Introduction
Sexually transmitted infections (STIs) contribute to the majority of reportable communicable diseases worldwide. More than a million STIs are acquired every day worldwide, with an estimated 357 million new infections annually with gonorrhea, chlamydia, syphilis, or trichomoniasis. Furthermore, there are emerging STIs such as Mycoplasma genitalium and viral STIs such as genital herpes that are highly prevalent on a global scale. The growing threat of antimicrobial resistance in Neisseria gonorrhoeae and M. genitalium underscores the need for enhanced public health strategies, novel diagnostics, and therapeutic agents for STIs.
In 2018, the Centers for Disease Control and Prevention (CDC) reported over 1.7 million cases of chlamydial infections, over 580,000 cases of gonococcal infections, and over 115,000 cases of syphilis in the United States. Adolescents and young adults 15 to 24 years of age account for half of the new STIs that occur in the United States each year. African Americans and men who have sex with men (MSM) in the United States are disproportionately affected by STIs, with the highest rates of bacterial STIs among all other racial/ethnic groups and compared with heterosexual persons, respectively.
A practical approach to STIs requires knowledge of the main clinical syndromes in men and women, including urethritis, vaginitis, cervicitis, pelvic inflammatory disease (PID), epididymitis, and genital ulcer disease (GUD)—and their associated pathogens ( Table 17.1 ). Empiric therapy is generally recommended for STI syndromes to prevent sequelae (such as PID and infertility) and transmission to sexual partners. However, targeted therapy based on diagnostic testing is ideal for persons who are asymptomatic, are likely to return for treatment as needed, and/or are at lower risk for complications (e.g., nonpregnant women or persons not infected with human immunodeficiency virus [HIV]).
| Clinical Syndrome | Major Infectious Agents | Diagnostic Testing Options |
|---|---|---|
| Urethritis (men) | Neisseria gonorrhoeae , Chlamydia trachomatis , Mycoplasma genitalium , Trichomonas vaginalis , herpes simplex virus type 2, adenovirus | POC tests: Urethral swab for Gram stain or methylene blue stain for NG and WBCs (nongonococcal urethritis) NAATs: Urine or urethral swab for NG/CT, MG, TV; lesion swab for HSV if present |
| Urethritis (women) | Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis | POC tests: Vaginal swab for TV by wet mount microscopy; vaginal swabs or urine for rapid TV test Culture: Vaginal swab for TV, urine for culture (as needed) NAATs: Cervical/vaginal swabs or urine for NG/CT, TV Urinalysis and microscopy as needed |
| Vaginitis | Bacterial vaginosis, Trichomonas vaginalis, Candida albicans | POC tests: Vaginal swabs for wet mount microscopy for BV, TV, and Candida ; vaginal swabs for BV Gram stain or sialidase activity (BV); vaginal swabs for TV antigen or helicase dependent amplification tests Culture: Vaginal swab for TV NAATs: Vaginal swabs for TV |
| Cervicitis | Neisseria gonorrhoeae, Chlamydia trachomatis , Mycoplasma genitalium, Trichomonas vaginalis, herpes simplex virus type 2 | NAATs: Cervical/vaginal swabs or urine for NG, CT, MG, TV; lesion swab from HSV if present |
| Pelvic inflammatory disease | Neisseria gonorrhoeae, Chlamydia trachomatis, anaerobic bacteria | NAATs: Cervical/vaginal swabs or urine for NG, CT |
| Epididymitis | Neisseria gonorrhoeae, Chlamydia trachomatis | NAATs: Urine or urethral swab for NG, CT |
| Proctitis | Neisseria gonorrhoeae, Chlamydia trachomatis (including L serovars), Mycoplasma genitalium, Treponema pallidum , herpes simplex virus types 1 or 2 | POC tests: Rectal swab for Gram stain NAATs: Rectal swabs for NG, CT, HSV Dark-field microscopy and serology: TP |
| Pharyngitis | Neisseria gonorrhoeae, Chlamydia trachomatis, herpes simplex virus | NAATs: Oral swabs for NG, CT; lesion swab for HSV if present |
| Genital ulcers | Herpes simplex virus types 1 or 2, Treponema pallidum (syphilis), Haemophilus ducreyi (chancroid), Chlamydia trachomatis L serovars: (lymphogranuloma venereum ) | POC tests: Type-specific serology for HSV Culture: Lesion swabs for HSV NAATs: Lesion swabs for HSV; lesion or rectal swabs, and lymph node specimens for CT (not FDA cleared, but commercially available) Dark-field microscopy and serology: TP Serology: CT/LGV |
| Non-ulcerative genital lesions | Human papillomavirus 6, 11 (genital warts), molluscum contagiosum | Visual inspection Biopsy for lesions that are atypical, have no response to therapy, immunocompromised patients |
Adverse outcomes from STIs in pregnant women include premature rupture of membranes (PROM), preterm birth, neonatal ophthalmic infections, neonatal pneumonia, and fetal deaths. In addition to a heightened risk for complications (e.g., neurosyphilis) among HIV coinfected persons, STIs can increase the risk for HIV acquisition and transmission twofold to fivefold.
