Syphilis: CDC Diagnosis and Treatment Guidelines

WHAT IS IT?

Syphilis is a sexually transmitted infection caused by Treponema pallidum.  Symptoms, diagnostic tests and treatment vary depending on stage of the disease. The syphilis rate has continued to increase in the US over the past decade. Without treatment, syphilis can damage the brain, nerves, eyes, and cardiovascular system.

Screening for Syphilis

Who to Screen

• The USPSTF task force recommends screening for the following populations (Grade A recommendation: “Offer or provide this service”)
  • Asymptomatic, nonpregnant adolescents and adults who are at increased risk for syphilis infection
  • All pregnant women early in pregnancy
  • Factors associated with increased risk for syphilis include
    • Higher prevalence of infection in particular communities
    • Sociodemographic and behavioral factors (e.g., multiple sex partners, prevalence of syphilis is higher in males, men who have sex with men, drug use, persons living with HIV, young adults, and persons with a history of incarceration, sex work, or military service)

How to Screen

• Traditional screening: Initial “nontreponemal” antibody test (i.e., Venereal Disease Research Laboratory [VDRL] test or rapid plasma reagin [RPR] test) to detect biomarkers released from damage caused by syphilis infection, followed by a confirmatory “treponemal” antibody detection test (i.e., fluorescent treponemal antibody absorption [FTA-ABS] or T pallidum particle agglutination test [TP-PA])
• Reverse sequence screening algorithm: Automated treponemal test (such as an enzyme-linked [EIA], chemiluminescence [CIA], or multiplex flow immunoassay [immunoblot]) performed first, followed by a nontreponemal test
  • If the test results of the reverse sequence algorithm are discordant, a second treponemal test (preferably using a different treponemal antibody) is performed

Primary Syphilis

Early disease, characterized by an ulcer or chancre at the infection site approximately 3 weeks after infection

• Diagnosis
  • Darkfield examination and molecular tests of fluid/tissue for T. pallidum are definitive methods or
  • Presumptive diagnosis requires both a (1) nontreponemal test (VDRL or RPR) and (2) a treponemal test (FTA-ABS, EIA, CIAs and immunoblots, rapid treponemal tests or TP-PA)
• Treatment
  • Benzathine penicillin G 2.4 million units IM in a single dose

Secondary Syphilis

Symptoms can be diffuse and variable  

• Symptoms
  • Skin rash (classically with involvement of palms and soles) | Mucocutaneous lesions | Lymphadenopathyn | Fever | Alopecia | Ocular symptoms | Headache | Hepatitis
  •  Typically develops several weeks to months after primary infection
• Diagnosis
  • Same as for primary syphilis
• Treatment
  • Same as for primary syphilis

Latent Syphilis

No symptoms and no current evidence of primary, secondary, or tertiary disease

• Diagnosis of early latent syphilis
  • Documented seroconversion or sustained ( >2 weeks) fourfold or greater increase in nontreponemal test or unequivocal symptoms of primary/secondary syphilis or a sex partner with documented primary/secondary syphilis all within the past year
• Treatment
  • Early latent (acquired within 1 yr): Benzathine penicillin G 2.4 million units IM single dose
  • Late latent (acquired > 1 yr): Benzathine penicillin G 7.2 million units total given IM in 3 weekly doses of 2.4 million units each

Tertiary Syphilis

Gummas, cardiovascular syphilis (CNS involvement (for neurosyphilis treatment, see below) 

• Diagnosis
  • Appearance of soft skin lesions and ulcers
  • CXR shows linear calcifications of aorta
  • Perform LP to rule out neurosyphilis
• Treatment
  • Benzathine penicillin G 7.2 million units administered as 3 weekly doses of 2.4 million units

Neurosyphilis

Note: Can occur at any stage | Includes cranial nerve dysfunction, meningitis, stroke, altered mental status, auditory/ophthalmic abnormalities | Tabes dorsalis and paresis are late manifestations and can occur 10 to 30 years after infection 

• Diagnosis
  • Lumbar puncture: Test CSF for white blood cell count, protein and VDRL
• Treatment
  • 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 daily plus probenicid 500 mg orally 4 times daily, for 10 to 14 days

Note: The durations of the recommended and alternative regimens for neurosyphilis are shorter than the duration of the regimen used for latent syphilis | Therefore, benzathine penicillin, 2.4 million units IM once per week for 1 to 3 weeks, can be considered after completion of these neurosyphilis treatment regimens to provide a comparable total duration of therapy

KEY CLINICAL POINTS:

