Urethritis: causes, symptoms, diagnosis, treatment

Urethritis is an inflammation of the urethral mucosa. It manifests as burning and pain during urination (dysuria), itching, redness of the external urethral opening, and various types of discharge. In men, symptoms are usually more pronounced (especially with gonorrhea), while in women, they often masquerade as cystitis or cervicitis and require careful investigation. It is important to distinguish urethritis from bladder infections: with urethritis, the initial site of urination is most often affected, and a general urine analysis may be "modest" or normal. [1]

Etiologically, urethritis is divided into gonococcal (caused by Neisseria gonorrhoeae ) and non-gonococcal (including Chlamydia trachomatis, Mycoplasma genitalium, Trichomonas vaginalis, and, less commonly, adenoviruses and herpes simplex virus, as well as mixed bacterial flora). In real-world practice, a significant proportion of cases remain undetected even with extensive testing: in such cases, the diagnosis is formulated as non-specific urethritis. The choice of treatment and the prevention of infection transmission to partners depend on the correct diagnostic algorithm. [2]

A key modern feature is the mandatory use of nucleic acid amplification tests (NAATs) on the "first portion" of urine in men and from appropriate anatomical locations in women/MSM (oropharynx, rectum), as well as systematic confirmation of inflammation with simple "screening" tests (leukocyte esterase and/or ≥10 leukocytes per high-power field in the sediment of the first portion of urine, microscopy of the smear). This helps not to miss gonorrhea/chlamydia and rationally use antibiotics. [3]

Antimicrobial resistance is a second major challenge. For gonorrhea, resistance to ciprofloxacin has increased globally, while susceptibility to azithromycin has decreased; rare cases of resistance to ceftriaxone have already been described. Macrolide resistance is widespread among M. genitalium. Therefore, initial regimens and management during symptomatic treatment are strictly regulated. [4]

Code according to ICD-10 and ICD-11

In ICD-10, urethritis and urethral syndrome are coded in block N34: N34.0 "Urethral abscess", N34.1 "Nonspecific urethritis", N34.2 "Other urethritis", N34.3 "Urethral syndrome, unspecified". It is permitted to add codes B95-B97 to indicate the infectious agent (e.g., with a documented etiology). This is convenient when the laboratory confirms a specific pathogen in a clinical diagnosis of "urethritis". [5]

In ICD-11, the corresponding section is GC02 "Urethritis and urethral syndrome," which includes GC02.1 "Nonspecific urethritis," GC02.Y "Other specified urethritis and urethral syndrome," and GC02.Z "Urethritis and urethral syndrome, unspecified." ICD-11 supports post-coordination (modifiers for pathogen/location/special conditions can be added), which improves coding accuracy. [6]

Table 1. ICD codes for urethritis

Classifier	Code	Name	When to use
ICD-10	N34.1	Nonspecific urethritis	When the pathogen is not identified/common STIs are excluded. [7]
ICD-10	N34.2	Other urethritis	When the "non-gonococcal" causative agent is known. [8]
ICD-10	N34.3	Urethral syndrome, unspecified	For urethral symptoms without proven inflammation. [9]
ICD-11	GC02.1	Nonspecific urethritis	Base code for NSU. [10]
ICD-11	GC02.Y/GC02.Z	Specified/unspecified urethritis	For rare/mixed scenarios. [11]

Epidemiology

Gonorrhea is a key etiologic factor for urethritis: according to the World Health Organization, approximately 82,400,000 new cases were registered in individuals aged 15-49 in 2020; the highest burden is observed in priority groups and regions. These data are important because gonorrhea often presents extragenitally and maintains hidden transmission. [12]

For non-gonococcal urethritis, the overall estimates of the proportions of pathogens according to the CDC are: Chlamydia trachomatis - less than 50%; Mycoplasma genitalium - approximately 10-25% and up to 40% among persistent/recurrent cases; Trichomonas vaginalis in men - 0.5-3.6% in a number of countries (variable by region and population). A significant portion of NGU remains etiologically undetected even with extensive diagnostics. [13]