The key components of STI management include routinely obtaining sexual history (regardless of age), screening of at-risk individuals, testing of symptomatic persons for definitive diagnosis, initiation of appropriate therapy, and evaluation and treatment of sexual partners. A nonjudgmental approach is important to obtaining a thorough sexual history; clinicians should encourage an open dialogue with patients, with questions regarding sexual practices ( Table 17.2 ). Many individuals with suspected STIs present for initial care at primary care centers, urgent care centers, and emergency departments. Therefore physicians in training and noninfectious disease clinicians can play a vital role in increasing awareness of sexual health issues in their practice, early disease recognition and diagnosis, and optimizing STI management.
| Taking a Sexual History |
|---|
| I am going to ask you a few questions about your sexual health and sexual practices. I understand that these questions are very personal, but they are important for your overall health. |
| Just so you know, I ask all of my patients these questions, regardless of age, gender, or marital status. Like the rest of your visits, this information is kept in strict confidence. Do you have any questions before we get started? |
| Sexual Partners |
| Are you currently sexually active? If no, when were you last sexually active? |
| In the last 2 months, how many sexual partners have you had? |
| Are your sexual partners men, women, or both? (If the patient answers “both,” repeat the earlier question for both genders) |
| Sexual Practice |
| Do you and your partner(s) use any protection against sexually transmitted diseases (STDs)? |
| If so, what kind of protection do you use? |
| How often do you use this protection? |
| Past History of STDs |
| Have you ever been diagnosed with an STD? When? How were you treated? |
| Has your current partner or any former partners ever been diagnosed or treated for an STD? |
| Have you ever been tested for HIV or other STDs? Would you like to be tested? |
| Additional Questions |
| Are you or your partner using contraception or practicing any form of birth control? |
| What other concerns or questions regarding your sexual health or sexual practices would you like to discuss? |
Sexually Transmitted Syndromes
Urethritis
Urethritis (inflammation of the urethra) in men is typically characterized by urethral discomfort and a penile discharge, which may be clear or mucoid, mucopurulent, or purulent in appearance. Traditionally, urethritis has been differentiated into gonococcal or nongonococcal urethritis (NGU). N. gonorrhoeae is most common among men 15 to 24 years of age. Chlamydia trachomatis, M. genitalium, and Trichomonas vaginalis (trichomoniasis) (see Table 17.2 ) contribute to approximately 30% to 40%, 25% to 30%, and 10%, respectively, of infections among men with NGU. Less common causes of urethritis include herpes virus simplex-1 (HSV-1), HSV-2, N. meningitidis , and adenovirus (especially among MSM).
Urethritis in women may occur with concomitant cervicitis and vaginitis due to gonorrhea, chlamydia, or trichomonas. Urethritis should be differentiated from acute cystitis with laboratory testing, which is associated with abrupt onset of dysuria accompanied by frequency, urgency, suprapubic tenderness, or low back pain.
Clinical Presentation
Men may report an acute onset of dysuria, penile itching, irritation, or discomfort 2 to 5 days after sexual exposure, followed by a purulent discharge. Although this presentation is more suggestive of gonococcal urethritis, the color of the discharge may be indistinguishable among the bacterial STIs. A history of symptom onset 1 to 3 weeks after an exposure, accompanied by a scant, mucoid discharge is more consistent with chlamydial urethritis. Patients with NGU may report an intermittent discharge or crusting at the meatus. Despite treatment for NGU, a proportion of men will have persistent symptoms. In these patients, it is important to distinguish reinfections due to repeated sexual exposures from treatment failures.
