Which one of the following is the preferred method to diagnose chlamydial urethritis in men?

Gonococcal and Nongonococcal Urethritis

The classic specific etiologic agent of acute urethritis isN. gonorrhoeae. Urethral infection of all other causes is referred to collectively as NGU (Table 107.3). As with gonorrhea, NGU is a sexually acquired condition. NGU is more common than gonorrhea in the United States and in much of the developed world. In some developing areas, however, gonorrhea accounts for up to 80% of cases of acute urethritis.23–25 Similar to many other sexually transmitted diseases (STDs), gonococcal urethritis and NGU have an increased incidence during the summer months, presumably because of a seasonal increase in sexual activity.

Compared with gonococci, the organisms that cause NGU may be relatively less prevalent among MSM than among heterosexual men with urethritis. In a study of men who had urethritis, Ciemins and colleagues26 recovered gonococci from 45% of MSM and from 26% of men who have sex with women. Examining consecutive men attending an STD clinic, Stamm and colleagues27 recovered gonococci from 12% of heterosexual men and 25% of MSM; in contrast, chlamydiae were recovered from 14% of heterosexual men but only 5% of MSM. Other studies demonstrate similar findings.28–30 Studies have associated fellatio with the acquisition of gonococcal urethritis and NGU in MSM but not in heterosexual men.31,32

Urethritis may facilitate transmission of human immunodeficiency virus (HIV). Among patients infected with HIV, the quantity of HIV in urethral secretions is increased if the man has concomitant chlamydial or gonococcal urethritis. Treatment of urethritis reduces the urethral viral load.33

The clinical spectrum of gonorrhea differs from that of NGU, but there is sufficient overlap that an accurate diagnosis must be based on examination of the urethral specimen. Of men who acquire urethral gonorrhea, 75% develop symptoms within 4 days, and 80% to 90% do so within 2 weeks.34 The incubation period for NGU is much more variable and is often longer. Incubation periods ranging from 2 to 35 days have been described, but almost 50% of men with NGU developed urethral symptoms within 4 days.34 Therefore an incubation period of less than 1 week is not a reliable factor in the differential diagnosis. The incubation period of either infection can be prolonged by the ingestion of subcurative doses of antibiotics.

The urethral discharge is described as frankly purulent in three-fourths of patients with gonorrhea (Fig. 107.2) but in only 11% to 33% of patients with NGU.7,35 A purulent discharge issuing from the meatus without stripping of the urethra correlates strongly with the diagnosis of gonorrhea but is also seen in 4% of patients with NGU.7,35 Mucopurulent discharge (Fig. 107.3), consisting of thin, cloudy fluid or mucoid fluid with purulent flecks, is seen in about 50% of patients with NGU but in only 25% of patients with symptomatic gonorrhea.7,35 The discharge is completely clear and moderately viscid in 10% to 50% of patients with NGU, principally patients who are minimally symptomatic, but in only 4% of symptomatic patients with gonorrhea.7,35,36 A diagnosis based on the clinical characteristics of the urethral discharge is unreliable and correctly identifies the causative disorder in only 73% of all cases, even under optimal circumstances.35 Microscopic examination always should be part of the initial evaluation.

Cervicitis and Urethritis

The cervix is the most common site ofC. trachomatis infection in women. Indeed, mucopurulent cervicitis caused byC. trachomatis has been called the female counterpart of male NGU.125 However, only a minority of patients have the classic presentation of mucopurulent cervicitis with discharge of mucus and pus from the cervical os and easily induced endocervical bleeding by gentle passage of a cotton swab through the os.125,311 Instead, approximately 70% of women with endocervical infection are asymptomatic or have mild symptoms, such as vaginal discharge and bleeding, mild abdominal pain, or dysuria.270 Vaginal discharge is likely due to endocervical rather than vaginal infection becauseC. trachomatis cannot infect the squamous epithelium of the adult vagina. However, vaginitis can be present in girls because the vagina is lined with transitional cell epithelium before puberty. Dysuria may reflect concurrent urethral infection. On examination, the cervix may appear normal or may exhibit edema, erythema, and hypertrophy. Diagnostic testing with a NAAT is necessary to distinguish betweenC. trachomatis andN. gonorrhoeae as the two common causes of cervicitis.

