Continuing Education Activity

Urethritis is a lower urinary tract infection that causes inflammation of the urethra—the fibromuscular tube responsible for expelling urine from the body in both males and females. In males, the urethra serves as the passage for the expulsion of semen from the body as well. Urethritis is commonly associated with sexually transmitted infections (STIs) and is classified as either gonococcal or nongonococcal. Neisseria gonorrhoeae and Chlamydia trachomatis are the main causative agents of this condition. The most common symptom of urethritis is urethral discharge.

Testing and treatment are crucial to prevent the spread of STIs. Diagnosis depends on a comprehensive patient history, physical examination, and appropriate laboratory tests to confirm the presence of infection. Although symptoms may resolve spontaneously, antibiotic treatment is usually advised, particularly in cases where infection is confirmed or for sexual partners of affected individuals. This activity examines the evaluation and management of urethritis, highlighting the essential role of interprofessional healthcare teams and their collaboration within the medical field. Such collaboration ensures well-coordinated care, leading to enhanced outcomes for affected patients and effective management and prevention of the further spread of STIs.

Objectives:

• Identify the diverse range of causative organisms associated with urethritis, including but not limited to Neisseria gonorrhoeae and Chlamydia trachomatis.

• Screen patients at risk for urethritis by obtaining a thorough sexual history and performing appropriate diagnostic tests, including nucleic acid amplification tests and microscopy.

• Select appropriate antimicrobial agents for treating urethritis, considering antimicrobial resistance patterns and patient factors such as allergies and pregnancy.

• Collaborate with interprofessional healthcare teams to ensure comprehensive care for patients with urethritis, addressing medical and psychosocial needs.

Introduction

Urethritis is a lower urinary tract infection (UTI) that causes inflammation of the urethra—the fibromuscular tube responsible for expelling urine from the body in both males and females. In males, the urethra serves as the passage for the expulsion of semen from the body as well. Urethritis is commonly associated with sexually transmitted infections (STIs) and is classified as either gonococcal or nongonococcal. Neisseria gonorrhoeae and Chlamydia trachomatis are the main causative agents of this condition and are considered STIs.[1] 

The most common symptom of urethritis is a urethral discharge.[2][3] The etiology of urethritis varies depending on geographical location and sexual practices, underscoring the importance of obtaining a detailed patient history. Furthermore, appropriate testing is essential to corroborate the patient's medical history.

Etiology

Inflammation of the urethra commonly stems from an infectious origin, with STIs being the primary cause.

Types of Sexually Transmitted Urethritis

Sexually transmitted urethritis is categorized into 2 types—nongonococcal urethritis, typically caused by C trachomatis or Mycoplasma genitalium, and gonococcal urethritis, resulting from infections with N gonorrhoeae.

Chlamydia trachomatis: C trachomatis is the most prevalent nongonococcal cause of urethritis and can be transmitted through sexual intercourse. This bacterium is a small, gram-negative obligate intracellular parasite with an average incubation period of 7 to 14 days.[4][5] Chlamydial urethritis is often asymptomatic and commonly associated with M genitalium and N gonorrhoeae (gonorrhea). C trachomatis and Ureaplasma urealyticum infections have been associated with male infertility and poor semen parameters, possibly due to an elevated rate of sperm DNA fragmentation or the production of antibodies.[6][7][8][9][10]

Neisseria gonorrhoea: N gonorrhoea is the leading cause of urethritis. N gonorrhoeae is a gram-negative diplococci bacteria transmitted through sexual intercourse with an incubation period of 2 to 5 days.[4][11] Patients are commonly coinfected with chlamydia.[4][5][11] Gonorrhea may also contribute to abnormal semen parameters and male infertility.[10]

Other specific infectious etiologies associated with urethritis include these pathogens:

• 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.[12]

• Candida spp are a common fungal yeast that can cause infections and irritation to the urogenital tract.[13][14]

• Corynebacterium glucuronolyticum, previously known as C seminale, is a diphtheroid bacterium that may also cause prostatitis in men.[15][16]

• Haemophilus influenzae is an uncommon cause of urethritis, usually transmitted through oral sex from respiratory secretions.[17]

• Herpes simplex virus (HSV), a double-stranded DNA virus, can cause a genital infection involving the urethra. Both types of HSVs (HSV-1 and HSV-2) can cause urethritis.[18][19]

• M genitalium causes recurrent or persistent urethritis and is a common causative agent in men with nongonococcal urethritis, not due to chlamydia. This organism is a microscopic, self-replicating bacteria that lacks a cell wall, which explains why it does not take up the gram stain.[20] Given its slow-growing and fastidious nature, M genitalium can be challenging to detect by culture. Only 50% of known infected specimens will demonstrate a positive culture even under optimal conditions.[3] 

