C. trachomatis genital infection is common. (3-5% of sexually active women attending UK General Practice^{1 2}) The chlamydia opportunistic screening pilot studies, involving women under 25, in Portsmouth and The Wirral have found higher prevalences of chlamydia (approximately 10%) than previously reported in selected populations ³ Currently the chlamydial prevalence in men as well as women in the general population is unknown. Both the follow up NATSAL study and the Chlamydia Screening Study (ClaSS), funded by the NHS Health Technology Assessment Programme) are addressing this. Infection in the community is sustained by unrecognised and thus untreated symptomless infection both in men4 and women. Complications cost at least £50 million annually in the United Kingdom.5 Approximately 40% of non-gonococcal urethritis is caused by C trachomatis.

· Asymptomatic in approximately 80%

· Post coital or intermenstrual bleeding

· Lower abdominal pain

· Purulent vaginal discharge

· Mucopurulent cervicitis and/or contact bleeding

· Asymptomatic in up to 50%.

· Urethral discharge

· Dysuria.

· The severity of these is variable and may be so mild as to be unnoticed by the patient.

· Age <25

· New sexual partner or more than one sexual partner in the recent years

· Lack of barrier contraception

· Use of oral contraceptive pill

· Women undergoing termination of pregnancy

· Pelvic inflammatory disease

· Fitz-Hugh-Curtis syndrome (perihepatitis)

· Tubal damage (infertility, ectopic pregnancy)

· Chronic pelvic pain (adhesions)

· Transmission to neonate (conjunctivitis, pneumonia)

· Epididymo-orchitis

· Adult conjunctivitis

· Sexually acquired reactive arthritis/Reiter’s syndrome (commoner in men)

Chlamydial diagnostics continues to be such a rapidly developing field that it is inappropriate to be proscriptive and prescriptive about methodology.2 There are also problems in interpreting many published trials because they use inappropriate reference standards: either culture, which is now known to be insensitive, or discrepant analysis, which overestimates both sensitivity and specificity.6 The ClaSS project will also investigate which specimen and which test is the most cost effective method for diagnosing Chlamydia trachomatis.

Table 1 summarises only trials involving head to head comparisons with nucleic acid amplification techniques (references available on request).

· High specificity - essential for medicolegal cases

· Expertise essential

· Expensive - method of choice for confirmation of other assays

· High sensitivity in experienced hands provided a cut off of 2 elementary bodies is used

· Labour intensive, needs skilled personnel

· Unsuitable for large numbers (>30/day)

· Can be used for confirmation of other assays

· Will accommodate all specimen types

· High specificity (assay dependent) when combined with confirmation assay

· Variable sensitivity (assay dependent)

· Inexpensive, suitable for large numbers

· Automatable

· High specificity

· High sensitivity - not consistently reported (see table 1). Inhibitors may be a problem, especially with urine specimens

· Expensive in staff, space, and consumables compared with EIA.

· Test costs may be decreased and sensitivity maintained by pooling of specimens. 7,8

· Needs particular care in laboratory to avoid contamination

· Transport delay >24 hours at room temperature reduces the sensitivity of the ligase chain reaction (LCR) on urine.9

· Storing urine overnight at 4oC or freeze thawing may enhance sensitivity.10

· Pregnancy may impair the performance of the LCR urine test (conflicting data), 10-12

· Ideal diagnostic test sensitivity is >90% with specificity >99%. The tests which most closely approach this are the NAATs. These perform better or at least as well as any of the other tests.

· Only the better performing EIAs should be used, with sensitivities >80% and where sensitivity comparisons against NAAT techniques have been carried out

· With EIAs, the technique of confirmation in the negative grey zone, either by DFA or NAAT, should be introduced. 13, 14 This improves sensisitivity by 5-30%

· Quality control to validate the sensitivity and specificity of the assay used by individual laboratories should be undertaken, in view of the reported wide range in the sensitivity of all tests. Both interlaboratory and intralaboratory control samples should be carried out .using both strong positives, negative and weakly reactive specimens.

· First voided urine sample is as good as, if not better than, a urethral swab.15, 16 The former is to be preferred because some patients find urethral swabbing painful and tolerate it poorly and thus there is the potential for obtaining an inadequate quality specimen. Patients should hold their urine at least 1 hour before being tested and preferably longer, as otherwise sensitivity is reduced (the optimum duration is not known).

· EIA should not be used for detecting C. trachomatis in the rectum or pharynx.

· first voided urine sample is the preferred specimen.17 (see above)

· Cervical swab is the best specimen.

· 10-20% additional positives will be detected by assaying an urethral specimen as well.18, 19 This can be combined with the cervical specimen for analysis. Urethral swabbing suffers from the same disadvantages as in men.

· Urine specimens perform significantly less well with EIA than cervical specimens and are not recommended.

· EIA should not be used for detecting C. trachomatis in the rectum or pharynx

· Cervical swabs consistently have sensitivities >80%.^{20, 21}

· Urine has reported sensitivities of 44-94%.^{11, 12, 20-24}

· Vulvo-vaginal swabs have a sensitivity >85%

Preliminary data suggests that testing for C. trachomatis may detect more cases when undertaken in the latter part of the menstrual cycle.^{22, 25, 26} This is further supported by the findings from a community based study in Denmark.²⁷

· The sample must contain cellular material. Swabs should be inserted inside the cervical os and firmly rotated against the endocervix.

· Inadequate specimens reduce the sensitivity of all diagnostic tests.28

· Urethral swab in men should be inserted 1-4cm inside and rotated once before removal.

