Male Urethritis 

Updated: Nov 29, 2021
Author: Michael C Plewa, MD; Chief Editor: Erik D Schraga, MD 

Overview

Practice Essentials

Urethral discharge, dysuria, and exposure to a sexually transmitted infection (STI) are frequent presentations of urethritis in the male population. Research has focused on cost-effective antibiotic therapy and concern for emergence of antibiotic resistance with both typical and atypical organisms. The goal of initial therapy is to optimize compliance and prevent recurrence of this disease, which is predominantly sexually transmitted.[1, 2, 3, 4, 5, 6, 7, 8]  Urethritis usually resolves without complications, even if left untreated, yet it can result in urethral stricture, stenosis, or abscess formation in rare cases. Urethritis can occur in a continuum with concomitant seminal vesiculitis and epididymitis.[9]  Recurrent urethritis may occur from reinfection, therapeutic failure, or "venereophobia," an old term describing fear of recurrence where men can induce urethral inflammation and drainage (negative by white blood cell or Gram stain criteria) by repeatedly milking the urethra, checking for infection.[10]  Urethritis is predominantly a disease of adolescent and adult men. The prevalence is greatest in men younger than 25 years.[11, 12, 13, 14, 15]

Neisseria gonorrhoeae causes gonococcal urethritis (GU) and is a gram-negative intracellular diplococcus that can also be involved in epididymitis, prostatitis, proctitis, septic arthritis, disseminated infection, pharyngitis, and osteomyelitis, as well as pelvic inflammatory disease, infertility, endometritis, Bartholin gland abscess in women, and conjunctivitis in neonates. The most common cause of nongonococcal urethritis (NGU) is Chlamydia trachomatis (15-40% of cases), followed by Mycoplasma genitalium (15-20% of cases). Other causes of NGU include Trichomonas vaginalis, herpes simplex virus, Epstein Barr virus, and Adenovirus.[7, 11, 16]

Diagnostic testing

Because gonorrhea and chlamydia are reportable to the state health departments in the United States,[11]  confirmatory diagnostic testing is recommended. Options include Gram stain, culture, direct immunofluorescence, enzyme immunoassay, polymerase chain reaction, nucleic acid hybridization, or nucleic acid amplification testing (NAAT). Nucleic acid amplification testing of a first-catch urine specimen is the most sensitive test (in a male) for gonorrhea or chlamydia. Sensitivity of NAAT testing for chlamydia is optimized by waiting a minimum of 20 minutes after a recent void,[17]  although prior experts recommended a 1-hour wait.

Testing for Trichomonas is too often neglected, but recommended, for recurrent or persistent symptoms. Wet mount preparations are insensitive, but NAAT and polymerase chain reaction (PCR) testing are highly sensitive for T. vaginalis from first-catch urine specimens. 

NAAT testing for M genitalium from first-catch urine, urethral, or penile meatal specimens is now FDA approved, although it may not be routinely available in many settings, and is recommended in cases of recurrent NGU.

For persistent infection following treatment, unrelated to reexposure, send a specimen to the Center for Disease Control and Prevention (CDC) for drug-resistance testing.

Rescreening for C trachomatis and N gonorrhoeae is recommended 3 months after treatment.

Human immunodeficiency virus (HIV) and syphilis testing is recommended on the initial visit for STI concern and again at follow-up.

Symptoms

Gonococcal urethritis (GU) has a more abrupt onset of symptoms, commonly within 3-4 days and usually within 7 days, with opaque yellow or white discharge and significant dysuria. Neisseria gonorrhoeae, the cause of gonococcal urethritis, is a gram-negative intracellular diplococcus. In contrast, non-GU (NGU) has an insidious onset, minimal dysuria, and scant or mucoid or clear discharge. Nongonococcal urethritis can be caused by various organisms.

Symptoms of urethritis spontaneously resolve over time, regardless of treatment. Administer antibiotics that cover both GU and NGU. Regardless of symptoms, administer antibiotics to the following individuals:

  • Patients with positive Gram stain or culture results

  • All sexual partners of the above patients

  • Patients with negative Gram stain results and a history consistent with urethritis who are not likely to return for follow-up and/or are likely to continue transmitting infection

Treatment

Antibiotic therapy should cover both gonococcal urethritis and nongonococcal urethritis. Current CDC guidelines recommend a higher single dose of 500 mg ceftriaxone IM for GU (1 g for men ≥ 150 kg), and doxycycline 100 mg orally twice daily for 7 days for NGU.[11] If concomitant treatment for NGU is not provided, the risk of postgonococcal urethritis is approximately 50%. In most situations, optimal treatment is with the first dose of antibiotic administered in the emergency department or the physician's office.

