SEXUALLY TRANSMITTED DISEASES








Chlamydia | Chlamydia trachomatis

Epidemiology

  • Chlamydia is the most common bacterial infection in the U.S., with more than 1.5 million cases reported in 2015 alone. Since many patients are asymptomatic, the number of infections is likely much higher. Persons aged 15 - 24 years are at greater risk, as are women and blacks. In 2015, the reported prevalence of chlamydia infection among female blacks aged 14 - 24 years was 13.5%.
  • The transmission rate between infected and noninfected individuals during unprotected intercourse is around 70%

Symptoms

  • Up to 90% of chlamydia infections are asymptomatic. In women, the most common symptoms are cervical mucopurulent discharge and hypertrophic cervical ectopy (cervix swells and turns out). Other symptoms include dysuria, abnormal vaginal discharge, and postcoital bleeding. In men, urethral discharge, painful urination, and urethral itching may be present.
  • Adverse sequelae of chlamydial infections include pelvic inflammatory disease, ectopic pregnancy, and infertility

Screening

Diagnosis

  • For women, self- or clinician-collected vaginal swabs are the preferred sample type. A first catch urine sample is acceptable, but may miss up to 10% of infections.
  • For men, a first catch urine specimen is the preferred sample method
  • Oral and rectal swabs may be obtained in patients who engage in frequent oral or anal sex
  • Nucleic acid amplification tests (NAATs) are the recommended test method

Treatment overview

  • Spontaneous clearance occurs in about 20% of infected women
  • The risk of pelvic inflammatory disease is around 10% per year in untreated women
  • Test of cure is not recommended in nonpregnant patients with uncomplicated infections. The CDC recommends that all patients treated for chlamydia be retested 3 months after treatment.
  • Patients should abstain from intercourse for 7 days after single-dose therapy or until the completion of a 7-day regimen [1,2,3,13,17]

Treatment regimens (2021 CDC)

First line Alternative treatments

Studies

Azithromycin vs Doxycycline for Asymptomatic Rectal Chlamydia in Men Who Have Sex With Men, NEJM (2021) [PubMed abstract]
  • Design: Randomized controlled trial (N=625 | length = 4 weeks) in men who have sex with men that had a positive rectal chlamydia NAAT and were asymptomatic
  • Treatment: Azithromycin 1000 mg one time vs Doxycycline 100 mg twice daily for 7 days
  • Primary outcome: Negative rectal chlamydia NAAT at 4 weeks
  • Results:
    • Primary outcome: Azithromycin - 76.4%, Doxycycline - 96.9% (p<0.001)
  • Findings: A 7-day course of doxycycline was superior to single-dose azithromycin in the treatment of rectal chlamydia infection among men who have sex with men.
Azithromycin vs Doxycycline for Rectal Chlamydia in Men Who Have Sex With Men, Clin Infect Dis (2021) [PubMed abstract]
  • Design: Randomized controlled trial (N=135 | length = 4 weeks) in men who have sex with men that had a positive rectal chlamydia NAAT
  • Treatment: Azithromycin 1000 mg one time vs Doxycycline 100 mg twice daily for 7 days
  • Primary outcome: Negative rectal chlamydia NAAT at 4 weeks
  • Results:
    • Primary outcome: Azithromycin - 74%, Doxycycline - 100% (p<0.001)
  • Findings: A one-week course of doxycycline was significantly more effective than a single dose of azithromycin for the treatment of rectal chlamydia in men who have sex with men.
Azithromycin vs Doxycycline for Urogenital Chlamydia trachomatis Infection, NEJM (2015) [PubMed abstract]
  • Design: Randomized controlled trial (N=567 | length = 28 days) in youth with chlamydia
  • Treatment: Azithromycin 1 gram one time vs Doxycycline 100 mg twice daily for 7 days
  • Primary outcome: Treatment failure at 28 days after treatment initiation determined on the basis of nucleic acid amplification testing
  • Results:
    • Primary outcome: Azithromycin - 3.2%, Doxycycline - 0% (difference 3.2%, 95%CI [0.4 to 7.4%])
  • Findings: In the context of a closed population receiving directly observed treatment for urogenital chlamydia infection, the efficacy of azithromycin was 97%, and the efficacy of doxycycline was 100%. The noninferiority of azithromycin was not established in this setting.