• Penicillin Allergy
  • Patients with penicillin allergy should be desensitized and treated with penicillin whenever possible
  • Doxycycline 100 mg BID x 14 days or tetracycline 500 mg 4 times daily for 14 days can be used for nonpregnant penicillin-allergic patients with primary or secondary syphilis
• Counsel patients regarding Jarisch-Herxheimer reaction
  • Acute febrile reaction frequently accompanied by headache, myalgia, and fever
  • Occurs within initial 24 hours after initiation of any syphilis therapy
  • Reaction to treatment and not an allergic reaction to penicillin
  • Occurs most frequently among persons who have early syphilis (likely due to heavier bacterial loads at this stage)
  • Manage with antipyretics
• Nontreponemal titers decline after treatment and eventually become negative
• Treponemal tests remain positive for life
• Follow-up at
  • 6, 12, 18 and 24 months after therapy and should include serology
• If symptoms persist or recur, or there is a >4 fold increase in nontreponemal test titer persisting more than 2 weeks
  • consider reinfection or treatment failure
  • retreat and check HIV status
• Sexual transmission occurs only when mucocutaneous lesions are present and is uncommon after the first year
• Persons exposed sexually to those with primary, secondary or early latent syphilis should be evaluated clinically and serologically

Learn More – Primary Sources:

USPSTF: Screening for Syphilis Infection in Pregnant Women

USPSTF: Screening for Syphilis Infection in Nonpregnant Adolescents and Adults

CDC Sexually Transmitted Diseases: Syphilis

CDC: Syphilis Treatment Guidelines

Review Article: Syphilis Infection during Pregnancy: Fetal Risks and Clinical Management

BMJ Clinical Updates: Syphilis

CDC (MMWR): Missed Opportunities for Preventing Congenital Syphilis — United States, 2022

Screening for Sexually Transmitted Infections – Who, When and How Often?

SYNOPSIS:

There are an estimated 2.8 million new chlamydia infections each year in the US and 1.5 million new cases of gonorrhea diagnosed. The highest rates of both gonorrhea and chlamydia are reported in women aged 15 to 24. Symptoms are vague and sequelae can include pelvic inflammatory disease, ectopic pregnancy and infertility.  A full comprehensive sexual history may identify other risk factors to prompt more comprehensive screening for sexually transmitted infections

CLINICAL ACTIONS:

Sexually transmitted infections (STIs) are common with potential for serious long term outcomes, and remain a serious public health concern.  Here, we outline the recommendations for screening for STIs by population:

Adults

• Annual screening for gonorrhea and chlamydia is recommended for all sexually active women < 25 years | Evidence is insufficient for routine testing of gonorrhea and chlamydia in heterosexual men | Consider screening young men in high prevalence clinical settings e.g., adolescent clinics, correctional facilities, STI/sexual health clinic
  • Re-testing is recommended 3 months after treatment due to high re-infection rates
  • Screening is recommended for adults >25 years old at increased risk for infection (new partner, multiple partners, or a partner who has an STI)
  • Consider testing for rectal chlamydia and pharyngeal gonorrhea based on sexual history practices
  • Annual testing is recommended for men who have sex with men (MSM) at sites of contact (urethra, rectum)and every 3-6 months if at higher risk e.g. MSM on PrEP, HIV infection, or if they or their sex partners have multiple partners
  • Transgender and Gender Diverse Persons screening adapted based on anatomy
• Screening for syphilis is based on risk profile, with higher risk including history of incarceration, transactional sex work, geography, or male younger than 29 years old
  • Annual screening for sexually active MSM | 3 to 6 months if at increased risk
  • Annual screening for syphilis is recommended in transgender and gender diverse persons
• Screening for HIV should be performed in all adults aged 13-64 and who seek evaluation and treatment for STIs | Annual HIV screening is recommended for MSM with more than one sexual partner, with consideration for more frequent 3-6 month intervals for testing
• Consider type-specific HSV serologic testing in patients presenting for an STI evaluation | Note: USPSTF “recommends against routine serologic screening for genital HSV infection in asymptomatic adolescents and adults, including those who are pregnant”
• Consider screening for trichomonas in high-prevalence settings or patients at higher risk for infection (multiple sex partners, transactional sex, drug misuse, or a history of STI or incarceration)
• Screening for hepatitis B (HBV) should include all adults aged 18 years and older
  • At least once in their lifetime using a triple panel test
  • Screen pregnant people for hepatitis B surface antigen (HBsAg) during each pregnancy regardless of vaccination status and history of testing
  • Expand periodic risk-based testing to include people incarcerated, people with a history of sexually transmitted infections or multiple sex partners, and people with hepatitis C virus infection
  • Test anyone who requests HBV testing regardless of disclosure of risk
• Screening for hepatitis C infection (HCV) should include all adults over age 18 years except in settings with HCV positivity < 0.1%
  • All persons with risk factors (eg., persons with HIV, prior recipients of blood transfusions, persons who ever injected drugs and shared needles, and persons who are born to an HCV-infected mother) should be tested for HCV, with periodic testing while risk factors persist

