Urethritis

OVERVIEW: What every practitioner needs to know

Are you sure your patient has urethritis? What should you expect to find?

There are several cardinal features of urethritis, most of which are the result of urethral inflammation. Lack of symptoms is common in women; however, when symptoms arise, they typically include urinary frequency, dysuria, and vaginal discharge that is often malodorous. Although men may also present without symptoms, they typically complain of penile discharge, dysuria, and genital pain or heaviness. Penile discharge tends to be more prominent in the morning and may be purulent or mucopurulent. If men have prostatic involvement, they may also complain of nocturia and urinary urgency. Common to both sexes is urethral tenderness, erythema, and pruritis.

On examination of the genital area, signs of urethral inflammation or evidence of other sexually transmitted infections may be found. Tenderness may be elicited on palpation of the testes, spermatic cords, epididymis, and lymph nodes, primarily the inguinal nodes. Lesions and nits may be seen in pubic hair if pubic lice are also present. On urethral examination, spontaneous discharge and, specifically in men, erythema and crusting of the meatus may be found. If there is no spontaneous discharge initially seen, one may strip the urethra, which will often cause expulsion of discharge located more proximally in the urethra. In men, bleeding from the rectum or pus in the rectum may be seen if gonococcal proctitis is present. In women, a pelvic examination should be performed, during which evidence of cervicitis with associated tenderness may be found.

Although the aforementioned is a limited examination of the genital area, if dissemination has occurred, a complete physical examination should be performed. Arthritis and tenosynovitis may be found on joint examination. If hepatitis has occurred, patients may be jaundiced with hepatomegaly and hepatic tenderness in addition to other stigmata of cirrhosis. A thorough cardiovascular examination should be performed to evaluate for evidence of murmurs associated with endocarditis or myocarditis in addition to other classical changes: splinter hemorrhages, Roth spots, Janeway lesions, and Osler nodes. A full neurological examination may reveal neck stiffness as a sign of meningitis in addition to a positive Kernig or Brudzinski sign.

How did the patient develop urethritis? What was the primary source from which the infection spread?

Most etiologies of urethritis are infectious and most commonly the result of sexual transmission.

Because there are numerous asymptomatic patients, there is a known and expected underreporting of urethritis. Therefore, the prevalence is underestimated. The Centers for Disease Control and Prevention (CDC) estimates that approximately 700,000 or more persons acquire gonorrhea every year in the United States.

2009 statistics

Gonorrhea: 301,174 total cases and 105.7 cases per 100,000 population
Chlamydia: 1,244,180 total cases and 409.2 cases per 100,000 population
Those patients between the 15 and 19 years of age are most often infected with Chlamydia trachomatis, whereas those patients between 20 and 24 years of age are the second most commonly infected with this species.
C. trachomatis infection is reported more in women, likely secondary to increased screening practices.
Neisseria gonorrhoeae is reported more commonly in men, of whom approximately 50% are without symptoms.
In patients of higher socioeconomic status, nongonococcal urethritis is more common.

Which individuals are at greater risk of developing urethritis?

The predisposing factors for urethritis are multiple sexual partners, unsafe sexual practices, a current sexually transmitted infection (STI), and recent urethral instrumentation.

Beware: there are other diseases that can mimic urethritis:

Other diseases that can mimic urethritis include:

Acute cystitis
Acute pyelonephritis
Bacterial vulvovaginitis
Mucopurulent cervicitis
Prostatitis
Trichomoniasis

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

Typically, peripheral blood examination is not performed as part of the initial work-up of patients presenting with symptoms of urethritis. However, if done, you may expect to find a peripheral neutrophilic leukocytosis with a shift to the left, bands, or toxic granulations on the differential.

