Urethral Discharge.Essentials of Diagnosis of urethral discharge.
Spontaneous urethral discharge.
Burning with urination.
Purulent or mucoid exudate with urethral stripping.
More than 5 white blood cells (WBCs) per high-power field of urethral exudate.
General Considerations
Urethral discharge is characterized by abnormal purulent or mucoid secretions from the penis or, rarely, the female urethra. Urethral discharge reflects inflammation of the urethra usually caused by infection. Urethritis is defined as the presence of leukorrhea and urethral inflammation. Clinically, urethritis in men is characterized by urethral discharge and is often accompanied by dysuria. Leukorrhea has been defined as the presence of more than 5 WBCs per high-power field in a urethral swab specimen, using either Gram stain or other cellular stain (eg, Wright or methylene blue).
Epidemiology & Pathogenesis
Urethral discharge can occur in sexually active persons of all ages but is most common in young adults, the age group in which the prevalence of Chlamydia trachomatis and Neisseria gonorrhoeae infection is highest. High rates of urethritis also occur in men who have sex with men. Urethral discharge occurs after urethral infection in persons exposed to infectious agents during oral, vaginal, or anal intercourse.
The most common etiology of urethral discharge is N gonorrhoeae, followed by C trachomatis. These two organisms account for about 40% of cases of urethritis. Although historically urethritis has been differentiated into gonococcal urethritis versus nongonococcal urethritis (NGU), with the discovery of additional causes of urethritis that dichotomy has little clinical relevance. The other major putative organisms that have been associated with sexually transmitted NGU include Mycoplasma genitalium, Trichomonas vaginalis, herpes simplex virus, and adenovirus (see Table 3–1). The role that Mycoplasma hominis and Ureaplasma urealyticum play in urethritis remains unproven.
| Table 3–1. Pathogens that Can Cause Sexually Transmitted Urethritis.a
| | | Common causes | | Neisseria gonorrhoeae | | Chlamydia trachomatis | | Mycoplasma genitalium | | Trichomonas vaginalis | | Herpes simplex virus | | Rare causes | | Ureaplasma urealyticum | | Escherichia coli | | Anaerobic bacteria | | Adenovirus | |
aListed from most to least common. |
N Gonorrhoeae
Urethral discharge is most commonly associated with gonorrhea. Infection with these gram-negative diplococci can occur after oral, vaginal, or anal intercourse, with symptoms developing between 1 and 3 days after exposure.
C trachomatis
In early studies that largely relied on culture methods, Chlamydia was found to account for a relatively small proportion of cases of NGU. In three large studies performed at STD clinics in the 1980s and 1990s, Chlamydia was identified in 19–31% of patients. On average one third but in some studies up to 60% of patients with gonococcal urethritis may have coinfection with C trachomatis.
M Genitalium
This organism was first identified as a cause of NGU in 1981. It is very difficult to grow in culture, and diagnostic surveys have been performed in research settings with nucleic acid amplification tests. Some investigators have suggested that M genitalium is responsible for 15–25% of cases of NGU; others cite a much lower percentage. A large review of the literature conducted in 2002 found that patients with NGU were 2.5 times more likely to have M genitalium isolated from their genitourinary tract than patients without urethritis (20% compared with 8%). However, it is difficult to determine the exact relationships between this organism and other urethral pathogens. Although diagnosis of M genitalium infection is currently limited to research settings, commercial assays for M genitalium are in development.
T Vaginalis
Urethritis accompanying Trichomonas infection is usually associated with minimal discharge. Not surprisingly, men with trichomonas-related urethritis are much more likely to have been exposed to women with trichomonas-related vaginitis. One of the more intriguing questions in understanding the epidemiology of Trichomonas infection in men is identification of the anatomic source. Trichomonas infection is very difficult to identify in the urethra in male contacts of women who have trichomoniasis. Several investigators have proposed that Trichomonas is sequestered in the prostate gland and may be a cause of prostatitis.
Herpes Simplex Virus
Up to sixty percent of men with primary herpes infection have associated herpes NGU. A clinical clue to herpes as an etiology is that the urethral inflammatory cells are lymphocytes, and patients present with pain on urination and minimal discharge. Often, patients are treated empirically for NGU; however, because of the natural history of genital herpes (resolution within 5–7 days), the resolution of symptoms is often attributed to treatment for other organisms. Intraurethral herpes infection should be suspected when the primary manifestation is severe dysuria. In these patients, a urethral culture or, if available, a nucleic acid amplification test (polymerase chain reaction) for herpes may be positive. Occasionally, herpetic lesions are seen at the meatus.
