From 2014 to 2019, U.S. rates of sexually transmitted infections (STIs) increased for chlamydia (19%), gonorrhea (56%), primary and secondary syphilis (74%), and congenital syphilis (279%).¹ The combined epidemics of STIs and opioid use, compounded by reduced screening and treatment opportunities during the COVID-19 pandemic, will likely further exacerbate this trend. Family physicians can reduce infection rates by discussing sexual history, especially with teens and young adults, ordering screening tests and treatment based on the 2021 Centers for Disease Control and Prevention (CDC) STI treatment guidelines (Table 1²), and collaborating with public health departments for disease reporting and partner services.

Prevention

Taking a thorough sexual history using gender-inclusive and sexual orientation–inclusive language can improve rapport, ensure appropriate screening of all sites of exposure, and allow for a focused and patient-specific discussion of risk reduction. Include the Five P's—partners, practices, protection from STIs, past STIs, and pregnancy intention— in the discussion.³ The U.S. Preventive Services Task Force recommends behavioral counseling with a focus on condom use and decreasing sexual risk behaviors.⁴ Physicians should encourage vaccination against hepatitis A, hepatitis B, and human papillomavirus, as recommended for age and additional risk factors such as sexual acts that risk fecal–oral and blood-borne exposure (Table 2).²

HIV preexposure prophylaxis (PrEP) with emtricitabine and tenofovir alafenamide (Descovy; for those with a creatinine clearance of 30 mL per minute per 1.73 m² [0.50 mL per second per m²] or more, not at risk of vaginal HIV exposure) or emtricitabine and tenofovir disoproxil fumarate (Truvada; creatinine clearance of 60 mL per minute per 1.73 m² [1.00 mL per second per m²] or more) is safe and effective. The U.S. Preventive Services Task Force recommends offering PrEP to individuals at risk, including those who have had gonorrhea or syphilis during the previous six months, those who share drug injection equipment, those who are HIV-negative but whose sex partner has HIV infection, and those with inconsistent use of condoms during receptive or insertive anal sex.⁵

Expedited partner therapy, the provision of medication to sex partners of people with STIs without examination or testing of the partner, has been shown to reduce the spread of infection at the community level and prevent reinfection of the index case.^6,7 The American Academy of Family Physicians advocates for the use of expedited partner therapy whenever possible to help address increasing rates of STIs. ⁸ Cefixime (Suprax), with a dosing increase to 800 mg, is the recommended expedited partner therapy regimen for gonorrhea (Table 1²), with the addition of doxycycline, 100 mg twice daily for seven days, if concurrent chlamydia has not been excluded. There are no changes to the recommended expedited partner therapy regimen for chlamydial infection (i.e., 1 g of azithromycin [Zithromax] in a single oral dose or 100 mg of doxycycline given twice daily for seven days).

ANTIBIOTIC STEWARDSHIP

The new guidelines highlight antibiotic stewardship in addressing patient-reported penicillin allergy.² Although as many as 10% of patients report a penicillin allergy, 90% of those patients tolerate penicillins when allergy tested.⁹ Physicians should carefully define allergies, separating those with reactions mediated by immunoglobulin E (IgE) from those experiencing common adverse effects. The PEN-FAST rule is a validated clinical tool to guide risk assessment and treatment decisions (Table 3).⁹ Physicians should use ceftriaxone and penicillins when risk of true allergy is low and consider penicillin allergy testing for those with possible allergy to preserve treatment options.

Urethritis and Cervicitis

Urethritis is characterized by dysuria, urethral pruritus or burning, and/or visible discharge. Neisseria gonorrhoeae and Chlamydia trachomatis are the most common causes, but Mycoplasma genitalium is increasingly recognized as an important cause of urethritis, particularly in patients presumptively treated for chlamydial infection with persistent symptoms.¹⁰ Patients with suspected urethritis should be evaluated for gonorrhea and chlamydia using nucleic acid amplification testing, and patients with persistent symptoms should be tested for M. genitalium infection.^2,11 Other causative organisms, including Neisseria meningitidis and Trichomonas vaginalis, have also been implicated in urethritis.

Patients with cervicitis are often asymptomatic; vaginal discharge is variable, and clinical examination may reveal mucopurulent cervical discharge, hyperemia, ectopy, or friability. C. trachomatis and N. gonorrhoeae are the most common etiologies. Untreated infection can progress to the upper genital tract, causing pelvic inflammatory disease.