Results that confirm the diagnosis

Proper sequence of diagnostic testing

1. Gram stain

2. Leukocyte esterase test

3. Microscopic examination

4. Divided urine sample examination

5. Culture

6. Non-culture tests (e.g., ligase chain reaction, direct fluorescent antibody, and enzyme immunoassay (EIA))

Gram-stained urethral smear: Finding a few or more polymorphonuclear leukocytes or gram-negative intracellular diplococci is a characteristic finding of N. gonorrhoeae.
First-void urine: A leukocyte esterase positivity or at least 10 WBC/hpf.
Divided urine specimen (men): Mucoid strands in the first-void urine sample, but not present in the second sample, is a characteristic of C. trachomatis urethritis. In addition, the sediment of each sample may be microscopically examined for neutrophils (PMNs).
Endourethral cultures: Urethral discharge cultures on proper selective media will provide a definitive diagnosis.
Non-culture tests: Nucleic acid amplification tests, such as the ligase chain reaction, on the first-void sample of urine can definitively diagnosis either C. trachomatis or N. gonorrhoeae. Direct fluorescent antibody (DFA) testing and enzyme immunoassay (EIA) can also be used to identify C. trachomatis

What imaging studies will be helpful in making or excluding the diagnosis of urethritis?

Imaging is not typically performed as part of the work-up of urethritis.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has urethritis, what therapies should you initiate immediately?

If the practitioner has concern that the patient is at high risk for infection and is not likely to return to subsequent visits, empiric treatment should be administered and should cover both non-gonococcal and gonococcal urethritis.

1. Anti-infective agents

If I am not sure what pathogen is causing the infection, what anti-infective should I order?

The mainstay of treatment for non-gonococcal urethritis (NGU) is doxycycline and azithromycin; however, there are a variety of regimens that have been employed.

Tetracyclines are commonly prescribed for a 7-day course, with reports that longer courses do not change outcomes. Typical doses are 500mg four times daily. Doxycycline can be prescribed at 100mg twice daily for 7 days. Minocycline can be used, but reports of dizziness may preclude compliance.

Azithromycin has activity against C. trachomatis and U. urealyticum and can be administered in a single oral dose of 1000 mg. It also has a longer half-life and is well tolerated.

Erythromycin is used for chlamydial infections and has activity against tetracycline-resistant ureaplasma infections. It has also been reported to achieve higher levels in the prostate. The major limiting factor is gastrointestinal (GI) upset. Typical dosing is 500mg four times daily for a 7-day course, but, if side effects arise, you may try 250mg four times daily for a 14-day course.

Fluoroquinolones have been extensively evaluated, and it has been found that oflaxacin is preferred over ciprofloxacin; the latter was found to be ineffective. The dosing is 300mg twice daily for 7 days. Levofloxacin, 500 mg daily for 7 days, is also effective.

Sulfamethoxazole-trimethoprim has been used effectively to treat chlamydial infections.

Because the incidence of coinfection with chlamydia and gonorrhea is very common, it has been recommended that uncomplicated gonococcal urethritis should be treated with a two drug regimen. A single dose of a cephalosporin or fluoroquinolone should be administered with doxycycline or azithromycin to complete a 7-day course.

Treatment for infection with trichomonas is metronidazole 500mg twice daily for 7 days or as a single dose of 2000mg.

In patients who are treated initially with doxycycline for NGU in whom symptoms persist, the practitioner should consider doxycycline-resistant Ureaplasma or infection with Trichomonas. These two bacteria are very difficult to differentiate clinically, thus, the patient should be empirically treated with a one-time 2g oral dose of metronidazole. This dose should be followed by a single dose of azithromycin 1g orally or erythromycin at a dose of 500mg daily for a total of 7 days. These treatments should be given at a period of 2 hours after the initial dose of metronidazole in an attempt to reduce GI discomfort. It is also of high importance that their partners receive similar treatment.

Specifically in men, if symptoms persist despite appropriate therapy, the patient should be questioned about reexposure and the practitioner should ensure that all sexual partners have also been treated appropriately. In the case of reexposure, retreatment is warranted. If reexposure is not the case, you should consider that the pathogens may be in an “antibiotic-protected site” (i.e., the prostate). In these cases, the male patient should be treated with a 21-day course of erythromycin. If the patient continues to have recurrent symptoms, they should be referred to a urologist. In these situations, it is not uncommon to have anatomic abnormalities, such as an obstruction or urethral stricture.

In the case of pregnancy, one may substitute erythromycin, amoxicillin, clindamycin, or azithromycin for doxycycline.

See Table I, Treatment options for urethritis.

Table I.

