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Urethritis

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Last Update: January 6, 2019.

Introduction

Urethritis is inflammation of the urethra and is a lower urinary tract infection.

The urethra is a fibro-muscular tube that urine exits the body through, and semen in males. 

Urethritis is characterized as gonococcal or nongonococcal.

Urethritis has a strong association with sexually transmitted infection (STI).

Neisseria gonorrhea and Chlamydia trachomatis are the most common causative organisms of STI.[1]

The most common symptom of urethritis is urethral discharge.[2][3]

Etiology

Inflammation of the urethra is most frequently an infectious etiology, with STIs being the most common cause. Sexually transmitted urethritis has two classifications: gonococcal urethritis (GCU) following infection with Neisseria gonorrhea or nongonococcal urethritis (NGU). 

Other etiologic agents associated with urethritis include:

  1. Neisseria gonorrhea is the leading cause of urethritis. Neisseria gonorrhea is a gram-negative diplococci bacteria transmitted through sexual intercourse. Patients are commonly co-infected with Chlamydia trachomatis. The incubation period is 2-5 days. 
  2. Chlamydia trachomatis is the most common nongonococcal cause of urethritis and is transmittable through sexual intercourse. Chlamydia trachomatis is a small gram-negative obligate intracellular parasite. It is commonly co-infected with Mycoplasma genitalium and Neisseria gonorrhea.  The incubation period is usually 7-14 days. 
  3. Mycoplasma genitalium can cause recurrent or persistent urethritis and is commonly the causative agent in men with nongonococcal urethritis.  This organism is small self-replicating bacteria lacking a cell wall. This organism can be difficult to detect given its slow-growing nature.[3]
  4. Neisseria meningitides is a gram-negative diplococcus and colonizes the nasopharynx. Transmission of this organism is commonly through fellatio. It is a less common cause of urethritis. 
  5. Herpes Simplex virus - double stranded DNA virus. 
  6. Adenovirus- Adenovirus is an uncommon cause of urethritis in men, it should be considered in all males presenting with dysuria, meatitis, and associated conjunctivitis or constitutional symptoms.[4]
  7. Treponema pallidum - from an endourethral syphilitic chancre can lead to urethritis; uncommon.
  8. Hemophilus influenza is an uncommon cause of urethritis transmitted through oral sex from respiratory secretions. 
  9. Trichomonas vaginalis.
  10. Ureaplasma urealyticum and ureaplasma parvum; some studies show ureaplasma has uncommon links to urethritis.  In patients that have tested positive, it is usually in younger men and men with fewer sexual partners.  This causative agent should be of suspicion when other identifiable etiologies of nongonococcal urethritis are absent.[5]
  11. Candida species (yeast).[6]
  12. Trauma is a less commonly a cause of urethritis, but it can occur with intermittent catheterization or after urethral instrumentation or foreign body insertion.
  13. Irritation of the genital area may also result in urethritis from:
    • Rubbing or pressure resulting from tight clothing or sex
    • Physical activity including activities like bicycle riding
    • Irritants to include soap, body powder, and spermicides
    • Insufficient female hormone estrogen causes the tissues of the urethra and bladder to get thinner and drier after menopause, which is a common cause of urethritis in older women.

Epidemiology

Urethritis has an incidence of 4 million Americans each year. The incidence of Neisseria gonorrhea is estimated at over 600,000 new cases annually, and the incidence of nongonococcal urethritis is approximately 3 million new cases annually.

In one study of 424 men presenting with signs and symptoms of acute urethritis, 127 (30%) has infections of N. gonorrhea. In 297 males with nongonococcal urethritis, C. trachomatis was the infectious agent in 143 (48.1%). In 154 men presenting with non-chlamydial nongonococcal urethritis, The agents detected were: M. genitalium (22.7%), M. hominis (5.8%), U. urealyticum (19.5%), U. parvum (9.1%), H influenzae (14.3%), human adenovirus (16.2%), N meningitidis (3.9%), T vaginalis (1.3%), and various forms of herpes simplex virus 1 (7.1%) and 2 (2.6%).[2]

Urethritis is more commonly diagnosed in males.[2] Risk factors include young age, unprotected sexual intercourse, and multiple sexual partners. 