Viral causes are less common but clinically recognizable: adenoviral urethritis is associated with myasitis and may be combined with conjunctivitis; herpetic urethritis causes intense dysuria with scanty discharge, often with rashes appearing 1-3 days after the onset of urethral pain. These scenarios should be kept in mind if NAAT results for gonorrhea/chlamydia are negative. [14]

Table 2. Etiology of urethritis: landmarks by lobes

Pathogen	Estimated share/notes
Neisseria gonorrhoeae	The leading bacterial cause of acute urethritis in men; extragenital localization is significant. [15]
Chlamydia trachomatis	<50% among NSU. [16]
Mycoplasma genitalium	10-25% NGU; ≈40% persistent/recurrent NGU. [17]
Trichomonas vaginalis (men)	0.5–3.6% in developed countries; variable. [18]
Viruses (adenovirus, HSV)	Rare cause; typical clinical clues. [19]

Reasons

The causes of urethritis are divided into sexually transmitted infections and conventionally "non-infectious" triggers. The former group includes gonorrhea, chlamydia, mycoplasma genitalium, trichomonas, and, less commonly, viruses. For adequate therapy, it is important to understand the local structure of the pathogens and their resistance, as well as to address extragenital lesions (oropharynx, rectum). [20]

Non-infectious factors include chemical/mechanical irritation (aggressive gels, excessive intimate procedures, prolonged cycling), radiation injury, catheterization, and urethral manipulation. However, even in the presence of such factors, the standard recommends excluding major STIs. [21]

Risk factors

Risk is increased by unprotected sexual intercourse, multiple or new partners, oral and anal sex practices, a history of STIs, and lack of regular screening. Asymptomatic extragenital lesions (especially the oropharynx) play a significant role, supporting the circulation of infection and reinfection within couples and networks. [22]

Socio-behavioral barriers (limited access to sexual health services, stigma) lead to late diagnosis and self-treatment, which increases prevalence and persistence. Regular testing and adequate partner information are key to prevention. [23]

Table 3. Risk factors for urethritis

Factor	How does it increase the risk?
Sexual intercourse without barrier protection	Direct transmission of pathogens
Asymptomatic extragenital lesions	"Hidden" reservoir, reinfection. [24]
History of STIs, lack of regular screening	High-risk marker; missed cases. [25]
Chemical/mechanical irritation	Mucosal barrier disruption, symptoms without infection

Pathogenesis

Bacterial pathogens adhere to the columnar epithelium of the urethra, causing neutrophilic inflammation. N. gonorrhoeae is characterized by rapid reproduction and pronounced purulent exudate; C. trachomatis and M. genitalium often produce more "modest" mucous discharge against a background of noticeable dysuria. Viruses (adenovirus/HSV) induce pronounced neuroinflammation: pain may precede the appearance of the rash. [26]

The development of resistance is of particular importance: for gonorrhea, the oropharynx serves as an "incubator" for resistance; for M. genitalium, a single dose of azithromycin can "select" macrolide resistance. Therefore, modern regimens avoid azithromycin monotherapy for NGU and use stepwise approaches. [27]

Symptoms

Classic complaints include burning/pain during urination, itching, redness of the external urethral opening, and discharge (ranging from mucous to purulent). Gonorrhea in men often produces profuse purulent discharge and an acute onset 1-7 days after exposure. Chlamydia/mycoplasma present a more subtle picture, but they are often responsible for persistent symptoms. [28]

Viral urethritis is suspected in the presence of intense dysuria with scanty discharge, mesitis, conjunctivitis (adenovirus), and the late appearance of painful vesicles (herpes). In women, the symptoms of urethritis can overlap with cystitis and cervicitis, so it is important to assess all risk sites and perform NAAT. [29]

Table 4. Clinical clues to probable etiology

Sign	Probable cause
Copious purulent discharge, acute onset	Gonorrhea ( N. gonorrhoeae )
Modest mucous discharge, persistent dysuria	Chlamydia, M. genitalium
Burning pain, itching, conjunctivitis	Adenoviral urethritis. [30]
Intense pain, then rash	Herpetic urethritis