Genital warts

Overview

  • Ninety percent of genital warts are caused by HPV 6 and 11. The Gardasil® vaccines protect against both strains (see HPV vaccine below).
  • In women, genital warts typically occur around the introitus. In men, the most common areas are under the foreskin of the uncircumcised penis and on the shaft of the circumcised penis. Warts are also found on the cervix, vagina, urethra, perineum, perianal skin, and scrotum. Intra-anal warts are observed predominantly in persons who have had receptive anal intercourse, but they can also occur in men and women who do not have a history of anal sexual contact.

Treatment overview

  • If left untreated, genital warts might go away, stay the same, or grow in size or number
  • Women with genital warts do not need to get Pap tests more often than recommended
  • Genital warts are not associated with the development of anogenital cancers
  • It's unclear if treatment reduces the risk of transmitting HPV infection
  • Newborns born to women with genital warts can sometimes develop respiratory papillomatosis (warts of the larynx). This condition is very rare. It is unclear if cesarean section prevents respiratory papillomatosis; therefore, cesarean delivery should not be performed solely to prevent transmission of HPV infection to the newborn
  • Many persons with warts on the anal mucosa also have warts on the rectal mucosa and may need evaluation with anoscopy [2,17]

Treatment (2021 CDC)

Patient-applied
  • Podofilox (Condylox®) 0.5% solution and gel - Apply twice daily for 3 consecutive days, then discontinue for 4 consecutive days. This one week cycle of treatment may be repeated until there is no visible wart tissue or for a maximum of four cycles. Safety and effectiveness of more than four treatment cycles has not been established. Apply to warts with the applicator tip or finger. Application on the surrounding normal tissue should be minimized. Treatment should be limited to 10 cm² or less of wart tissue and to no more than 0.5 g of the gel per day. Care should be taken to allow the gel to dry before allowing the return of opposing skin surfaces to their normal positions. Patients should be instructed to wash their hands thoroughly before and after each application. Solution comes in 3.5 ml bottle. Gel comes in 3.5 g tube. Solution ($) | Gel ($$$$)
  • Imiquimod (Aldara®) 5% cream - Apply 3 times per week to external genital/perianal warts. Continue until there is total clearance of the genital/perianal warts or for a maximum of 16 weeks. Apply prior to normal sleeping hours and leave on the skin for 6 -10 hours, then remove with mild soap and water. A thin layer of cream should be applied to the wart area and rubbed in until the cream is no longer visible. Local skin reactions at the treatment site are common. Comes in single use packet in boxes with 12 - 24 packets. ($ for 12 packets)
  • Imiquimod (Zyclara®) 3.75% cream - Apply a thin layer of cream once daily to the external genital/perianal warts until total clearance or for up to 8 weeks. Apply prior to normal sleeping hours and leave on skin for approximately 8 hours, then remove by washing the area with mild soap and water. Comes in 7.5 g pump and box with 28 dose packets. ($$$$ for 28 packets and one pump)
  • Sinecatechins (Veregen®) 15% ointment - Apply three times per day to all external genital and perianal warts. Continue until complete clearance of all warts or a maximum of 16 weeks. Apply 0.5 cm strand of ointment to each wart using a finger, dabbing it on to ensure complete coverage and leaving a thin layer of the ointment on the warts. Patients should wash their hands before and after application. Local skin reactions are common. Comes in 15 and 30 g tube. ($$$$)
Provider-applied
  • Cryotherapy with liquid nitrogen or cryoprobe - repeat applications every 1–2 weeks
  • Podophyllin resin 10%–25% in a compound tincture of benzoin
  • Trichloroacetic acid (TCA) or Bichloroacetic acid (BCA) 80%–90%
  • Surgical removal either by tangential scissor excision, tangential shave excision, curettage, laser, or electrosurgery

Gonorrhea | Neisseria gonorrhoeae

Symptoms

  • In men, symptoms of urethral discharge and burning are typically present
  • In women, gonorrhea is often asymptomatic. Symptomatic women may have vaginal discharge, burning with urination, and abnormal vaginal bleeding. Adverse sequelae of gonorrhea infections include pelvic inflammatory disease, ectopic pregnancy, and infertility.

