CDC surveillance data show that from 2016 to 2020, increases were observed in syphilis and gonorrhea [1]. More than 20 million new STI cases occurred, with people 15 to 24 years of age accounting for around 50% of new cases. The annual estimated direct medical cost of STIs is $16 billion [2]. Most costs are attributable to HIV ($13.7 billion), chlamydia ($691 million), gonorrhea ($271 million), and herpes simplex virus-2 (HSV-2) ($91 million) [1].

Risk factors also determine STI screening frequency. Sexually active MSM (regardless of HIV status) should be screened for oral gonorrhea and for rectal gonorrhea and chlamydia at least annually (depending on reported sex practices) and every three to six months when risk behaviors persist or if they or their sexual partners have multiple partners [24]. STI risk factors that help determine screening frequency for any given person include [4]:

For decades, partner services programs have been a foundation of state and local public health department STI control. Standard STI partner services identify, locate, and notify sex partners of infected persons to offer referral to evaluation, treatment, and care. The objective of partner services programs is to interrupt the chain of STI transmission at a level sufficient to reduce morbidity, achieved by identifying and treating undiagnosed STIs. Partner services intervene in disease progression (including incubating disease) and prevent serious sequelae, such as congenital syphilis. Partner services also contribute to understanding STI epidemiology by collecting data [31].

The main route of infection is through penetrative sexual intercourse, but chlamydia can be detected in the conjunctiva and oropharynx without genital infection. Chlamydia infection is highly transmittable. Up to 75% of persons become infected by sex partners with chlamydia, but with asymptomatic infection the norm in men and women, most infected persons are unaware of their status. As noted, up to 30% of untreated women develop PID and associated infertility, debilitating chronic pelvic pain, or life-threatening tubal pregnancy. Chlamydia and other inflammatory STIs can facilitate HIV transmission. Infected pregnant women can transmit Chlamydia to their infants during delivery, potentially leading to pneumonia and ophthalmia neonatorum, a cause of blindness [27,36].

Gonorrhea results from infection by the bacterium N. gonorrhoeae and can affect the cervix, uterus, and fallopian tubes in women, and the urethra, mouth, throat, eyes, and anus of both sexes and manifest as urethritis, cervicitis, proctitis, salpingitis, or pharyngitis [1]. If untreated, gonococcal infection may disseminate to distant sites (e.g., joints) and become a life-threatening illness [51,52]. At an estimated 820,000 new infections annually, gonorrhea is the second most commonly reported bacterial STI in the United States [34].

Syphilis is a multistage, multisystem STI caused by infection with Treponema pallidum, a spirochete (i.e., a treponeme) bacterium. Transmission occurs through direct contact with an infectious chancre (lesion) or through vertical transmission during pregnancy. The site of bacterial entry in heterosexual patients is typically genital. In MSM, extragenital sites (e.g., anal, rectal, oral) infected through oral-anal or genital-anal contact account for 32% to 36% of transmissions [69]. The clinical course is highly variable [1].

Untreated syphilis can progress through stages of primary, secondary, latent (early and late), and tertiary disease. Syphilis is infectious and transmittable during early disease (primary, secondary, early latent). Clinical manifestations of syphilis vary by stage [7,51,52,69,70].

Rash, mucocutaneous lesions, and generalized lymphadenopathy, the "classical triad" reflecting multisystem involvement, develop 4 to 10 weeks after the initial chancre [71]. Roughly 1% to 2% of patients develop neurologic complications during secondary syphilis.

Tertiary (late) syphilis occurs 10 to 40 years after initial infection in 33% of untreated patients. Inflammatory lesions can develop in bone (osteitis), skin (gummatous lesions), connective tissues of the cardiovascular system (aortitis, coronary vessel disease), and less often, in the respiratory tract, reproductive organs, lymph nodes, liver, or brain/CNS. This stage is potentially fatal.

Lymphogranuloma venereum is endemic in parts of Africa, India, Southeast Asia, South America, and the Caribbean but occurs sporadically in the United States. Most patients diagnosed with lymphogranuloma venereum are MSM. Lymphogranuloma venereum has been a non-reportable STI in the United States since 1994, and prevalence rates are difficult to estimate. However, lymphogranuloma venereum has been tracked since 2004 in the UK, where 99% of lymphogranuloma venereum cases occur in MSM, frequently involved in dense sexual networks associated with the sex party scene and without obvious link to known lymphogranuloma venereum-endemic countries. MSM show a strong association between HIV and lymphogranuloma venereum, and compared with MSM with rectal chlamydial infection, those with rectal lymphogranuloma venereum are more likely to have proctitis symptoms and HIV infection [91,92,93].