Pathophysiology

Inflammation of the urethra is more frequently infectious than posttraumatic, with sexually transmitted infections (STIs) being the most common cause. Sexually transmitted urethritis is classified either as gonococcal urethritis (GU) following infection with Neisseria gonorrhoeae or as nongonococcal urethritis (NGU).

For cases of NGU, Chlamydia trachomatis remains a primary concern, although Mycoplasma genitalium and Trichomonas vaginalis are increasingly recognized as important pathogens, and, less commonly, Ureaplasma parvum, Ureaplasma urealyticum, Mycoplasma hominis, and Gardnerella vaginalis.[18, 19, 20]

In one study of 424 men with signs and symptoms of acute urthritis, 127 (30%) were found to be infected with N gonorrhoeae. In 297 men with nongonococcal urethritis, C trachomatis was detected in 143 (48.1%). In 154 men with nonchlamydial nongonococcal urethritis, M genitalium (22.7%), M hominis (5.8%), U parvum (9.1%), U urealyticum (19.5%), H influenzae (14.3%), N meningitidis (3.9%), T vaginalis (1.3%), human adenovirus (16.2%), and herpes simplex virus types 1 (7.1%) and 2 (2.6%) were detected.[21]

M genitalium, not routinely tested by NAAT or PCR in many locations, may cause up to 10-30% of NGU cases[1, 2, 22] and, like chlamydia, may be associated with human immunodeficiency virus (HIV), human papillomavirus (HPV), and herpes simplex transmission and infection. M genitalium has been associated with treatment failure of previously recommended single-dose therapy because of macrolide resistance,[3, 4, 23, 24, 25, 22, 26]  with potential for quinolone resistance as well.[4, 24, 25, 27]  Couldwell et al described rates of resistance of 15% for quinolones and 43% for macrolides in 143 M genitalium specimens in Australia.[25]

Idiopathic urethritis, defined as urethritis in the absence of nucleic acid amplification testing (NAAT) evidence for the most common infectious causes (N gonorrhoeae, C trachomatis, M genitalium, and T vaginalis), may be considered the largest category.[28, 29]

Unusual infectious causes of urethritis include herpes genitalis, syphilis, mycobacterium, adenovirus, and cytomegalovirus, as well as typical bacteria (usually gram-negative rods) associated with cystitis in the presence of urethral stricture or following insertive anal sex.

Urethritis following trauma is less common, but it can occur with intermittent catheterization or after urethral instrumentation or foreign body insertion. Fewer than 20% of patients practicing intermittent catheterization suffer urethritis; however, use of latex instead of silicone catheters significantly increases this risk. Symptoms of urethritis (urethral syndrome) can also be due to sensitivity to chemicals in spermicidal or contraceptive jellies or foams.

Idiopathic urethritis of childhood is of uncertain cause, perhaps related to dysfunctional elimination syndrome,[30] and presents as blood-stained urethral discharge, bleeding between micturition, or dysuria in the 5- to 15-year-old male, and it can result in urethral stricture.[31, 32]

Urethritis involves local mucous membrane epithelial cell damage or invasion by an infectious agent (bacterial, viral, or fungal) followed by inflammatory changes, including accumulation of leukocytes and chemical mediators (antibodies, cytokines, and interleukins) with resultant swelling, discharge, and pain.

 

Presentation

History

The majority of patients with urethritis are symptomatic and may experience any of the following symptoms:

  • Urethral discharge, purulent or mucopurulent
  • Dysuria
  • Urethral pruritus
  • Hematuria or hemospermia
  • Painful intercourse or ejaculation

Asymptomatic urethritis is common (16%)[33] and typically nongonococcal in etiology. Patients may be detected with partner screening for STIs or with physical examination revealing unrecognized urethral discharge.[33, 34]

Gonococcal urethritis (GU) has a more abrupt onset of symptoms, commonly within 3-4 days and usually within 7 days, with opaque yellow or white discharge and significant dysuria.

In contrast, NGU has insidious onset, minimal dysuria, and scant or mucoid or clear discharge.