M Hominis and U Urealyticum
These species have had a putative association with urethritis for more than 30 years. Although both organisms are associated with sexual activity, few well-controlled studies have demonstrated that they are isolated more frequently from individuals with urethritis than from normal controls. Therefore, whether these species represent true pathogens or urethral colonizers has yet to be determined.
Other Etiologies
Because of the large number of cases of NGU that are not associated with an identifiable pathogen, there has been substantial interest in a nonherpetic viral cause. Adenovirus has been associated with NGU, especially in persons who have had insertive oral sexual exposure. However, one criticism in such cases is the possibility that, similar to the situation with Mycoplasma and Ureaplasma, the isolation of an organism does not confirm that the organism is pathogenic.
In men who have sex with men who have had insertive rectal intercourse, anaerobic bacteria and enteric organisms (eg, Escherichia coli) occasionally cause urethritis.
Finally, some cases of NGU do not appear to be associated with the traditional sexually transmitted organisms; possible underlying etiologies include contact dermatitis and immunologic disorders.
Anagrius C, Lore B, Jensen JS. Mycoplasma genitalium. Prevalence, clinical significance and transmission. Sex Transm Infect 2005;81:458ñ-462. (Current review of the epidemiology and clinical manifestations of M genitalium.) ) [PMID: 16326846]
Bradshaw CS, Tabrizi SN, Read TR, et al. Etiologies of nongonococcal urethritis: Bacteria, viruses, and the association with orogenital exposure. J Infect Dis 2006;193:336–345. (Comprehensive clinical assessment demonstrating that herpes simplex virus type 1 and adenovirus are major causes of NGU, especially in patients with orogenital exposure.) [PMID: 8480958]
Krieger JN, Jenny C, Verdon M, et al. Clinical manifestations of trichomoniasis in men. Ann Intern Med 1993;118:844–849. (Classic article describing the role of trichomonas in NGU.) [PMID: 16388480]
Clinical Findings
Symptoms and Signs
All patients who are evaluated for sexually transmitted diseases should be evaluated for urethritis. Urethral evaluation should occur a minimum of 2 hours after the last voided urine, because recent voiding can reduce the sensitivity of microbiologic testing.
The typical presenting symptoms of urethritis are dysuria or discharge. With gonococcal urethritis, the discharge is more likely to be purulent, although this should not be used alone to either rule in or rule out gonococcal infection. The discharge of NGU is typically mucoid or watery. If no spontaneous discharge is evident, the clinician should perform urethral stripping ("milking" the urethra three to four times from the base of the penis distally to the meatus), which will yield urethral exudate in a majority of patients with asymptomatic NGU.
Laboratory Findings
Ideally, a smear of urethral exudates and Gram stain should be performed. If no spontaneous or induced discharge is present, a urethral smear is prepared by inserting a narrow swab (eg, calcium alginate swab) 2 cm into the urethra, rotating the swab, and withdrawing it. Exudate from the swab is then rolled onto a glass slide for staining and examination. In settings where Gram stain is not available, an alternative means to identify urethral inflammation is leukocyte esterase testing performed on 15 mL of the first-voided urine, using a criterion of +1 leukocytes on the leukocyte esterase test strip.
Unfortunately, microscopy and rapid testing are not available in most clinical settings in which acute urethritis is seen, thus precluding an on-site diagnosis.
In clinical practice, most of the organisms associated with NGU, such as Chlamydia and Mycoplasma, are susceptible to macrolide (eg, erythromycin), azalide (azithromycin), or tetracycline (eg, doxycycline) antibiotics. Results of organism-specific diagnostic tests typically are not available for several days. With the lack of on-site diagnostic testing, syndromic clinical management is common practice.
Clinical Findings
Symptoms and Signs
All patients who are evaluated for sexually transmitted diseases should be evaluated for urethritis. Urethral evaluation should occur a minimum of 2 hours after the last voided urine, because recent voiding can reduce the sensitivity of microbiologic testing.
The typical presenting symptoms of urethritis are dysuria or discharge. With gonococcal urethritis, the discharge is more likely to be purulent, although this should not be used alone to either rule in or rule out gonococcal infection. The discharge of NGU is typically mucoid or watery. If no spontaneous discharge is evident, the clinician should perform urethral stripping ("milking" the urethra three to four times from the base of the penis distally to the meatus), which will yield urethral exudate in a majority of patients with asymptomatic NGU.