Bacterial vaginosis is the most common cause of abnormal vaginal discharge in women of childbearing age. Normally, hydrogen peroxide-producing lactobacilli are the dominant vaginal bacteria and maintain vaginal pH <4.5. In bacterial vaginosis, the pH rises above 4.5, up to 6.0. Lactobacilli remain present, but flora becomes dominated by anaerobic and facultative anaerobic bacteria in concentrations up to 1,000 times greater than normal. Gardnerella vaginalis and Atopobium vagainae are critical to bacterial vaginosis etiology; other commonly found bacteria belong to Prevotella, Mobiluncus, Clostridiales, Leptotrichia, and Sneathia species and Mycoplasma hominis [99,100]. Risk factors for bacterial vaginosis include frequent vaginal douching, antibiotic use, poor hygiene, receptive oral sex, lack of condom use, multiple or a new sex partner, smoking, presence of STIs (chlamydia or herpes in particular), poorly controlled diabetes, dermatitis, and immune system disorders [102].

Acute epididymitis is inflammation of the epididymis with an acute onset of unilateral testicular pain and swelling, often with tenderness of the epididymis and vas deferens, and occasionally with erythema and edema of the overlying skin. Testis involvement is termed epididymo-orchitis. Sexually transmitted acute epididymitis usually is accompanied by urethritis, typically asymptomatic [117]. Clinicians should be vigilant for non-infectious testicular (spermatic cord) torsion in men who present with a sudden onset of symptoms associated with epididymitis, as this condition is a surgical emergency [117].

Chancroid is an STI characterized by painful genital ulceration and inflammatory inguinal adenopathy caused by infection with Haemophilus ducreyi [1]. Chancroid has been widespread in areas of the world where STI control is inadequate, often transmitted by female sex workers with little access to care. Chancroid can only be transmitted when ulceration is present [124]. The importance of chancroid as an STI became elevated in the 1980s when its role in HIV transmission was apparent; risk of HIV transmission increases by 10- to 50-fold from sexual exposure to a person with H. ducreyi and HIV co-infection [124].

Granuloma inguinale is characterized by slowly progressive, painless, red, raised, and ulcerated skin lesions. Regional lymphadenopathy is uncommon. Common sites of infection include [128,129]:

First identified in the early 1980s, Mycoplasma genitalium causes nongonococcal urethritis in men. It is detected in 10% to 30% of men presenting with nonchlamydial nongonococcal urethritis and up to 40% with chronic nongonococcal urethritis [131]. The recent emergence and spread of M. genitalium are concerning because of increasing antimicrobial resistance to macrolides, the preferred mode of antibiotic treatment. The penicillins, cephalosporins, and other beta-lactam antibiotics disrupt bacterial cell wall synthesis and are ineffective against M. genitalium, which lacks a cell wall [132]. The prevalence of resistance to oral single-dose azithromycin 1 g (the common first-line treatment of urogenital M. genitalium) ranges from 44% to 90% in the United States, Canada, and Western Europe [4,131].

Penicillin is the foundation of antimicrobial treatment for syphilis infection, but some patients have histories of penicillin allergy. The estimated prevalence of penicillin allergy in the United States is 8% to 10%; this may be higher in hospitalized patients [136,137]. Penicillin allergy imposes a therapeutic quandary, because 10% to 15% of these patients are at risk for an IgE-mediated allergic response to penicillin, with anaphylaxis, bronchospasm, urticaria, or angioedema. Anaphylactic reactions to penicillin can be fatal, and penicillin should be avoided in these patients unless they undergo induction of drug tolerance, termed "desensitization," to temporarily eliminate IgE-mediated hypersensitivity [65,138,139,140].

Many patients with a reported history of penicillin allergy have other types of adverse drug reactions or lose their penicillin sensitivity over time, and in these cases, penicillin can be safely used. Because of the increasing evidence that most persons with documented penicillin allergy do not actually have sensitivity to penicillins and associated beta-lactams, clinicians should make efforts to delabel these patients, if at all possible. Penicillin skin testing with the major and minor determinants of penicillin reliably identifies patients at high risk for IgE-mediated reactions to penicillin [139,141]. Many tests have used the major determinants only, but without minor determinants, 1% to 10% of patients with true allergy will show false-negative results and risk serious or fatal reactions to penicillin. Patients with a history of severe non-IgE-mediated reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, interstitial nephritis, hemolytic anemia) are not candidates for skin testing or challenge and should avoid penicillins indefinitely [141,142,143].