Screening

  • Women: see STD screening recommendations in women
  • Men: current guidelines do not recommend routine screening in all men. Men who have sex with men are at increased risk and may benefit from annual screening.

Diagnosis

  • For women, self- or clinician-collected vaginal swabs are the preferred sample type. A first catch urine sample is acceptable, but may miss up to 10% of infections.
  • For men, a first catch urine specimen is the preferred sample method.
  • Oral and rectal swabs may be obtained in patients who engage in frequent oral or anal sex
  • Nucleic acid amplification tests (NAATs) are the recommended test method [3]

Treatment overview

  • Gonorrhea infections are often accompanied by chlamydia infections
  • Patients who are treated for pharyngeal gonorrhea should have a test of cure 7 - 14 days later. Test of cure is not necessary for uncomplicated urogenital or rectal gonorrhea. The CDC recommends that all patients treated for gonorrhea be retested 3 months after treatment.
  • Patients should abstain from intercourse for 7 days after single-dose therapy or until the completion of a 7-day regimen [2]

Treatment regimens (2021 CDC)

First line (cervical, urethral, and rectal)
  • Patients weighing < 150 kg (330 lbs): Ceftriaxone 500 mg IM single dose ($)
  • Patients weighing ≥ 150 kg (330 lbs): Ceftriaxone 1000 mg IM single dose ($)
  • If chlamydial infection has not been excluded, providers should treat for chlamydia with doxycycline 100 mg orally twice daily for 7 days. During pregnancy, azithromycin 1 g as a single dose is recommended to treat chlamydia.
Alternative treatments (cervical, urethral, and rectal)
  • Azithromycin 2000 mg single dose +
    • Gentamicin 240 mg IM single dose ($$)
  • Cefixime 800 mg single dose. If treating with cefixime, and chlamydial infection has not been excluded, providers should treat for chlamydia with doxycycline 100 mg orally twice daily for 7 days. During pregnancy, azithromycin 1 g as a single dose is recommended to treat chlamydia. ($)
  • Azithromycin 2000 mg single dose +
First line (pharyngeal)
  • Patients weighing < 150 kg (330 lbs): Ceftriaxone 500 mg IM single dose ($)
  • Patients weighing ≥ 150 kg (330 lbs): Ceftriaxone 1000 mg IM single dose ($)
  • If chlamydia coinfection is identified when pharyngeal gonorrhea testing is performed, providers should treat for chlamydia with doxycycline 100 mg orally twice a day for 7 days. During pregnancy, azithromycin 1 g as a single dose is recommended to treat chlamydia.
  • No reliable alternative treatments are available for pharyngeal gonorrhea. For persons with a history of a beta-lactam allergy, a thorough assessment of the reaction is recommended. For persons with an anaphylactic or other severe reaction (e.g., Stevens Johnson syndrome) to ceftriaxone, consult an infectious disease specialist for an alternative treatment recommendation.
Alternative treatments (pharyngeal)

Studies

Gentamicin vs Ceftriaxone for Gonorrhea, Lancet (2019) [PubMed abstract]
  • Design: Randomized controlled trial (N=720 | length = 2 weeks) in adults with uncomplicated genital, rectal, or pharyngeal gonorrhea presenting to clinics in England
  • Treatment: Gentamicin 240 mg IM vs Ceftriaxone 500 mg IM. All participants also received azithromycin 1 gram.
  • Primary outcome: Clearance of Neisseria gonorrhea at all initially infected sites, defined as a negative nucleic acid amplification test 2 weeks post-treatment
  • Results:
    • Primary outcome: Gentamicin - 91%, Ceftriaxone - 98% (difference –6.4%, 95%CI [–10.4% to –2.4%])
  • Findings: Gentamicin is not appropriate as first-line treatment for gonorrhea but remains potentially useful for patients with isolated genital infection, or for patients who are allergic or intolerant to ceftriaxone, or harbour a ceftriaxone-resistant isolate. Further research is required to identify and test new alternatives to ceftriaxone for the treatment of gonorrhoea.
Gentamicin vs Gemifloxacin for Gonorrhea, Clin Infect Dis (2015) [PubMed abstract]
  • Design: Randomized controlled trial (N=401 | length = 17 days) in patients with uncomplicated urogenital gonorrhea presenting to 5 clinic sites in the U.S.
  • Treatment: Gentamicin 240 mg IM vs Gemifloxacin 320 mg by mouth. All patients also received azithromycin 2 grams.
  • Primary outcome: Microbiological cure of urogenital infections (negative follow-up culture) at 10-17 days after treatment
  • Results:
    • Primary outcome: Gentamicin - 100%, Gemifloxacin - 99.5%
  • Findings: Gentamicin/azithromycin and gemifloxacin/azithromycin were highly effective for treatment of urogenital gonorrhea. Gastrointestinal adverse events may limit routine use. These non-cephalosporin-based regimens may be useful alternative options for patients who cannot be treated with cephalosporin antimicrobials. Additional treatment options for gonorrhea are needed.