• N meningitides is a gram-negative diplococcus that colonizes the nasopharynx. Transmission of this organism occurs through oral sex and is a less common cause of urethritis.[20]

• Treponema pallidum may uncommonly cause urethritis from an endourethral syphilitic chancre.[21][22]

• Trichomonas vaginalis, a flagellated parasitic protozoal STI, is a common infection affecting the urogenital tract of both men and women.[23]

• U urealyticum and U parvum are not commonly associated with urethritis but can still cause the condition.[24] These bacteria are usually present in younger men and men with fewer sexual partners. Ureaplasma should be considered when other identifiable etiologies of nongonococcal urethritis are absent.[13][25]

Non-Infectious Urethritis Etiologies 

• Irritation: Irritation of the genital area causing urethritis, which can result from the following:
  • Rubbing or pressure resulting from tight clothing or sex.
  • Physical activities, including bicycling and horseback riding.
  • Irritants, including various soaps, body powders, douches, and spermicides.

Menopausal females with insufficient estrogen levels may develop urethritis due to atrophic vaginitis—a condition characterized by thinning and drying of the tissues of the urethra and bladder, leading to irritation.[26] This is a prevalent cause of urethritis in older women.

• Trauma: Trauma is an uncommon cause of urethritis. However, inflammation and irritation may occur with intermittent catheterization, after urethral instrumentation, or from foreign body insertion. 

Epidemiology

Urethritis affects approximately 4 million Americans each year.[27] The incidence of N gonorrhoeae is estimated to be over 600,000 new cases annually, while nongonococcal urethritis accounts for approximately 3 million new cases yearly. On a global scale, there are roughly 62 million new cases of gonococcal urethritis and 89 million new cases of nongonococcal urethritis annually.

In a study involving 424 males exhibiting signs and symptoms of acute urethritis, 127 (30%) males were found to have infections of N gonorrhoeae. Among the remaining 297 males with nongonococcal urethritis, nearly half (48%) were attributed to C trachomatis, with 143 infections detected. In the subset of 154 males presenting with non-chlamydial nongonococcal urethritis, the identified agents were as follows:[2]

• M genitalium (22.7%)
• U urealyticum (19.5%)
• Human adenovirus (16.2%)
• H influenzae (14.3%)
• U parvum (9.1%)
• HSV-1 (7.1%) and HSV-2 (2.6%)
• M hominis (5.8%)
• N meningitidis (3.9%)
• T vaginalis (1.3%)

Urethritis is more commonly diagnosed in males, potentially due to the fact that up to 75% of females with the condition are asymptomatic or exhibit symptoms of cervicitis, cystitis, or vaginitis.[2][28]

Risk factors for urethritis include young age, unprotected sexual intercourse, men having sex with men, and having multiple sexual partners. Individuals between the ages of 20 and 24 are the most commonly affected age group.

• N gonorrhoeae is one of the most common STIs and and is responsible for gonococcal urethritis in males and cervicitis in females.[4][11][25]

• C trachomatis is also among the most common STIs and is the leading cause of nongonococcal urethritis in men and cervicitis in women.[4][5] The organism typically affects the columnar epithelium of the urethral mucosa and leads to cellular death after replicating in these cells.[29]

• T vaginalis infections are also prevalent; however, prevalence is difficult to quantify due to many asymptomatic cases, and these infections are not required to be reported to public health departments.[30] T vaginalis is also a common cause of nongonococcal urethritis in Africa, as it is found in 20% of men with urethritis.[31][32]
• M genitalium is the second most common causative agent of urethritis in men, found in approximately 15% to 25% of cases of male nongonococcal urethritis.[3][24][33][34]

Pathophysiology

Urethritis is diagnosed based on any of the following signs or laboratory tests:[23][35]

• Urethral mucopurulent or purulent discharge.

• Gram stain of urethral secretions revealing 2 or more white blood cells (WBCs) per oil immersion field. Gram stain is the preferred rapid diagnostic test for the initial assessment of urethritis, offering high sensitivity and specificity in documenting both urethritis and the presence (or absence) of gonococcal infections.

• A positive leukocyte esterase test on first-void urine or a microscopic examination of first-void urine sediment reveals 10 or more WBCs per high-power field.

• Utilization of nucleic acid amplification testing (NAAT).

