EUROPEAN UROLOGY SUPPLEMENTS 16 (2017) 144–148

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Urethritis in Men and Women

Oliver W. Hakenberg *, Nina Harke, Florian Wagenlehner

Department of Urology, Rostock Universiity, Rostock, Germany

Article info Abstract

Keywords: Urethritis is usually caused by sexually transmissible organisms. Sexually transmit-

Urethritis ted diseases (STDs) increase the risk of acquiring other STDs, which is why patients
Chlamydia presenting with urethritis should generally be examined for other STDs as well, and
Mycoplasma examination and treatment of sexual partners are necessary. Standard diagnosis is
Gonococcal made via stains of urethral swabs or urine, but modern microbiological diagnostic
Trichomonas methods such as nucleic acid amplification techniques achieve higher diagnostic
accuracy. In non-gonococcal urethritis, a causative organism can often not be
isolated. Antibiotic treatment is usually based on current epidemiologic data.
# 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

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* Corresponding author. Department of Urology, University Hospital Rostock, Ernst-Heydemann-
Strasse 6, Rostock D-18055, Germany. Tel. +49 381 4947801; Fax: +49 381 4947802.
E-mail address: oliver.hakenberg@med.uni-rostock.de (O.W. Hakenberg).

1. Introduction sudden. Asymptomatic cases are common, accounting for

Urethritis is characterized by urethral discharge, dysuria, and/
or itching. The etiology can be infectious or noninfectious.
Infectious urethritis is differentiated into gonococcal urethri-
tis (the ‘‘classic’’ form of infective urethritis), caused by
Neisseria gonorrhoeae, and non-gonococcal urethritis (NGU),
which is most often caused by either Chlamydia trachomatis or
Mycoplasma genitalium [1,2]. In addition, but distinctly less
common, infectious NGU can also be caused by Trichomonas
vaginalis, Gardnerella vaginalis, Ureaplasma urealyticum, her-
pes simplex virus (HSV), and adenoviruses [1,3].
2. Clinical picture
A urethral discharge that is putrid or watery, dysuria, and/or
urethral or perimeatal irritation or itching characterize the
clinical picture (Fig. 1). The onset may be insiduous or
approximately 30–50% of cases among men and more
among women [4].
The clinical picture and macroscopic assessment of the
urethral discharge do not allow a clear-cut diagnosis other
than suspicion of urethritis. Therefore, the discharge must
be examined microscopically to establish the presence of
inflammation. The microscopic and laboratory findings
suggesting the presence of inflammation of the urethra are:
 A discharge on clinical examination;
 A high number of polymorphonuclear leucocytes in a
Gram-stained smear of the discharge (2 leucocytes per
high-power field [1000]);
 A high number of polymorphonuclear leucocytes in the
sediment of first-void urine (stained or unstained; 10
leucocytes at 400 magnification); and

