Urethritis Symptom.

Essentials of Diagnosis Urethritis  Symptom

 Requires objective signs of urethral inflammation.

Nongonococcal Urethritis Symptom 

 Absence of gram-negative intracellular diplococci on Gram stain.

 Mucopurulent or purulent discharge, Gram stain of urethral secretions indicating 5 white blood cells (WBCs) per high-power field (HPF), positive leukocyte esterase test, or 10 WBCs per HPF on spun urine sediment.

Persistent Urethritis

 No standard definition; has been defined as urethritis that fails to resolve or substantially improve within 1 week of initiating therapy.

Recurrent Urethritis

 No standard definition; has been defined as the return of urethritis within 6 weeks following an initial response to therapy.

General Considerations Urethritis Symptom 

An estimated two million cases of nongonococcal urethritis (NGU) occur in the United States each year. Approximately 30 to 50% of these cases are caused by Chlamydia trachomatis, although in some studies the proportion caused by chlamydia is lower. Many etiologies have been proposed for the remaining cases of NGU, but the most consistent associations have been found with Mycoplasma genitalium, Ureaplasma urealyticum, herpes simplex virus (HSV), and Trichomonas vaginalis. Even with extensive evaluations, in 25 30% of cases of NGU, no microbiologic cause can be identified. The association between Ureaplasma and NGU has not been clearly established and remains controversial; however, it has been suggested that serovars 2, 5, 8, and 9 of U urealyticum are associated with NGU whereas other serovars are not.

Following treatment for chlamydial urethritis, 10–20% of patients have persistent or recurrent urethritis. However, in nonchlamydial NGU, failure rates in excess of 50% often are reported. When a patient returns with symptoms consistent with urethritis following treatment for NGU, urethritis must be objectively documented. Furthermore, it is important to confirm adherence with previous therapy and to assess the possibility the patient has been reinfected by a new or untreated sex partner.

There are no widely accepted definitions for persistent or recurrent NGU (PRNGU), and none are provided in the 2006 treatment guidelines for sexually transmitted diseases provided by the Centers for Disease Control and Prevention. For the purposes of this chapter, we define persistent urethritis as urethritis that has not substantially improved within 1 week of initiating therapy for NGU. This definition was chosen because the majority of cases of NGU respond to therapy within this time. Recurrent urethritis is defined as urethritis occurring within 6 weeks of a previous episode of NGU. Some men have persistent or recurrent episodes of nonchlamydial NGU over a long period of time. However, the longer the duration between episodes of urethritis in a sexually active man, the greater is the likelihood that reinfection is the cause.

Infectious Causes

The causes of PRNGU are poorly understood. After reinfection and poor adherence to treatment have been ruled out, the clinician should consider other infectious causes. Possible infectious causes of PRNGU include genital mycoplasmas (eg, U urealyticum or M genitalium), T vaginalis, HSV, an antimicrobial-resistant strain of Chlamydia, and a prostatic nidus of infection. However, in only a minority of cases is a microbiologic cause found, even after extensive investigation.

M genitalium, detected by polymerase chain reaction (PCR), is reported to cause 7–50% of cases of NGU. Although the microbiology of PRNGU is less well defined, in one report 21% of patients were infected with M genitalium. Data are sparse, but it appears that macrolide antibiotics, in particular azithromycin, are more effective than tetracyclines in eradicating M genitalium in men with urethritis and women with cervicitis. Such clinical data correspond with in vitro data demonstrating that M genitalium is less susceptible to tetracyclines than macrolides. Some fluoroquinolones have bacteriocidal activity against mycoplasmas; however, in one study a 14-day course of levofloxacin at a dose of 100 mg three times daily failed to eradicate M genitalium in 67% of cases as detected by PCR. Although the best results in treating M genitalium have been reported with macrolides, relapses still occur. In one study, after erythromycin treatment of M genitalium PRNGU, symptomatic relapses occurred both in the presence and absence of M genitalium infection at baseline. These observations raise questions as to the role of M genitalium in the pathogenesis of PRNGU but may also be explained by a lack of sensitivity of detection techniques for M genitalium, intermittent shedding of organisms, or an immunologic basis for urethritis following M genitalium infection.

