Urethritis

OVERVIEW: What every practitioner needs to know

Urethritis is a condition of inflammation of the urethra, resulting from infectious and noninfectious causes. N. gonorrhoeae and C.
trachomatis are clinically important sexually transmitted causes of urethritis, and Mycoplasma genitalium is also a significant cause of urethritis. All patients with suspected urethritis should be tested for gonorrhea and chlamydia, and presumptive therapy should include coverage for N. gonorrhoeae and C. trachomatis.For uncomplicated gonococcal urethritis, the CDC now recommends ceftriaxone 250 mg IM in a single dose. If IM ceftriaxone is not an option, an alternative treatment is cefixime 400 mg orally in a single dose. The recommended regimen for chlamydial urethritis is azithromycin 1 gram orally in a single dose or doxycycline 100 mg orally twice a day for 7days. When treating for both chlamydia and gonorrhea, the recommended regimen is a single-dose injectable cephalosporin PLUS azithromycin or doxycycline.

Are you sure your patient has urethritis? What are the typical findings for this disease?

The key symptoms of urethritis include dysuria, urethral discharge, frequency, urgency, and urethral pruritus. The key signs include urethral irritation, erythema, scant or profuse discharge, and in severe cases, meatitis.

1. Many cases of infectious urethritis, especially from sexually transmitted pathogens, are asymptomatic.

Traditionally, infectious urethritis has been divided into two categories: gonococcal urethritis, caused by N. gonorrhoeae, and nongonococcal urethritis (NGU), caused by organisms other than N. gonorrhoeae
. The most common causes of nongonococcal urethritis in the United States are C. trachomatis (15%-40%), M. genitalium (15%-25%), and to lesser degrees, T. vaginalis (2-5%), herpes simplex virus, and adenovirus. Other Mycoplasma species and Ureaplasma are inconsistent etiologic agents. An uncommon cause of NGU is enteric bacteria, associated with insertive anal intercourse.

Differentiating Gonococcal from Nongonococcal urethritis

Gonococcal urethritis, when symptomatic, has a typical presentation. Men complain of dysuria, urinary frequency, and often a profuse, purulent urethral discharge. Lack of purulent urethral discharge does not rule out gonorrhea, as 25% of cases of gonococcal urethritis in males present with scant discharge. The presentation may be acute, with all symptoms appearing with a void only hours or days after infection. Most are symptomatic at 2 to 5 days (range 1-14 days) after exposure. Commonly, erythema and edema of the urethral meatus are present. In women, there is a higher likelihood of asymptomatic or unrecognized symptoms. Abnormal vaginal discharge, menorrhagia, dysuria, and irregular menstrual bleeding are characteristic symptoms associated with gonococcal infection.

A presumptive diagnosis of gonococcal urethritis can be made with identification of Gram-negative intracellular diplococci on Gram stain of urethral or endocervical discharge.

Nongonococcal urethritis typically presents with dysuria, frequency, and clear, mucoid, or purulent urethral discharge. The presentation of symptoms is usually subacute, with symptoms that progress and may worsen over time, and further removed from the episode of sexual activity that infected the individual, as compared to gonococcal disease.

Chlamydia has a typical incubation period of 7-21 days from infection to development of symptoms. Physical examination may reveal urethral discharge, erythema, or edema.

In the case of herpes simplex virus, severe meatitis may be present. A presumptive diagnosis of nongonococcal urethritis can be made in the case of urethral discharge with the absence of Gram negative intracellular diplococci and 5 or more polymorphonuclear cells per oil immersion field on a smear of an intraurethral swab. Alternatively, a positive leukocyte esterase test on a first-void urine or microscopic examination of a urine sediment showing 10 or more polymorphonuclear cells per high power field presumes the diagnosis.

Definitive diagnosis of gonorrhea and chlamydia requires a culture, nucleic acid hybridization test, or nucleic acid amplification tests. Culture and nucleic acid hybridization tests require the more invasive urethral swab sampling, while nucleic acid amplification can be performed on urine specimens. The Centers for Disease Control and Prevention (CDC) recommends testing to determine the specific etiology of urethritis because both chlamydia and gonorrhea are reportable conditions to health departments, and specific diagnosis might improve partner notification and treatment.

What other disease/condition shares some of these symptoms?

