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Urethral discharge is the most frequent sexually transmitted disorder occurring in men. In the majority of patients, the discharge has an infectious pathogenesis. If the urethral discharge is not caused by Neisseria gonorrhoeae, the patient has nongonococcal urethritis (NGU). These two forms of urethritis, however, are not mutually exclusive, as coinfection with N. gonorrhoeae and Chlamydia or Ureaplasma occurs in 15% to 25% of heterosexual men with urethritis.
NGU is the most common sexually transmitted disease in men and results in about 4 to 6 million visits yearly in the United States. The Centers for Disease Control estimates that there are two and one-half times as many cases of NGU as cases of gonorrhea in men. Whereas the incidence of gonorrhea has declined recently, the proportion of organisms with penicillin resistance is increasing in most areas of the United States. Which type of infection is present depends on the population studied. The highest proportion of NGU cases occurs in college students seen at student health clinics, with rates of 80% to 90% reported. In sexually transmitted disease clinics, cases of gonorrhea appear to be slightly more numerous.
Several organisms are implicated as causes of acute NGU. Chlamydia trachomatis is isolated in 30% to 40% of patients with NGU. Chlamydia is also recovered from the endocervix of about 70% of women whose partners have chlamydial NGU. A recent study indicated that the frequency of Chlamydia infection is decreasing. The organism was found to cause only 15% of cases of urethritis. Ureaplasma urealyticum is thought to be responsible for 20% to 25% of cases of NGU. There is a higher incidence of U. urealyticum in men having their first episode of NGU. Other, infrequent infectious causes of NGU, which account for 1% to 5% of cases, are Trichomonas vaginalis, herpes simplex virus, Mycoplasma genitalium, and Candida. M. genitalium has been found to cause between 12% and 50% of cases of urethritis. The cause of the remaining 20% to 30% of NGU cases is unknown. Thirty to forty percent of patients who do not have intercourse with a new or untreated partner have recurrent urethral discharge within 6 weeks of appropriate therapy for NGU. Most men with recurrent NGU are culture-negative for Chlamydia and Ureaplasma, and the cause remains unknown. Resistant Ureaplasma is implicated as a cause of urethritis that fails to improve following a course of tetracycline. Chlamydia appears to be an infrequent cause of persistent or recurrent urethritis. T. vaginalis accounts for only a minority of cases of persistent NGU.
Clinically, gonococcal urethritis has an abrupt onset, with an incubation period of 1 to 7 days. The discharge tends to be purulent, and dysuria is a frequently associated syndrome. The clinical picture of NGU is different, with a gradual onset, an incubation period of 10 to 14 days, and mucoid discharge. The symptoms are milder, and patients often wait several days before seeking care. NGU has a tendency to recur, and a prior history of urethritis is common. There is overlap between the symptoms of the two conditions, and a Gram’s stain and culture of the discharge are essential for diagnosis. Both N. gonorrhoeae and Chlamydia can cause asymptomatic urethral infections. About 10% of NGU cases are asymptomatic.
When a male patient presents with a discharge or dysuria, or both, the physician should obtain material for Gram’s stain and culture by stripping the distal urethra. If no discharge is present or asymptomatic gonorrhea is suspected, a calcium alginate nasopharyngeal swab should be inserted 2 cm into the urethra to obtain a specimen for Gram’s stain and culture. Voiding within 2 hours of the examination may interfere with obtaining material for smear. The Gram’s-stained specimen shows neutrophils that contain several intracellular gram-negative diplococci in 95% of patients with gonorrhea. The Gram’s-stained smear may require a careful search, as the distribution of organisms is uneven. Most neutrophils contain no organisms, and a few cells are loaded with gram-negative diplococci. The hallmark of urethritis is the presence of polymorphonuclear leukocytes (PMNs) on a Gram’s-stained smear of urethral discharge. The presence of at least four PMNs per oil-immersion field (1,000×) indicates urethral inflammation.

Patients who are symptomatic but have no evidence of a urethral discharge should have their first 10 mL of urine examined for the presence of PMNs. The urine sample should be centrifuged and the sediment examined for PMNs. Pyuria is defined as the presence of 15 or more PMNs per high-dry field (400×). In some patients with Chla-mydia isolated, however, urethral Gram’s-stained smears and first-voided urine lack enough PMNs to fulfill these criteria for urethral inflammation. In two studies, nearly one third of the patients who had Chlamydia isolated did not show evidence of urethral inflammation.
The Gram’s stain is also highly sensitive (95%) in the diagnosis of NGU. The smear shows neutrophils without intracellular diplococci; this is confirmed by a culture that is negative for the gonococcus. For many clinicians, the diagnosis of NGU depends on the exclusion of gonococcal infection, as cultures for Chlamydia may not be readily available. The swab should be inoculated into an appropriate selective medium (e.g., Thayer-Martin, Martin-Lewis) at room temperature, or inoculated onto a transport system (e.g., Transgrow, Jembec) that yields a carbon dioxide-containing environment. A serologic test for syphilis should always be obtained. In patients with persistent or recurrent NGU, a wet preparation of the urethral discharge may reveal Trichomonas.
