Continuing Education Activity

Urethritis is a lower urinary tract infection causing inflammation of the urethra, a fibromuscular tube through which urine exits the body in both males and females and through which semen exits the body in males. Urethritis is strongly associated with sexually transmitted infections and is characterized as gonococcal or nongonococcal. The most common symptom of urethritis is urethral discharge. This activity reviews the evaluation and management of urethritis and highlights the role of interprofessional team members in collaborating to provide well-coordinated care and enhance outcomes for affected patients.

Objectives:

• Identify the etiology of urethritis.
• Review the epidemiology of urethritis.
• Outline the treatment and management options available for urethritis.
• Explain interprofessional team strategies for improving care and outcomes in patients with urethritis.

Introduction

Urethritis is inflammation of the urethra and is a lower urinary tract infection. The urethra is a fibromuscular tube through which urine exits the body in both males and females and semen in males. Urethritis has a strong association with sexually transmitted infections (STIs). Urethritis is characterized as gonococcal or nongonococcal infections. Neisseria gonorrhea and Chlamydia trachomatis are the most common causative organisms of STIs.[1] The most common symptom of urethritis is urethral discharge.[2][3]

Etiology

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

• Neisseria gonorrhea is the leading cause of urethritis. Neisseria gonorrhea is a gram-negative diplococci bacteria transmitted through sexual intercourse. The incubation period is 2-5 days. Patients are commonly co-infected with Chlamydia trachomatis.
• Chlamydia trachomatis is the most common nongonococcal cause of urethritis and is also transmittable through sexual intercourse. Chlamydia trachomatis is a small gram-negative obligate intracellular parasitic bacteria. The incubation period is usually 7-14 days. It is commonly co-infected with Mycoplasma genitalium and Neisseria gonorrhea.

Other infectious etiologies associated with urethritis include:

• Mycoplasma genitalium is a cause of recurrent or persistent urethritis and is commonly a 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]
• Trichomonas vaginalis, a flagellated parasitic protozoal STI, is a common infection affecting the urogenital tract of both men and women. [4]
• Herpes Simplex virus, a double-stranded DNA virus, can cause a genital infection involving the urethra. 
• Adenovirus is an uncommon cause of urethritis in men. However, it should be considered in all males presenting with dysuria, meatitis, and associated conjunctivitis or constitutional symptoms.[5]
• Treponema pallidum may cause urethritis from an endourethral syphilitic chancre; uncommon.
• Haemophilus influenzae is an uncommon cause of urethritis transmitted through oral sex from respiratory secretions.
• Neisseria meningitides is a gram-negative diplococcus that colonizes the nasopharynx. Transmission of this organism is through oral sex and is a less common cause of urethritis.
• 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.[6]
• Candida species are a common fungal yeast that can cause infections and irritation to the urogenital tract.[7]

Non-infectious etiologies associated with urethritis include:

• Trauma is less commonly the cause of urethritis. However, inflammation and irritation may occur with intermittent catheterization, after urethral instrumentation, or from foreign body insertion.
• Irritation of the genital area may also result in urethritis from:
  • Rubbing or pressure resulting from tight clothing or sex.
  • Physical activity including activities such as bicycle riding.
  • Irritants including various soaps, body powders, and spermicides.
  • Menopausal females with insufficient estrogen levels may develop urethritis due to the tissues of the urethra and bladder becoming thinner and dryer, causing irritation. This is a very common cause of urethritis in older women.

Epidemiology

Urethritis has an incidence of affecting 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, of which 127 (30%) had infections of N. gonorrhea. In the other 297 males with nongonococcal urethritis, the infectious agent in almost half of them was C. trachomatis, with 143 (48.1%) infections. In 154 men presenting with non-chlamydial nongonococcal urethritis, the agents detected were: M. genitalium (22.7%), U. urealyticum (19.5%), human adenovirus (16.2%), H. influenzae (14.3%), U. parvum (9.1%), M. hominis (5.8%), 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.[6]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. Trichomonas vaginalis infections are also very common; however, prevalence is difficult to quantify due to many asymptomatic cases, and these infections are not required to be reported to public health departments. Vaginalis is also a common cause of nongonococcal urethritis in Africa.[8]Mycoplasma genitalium is the causative agent in approximately 15-20% of nongonococcal urethritis in men.[3]

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

Pathophysiology

Urethritis is documented based on any of the following signs or laboratory tests [9][4]:

• Urethral mucopurulent or purulent discharge.
• Gram stain of urethral secretions showing >2 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.
• Positive leukocyte esterase test on first-void urine or microscopic exam of a first-void urine sediment showing greater than 10 WBC per high-power field.

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 the herpes simplex virus.[3]

Neisseria gonorrhea is often associated with copious purulent or mucopurulent urethral discharge in men or can be asymptomatic.  In women, urethritis is often associated with cervicitis or may be asymptomatic. If symptoms are present, 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 and urethral discharge. Females with urethritis usually also have cervicitis. Female patients may report dysuria, urgency, or frequency.  Symptoms of cervicitis include intermenstrual vaginal bleeding, post-coital bleeding, and changes in vaginal discharge. Cervicitis symptoms may be the reported chief complaint of females with urethritis. Males that are symptomatic may complain of mucoid or watery discharge and dysuria.  A small number of patients with chlamydial urethritis may develop reactive urethritis triad. 

Mycoplasma genitalium infections are commonly 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][6]

Herpes simplex virus usually presents with intense dysuria. On physical examination, a limited amount of discharge can be present and commonly meatitis and balanitis. The majority of patients may not have herpetic lesions present at the time of examination but generally presents shortly after. 