http://dx.doi.org/10.1016/j.eursup.2017.01.002
1569-9056/# 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.
 EUROPEAN UROLOGY SUPPLEMENTS 16 (2017) 144–148
 A positive leucocyte esterase test on urine dipstick (first-
void portion).
3. Etiology and diagnosis of urethritis
The great majority of urethritis cases are caused by infective
etiologies. Other noninfective causes are very rare (see
below).
3.1. Neisseria gonorrhoeae
Gonococcal urethritis is the best known and clinically most
obvious form of urethritis. It is caused by infection with
N. gonorrhoeae, an intracellular, aerobic, oxidase-positive
diplococcus (Fig. 2). Gonococci grow only on special culture
media, such as chocolate agar and Thayer-Martin agar, with
CO2 enrichment. The incubation time is 2–7 d. Gonococcal
urethritis used to be considered the classic form of
urethritis. This is why classification of infectious urethritis
still differentiates between gonoccal and non-gonococcal
urethritis.
For a quick diagnosis, Gram staining of the urethral
secretion should be performed (Fig. 2). This has sensitivity
of 95% and specificity of 99.9% in men for diagnosis of
gonococcal urethritis [5,6]. Alternatively, a simpler methy-
lene blue/gentian violet stain can be used, which does not
require heat fixation and performs similarly well [4].
Fig. 1 – Clinical picture of gonococcal urethritis with a putrid urethral
discharge (courtesy of S. Schubert).
Fig. 2 – Neisseria gonorrhoeae: intracellular Gram-negative diplococci in
a urethral smear.
145
3.2. Non-gonococcal urethritis
NGU be caused by a variety of organisms, most commonly
C. trachomatis, M. genitalium, or T. vaginalis, less comonly
G. vaginalis or U. urealyticum, and rarely by herpes simplex
virus. However, despite advances in the diagnosis of NGU,
determination of an identifiable pathogen is not possible in
many cases (up to 50%) [7].
3.2.1. Mycoplasmas
Mycoplasmas are the smallest free-living organisms. In the
urogenital tract, M. genitalium, U. urealyticum, U. parvum,
and M. hominis can be differentiated, of which the two latter
are discussed to be not pathogenic in humans. Mycoplas-
mas, in contrast to most other bacteria, do not have a cell
wall and cannot be grown on standard media.
3.2.1.1. M. genitalium. Mycoplasma accounts for 10–35% of
NGU cases, while its prevalence among healthy men and
women is only approximately 1–3% [8]. It is easily
transmitted by sexual contact. In women, M. genitalium is
associated with urethritis, cervicitis, endometritis, pelvic
inflammatory disease, and disorders of fertility (pre-term
birth, spontaneous abortion, and tubal factor infertility).
In men, persistence after ineffective treatment may have
important implications for greater susceptibility to HIV
infection. M. genitalium is considered to be slightly less
contagious during sexual contact than C. trachomatis. The
incubation time is estimated to be 14 d.
The only useful method for diagnosis is NAT for urine
samples or urethral, vaginal, or cervical swabs. Sexual
contacts within the previous 3 mo should be examined. The
high rate of resistance to primary treatment with macro-
lides is increasing, which is why a post-treatment
reassessment is required.
3.2.1.2. U. urealyticum. There has been a great deal of
disagreement about the role of the mycoplasma family
member Ureaplasma in NGU. Ureaplasma can be isolated in
urethral swabs from asymptomatic men in 30–40% of cases,
but the association with NGU is controversial because older
studies did not differentiate between U. urealyticum and
U. parvum. While the latter is a nonpathogenic component
of the urethral flora, U. urealyticum seems to be a likely
cause of NGU, although probably in only a small number of
cases [4,9]. This etiology should therefore be considered in
men without other identifiable NGU etiologies.
3.2.2. C. trachomatis
Chlamydiae are very old bacteria in terms of evolutionary