Ceftriaxone monotherapy is now recommended as the treatment of choice for gonorrhea (Table 1²). Previous CDC guidelines recommended routine dual-therapy regimens in an effort to stave off emerging drug resistance. However, new guidance reflects concerns for antimicrobial steward-ship and potential harm from overuse of antibiotics. Thus, co-treatment for gonorrhea with azithromycin or doxycycline is no longer recommended. Test-of-cure is not necessary for people with urogenital or rectal gonorrhea but is recommended 14 days after treatment for patients with pharyngeal infection.

Doxycycline has emerged as the treatment of choice for chlamydial infections (Table 1²). Recent clinical trials and meta-analyses showed higher rates of microbiologic treatment failure among men and women treated with azithromycin compared with doxycycline.^12–14 Azithromycin, 1 g in a single oral dose, remains an alternative regimen and is the recommended treatment for pregnant patients. It may also be considered for those with confidentiality concerns or those unable to adhere to seven-day regimens.

Patients diagnosed with M. genitalium should ideally be treated in a two-stage approach using resistance-guided therapy. Initial treatment with doxycycline reduces organism load and facilitates organism clearance, followed by either azithromycin if the M. genitalium isolate is macrolide-sensitive or moxifloxacin (Avelox) if the isolate is macrolide-resistant or if resistance testing is unavailable (Table 1²).

Extragenital Infection

Chlamydia and gonorrhea are also causes of extragenital infection (e.g., rectum, pharynx).^15,16 Pharyngeal gonorrhea is mostly asymptomatic, fairly common, and a major driver of community spread with the potential to increase antibiotic resistance. Several studies have shown markedly increased detection of infection with universal extragenital testing in sexually active patients.^15,17 Rectal chlamydia is as common in cisgender women as in men who have sex with men, even in those who do not report receptive anal intercourse.¹⁸ Wider use of nucleic acid amplification testing to screen for asymptomatic rectal and pharyngeal infection is recommended, including the option of patient-collected specimens, which are reliable and have high patient acceptability.^19,20

STIs involving the rectum can cause proctitis or proctocolitis, characterized by anorectal pain, tenesmus, rectal discharge, diarrhea, or abdominal cramping. The most commonly detected pathogens are N. gonorrhoeae, C. trachomatis, Treponema pallidum, and herpes simplex virus (HSV). Diagnosis is ideally achieved through anoscopy, with Gram stain smear of anorectal exudate and nucleic acid amplification testing for gonorrhea, chlamydia, and HSV and serology for syphilis. Recommended empiric treatment for acute proctitis is ceftriaxone and doxycycline (Table 1²). If C. trachomatis is detected and the patient has severe symptoms suggestive of lymphogranuloma venereum (rectal ulcers, anal discharge, bleeding, tenesmus), doxycycline should be continued for 21 days. Further treatment should be directed toward specific pathogens that are identified.

Vaginitis

Vaginitis tops the list of gynecologic diagnoses in primary care.²¹ Bacterial vaginosis, a vaginal dysbiosis with a predominance of anaerobic bacteria replacing the Lactobacillus species, is the most common cause of vaginal discharge. Having bacterial vaginosis increases the risk of STI acquisition, including HIV ²²; however, testing and treatment are recommended only for symptomatic patients.^2,23 The U.S. Preventive Services Task Force recommends against routine screening of asymptomatic patients, including pregnant people not at risk for preterm delivery.²³ Data are still limited for how to best address recurrent bacterial vaginosis. The new guidelines offer options for suppressive therapy with various regimens (Table 4).²

Trichomoniasis, caused by Trichomonas vaginalis, is the most common nonviral STI; rates are highest in women 40 years and older.^24,25 Vaginal infection is often asymptomatic and can last years. Physicians should test symptomatic patients with vaginal discharge at presentation and annually test asymptomatic women who have HIV. Also, physicians should consider testing asymptomatic patients in high-prevalence settings and those with risk factors for STI. Although wet mount is commonly used at low cost, it has low sensitivity.^26,27 A negative result on wet mount should be confirmed with higher sensitivity molecular diagnostic testing. Vaginal infection is treated with a seven-day course of metronidazole (Flagyl), 500 mg twice per day, because this shows superior effectiveness compared with the previous single 2-g dose recommendation.²⁸ Penile infection should be treated with a single 2-g dose of metronidazole. Partners should be referred for presumptive treatment with consideration of expedited partner therapy where permissible by law. Persistent trichomoniasis should be treated, after confirming no risk of reinfection, with increased daily dosing of 2-g metronidazole or tinidazole for seven days. For further persistence without reexposure risks, drug-resistance testing is recommended.