Herpes simplex | Genital herpes

Epidemiology

  • Genital herpes is caused by herpes simplex virus (HSV). There are two types of herpes simplex virus, type 1 and type 2. HSV-1 causes herpes labialis (fever blisters) and genital herpes, while HSV-2 only causes genital herpes.
  • In the U.S., the prevalence of HSV-1 among persons 14 - 49 years is 54%, and the prevalence of HSV-2 is around 12 - 16%. [7,8,17]

Symptoms

  • Symptoms typically appear 4 - 7 days after exposure. Classic symptoms of HSV include clusters of vesicles on a red base that develop on the external genitalia and surrounding tissue. Lesions are often painful, itchy, and progress to ulcers and crusts that resolve over 2 - 3 weeks. In more severe cases, inguinal lymphadenopathy, fever, and malaise may develop.
  • Atypical symptoms are common, and many infections go unrecognized due to mild or no symptoms. In one study, 74% of genital HSV-1 infections and 63% of HSV-2 infections were asymptomatic. Patients who are seropositive for HSV-1 are more likely to be asymptomatic when infected with HSV-2. [4,7,8]

Diagnosis

  • Lesion testing - HSV DNA PCR testing is preferred. The sensitivity of PCR approaches 100% if vesicles or wet ulcers are present. Viral cultures have reduced sensitivity and are no longer recommended. [2,8]
  • Serological testing - Serum antibody testing (IgG, IgM) for HSV is available. IgM testing can detect recent infection, but it is not type-specific and may be positive during recurrent oral and genital episodes. IgG antibody testing is type-specific. After an initial infection, IgG antibodies may take from 3 weeks to 3 months to appear. The sensitivity of IgG testing for HSV-2 is 80 - 98%, with a specificity of 93 - 97%. Sensitivity for HSV-1 is 69 - 98%, with a specificity of 92 - 95%. [2,8]

Recurrence

  • After an initial outbreak of HSV-2, 70 - 90% of patients will have a recurrence within the first year, with an overall average of 4 episoes in the first year
  • After an initial outbreak of HSV-1, 20 - 50% of patients will have a recurrence within a year, with a median of 1.3 episodes in the first year
  • Recurrent outbreaks are often shorter (5 - 10 days) and less severe. Genital herpes is a lifelong infection. [7,8]

Transmission

  • The risk of transmission is greatest when sores are present, but transfer may also occur when sores are absent
  • In patients with HSV-2, asymptomatic viral shedding occurs on 10 - 30% of days, and suppressive antiviral therapy reduces the number to < 7%, thus lowering the rate of transmission. Asymptomatic shedding is less common with HSV-1, occurring on 12.1% of days after 2 months of infection and dropping to 7.1% at 11 months.
  • Development of acyclovir resistance with suppressive therapy is rare in immunocompetent patients. [8,19]

Screening recommendations

  • The USPSTF recommends against screening for genital herpes in asymptomatic individuals, including pregnant women [7]

Treatment overview

  • Antiviral therapy initiated within 24 hours of symptom onset reduces the overall length of symptoms by 1 - 2 days
  • In studies, suppressive therapy reduced the risk of recurrence from 80 - 85% to 25 - 30% over 4 months. [8]

Treatment regimens (2021 CDC)