development, and there are three species that are pathogenic in
humans: C. trachomatis, C. psittaci, and C. pneumoniae. These are
small Gram-negative bacteria that live as intracellular para-
sites, which is why they were originally thought to be large
viruses [10]. Their intracellular existence predisposes to long-
persisting infections. The primary target organs for C.
trachomatis are the epithelium of the urethra in males and
of the cervix in women, but the mucosa of the rectum and the
conjuctiva can also be infected [11].
146 EUROPEAN UROLOGY SUPPLEMENTS 16 (2017) 144–148
Some serotypes cause human trachoma in tropical
climates, while serotypes D–K are sexually transmissible
and are among the most common sexually transmitted
diseases (STDs). The prevalence in the general population in
the USA is 1.4% in men and 2.0% in women, but is higher in
other countries [12].
Infections are often asymptomatic in women (70%),
while most infections in men are symptomatic (70%)
[11]. Chlamydia infections account for approximately
25–50% of all cases of male urethritis. In females, cervicitis
and/or urethritis result from infections, and C. trachomatis
can be transmitted to the newborn during vaginal delivery.
In some, chronic pelvic inflammatory disease with infertili-
ty may result. In men, ascending infection can result in
epidiymo-orchitis, prostatitis, and infertility. In rare cases,
urethritis can result in urethral stricture formation. Reactive
arthritis, especially in HLA-B27–positive patients, may
result from chlamydial infection, and in rare cases the
clinical triad of arthritis, urethritis, and conjunctivitis may
occur (Reiter’s syndrome).
Chlamydiae can only be grown in cell culture. The
diagnosis is much faster using NATs from any clinical
medium (swabs, urine, tissue). Serology for antibodies
against C. trachomatis is questionably only relevant in
reproductive medicine, when infertility may result from
persisting infection. Testing for chlamydia should be
accompanied by investigations for other STDs.
3.2.3. T. vaginalis
Trichomonas are not bacteria but protozoans, small, single-
celled organisms that can usually be detected and diag-
nosed microscopically from urethral smears. Culture is
possible, but is often not successful.
As a cause of NGU, T. vaginalis accounts for 2–13% of cases
in the USA, where it is more common among Afro-
Americans, but in Europe it is uncommon as a cause of
urethritis [13]. T. vaginalis infection is asymptomatic or only
mildly symptomatic in 70–85% of all cases in both sexes.
Therefore, undiagnosed and untreated infections can persist
for months or years. If a T. vaginalis infection becomes
distinctly symptomatic, it leads to a diffuse, foul-smelling,
and often yellowish-green vaginal discharge in women. In
men, symptomatic infection can lead to overt urethritis or
become symptomatic as epididymitis or a prostatitis.
Infection with T. vaginalis increases the risk of acquiring
HIV two- to threefold [14].
Instant microscopy was the diagnostic procedure most
commonly used for a long time, but this has limited
sensitivity of only 50–65% [15]. The NATs developed in
recent years have much greater diagnostic value, with
sensitivity and specificity of 95–100% [16]. NATs increase
the diagnostic rate considerably [15] and should therefore
be used on urethral or vaginal swabs or urine. Investigations
for other STDs (chlamydia, gonorrhea, HIV) should be
conducted, and partner examination is recommended.
3.2.4. G. vaginalis
This organism is a mostly anaerobic bacterium with
variable Gram staining; it has been found in a significant
number of cases of symptomatic NGU after exclusion of
other known causes. It is highly prevalent in completely
asymptomatic men (up to 40%) [17]. However, it is mostly
an infection in females, in whom it may be asymptomatic,
but it can cause ‘‘bacterial vaginosis’’, with a foul-smelling