Urethritis in men has the potential to result in infertility. In women, 10% to 40% of those with urethritis may advance to pelvic inflammatory disease, even among individuals who are initially asymptomatic.

Histopathology

Microscopic examination of the discharge from gonococcal urethritis typically shows gram-negative intracellular diplococci, which correspond to N gonorrhoeae.

A similar microscopic evaluation will reveal leukocytes without evidence of intracellular diplococci in patients with nongonococcal urethritis. The primary cause of nongonococcal urethritis is C trachomatis, which, like N gonorrhoeae, is an intracellular bacterial organism. However, C trachomatis lacks cell wall peptidoglycans, resulting in its inability to take up visible gram staining.[36] 

History and Physical

Urethritis is commonly asymptomatic, especially in women. However, if symptoms do occur, their presentation varies depending on the causative organism, commonly manifesting as dysuria or urethral discharge.

Symptoms of Urethritis

Symptoms of urethritis may include dysuria, pruritus, burning, and discharge at the urethral meatus. The presence of frank purulent discharge typically indicates gonorrhea as the causative agent, while dysuria alone is frequently associated with chlamydia. If the patient experiences dysuria alongside painful genital ulcers, the causative organism is likely to be HSV.[3] Notably, 25% to 40% of men with nongonococcal urethritis may remain asymptomatic.[37]

Typical symptoms of urethritis include the following:

• Dysuria (in men): Usually localized to the meatus or distal penis, worst during the first-morning void, and exacerbated by alcohol consumption. 

• Orchalgia: Male patients may experience testicular pain.

• Menstrual variation (in women): Symptoms may worsen during the menstrual cycle occasionally.

• Systemic symptoms: These symptoms, including chills, diaphoresis, fever, malaise, and nausea are generally absent.

• Urethral discharge: It may be brown, clear, cloudy, green, white, yellow, or blood-tinged. The presence of discharge is not necessarily related to sexual activity.
  • A thick yellow-greenish discharge would be typical of gonorrhea
  • A thick but clear or whitish discharge would be more characteristic of chlamydia.

• Urethral itching or stinging may occur when not voiding.

• Urinary frequency, urgency, and other voiding symptoms are typically absent, except as noted.

Adenovirus: Adenovirus commonly presents with intense dysuria rather than urethral irritation, aiding in its differentiation from other causes of nongonococcal urethritis. It is typically transmitted through oral sex, with upper respiratory tract symptoms occurring generally during the fall and winter months. Patients usually do not report urethral discharge.[2][25]

C glucuronolyticum: C glucuronolyticum is an uncommon etiology of urethritis, frequently observed subsequent to chlamydia treatment.[38] It typically primarily causes dysuria and produces a small-to-moderate clear discharge.[39]

C trachomatis: C trachomatis typically presents asymptomatically; however, symptomatic individuals may experience dysuria and urethral discharge.

• In cases of urethritis in females, cervicitis is often concurrent. Symptoms may manifest as dysuria, urgency, or frequency.

• Cervicitis symptoms encompass intermenstrual vaginal bleeding, post-coital bleeding, and alterations in vaginal discharge. These symptoms may also serve as the primary complaint in females with urethritis.

• Symptomatic males may present with a mucoid or thick whitish or clear discharge, alongside dysuria. Painful ejaculation and meatal soreness may also be observed.

• C trachomatis infection can lead to male infertility due to abnormal sperm parameters, affecting 15% to 40% of nongonococcal urethritis cases.

Herpes simplex virus: HSV usually presents with intense dysuria. During a physical examination, a small amount of discharge, often accompanied by meatitis and balanitis, may be observed. Although herpetic lesions may not be evident in many patients during the examination, they commonly appear shortly thereafter. 

M genitalium: These infections are commonly asymptomatic; however, when present, symptoms may include dysuria, purulent or mucopurulent urethral discharge, urethral pruritus, balanitis, and posthitis. Unlike infections caused by N gonorrhoeae, urethral discharge associated with M genitalium may not always be apparent. This organism can induce both acute and persistent urethritis in men, potentially leading to male infertility.[3][8][9][25][40] Cultures for M genitalium are notoriously challenging and often unsuccessful, even in confirmed cases, making NAAT the sole reliable method for definitive diagnosis.