Urinary frequency and urgency typically are absent. If present, either should suggest prostatitis or cystitis.

Systemic symptoms (eg, fever, chills, sweats, nausea) are typically absent but, if present, may suggest disseminated gonococcemia, pyelonephritis, orchitis, or other infection.

Ask about number and sex of sexual partners and condom use.

Ask about history of STIs, including previous urethritis.

Ask about recent urethral catheterization or instrumentation, either medical or self-induced (eg, foreign body).

Ask about the following systemic symptoms of disseminated gonococcal, chlamydial, or mycoplasmal infections:

Physical

Male urethritis as a localized inflammatory process would not be expected to result in the appearance of toxicity or significant abnormal vital signs, including fever. Systemic findings of sepsis such as fever or hypotension should prompt consideration of another disease process.

Examine the urethral meatus for skin lesion, stricture, or obvious urethral discharge. The urethral meatus may appear inflamed with tenderness, erythema, and possibly swelling. Urethral discharge, whether purulent or mucopurulent, secures the diagnosis.

Palpate along the urethra for areas of fluctuance, tenderness, or warmth suggestive of abscess or for firmness suggestive of foreign body.

Have the patient strip (milk) the urethra outwards to express discharge.

Physical examination is important in men at risk for STIs, especially those previously treated for urethritis, even if without symptoms, since as many as 10% of asymptomatic cases will have findings.[35]

Examine the testes and epididymis for swelling, tenderness, or warmth suggestive of orchitis or epididymitis.

Examine the foreskin and glans for evidence of balanitis or posthitis, which may be associated with M genitalium infection.[36]

Palpate the prostate for tenderness or bogginess suggestive of prostatitis.

Look at the skin of the penis, scrotum, and groin for lesions indicative of other STIs, such as herpes simplex, syphilis (including condyloma acuminatum), lymphogranuloma venereum, or chancroid.

In patients with symptoms suggestive of disseminated gonococcal, chlamydial, or mycoplasmal disease, the remainder of the physical examination should assess the pharynx, joints, skin, conjunctivae, tympanic membranes, and lungs.

Causes

Promiscuous or unprotected sex is a significant risk factor for urethritis or other sexually transmitted infections (STIs).

Gonococcal urethritis

N gonorrhoeae, the cause of gonococcal urethritis (GU), is a gram-negative intracellular diplococcus, which can also be involved in epididymitis, prostatitis, proctitis, septic arthritis, disseminated infection, pharyngitis, and osteomyelitis, as well as pelvic inflammatory disease, infertility, endometritis, Bartholin gland abscess in women, and conjunctivitis in neonates. GU typically causes a discharge.

Nongonococcal urethritis

Nongonococcal urethritis (NGU) can be caused by various organisms (see list below). A study of 293 symptomatic young heterosexual men with NGU detected C trachomatis in 44%, M genitalium in 31%, T vaginalis in 13%, and no detectable pathogen in 28%.[2]

In a study of 424 men with signs and symptoms of acute urthritis, 127 (30%) were found to be infected with N gonorrhoeae. In 297 men with nongonococcal urethritis, C trachomatis was detected in 143 (48.1%). In 154 men with nonchlamydial nongonococcal urethritis, M genitalium (22.7%), M hominis (5.8%), U parvum (9.1%), U urealyticum (19.5%), H influenzae (14.3%), N meningitidis (3.9%), T vaginalis (1.3%), human adenovirus (16.2%), and herpes simplex virus type 1 (7.1%) and type 2 (2.6%) were detected.[21]

The etiology of nongonococcal urethritis often cannot be determined in 30-40% of patients, according to some studies. In a Swedish study, the etiology in at least 24% of patients with acute nongonococcal urethritis could not be identified.[37]

C trachomatis, an obligate intracellular organism, is likely the most common nongonococcal cause of urethritis, present in as many as 43% of NGU cases.[1] This organism can also be involved in prostatitis, proctitis, epididymitis, and lymphogranuloma venereum, as well as pelvic inflammatory disease, chronic pelvic pain and infertility in women, and trachoma and neonatal pneumonia.