Women with urethritis may present with dysuria, frequency, and lower abdominal pain. Dysuria may be classified as internal or external (due to contact of urine with the inflamed perineum). The symptoms of classic urinary tract infection such as fever, chills, urgency, and hematuria are not a feature of urethritis.
Evaluation and Diagnosis
The male genitourinary examination should include an inspection of the urethral meatus for erythema or visible discharge; if none is evident, the urethra should be milked from the base of the penis to the meatus. If a Gram stain or methylene blue (MB) stain is available as a point-of-care (POC) test, a calcium alginate swab should be used to collect a sample of the penile discharge at the meatus or from within the urethra by inserting a swab 2 to 3 cm into the urethra and then rolling the specimen onto a glass slide.
The presence of urethritis should be confirmed by one or more of the following findings: (1) mucopurulent or purulent discharge ( Fig. 17.1 ); (2) ≥2 white blood cells (WBCs) per oil immersion field from a urethral Gram stain or MB stain; and (3) a positive leukocyte esterase test on first-voided urine (the first 10 to 15 mL after voiding) or (4) the presence of ≥10 WBCs per high-power field in the spun sediment. Gonococcal urethritis is diagnosed by the finding of Gram-negative intracellular diplococci in the urethral exudate. NGU is defined by the absence of Gram-negative intracellular diplococci and presence of ≥2 WBCs per oil immersion field.
All men with urethritis should undergo testing for gonorrhea and chlamydia, which are typically combined in nucleic acid amplification tests (NAATs) using a first-void urine sample or a urethral swab (see Table 17.1 ) (see sections on gonorrhea and chlamydia). Recently, NAATs for detection of trichomonal infections and M. genitalium in men have received approval from the US Food and Drug Administration (FDA). Patients should also be screened for syphilis and offered tests for HIV. Among men with persistent or recurrent symptoms despite appropriate therapy, the presence of urethritis should be documented by the objective criteria noted earlier, with repeat STI testing depending on the likelihood of reinfection or treatment failure.
Women with symptoms of urethritis and risk for STIs based on the sexual history should undergo evaluation for vaginitis or cervicitis (see later). POC tests should include testing for trichomoniasis with vaginal swabs for wet mount microcopy or rapid testing (see Table 17.1 ). A urinalysis may reveal pyuria and a positive leukocyte esterase due to urethral inflammation, whereas a urinalysis in the setting of cystitis should have accompanying nitrites or blood present. Vaginal or cervical swabs should be obtained for gonorrhea, chlamydia, and T. vaginalis NAATs if POC tests are not available for the latter (see Table 17.1 ). In women, NAAT detection for gonorrhea, chlamydia, and trichomonas can be performed from urine, but have lower sensitivities compared with other specimens.
Treatment
Presumptive treatment for symptomatic patients with objective evidence of urethritis is recommended by the CDC to prevent complications and transmission of associated STIs. Targeted therapy based on NAAT results should be considered for individuals with minimal symptoms or those willing to abstain from sex until after diagnosis and treatment.
If gonorrhea is suspected based on the clinical presentation and/or POC tests, treat with ceftriaxone 250 mg as an intramuscular (IM) injection in the deltoid area plus azithromycin 1.0 g orally in a single dose ( Table 17.3 ). Azithromycin is currently considered part of dual therapy for gonorrhea to minimize the development of antimicrobial resistance; however, azithromycin also has activity against C. trachomatis and M. genitalium. Patients treated with the recommended regimens need not return for a test of cure. However, if patients have persistent symptoms (given there is no reexposure), a culture for N. gonorrhoeae should be obtained and tested for antibiotic susceptibility. There have been concerns regarding increasing drug resistance among N. gonorrhoeae isolates worldwide to available antimicrobials used for treatment, including the fluoroquinolones, which should be avoided for therapy. In the United States, the proportion of gonococcal isolates with resistance to ceftriaxone remains low at <0.5%, but there has been an increase in azithromycin resistance to >4.0%.