N gonorrhoea: N gonorrhoeae infections in men often present with copious purulent or mucopurulent yellowish-greenish urethral discharge, although they can also be asymptomatic. In women, gonorrheal urethritis is often associated with cervicitis or may be asymptomatic. Among those experiencing urinary symptoms, dysuria is the most prevalent. Additional symptoms in women may include frequency and urgency.[2]

The genitourinary examination usually shows scant urethral serous discharge as well as meatitis and balanitis. A comprehensive physical examination is crucial as associated constitutional symptoms and conjunctivitis can aid in the diagnosis.[2][25]

Other organisms can be causative agents of urethritis, such as enteric organisms introduced via rectal exposure, such as gram-negative rods typically associated with UTIs or anal intercourse. Pathogens such as Haemophilus spp, N meningitides, Moraxella catarrhalis, and Streptococcus pneumonia, which are linked to oral sex, can also cause nongonococcal urethritis.[25]

Many patients, including approximately 25% of those with nongonococcal urethritis, are asymptomatic and seek medical attention through partner screening. Furthermore, up to 75% of women with chlamydia infection remain asymptomatic.

Physical Examination

During the physical examination of male patients, attention should be given to the abdomen, pelvis, and genitalia, incorporating the following steps:[33][34]

• The physician should inspect the patient's underwear for signs of discharge or urethral secretions.

• Palpation of the abdomen should be performed to identify any tenderness or discomfort, especially in the suprapubic area.

• Careful examination of the penis and external genitalia is necessary to detect any skin lesions indicative of an STI.

• For uncircumcised individuals, the examiner should retract the foreskin and inspect for lesions or meatitis, and also check for any urethral secretions.

• The urethral meatus should be assessed, and the urethra along the penile shaft should be palpated to detect abscess formation or foreign bodies.

• Examining the patient shortly after voiding may not yield productive results, as urination could wash away evidence of a discharge. Therefore, it is optimal if the patient refrains from voiding for at least 2 hours before the examination.

• The examiner should collect both a first voided sample and a mid-stream urine specimen.

• A bilateral testicular examination should be conducted to identify signs of inflammation or infection.

• The examiner should check for palpable inguinal lymphadenopathy.

• A digital rectal examination of the prostate should be performed if necessary.

• If needed, a specimen of the urethral discharge can be obtained by gently "milking" the penis. This involves compressing the ventral surface of the urethra with a gloved finger, starting at the base of the penis and moving slowly toward the glans.

Female patients should be positioned in the lithotomy or frog-leg position for examination. The examination should include the following steps:

• The physician should conduct a visual inspection of the skin and external genitalia to detect any potential lesions associated with STIs.

• The urethra should be examined to identify any signs of inflammation or discharge.

• The examiner should conduct a complete pelvic examination, including the urethra, anterior vaginal surface, cervix, and adnexa.

• Stripping of the urethra can be performed by positioning a finger proximally on the anterior vaginal wall, then pressing the finger anteriorly while advancing it toward the urethral meatus to express a specimen for testing.

Evaluation

Urethritis is suspected clinically when any sexually active patient presents with symptoms such as urethral pruritus, discharge, or dysuria. Urethritis is primarily diagnosed based on clinical assessment, medical history, and physical examination. However, specific diagnostic laboratory tests are used for a more precise diagnosis.[31]  

A diagnosis of urethritis is typically established based on examination revealing evidence of any of the following:

• Mucopurulent or purulent discharge from the urethral meatus.

• Detection of 2 or more WBCs per oil immersion field from a gram stain of a urethral swab.[41]

• Positive leukocyte esterase and/or the presence of 10 or more WBCs per high-power field of the first-voided urine in the absence of a UTI.

Urinalysis alone is not diagnostic for urethritis, although the first voided urine sample can be utilized for testing such as NAATs and cultures. Urinalysis can help identify or rule out a UTI. Notably, over 30% of patients with nongonococcal urethritis may not exhibit WBCs in their urine.

Gram-negative intracellular diplococci observed on microscopic examination of the discharge or a positive methylene blue/gentian violet (MB/GV) smear typically indicate gonococcal urethritis. In the absence of such findings, it is classified as nongonococcal urethritis.[31][33][34][42][43][44] A more specific diagnosis depends on the availability of additional testing, such as NAAT. 

All patients diagnosed with urethritis should undergo testing for C trachomatis and N gonorrhoeae. The preferred method is typically NAAT performed on a first-voided urine sample, endourethral swab, or endocervical sample. Additionally, NAAT for T vaginalis should be considered, as well as testing for M genitalium if available.

Additional laboratory studies may include the following:[4][5][21][30][45]

• Cervical or endourethral cultures.

• Fungal testing with a potassium hydroxide preparation.

• Gram staining.

• Nasopharyngeal and rectal swabs for N gonorrhoeae are recommended for men who have sex with men or have had exposure.

• NAAT for C trachomatis, N gonorrhea, and T vaginalis.