Initial episode
  • Acyclovir
    • 400 mg 3 times a day for 7 - 10 days ($)
    • 200 mg 5 times a day for 7 - 10 days ($)
  • Famciclovir 250 mg 3 times a day for 7 - 10 days ($)
  • Valacyclovir 1000 mg twice a day for 7 - 10 days ($)
Recurrent episodes
  • Acyclovir
    • 800 mg twice a day for 5 days ($)
    • 800 mg 3 times a day for 2 days ($)
    • 400 mg 3 times a day for 5 days ($)
  • Famciclovir
    • 1000 mg twice daily for 1 day ($)
    • 125 mg twice daily for 5 days ($)
    • 500 mg once, followed by 250 mg twice daily for 2 days ($)
  • Valacyclovir
    • 500 mg twice daily for 3 days ($)
    • 1000 mg once daily for 5 days ($)
Suppressive therapy
  • Acyclovir 400 mg twice daily ($)
  • Famciclovir 250 mg twice daily ($$)
  • Valacyclovir 500 - 1000 mg once daily (For patients with ≥ 10 episodes a year, 1000 mg a day is preferred) ($-$$)
  • Pregnant women: in pregnant women, acyclovir 400 mg three times a day or valacyclovir 500 mg twice daily are recommended starting at 36 weeks' gestation
Topical (not CDC recommended)

Human papillomavirus (HPV)

Overview

  • HPV is the most common sexually transmitted infection. There are over 100 different HPV types. Types that are known to cause cancer are called high-risk types. Types that are not associated with cancer but may cause warts are called low-risk types.
  • High-risk HPV types include: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, or 68
  • High-risk HPV has been associated with a higher risk for cancer of the cervix, vagina, penis, anus, and oropharynx in both men and women. HPV types 16 and 18 are found in 70% of cervical cancers. HPV types 31, 33, 45, 52, and 58 are the next most common types associated with cervical cancer. These types were added to Gardasil to make the Gardasil 9 vaccine.
  • HPV types 6 and 11 cause 90% of genital warts

Prevalence


Prevalence of HPV infection in adults 18 - 69 years (U.S. 2011 - 2014)
HPV type Entire population Men Women
Any genital HPV 43% 45% 40%
High-risk genital HPV 23% 25% 20%
Any oral HPV 7% 12% 3%
High-risk oral HPV 4% 7% 1%

Vaccine

  • The Gardasil vaccine helps protect against HPV Types 6, 11, 16, and 18
  • The Gardasil 9 vaccine helps protect against HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58
  • The Gardasil vaccines may be given starting at age 11 years. In 2018, Gardasil 9 was FDA-approved for use in men and women through age 45.
  • Several observational studies have found that HPV vaccines are effective in preventing cervical cancer [PMID 32997908, PMID 34741816]
  • In 2020, Gardasil 9 was FDA-approved for the prevention of anal, oropharyngeal and other head and neck cancers caused by HPV types 16, 18, 31, 33, 45, 52, and 58 in boys and men. This indication was based on Gardasil's ability to prevent infection with HPV types associated with these cancers and not on any actual trial that showed a decrease in cancer incidence.
  • See screening and immunization recommendations for Gardasil vaccination schedules
  • A study among women who inadvertently received the Gardasil vaccine during pregnancy found that it did not increase the risk of spontaneous abortion [PMID 29889760].

Treatment

  • HPV infection in itself is not treatable
  • The sequelae of HPV infection (e.g. genital warts, cervical dysplasia, cervical cancer) are treatable
  • Cervical cancer screening with PAP smears is primarily performed to screen for cervical dysplasia and cervical cancer caused by HPV. See PAP guidelines for more information.

Studies

The HIM Cohort Study: Incidence and clearance of oral human papillomavirus infection in men, Lancet (2013) [PubMed abstract]
  • A nested cohort study in the Lancet looked at the incidence and clearance of oral HPV infection in men
  • The study included 1626 men with a median age of 32 years. The study protocol called for rinse and gargle samples that were sent for HPV testing every 6 months for 4 years. The incidence of new oral HPV infections, and the clearance of these infections were evaluated.
  • The following was seen:
    • During the first 12 months of follow-up, 4.4% of men acquired any oral HPV infection
    • During the first 12 months of follow-up, 1.7% of men acquired an oral oncogenic HPV infection
    • Most new oral HPV infections cleared within 1 year (45 out of 81)
    • Most new oral oncogenic HPV infections cleared within 1 year (18 out of 24)
    • Median time to clearance was 6.9 months for any HPV infection, and 6.3 months for oncogenic HPV infections
    • Men who were single, divorced, separated, or widowed had a higher risk of oncogenic HPV infection than those who were married or cohabiting
    • Former and current smokers had a higher risk of oncogenic HPV infection than nonsmokers
  • Findings: Newly acquired oral oncogenic HPV infections in healthy men were rare and most were cleared within 1 year. Additional studies into the natural history of HPV are needed to inform development of infection-related prevention efforts.