Mycoplasma organisms are non–cell-walled organisms associated with mucosal surfaces. Both Mycoplasma and Ureaplasma species can cause urethritis, pyelonephritis, pelvic inflammatory disease, infertility and endometritis in women, and chorioamnionitis, neonatal pneumonia, bacteremia, and meningitis in infants. Rarely, these can result in infectious arthritis, osteomyelitis, abscess, and even struvite kidney stones. They each can be transmitted sexually as well as vertically from mother to infant. These organisms are not routinely tested for in urethritis, since PCR is not yet clinically available in most settings. Specialized culture media and growing conditions are required, and use of a calcium alginate swab is necessary for isolation.

With M genitalium and M hominis, special techniques, such as nucleic acid amplification test (NAAT), may be necessary to differentiate between Mycoplasma and Ureaplasma species and are not typically available in the clinical setting. M genitalium may be the second most common cause of NGU and should be considered in cases of refractory NGU and in NGU testing negative for N gonorrhoea and C trachomatis.[38]

With regard to U parvum and U urealyticum, Ureaplasma, previously thought to be nonpathogenic, and part of normal genital flora in as many as 70% of sexually active humans, have been determined to be associated with urethritis, especially when present in high numbers.[39]

Trichomonas is a single-celled, motile parasite, easily visible on wet mount, which infects the squamous epithelium of the genital tract. Trichomonas is the most common non-viral cause of STI worldwide. Prevalence may be underestimated due to low sensitivity of wet mount testing or culture results. As many as 70% of male sexual partners of women with T vaginalis will also be transiently colonized. Although commonly transmitted sexually, T vaginalis can also be transmitted via fomites. Men with T vaginalis are more often asymptomatic carriers, but T vaginalis can cause urethritis and may also be involved in prostatitis, epididymitis, and balanoposthitis. In women, vaginitis is typical, but T vaginalis can coexist with other organisms in pelvic inflammatory disease, endometritis, Bartholin gland abscess, postoperative infections (cuff cellulitis), and cervical neoplasia; and during pregnancy, T vaginalis can also result in preterm delivery and low birth weight infants.

The prevalence of T vaginalis may be decreasing in some regions. Lewis et al reported T vaginalis prevalence decreased from 13% to 5% in South Africa.[40]

Gardnerella is a gram-negative anaerobic organism existing in a biofilm on mucosal surfaces. Previously considered nonpathogenic in males, G vaginalis is now thought to be associated with male urethritis, cystitis, and balanoposthitis, as well as sepsis, pulmonary abscess, perinephric abscess, or osteomyelitis. As many as 80% of male sexual partners of women with bacterial vaginosis are colonized. In women, G vaginalis is involved in pelvic inflammatory disease, endometritis, infertility, postoperative infections (cuff cellulitis), preterm labor (and low birth weight infants), chorioamnionitis, and cervical neoplasia.

Other

Rare infectious causes of urethritis include herpes genitalis, syphilis, mycobacterium, N meningitidis, H influenzae, Streptococcus species , Candida species, adenovirus, and cytomegalovirus, as well as typical bacteria (usually gram-negative rods) associated with cystitis in the presence of urethral stricture or following insertive anal sex.

Idiopathic urethritis, which is defined by some as urethral symptoms without NAAT evidence of the 4 most common causes (N gonorrhoeae, C trachomatis, T vaginalis, and M genitalium),[28] is a common classification of urethritis in young men.[41]

 

DDx

 

Workup

Laboratory Studies

Because gonorrhea and chlamydia are reportable to the state health departments in the United States,[11]  confirmatory diagnostic testing is recommended. Options include Gram stain, culture, direct immunofluorescence, enzyme immunoassay, polymerase chain reaction, nucleic acid hybridization, or nucleic acid amplification testing (NAAT), with NAAT being the most sensitive.

When urine testing is not available, a urethral swab specimen may be obtained by inserting a Dacron or calcium alginate swab a centimeter into the urethra and gently twisting. Testing of the discharge itself is less sensitive and not recommended. The sensitivity of urethral swab testing is diminished by recent voiding.

Gram stain microscopy may not be necessary if the patient will be treated empirically for both GU and NGU. Gram stain microscopy with gram-negative intracellular diplococci indicates gonococcal infection. A negative Gram stain usually indicates NGU, but it does not completely exclude gonococcal infection.[42]

The presence of more than 5 WBC per oil immersion field on Gram stain of urethral secretions secures the diagnosis of urethritis. However, this classic cutoff of 5 WBC has sensitivity for infection by Neisseria gonorrhoeae, Chlamydia trachomatis, and Ureaplasma urealyticum of 80%, 23%, and 11%, respectively.[42] Some suggest the use of the presence of 2 or more polymorphonucleocytes per high-power field to diagnose urethritis.[43]

Urine testing

NAAT of a urine specimen is the most sensitive test (in a male) for gonorrhea or chlamydia. Sensitivity of NAAT testing for chlamydia is optimized by waiting a minimum of 20 minutes after a recent void,[17] although prior experts recommended a 1-hour wait.