In addition to the traditional methods of diagnosing gonorrhea by using Gram’s stain and culture, rapid diagnostic tests have become commercially available. One test, Gonozyme, is an enzyme immunoassay that can detect gonococcal antigens in urethral, endocervical, and urine specimens. The test requires about 1 hour to perform. For men with a urethral discharge, the immunoassay is essentially equivalent in sensitivity and specificity to the Gram’s stain. The Gram’s stain, however, is still less expensive and more rapid. For asymptomatic urethral gonorrhea, the Gram’s stain has a sensitivity of only 40% in comparison with the culture. In one study of asymptomatic male patients with gonococcal urethritis, the immunoassay for gonococcal antigen had a sensitivity of only 67%. In women with endocervical gonorrhea, the results of the immunoassay were better than those from the Gram’s stain (78% vs. 48%). The sensitivity of a single endocervical culture for gonorrhea is about 85%. The immunoassay also appears to be a useful method for the diagnosis of gonorrhea in mailed specimens.
Another rapid test (Gen-Probe PACE 2) utilizes a nonisotopic DNA probe to detect C. trachomatis and N. gonorrhoeae from the same specimen. The nucleic acid probes are highly specific and can screen large numbers of specimens. The test is expensive and appears to be less sensitive than culture for male urethral specimens. With first-voided urine samples, the leukocyte esterase test can be used to screen for both gonorrhea and NGU. The sensitivity of this nonspecific test is about 80%, and it can be used to identify patients who need further testing.
A number of rapid tests have been developed for diagnosing chlamydial infections. One, a direct immunofluorescent test (Micro Trak), uses a monoclonal antibody conjugated with fluorescein isothiocyanate. The test, which takes about 30 minutes, requires expertise with immunofluorescent microscopy. In one report, the test had a 93% sensitivity and 96% specificity. The other test is an enzyme immunoassay (Chlamydiazyme); it takes 4 hours to perform and has shown a sensitivity of 80% and specificity of 98%. Tests using the polymerase chain reaction (PCR) and ligase chain reaction (LCR) and transcription mediated amplification (TMA) are also available to detect C. trachomatis. The cell culture has been the gold standard for diagnosis, and it is too early to determine the role of the various nonculture tests such as PCR, LCR, TMA in the diagnosis of chlamydial infections. The highly sensitive PCR- and LCR-based assays appear to be useful to screen the urine of asymptomatic men. Patients prefer noninvasive tests on urine to the use of urethral swab specimens.
Because 15% to 20% of heterosexual men with gonococcal urethritis have simultaneous chlamydial urethritis, therapy must be directed against both pathogens. Penicillin-resistant and tetracycline-resistant strains of N. gonorrhoeae occur frequently, so that penicillin, ampicillin, and tetracycline are no longer recommended. Ceftriaxone administered in a dose of 125 mg intramuscularly is the drug of choice. Ceftriaxone is also likely to be effective against incubating syphilis. A single 400-mg dose of cefixime, administered orally, appears to be as effective as ceftriaxone. Alternatives for penicillin- and cephalosporin-allergic patients with genital or rectal gonorrhea include IM spectinomycin or an oral quinolone such as ciprofloxacin (500 mg once), ofloxacin (400 mg once), or trovafloxacin (100 mg once). Spectinomycin is not recommended for the treatment of pharyngeal gonorrhea, but ceftriaxone and ciprofloxacin appear effective. Men treated with ceftriaxone, cefixime, a single dose of a quinolone, or spectinomycin, which are adequate drugs for gonorrhea, have a persistent mucoid discharge (so-called postgonococcal urethritis) if Chlamydia or Ureaplasma infection is also present.
Following treatment of gonorrhea with one of the single-dose regimens, patients should be given a single dose of azithromycin or a 7-day course of doxycycline or tetracycline for coexisting chlamydial infection. Azithromycin is preferred because a single dose improves compliance. Erythromycin (1 g/d) may be substituted for tetracycline. Ofloxacin but not ciprofloxacin administered for a 7-day course is another alternative drug for Chlamydia infection. M. genitalium responds to doxycycline, azithromycin, or erythromycin. A repeated culture is not necessary after treatment unless the patient remains symptomatic or has a recurrence.