Laboratory Findings
Ideally, a smear of urethral exudates and Gram stain should be performed. If no spontaneous or induced discharge is present, a urethral smear is prepared by inserting a narrow swab (eg, calcium alginate swab) 2 cm into the urethra, rotating the swab, and withdrawing it. Exudate from the swab is then rolled onto a glass slide for staining and examination. In settings where Gram stain is not available, an alternative means to identify urethral inflammation is leukocyte esterase testing performed on 15 mL of the first-voided urine, using a criterion of +1 leukocytes on the leukocyte esterase test strip.
Unfortunately, microscopy and rapid testing are not available in most clinical settings in which acute urethritis is seen, thus precluding an on-site diagnosis.
In clinical practice, most of the organisms associated with NGU, such as Chlamydia and Mycoplasma, are susceptible to macrolide (eg, erythromycin), azalide (azithromycin), or tetracycline (eg, doxycycline) antibiotics. Results of organism-specific diagnostic tests typically are not available for several days. With the lack of on-site diagnostic testing, syndromic clinical management is common practice. This approach is outlined in Figure 3–1. As with all STD evaluations, obtaining a thorough history is essential.
Algorithm for the diagnosis and management of urethritis. GC = gonococcal infection; GNID = gram-negative intracellular diplococci; HPF = high-power field; LET = leukocyte esterase test; NGU = nongonococcal urethritis. (Reproduced with permission from Burstein G, Zenilman JM. Non-gonococcal urethritis—A new paradigm. Clin Infect Dis 1999;28:S72.)
Diagnostic Tests
With the advent of highly sensitive nucleic acid amplification tests, diagnostic testing can be performed using urine as the testing substrate, obviating the need to collect a urethral swab specimen. Ideally testing should include assays for N gonorrhoeae and C trachomatis. All patients evaluated for sexually transmitted diseases should also undergo serologic testing for syphilis, as well as HIV testing. Despite the increased logistical problems, costs, and follow-up issues involved in diagnostic testing, such testing is essential to assure proper treatment and to facilitate partner management. Because gonococcal and chlamydial infections are exclusively sexually acquired, partner notification for these infections should be based on a confirmed laboratory result.
Differential Diagnosis
The major differential diagnosis is between gonorrhea, chlamydia, urethritis due to Mycoplasma, T vaginalis, and herpes simplex. If microscopy is available, gonococcal urethritis can be excluded on the basis of a Gram stain of the urethral exudate. Noninfectious causes of urethritis should also be considered; these causes may be suggested by the history and include urethral trauma from recent catheterization or sex play, and autoimmune conditions such as Reiter syndrome.
As a general rule, urethritis in men younger than 40 years of age who have not undergone invasive urologic procedures (eg, catheterization, cystoscopy) can be presumed to be sexually acquired. Older men, especially those with systemic diseases such as diabetes and prostatic hypertrophy, are susceptible to urinary tract infections, which can mimic urethritis. In all cases, however, a careful sexual history and evaluation should be obtained in patients who are sexually active.
Complications
Epididymitis can result from urethral infection with Chlamydia or N gonorrhoeae and must be differentiated from testicular torsion. Acute prostatitis is often considered to be a potential complication of urethral infection in patients with persistent or recurrent urethritis. Prostatitis can often be excluded by a normal prostate examination. Rarely, chronic urethritis can result in urethral stricture. Complications specific to individual organisms may occur in patients with untreated gonorrhea who progress to disseminated gonococcal infection or those with chlamydial infection who have immune-mediated reactive arthritis (formerly known as Reiter syndrome); however, these complications are rare.
Treatment
Pharmacotherapy
Patients who present with a purulent discharge or who reside in or have visited an area that is endemic for gonorrhea should be offered treatment for both gonorrhea and chlamydia. Areas that are hyperendemic for gonorrhea include many urban environments, the southeastern United States, and developing countries. Current treatment recommendations for gonorrhea include ceftriaxone, 125 mg intramuscularly, or cefixime, 400 mg orally once. Cefixime, however, is not commercially available in the United States and many authorities recommend another third-generation cephalosporin, cefpodoxime, 400 mg once orally instead. Because of the increased incidence of fluoroquinolone-resistant gonorrhea (almost 40%) on the East and West coasts of the United States in men who have sex with men, these drugs should not be used in the treatment of that population. As of 2006, fluoroquinolones continue to be recommended for treatment of gonorrhea in heterosexuals, except in Hawaii and California. If fluoroquinolones are used in populations where quinolone resistance is common, a "test of cure" is recommended.
