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National Guideline on the Management of Non-gonococcal Urethritis
Clinical Effectiveness Group (Association for Genitourinary Medicine and the Medical
Society for the Study of Venereal Diseases)
Introduction
Urethritis, or inflammation of the urethra, is a multifactorial condition which is primarily
sexually acquired. It is characterised by discharge and/or dysuria but may be asymptomatic.
The diagnosis of urethritis is confirmed by demonstrating an excess of polymorphonuclear
leucocytes (PMNLs) in the anterior urethra. This is usually undertaken using a urethral smear,
but a first pass urine specimen (FPU) can also be used. Urethritis is described as either
gonococcal, when Neisseria gonorrhoeae is detected or non-gonococcal (NGU) when it is not.
Mucopurulent cervicitis is the female equivalent with approximately 40% of cases being due to
infection with Chlamydia trachomatis.
Aetiology
Chlamydia trachomatis is the commonest cause of NGU accounting for 30-50% of cases.
Ureaplasma urealyticum (ureaplasmas) and Mycoplasma genitalium probably cause urethritis
and account for 10-20% of cases respectively. 1-5 Trichomonas vaginalis has been reported in
1-17% of cases of NGU. It is likely that the relative importance of T. vaginalis as a cause of
NGU depends on the prevalence of the infection within the community.5-7 N. meningitidis,
Herpes simplex virus, Candida sp., bacterial urinary tract infection, urethral stricture and
foreign bodies probably account for only a small proportion of cases (<10%). There is also a
possible association with bacterial vaginosis.8,9
1
Between 20-30% of men with NGU have no organism detected. Asymptomatic urethritis,
without an observable discharge, may have a different aetiology from symptomatic urethritis,
with C trachomatis being detected less frequently.10-12
It is assumed that the aetiological agent of sexually acquired male NGU could potentially cause
genital tract inflammation in women, in particular pelvic inflammatory disease (PID). This is
unquestionably the case with chlamydial and gonococcal infection but remains to be
substantiated for other causes. However, as the aetiology of PID is unknown in 40-60% of
cases, this assumption remains a possibility.
Clinical features
SYMPTOMS
• Urethral discharge
• Dysuria
• Penile irritation
• Asymptomatic
SIGNS
• Urethral discharge. This may only be present on urethral massage. It can also be found in a
significant proportion of patients with asymptomatic urethritis.
• Normal examination
COMPLICATIONS
• Epididymo-orchitis
• Sexually acquired reactive arthritis / Reiter’s syndrome
These are infrequent, occurring in fewer than 1% of cases though incomplete forms may be
more common.
2
Diagnosis
The diagnosis of urethritis must be confirmed by demonstrating PMNLs in the anterior urethra.
This can be by means of:
(i)
A Gram stained urethral smear containing
>=5 PMNL per high-power (x1000)
microscopic field (averaged over five fields with greatest concentration of PMNLs).10
and/or
(ii)
a Gram stained preparation from a FPU specimen, containing >=10 PMNL per high-
power (x1000) microscopic field (averaged over five fields with greatest concentration of
PMNLs).
§
Either test can be used: Both tests will identify cases missed by the other test.12
§
The quality of the smear is heavily dependent on how the smear is taken
§
Either a 5 mm plastic loop or cotton-tipped swab can be used. There are no published data
comparing the two but the former appears to be less traumatic to the patient.
§
Positive leucocyte esterase activity on FPU specimen is correlates with NGU and is
considered diagnostic by some authorities.13 However, it does not have adequate sensitivity to
be considered a reliable rapid diagnostic test for NGU.14
15
The sensitivity of the above tests is affected by the period since last passing urine. The optimum
time to ensure a definite diagnosis in a symptomatic man is not known.
Four hours is
conventional.
Symptomatic patients in whom no urethritis is detected initially, should be retested having held
their urine overnight. Empirical treatment of these patients is not recommended unless they
have an observable mucopurulent/purulent discharge or are at high risk of infection and are
unlikely to return for repeat evaluation.
3
INVESTIGATIONS
• All patients should have a urethral culture for N. gonorrhoeae .
• C trachomatis should also be sought (see guideline on chlamydia).
•
Urinalysis of the mid-stream urine (MSU) specimen, may be useful, using a dipstick which
contains leucocyte esterase and nitrites, in addition to testing for blood, protein and glucose.16
In positive cases an MSU specimen should be sent for microscopy and culture.
•
Formerly, the two glass test was used to diagnose NGU and to differentiate it from urinary
tract infection. This test, however, has an unacceptably low specificity and sensitivity. 17
Management
GENERAL ADVICE
The following should be discussed and clear written information provided:
• A detailed explanation of what NGU is and what causes it, with particular emphasis on the
long term implications for the health of the patient and his partner.
