the definition of “seroresistance”?
After the treatment of syphilis, this is a certain state of the body, which is characterized by the absence of a decrease in titers of reagins in the RM by 4 times or more within a year after the end of specific treatment or by maintaining positive (weakly positive) results for more than 2 years in early and 3 years in late forms of syphilis . In the case of a more than 4-fold decrease in titers within 1 year, further preservation of positive or weakly positive microreaction results for 2 years can be assessed as a delayed negative seroreaction. Identification of antitreponemal IgM in patients with seroresistant blood is an indication for additional therapy, the outcome of which is most often successful. The absence of IgM casts doubt on the success of additional therapy, but if additional treatment has already been carried out in these patients before, then repeated courses are inappropriate.
Can it be argued that the long-term maintenance of positive serological reactions after the treatment of syphilis has any negative impact on the state of health in general? We are talking about the influence of the causes that underlie seroresistance. Studies of health indicators of persons with positive reactions of the standard serological complex 15–20 years after the end of specific treatment have shown that, in addition to disorders in the psychoemotional sphere in comparable age groups, the frequency of lesions of the cardiovascular and nervous systems in persons with seroresistant is significantly higher than in those who have recovered from syphilis and achieved complete negativity of the TFR (K.A. Yuldashev, 1966). This paper analyzes the results of treatment of patients with the use of heavy metal preparations, which does not allow us to exclude the possibility of their damaging effect on parenchymal organs and the nervous system. Obviously, this issue requires further study, taking into account the currently used treatment regimens for patients with syphilis, as well as new opportunities for serological diagnostics.