T vaginalis is an established cause of acute NGU, but there are few data on its role in PRNGU. Not surprisingly, if trichomonas were causing NGU it would not be expected to respond to conventional NGU therapy and thus could result in PRNGU. The reported prevalence of trichomonas in cases of NGU varies from 1% to 68%, with a median prevalence of 11%. The large variation in the prevalence of trichomonas in cases of NGU is likely due to the differences in the study populations and the detection methods used. In men, detection of trichomonas is difficult and the direct microscopic examination of a wet mount preparation has poor sensitivity. Although culture and PCR are superior to the wet mount, neither method is widely available. In one study of PRNGU, trichomonas was isolated in 6% of cases using culture techniques. However, given the scarcity of reports detailing the microbiology of PRNGU, the actual percentage of cases caused by trichomonas may differ greatly from this estimate.

HSV types 1 and 2 can cause NGU, even in the absence of genital lesions. Researchers have documented HSV types 1 and 2 in 2–12% of cases of NGU, more commonly in primary HSV than with recurrences of HSV.

Less likely causes of PRNGU include antimicrobial-resistant chlamydial infections. One report in 2000 described three patients with NGU caused by chlamydia resistant to doxycycline, azithromycin, and ofloxacin and subsequent treatment failure. Further cases have not been reported, but no systematic surveillance for antimicrobial resistance in chlamydia exists. Another possible cause of PRNGU is infection of the prostate, which can serve as a persistent nidus of infection. Prostatic infection is usually associated with symptoms and signs of prostatitis—urinary hesitancy, urgency, incomplete voiding, and prostatic tenderness—and requires a longer duration of treatment (6 or more weeks).

Noninfectious Causes

Noninfectious causes of PRNGU include an immunologic reaction to chlamydial heat-shock protein, Reiter syndrome, Kawasaki disorder, urethral strictures, foreign bodies, and periurethral fistulas. Generally, however, there is no reason to consider such possible causes in the absence of other manifestations associated with such syndromes.

Clinical Findings

Urethritis Symptoms and Signs

Patients with PRNGU generally complain of dysuria and may report clear, mucoid, mucopurulent, or purulent discharge. They may also have nonspecific genital complaints, similar to those described in men with chronic prostatitis. Objective evidence of urethritis is most likely to be present before the first void in the morning. "Milking" the urethra (ie, manually stripping the penis from its base to the meatus) may be necessary to demonstrate discharge; however, discharge is not present in all patients with PRNGU.

Laboratory Findings

Nongonococcal urethritis is diagnosed by absence of gram-negative diplococci on Gram stain and presence of any of the following signs: mucopurulent or purulent discharge, Gram stain of urethral secretions indicating 5 or more WBCs per HPF, positive leukocyte esterase test, or 10 or more WBCs per HPF on spun urine sediment.

Special Tests

It is recommended that identification of chlamydia and gonorrhea be pursued by nucleic acid amplification tests in men with PRNGU, regardless of whether a pathogen was identified at the time of initial presentation with NGU. Tests for Ureaplasma and M genitalium are not routinely available, and the results generally would not change management. Urethral culture or PCR for T vaginalis, if available, may be helpful. However, given the lack of availability of these tests in most clinics, we recommend treating men with PRNGU empirically with metronidazole as described later in this chapter. Testing for HSV is generally not recommended. However, culture or PCR of a urethral specimen for HSV is a reasonable step if the patient has clear discharge, a recent history of contact with an HSV-positive source, or a clinical syndrome otherwise consistent with HSV.

Repeated microbiologic evaluations in PRNGU have low yield and are not recommended unless the patient gives a history of continued sexual exposures to new or untreated partners.

Differential Diagnosis

The differential diagnosis of PRNGU is limited. When a patient has persistent or recurrent symptoms of dysuria, the importance of objectively documenting urethritis cannot be overemphasized. Not infrequently in such men, no objective evidence of urethritis can be found, and multiple examinations may be necessary to convince the patient. For those with evidence of urethritis, additional considerations include prostatitis, urinary tract infections, and anatomic urethral abnormalities.

Prostatitis

Although urethritis is not typical of prostatitis syndromes, evidence of prostatitis can be found in some men with PRNGU. The current National Institutes of Health classification divides prostatitis into the following categories: acute prostatitis; chronic bacterial prostatitis; chronic prostatitis/pelvic pain syndrome; inflammatory, chronic prostatitis/pelvic pain syndrome; noninflammatory and asymptomatic inflammatory prostatitis. No more than 5% of men with prostatitis have an identifiable bacterial cause, and the bacteria known to cause urethritis have not been shown to be important in the etiology of prostatitis. It is generally not worthwhile to perform a workup for prostatitis in men with PRNGU because the urethral inflammation in PRNGU can complicate the evaluation and the empiric treatment regimens overlap.