Organism	Antibiotic	Dose	Alternative
C. trachomatis	Azithromycin OR Doxycycline	1g PO once100mg PO BID x 7 days	Erythromycin 500mg PO QID x 7 days ORLevofloxacin 500mg PO QD x 7 days OROflaxacin 300mg PO BID x 7 days
N. gonorrhoeae	Ceftriaxone	125mg IM once	Cefixime 400mg PO once
M. genitalum	Azithromycin	1g PO once
U. urealyticum	Doxycycline	100mg PO BID x 7 days	Azithromycin 1g PO once ORLevofloxacin 500mg PO QD x 7 days
T. vaginalis	Metronidazole	2g PO once
Herpes Simplex Virus	Acyclovir	400mg PO TID OR200mg PO 5x/day x 7-10 days	Famciclovir 250mg PO TID x 7-10 days ORValacyclovir 1000mg PO BID x 7-10 days

What complications could arise as a consequence of urethritis?

What should you tell the family about the patient’s prognosis?

Although complications of urethritis are uncommon, they do exist. Examples of such complications in men include cystitis, orchitis, prostatitis, epididymitis, and urethral stricture after severe infection. Examples of complications seen in women are cystitis, cervicitis, and pelvic inflammatory disease (PID).
Neonatal syndromes have been seen after the diagnosis of urethritis is made when the mother is pregnant. Certain pathogens, T. pallidum and N. gonnorheae, have been shown to lead to neonatal pneumonia, spontaneous abortions, premature delivery, stillbirth, low birth weight, and certain congenital abnormalities.
Other sequelae of urethritis not commonly thought of are lymphogranuloma venereum, Fournier’s gangrene, and paraurethral gland infections.
Lymphogranuloma venereum is commonly seen with certain serotypes of C. trachomatis and is often asymptomatic or associated with constitutional symptoms but can lead to strictures and fistulae.
Fournier’s gangrene is commonly associated with gram-negative rods, aerobic gram-positive cocci, and anaerobes and carries a reported mortality rate as high as 45%.
Paraurethral gland infections vary by the organism isolated in culture.
Urethritis is also seen as one of the elements of reactive arthritis (formerly Reiter’s syndrome). The other elements are uveitis, arthritis, and commonly skin and mucous membrane lesions. It has been reported that 1-2% of cases of non-gonococcal urethritis result in reactive arthritis.
Lastly, an oculogenital syndrome has been described in about 4% of patients and is associated with non-gonococcoal urethritis and conjunctivitis.
Prognosis is typically very good if the diagnosis is made early and treated properly. However, if the patient develops complications because of late diagnosis, improper treatment, or a prolonged and protracted course, the prognosis can vary based on the specific complication.
Mortality is rather uncommon and deemed minimal in cases of gonococcal urethritis (GCU) or NGU.
It has been reported that 10-40% of female patients develop PID, which may subsequently lead to infertility or an ectopic pregnancy. This is typically seen as a consequence of post-inflammatory scarring of the fallopian tubes. Reactive arthritis and disseminated gonococcal infections have been reported to occur in less than 1% of female patients.
In male patients, morbidity is much less common, occurring in approximately 1-2%. This is typically seen in the form of urethral strictures or urethral stenosis, again, as a consequence of post-inflammatory scarring.

How do you contract urethritis and how frequent is this disease?

The most common etiology of acute urethritis is N. gonorrhoeae, which leads to GCU. All other etiologies of urethritis are deemed NGU. NGU is seen two times as often as GCU in the United States. Of all sexually transmitted diseases occurring in men, NGU has been reported as the most common, accounting for up to 6 million visits per year. More often than not, NGU is seen in the higher socioeconomic population. GCU is seen more frequently in homosexual men.

It has been reported that 4 million Americans are diagnosed with urethritis annually. The incidence of GCU has been reported at greater than 700,000 new cases yearly. The incidence of NGU has been reported at approximately 3 million new cases yearly. It should be mentioned that the diagnosis of urethritis is significantly underreported. Since 2000, GCU has been on a steady decline, whereas NGU has been steadily increasing.

Urethritis is the result of bacterial spread via a few different mechanisms in the overwhelming majority of cases. However, herpes simplex virus (HSV) is a rare cause of NGU.

Non-infectious urethritis is commonly associated with chronic irritation of the urethra. Rarely, non-infectious urethritis may be the result of foreign body insertion into the urethra, leading to a mechanical urethritis. It has also been reported that a chemical irritation to the urethra, such as with spermicides, can led to urethritis.

NGU and GCU are more often than not, acquired by sexual transmission.

What pathogens are responsible for this disease?