A first-void urine specimen with positive leukocyte esterase or ≥10 white blood cells per high-power field is sensitive for urethritis, but this result may also occur with cystitis, pyelonephritis, and prostatitis. Leukocytes are commonly absent in midstream specimens in patients with GU, as well as even first-void specimens from patients with NGU. Leukocyte esterase testing may be as accurate as a urethral smear in asymptomatic partners in STD clinics.

Urinalysis may also visibly identify T vaginalis infection, although NAAT and PCR assays are more sensitive, and multiple specimens may be necessary for confirmation.[44] Because of the high transmission rate, male sex partners of infected women can be presumed to also carry T vaginalis. NAAT and PCR testing for M genitalium may be available in some settings,[25] but it is not universally available.[7]

Screen for HIV and syphilis serology (Venereal Disease Research Laboratory [VDRL] test or rapid plasma reagin test).

For refractory urethritis, test first-void urine for T vaginalis, test for M genitalium by NAAT, and consider sending a specimen to the CDC for resistance testing.[11]

 

Treatment

Emergency Department Care

Recurrent or persistent symptoms should prompt culture for N gonorrhoeae to determine resistance, as well as evaluation or treatment for T vaginalis and Mycoplasma and Ureaplasma species.

Retesting in 3 months is recommended for men with gonococcal urethritis (GU).

Refer patients to their primary physician, urologist, or local health department for follow-up care.

Instruct patients regarding abstinence from sex for 1 week (or until therapy is complete and symptoms have resolved) and safe sex practices (condom use) thereafter. Sexual partners should be referred for evaluation and treatment.  Consider expedited partner therapy (EPT), in states where this is allowed, for partners who do not have timely access to treatment. This includes all sexual partners of the patient with GU during the last 60 days or the most recent sexual partner if last intercourse was more than 60 days before symptoms.

Complications

Urethritis can rarely result in urethral stricture, urethral stenosis, or periurethral abscess formation.

Chronic prostatitis, diagnosed when symptoms of urinary discomfort persist beyond 3 months, and epididymitis can follow untreated urethritis.

Urethritis may recur. Recurrence may be less likely because of noncompliance with treatment than was previously thought[45]  and should prompt consideration for atypical infections, including M genitalium and trichomonal infections.

Venereophobia, inflammation of the urethra resulting from persistent milking of the urethra for fear of recurrence, may develop.

Organisms involved in urethritis may also result in epididymitis, balanoposthitis, cystitis, and, rarely, sepsis, osteomyelitis, abscess formation, and septic arthritis.

Pharyngeal infection with Neisseria gonorrhoeae or Chlamydia trachomatis can occur. The prevalence of these organisms in the pharynx of men with urethritis may be as high as 20% and 6%, respectively.[46]

Gonorrhea can become disseminated and also result in septic arthritis.

Reactive arthritis following chlamydial infection is uncommon.

Infertility in men following untreated urethritis is rare.

The greatest risk, especially in asymptomatic men with NGU, is sexual transmission during unprotected sex.

Sexual transmission of GU or NGU to women may lead to cervical neoplasia, postoperative infections (cuff cellulitis or abscess), Bartholin gland abscess, endometritis, cervicitis, pelvic inflammatory disease, tubo-ovarian abscess, scarring of the fallopian tube, and infertility. Pregnant women may experience preterm labor resulting in low birth weight newborns who may also be at risk for chorioamnionitis, meningitis, pneumonia, and conjunctivitis.

 

Guidelines

Guidelines Summary

Center for Disease Control and Prevention (CDC)

According to the CDC, urethritis can be documented on the basis of any of the following signs or laboratory tests[11] :

  • Mucoid, mucopurulent, or purulent discharge on examination.

  • Gram stain is highly sensitive and specific for documenting both urethritis and the presence or absence of gonococcal infection; methylene blue (MB) or gentian violet (GV) stain of urethral secretions is an alternative POC diagnostic test with performance characteristics similar to Gram stain; thus, the cutoff number for WBCs per oil immersion field should be the same.