Classification, forms and stages

Clinically, a distinction is made between gonococcal urethritis and non-gonococcal urethritis (NGU). The latter includes chlamydial, mycoplasmal, trichomonas, viral, and mixed variants. The course of the disease is classified as acute (days/weeks), persistent (symptoms after therapy), and recurrent (a new episode after cure/reinfection). [31]

Based on the presence of complications, a distinction is made between uncomplicated urethritis (local symptoms) and complicated urethritis (epididymitis, prostatitis, inflammatory diseases of the pelvic organs, dissemination of gonorrhea), which affects the scope of examination and treatment. [32]

Complications and consequences

In men, untreated epididymitis and prostatitis are possible, while in women, pelvic inflammatory disease, tuboperitoneal complications, and fertility problems are possible. Any urethral infection increases the risk of transmission and acquisition of the human immunodeficiency virus. Gonorrhea can develop into a disseminated form with arthritis and skin manifestations. [33]

At the population level, resistance of pathogens poses a risk, leading to treatment failure and the spread of infection. Therefore, culture and susceptibility testing are important when failure is suspected, especially for gonorrhea and pharyngeal localization. [34]

When to see a doctor

Immediately - with severe dysuria, urethral discharge (especially purulent), scrotal pain, fever, lower abdominal/pelvic pain, and urinary retention. These signs may indicate complications and require in-person evaluation. [35]

Even with moderate symptoms, it is important to be tested for sexually transmitted infections and to cover all risk areas according to the contact history (urogenital, oropharynx, rectum) in order not to miss hidden foci and break the chain of transmission. [36]

Diagnostics

Step 1. Confirm the presence of urethral inflammation. Signs include: urethral discharge; ≥2 leukocytes per high-power field (immersion) on urethral smear; a positive leukocyte esterase reaction in the first-void urine; or ≥10 leukocytes per high-power field on first-void urine sediment. These simple tests are readily available and have a high negative predictive value. [37]

Step 2. Identify the pathogen using NAAT tests. Everyone should have NAAT tests for C. trachomatis and N. gonorrhoeae: for men, the optimal sample is the first portion of urine; additional swabs are taken from the oropharynx/rectum at the appropriate risk. This is the most sensitive method; self-collection of samples is permitted during instruction. [38]

Step 3. Additional tests if indicated. If symptoms persist/recur after standard therapy, perform NAAT for M. genitalium with a macrolide resistance test as a recommended option; in heterosexual men, perform a test for T. vaginalis (in regions with a significant prevalence). If a viral cause is suspected, perform polymerase chain reaction from lesions/first urine sample and a dynamic examination. [39]

Step 4. Culture and susceptibility testing – targeted. This is performed when treatment failure of gonorrhea is suspected, when localization is pharyngeal, for surveillance purposes, and in special legal situations. This provides susceptibility data and allows for therapy adaptation. [40]

Table 5. Mini-algorithm for diagnosing urethritis

Stage	What to do	For what
Confirm inflammation	Leukocyte esterase and/or ≥10 leukocytes/field of view in the sediment of the "first portion" of urine; or microscopy of a smear	Prove urethritis even if there is no discharge. [41]
Mandatory NAATs	C. trachomatis + N. gonorrhoeae (first portion of urine in men; extragenital smears according to risk)	The most sensitive method. [42]
In case of persistence	NAAT for M. genitalium ± resistance test; appropriate T. vaginalis	Frequent culprits of the "stubborn" NSU. [43]
Failure/throat	Culture + sensitivity	Correction of therapy and supervision. [44]

Differential diagnosis

Urethritis is distinguished from cystitis (pronounced pollakiuria/suprapubic pain, bacteriuria and pyuria in the midstream urine), prostatitis (perineal pain/ejaculatory pain, prostate tenderness), and non-infectious urethral irritation. Infectious "doppelgangers" include adenoviral urethritis (meititis, conjunctivitis) and herpetic urethritis (late eruptions). Laboratory verification is decisive. [45]