Acute urethral syndrome is defined as dysuria and urinary frequency with fewer than 105 organisms per milliliter of urine.312 In one study of 59 women with this syndrome, 42 also had pyuria and 11 of the 42 were infected withC. trachomatis, as were 3 of 66 women without symptoms and 1 of 35 women with cystitis related toE. coli. Most of the remainder of the women with pyuria and acute urethral syndrome had low urine concentrations ofE. coli orStaphylococcus saprophyticus demonstrated by culture of urine obtained by suprapubic aspiration.312 Young, sexually active women with this clinical syndrome should be evaluated for possibleC. trachomatis infection, and they respond to appropriate antibiotics such as doxycycline.C. trachomatis has also been isolated from the Bartholin glands in women with bartholinitis.

C. trachomatis has been associated with cervical cancer in seroepidemiologic studies and proposed as a cofactor for human papillomavirus (HPV) in the development of this common cancer in women. In a meta-analysis of 19 retrospective studies and 3 prospective studies,C. trachomatis infection in women was significantly associated with increased risk of cervical cancer (odds ratio [OR], 2.21; 95% confidence interval [CI], 1.88–2.61).68 The risk was present withC. trachomatis as an independent factor (OR, 1.76; 95% CI, 1.03–3.01), and increased when there was also HPV infection (OR, 4.03; 95% CI, 3.15–5.16).68 Case-control studies have found an association between cervical dysplasia or neoplasia andC. trachomatis infection.313–317 This association has been noted for both cervical squamous cell carcinoma and cervical adenocarcinoma,68 and is more pronounced for specific strains ofC. trachomatis.318,319 Coinfection withC. trachomatis was associated with more prolonged shedding of HPV in a longitudinal study of adolescents.320 Biologic support for a cofactor role comes from studies indicating thatC. trachomatis infection may cause chromosomal and genetic instability and induce cellular transformation, as described earlier in the “Chlamydial Biology” section. Chronic inflammation induced byChlamydia could also potentially contribute to cancer development.

Laboratory TestS

•

Document the presence of urethritis with any of the following:

Mucopurulent or purulent discharge in males

Gram stain of urethral discharge showing more than 5 white blood cells (WBCs) (preferred method of diagnosis) per oil immersion field on a gram‐stained smear of urethral secretions

Positive leukocyte esterase test on first‐void urine or microscopic exam of first‐void urine with more than 10 WBCs per high‐power field

Intracellular (within polymorphonuclear leukocytes) gram‐negative diplococci in a gram‐stained urethral discharge specimen for gonorrhea

Newer DNA amplification assays (polymerase chain reaction [PCR] and ligase chain reaction) for N. gonorrhoeae and C. trachomatis are largely replacing traditional cultures because of their greater sensitivity and ease and convenience of patient sample collection.

For males with urethritis who have a purulent discharge:

Perform Gram stain on urethral discharge.

Send swab of discharge for PCR test for N. gonorrhoeae and C. trachomatis.

With both N. gonorrhoeae and C. trachomatis, treat for infection.

For males with urethritis but no discharge:

Send first 15 mL of a first‐voided urine for PCR test for N. gonorrhoeae and C. trachomatis.

Send urine for urinalysis and urine culture.

Defer therapy until test results for N. gonorrhoeae and C. trachomatis are available, except in patients unlikely to return for follow‐up evaluation, in which case treatment should be given for both gonorrheal and chlamydial infection.

If opted for, culture N. gonorrhoeae on Thayer‐Martin medium/chocolate agar:

Males: proper culture is obtained by inserting a small, non‐cotton swab 2 to 3 cm into the urethra and plating the specimen immediately onto appropriate culture media.

Females: proper culture is obtained by first wiping the exocervix and then placing a non‐cotton swab into the cervical os and rotating the swab several times; the specimen is then immediately plated onto appropriate culture media.

C. trachomatis culture: the swab is placed into Chlamydia transport media.

Viral culture should be done for herpes simplex when suspected.

Treatment

Regimen for uncomplicated gonococcal infections of the cervix, urethra, or rectum:1

Ceftriaxone 500 mg IM as a single dose for persons weighing <150 kg (300 lb)

For persons weighing ≥ 150 kg (300 lb), 1 g of IM ceftriaxone should be administered.

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.

It is imperative to appropriately counsel patients on the avoidance of intercourse or use of barrier protection until a cure has been obtained and sexual partners have been evaluated. Once treated, patients should be advised to abstain from sex for 7 days.

A test of cure is not necessary for men treated with these first-line agents.

Alternative regimens for uncomplicated gonococcal infections of the cervix, urethra, or rectum if ceftriaxone is not available:

Gentamicin 240 mg IM as a single dose plus azithromycin 2 g orally as a single dose.

Cefixime 800 mg orally as a 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.