Urinary Tract Infection

In men, isolated acute cystitis is uncommon, and the majority of cases are due to anatomic or functional abnormalities, including prostatic hypertrophy or genitourinary instrumentation. Men with cystitis present with dysuria, frequency, and suprapubic pain. PRNGU can usually be distinguished from cystitis by the symptom profile and objective evidence of urethritis.

Other Conditions

Associations with urethritis have been found with urethral strictures, periurethral abscesses, intraurethral condylomata acuminata, and foreign bodies. The etiologies of urethral strictures include trauma, inflammation (including postinfectious causes), and congenital abnormalities. Patients should be asked about possible urethral trauma, as well as insertion of devices or medications into the urethra. Anatomic abnormalities can be definitively diagnosed by endoscopic evaluation, but only a small minority of patients with PRNGU is found to have anatomic abnormalities. Patients with an anatomic cause of urethritis frequently complain of urinary outflow obstruction. In general, however, if a patient has normal urinary flow as measured by a uroflow study, he is unlikely to have a clinically important anatomic abnormality that would benefit from endoscopic evaluation.

Complications

Patients with PRNGU and their partners have not been demonstrated to have any significant morbidity. Specifically, there are no data to suggest an association between PRNGU and infertility or upper genital tract disease in patientsí female partners.

Treatment

The management of patients with PRNGU is largely empiric. Urethritis should be documented in all patients presenting with persistent or recurrent symptoms. If no objective evidence of NGU is found, patients should be reassured (ie, that there is no inflammation suggestive of persistent infection) and reexamined at a later date if symptoms persist. If there is objective evidence of NGU, management strategies are as follows. If the patient was not adherent with therapy or was not abstinent from sexual contact until symptoms had resolved and treatment of both patient and partners was completed (or 7 days after single-dose azithromycin therapy), the patient (and partners) should be retreated with the original regimen. If the patient and his partners were adherent with recommended therapy, the clinician should reevaluate for gonorrhea and chlamydia. Some authorities recommend performing culture (or PCR) for trichomonas prior to empiric treatment, but as mentioned previously, these tests are not routinely available, and wet mount has poor sensitivity for trichomonas in men. Evaluation for HSV is low yield and generally not recommended.

Optimal treatment of PRNGU has not been defined, and different regimens have not been compared prospectively. It is our recommendation that at the first visit for PRNGU the patient be treated with 1 g of azithromycin orally as a single dose (or a 7-day course of erythromycin, 500 mg orally four times daily) and 2 g of metronidazole orally once. If the patient returns with PRNGU and no new exposures are identified, we do not recommend further evaluation for gonorrhea and chlamydia. In such men, we recommend a 3-week course of erythromycin, 500 mg orally four times daily. Others recommend doxycycline, 100 mg orally twice daily for 3 weeks, or ofloxacin, 300 mg orally twice daily for 1 week (levofloxacin, 500 mg/d orally, should be as effective). After a prolonged course of antibiotics, it is unlikely that further treatment with antimicrobials will be beneficial. However, consideration should be given to chronic prostatitis as a cause of PRNGU, and some practitioners recommend a longer empiric course of antibiotics (eg, a 4- to 6-week course of fluoroquinolones) for patients who continue to have

symptomatic urethritis.

The only randomized, controlled study of treatment of PRNGU compared a 3-week course of erythromycin, 500 mg orally four times daily, with placebo and demonstrated improvement in signs and symptoms with treatment. However, many men in this study had been exposed to multiple antibiotic courses prior to enrollment in the study.

No data are available to support further evaluation or treatment of previously treated asymptomatic partners of patients with PRNGU unless the cause of the PRNGU was documented to be chlamydia or trichomonas.

 When to Refer to a Specialist

Following the initial antimicrobial course for NGU, retreatment with a macrolide antibiotic and metronidazole, and an extended course of erythromycin, the clinician should consider referring patients with PRNGU to a urologist for further evaluation. However, as detailed previously, the urologic evaluation rarely identifies an anatomic cause for urethritis.

Prognosis

Most patients with PRNGU improve following initial retreatment with a macrolide antibiotic and metronidazole, and many of the remaining cases resolve after an extended course of erythromycin therapy. In many of those whose disease recurs or does not improve following those treatments, symptoms resolve spontaneously over time. As previously noted, patients can be reassured that there is no documented association between PRNGU and any serious sequelae.