Neisseria gonorrhea is one of the most common sexually transmitted diseases and the bacterial cause of gonococcal urethritis in males and cervicitis in females.[5]

Chlamydia trachomatis is among the most common sexually transmitted diseases. It is the most common cause of nongonococcal urethritis in males and cervicitis in females.  

Mycoplasma genitalium is the causative agent in 15-20% of nongonococcal urethritis in men.[3]

Trichomonas vaginalis is a common cause of nongonococcal urethritis in Africa.[7]

For cases of NGU, Chlamydia trachomatis continues to be a primary concern, although Trichomonas vaginalis and Mycoplasma genitalium are increasingly recognized as significant pathogens, and less commonly Ureaplasma parvum, Ureaplasma urealyticum, Mycoplasma hominis, and Gardnerella vaginalis.

Pathophysiology

Urethritis is documented based on any of the following signs or laboratory tests:

  • Mucopurulent or purulent discharge.
  • Gram stain of urethral secretions showing >5 WBC per oil immersion field. Gram stain is the rapid diagnostic test of choice for testing urethritis. It has high sensitivity and specificity for documenting both urethritis and the presence (or absence) of gonococcal infection. Establishing gonococcal infection is by documenting white blood cells containing GNID.
  • Positive leukocyte esterase test on first-void urine or microscopic exam of first-void urine sediment showing >10 WBC per high-power field.[8]

History and Physical

Urethritis is commonly asymptomatic; if symptomatic the symptoms vary based on the causative organism.

Symptoms of urethritis may include dysuria, pruritus, burning and discharge at the urethral meatus.  Frank purulent discharge suggests gonorrhea as the causative organism. Dysuria alone is common among chlamydia. If the patient has dysuria with painful genital ulcers, the causative organism is most likely herpes simplex virus.[3]

Neisseria gonorrhea is often associated with copious purulent or mucopurulent urethral discharge in men and can be asymptomatic.  In women, urethritis is often associated with cervicitis and can be asymptomatic. If symptoms are presents, dysuria is the most common.  Other symptoms in women can include frequency and urgency.[2]

Chlamydia trachomatis is most commonly asymptomatic. Symptomatic patients can have dysuria, urethral discharge. Females with urethritis usually have cervicitis as well and often are asymptomatic. Female patients may report dysuria, urgency or frequency.  Symptoms of cervicitis include intermenstrual vaginal bleeding, post-coital bleeding, and changes in vaginal discharge, which can be the reported chief complaint of females with urethritis. Males that are symptomatic can complain of mucoid or watery discharge, dysuria.  A small number of patients with chlamydia urethritis may develop reactive urethritis triad. 

Mycoplasma genitalium infections are usually asymptomatic, however; symptoms may include dysuria, purulent or mucopurulent urethral discharge, urethral pruritus, balanitis, and posthitis. The urethral discharge is commonly associated with this organism but, is not always evident in contrast to the Neisseria gonorrhea infections. It can cause acute and persistent urethritis in men.[3][5]

Herpes simplex virus usually presents with intense dysuria, and on physical examination, a limited amount of discharge can be present and commonly meatitis and balanitis. Majority of patients may not have herpetic lesions present on physical examination. 

Adenovirus commonly presents with intense dysuria instead of urethral irritation than other causes of nongonococcal urethritis. Usually transmitted by oral sex with upper respiratory tract symptoms generally during fall and winter months. Patients usually do not report urethral discharge. Physical examination usually shows scant urethral serous discharge; meatitis and balanitis are often present and may demonstrate associated constitutional symptoms and conjunctivitis.[2][5]

Some data indicate that enteric organisms are causative agents of urethritis from rectal exposure — gram-negative rods from urinary tract infections or insertive anal sex. Hemophilus species, Neisseria meningitides, Moraxella catarrhalis, and Streptococcus pneumonia are pathogens associated with insertive oral sex causes of NGU.[5]