• Pregnancy testing as appropriate.

• STI testing, including serology for syphilis (rapid plasma reagin and Venereal Diseases Research Laboratory) and HIV.

• Urinalysis for identifying UTIs and cystitis.

• Wet mount, cultures, or NAAT are viable methods for detecting T vaginalis. 
  • Wet mounts are inexpensive but not as sensitive as cultures or NAAT.
  • Wet mounts must be conducted quickly after obtaining the specimen, as sensitivity decreases to only 20% after 1 hour.[46]
  • NAAT testing is highly sensitive and recommended even if a wet mount study yields negative results. Reported sensitivity ranges from 95% to 100%, with a corresponding specificity of 95% to 100%.[47][48][49]

The gram stain test has traditionally been the gold standard for diagnosing urethritis. However, a newer technique, the MB/GV smear, has emerged as a promising alternative to gram staining. Unlike gram staining, MB/GV does not require heat fixation and yields very similar results. Research by Taylor et al demonstrated that both gram stain and MB/GV exhibited a sensitivity of 97.3% for detecting gonococcal infections compared to cultures.[25][50] The specificity of both methods was found to be 99.6%. Further investigation revealed a 100% correlation between gram stain and MB/GV for detecting N gonorrhoeae.[25][50]

N gonorrhoeae is usually diagnosed with NAAT on a first-catch urine specimen, cervical, or urethral swab. The presence of gram-negative intracellular diplococci on microscopic examination of a urethral swab strongly suggests gonorrhea. Urethral culture provides essential information regarding antibiotic resistance. Additional diagnostic procedures include microscopy for males, urine and urethral cultures, antigen detection, and genetic probe testing using endocervical or urethral swabs.

C trachomatis can be diagnosed in females based on urinalysis showing pyuria without organisms reported on gram stain or culture. Typically, no organisms are observed on gram stain due to the organism's nature as a small gram-negative obligate intracellular parasitic bacterium. In sexually active young female patients presenting with pyuria but no bacteriuria, there should be a strong suspicion of urethritis caused by C trachomatis. The preferred laboratory test is NAAT, which uses a first-voided urine specimen. Other available tests include urethral and vaginal cultures, antigen detection, and genetic probes.[25]

Diagnosing M genitalium can be challenging, as the only definitive test is NAAT, which was approved by the US Food and Drug Administration (FDA) only in 2019 and is not yet widely available in most clinical settings.[24] Despite this limitation, it is crucial to consider M genitalium as it is the second most common cause of nongonococcal urethritis after C trachomatis, accounting for 15% to 25% of all nongonococcal urethritis cases in the United States. Furthermore, it should be suspected, particularly in patients with persistent or recurrent urethritis.[51][52][53][54][55] In addition, M genitalium may also coexist with N gonorrhoeae and C trachomatis infections in about 20% of cases.[56]

Haemophilus is becoming an increasingly common causative organism in nongonococcal urethritis, particularly among men and individuals who engage in oral sexual contact.[2][57][58][59][60]

Reactive Arthritis 

Reactive arthritis is characterized by a combination of arthritis, conjunctivitis, and urethritis, although relatively few patients will exhibit the classic triad.[61] Typically, urethritis precedes the onset of arthritis. This rare condition is most commonly observed in younger men during their second or third decades of life. The condition was formerly known as Reiter syndrome, a term that is no longer used.[61][62]

The condition typically develops a few days to several weeks after a gastrointestinal or genitourinary infection, particularly from C trachomatis, but may also include N gonorrhoeae, M hominins, and U urealyticum. Furthermore, it is believed that the disorder reflects an atypical, unusual autoimmune response triggered by an infection.[61] 

The diagnosis of reactive arthritis is usually established based on clinical findings, which may include urethritis and urinary symptoms, as well as the involvement of the metatarsophalangeal joints. Elevated serum C-reactive protein levels and HLA-B27 (a WBC surface antigen and genetic marker for autoimmunity) are often observed.[23][61][62]

Treatment for reactive arthritis is mostly symptomatic. This typically involves using nonsteroidal anti-inflammatory drugs (NSAIDs), rheumatic drugs such as sulphasalazine, and extended courses of antibiotics if there is evidence of ongoing infection. In certain instances, intra-articular steroid injections, methotrexate, and azathioprine may provide relief, especially for patients who have not responded well to NSAIDs. Please see StatPearls' companion resource, "Reactive Arthritis," for further information.[61]

Treatment / Management

Generally, urethritis symptoms will resolve over time, even without treatment. However, treatment is still recommended.