Frequency or urgency, which are key symptoms in urethritis, are also commonly seen in a number of other associated and unrelated conditions, including bacterial cystitis, pyelonephritis, diabetes mellitus, diabetes insipidus, and viral infections such as influenza or adenovirus, as well as conditions of enuresis, including primary enuresis in younger children.

Individuals with anxiety disorders may present with frequency or urgency, increased in times of stress.

Acute or chronic prostatitis can cause perineal, penile, or pelvic discomfort as well as irritative voiding symptoms.

In females, irritative voiding symptoms can be seen with chronic pelvic pain syndrome.

A critical differentiation of urethritis from these conditions is frank urethral irritation supported by history, physical examination, or laboratory evidence.Important historical supports include a history of dysuria, perhaps in conjunction with a history of mechanical irritation (e.g. scratching, manipulating), chemical irritation (e.g. new soaps, bubble bath, topical ointments), or contact or allergic irritation (e.g., new undergarments, new detergents).

Visual evidence of inflammation or irritation of the urethra or meatus on physical exam confirms the diagnosis, but is not always obvious or appreciated by the examiner.

Laboratory evidence of urethritis includes: Gram stain of urethral secretions in men showing 5 or more white blood cells per oil immersion field, or intracellular Gram-negative diplococci; positive leukocyte esterase test on first-void urine sediment ; or first-void urine sediment demonstrating 10 or more white blood cells per high powered field.

What caused this disease to develop at this time?

• Chlamydia and gonorrhea are sexually transmitted infections that are most likely to infect young adults.

• Risk factors for chlamydia infection include younger age, presence of cervical ectopy, female gender, multiple sexual partners, recent initiation with a new sexual partner, living in a high prevalence area, prior history of sexually transmitted disease, nonwhite race (with African American predominance), and young age at sexual debut. The rate of chlamydia infection in the United States is highest among 15 to 19-year-old women, and the median chlamydia test positivity is approximately 6% in women aged 15 to 24 years screened during family planning clinic visits in all states. Urethritis is the most common problem associated with C. trachomatisin men and is more often asymptomatic than gonococcal urethral infection.

• Risk factors for gonorrhea infection are similar to risk factors for chlamydia. The primary risk factor is young age, with 60% of reported cases in 15 to 24-year-olds, and 80% of reported cases in persons younger than 30. In the United States, the rates of gonorrhea are highest in the South and among African Americans.

• Chlamydia and gonorrhea are transmitted during vaginal, anal or oral sex, and to infants during vaginal delivery. Biologic factors such as cervical ectopy, psychosocial factors such as ability to manage a sexual relationship, frequency of intercourse, low rates of appropriate or consistent use of barrier protection, and early age of first intercourse combine to account for reasons for the highest rate of infection in 15 to 19-year-olds.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

• When urethritis is suspected based on history and physical examination, clinicians should obtain laboratory studies to obtain objective evidence of urethral inflammation, by proving the presence of white blood cells, microorganisms, or both. The presence of mucopurulent or purulent discharge on examination is evidence by itself that urethritis is present.

• The Gram stain is the preferred rapid diagnostic test for evaluating urethritis. The Gram stain is sensitive and specific for documenting both urethral white blood cells and the presence or absence of gonococcal infection.

• If non-purulent secretion is present, then objective evidence of inflammation could include any of the following: Gram stain of urethral secretion with 5 or more white blood cells per oil immersion field, positive leukocyte esterase test on a first-void urine specimen, or microscopic examination of a first-void urine sediment demonstrating 10 or more white blood cells per high power field. If Gram stain shows white blood cells containing gram negative intracellular diplococci, then gonococcal infection is proven.

• All patients with confirmed or suspected urethritis should be tested for gonorrhea and chlamydia. Based upon patient risk for other sexually transmitted diseases, additional testing may also be warranted. In the presence of objective evidence of urethritis, treatment for gonorrhea and chlamydia should be provided, and specific diagnostic testing should be sent to confirm the offending agent. Nucleic acid amplification tests are preferred in particular for the detection of chlamydia infection because of their higher sensitivity than other testing modalities.

• If clinic-based diagnostic tools are not available, patients should be treated with drug regimens effective against both gonorrhea and chlamydia, and specific testing for gonorrhea and chlamydia should be performed.

• If clinic-based diagnostic tools do not identify urethritis by these objective lab criteria, testing for chlamydia and gonorrhea using nucleic acid amplification tests (NAAT) is still warranted because some men with chlamydial and gonococcal infection by NAAT will have no polymorphonuclear leukocytes on gram stain. In this context, however, the CDC recommends empiric treatment of symptomatic males only for men at high risk for infection who are unlikely to return for follow-up evaluation.