Adenovirus commonly presents with intense dysuria instead of urethral irritation, which helps differentiates it from 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. The genitourinary examination usually shows scant urethral serous discharge as well as meatitis and balanitis. It is important to perform a complete physical examination as associated constitutional symptoms and conjunctivitis assist in the diagnosis.[2][6]

Some data indicate that enteric organisms are causative agents of urethritis from rectal exposure — gram-negative rods from urinary tract infections or anal sex. Haemophilus species, Neisseria meningitides, Moraxella catarrhalis, and Streptococcus pneumonia are pathogens associated with oral sex causing NGU.[6]

Evaluation

Urethritis is clinically suspected when any sexually active patient 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.[8]  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 the 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. [10] 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 a 100% correlation between Gram stain and MB/GV for the detection of GC.[6]

Neisseria gonorrhea is diagnosed initially with nucleic acid amplification testing with first-catch urine or urethral swab. Urethral swab Gram stain exhibits gram-negative diplococci bacteria. 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. No organisms are generally seen on Gram stain due to the organism being a small gram-negative obligate intracellular parasitic bacteria. 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 the Nucleic acid amplification test with a first-void urine.  Other available tests are urethral culture, vaginal culture, antigen detection, and genetic probes.[6]

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

Therapy should be directed based on the offending agent causing the urethritis.

Gonococcal urethritis: the recommended treatment of choice is a single dose of ceftriaxone 500 mg intramuscular injection. If chlamydia has not been excluded, treatment with doxycycline 100 mg twice a day for 7 days is added. 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 500 mg 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 500 mg orally three times daily for seven days
• Erythromycin base 500 mg orally four times daily for seven days
• Erythromycin base 250 mg orally four times a day for 14 days
• Erythromycin ethyl succinate 800 mg orally four times daily for seven days
• Erythromycin ethyl succinate 400 mg orally four times a day for 14 days

In females who are pregnant or lactating, the following medication treatment 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 azithromycin. 

Mycoplasma genitalium: the recommended antibiotic of choice is azithromycin 1 gram orally as a single dose, similar to treating Chlamydia. For those patients' infections resistant to treatment with azithromycin, moxifloxacin is a treatment alternative.[2][3][9]

Trichomonas vaginalis urethritis, including pregnant patients, should be treated with seven days of metronidazole 500 mg orally twice a day. Tolerance in pregnancy may be reduced due to significant nausea or vomiting, so the length of treatment may be allowed to vary from five to seven days. [11]

The treatment regimens for the more common causes of urethritis are stated above. For the less common causes, the therapy still depends on the etiology. An example of urethritis caused by irritants from clothing, the therapy would include changes in soap and the reduction of friction with less tight-fitting clothing. Another example is that adenovirus is treated with supportive care involving hydration, NSAIDs, and bed rest due to no current medical therapy approved, and is a self-limiting illness.

Differential Diagnosis

Genitourinary infections may affect one or more portions of the genitourinary tract simultaneously or independently. Other causes of similar symptoms in males include prostatitis, epididymitis, cystitis, proctitis, and chemical irritation. The differential diagnosis in female patients includes cervicitis, cystitis, and vaginitis.

Prognosis

Patients have an excellent prognosis with a high rate of cure when diagnosed and treated appropriately. Treatment for sexual partners should be addressed when appropriate for specific infectious organisms. Unfortunately, sexually active individuals are commonly reinfected by untreated partners. With persistent urethritis after treatment for the most common organisms, it is important to investigate for co-infections and other less common causative agents.  It is important for prompt identification and treatment as several of the causative organisms do carry the risk for unpleasant and damaging complications.

Complications

Complications for the most common causes of urethritis, including those from Neisseria gonorrhea, have shown associations with some rare complications, including penile edema, periurethral abscesses, post-inflammatory urethral strictures, and penile lymphangitis. Conditions associated with Chlamydia trachomatis complications include pelvic inflammatory disease, infertility, ectopic pregnancy, Fitz-Hugh-Curtis syndrome, proctitis, and reactive arthritis. A complete reactive arthritis triad, also known as Reiter syndrome, includes urethritis, uveitis, and arthritis. This is a rare disease that may be caused by Chlamydia trachomatis and involve acute epididymitis, orchitis, and prostatitis.[6]

Deterrence and Patient Education

If an STI was diagnosed, it is important to educate the patient on safe sexual practices. This includes discussing with the patient for them to inform their partner(s) and encourage them to have themselves evaluated by a health care professional and pursue appropriate treatment. It is important to stress the likelihood of how a recurrence can occur even if their partner(s) are asymptomatic as they may have asymptomatic infections. Patients should be educated on refraining from intercourse until both the patient and partner(s) have been successfully treated and are without symptoms.

Enhancing Healthcare Team Outcomes

Diagnosing urethritis can be a challenge if patients do not feel comfortable discussing their sexual practices. For patients to feel at ease and disclose important history, a robust doctor-patient relationship must exist. Doctors should work closely with other staff to ensure patient comfort and a non-judgemental environment. 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. 

Clinicians should work closely with a pharmacist to ensure the best antibiotic choices for treatment, with the pharmacist verifying appropriate coverage, dosing, and duration. Patient and community safety are affected by ensuring the prescribing of the best antibiotic and medication compliance. Nursing can chart progress and counsel the patient on compliance, as well as answer any patient questions and report concerns or results to the clinical team. The patient's confidentiality is a priority, as well as reporting diseases. 

Having an interprofessional team approach to testing and treating patients will maximize patient care benefits and medication compliance while eradicating the disease. [Level 5]