Master the diagnosis and management of common STIs (sexually transmitted infections) with tips from expert, Dana Dunne MD, Associate Professor of Medicine in Infectious Diseases at Yale. Topics include: the stages and many presentations of syphilis, syphilis treatment and counseling, the natural history, diagnosis, and screening guidelines for gonorrhea and chlamydia, treatment options in the age of growing resistance, and a discussion of partner notification and treatment.
Written and produced by: Bryan Brown MD
Hosts: Bryan Brown MD, Paul Williams MD, Matthew Watto MD
Guest: Dana Dunne MD
Special thanks to Kate Grant MBChB, Dip GUMed for her contribution of knowledge and artwork.
ALL STI guidelines for USA and UK can be accessed through the following links
While it is easy to remember to take a sexual history when a patient presents with a genital complaint such as urethral or vaginal discharge, it is also important to make routine sexual history part of everyday practice. A key example is in evaluation of rash.
Consider starting with open-ended questions like “I’m going to ask about your sexual partners.”
After contact with an infectious lesion on an infected individual, there is a 30% likelihood that the exposed person will contract syphilis. The average incubation from contact to the chancre is about 30 days, but ranges from 10 to 90.
Primary syphilis presents classically with a solitary lesion called a chancre. The chancre starts as a papule at site of inoculation. This usually occurs on mucous membranes, with common sites including the lower third of labia and penile shaft. Chancres can also form in the anus in those exposed through anal receptive intercourse, and can also occur in the mouth after receptive oral intercourse. There are case reports of lesions on the breast and hands, but these are rarer. A chancre will disappear without any treatment in 2-8 weeks.
Over time, the initial papule ulcerates, yet is classically painless. It is sometimes referred to the “hard chancre,” because it is firm if squeezed. This firmness and painlessness are attributable to T. pallidum’s ability to produce a more limited immune response, with some plasma cells, lymphocytes, and the deposition of collagen. In Dr. Dunne’s words, it does not make “much of a ruckus.” A mimicking condition caused by a Haemophilus species called “chancroid” is softer, painful, and more purulent, which are attributable to the more robust immune response this organism creates compared to syphilis.
Spirochetes then replicate again and disseminate hematogenously. Collectively, the manifestations of this spread to distant sites are termed secondary syphilis.
One key, typical symptom of secondary syphilis is a rash. This rash can be found diffusely over the body or in more limited distributions, sometimes only a few macules. Importantly, this rash can involve the palms and soles, though only does so about half the time. In other words, involvement of the palms and soles in a host with risk factors should generate a high positive predictive value for syphilis, though the absence of this finding may not fully exclude the possibility. The typical lesions of this rash are copper-colored macules, though can appear more hyperpigmented in people of darker skin. In Dr. Dunne’s experience, these macules seem to be more hyperkeratotic in patients with HIV. The dry lesions on the palms are not high yield for seeing organisms on dark field. Thus, Dr. Dunne would not be concerned about shaking hands in the context of these lesions, and there has not been a signal identified for nosocomial spread via this route.
Oral lesions may also be noted in secondary syphilis (note that this is regardless of whether direct exposure or chancre formation occurred in the mouth). “Mucus patches” are lesions found often on the lips, tonsils, or posterior pharyngeal wall, which may have the appearance of “snail tracks” crawling over the area. These lesions can be subtle in appearance, yet are highly infectious.
In the scrotum, secondary lesions can form which initially may be subtle. They may initially mimic tinea cruris or eczema, and thus be easy to miss. Eventually, some patient develop heaped up lesions in intertriginous areas under breast, groin, gluteal cleft known as Condylomata lata. These are whiter, flat-topped, and may resemble warts. These are particularly teeming with organisms and thus infectious.
Alopecia areata, a form of patchy hair loss, may also be seen.
In addition to mucocutaneous manifestations, secondary syphilis may also impact other organ systems.
Secondary syphilis affecting the nervous system is referred to as “symptomatic early neurosyphilis.” This may include various cranial nerve palsies, including sensorineural hearing loss with or without vertigo. Aseptic meningitis may also occur. In Dr. Dunne’s experience, some such patients may experience mild constitutional symptoms like malaise and adenopathy. Consequently, patients may attribute their symptoms to a respiratory virus and not present for care.
Ocular syphilis may manifest as anterior or posterior uveitis. Do not forget to consider syphilis in an at-risk host. Take a sexual history when a patient presents with an ocular concern.
Syphilitic hepatitis may develop, which classically presents with an alkaline phosphatase elevation out of proportion to transaminase elevation.
Nephrotic syndrome may also occur!
Latent syphilis refers to those people infected beyond the period of primary and secondary infection. In other words, these patients will have diagnostic tests consistent with ongoing infection, have not been previously treated, and will not have symptoms consistent with primary or secondary syphilis.