• Side effects of treatment and importance of complying fully with it.
• The importance of their sex partner(s) being evaluated and treated
• Advised to abstain from sexual intercourse until they have completed therapy and his
partner(s) have been treated.
• Advice on safer sex
Treatment
Treatment should be initiated as soon as the diagnosis is made. Ideally treatment should be
effective (microbiological cure rate for C. trachomatis >95%), easy to take (not more than
twice daily), with a low side-effect profile, and cause minimal interference with daily lifestyle.
In general, regimens which are effective against C. trachomatis are also effective in NGU.
Assessing treatments is problematic as there are methodological difficulties in defining efficacy
(see below).
4
RECOMMENDED REGIMENS (GRADE OF RECOMMENDATION A)
§
Doxycycline 100mg twice a day for 7 days (level of evidence Ib)
or
§
Azithromycin 1g orally in a single dose (Ib)
ALTERNATIVE REGIMENS (A)
§
Erythromycin 500mg twice daily for 14 days (Ib)
or
§
Ofloxacin 200mg twice a day or 400mg once a day for 7 days (Ib)
COMPLIANCE WITH THERAPY
Whilst single dose therapy has the advantage of improved compliance, azithromycin has not
been shown to be more effective in clinical studies than doxycycline. There is evidence to show
that in general compliance is improved where there is a positive therapeutic relationship
between the patient and the doctor (see guideline on chlamydia).
In those patients with erratic health care seeking behaviour, in whom compliance is anticipated
to be poor, an argument can be made for prescribing azithromycin. (see guideline on
chlamydia)
Sexual contacts/partners
• All sexual partners at risk should be assessed and offered epidemiological treatment,
maintaining patient confidentiality. The duration of “look back” is arbitrary; 4 weeks is
suggested for symptomatic men and up to 6 months for asymptomatic men.
• The treatment regimen used should be as detailed for uncomplicated C. trachomatis
infection
5
• If C trachomatis or N gonorrhoeae are detected it is particularly important to ensure that all
sexual partner(s) potentially at risk have been notified.
• Details of all contacts should be obtained at the first visit. Consent should also be obtained
to contact either the patient or his partners if tests for C trachomatis or N gonorrhoeae are
found to be positive. This ensures that if the index patient does not reattend, he can contacted
and/or provider referral can be initiated for sexual contacts.
• Female contacts of men with chlamydial urethritis should be treated regardless of the results
of chlamydia isolation (Ib).
• Concurrent treatment of the sexual partner of men with chlamydia negative NGU may result
in an improved response in some patients, and a possible reduction in female morbidity (III).
This has not been evaluated in randomised prospective studies. NGU cohort studies have
looked at the effect on response of urethritis and have produced conflicting conclusions.
18 19
There are reports of patients with persistent or recurrent urethritis being cured only after their
sexual partner received appropriate treatment. 20 There is evidence that at least some men with
“chlamydia-negative” NGU have partners who are chlamydia-positive.21,
22
In addition,
asymptomatic C. trachomatis infection can be cleared without treatment, whether these men
have NGU is unknown.23
Follow up for patients with NGU
This is an important part of the management of NGU and should take place 2 weeks after
initiating therapy . However, some patients may not choose
to return, emphasising the
importance of the initial consultation. Follow up has a number of objectives including:
• Following up partner notification
• Reinforcing health education
• Providing reassurance
• Assessment of treatment compliance and efficacy
• Repeat urethral smear and FPU specimen to look for persistent urethritis only if patient is
symptomatic or has a urethral discharge on examination(test of cure).4
6
Persistent/recurrent NGU
There is no consensus of opinion in either diagnosis or management of this condition. Its
aetiology is probably multifactorial.
NGU
4,7,19,25-228
4,7,19,24,25
. It occurs in 20-60% of men treated for acute
and it is unknown whether patients who have asymptomatic urethritis at
follow-up are more likely to have an acute relapse compared to those with no urethritis at
follow-up. Horner et al.
have recently defined chronic NGU as persistent or recurrent
urethritis occurring 30-92 days following treatment of acute NGU.4 They argue that this is
clinically pragmatic.
Persistent chlamydial infection is only rarely detected, providing the patient and partner(s) have
complied with treatment.
7, 24-26
There is evidence that ureaplasmas and M. genitalium may be
important in the aetiology of chronic NGU with either symptoms or signs.4
There is no evidence that female partners of men with persistent/recurrent NGU are at
increased risk of pelvic inflammatory disease.