• Partners of patients treated empirically should be evaluated and treated if indicated.

Would imaging studies be helpful? If so, which ones?

• Imaging studies are not helpful nor indicated in the diagnosis of urethritis. If pyelonephritis is considered in the differential diagnosis, a renal ultrasound to rule out abscess or other radiologic studies may be considered as appropriate to assist with diagnosis of the other conditions.

If you are able to confirm that the patient has urethritis, what treatment should be initiated?

• Treatment of urethritis should be initiated as soon as possible after presumptive or confirmed diagnosis, and should cover the appropriate organisms. The recommended regimen for chlamydial urethritis that is uncomplicated by upper tract disease, such as epididymitis in a male, is azithromycin 1 gram orally in a single dose or doxycycline 100 mg orally twice a day for 7 days. Alternative regimens include erythromycin base 500 mg orally four times a day for 7 days, or erythromycin ethylsuccinate 800 mg orally four times a day for 7 days, or levofloxacin 500 mg orally once daily for 7 days, or ofloxacin 300 mg orally twice a day for 7 days.

• For uncomplicated gonococcal urethritis, the CDC now recommends ceftriaxone 250 mg IM in a single dose. Note that this is a change from the previous recommended dose of 125 mg because there is an increasingly wide geographic distribution of isolates showing decreased susceptibility to cephalosporins in vitro, increasing reports of 125 mg ceftriaxone treatment failures, improved efficacy of ceftriaxone 250 mg for eradication of pharyngeal infection which may be concurrent and is often unrecognized, and it allows for a uniform dosing recommendation for uncomplicated gonococcal disease, irrespective of infected site. If IM ceftriaxone is not an option, an alternative treatment is cefixime 400 mg orally in a single dose.

• When treating for both chlamydia and gonorrhea, the recommended regimen is a single-dose injectable cephalosporin PLUS azithromycin or doxycycline as above.

• To minimize transmission, infected individuals should abstain from sexual intercourse for at least 7 days after single dose therapy or until completion of a 7 day regimen, provided their symptoms have resolved. In addition, no return to sexual activity with prior partners should occur until those sex partners complete treatment.

• All sexual partners within the preceding 60 days should be referred for evaluation, testing, and empiric treatment for chlamydia or specific treatment based on diagnosis.

• If urethritis is a new sexually transmitted disease for the patient, testing for other infections, including syphilis and HIV, is recommended.

• Azithromycin is more effective than doxycycline for treatment of M. genitalium, the third most common cause of urethritis, and is probably more effective for U. urealyticum, another possible cause of infectious urethritis.

• Gonococcal urethritis, chlamydial urethritis, and nongonococcal, nonchlamydial urethritis might increase the risk for HIV transmission. Patients with HIV and urethritis should receive the same treatment regimen as those who are HIV negative.

• Patients should be instructed to return for evaluation if symptoms persist or recur after completion of therapy. In the context of recurrent or persistent urethritis, re-treatment is indicated if the patient did not comply with therapy or if they were re-exposed to an untreated sex partner. Treatment with azithromycin is reasonable, if the patient was initially treated with doxycycline, in order to cover for M. genitalium
  and U. urealyticum. T. vaginalis is also a known cause of urethritis, particularly in men who have vaginal intercourse with infected women. It is unlikely that men who exclusively have sex with men will benefit from therapy for T. vaginalis. Appropriate treatment for T. vaginalis is metronidazole 2 g orally in a single dose or tinidazole 2 g orally in a single dose.

What are the adverse effects associated with each treatment option?

Antibiotic treatments are usually well tolerated. Medication allergies should be confirmed prior to administration.

What are the possible outcomes of urethritis?

Most cases of uncomplicated urethritis are easily treated with short-course or single-dose antibiotics. Complications of untreated urethritis in men might include epididymitis, orchitis, or prostatitis. In women, untreated urethritis may lead to pelvic inflammatory disease, cystitis, or pyelonephritis. Persistent urethritis may facilitate HIV transmission and infection.

What causes this disease and how frequent is it?