If purulent discharge is abundant and incubation periods are rapid, consider gonorrhea; if discharge is lighter, consider chlamydia/mycoplasma; if persistent after doxycycline, consider M. genitalium or T. vaginalis. In women, urethritis often coexists with cervicitis, so the cervix is assessed and appropriate smears are taken. [46]

Treatment

The first step is to determine whether there is evidence of urethritis and whether testing was performed immediately. If microscopy/testing is not available and the patient with high-risk factors is unlikely to return for results, the CDC recommends empirical therapy that is active against both gonorrhea and chlamydia (see below). In most situations, rapid testing with initiation of treatment based on results is preferred. [47]

If gonorrhea is likely (classic presentation, microscopy reveals intracellular gram-negative diplococci, high risk, or NAAT results are not yet available), the recommended regimen is ceftriaxone 500 mg intramuscularly once (for body weight ≥150 kg - 1,000 mg). If chlamydial co-infection cannot be ruled out, add doxycycline 100 mg twice daily for 7 days. For pharyngeal localization, a cure check is mandatory after 7-14 days. [48]

The initial regimen for non-gonococcal urethritis (when gonorrhea has been excluded by NAAT/microscopy) is doxycycline 100 mg twice daily for 7 days. This covers chlamydia and reduces the bacterial load of M. genitalium, increasing the effectiveness of subsequent steps if it is detected. Azithromycin as monotherapy for NGU is less commonly used in current guidelines due to the risk of macrolide resistance, particularly in M. genitalium. [49]

If symptoms persist/recur after a correct course of doxycycline and gonorrhea has been excluded, the next mandatory step is testing for M. genitalium (preferably with macrolide resistance testing). The CDC's recommended "two-step" approach is: doxycycline 100 mg twice daily for 7 days, then, if macrolide-resistant, moxifloxacin 400 mg once daily for 7 days; if macrolide-sensitive, high-dose azithromycin stepped at 1,000 mg on day 1, then 500 mg once daily for 3 days (for a total of 2.5 g). If resistance testing is not available, doxycycline 7 days → moxifloxacin 400 mg once daily for 7 days. [50]

In heterosexual men in areas where T. vaginalis is more common, testing and treatment for trichomonas infection (metronidazole 2,000 mg once daily or 500 mg twice daily for 7 days, based on results and local recommendations) are appropriate if symptoms persist. The prevalence of T. vaginalis in men is generally low but varies significantly between countries and groups.[51]

Viral urethritis is treated etiotropically when indicated: herpetic urethritis is treated with systemic antiviral drugs (acyclovir/valaciclovir) according to standards for genital herpes; adenoviral urethritis is treated with supportive therapy (pain relief, hydration), taking into account the self-limiting course; bacterial co-infections are excluded. In both cases, symptomatic care is important (pain relief, local measures, urination in warm water). [52]

Symptomatic support for any urethritis includes nonsteroidal anti-inflammatory drugs for pain, adequate hydration, and avoiding irritating hygiene products. For severe pain at the urethral orifice, short-term local anesthetics are acceptable (subject to physician approval). For scrotal pain and suspected epididymitis, rest, scrotal elevation, nonsteroidal anti-inflammatory drugs, and antibacterial therapy according to current recommendations are recommended. [53]

Partner management is a mandatory part of treatment. All sexual partners within the past 60 days should be informed, examined, and treated if necessary. Some jurisdictions allow "expedited partner therapy" (EPT), whereby partners are given medication/prescriptions without an in-person visit—this reduces the patient's risk of reinfection. After therapy, abstinence from sexual intercourse is recommended for at least 7 days and until symptoms resolve and partners are treated. [54]

Routine monitoring of cure is not necessary for urogenital gonorrhea/chlamydia if standard regimens have been used and symptoms have resolved. However, for pharyngeal gonorrhea, it is mandatory for everyone; it is also indicated in cases of alternative regimens, pregnancy, doubts about compliance, and persistent symptoms. If treatment failure of gonorrhea is suspected, culture and susceptibility testing should be performed, and specialists/health care should be contacted. [55]