In cases of suspected cephalosporin treatment failure, clinicians should obtain relevant clinical specimens for culture and antimicrobial susceptibility testing, consult an infectious disease specialist or STD clinical expert (http:// www.stdccn.org/) for guidance in clinical management, and report the case to CDC through state and local public health authorities within 24 hr. Health departments should prioritize notification and culture evaluation for the patient’s sex partner(s) from the preceding 60 days for those with suspected cephalosporin treatment failure or persons whose gonococcal isolates demonstrate reduced susceptibility to cephalosporins.

A test of cure is unnecessary for persons with uncomplicated urogenital or rectal gonorrhea who are treated with any of the recommended or alternative regimens; however, for persons with pharyngeal gonorrhea, a test of cure is recommended, using culture or nucleic acid amplification tests 7 to 14 days after initial treatment, regardless of the treatment regimen. Because reinfection within 12 mo ranges from 7% to 12% among persons previously treated for gonorrhea, persons who have been treated for gonorrhea should be retested 3 mo after treatment regardless of whether they believe their sex partners were treated. If retesting at 3 mo is not possible, clinicians should retest within 12 mo after initial treatment.

Pathophysiology

Both gonococcal and nongonococcal urethritis are acquired during sexual intercourse. While the gonococcal form is caused by N. gonorrhoeae after an incubation period of 3-10 days, nonconococcal urethritis is caused by several bacteria, most commonly C. trachomatis, Ureaplasma urealyticum, Trichomonas vaginalis, Herpes simplex virus, and cytomegalovirus. C. trachomatis is recovered from the urethra in 25-60% of men with nongonococcal urethritis, incubation period of which is 7 to 21 days. In addition, approximately 4-35% of the gonococcal cases harbor concomitant C. trachomatis.

Urethritis

Urethritis is an inflammation of the urethra, which has many possible etiologies: chemical irritation, trauma, foreign body, systemic inflammatory disease, allergic reaction, or infection. In comparison to adults, pediatric patients with urethritis are much less likely to have an infection as the source of the inflammation. The history of the presen-ting illness may include contact with irritants such as soaps or bubble bath, trauma from catheter placement or other foreign body, systemic illness and rash, or concern of sexual assault in small children or history of sexual activity in adolescents. Catheters made of latex are more likely to cause an allergic reaction in the urethra than are silicon catheters.12

Presenting signs and symptoms may include discomfort with urination, urinary frequency and urgency, itching and pain in the genital area, and hematuria or blood seen on the underpants. The urethral inflammation may be also associated with vaginitis or vulvovaginitis. Kawasaki disease, a pediatric multisystem vasculitis, is also associated with sterile pyuria and urethritis.13

A urine specimen should be obtained to look for white blood cells and red blood cells on microscopy and a culture sent to evaluate for infection. If sexually transmitted infections are suspected by history, studies to detect C. trachomatis and N. gonorrhoeae should be specifically obtained since routine bacterial urine cultures will not detect those infections.

Clinical Manifestations and Differential Diagnosis

Symptomatic urethritis in adolescent males is characterized by dysuria, urethral discharge, or urethral pruritus. Discharge can be mucoid, mucopurulent, or purulent. Gonococcal urethritis compared with NGU usually has a shorter incubation period, more acute onset, and more profuse discharge (Table 51.1).1 Discharge in patients with NGU can be so scant that it is only noticed in the morning or is apparent as crusting on the meatus or as stains in underwear.1 Urethral infection with N. gonorrhoeae and the various organisms causing NGU also can be asymptomatic.43

Urethritis must be differentiated from UTI, particularly in adolescent boys with dysuria but no discharge. In contrast to UTI, frequency, hematuria, and urgency are uncommon in urethritis. However, if the male adolescent is sexually active, pyuria is more likely to be caused by urethritis than UTI because UTI is uncommon in this age group. A focused STI history (see Chapter 49) and thorough medical history can help establish relative risks of urethritis and UTI.

In adolescent girls, dysuria is the cardinal feature of urethritis, which must be differentiated from acute bacterial cystitis and vulvovaginitis (Table 51.2). The literature differentiates internal and external dysuria. Internal dysuria is pain that is felt internally during voiding. External dysuria is discomfort that is felt as urine passes over the labia.7 Internal dysuria, urinary frequency, and isolation of more than 102 uropathogens per milliliter of voided urine suggest acute bacterial cystitis; isolation of 102 or fewer uropathogens per milliliter suggests acute urethritis due to STI pathogens.6 Pain that is felt internally only at the end of urination is consistent with bacterial cystitis.7 External dysuria can occur with vulvovaginitis. Female adolescents can have vaginitis alone or a concurrent UTI and may not be able to adequately distinguish between internal and external dysuria.7,44 Any female patient suspected of having urethritis requires an STI-directed history and physical examination to identify other STIs or STI syndromes (e.g., pelvic inflammatory disease [PID]).