Persons living with HIV

• At first HIV evaluation and annually afterwards, screen for
  • Gonorrhea
  • Chlamydia
  • Syphilis
  • Hepatitis B surface antigen and Hepatitis B immunity
  • Hepatitis C screening for all persons with HIV and subsequent annual testing for MSM
• Specifically for women with HIV
  • Screen for trichomonas for women at first evaluation and annually afterwards
  • Women should be screened within 1 year of sexual activity with testing repeat 6 months later | 3 normal and consecutive pap tests, screening can be spaced out to every 3 years

The USPSTF 2021 update

…recommends screening for chlamydia in all sexually active women 24 years or younger and in women 25 years or older who are at increased risk for infection. (B recommendation) …recommends screening for gonorrhea in all sexually active women 24 years or younger and in women 25 years or older who are at increased risk for infection. (B recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for chlamydia and gonorrhea in men

KEY POINTS:

• Screen sexually active women ≥ 25 for gonorrhea and chlamydia if at increased risk
• More comprehensive screening for STIs include evaluation for trichomonas, syphilis, HIV, Hepatitis B and Hepatitis C
• CDC has updated guidelines to recommend universal hepatitis C and hepatitis B screening in all adults

Learn More – Primary Sources:

CDC: Sexually Transmitted Infections Treatment Guidelines 2021

CDC: A Guide to Taking a Sexual History

CDC Recommendations for Hepatitis C Screening Among Adults — United States, 2020

CDC: Screening and Testing Recommendations for Chronic Hepatitis B Virus Infection (HBV)

USPSTF: Screening for Hepatitis B Virus Infection in Adolescents and Adults

Map: Prevalence of hepatitis B virus infection

USPSTF: Screening for Chlamydia and Gonorrhea

USPSTF: Serologic Screening for Genital Herpes Infection: US Preventive Services Task Force Recommendation Statement

Trichomoniasis: CDC Diagnosis and Treatment Guidelines

SYNOPSIS: 

Trichomoniasis is the most prevalent nonviral sexually transmitted infection worldwide.  The U.S. population-based T. vaginalis prevalence is 2.1% among females and 0.5% among males, with the highest rates among Black females (9.6%) and Black males (3.6%), compared with non-Hispanic White women (0.8%) and Hispanic women (1.4%) The majority of persons who have trichomoniasis (70%–85%) either have minimal or no genital symptoms, and untreated infections might last from months to years, however, data are lacking on whether screening and treatment for asymptomatic trichomoniasis is beneficial. Decisions about screening might be informed by local epidemiology of T. vaginalis infection rates. 

CLINICAL ACTIONS: 

Male: Urethritis| Epididymitis | Prostatitis 

Women: Vaginal Discharge| Vulvar Irritation 

Diagnostic testing for T. vaginalis should be performed in women seeking care for vaginal discharge (yellow-green, with or without irritation). Screening might be considered for women receiving care in high-prevalence settings.

Diagnosis 

• Perform nucleic acid amplification testing (NAAT), which detects T. vaginalis genetic material, is highly sensitive and which is three to five times more likely to identify T. vaginalis infections than wet-mount microscopy, a method with poor sensitivity
• Culture was considered the gold standard before molecular testing and is less sensitive than newer tests
• If wet preparations are used, despite lower sensitivities, slides should be evaluated immediately as sensitivity declines with time
• If negative, consider follow up with a NAAT to make sure infection is truly not present
• T. vaginalis may be an incidental finding on a Pap test, neither conventional nor liquid-based Pap tests are considered diagnostic tests for Trichomoniasis, because false negatives and false positives can occur

KEY POINTS:

The nitroimidazoles are the only class of antimicrobial medications known to be effective against T. vaginalis infections. Of these drugs, metronidazole and tinidazole have been cleared by FDA for the oral or parenteral treatment of trichomoniasis.

The CDC recommends the following

• Women
  • Metronidazole 500 mg 2 times/day for 7 days
• Men
  • Metronidazole 2 g orally in a single dose

• Alternative regimen for men and women
  • Tinidazole 2 g orally in a single dose

Note: ACOG also recommends metronidazole 500 mg orally twice a day for 7 days as the recommended treatment option with tinidazole, 2 g orally in a single dose as the alternative regimen 