Evaluation

Urethritis is clinically suspected when any sexually active man who presents with symptoms consistent with urethritis including pruritus, discharge or dysuria. Urethritis is mostly a clinical diagnosis based on history and physical examination, however; there are some specific diagnostic laboratory tests utilized.[7]  Diagnosis is made based on examination showing evidence of mucopurulent or purulent discharge, >2 WBC per oil immersion field from gram stain of a urethral swab, positive leukocyte esterase and/or presence of >10 WBCs per high-power field of the first-void urine. Diagnosis depends on the availability of point-of-care testing.   The gram stain test has been traditionally the gold standard for diagnosis of urethritis.   A new technique (methylene blue/gentian violet [MB/GV] smear) has had reports as an alternative to Gram staining. MB/GV does not require heat fixation and has very similar performance characteristics to Gram stain. Taylor et al. [9] found the sensitivity of both Gram stain and MB/GV to be 97.3% for the detection of gonococcal infection compared with culture. The specificity of Gram stain and MB/GV was 99.6%, and investigation showed 100% correlation between Gram stain and MB/GV for the detection of GC.[5]

Neisseria gonorrhea is diagnosed initially with nucleic acid amplification testing with first-catch urine or urethral swab. A urethral culture provides essential information regarding antibiotic resistance. Other diagnostic testing includes microscopy for males, culture, urethral culture, antigen detection, and endocervical or urethral swabs used with genetic probe methods.  

Chlamydia trachomatis is diagnosable in females based on urinalysis revealing pyuria with no organisms reported on Gram stain or culture. In sexually active young female patients with pyuria and no bacteriuria, there should be a strong suspicion of urethritis caused by chlamydia. The laboratory test of choice is Nucleic acid amplification test with first-void urine.  Other available tests are urethral culture, vaginal culture, antigen detection, genetic probes.[5]

Mycoplasma genitalium diagnosis can be difficult, however; the only FDA approved test is nucleic acid amplification tests which in most clinical settings are widely unavailable.

Treatment / Management

Gonococcal urethritis: the recommended treatment of choice is a single dose of ceftriaxone 250mg intramuscular injection and a single dose of oral 1 gram of azithromycin to cover for coinfection with chlamydia. Neisseria meningitides urethritis is treated the same. 

Nongonococcal urethritis: the recommended treatment:

Chlamydia trachomatis: The treatment of choice is a single dose of 1 gram of oral azithromycin or 100mg doxycycline twice a day for seven days. Alternative treatment options are ofloxacin 300mg orally twice daily for seven days or levofloxacin 500mg orally once a day for seven days.  If coinfected with gonorrhea treatment with one dose of 250mg  ceftriaxone intramuscular injection in addition to 1 gram oral single dose azithromycin.  In pregnant females, 1 gram orally of azithromycin is the recommended treatment. If pregnant females are unable to tolerate recommended treatment, these patients should have treatment with one of the following regimens:

  • Amoxicillin 500mg orally three times daily for seven days
  • Erythromycin base 500mg orally four times daily for seven days
  • Erythromycin base 250mg orally four times a day for 14 days
  • Erythromycin ethyl succinate 800mg orally four times daily for seven days
  • Erythromycin ethyl succinate 400mg orally four times a day for 14 days

In females who are pregnant or lactating the following medication treatments options are contraindicated- levofloxacin, ofloxacin, erythromycin estolate,  and doxycycline. 

All patients should undergo repeat testing three months after treatment and reinfection should receive therapy with of azithromycin. 

Mycoplasma genitalium: the recommended antibiotic of choice is azithromycin 1 gram orally as a single dose. For those patients resistant to treatment with azithromycin, moxifloxacin is a treatment alternative.[2][3][8]

Differential Diagnosis

Other causes of similar symptoms in males include prostatitis, epididymitis, cystitis, proctitis and chemical irritation.

Differential diagnosis in female patients include cervicitis, cystitis, vaginitis.