grey vaginal discharge of pH 5.0–5.5 that contains ‘‘clue
cells’’ (mucosal cells with Gardnerella adhering to the cell
surface). Although it can result in NGU in men, asymptom-
atic infection in men is of epidemiologic importance. The
diagnosis can be made via microscopy of stained swabs or
via culture.
3.2.5. Herpes simplex virus
Urethritis as part of the clinical picture is seen in 15–30% of
patients with primary herpes simplex infections. Both
herpes simplex virus 1 and 2 have been isolated as infective
agents in 3% and 2%, respectively, of NGU cases [18].
3.2.6. Adenoviruses
Adenoviruses as an etiological agent in urethritis have been
identified in rare cases in which no other infectious causes
could be identified. All the cases reported recent oral sex
and there was a clustering of cases in autumn and winter
[19].
3.2.7. Uncertainties and unknowns
Advances in microbiological technology such as high-
throughput sequencing have shown that the microbiome
of the male urethra in cases with unexplained NGU can be
complex, with more than 50 genera of organisms identified
[20]. Complex microbiological communities have been
detected in the urine and prostatic secretions of men with
chronic prostatitis syndrome [21]. It therefore seems that
the microbiology of the urethra can consist of a multitude of
organisms that may cause the clinical picture of urethritis
and are likely to be related to other genitourinary disease
conditions in men. Often, clear-cut identification of one
infective causative agent may not be possible.
3.3. Noninfective rare causes of urethritis
In rare instances, urethritis may be due to other causes that
can be considered for the differential diagnoses in unclear
cases. Allergic urethritis has been described in men whose
female partners use vaginal contraceptives; it may also occur
after instillation of lubricants into the urethra. Mechanical
urethritis as a result of manipulation is a possibility.
Catheter-induced urethritis is due to bacterial colonization
and is often associated with urinary tract infection. In
immunosuppressed patients, fungal urethritis can occur.
3.4. Making the diagnosis
The clinical picture should be confirmed by investigating
the discharge or urine to confirm the presence of infection
and, if possible, of a known pathogen. The point-of-care test
is the traditional Gram stain (or methyleneblue/gentiana
violet stain). Gonococcal infection can be diagnosed
accurately via this technique.
 EUROPEAN UROLOGY SUPPLEMENTS 16 (2017) 144–148
For NGU, the sensitivity of the Gram stain is highly
dependent on the technique used (swab vs loop vs spatula),
and a substantial number of eventually pathogen-positive
cases may be missed.
NATs are more sensitive than simple stains in NGU. The
cost of these techniques is decreasing and their use is
recommended because of their high sensitivity and
specificity, since a specific diagnosis might reduce compli-
cations, reinfections, and transmissions [1]. T. vaginalis is
difficult to diagnose in men, as microscopy and culture
show limited sensitivity. In refractory cases after exclusion
of other pathogens, NATs may be useful, especially for men
whose female partners have T. vaginalis. Similarly, diagnosis
of Mycoplasma infection may require NATs.
4. Treatment
4.1. Gonococcal urethritis
Treatment is empiric in that antibiotics effective against
both N. gonorrhoeae and C. trachomatis should be given
[1,7]. In most countries in Europe, there are high rates of
penicillin-resistant (80%) as well as fluoroquinolone-resis-
tant (74%) N. gonorrhoeae [22–25].
Empirical treatment is with ceftriaxone 1 g iintrave-
nously or intramuscularly plus a single dose of azithromy-
cin 1.5 g orally. This combination is recommended because
C. trachomatis should be treated at the same time as
treatment of gonococcal urethritis. Cefixim is an orally
active treatment option, but it has been repeatedly