In prepubertal boys and girls, urethritis due to STI pathogens can manifest with dysuria and urethral or vaginal discharge. There may be vague lower abdominal pain, unwillingness to void, and in boys, irritation in the distal urethra or meatus. Dysuria in a prepubertal child is much more likely to be caused by UTI than urethritis associated with STI. Urethritis is more probable in the setting of a discharge or a history of sexual abuse, especially if genital-to-genital contact has occurred.

Urethritis

Urethritis is characterized by some combination of urethral discharge and dysuria, but prostatitis can cause similar complaints. Urethritis is caused by a limited group of pathogens (see Table 293-1) that may be difficult to visualize microscopically or grow in culture. Accordingly, empirical therapy is provided to treat a spectrum of potentially causative organisms.

Urethritis is diagnosed when one or more of the following are demonstrated: (1) mucopurulent or purulent urethral discharge, (2) Gram stain of urethral secretions demonstrating 5 or more leukocytes per oil immersion microscopic field, (3) positive leukocyte esterase test on first-void urine, or (4) microscopic examination of first-void urine demonstrating 10 or more leukocytes per high-power field. If no discharge can be expressed from the urethral meatus, a calcium alginate swab can be inserted 5 mm into the urethra; the material collected is transferred to a slide by rolling the swab along the glass.

A Gram stain of urethral discharge is a simple and rapid diagnostic test to document both urethritis and gonococcal infection (Chapter 307), characterized by the detection of leukocytes containing intracellular gram-negative diplococci. Confirmation of gonococcal urethritis does not rule out concomitant infection with Chlamydia or Mycoplasma. As culture and Gram stain have become less popular or less available, nucleic acid amplification tests (NAATs) that are highly sensitive and specific for the detection of organisms have been used routinely. NAATs for gonorrhea, Chlamydia, and Trichomonas can be applied to first-voided urine samples (the meatus is intentionally not cleaned so that the urine is contaminated with these organisms) and/or urethral swab material. Specific diagnosis may enhance the management of sexual partners, and the results from such tests should be reported to the health department. However, in practice, patients and (in most cases) sexual partners must be treated before the results of these tests are available.

Treatment for urethritis should be initiated as soon as possible after the clinical diagnosis and should be directly observed if feasible (Table 293-2). N. gonorrhoeae (Chapter 307) has become resistant to many antimicrobials, including quinolones, so the choice of optimal therapies is limited.1 Dual therapy with azithromycin and ceftriaxone increases the cure rate of uncomplicated urogenital, anorectal, and pharyngeal gonorrhea. Azithromycin can also be expected to cure most causes of nongonococcal urethritis (NGU), including those caused by Mycoplasma genitalium, an increasingly recognized cause of NGU.2 T. vaginalis, which is susceptible to metronidazole or tinidazole, also causes urethritis and should be considered in the face of NGU treatment failure.

Women with urethritis present with some combination of dysuria and pyuria, which must be differentiated from bacterial cystitis. Because treatment for urinary tract pathogens may also resolve urethritis, the clinician treating a presumed bladder infection should consider an STD as well.

Urethritis and Cystitis

Urethritis, a common component of STDs, is inflammation of the urethra. It may be caused by bacteria or viruses, especially those that cause gonorrhea (Neisseria gonococcus) and chlamydia (Chlamydia trachomatis), as well as the herpes simplex virus. Urethritis that is not associated with a gonococcal infection is often referred to as nonspecific urethritis. This disorder can occur in men and women; however, symptoms are most common in men and include painful, frequent, and difficult urination; blood or discharge in the urine; tenderness and swelling of the penis; and pain with intercourse. Symptoms in women include frequent and painful urination. The disease organisms can pass up the urethra to the urinary bladder, causing its infection or inflammation (cystitis), with fever and abdominal pain. Bladder infections can also be caused by E. coli or other bacteria normally resident in feces. This can be the result of poor hygiene. Frequent sexual activity can facilitate passage of E. coli into the urethra and eventually into the urinary bladder. Chemical exposure, such as from soaps, lotions, or spermicides, and mechanical stress or trauma can also irritate the urethra and increase the risk of urethritis and cystitis.

Symptoms of cystitis include a desire to urinate frequently, a burning pain when urinating, hazy urine often tinged with blood, and backache. Cystitis can be treated with antibiotics. A medication for pain often is given with the antibiotic. Individuals suffering from urethritis should abstain from coitus.