DIAGNOSIS OF PERSISTENT/RECURRENT NGU
• Urethral smear and FPU specimen to evaluate PMNLs (as for NGU).
• If patient symptomatic with no objective evidence of NGU, an early morning smear should
be undertaken and if negative reassure.
MANAGEMENT OF PERSISTENT/RECURRENT NGU
• Ensure patient has completed initial course of therapy. If not consider re-prescribing initial
treatment.
• Ensure sexual partner(s) have been treated and re-infection is not a possible cause.
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• If patient has no signs or symptoms consider re-assurance .
RECOMMENDED REGIMENS - (C)
Patient symptomatic or an observable discharge present4, 24, 26, 29
§
Erythromycin500mg four times a day for two weeks
plus
§
Metronidazole 400mg twice a day for five days
CONTINUING SYMPTOMS
There is only limited evidence on how best to manage patients who either remain symptomatic
following a second course of treatment or who have frequent recurrences after treatment.
§
Erythromycin 500 mg four times daily for 3 weeks may help.29
§
Urological investigation is usually normal unless the patient has urinary flow problems.
30
§
Chronic abacterial prostatitis (see guideline on prostatitis) and psychosexual causes
should be considered in the differential diagnosis.
§
7, 29-31
There is no evidence to suggest that patients with microscopic urethritis but who have
no signs or symptoms after two courses of treatment are persistently infected. They should be
reassured
§
Retreatment of the sexual partner may be helpful in recurrent urethritis as it may be due
to re-infection. This has not been evaluated in clinical studies.
§
For men with persistent urethritis, there is no evidence that retreatment of an
appropriately treated sexual partner is beneficial.
Auditable outcome measures
§
Compliance with clinical standards of care.
§
Partner notification
8
§
Patient’s knowledge of non-gonococcal urethritis and how to reduce the risk of
acquiring it.
Acknowledgements
We wish to thank the following for their valuable contributions to this Guideline: Chris Arnatt,
Mark Fitzgerald, Sarah Chippindale, Frances Cowan, Jan Clarke, Karen Rogstad, David Hicks,
Alison Sutton,
Author and Centre
Dr Patrick J Horner, Department of Genitourinary Medicine, The Milne Centre,
Bristol Royal Infirmary. Dr Mohsen Shahmanesh, Department of Genitourinary Medicine,
Whittall Street Clinic, Birmingham.
Membership of the CEG
Clinical Effectiveness Group: Chairman, Keith Radcliffe (MSSVD); Imtyaz Ahmed-Jushuf
(AGUM); Jan Welch (MSSVD); Mark FitzGerald (AGUM); Janet Wilson (Royal College of
Physicians GU Medicine Committee).
Conflict of interests
None
Evidence base
MEDLINE searches for 1970 to present using keywords “Non-gonococcal urethritis”, “nongonococcal
urethritis”, “ non-specific urethritis”, “NGU”, “NSU”.
The Cochrane library for 1970 to the present using keywords “Non-gonococcal urethritis”,
“nongonococcal urethritis”, “non-specific urethritis”, “NGU”, “NSU”.
1. Taylor-Robinson D. The history of non-gonococcal urethritis. Sex Transm Dis 1996; 23:
86-91
2. Horner PJ., Gilroy CB., Thomas BJ. et al . Association of Mycoplasma genitalium with
acute non-gonococcal urethritis. Lancet, 1993; 342: 82-5.
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3. Jensen JS., Orsum R., Dohn B. et al. Mycoplasma genitalium: a cause of male urethritis?
Genitourin Med, 1993; 69: 265-69.
4. Horner PJ, Thomas B, Gilroy CB, Egger M, Taylor-Robinson D. The role of Mycoplasma
genitalium and Ureaplasma urealyticum in acute and chronic non-gonococcal urethritis.
Accepted Clin Infect Dis 2000
5. Schwartz MA, Hooton TM.. Etiology of nongonococcal nonchlamydial urethritis.
Dermatologic Clinics 1998 ; 16(4) :727-33
6. Krieger, J.N., Jenny, C., Verdon, M. et al. Clinical manifestations of trichomoniasis in men.
Ann Intern Med 1993;118: 844-9.
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Handbook of Genitourinary Medicine. Eds: Barton SE, Hay PE. Arnold, London 1999.
8. Arumainayagam JT.,De Silva Y, Shahmanesh M. Anaerobic vaginosis: Study of male sexual
partners. Int J STD & AIDS, 1991;2:102-104.
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non-gonococcal urethritis and bacterial vaginosis and the implications for patients and their
sexual partners. Genitourin Med 1997; 73:373-7.
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