Antibiotic treatment is recommended for the following situations:[33][34]

• Patients with positive gram stain or cultures.

• Sexual contact with these patients.

• Patients with clinical urethritis who have negative gram stains or cultures but who are unlikely to return for follow-up.

In cases where a specific cause cannot be identified, or follow-up is challenging, antibiotics that target both gonococcal and nongonococcal organisms are advised, regardless of symptoms.[33][34] A recommended regimen includes ceftriaxone 250 mg administered intramuscularly, combined with either azithromycin 1 g administered orally as a single dose or doxycycline 100 mg taken orally twice daily for 7 days.

The current recommended Centers for Disease Control and Prevention (CDC) regimens for treating urethritis are mentioned below.[33][34]

Gonococcal Urethritis

The recommended treatment for gonococcal urethritis is a single dose of ceftriaxone 500 mg administered intramuscularly (IM) or intravenously (IV) for patients with a body weight of less than 150 kg.[63] For patients with a body weight of 150 kg or more, 1 g of ceftriaxone IM/IV is recommended.[63] If C trachomatis infection has not been definitively ruled out, additional treatment with doxycycline 100 mg taken orally twice daily for 7 days should be administered. Urethritis caused by N meningitidis is treated similarly. Alternative agents include a single dose of gentamicin 240 mg IM combined with azithromycin 2 g orally or cefixime 800 mg orally.[64]

Aztreonam 2 g and spectinomycin (unavailable in the United States) demonstrate effectiveness against gonococcal urethritis but not pharyngitis; therefore, these drugs are not currently recommended or preferred.[65][66][67] Quinolones and oral cephalosporins are not recommended due to significant bacterial resistance. Azithromycin alone is also no longer recommended because of the relative ease of inducing bacterial resistance to this antimicrobial.[68][33][34][68]

Nongonococcal Urethritis

Nongonococcal urethritis typically warrants empiric therapy with doxycycline 100 mg twice daily for 7 days, unless otherwise indicated. Modification of treatment may occur based on the identification of a specific causative organism. However, empiric regimens are often utilized, as no specific causative organism is detected in approximately 35% to 50% of cases of nongonococcal urethritis.[33][34][69][70]

C trachomatis and empiric therapy: For C trachomatis, the preferred treatment is doxycycline 100 mg orally twice daily for 7 days. An alternative regimen includes azithromycin 500 mg taken orally as a single dose, followed by 250 mg orally daily for 4 days (preferred), or 1 g orally as a single dose (common for compliance concerns).

While doxycycline is highly effective against C trachomatis and moderately effective against M genitalium, azithromycin shows increasing reports of failure against Chlamydia and Mycoplasma spp. However, multiday azithromycin regimens appear to offer improved efficacy.[71][72][73][74][75][76]

Erythromycin is generally not recommended due to its frequent dosing schedule, which often leads to poor compliance, and relatively high incidence of gastrointestinal adverse effects. Quinolones are also not recommended due to increasing bacterial resistance and relatively low efficacy, especially against M genitalium. For patients coinfected with gonorrhea, treatment involves one dose of 500 mg ceftriaxone IM, along with a single oral dose of 1 g azithromycin. Repeat testing for all patients is advised 3 months after treatment. 

Treatment failure: Treatment failure with initial doxycycline therapy is anticipated in approximately 6% to 12% of patients with chlamydial urethritis.[77] The primary cause of persistent or recurrent nongonococcal urethritis is often M genitalium.[78] Consequently, patients experiencing initial doxycycline treatment failure, early reinfections, or recurrent nongonococcal urethritis should be managed with azithromycin or alternative therapies guided by sensitivity testing.[77] Notably, higher dosages of azithromycin are ineffective if the standard regimen proves unsuccessful.

In cases where antibiotic sensitivities for M genitalium are unavailable, an alternative approach involves initiating doxycycline 100 mg orally twice daily for 7 days, followed by moxifloxacin 400 mg orally daily for an additional week.[79] If this regimen proves ineffective, T vaginalis infection is probable, prompting NAAT for confirmation. In regions with a high incidence of T vaginalis, healthcare providers may consider administering a single oral dose of metronidazole 2 g.[23]

Pregnant females: The recommended therapy for pregnant females is the same as that for non-pregnant women. Azithromycin 1 g orally is the recommended treatment for C trachomatis and as empiric therapy when the causative organism cannot be identified.