• Alcohol consumption should be avoided during treatment with nitroimidazoles
  • To reduce the possibility of a disulfiram-like reaction, abstinence from alcohol use should continue for 24 hours after completion of metronidazole or 72 hours after completion of tinidazole
• Providers should advise persons infected with T. vaginalis to abstain from sex until they and their sex partners are treated (i.e., when therapy has been completed and any symptoms have resolved)
  • Testing for other STDs including HIV should be performed in persons infected with T. vaginalis
• Retest for T. vaginalis is recommended for all sexually active women within 3 months following initial treatment
  • Testing by NAAT can be conducted as soon as 2 weeks after treatment
• Treat current partners to avoid reinfection and further transmission
  • Partners should be advised to abstain from intercourse until they and their sex partners have been adequately treated and any symptoms have resolved
  • In States where legally allowed (see Learn More below), consider Expedited Partner Therapy (EPT) which allows the patient herself to provide medications to her partner when there are limited public health services to treat a partner, or concern that the partner will not have access to treatment

Pregnancy

• T. vaginalis infection is associated with two to threefold increased risk for HIV acquisition, preterm birth, and other adverse pregnancy outcomes among pregnant women
  • However, some trials have not shown improvement in perinatal morbidity with treatment
• Symptomatic pregnant women, regardless of pregnancy stage, should be tested and considered for treatment with metronidazole
  • Tinidazole should be avoided for pregnant women
• The benefit of routine screening for T. vaginalis in asymptomatic pregnant women has not been established

HIV

• Among women with HIV infection, up to 53% are also infected with T. vaginalis which has been associated with an increased risk for PID
• Routine screening of asymptomatic women with HIV infection for T. vaginalis is recommended on entry to care, and then annually
  • Pregnant women, including those who are asymptomatic, should be screened and treated as necessary because T. vaginalis infection is a risk factor for vertical HIV transmission
• The recommended regimen in the setting of HIV is as follows
  • Metronidazole 500 mg twice daily for 7 days
• Retest in 3 months with NAAT

Learn More – Primary Sources:

CDC: Trichomoniasis Treatment Guidelines

CDC: Trichomoniasis Fact Sheet for Your Patients

CDC: Expedited Partner Therapy 

ACOG Practice Bulletin 215: Vaginitis in Nonpregnant Patients

Optimizing Contraception for the HIV-positive Woman

The ideal contraceptive for an HIV-positive woman prevents pregnancy as well as transmission of HIV and STDs.  Dual contraception using condoms plus an additional contraceptive is the best strategy. Preexposure (PrEP) and postexposure (PEP) prophylaxis should be available to partners regardless of contraceptive method used.

There does not appear to be an association between the use of non-injectable hormonal contraception and risk of HIV acquisition. Studies regarding the risk of HIV acquisition with the use of progestin only DMPA injectable are conflicting, and the CDC continues to recommend it.

SUMMARY:

• Combined hormonal contraception (pill, patch and ring) and progestin-only pills
  • Considered MEC cat. 1 for patient who are not on antiretrovirals or are not clinically well
  • For patients who are taking antiretrovirals, can decrease hormone levels but are still considered safe (either cat. 1 or 2 depending on which antiretroviral is being used)
  • Protease inhibitors, pharmacologic boosters, and efavirenz can cause decreased effectiveness of hormonal contraception
  • Fostemsavir: can cause increased levels of ethinyl estradiol and raise risk of thromboembolic events. Dosing of ethinyl estradiol should not be higher than 30 mcg daily.
• Contraceptive implants are highly effective and benefits outweigh risks in HIV positive women (MEC cat. 1)
• Injectable depot medroxyprogesterone acetate (DMPA) is safe and effective (MEC cat. 1) and does not appear to have interactions with antiretrovirals
  • Studies regarding increased risk of HIV transmission and acquisition are conflicting.
• Intrauterine devices, both copper containing and levonorgestrel-releasing
  • MEC cat. 1 for women with HIV who are clinically well and on antiretrovirals, with no known drug interactions with antiretrovirals
  • For women with HIV who are not clinically well or not on antiretrovirals, initiation of IUD is considered MEC cat. 2, but continuation for an already placed IUD is cat.1
  • Limited data suggest a low risk of pelvic inflammatory disease and no changes in genital shedding of HIV RNA
• Condoms reduce transmission of HIV between discordant partners but are not represent optimal contraception, with an annual pregnancy rate of over 15% per year. Should be used concurrently with another contraceptive method
• Spermicides: not recommended due to potential of causing genital lesions
  • Nonoxynol-9, the active ingredient in most formulations, can cause genital lesions and may increase the likelihood of HIV transmission to a partner

KEY POINTS:

• HIV infection does not pose a barrier to sterilization, which remains an appropriate contraceptive option
• Emergency contraception including hormone based (progestin-only pills, ulipristal acetate, combined oral contraceptives) and the copper IUD should be offered to HIV positive women whenever appropriate
• Spermicides and are not recommended

Learn More – Primary Sources:

CDC United States medical eligibility criteria for contraceptive use, 2016

Contraception: Contraceptive failure in the United States