| Pathogens | Primary Therapy | Alternative Therapies and Treatment for Recurrences |
|---|---|---|
| Urethritis, nongonococcal | Azithromycin 1.0 g PO in single dose OR doxycycline 100 mg PO BID × 7 days | Levofloxacin 500 mg PO in single dose × 7 days OR ofloxacin 300 mg PO BID × 7 days Persistent NGU: Moxifloxacin 400 mg PO BID for 7 days PLUS metronidazole 2 g PO in a single dose |
| Cervicitis | Ceftriaxone 250 mg IM × 1 PLUS azithromycin 1.0 g PO in single dose | |
| Bacterial vaginosis | Metronidazole 500 mg PO BID × 7 days OR Metrogel 5 g intravaginally once daily for 5 days OR clindamycin cream 5gm intravaginally at bedtime for 7 days | Tinidazole 2 g PO daily for 2 days OR 1 g daily for 5 days OR secnidazole 2 g PO in a single dose OR clindamycin 300 mg PO BID for 7 days Recurrent BV: Metronidazole 2 g PO with fluconazole 150 mg PO in a single dose monthly Metrogel 0.75% twice weekly for 4 to 6 months |
| Pelvic inflammatory disease | Inpatient therapy: Cefotetan 2 g IV every 12 hours PLUS doxycycline 100 mg PO or IV every 12 hours OR cefoxitin 2 g IV every 6 hours PLUS doxycycline 100 mg PO or IV every 12 hours OR clindamycin 900 mg IV every 8 hours PLUS gentamicin 2 mg/kg loading dose IV followed by 1.5 mg/kg every 8 hours Outpatient therapy: Ceftriaxone 250 mg IM × 1 OR cefoxitin 2 g IM in a single dose and probenecid 1.0 g PO administered concurrently in a single dose PLUS doxycycline 100 mg PO BID × 14 days WITH or WITHOUT metronidazole 500 mg PO BID × 14 days | Inpatient therapy: Ampicillin/sulbactam 3 g IV every 6 hours PLUS doxycycline 100 mg orally or IV every 12 hours Outpatient therapy: Ceftriaxone 250 mg IM × 1 PLUS azithromycin 1 g PO every week × 2 weeks OR levofloxacin 500 mg PO once daily OR ofloxacin 400 mg twice daily OR moxifloxacin 400 mg orally once daily for 14 days, PLUS metronidazole 500 mg PO BID for 14 days |
| Epididymitis | Ceftriaxone 250 mg IM × 1 PLUS doxycycline 100 mg PO BID × 10 days | Therapy for STIs and enteric pathogens: Ceftriaxone 250 mg IM in a single dose PLUS levofloxacin 500 mg PO once a day for 10 days OR ofloxacin 300 mg PO twice a day for 10 days Therapy for enteric pathogens: Levofloxacin 500 mg PO once a day for 10 days OR ofloxacin 300 mg PO twice a day for 10 days |
| Proctitis | Ceftriaxone 250 mg IM × 1 PLUS doxycycline 100 mg PO BID × 7 days | Therapy for LGV: Doxycycline 100 mg PO BID × 3 weeks |
For suspected NGU, the recommended therapy is azithromycin 1.0 g orally in a single dose, which provides empiric coverage for both chlamydial and M. genitalium infections. Doxycycline for 7 days may be more effective for chlamydial infections than azithromycin, but achieves only 30% cure rates for M. genitalium. Men with persistent urethritis should receive therapy with moxifloxacin 400 mg orally once daily for 7 days plus metronidazole 2 g orally in a single dose for presumptive azithromycin-resistant M. genitalium and trichomonal infections, respectively (see Table 17.3 ). Women with urethritis but without symptoms associated with cystitis (e.g., urinary frequency) should receive presumptive therapy for STIs, especially if there are signs or symptoms associated with concomitant vaginitis or cervicitis on evaluation. Patients who have persistent or chronic urethritis despite moxifloxacin therapy should be referred to a urologist or gynecologist for an additional evaluation. The differential diagnosis of bacterial cystitis, prostatitis, epididymitis, and Reiter syndrome should be considered in those individuals.
Management
Patients should be advised to abstain from sex or use condoms until they and their sexual partner(s) have been adequately treated, typically for 7 days after single-dose therapy. There is no need for follow-up unless there are recurrent or persistent symptoms.