If pregnant females cannot tolerate the recommended treatment, they should receive one of the following regimens:

• Amoxicillin 500 mg orally 3 times daily for 7 days
• Erythromycin base 500 mg orally 4 times daily for 7 days
• Erythromycin base 250 mg orally 4 times a day for 14 days
• Erythromycin ethyl succinate 800 mg orally 4 times daily for 7 days
• Erythromycin ethyl succinate 400 mg orally 4 times a day for 14 days

Fluoroquinolones, erythromycin, and doxycycline are contraindicated for medication treatment options in pregnant or lactating females.

C glucuronolyticum: This organism generally exhibits significant resistance to many commonly used antibiotics.[34] Therefore, specific therapy depends greatly on the culture and sensitivity results.

H influenzae: Urethritis caused by H influenzae can pose challenges in treatment due to increasing bacterial resistance, particularly against azithromycin and beta-lactamase production.[58][59][60] Therefore, therapy should be based on specific culture and sensitivity outcomes, as well as regional resistance patterns.

M genitalium: For M genitalium infections, the recommended antibiotic is a single oral dose of azithromycin 1 g. In cases where azithromycin resistance is present, the recommended alternative treatment is moxifloxacin 400 mg orally daily for 1 week.[2][3][35][55][80] 

If a persistent infection is evident despite the aforementioned protocol, clinicians may consider prescribing doxycycline or minocycline 100 mg orally twice daily for 14 days. Alternatively, pristinamycin 1 g orally 4 times daily for 10 days (unavailable in the United States) may be an option.[81] Complicated infections with M genitalium may require treatment with moxifloxacin 400 mg orally daily for 2 weeks.

Fluoroquinolone resistance rates are on the rise and are currently estimated at about 10%.[82] While tinidazole exhibits promising antimicrobial activity against M genitalium, its clinical use lacks sufficient supporting evidence from studies.[82] Several other antibiotics demonstrate strong in-vitro efficacy against this organism; however, their clinical effectiveness has not yet been studied clinically.[55]

T vaginalis: In women, treatment for T vaginalis infection involves a 7-day course of metronidazole 500 mg orally twice daily, including pregnant patients, which demonstrates greater efficacy compared to a single dose of 2 g metronidazole or tinidazole.[83] For men, a single dose of 2 g metronidazole is recommended, with tinidazole being an alternative option.[83] 

Sexual partners of affected patients should undergo treatment as well. Pregnancy may decrease tolerance to medications, particularly due to significant nausea or vomiting, necessitating potential adjustments in treatment duration.[84] This consideration is also pertinent for patients with undetermined urethritis, especially in regions with a high prevalence of Trichomonas infections.[83] 

For less common causes of urethritis, treatment varies according to the underlying etiology. For instance, if urethritis is caused by irritants from clothing, management would involve changing soap and wearing less tight-fitting clothing to reduce friction. In the case of urethritis caused by adenovirus, supportive care is recommended, including hydration, NSAIDs, and bed rest, as the illness typically resolves independently.

Differential Diagnosis

Genitourinary and sexually transmitted infections may affect one or more portions of the genitourinary tract, simultaneously or independently, including the urethra.[4] UTIs, reactive arthritis, and interstitial cystitis may also cause symptoms similar to urethritis.[85]

Some cases of dysuria may be idiopathic, meaning an underlying cause cannot be determined.[85] In males, other potential causes of similar symptoms include prostatitis, epididymitis, cystitis, proctitis, orchitis, epididymitis, chancroid, human papillomavirus, urethral trauma, urethral strictures, and chemical irritation.

For female patients, the differential diagnoses include cervicitis, cystitis, pelvic inflammatory disease, proctitis, urethral pain syndrome, and vaginitis.

Prognosis

Patients generally have an excellent prognosis with a high cure rate when diagnosed and treated appropriately. Notably, it is crucial to address treatment for sexual partners when necessary, particularly for specific infectious organisms. Unfortunately, sexually active individuals are commonly reinfected by their untreated partners.

In cases of persistent urethritis after treatment for the most likely organisms, it is important to investigate for coinfections and other less common causative agents. Prompt identification and treatment are important, as several of these causative organisms carry the risk of causing damaging complications.

Nongonococcal urethritis is essentially a self-limited disorder that generally resolves without complications in most cases.

Complications

Complications from the most common causes of urethritis, including those caused by N gonorrhoeae, have been associated with male infertility, unexplained penile edema, periurethral abscesses, postinflammatory urethral strictures, and penile lymphangitis. Other rare complications include epididymitis, proctitis, and reactive arthritis.

Complications from nongonococcal urethritis are more commonly observed in women, with rates of up to 40%, compared to men. These complications often include pelvic inflammatory disease.