associated with treatment failures and is no longer
considered a first choice [1,26]. Specific treatment, only if
based on microbiological isolation and sensitivity testing,
can be a single oral dose of cefixime (400 mg), levofloxacine
(500 mg), ofloxacine (400 mg), or azithromycin (1.5 g) [7].
If there is no treatment response, additional investiga-
tions for T. vaginalis (microscopy, NAT) and M. genitalium
(NAT) should be considered.
4.2. C. trachomatis
Macrolides and tetracyclines are effective for treatment.
Oral doxycycline 100 mg twice daily is given for 1 wk; an
alternative is azithromycin (1.5 g orally as a single dose).
Treatment efficacy should be checked by retesting, and
partner examination should be recommended [26]. Among
the fluoroqinolones, ciprofloxacin has no reliable activity
against C. trachomatis; instead, ofloxacin or levofloxacin is
recommended.
4.3. M. genitalium
Antibiotics effective against Mycoplasma are tetracyclines,
macrolides, and often fluoroquinolones. Doxycycline now
has very limited efficacy (30–40%), while azithromycin used
to have a cure rate of 85% with a single-shot treatment of 1 g
[27]. However, the development of macrolide resistance is
probably due to this single-shot regimen with azithromy-
cine, and has been supplanted by a 7-d oral treatment
147
regimen (500 mg initially, followed by 250 mg daily for 7 d)
[28].
An alternative and the recommended second-line
treatment in refractory cases is moxifloxacin given orally
(400 mg once daily) for 10–14 d, with a cure rate of nearly
100% [7,28]. Failing this, there is one reserve drug available,
pristinamycin, although testing has been rather limited and
the drug is not readily available in many countries.
Positive tests for mycoplasma should be followed by
testing for macrolide resistance [8]. There are not sufficient
data to assess the efficacy of fluoroquinolones such as
ciprofloxacine or levofloxacine in this situation.
4.4. T. vaginalis
Treatment with a single oral dose of either metronidazole
(2 g) or tinidazole (2 g) is usually effective. Metroniodazole
can be given for a longer period of 7 d (500 mg twice daily
orally) if symptoms persist.
5. Multiple testing
Cases with urethritis should always be examined for the
presence of other STDs (eg, HIV, syphilis) [1]. Sexual
partners during the previous 60 d should also be examined
[27]. Patients should abstain from sexual activity during
treatment and for 7 d after its completion. Treatment
efficacy should be assessed via NATs 4 wk after treatment
completion at the earliest.
6. Recurrence and/or persistence
From research studies it is well known that persistence
without symptoms is quite common for NGU. In clinical
practice, however, asymptomatic men will not re-present to
clinics after treatment. It is therefore advisable to establish
treatment efficacy via routine repeat investigation.
In cases of suspected persistence or reinfection, the
presence of inflammation should again be established.
Persistence seems to be more likely to occur with
Mycoplasma spp. than with either Trichomonas or
Chlamydia [29]. For treatment of persistent NGU, oral
moxifloxacin 400 mg for 7 d is recommended for
Mycoplasma spp., and either metronidazole or tinidazole
for Trichomonas after initial treatment with azithromycin. If
the initial treatment was with doxycycline or a fluoroquin-
olone, then azithromycin should be given.
7. Conclusions
Urethritis is usually caused by sexually transmissible
organisms. The diagnosis is still made via stains of urethral
swabs or urine, although NATs may sometimes be prefera-
ble. There is a high rate of resistance in gonococcal urethritis,
so current treatment recommendations should be based on
epidemiological data. In NGU, a causative organism can often
not be isolated, and treatment then has to be empirical.
Partner evaluation and treatment are required.
148 EUROPEAN UROLOGY SUPPLEMENTS 16 (2017) 144–148