Sexual partners of persons with urethritis within the preceding 60 days should be evaluated and treated appropriately as the initial patient. For heterosexual men and women with suspected or confirmed gonococcal infections, expedited partner therapy (EPT) can be offered with cefixime 400 mg and azithromycin 1 g orally in single doses. EPT is permissible in 44 states and the District of Columbia and allows the index patient to deliver therapy to the exposed partners. Written materials should accompany the provision of medications to educate partners about their exposure, the importance of therapy, and when to seek clinical evaluation for adverse reactions or complications. EPT may also be provided to sexual partners of index patients with chlamydial infection with azithromycin 1 g orally in a single dose.
Vaginitis
An abnormal vaginal discharge may be due to vaginitis or vaginosis, cervicitis, or occasionally endometritis. The three most common causes of vaginal discharge are bacterial vaginosis (BV), vulvovaginal candidiasis (VVC), and trichomoniasis. An abnormal vaginal discharge may also result from cervicitis caused by N. gonorrhoeae , C. trachomatis , and M. genitalium (see Table 17.1 ). Although controversy remains on whether BV is sexually transmitted, trichomoniasis is one of the most common STIs. VVC is not sexually transmitted, but it is discussed briefly in this section, as it is frequently diagnosed in women with vaginitis.
BV results from a disruption of the normal vaginal flora, which consists primarily of Lactobacillus spp., with anaerobes, Gardnerella vaginalis, and Mycoplasma hominis . Risk factors associated with BV include a history of multiple sexual partners, douching, intrauterine device use, and prior pregnancy. Recurrent BV can occur in 25% to 30% of women due to persistent changes in the normal vaginal microbiome. BV has been known to cause upper genital tract disease, including PID, and has been associated with PROM, preterm labor, preterm birth, low birth weight, chorioamnionitis, and postcaesarean and postpartum endometritis.
T. vaginalis is a protozoan that infects the cervical and vaginal epithelial cells leading to vaginitis and cervicitis. It has also been isolated from the urethra, Bartholin glands, and Skene glands, which surround the vaginal opening and secrete mucus in women. In women, trichomoniasis is also associated with PID, infertility, and adverse pregnancy outcomes, including PROM, premature labor and low-birth-weight infants.
Clinical Presentation
Women with BV usually report an abnormal and malodorous (“fishy smelling”) vaginal discharge that may be grayish or white in appearance without any vaginal irritation. Symptoms more suggestive of VVC include vulvar pruritus and vaginal discharge that may appear white, curdlike, or as a thin watery liquid. Women with acute vaginitis due to trichomoniasis may present with a yellow or green vaginal discharge accompanied with pruritus, dysuria, and dyspareunia (persistent or recurrent genital pain with sexual intercourse). A more chronic vaginal discharge due to trichomoniasis can present as scanty vaginal discharge with mild pruritis and dyspareunia.
Evaluation and Diagnosis
Women with symptoms of vaginitis should undergo a pelvic examination to visualize the vaginal mucosa and cervix and to determine the presence of vaginal and/or cervical discharge. The color and consistency of the vaginal discharge and whether it adheres to the vaginal walls should be noted. The vaginal wall and cervix should be inspected for punctate hemorrhages (called colpitis macularis or “strawberry cervix” ) associated with T. vaginalis , although this is present in only a minority of women with trichomoniasis.
Vaginal fluid should be assessed for vaginal pH (using a pH strip of the vaginal secretions from the speculum) and presence of a fishy odor characteristic of BV. Vaginal specimens should be collected for POC tests (see Table 17.1 ) such as wet mount microscopy (WM), if available. A swab is used to collect material from the vaginal fornix and should be placed into 0.5 to 1.0 mL of normal saline. A drop of the saline preparation is placed on a slide and viewed with a microscope.
BV can be diagnosed based on the pelvic examination and WM using the Amsel criteria, which require three of the following: a homogeneous, thin, white discharge that smoothly coats the vaginal walls; “clue cells” (which refers to vaginal epithelial cells studded with adherent coccobacilli on microscopic examination; Fig. 17.2 ); a pH of vaginal fluid >4.5; and a positive “whiff test,” or a fishy odor of vaginal discharge with the addition of 10% potassium hydroxide (KOH) on the vaginal swab or speculum. A vaginal pH >4.5 and a positive “whiff” test upon the addition of KOH may be present in both BV and trichomoniasis; concurrent infections are common in women with vaginitis.