Mycoplasma genitalium

Overview

  • Mycoplasma genitalium (M. genitalium) is a sexually transmitted bacterium that was first identified in 1980. Because it is a relatively new discovery, it is not as widely known or understood as other STDs.
  • In men, it causes urethral inflammation and burning and is believed to be the source of up to 40% of cases of persistent or recurrent urethritis. In women, it can cause vaginal discharge and cervicitis, but it is frequently asymptomatic.
  • Men with recurrent or unexplained urethritis should be tested for M. genitalium, as should women with recurrent cervicitis [16,17]

Diagnosis

  • In 2019, the FDA approved the Aptima M. genitalium nucleic acid amplification tests (NAATs) for urine, urethral, penile meatal, endocervical, and vaginal swabs
  • In studies, the test identified M. genitalium in approximately 90% of vaginal, male urethral, male urine, and penile samples. It correctly identified M. genitalium in female urine and endocervical samples 78% and 82% percent of the time, respectively. Vaginal swabs are preferred in women; however, urine and endocervical swabs may also be used.
  • The test correctly identified samples that did not have M. genitalium 98% percent of the time.

Treatment (2021 CDC)

If resistant to macrolides or resistance testing is not available
  • Doxycycline 100 mg twice daily for 7 days, followed by moxifloxacin 400 mg once daily for 7 days
  • A study published in 2020 found that up to 65% of M. genitalium infections harbored mutations that are associated with resistance to macrolides [PMID 32185385]
If macrolide sensitive
  • Doxycycline 100 mg twice daily for 7 days, followed by azithromycin 1 gram initial dose, followed by 500 mg once daily for 3 additional days (2.5 grams total)

Syphilis | Treponema pallidum

Epidemiology

  • Syphilis is an infection caused by the Treponema pallidum bacteria. If untreated, the infection becomes chronic and progresses through clinical stages that have different features and sequelae.
  • More than 5 million new cases of syphilis are diagnosed each year, with homosexual men, IV drug users, and lower socioeconomic individuals disproportionately affected.
  • Syphilitic genital ulcers facilitate the transmission of HIV, and in some studies, up to 40% of people diagnosed with early syphilis are also HIV positive.

Transmission

  • Excluding congenital syphilis, syphilis is primarily transmitted through direct contact with syphilitic lesions. Infectious lesions include the ulcers seen in primary syphilis and the mucocutaneous lesions that appear in secondary syphilis. Once the infection has been acquired, it takes about 3 weeks for the primary lesion to appear at the site of infection. Lesions may be mild and nontender, causing them to go unnoticed.
  • Syphilis is transmissible during the first 2 - 3 years of infection, after which sexual transmission is rare

Syphilis stages

Primary syphilis
  • Primary syphilis is marked by the appearance of an ulcer or chancre at the site of infection. Lesions may appear anywhere inoculation has occurred, including skin surfaces of the anogenital region, the vaginal mucosa, and the cervix. Lesions have also been documented on the hands and in the mouth and throat. Surrounding lymphadenopathy may or may not be present. Lesions may be nontender and go unnoticed. (primary and secondary syphilis images)
  • Without treatment, primary lesions resolve within 3 - 6 weeks. With treatment, they resolve within days.