Unfortunately, about 33% of patients have persistent or recurrent NGU within 6 weeks of initiation of therapy. The rate of recurrence is the same after 3 weeks of initial therapy as with 1 week. The results of therapy are best if Chlamydia is isolated initially, not as good if Ureaplasma is present, and poor if neither organism is present initially. Tetracycline-resistant Chlamydia is not a problem with recurrent NGU, but resistant Ureaplasma has been reported. Erythromycin (2 g/d orally) administered for 7 days is effective against Chlamydia and tetracycline-resistant Ureaplasma. Trimethoprim-sulfamethoxazole is effective against Chlamydia but lacks activity against Ureaplasma. Every effort should be made to treat both male and female sex partners of infected patients to prevent reinfection.
Management of recurrent NGU is a difficult problem. The cause is usually unknown. The following must be considered as possible causes of failure to respond or of recurrence: (a) reinfection, (b) patient noncompliance, (c) mixed infection, (d) T. vaginalis urethritis, (e) resistant Ureaplasma, (f) herpes simplex virus infection, (g) foreign bodies, and (h) trauma (mainly “milking” the urethra). Optimal management is unclear. A urologic evaluation may be beneficial for a minority of patients with unresponsive urethritis. If the patient was compliant with the initial regimen and renewed exposure can be excluded, then metronidazole (2 g orally in a single dose) plus erythromycin (2g/d) for a week is recommended. (N.M.G.)
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Observation is the therapy of choice if known uropathogens are excluded.
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The InPouch TV test was better than the wet preparation to make the diagnosis of trichomoniasis and was usually (91%) positive in 24 to 48 hours.
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About 60% of men and 75% of women with Chlamydia are asymptomatic. These new tests (PCR and LCR) are more sensitive than enzyme-linked immunosorbent assays, but at two to three times the cost.
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Use of an LCR assay had a sensitivity of 94%, which was better than the Chlamydia culture yield (85%).
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An increase (16%) in ciprofloxacin-resistant N. gonorrhoeae was noted.
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Evidence is given that Chlamydia is a frequent cause of NGU. Chlamydia organisms were isolated from 42% of patients with NGU and from 7% of controls.
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Classic review.
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Ciprofloxacin is effective in treating gonococcal urethritis but not chlamydial urethritis in male patients.
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A 3-week course of erythromycin (2 g/d) was more effective than placebo for male patients with persistent or recurrent NGU.
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Another cause of NGU.
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Uses a nonisotopic DNA probe for the direct detection of organisms based on a chemiluminescent detection system.
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Classic. Mycoplasma hominis does not appear to be major cause of NGU.
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Gram’s stain is highly sensitive in the diagnosis of gonococcal urethritis and NGU.
Jones MF, et al. Detection of Chlamydia trachomatis in genital specimens by the Chlamydiazyme test. J Clin Microbiol 1984;20:465.
A 4-hour assay with a sensitivity of 81% and specificity of 98%.
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Ceftriaxone is highly effective for urethral, pharyngeal, and rectal gonococci, including b-lactamase-positive strains.
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A single 1-g dose of azithromycin was highly effective for the treatment of genital chlamydial infections.
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A PCR for C. trachomatis from urethral swabs compared favorably with a direct immunofluorescence test using monoclonal antibodies (Micro Trak).
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Cefixime in a dose of 400 mg orally was highly effective (98%) for the treatment of uncomplicated gonococcal urethritis in men and cervicitis.
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Asymptomatic Chlamydia infection was noted in 11% of male personnel.
Schachter J, et al. Noninvasive tests for diagnosis of Chlamydia trachomatis infection: application of ligase chain reaction to first-catch urine specimens of women. J Infect Dis 1995;172:1411–1414.
An LCR assay was better than the chlamydial culture in diagnosing infection in women by means of first-voided urine specimens.
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For urine specimens, the enzyme immunoassay (Chlamydiazyme) to detect the presence of chlamydial antigen had a sensitivity of 42% in men with minimal or no symptoms of urethritis. The leukocyte esterase test had a higher sensitivity (88%), but its nonspecificity limits its use as a specific diagnostic test.
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Sensitivity equal to that of Gram’s stain in male patients and significantly better than that of cervical Gram’s stain in female patients.
Stamm WE, et al. Azithromycin for empirical treatment of the nongonococcal urethritis syndrome in men. A randomized double-blind study. JAMA 1995;274:545–549.
Use of a single dose of azithromycin was as effective as 1 week of doxycycline for NGU.
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A cause of persistent but not recurrent NGU.
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Criteria for the diagnosis of NGU included at least four neutrophils per high-power field in Gram’s-stained smears of urethral discharge and a negative culture for N. gonorrhoeae. Gardnerella, group B streptococci, and yeasts were not found as causative organisms of NGU.
Wong ES, et al. Clinical and microbiological features of persistent or recurrent nongonococcal urethritis in men. J Infect Dis 1988;158:1098.
Ninety percent of patients with urethritis caused by C. trachomatis and 70% of cases caused by U. urealyticum responded to antimicrobials. When neither organism is involved, more than 50% of cases persist or relapse. The physician should culture or treat for T. vaginalis when a second course of antimicrobials fails.

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