    • Presumed gonococcal infection is established by the presence of WBCs containing gram-negative intracellular diplococci (GNID) in Gram stain or intracellular purple diplococci in MB or GV smears; men should be tested for C trachomatis and N gonorrhoeae by nucleic acid amplification testing (NAATs) and presumptively treated and managed accordingly for gonococcal infection.

    • If no intracellular gram-negative or purple diplococci are present, men should receive  (NAATs) for C trachomatis and N gonorrhoeae and can be managed for NGU as recommended.

    • Gram stain of urethral secretions with ≥2 WBCs per oil immersion field. The microscopy diagnostic cutoff might vary, depending on background prevalence (≥2 WBCs/high power field [HPF] in high-prevalence settings [STI clinics] or ≥5 WBCs/HPF in lower-prevalence settings).

  • Positive leukocyte esterase test on first-void urine or microscopic examination of sediment from a spun first-void urine demonstrating ≥10 WBCs/HPF.

Recommended Regimen for Gonococcal Urethritis

Recommended regimen for GU is ceftriaxaone 500 mg IM single dose, or 1 g IM for persons ≥ 150 kg.[11] Alternative choices include a single-dose of cefixime 800 mg orally, or gentamicin 240 mg IM single dose with azithromycin 2 g orally in a single dose for patients with cephalosporin allergy.

Recommended Regimen for Nongonococcal Urethritis

Recommended regimen for NGU is doxycycline 100 mg orally 2 times/day for 7 days;[11] alternative regimens are (1) azithromycin 500 mg orally in a single dose, followed by 250 mg orally daily for 4 days, or (2) azithromycin 1 g orally in a single dose.

Erythromycin is no longer recommended for NGU because of gastrointestinal side effects and dosing frequency. Levofloxacin is no longer recommended for NGU because of inferior efficacy, especially for M genitalium.

 

 

Medication

Medication Summary

In the emergency department, antibiotic therapy for urethritis is administered to cover both gonococcal urethritis (GU) and nongonococcal urethritis (NGU), since results of NAAT testing may not be immediately available, and compliance with outpatient treatment and follow-up may be uncertain. Consider presumptive treatment for T vaginalis, or base treatment on evidence of this organism on first catch urine microscopy (which may be insensitive) or NAAT.

Therapy for GU

The primary antibiotic choice recommended by the 2020 CDC updated guidelines[11, 47] in the treatment of GU is ceftriaxone 500 mg IM single dose, or 1 g IM for persons ≥ 150 kg.  For the ceftriaxone 1 g IM dose, use 2 separate syringes, and to minimize pain, consider diluting with 2.1 mL of 1% lidocaine. If the patient already has an intravenous (IV) line, the ceftriaxone can be given IV instead of IM. Alternative choices include a single-dose of cefixime 800 mg by mouth (despite concerns for less-than-ideal bactericidal blood levels), or gentamicin 240 mg IM single dose with azithromycin 2 g PO in a single dose for patients with cephalosporin allergy.[11]  The results of a single-arm open label clinical trial of aztreonam suggest that it may be an effective alternative treatment for men with beta-lactam allergies.[48]

Routine dual treatment with single dose azithromycin for GU is no longer recommended by the CDC.  Although monotherapy with azithromycin 2 g by mouth has previously been demonstrated to be 99.2% effective against uncomplicated urogenital gonorrhea, it is no longer recommended by the Centers for Disease Control and Prevention (CDC) because of concerns about effects on the microbiome and the ease with which N. gonorrhoeae can develop resistance to macrolides, the high proportion of isolates with decreased susceptibility to azithromycin, and documented azithromycin treatment failures.[11]

Quinolone resistance has increase worldwide, at approximately 21%,[49] and is common in Asia, the Pacific, Europe, and the Middle East, as well as in some parts of the United States.[50] Quinolone-resistant GU is also more prevalent in men who have sex with men. Because of increasing resistance, quinolones (eg, ciprofloxacin 500 mg PO single dose, levofloxacin 250 mg PO single dose, or ofloxacin 400 mg PO single dose) are not currently recommended by the CDC for routine or alternative regimens.[11]  The recommendation was based on analysis of new data from the CDC's Gonococcal Isolate Surveillance Project (GISP). The data from GISP showed the proportion of gonorrhea cases in heterosexual men that were fluoroquinolone-resistant (QRNG) reached 6.7%, an 11-fold increase from 0.6% in 2001.[51]  

During 2007, emergence of fluoroquinolone-resistant N gonorrhoeae in the United States prompted the CDC to cease recommending fluoroquinolones for gonorrhea treatment, leaving cephalosporins as the only remaining class of antimicrobials available for gonorrhea treatment in the United States.[11]   For more information see the CDC's Antibiotic-Resistant Gonorrhea Web site. 