Secondary syphilis
  • Secondary syphilis occurs when the infection disseminates in the bloodstream. A painless macular skin rash that frequently involves the palms and soles of the feet is a hallmark of secondary syphilis, but the rash may be subtle and variable in appearance, causing it to be misdiagnosed. Highly-infectious mucocutaneous lesions also occur along with fever, lymphadenopathy, and generalized malaise. (primary and secondary syphilis images)
  • Without treatment, symptoms of secondary syphilis typically resolve in weeks to months

Early latent syphilis
  • After the symptoms of secondary syphilis resolve, the early latent stage begins. Early latent syphilis is defined as syphilis infection in a person who is currently asymptomatic and known to have acquired the infection within the past year.
  • About 25% of patients with early latent syphilis will have a recurrent secondary syphilis syndrome

Latent syphilis
  • Latent syphilis is defined as asymptomatic infection for > 1 year or unknown duration
  • About one-third of patients with untreated latent syphilis will go on to develop tertiary syphilis or neurosyphilis

Tertiary syphilis
  • If latent syphilis remains untreated, about one-third of patients will develop either tertiary syphilis or neurosyphilis. These late stages of infection typically occur years to decades after the primary infection.
  • Tertiary syphilis includes cardiac disease and gummatous (granulomatous) lesions of skin, bone, and organs. Cardiac syphilis may present as ascending aortic aneurysm, aortic valve disease, or coronary artery disease. Gummatous lesions may form anywhere and produce symptoms through their mass effect and inflammation.

Neurosyphilis
  • Treponema invades the central nervous system within days of the primary infection, but most people remain asymptomatic. After many years of untreated infection, symptomatic neurosyphilis develops in about 10 - 20% of affected individuals.
  • Symptomatic neurosyphilis is marked by two clinical syndromes - general paresis and tabes dorsalis. General paresis causes progressive dementia, delusions, behavioral and personality changes, repetitive speech, and tremors. Tabes dorsalis causes ataxia, lighting pain in the legs and trunk, loss of proprioception, Charcot joints, Romberg's sign, and Argyll Robertson pupils (constriction of the pupils when the eyes are focused on a nearby object but not when the pupil is illuminated).
  • Neurosyphilis may also present as stroke and cranial nerve abnormalities if vasculitis develops

Diagnosis

Overview
  • Syphilis tests are antibody tests that are divided into "nontreponemal tests" and "treponemal tests."
  • Nontreponemal tests (RPR, VDRL) detect nonspecific antibodies that are released in response to a syphilis infection. Because the antibodies are nonspecific, they can also be positive in other conditions (e.g. pregnancy, malignancy, antiphospholipid antibody syndrome)
  • Treponemal tests (FTA-ABS, TP-PA) detect antibodies that are specific for Treponema pallidum antigens
  • Nontreponemal tests are typically done first because they are cheaper and easier to perform. If a nontreponemal test is positive, then a treponemal test is performed to confirm infection.
  • Nontreponemal tests are also useful for monitoring response to treatment because their titers fluctuate with disease activity. Treponemal tests are not helpful for monitoring disease activity.

RPR (Rapid plasma reagin)
  • RPR is a nontreponemal test that detects antibodies against syphilis. If the RPR is positive, it is confirmed with a treponemal test.
  • The RPR will typically turn positive 4 - 6 weeks after initial infection
  • RPR levels fluctuate with disease activity, and they can be used to measure response to therapy. A fourfold change in RPR titer (ex. 1:16 to 1:4) is considered a clinically significant difference between two RPR tests.
  • After successful treatment, 15 - 41% of patients will continue to have a low RPR titer
  • Patients with antiphospholipid antibodies may also have a positive RPR test. This occurs because the antigen in the RPR test contains cardiolipin, a phospholipid. Other conditions that can cause a positive test include pregnancy, chronic infections (e.g. HIV, mycobacterium), and malignancy.

  • RPR has a specificity of 98% (93-99)
  • Reference [9]
RPR sensitivity in syphilis stages
Primary Secondary Latent Tertiary
86% (77 - 100) 100% 98% (95 - 100) 73%

VDRL (Venereal Disease Research Laboratory)
  • The VDRL is a nontreponemal test that detects antibodies against syphilis. The RPR test is typically preferred over the VDRL test for syphilis screening.
  • When testing CSF samples for neurosyphilis, the VDRL test is preferred over the RPR test because it is more sensitive

FTA-ABS (Fluorescent treponemal antibody absorption)
  • The FTA-ABS test is a treponemal test that detects antibodies specific for Treponema pallidum. It is used to confirm a positive nontreponemal test.
  • FTA-ABS is not useful for monitoring disease activity or response to treatment, and it remains positive for life

