• • Requires objective signs of urethral inflammation.

Nongonococcal Urethritis

• • 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.

An estimated two million cases of nongonococcal urethritis (NGU) occur in the United States each year. Approximately 30–50% 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).