If the patient is a homosexual man or has a history of insertive rectal intercourse, the clinician should consider the possibility of enteric or anaerobic infection. Treatment for those infections is similar to treatment for gonorrhea. All patients should be treated presumptively for the other causative agents of urethritis (see earlier discussion and Table 3–1) with azithromycin, 1 g as a single dose. An alternative regimen is to administer doxycycline, 100 mg twice daily for 7 days. Azithromycin is preferred for patients with NGU because clinical trial data suggest that treatment success rates for M genitalium are higher when azithromycin rather than a tetracycline is used. Azithromycin, however, does not treat incubating syphilis, so some public health authorities recommend the use of tetracycline (doxycycline) in the treatment of NGU in populations at high risk for syphilis.
Partners of patients with gonococcal or chlamydial infection must be treated. Patient-delivered partner therapy has been shown to be safe and highly effective in heterosexual men and women, and this option, if available, should be used.
In addition, patients with gonococcal or chlamydial urethritis should return at 3 months for repeat testing to rule out reinfection. Some studies have shown rates of reinfection in adequately treated patients to be as high as 20% at 3 months.
Clinical Challenges
One of the biggest challenges to the clinician is presented by the patient who reports urethral "tingling" without discharge. Approximately one third of patients with clinically demonstrable urethritis do not have discharge. If the results of diagnostic evaluation are negative, these patients should be informed that no infection is present and that the urethral discomfort will resolve spontaneously. It is not uncommon for patients to experience urethral symptoms after sexual experiences they later regret, suggesting a psychological cause to their physical complaints. Testing and informing the patient of the negative test results is often associated with resolution of symptoms. Empiric treatment for urethral symptoms without objective evidence of urethritis is not recommended
Burstein G, Zenilman JM. Non-gonococcal urethritis—-A new paradigm. Clin Infect Dis 1999;28(suppl 1):S66–S73. (Comprehensive review of the diagnosis and treatment of NGU, which served as the background paper for the 1999 STD treatment guidelines. Includes algorithms for diagnosis and management.) [PMID: 10028111]
Horner PJ. European guideline for the management of urethritis. Int J STD AIDS 2001;12(suppl 3):63–67. (Comprehensive European guidelines for the management of urethritis.) [PMID: 11589800]
Kissinger P, Mohammed H, Richardson-Alston G, et al. Patient-delivered partner treatment for male urethritis: A randomized controlled trial. Clin Infect Dis 2005;41:623–629. (Seminal article that describes the use of patient-delivered therapy for treating partners of patients with gonococcal or chlamydial infection, using reinfection as the outcome.) [PMID: 16080084]
When to Refer to a Specialist
If objective signs of urethritis persist after proper treatment and reinfection or nonadherence is unlikely, then referral to an infectious disease specialist or urologist may be necessary. Those specialists often have access to additional diagnostic tests for less common or antimicrobial-resistant pathogens. Rarely, cystoscopy may be indicated to rule out structural urethral or bladder disease. In cases of urethritis complicated by epididymitis or disseminated disease, referral may be indicated to exclude testicular torsion or initiate intravenous therapy, respectively.
Prognosis
Most cases (95%) of urethritis are adequately treated with the recommended antibiotics, leading to rapid resolution of symptoms. Urethral discharge generally resolves within 24–48 hours; however, dysuria and urethral discomfort may persist for up to 7 days. Although antimicrobial treatment usually renders patients noninfectious within 1–2 days, it is recommended that they abstain from sexual intercourse for 7 days following the initiation of treatment to prevent further transmission.
Despite appropriate diagnosis and treatment, many clinicians will encounter patients who have chronic urethral symptoms of unknown etiology. These patients often have associated affective or obsessive-compulsive disorders, in which the presence of chronic urethral complaints represents expression of the underlying psychological disorder.
Practice Points
Urethral evaluation should occur a minimum of 2 hours after the last voided urine, because recent voiding can reduce the sensitivity of microbiologic testing.
All patients evaluated for sexually transmitted diseases should also undergo serologic testing for syphilis, as well as HIV testing.
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