• Epidemiology

  These issues were previously addressed above, and repeated here:

  Gonococcal urethritis is caused by N. gonorrhoeae
  , and nongonococcal urethritis (NGU) is caused by organisms other than N.
  gonorrhoeae. The most common causes of nongonococcal urethritis in the United States are C. trachomatis (15-40%), M. genitalium (15-25%), and, to lesser degrees, T.vaginalis
  (2%-5%), herpes simplex virus, and adenovirus. Other Mycoplasma species and Ureaplasma are inconsistent etiologic agents. An uncommon cause of NGU is enteric bacteria, associated with insertive anal intercourse.

  Chlamydia and gonorrhea are sexually transmitted infections that are most likely to infect young adults. Risk factors for chlamydia infection include younger age, presence of cervical ectopy, female gender, multiple sexual partners, recent initiation with a new sexual partner, living in a high prevalence area, prior history of sexually transmitted disease, nonwhite race (with African American predominance), and young age at sexual debut. The rate of chlamydia infection in the United States is highest among 15 to 19-year-old women, and the median chlamydia test positivity is approximately 6% in women aged 15 to 24 years screened during family planning clinic visits in all states. Urethritis is the most common problem acsociated with C. trachomatis in men and is more often asymptomatic than gonococcal urethral infection.

  Risk factors for gonorrhea infection are similar to risk factors for chlamydia. The primary risk factor is young age, with 60% of reported cases in 15 to 24-year-olds, and 80% of reported cases in persons younger than 30. In the United States, the rates of gonorrhea are highest in the South and among African Americans.

  Chlamydia and gonorrhea are transmitted during vaginal, anal, or oral sex, and to infants during vaginal delivery. Biologic factors such as cervical ectopy, psychosocial factors such as ability to manage a sexual relationship, frequency of intercourse, low rates of appropriate or consistent use of barrier protection, and early age of first intercourse combine to account for reasons for the highest rate of infection in 15 to 19-year-olds.

How do these pathogens/genes/exposures cause the disease?

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Other clinical manifestations that might help with diagnosis and management

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What complications might you expect from the disease or treatment of the disease?

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Are additional laboratory studies available; even some that are not widely available?

A growing number of nucleic acid amplification techniques exist for additional sexually transmitted diseases, including polymerase chain reaction (PCR) or transcription-mediated amplification (TMA) for trichomonas.

How can urethritis be prevented?

Empiric treatment for exposed sex partners is an important secondary prevention measure.

Consistent and appropriate use of barrier protection, abstinence, and limiting exposure and re-exposure to infected partners are the most important behavioral factors that prevent the acquisition and reacquisition of urethritis.

What is the evidence?

Bradshaw, CS, Tabrizi, SN, Read, TR. “Etiologies of nongonococcal urethritis: bacteria, viruses, and the association with orogenital exposure”. J Infect Dis. vol. 193. 2006. pp. 336-45. (This is a nice review of causes of NGU.)

Workowski, KA, Berman, S. “Centers for Disease Control and Prevention (CDC). Sexually Transmitted Diseases Treatment Guidelines, 2010”. MMWR Recomm Rep. vol. 59(No. RR-12). 2010. pp. 40-69. (These updated STD guidelines include recommendations for increased IM dosing of ceftriaxone for uncomplicated urethritis, and are based upon current evidence and expert opinion.)

Geisler, WM, Yu, S, Hook, EW. “Chlamydial and gonococcal infection in men without polymorphonuclear leukocytes on gram stain: implications for diagnostic approach and management”. Sex Transm Dis. vol. 32. 2005. pp. 630-4. (This important study supports the need to perform gonorrhea and chlamydia testing even without objective signs of urethritis.)

Manhart, LE, Holmes, KK, Hughes, JP. “Mycoplasma genitalium among young adults in the United States: an emerging sexually transmitted infection”. Am J Public Health. vol. 97. 2007. pp. 1118-25. (This study supports the recognition of
Mycoplasma genitalium as a significant cause of urethritis in the United States.)

Mena, LA, Mroczkowski, TF, Nsuami, M. “A randomized comparison of azithromycin and doxycycline for the treatment of Mycoplasma genitalium-positive urethritis in men”. Clin Infect Dis. vol. 48. 2009. pp. 1649-54. (This is a strong study supporting the benefit of azithromycin over doxycycline for the treatment of Mycoplasma genitalium-positive urethritis in men. Unfortunately, there is still no easy way to identify patients with Mycoplasma genitalium prior to initiating therapy.)

Ongoing controversies regarding etiology, diagnosis, treatment

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