TP-PA (Treponema pallidum particle agglutination)
  • TP-PA is a treponemal test that detects antibodies specific for Treponema pallidum. It is used to confirm a positive nontreponemal test.
  • TP-PA is not useful for monitoring disease activity or response to treatment, and it remains positive for life

Screening recommendations

Follow-up testing

  • Primary and secondary - perform RPR titer at 6 and 12 months. A fourfold decrease in baseline titer by 12 months is considered treatment success if no symptoms are present.
  • Latent - perform RPR titer at 6, 12, and 24 months. A fourfold decrease in baseline titer by 24 months is considered treatment success if no symptoms are present.
  • Neurosyphilis - recheck CSF every 6 months until normal

Treatment overview

  • Penicillin remains a highly effective treatment for syphilis
  • About 10 - 35% of treated patients will develop a syndrome called a Jarisch-Herxheimer reaction which is marked by fever, rash, malaise, headache, and myalgias that occur within the first 24 hours of treatment. It is typically self-limited and resolves within a day. [2,6,9,10,14,15,18]

Treatment regimens (2021 CDC)

Primary, secondary, and early latent syphilis Latent syphilis Tertiary syphilis
  • NOTE: Bicillin L-A should be used, NOT Bicillin C-R (benzathine-procaine)
Neurosyphilis
  • Preferred: Aqueous crystalline penicillin G 18 – 24 million units per day administered as 3 – 4 million units IV every 4 hours or as a continuous infusion for 10 – 14 days ($$$$)
  • Alternative: Procaine penicillin 2.4 million units IM once daily + probenecid 500 mg orally four times a day for 10 – 14 days ($$$$)

Treatment - Penicillin allergic

Primary and secondary syphilis
  • ✝Azithromycin is a last resort; other treatments are preferred
Latent syphilis Neurosyphilis
  • Ceftriaxone 1 - 2 grams IM/IV daily for 10 - 14 days ($)
  • NOTE: the effectiveness of these regimens has not been studied extensively

Treatment - Other

Primary, secondary, early latent, latent syphilis

Trichomoniasis | T. vaginalis

Overview

  • Trichomoniasis is caused by the protozoan T. vaginalis. It is the most prevalent nonviral sexually transmitted infection.
  • In the U.S, the overall prevalence of trichomoniasis is 2.1% in women and 0.5% in men. Blacks have higher infection rates than other races, with 9.6% of females and 3.6% of males affected.
  • Trichomoniasis has been associated with an increased risk of preterm birth, premature rupture of membranes, and infants who are small for gestational age.

Symptoms

  • Most patients are asymptomatic (85% of women and 77% of men)
  • Female symptoms include malodorous, yellow-green vaginal discharge and vulvar irritation. Male symptoms include urethral inflammation, discharge, burning, and tingling.

Diagnosis

  • Trichomoniasis may be diagnosed by direct microscopic visualization of vaginal secretions, culture of vaginal or urethral (men) swabs, or through Nucleic Acid Amplification Tests (NAATs) performed on swabs and urine specimens
  • Direct microscopic visualization has low sensitivity (50 - 60%). NAATs like the APTIMA T. vaginalis assay have high sensitivities (> 95%) and are preferred. [2,5,11,12,17]

Treatment (2021 CDC)

First line Alternative
  • NOTE: Partners of infected individuals should also be treated

Studies

Single dose Metronidazole vs 7 days of Metronidazole for trichomoniasis, Lancet ID (2018) [PubMed abstract]
  • Design: Randomized controlled trial (N=623 | length = 4 weeks) in women positive for Trichomonas vaginalis infection according to clinical screening
  • Treatment: Metronidazole 2 grams one time vs Metronidazole 500 mg twice daily for 7 days
  • Primary outcome: T vaginalis infection at test-of-cure 4 weeks after treatment
  • Results:
    • Primary outcome: One time dose - 19%, Seven days of treatment - 11% (p<0.0001)
  • Findings: The 7-day-dose metronidazole should be the preferred treatment for trichomoniasis among women


Pricing legend
  • $ = 0 - $50
  • $$ = $51 - $100
  • $$$ = $101 - $150
  • $$$$ = > $150
  • Pricing based on one month of therapy at standard dosing in an adult
  • Pricing based on information from GoodRX.com®
  • Pricing may vary by region and availability