Finally, patient education: explain how to properly provide a "first portion" of urine (the first 10-20 ml without prior washing), why extragenital swabs are important based on exposure history, and how to deal with relapse (early visit, repeat testing for M. genitalium and T. vaginalis as indicated). This is critical to breaking the "ping-pong" in the couple and reducing resistance. [56]

Table 6. Treatment according to clinical scenarios (guidelines)

Scenario	Recommended tactics
Suspected gonorrhea / no ready NAAT	Ceftriaxone 500 mg IM once (≥150 kg - 1000 mg) ± doxycycline 100 mg 2×/day for 7 days, if chlamydia is not excluded; for the throat - monitoring of cure is mandatory for 7-14 days. [57]
NSU (gonorrhea excluded)	Doxycycline 100 mg 2×/day for 7 days. [58]
Persistence/relapse	NAAT for M. genitalium (± resistance) and T. vaginalis by region; stepwise regimens for M. genitalium (doxycycline → moxifloxacin for 7 days; or doxycycline → high-dose azithromycin for macrolide-susceptible). [59]
Viral urethritis	HSV - systemic antiviral; adenovirus - maintenance therapy. [60]
Partners/behavior	Inform and treat partners; EPT where permitted; abstinence ≥7 days and until symptoms resolve. [61]

Prevention

Barrier methods for all types of contact (including oral-genital) and regular screening in risk groups are the basis for preventing urethritis and its complications. Screening should cover areas of exposure based on medical history (urogenital, oropharynx, rectum); many samples can be safely collected independently after instruction. [62]

Informational support for couples, a reduction in anonymous contacts, prompt treatment for symptoms, and post-treatment monitoring for partners reduce reinfections. Avoiding self-medication and "accidental" antibiotics is critical for containing resistance. [63]

Table 7. Primary and secondary prevention

Measure	For what
Condoms/barrier methods	Reduces transmission at all types of contact
Regular NAAT screening	Detection of asymptomatic lesions (including oropharynx/rectum). [64]
Partner information and treatment (EPT where permitted)	Fewer reinfections and outbreaks. [65]
Avoid self-medication with antibiotics	Decreased stability

Forecast

With adequate therapy, symptoms of urogenital urethritis usually subside within 1-3 days, with complete resolution by days 7-14. Adverse outcomes are associated with non-compliance with recommendations (abstinence, partner treatment), failure to perform extragenital screening, and pathogen resistance. [66]

Persistent cases are more often caused by M. genitalium and less often by T. vaginalis; in these scenarios, the prognosis is improved with stepwise regimens and paired management. Viral forms are usually self-limited (adenovirus) or respond well to antiviral therapy (herpes) if started early.[67]

Table 8. Factors influencing outcome

Factor	Influence
Initial therapy according to recommendations (ceftriaxone/doxycycline)	Improves
Testing and treatment of partners, covering all exposure areas	Improves
Failure/resistance (gonorrhea, M. genitalium )	Worsens; culture/stepping stones needed. [68]
Self-medication/delay of treatment	It makes it worse

FAQ

Should treatment be considered "just in case" if test results aren't yet available?
Only if there are signs of urethritis and there's a high probability the patient won't return for results—in that case, the CDC allows empirical treatment, which covers gonorrhea and chlamydia. In other cases, rapid tests and targeted therapy are preferred. [69]

Which test is the most accurate?
For men, NAAT is used on the "first portion" of urine (the first 10-20 ml without prior washing). In cases of high-risk exposure, swabs from the oropharynx and rectum are also mandatory—this helps identify "hidden" lesions. [70]

How many leukocytes in urine indicate urethritis?
The guideline is ≥10 leukocytes per field of view in the sediment of the "first portion" of urine and/or positive leukocyte esterase; when examining a smear, ≥2 leukocytes per immersion field. [71]

What if symptoms persist after doxycycline?
Reassess, exclude gonorrhea, test for M. genitalium (with resistance testing if available) and T. vaginalis by region; if M. genitalium is confirmed, use stepwise regimens (doxycycline → moxifloxacin for 7 days or doxycycline → high-dose azithromycin if macrolide-sensitive). [72]