Early latent syphilis is a term for patients who meet criteria for latent syphilis, but are within one year of initial infection. The reason for making this delineation is the effect on treatment. These patients can be treated with a single dose of penicillin identical to the regimen for primary or secondary syphilis. The onus is on the provider to become confident that the patient is within this window, either via documented seroconversion (i.e. negative a year or less ago and now found to be positive), documented or confidently reported prior symptoms that have since resolved (e.g. “I had a chancre six months ago”; “I had a syphilis infection in my eye three months ago and now I have no symptoms”).
For any patients for whom the time since infection has been longer than one year or the timing is unknown, they are presumed to have late latent syphilis, and thus would require the full regimen e.g. once weekly doses of penicillin for three weeks.
Of those with latent syphilis, 25% will go on to have late syphilis. Manifestations include:
NOTE: Patients with late syphilis should be referred to an infectious diseases specialist.
Acute HIV could also manifest as rash with vague constitutional symptoms in a host with similar risk factors.
Disseminated gonococcus may also cause rash, and has similar risk factors. Rather than the often-diffuse, more symmetrically distributed rash of syphilis, disseminated gonococcus usually causes tender pustules with a few peripheral lesions.
Rocky Mountain Spotted Fever is on the differential, particularly as another cause of rash involving the palms and soles. Host factors that should increase pretest probability include tick bites, or hiking. Of note, RMSF is not commonest near the Rocky Mountains, but rather in the mid-Atlantic states and in states around the Mississippi River Valley.
Atypical Measles is another syndrome of rash and fever, myalgias, and headache that may resemble the above, but is rare in the era of modern immunization programs.
The exact algorithm might differ depending on place of work and what that laboratory has established. Generally, two serologic tests are needed to make the diagnosis of syphilis. Using only a single type of test is insufficient. Syphilis serologic tests come in two main groups: Treponemal and nontreponemal tests.
These test for antibodies that are not specific for T. pallidum. They are found in associated with the immune response to this pathogen, as well as certain other conditions. Another benefit of the nontreponemal test is that it is quantitative, and the titre of positivity may reflect the level of immune activity, and thus contribute to understanding of disease activity and prior treatment. In addition, repeating the titre can help confirm cure, with a four-fold titre reduction representing appropriate response to penicillin treatment.
Historically, these include VDRL and RPR, which are essentially different versions that serve the same clinical purpose. They are both nonspecific, and may also be turned positive in other systemic diseases such as tuberculosis, rickettsial diseases, and endocarditis, as well as during pregnancy (Henao-Martínez et al. Neurology Clinical Practice 2014).
Historically, these non-treponemal tests were easier to run, and thus the traditional algorithms recommended beginning with the VDRL or RPR. If a patient has a positive non-treponemal test, they need to be followed up with a treponemal test.
These antibodies react directly to the organism. Thus, they are more specific tests. There are many types of treponemal tests.
Historically, the T. pallidum Particle Agglutination test, or TPPA, was formed. The CDC had recommended that if starting with non-treponemal, confirm with TPPA. TPPA was notably labor intensive, explaining why the traditional algorithm started with VDRL or RPR as described above. However, there are now newer treponemal tests that are easier to perform on large scale, taking advantage of chemiluminescence, ELISA, etc. See the reverse algorithm explanation below.
For the most part, the treponemal antibody stays positive forever. A few early exposures will get treatment and clear their treponemal antibody but that is the exception rather than the rule.
Perform the more specific *treponemal antibody test first. Then, if this is positive, reflex to a nontreponemal test (i.e. VDRL or RPR) to confirm. If this is also positive, the patient has or has had syphilis. As described above, the quantitative interpretation of the nontreponemal test may provide a hint to whether the patient has received prior treatment, though history from the patient or state health department records of prior treatment are also helpful.
The treponemal antibody test is an EIA test specific for T. pallidum. It is not the same as the labor intensive TPPA test, which is now only used as a “tie-breaker” when there is a discordance between the treponemal antibody and the nontreponemal (VDRL or RPR) tests.
If the first two tests (one treponemal and one nontreponemal) are discordant and the “tie-breaker”, TPPA, test is positive, then there are multiple possibilities.
The patient had a previous exposure and received treatment.
The patient has long standing infection and was NEVER treated. In some patients who have been exposed, even without treatment, the immune response to the spirochete becomes so quiescent that the nontreponemal test turns negative.
In an extremely recent exposure, the treponemal antibodies are positive, but the nontreponemal tests lag behind until the immune system mounts a response.
To stage the patient’s syphilis in conjunction with the test results, the history and physical is key. A thorough exam looking for stigmata of secondary syphilis as described above is appropriate. If no signs or symptoms, but both tests are positive, then the patient is presumed to have latent syphilis, and further characterized into early vs. late as described above.