Therapy for NGU

Current CDC guidelines recommend doxycycline 100 mg orally twice daily for 7 days.[11]   Due to concerns for treatment failures for chlamydia and possibility of antibiotic resistance in M genitalium, azithromycin is considered an inferior alternative, and can be given as a single dose of 500 mg orally, followed by 250 mg orally daily for 4 days, or as a one time single 1 g oral dose.[11]   The advantage of the single dose is compliance (especially when dosing is observed) and convenience, whereas the multiday regimen may minimize antibiotic resistance in M genitalium.

Doxycycline may have a higher clearance rate for Chlamydia than azithromycin[1, 2] ; however, azithromycin may be more effective than doxycycline for M genitalium[52, 53, 1, 2] and U urealyticum infections. In a follow-up study of 293 young heterosexual patients with NGU detected by NAAT, C trachomatis was present in 23% after azithromycin and 5% after doxycycline, whereas M genitalium was present in 68% after doxycycline and 33% after azithromycin.[2]

Caution has been expressed about single-dose azithromycin 1 g inducing macrolide resistance in M genitalium,[54, 55, 56]  despite ensuring compliance and successful treatment of cases of NGU in which test results are negative for Chlamydia, Mycoplasma, and Ureaplasma species.[57, 58] Because of this concern for induced macrolide resistance of M genitalium after single-dose azithromycin 1 g, some researchers have recommended initial treatment with 7 days of doxycycline 100 mg orally twice daily[24] or the extended azithromycin regimen (500 mg initially, then 250 mg daily for 4 days orally).[27, 56]

For patients in whom initial doxycycline therapy fails, treatment can be based on resistance testing (see section below: Therapy for recurrent or persistent urethritis), or empirically, with an extended azithromycin regimen (with less concern for macrolide resistance); then failures of the extended azithromycin regimen are treated with moxifloxacin 400 mg daily for 7 - 10 days.

Alternative initial regimens for NGU include 10 days of moxifloxacin 400 mg daily (which may be more effective than azithromycin for M genitalium,[59, 60, 61] although there is concern regarding emerging quinolone resistance.[5, 27, 24, 25]  Other choices could include 7 days of erythromycin base 500 mg 4 times daily, erythromycin ethylsuccinate 800 mg 4 times daily, ofloxacin 300 mg twice daily, levofloxacin 500 mg once daily,[6] or sitafloxacin 100 mg twice daily.[26] Minocycline or tetracycline is a reasonable alternative to doxycycline. Ciprofloxacin is ineffective against chlamydial infection. Combinations of probenecid with penicillin, amoxicillin, or ampicillin are no longer used because of resistance.

The CDC no longer recommends levofloxacin for treatment of NGU because of its inferior efficacy, especially for M genitalium.[11]

Therapy for T vaginalis

Consider empiric treatment for T vaginalis or base treatment, with single treatment of metronidazole or tinidazole 2 g orally, if  this organism is present on urinary microscopy or detected by NAAT.[11]

Antibiotic therapy with 2 g metronidazole or tinidazole is also recommended for sexual partners of individuals with documented Trichomonas, even if asymptomatic.

Therapy for recurrent or persistent urethritis

Recurrent symptoms may be related to reexposure (especially if the sexual partner also has not been treated), noncompliance, drug resistance, chronic nonbacterial prostatitis, or infection with T vaginalis, M genitalium, or U urealyticum. Noncompliance with medications may not be as important a factor in recurrent or persistent symptoms as previously thought[45] and should prompt consideration of atypical organisms.