Conflicts of interest [14] Kissinger P, Adamski A. Trichomoniasis and HIV interactions: a

review. Sex Transm Infect 2013;89:426–33.
[15] Roth AM, Williams JA, Ly R, et al. Changing sexually transmitted
The authors have nothing to disclose.
infection screening protocol will result in improved case finding for
Trichomonas vaginalis among high-risk female populations. Sex
Funding support Transm Dis 2011;38:398–400.
[16] Schwebke JR, Hobbs MM, Taylor SN, et al. Molecular testing for
None. Trichomonas vaginalis in women: results from a prospective U.S.
clinical trial. J Clin Microbiol 2011;49:4106–11.
[17] Frolund M, Dactu R, Ahrens P, Lidbrink P, Bjornelius P, Jensen JS. Is
References urethritis of unknown etiology caused by bacteria associated with
bacterial vaginosis? Sex Transm Infect 2011;87(Suppl):A276–7.
[1] Workowski KA, Bolan G. Centers for Disease Control. Sexually
[18] Frolund M, Lidbrink P, Cullberg M, Wikstrom A, Ahrens P, Jensen J.
transmitted diseases treatment guidelines, 2015. Morb Mortal
The association of Ureaplasma urealyticum with male non-gono-
Wkly Rep 2014;64(RR3):1–137.
coccal urethritis in heterosexual Sydney men. Sex Transm Infect
[2] Workowski KA, Berman S. Centers for Disease Control. Sexually
2011;87(Suppl):A303–4.
transmitted diseases treatment guidelines, 2010. Morb Mortal
[19] Bradshaw CS, Denham IM, Fairley CK. Characteristics of adenovirus
Wkly Rep 2010;59(RR12):1–110.
associated urethritis. Sex Transm Infect 2002;78:445–7.
[3] Bradshaw CS, Tabrizi SN, Read TR, et al. Etiologies of nongonococcal
[20] Ahrens P, Frolund M, Abu Al Soud A, et al. Bacteria in the first-void
urethritis: bacteria, viruses, and the association with orogenital
urine of urethritis patients and healthy controls analyzed by
exposure. J Infect Dis 2006;193:336–45.
454 high throughput sequencing. San Francisco, CA: American
[4] Bachmann LH, Manhart LE, Martin DH, Sena AC, Dimitriakoff JJ,
Society for Microbiology;; 2012: C2282.
Gaydos CA. Advances in the understanding and treatment of male
[21] Krieger JN, Riley DE, Roberts MC, Berger RE. Prokaryotic DNA
urethritis. Clin Infect Dis 2015;61(Suppl 8):S763–9.
sequences in patients with chronic idiopathic prostatitis. J Clin
[5] Abele-Horn M, Blenk H, Clad A, et al. Infektionen des weiblichen
Microbiol 1996;34:3120–8.
und des männlichen Genitaltraktes. In: Genitalinfektionen Teil I:
[22] Lewis DA. Global resistance of Neisseria gonorrhoeae: when theory
MiQ 10. Munich. Germany: Urban & Fischer; 2011.
becomes reality. Curr Opin Infect Dis 2014;27:62–7.
[6] Bartelsman M, Straetemans M, Vaughan K, et al. Comparison of two
[23] Ndowa F, Lusti-Narasimhan M, Unemo M. The serious threat of
Gram stain point-of-care systems for urogenital gonorrhoea among
multidrug-resistant and untreatable gonorrhoea: the pressing need
high-risk patients: diagnostic accuracy and cost-effectiveness be-
for global action to control the spread of antimicrobial resistance,
fore and after changing the screening algorithm at an STI clinic in
and mitigate the impact on sexual and reproductive health. Sex
Amsterdam. Sex Transm Infect 2014;90:358–62.
Transm Infect 2012;88:317–8.
[7] Wagenlehner FME, Brockmeyer NH, Discher T, Friese K, Wichelhaus
[24] Unemo M, Nicholas RA. Emergence of multidrug-resistant, exten-
TA. The presentation, diagnosis and treatment of sexually trans-
sively drug-resistant and untreatable gonorrhea. Future Microbiol
mitted infections. Dtsch Arztebl Int 2016;113:11–22.
2012;7:1401–22.
[8] Jensen JS, Cusini M, Gomberg H, Mai H. 2016 European guideline on
[25] Horn NN, Kresken M, Korber-Irrgang B, et al. Antimicrobial suscep-
Mycoplasma genitalium infections. J Eur Acad Derm Venerol
tibility and molecular epidemiology of Neisseria gonorrhoeae in
2016;30:1650–6.
Germany. Int J Med Microbiol 2014;304:586–91.
[9] Zhang N, Wang R, Li X, et al. Are Ureaplasma spp. a cause of
[26] Bremer V, Brockmeyer N, Buder S, et al. Gonorrhoe bei Erwachsenen
nongonococcal urethritis?. A systematic review and meta-analysis.
und Adoleszenten, AWMF online. 2013, www.awmf.org/leitlinien/
PLoS One 2014;9:e113771.
detail/ll/059-004.html.
[10] Jeffrey F, Peipert MD. Genital chlamydial infections. N Engl J Med
[27] Grabe M, Bartoletti R, Bjerklund Johansen TE, et al. Guidelines on
2003;349:2424–30.
urological infections.. Arnhem, The Netherlands: EAU Guidelines
[11] Bremer V, Brockmeyer NH, Frobenius W, et al. Infektionen mit
Office; 2015.
Chlamydia trachomatis, AWMF online. 2016, http://www.awmf.
[28] Anagrius C, Lore B, Jensen JS. Treatment of Mycoplasma genitalium.
org/uploads/tx_szleitlinien/059-005m_S2k_Chlamydia-trachomatis_
Observations from a Swedish STD clinic. PLOS One 2013;8:0061481.
Infektionen_2016-12.pdf.
[29] Sena AC, Lensing S, Rompalo A, et al. Chlamydia trachomatis,
[12] Torrone E, Papp J, Weinstock H. Prevalence of Chlamydia tracho-
Mycoplasma genitalium and Trichomonas vaginalis infections in
matis genital infection among persons aged 14-39 years—United
men with non-gonococcal urethritis: predictors and persistence
States 2007-2012. Morb Mort Wkly Rep 2014;63:834–8.
after therapy. J Infect Dis 2012;206:357–65.
[13] Ng A, Ross JD. Trichomonas vaginalis infection: how significant is it
in men presenting with recurrent or persistent symptoms of ure-
thritis? Int J STD AIDS 2016;27:63–5.