For neisseria gonorrhoeae, typically, about three-quarters of patients develop symptoms within 4 days and even higher, (80-90%, of patients) have symptoms within 14 days. The discharge seen is usually purulent and occurs in the absence of urethral stripping. You may also see a cloudy fluid, thin with purulent flecks, described as mucopurulent. This is seen in twice as many patients with GCU. It is not uncommon for symptoms to begin suddenly, and oftentimes patients remember the exact time symptoms started.
Chlamydia trachomatis is responsible for up to 50% of NGU cases.
Ureaplasma urealyticum
Trichomonas vaginalis is typically clinically indistinguishable from the other causes of NGU.
Mycoplasma genitalium

Herpes simplex virus: with primary genital infection, dysuria is reported by approximately 44% of men and 83% of women. A clear, mucoid discharge may be described by male patients, but this is typically deemed disproportionate to the degree of dysuria they may be experiencing. Typically, HSV as a diagnosis is rather obvious given the common genital lesions associated with the virus.

What other additional laboratory findings may be ordered?

You could see a rise in IgM and IgG antibody titers against U. urealyticum in some patients with NGU. Polymerase chain reaction (PCR) assays have been developed for M. genitalium. Nucleic acid amplification tests have been developed for T. vaginalis.

How can urethritis be prevented?

To date, there are no vaccines or prophylactic medications used to prevent the occurrence of urethritis. There are some common practices that may help decrease personal risk of obtaining urethritis and sexually transmitted infections. These include refraining from sexual activity (abstinence) and the use of the various forms of barrier protections, such as condoms. If the patient is using lotions, colognes, soaps, detergents, etc., that lead to irritation of the urethra with subsequent inflammation, they should be advised to stop using them.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

Krieger, JN, Kellerman, RD, Rackel, RE, Bope, ET. “Nongonococcal Urethritis”. Conn’s Current Therapy. 2010. pp. 759-760. (This reference provides an easy to read overview of the antimicrobial and non-antimicrobial management of urethritis)

Habif, TP, Habif, TP. ” Sexually Transmitted Bacterial Infections: Diseases Characterized by Urethritis and Cervicitis”. Clinical Dermatology. 2009. (This reference provides an in-depth look at the complications of urethritis in regards to the dermatologic system)

Ferri, FF. “Gonococcal Urethritis”. Ferri’s Clinical Advisor. 2010. pp. 1140-1141. (This reference provides an approach to the diagnosis, work-up, and management of gonococcal urethritis)

Carter, JD, Hudson, AP. “Reactive Arthritis: Clinical Aspects and Medical Management”. . vol. 35. 2009. pp. 21-44. (This reference provides a nice overview of the rheumatologic component to urethritis)

McCormack, W, Mandell, GL, Bennett, JE, Dolin, R. “Urethritis”. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. 2009. pp. 1485-94. (This text is a great overview of urethritis from all perspectives and included a subheadings for the various categories of urethritis)

Brill, JR. “Diagnosis and Treatment of Urethritis in Men”. . vol. 81. 2010. pp. 873-878. (This article is a great resource for the family practitioner or midlevel provider that is concise, but at the same time a very easy read)

“Sexually transmitted disease surveillance 2009, US Department of Health and Human Services, November 2010”. (This reference provides statistics as of 2009 for STDs)

McCormack, WM, Mandell, GL, Bennett, JE, Dolin, R. ” Urethritis”. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 2005. pp. 1347-55. (This reference provides an in-depth view of the infectious disease aspect of urethritis)

Krieger, JN, Gillenwater, JY, Grayhack, JT, Howards, SS, Mitchell, ME. “Urethritis: Etiology, Diagnosis, Treatment, and Complications”. Adult and Pediatric Urology. 2002. pp. 1849-1882. (This reference is a great detailed resource describing the complications of urethritis)

DRG CODES and expected length of stay

597 – Urethritis not sexually transmitted and urethral syndrome

597.8 – Other urethritis

597.81 – Urethral syndrome NOS

597.89 – Other urethritis

098.0 – Gonococcal urethritis

099.40 – Other nongonococcal urethritis

Patients are typically not admitted for uncomplicated urethritis, as this is typically evaluated and treated as an outpatient. Admissions would be feasible for severe complications that may require intravenous antibiotics or surgical/procedural interventions or specialized consultations.

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