This varies by state. Some states have dual reporting – lab and provider. The key is to know whether your state has only lab reporting or provider too. Dr. Dunne recommends identifying and reaching out to infection control providers or similar at your institution to learn the details in your state and health system.
This also varies by state. Syphilis is currently a high priority for public health departments, especially in patients with primary or secondary syphilis. These patients are highly infectious. Dr. Dunne encourages us to have the number for reporting to their state on speed dial.
Sex should be avoided for a week after syphilis treatment to ensure that the patient is no longer infectious.
Counsel patients that they might get the Jarisch-Herxheimer reaction with treatment. Acetaminophen should mitigate these symptoms. Throat swelling is more consistent with true allergy, and should be treated in an ED.
Counsel patients to reduce their number of partners, seek routine screening, and use condoms every time. Encourage partner testing.
Remind the patient that syphilis and other STIs can be transmitted through oral contact as well.
Test for HIV, other STIs. Discuss pre-exposure prophylaxis PrEP for HIV.
Gonorrhea, Chlamydia, and related conditions
Most people with any STI you can name have no symptoms. A basic principle is that many carriers of these pathogens are asymptomatic even while spreading to others. This justifies the need for screening asymptomatic women since complications can include pelvic inflammatory disease (PID) and infertility.
Men are more likely to be symptomatic with GC than chlamydia. Women are even more likely to be asymptomatic with either GC or chlamydia. But if symptoms are present, GC can give more bleeding between periods or heavy bleeding; discharge; and infections of accessory sex glands. Similarly, when subsequent pelvic inflammatory disease (PID) occurs in women, GC-related PID can be more acute, with more abscesses than chlamydia.
If under 25 and sexually active, screen for GC and chlamydia. This recommendation is supported by the age distribution for these infections. Namely, a very large percent of chlamydia occurs in this age group. https://www.cdc.gov/std/stats17/adolescents.htm
There are no guidelines for screening asymptomatic men in the USA, but there are in the UK, see link below. However, if a patient has a symptom, or requests screening (usually in the context of a new sexual partner or concern about exposure), they should be offered screening..
Ask where in the body may have been exposed. Explain that these questions are needed to know where to check for these infections. Dr. Dunne emphasizes that providers and trainees need to be practiced in explaining that this is not just “idle curiosity,” but rather a practical need to know where to put the swab.
Nucleic Acid Amplification Testing (NAAT) is now widespread. NAAT has a very high sensitivity, but specifically for the local site of exposure.
In men who are at risk for penile exposure, a urine NAAT for GC/chlamydia is highly sensitive. In particular, a “first catch specimen” should be acquired to preferentially sample the urethra. To do so, the patient directs their initial urinary stream into the specimen container, and then subsequently completes the void into the toilet.
In women who engage in vaginal intercourse, the urine NAAT is less sensitive, though may still be considered in a female patient specifically with urethritis symptoms like dysuria or discharge. Otherwise, an NAAT vaginal swab should be performed. In fact, women can be counseled to self-perform the vaginal swab, and this method has been FDA approved. Specific instructions can be found online or with the swab packaging. Generally, the swab is inserted similar to a tampon and swabbed around the vaginal canal for about twenty seconds, then removed and placed in a tube.
Similarly, for patients with potential anorectal exposure to STIs, an NAAT swab can be inserted by the patient or provider 2-3 cm into the rectal area. For patients with oropharyngeal exposure, the NAAT swab can be performed in a fashion resembling a throat culture such as those for strep pharyngitis. Dr. Dunne noted that epidemiologically, most rectal and pharyngeal GC/chlamydia has been in MSM, however some has occured in WSM, especially those with multiple partners or engaging in commercial sex work.
Dr. Dunne noted an exciting example of innovative, high-throughput, confidential STI screening being advertised in England. Their advertisement is found here: https://www.youtube.com/watch?v=UcUx6dbfTQ8
In practicality, many sites do not have the ability to perform gram stains. Often this requires proximity to an academic or large hospital with a laboratory that has completed the special approval process. Dr. Dunne considers it highly useful when available. It’s highly sensitive in symptomatic men. Additionally, patients are treated syndromically when a gram stain is lacking. Thus, they receive broader antibiotic coverage than is always indicated. Using a gram stain to rule out GC helps focus the treatment.
If your patient has expressible discharge, then send it for a STAT gram stain (if your lab can perform gram staining). An endourethral swab is not needed! Express some discharge, stain it, then still have the patient urinate in the cup for the NAAT.
Patients should be rescreened in three to four months. NOT for a “test of cure”, but rather to check for reinfection. In addition to treating the reinfection, this practice provides information about partners who may be the cause for reinfection and thus, need treatment.
NOTE: Test of cure should be performed 3-4 weeks after treatment.