A single dose of metronidazole 2 g orally or tinidazole 2 g orally should be used (especially if not given initially) for suspected Trichomonas. Recurrent trichomonal urethritis is often from reinfection, and retreatment is appropriate. Without re-exposure, metronidazole is dosed as 500 mg orally twice daily for 7 days.[11]

M genitalium can be a common cause of persistent urethritis. Failure rates after doxycycline therapy are high,[62] and azithromycin resistance and failure are increasing.[5, 52]  The current CDC guidelines recommend drug resistance testing (specimens can be sent to the CDC).[11]   For macrolide-sensitive infections, the following is recommended: doxycycline 100 mg orally 2 times a day for 7 days, followed by azithromycin 1 g orally as an initial dose and then 500 mg orally once daily for 3 additional days (2.5 g total). For macrolide-resistant infections or if testing is not available, the recommended treatment is doxycycline 100 mg orally 2 times a day for 7 days, followed by moxifloxacin 400 mg orally once daily for 7 days.[11]

Antibiotics

Class Summary

Antibiotics should aim to cover GU (high dose ceftriaxone IM) and NGU (doxycycline 100 mg orally twice daily for 7 days)'

Cefixime (Suprax)

Arrests bacterial cell wall synthesis and inhibits bacterial growth by binding to one or more penicillin-binding proteins.

Ceftriaxone (Rocephin)

Used because of increasing prevalence of penicillinase-producing N gonorrhoeae. Third-generation cephalosporin with broad-spectrum, gram-negative activity; lower efficacy against gram-positive organisms; higher efficacy against resistant organisms; arrests bacterial growth by binding to one or more penicillin-binding proteins.

Spectinomycin (Trobicin)

Structurally different from related aminoglycosides, inhibits protein synthesis in bacterial cells. Site of action is 30S ribosomal subunit. Used as alternative antimicrobial in treatment of urethral, endocervical, or rectal gonococcal infections in patients who cannot take cephalosporins or fluoroquinolones. Same regimen of this medication administered to pregnant women who are allergic to cephalosporins.

Azithromycin (Zithromax)

Used to treat mild to moderately severe infections caused by susceptible strains of microorganisms. Indicated for chlamydia and gonorrheal infections of genital tract.

Doxycycline (Dory, Bio-Tab)

Used in treatment of rectal syphilis. Inhibits protein synthesis and bacterial growth by binding with 30S and possibly 50S ribosomal subunits of susceptible bacteria.

Tetracycline (Sumycin)

Treats susceptible bacterial infections of both gram-positive and gram-negative organisms as well as mycoplasmal, chlamydial, and rickettsial infections. Inhibits bacterial protein synthesis by binding with 30S and possibly 50S ribosomal subunits of susceptible bacteria.

Minocycline (Dynacin, Minocin)

Treats infections caused by susceptible gram-negative and gram-positive organisms, in addition to susceptible chlamydial, rickettsial, and mycoplasmal infections.

Erythromycin (E-Mycin, Eryc, Ery-Tab)

Indicated for treatment of infections caused by susceptible strains of microorganisms, including Staphylococcus aureus. Inhibits RNA-dependent protein synthesis, possibly by stimulating dissociation of peptidyl tRNA from ribosomes, thus inhibiting bacterial growth. Twice-a-day dosing not recommended when doses greater than 1 g/d are administered.

Metronidazole (Flagyl)

Imidazole ring-based antibiotic active against various anaerobic bacteria and protozoa. Usually used in combination with other antimicrobial agents except when used for Clostridium difficile enterocolitis in which monotherapy is appropriate. Active against various anaerobic bacteria and protozoa. Appears to be absorbed into cells, and intermediate-metabolized compounds that are formed bind DNA and inhibit protein synthesis, causing cell death.

Antibiotic, Quinolone

Class Summary

The quinolone class antibiotics are no longer considered effective against GCU due to increasing resistance. However, these antibiotics are useful for NGU as initial alternative to or when refractory to initial treatment with azithromycin.

Moxifloxacin (Avelox)

Inhibits the A subunits of DNA gyrase, resulting in inhibition of bacterial DNA replication and transcription. Useful for refractory NGU secondary to Mycoplasma genitalium infection.

Ofloxacin (Floxin)

Treats GU only. Penetrates prostate well and is effective against N gonorrhea and C trachomatis. A derivative of pyridine carboxylic acid with broad-spectrum bactericidal effect. Useful for the treatment of NGU.

Levofloxacin (Levaquin)

For pseudomonal infections and infections due to multidrug resistant gram-negative organisms as well as atypical infections such as Chlamydia, Mycoplasma and Ureaplasma species.