Ulcerative Disease

Genital herpes and syphilis are the primary causes of genital ulcers in at-risk sexually active patients in the United States.² Both infections can also present as oral or perianal ulcers. Less common infectious causes include Haemophilus ducreyi (chancroid); C. trachomatis serovars L1, L2, and L3 (lymphogranuloma venereum); and Klebsiella granulomatis (granuloma inguinale [donovanosis]). A complete evaluation should include syphilis serology and HSV type–specific testing from the lesion. While awaiting test results, presumptive treatment of syphilis is important to reduce the risk of community transmission and of HSV to maximize effectiveness of therapy. The choice of presumptive therapy directed at syphilis or HSV should be guided by clinical presentation with consideration to syphilis incidence in the local population.

HSV-1 and -2 can cause anogenital ulceration. Confirming the type of HSV helps guide prognosis because HSV-1 presenting as genital lesions is less likely to recur. When collecting samples from a lesion, HSV nucleic acid amplification testing is more sensitive than culture, especially in the case of recurrent disease and healing lesions. HSV-2 antibody testing can aid in diagnosis when a clinical history is suspicious for genital herpes, but active lesions are not present, and it may be helpful to test and counsel partners of symptomatic patients with HSV-2.²

Syphilis rates continue to show an alarming upward trend. Although predominantly occurring in men who have sex with men, especially men of color younger than 30 years, an increased number of syphilis infections are occurring in women.¹ With more infections in women of reproductive age, congenital syphilis rates are rising sharply.¹ Physicians should test pregnant people with risk factors at intake, at 28 weeks' gestation, and at delivery (Table 5).² Many laboratories have transitioned to “reverse sequence syphilis screening,” in which an automated treponemal antibody test (e.g., enzyme immunoassay) is performed first, followed by a nontreponemal test (rapid plasma reagin [RPR] or Venereal Disease Research Laboratory [VDRL] test) for confirmation. Advantages include the ability to perform high volume testing quickly, earlier detection in recent infection, and increased detection of latent infection.²⁹ The risk of the reverse sequence algorithm is false-positive treponemal testing, especially in low-risk populations, that requires additional confirmation. Nontreponemal antibody titers (RPR/VDRL) decline over time and with treatment; thus, they are important for following treatment response and diagnosing reinfection. For patients with a history of previously treated syphilis infection, a fourfold increase in RPR or VDRL titer suggests reinfection and warrants repeat treatment. Treponemal antibodies, meanwhile, typically remain positive for life and are not helpful following initial diagnosis.

Preferred treatment remains parenteral penicillin G benzathine, 2.4 million units, with a single intramuscular dose given for infection of less than one year's duration, whereas infection persisting more than one year or of unknown duration should be treated with three consecutive weekly doses of 2.4 million units each. Physicians should ensure that the correct formulation of penicillin G benzathine (Bicillin L-A) is given for intramuscular injection. Erroneous substitution of shorter-acting penicillin G benzathine/penicillin G procaine (Bicillin C-R) does not adequately treat syphilis. A thorough evaluation for otic, ophthalmic, and neurologic symptoms is essential for anyone with syphilis because these complications can occur at any stage and require 10 to 14 days of treatment with intravenous aqueous crystalline penicillin G.

Health System Considerations

The COVID-19 pandemic brought multiple challenges to health care systems, including temporary clinic closures and shortages of staff, medications, and diagnostic testing kits.³⁰ These challenging times spurred innovations, such as telemedicine assessment and treatment of STI symptoms, patient-collected STI testing, and enhanced partnerships with pharmacies to provide injectable antibiotic treatment.³⁰ Disease intervention specialists, long employed in STI care, have provided a foundation for COVID-19 contact tracing. Collaborating with local public health entities and complying with mandatory reporting programs are crucial to combat rising rates of STIs. Additional free resources for physicians include the CDC 2021 STI Tx mobile app, the STD Clinical Consultation Network (https://stdccn.org/), and CME with the National STD Curriculum (https://www.std.uw.edu/).

This article updates a previous article on this topic by Van Vranken.³¹

Data Sources: The primary source for this article was the 2021 Centers for Disease Control and Prevention STI Treatment Guidelines published July 23, 2021. A PubMed search was completed using the key terms sexually transmitted infections, extragenital, chlamydia, gonorrhea, and prenatal syphilis screening. Additional searches included Essential Evidence Plus, U.S. Preventive Services Task Force, and the Cochrane database. Search dates: April 2020; August 2021; and February 28, 2022.