Urethral infections caused by C trachomatis may lead to various complications, including pelvic inflammatory disease, infertility, ectopic pregnancy, Fitz-Hugh-Curtis syndrome, proctitis, lymphogranuloma venereum, fistulas, strictures, and reactive arthritis.[23][86]

Complications of urethritis in pregnancy may include ectopic pregnancies, infertility, and pelvic inflammatory disease. 

• Newborns born to mothers with C trachomatis can develop eye problems such as conjunctivitis, iritis, neonatal bronchopulmonary dysplasia, and pneumonia.[87]

• The routine use of antibiotic eye ointment for all newborns has substantially reduced infectious ocular complications.[88] 

• Chlamydia urethritis can also result in lymphogranuloma venereum with lymphangitis, genital ulcers, lymphatic obstruction, and fistula formation.[89] Please see StatPearls' companion resource, "Lymphogranuloma Venereum," for further information.[89]

A complete reactive arthritis triad, previously known as Reiter syndrome, includes arthritis, conjunctivitis, and urethritis, typically occurring following a C trachomatis infection.[61] This rare syndrome is due to an altered immune system and may also cause acute epididymitis, orchitis, and prostatitis.[25][61]

Deterrence and Patient Education

If an STI is diagnosed, it is important to educate the patient on safe sexual practices. This includes discussing the importance of informing their partner(s) and encouraging them to seek medical attention. In addition, it is important to emphasize the possibility of recurrence even if their partner(s) are asymptomatic, as they may still have asymptomatic infections.

All of the recent sexual contacts (within 60 days) of patients diagnosed with urethritis caused by C trachomatis, N gonorrhoeae, or T vaginalis should be tested for these organisms and generally be treated for a possible infection unless specifically tested negative. Additionally, many experts recommend testing for M genitalium as well. Patients should be educated on refraining from intercourse until both the patient and partner(s) have been successfully treated and are without symptoms.

Known risk factors for urethritis include the following:

• Commercial sex workers
• Having multiple sexual partners with an increased number of sexual exposures
• Homeless individuals (best treated with single-dose therapy, where possible)
• Illegal drug users
• Intercourse with individuals known to have infections or previous STIs
• Intercourse without proper protection (condoms)
• Men having sex with men have the highest risk 
• Sexual activity beginning at a young age

Pearls and Other Issues

• The most common organisms causing urethritis are N gonorrhoeae, C trachomatis, and M genitalium.

• M genitalium and T vaginalis are the organisms most likely to be responsible for resistant or recurrent urethritis episodes.

• The most common presentation is dysuria and urethral discharge.

• N gonorrhoeae, C trachomatis, and M genitalium can all affect sperm parameters and may cause male infertility.[10]

• The diagnosis is based on a microscopic examination of the discharge or a swab of 2 or more or a first voided urine sample with 10 or more WBCs.

• No specific etiological cause can be found in up to about 35% of patients with nongonococcal urethritis.[39][90]

• If gonorrhea cannot be ruled out, initial therapy should include ceftriaxone (250 mg IM/IV) and doxycycline (100 mg BID for 7 days) to cover both gonococcal and nongonococcal organisms.

• Patients suspected of an STI should also be tested for syphilis and HIV.

• NAAT testing can be done for C trachomatis, N gonorrhoea, and T vaginalis as well as for M genitalium, if available.

• Patients should be instructed to avoid sex for 1 week and ensure treatment of their partners.

Enhancing Healthcare Team Outcomes

Diagnosing urethritis can be challenging if patients are hesitant to discuss their sexual practices. Establishing a robust doctor-patient relationship is crucial to fostering an environment where patients feel comfortable disclosing vital information. Physicians should collaborate with other healthcare staff to cultivate a supportive, comfortable, and nonjudgmental atmosphere. Clinicians should also collaborate closely with pharmacists to ensure optimal antibiotic selection for treatment. Pharmacists verify appropriate coverage, dosing, and duration. Additionally, physicians should not hesitate to seek assistance from infectious disease specialists when needed.

Nurses are critical in charting patient progress, providing counseling on medication compliance, addressing patient inquiries, and reporting any concerns or results to the clinical team. Social workers can assist patients who are uninsured or require additional community resources. Maintaining patient trust and confidentiality is paramount for all members of the healthcare team. Ensuring patient and community safety involves prescribing the most effective antibiotics and promoting medication compliance. Additionally, some STIs are mandated to be reported to public health agencies as required by law and regulation. By adopting an interprofessional team approach to testing and treating patients, healthcare providers can optimize patient care outcomes, enhance medication compliance, and effectively eradicate the disease.