Download the CDC’s STD Tx Guide App for free. It provides recommendations for first line and alternative treatments for GC, chlamydia, trichomoniasis, and other pathogens. Information is available about Unique clinical scenarios such as evaluating epididymitis, proctitis, and victims of sexual assault. Alternative treatments for allergy and pregnancy are included.
***NOTE: All of the front line regimens for these STIs in the CDC guidelines are single-day regimens. The main goal of this is adherence. For example, Dr. Dunne noted that a 7-day course of doxycycline as an alternative for chlamydia coverage had about 38% adherence.***
When GC has been ruled out (eg no diplococci present on gram stain). Give azithromycin 1 g orally in a single dose is first line. Alternate regimen = doxycycline 100 mg orally twice daily for 7 days (CDC 2015 Guidelines).
For suspected or confirmed localized GC infection (i.e. urethritis, cervicitis, and pharyngitis), single-dose ceftriaxone 250 mg IM PLUS azithromycin 1 g orally in a single dose is recommended. Alternative regimen = cefixime 400 mg orally in a single dose PLUS azithromycin 1 g orally in single dose. NOTE: Other sites of local infection such as proctitis and epididymitis, as well as disseminated GC, have differing recommendations for first line drugs and durations.
These have slightly different treatment regimens. Can be accessed through this link, with useful patient Info leaflets available also. British guidelines
The rise of antibiotic resistance in N. gonorrhoeae. ecdc-first-detected-cases-extensively-drug-resistant-gonorrhoea-threaten-future***. The CDC considers multidrug resistant gonorrhea to be an emergency. Thus, their recent GC treatment guidelines recommend the use of ceftriaxone (CTX) AND azithromycin, NOT to cotreat for chlamydia, BUT to double cover in case of resistant GC!!! In other words, if the CTX doesn’t get it, the macrolide might. Resistant strains of gonorrhea may require treatment with a carbapenem.
This organism has been increasingly appreciated as an independent predictor of cervicitis, male urethritis, PID, and adverse birth outcomes. There is a NAAT which has undergone some field testing but is not widely available in the USA or UK. It is something that will be increasingly available to test for in symptomatic patients, but the studies do not yet exist to justify any recommendations of screening in asymptomatic individuals. Of note, if non-GC urethritis is treated, the first line would be azithromycin which would cover most M. genitalium as well as chlamydia. However, in non-responders to azithromycin for non-GC urethritis, consider multiple possibilities: 1) trichomonas, as this organism has recently been shown to be responsible for far more male urethritis than previously appreciated, and 2) azithromycin-resistant mycoplasma. In this subset, there are small studies to show moxifloxacin is most effective. Dr. Dunne notes that doxycycline would not be as effective for these patients.
Jensen JS, Cusini M, Gomberg M, Moi H. 2016 European guideline on Mycoplasma genitalium infections. Journal of the European Academy of Dermatology and Venereology 2016; 30(10): 1650-6.
CDC Guidelines on emerging issues in treatment of M. Genitalium emerging.htm
BASHH guidelines Non-Gonococcal Urethritis https://www.bashh.org/guidelines
It is the provider’s duty to encourage partner notification. Use your local disease intervention specialists as a resource on how to approach partner notification in your area.
EPT now has legislative approval in the U.S. A physician is permitted to write a prescription for the partner of an infected patient. Depending on the state, a provider has more explicitly clarified prescription laws, which allow the writing or calling-in of treatment for up to three partners of the patient. Dr. Dunne noted that there are informational sheets available online for many states, which generally state that the partner should probably go to a clinic for full evaluation. Side effects and anticipatory guidance would also be delineated. Under this legislation, as long as this information is relayed, the physician will not be held accountable for the fact that he or she has not met the partner. Importantly, an honest, separate prescription should be written for the partner, rather than trying to double the number of pills in the one prescription for the patient.
The ability prescribe ceftriaxone as EPT varies by state. Some states only approve this for heterosexual couples because of opportunity loss if MSMs do not present to care and miss a screening opportunity for HIV and syphilis. In heterosexual couples, oral cefixime can be used as a substitute for ceftriaxone, under the condition that a negative pharyngeal swab can be acquired to prove genitorectal infection only. In light of the added complexity of EPT for GC, some states may only allow EPT for chlamydia. In summary, discussing local practices with a local expert in STIs is advised!
In the UK, patients are encouraged to discuss with partners, but confidential Contact Tracing is routinely offered by each clinic. No antibiotics are provided for contacts without first being seen.
Listeners will develop a both a practical and evidence based approach to the management of Syphilis, Gonorrhoea and Chlamydia
After listening to this episode listeners will…
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What?! "A gram for the clam." That didn't get a laugh out of you guys!?! Nothing but crickets after she delivered that one. You boys should be embarrassed. But seriously, thanks for another great episode chock full of the good stuff. I really appreciate your efforts.
Excellent Podcasts Thank You