Complications

Neisseria gonorrhea shows associations with some rare complications including penile edema, periurethral abscesses, post-inflammatory urethral strictures, and penile lymphangitis. 

Conditions associated with Chlamydia trachomatis include pelvic inflammatory disease, infertility, ectopic pregnancy, Fitz-Hugh-Curtis syndrome, proctitis, and reactive arthritis. 

Complete reactive arthritis triad also known as Reiter syndrome includes urethritis, uveitis and arthritis is a rare disease most commonly caused by Chlamydia trachomatis, acute epididymitis, orchitis, and prostatitis.[5]

Enhancing Healthcare Team Outcomes

Diagnosing urethritis can be a challenge if patients do not feel comfortable discussing their sexual practices. For the patients to feel at ease to disclose important history, a robust doctor-patient relationship must exist.  Doctors should work closely with other staff to ensure patient comfort and patient care. Pertinent history can lead to different suspected organisms, and since treatment is organism-specific, it is imperative to maintain and establish this relationship early on. 

Physicians should work closely with a pharmacist to ensure the best antibiotic choices for treatment. Patient and community safety are affected by ensuring prescription of the best antibiotic and medication compliance. The patient's confidentiality is a priority as well as reporting diseases. 

By having a team approach to testing and treating patients, it will maximize patient care benefit and medication compliance while eradicating the disease. 

Questions

To access free multiple choice questions on this topic, click here.

References

1.
Ito S, Hanaoka N, Shimuta K, Seike K, Tsuchiya T, Yasuda M, Yokoi S, Nakano M, Ohnishi M, Deguchi T. Male non-gonococcal urethritis: From microbiological etiologies to demographic and clinical features. Int. J. Urol. 2016 Apr;23(4):325-31. [PubMed: 26845624]
2.
Bachmann LH, Manhart LE, Martin DH, Seña AC, Dimitrakoff J, Jensen JS, Gaydos CA. Advances in the Understanding and Treatment of Male Urethritis. Clin. Infect. Dis. 2015 Dec 15;61 Suppl 8:S763-9. [PubMed: 26602615]
3.
Bradshaw CS, Tabrizi SN, Read TR, Garland SM, Hopkins CA, Moss LM, Fairley CK. Etiologies of nongonococcal urethritis: bacteria, viruses, and the association with orogenital exposure. J. Infect. Dis. 2006 Feb 01;193(3):336-45. [PubMed: 16388480]
4.
Totten PA, Schwartz MA, Sjöström KE, Kenny GE, Handsfield HH, Weiss JB, Whittington WL. Association of Mycoplasma genitalium with nongonococcal urethritis in heterosexual men. J. Infect. Dis. 2001 Jan 15;183(2):269-276. [PubMed: 11120932]
5.
Burstein GR, Zenilman JM. Nongonococcal urethritis--a new paradigm. Clin. Infect. Dis. 1999 Jan;28 Suppl 1:S66-73. [PubMed: 10028111]
6.
Bradshaw CS, Denham IM, Fairley CK. Characteristics of adenovirus associated urethritis. Sex Transm Infect. 2002 Dec;78(6):445-7. [PMC free article: PMC1758335] [PubMed: 12473808]
7.
Bedük Y, Manalp M. [Detection of candidiasis in non-gonococcal urethritis resistant to therapy]. Mikrobiyol Bul. 1986 Jul;20(3):190-5. [PubMed: 3561282]
8.
Workowski KA, Berman SM. Centers for Disease Control and Prevention Sexually Transmitted Disease Treatment Guidelines. Clin. Infect. Dis. 2011 Dec;53 Suppl 3:S59-63. [PubMed: 22080270]
9.
Taylor SN, DiCarlo RP, Martin DH. Comparison of methylene blue/gentian violet stain to Gram's stain for the rapid diagnosis of gonococcal urethritis in men. Sex Transm Dis. 2011 Nov;38(11):995-6. [PubMed: 21992973]
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Bookshelf ID: NBK537282PMID: 30725967

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