· There is no consensus on how to take a urethral swab in women.

· DIF is the only method that gives information concerning the quality of sample

All patients in whom C trachomatis is detected should be assessed for the presence of other sexually transmitted infections (grade of recommendation C)

· Doxycycline 100mg twice a day for 7 days

or

· Azithromycin 1gm orally in a single dose

ALTERNATIVE REGIMENS: (A)

· Erythromycin 500mg 4 times a day for 7 days

· Erythromycin 500mg 2 times a day for 14 days

· Deteclo 300mg 2 times a day for seven days

· Ofloxacin 200mg 2 times a day or 400mg once a day for 7 days

· Tetracycline 500mg 4 times a day for 7 days.

The majority of studies on the efficacy of antibiotic therapy have suffered from flaws in design. 29 Studies have often been small, and the duration of follow-up has usually only been short. In many studies no details were given on treatment of the sexual partner(s), and often no distinction made between persistence or re-infection in the study population at follow-up. In addition the majority of studies have used culture to detect C.

trachomatis. Doxycycline and Azithromycin have been the most rigorously investigated.

· These have been shown to have equal efficacy in clinical studies.29-31

· Azithromycin is considerably more expensive than Doxycycline.

· Azithromycin may be particularly useful in patients with erratic health-care seeking behaviour.32

· It is unknown whether 200mg twice a day is superior to 400mg once a day. There is no evidence to suggest that compliance with a once-a-day regimen is better than twicedaily regimens.33 Whether missing a dose with 400mg daily results in a less efficacious regimen than missing a dose with 200mg twice daily is unknown.

· Ofloxacin has similar efficacy to doxycycline and a better side-effect profile but is

· Erythromycin is less efficacious than either Azithromycin or Doxycycline.

· When taken four times a day, 20-25% may experience side-effects sufficient to cause the patient to discontinue treatment.34

· There are only limited data on erythromycin 500mg twice a day, with efficacy reported at between 73-95%.34-36 A 2 week course appears to be more efficacious than a 1 week course of 500mg twice a day, with a cure rate ³ 95% in a small study.^{34, 35}

OTHER TETRACYCLINES (1b)

· Deteclo is probably as efficacious as doxycycline.37 However, photosensitivity occurs more frequently and there are not as many data on efficacy if compliance is poor.

· Tetracycline 500mg is effective when taken four times a day for seven days. Compliance with such a regimen is likely to be poor, particularly in less motivated patients, and whether such a regimen would then be efficacious is unknown.

· Oxytetracycline 250mg four times a day has also been shown to be effective, although the published evidence is limited.³⁶

In general compliance with therapy is improved if there is a positive therapeutic relationship between the patient and the doctor.38 This can probably be improved if the following are applied (C):

· What chlamydia is and how it is transmitted

· it is a sexually transmitted infection

· if asymptomatic there is evidence that it could persist for months or even years

· it can be isolated from the throat and eye without detectable infection in the lower genital tract. 35, 39 It can therefore not always be assumed to be sexually acquired.⁴⁰

· The diagnosis of chlamydia, particularly:

· it is often asymptomatic especially in women

· whilst tests are accurate, no test is absolutely so

· The complications of untreated chlamydia

· Side effects and importance of complying fully with treatment and what to do if a dose is missed.

· Interaction between antibiotics and oral contraceptive pill.

· The importance of their sex partner(s) being evaluated and treated

· Advised to abstain from sexual intercourse until they have completed therapy and their partner has been treated

· Advice on safer sexual practices.

· Doxycycline and ofloxacin are contraindicated in pregnancy

· The safety of azithromycin in pregnancy and lactating mothers has not yet been fully assessed, although available data indicate that it is effective.

· Erythromycin has a significant side effect profile and is less than 95% effective. There are no trials of erythromycin 500mg twice a day for 14 days, which would be better tolerated than four times a day.

· Amoxycillin had a similar cure rate to erythromycin in a meta-analysis and had a much better side effect profile. 41 However, amoxycillin in vitro has been show to induce latency: there is therefore debate as to whether it is reliable. REGIMENS (1a,A)

· Erythromycin 500mg four times a day for 7 days

· Erythromycin 500 mg twice a day for 14 days

· Amoxycillin 500 mg three times a day for 7 days.

· All patients identified with C. trachomatis should be referred to a department of Genitourinary Medicine to discuss partner notification with a trained health adviser, where possible at initial diagnosis. This appears to be acceptable to patients diagnosed outside GUM departments as evidenced by the findings from the chlamydia pilot screening study in Portsmouth.3 The ClaSS project will evaluate whether this is more cost effective than partner notification undertaken in general practice.

· The method of partner notification agreed for each partner/contact identified should be documented.

· At subsequent follow-up, partner notification outcomes should be ascertained and documented

Only limited evaluation has taken place of the incubation period following exposure to the development of symptoms. In the United Kingdom42 an arbitrary cut-off of 4 weeks is used to identify those sexual partner(s) potentially at risk if the index male patient is symptomatic. As it is not known how long a patient can carry chlamydia asymptomatically, an arbitrary cut-off of 6 months, or until the last previous sexual partner (whichever is the longer time period), is used in women and asymptomatic men.

· Following up partner notification

· Reinforcing health education

· providing reassurance

· assessment of treatment efficacy/exclusion of re-infection

Patients do not need to be retested for C trachomatis after completing treatment with doxycycline or azithromycin unless symptoms persist of re-infection is suspected, as both are highly efficacious (C). A test of cure should be considered 3 weeks after the end of treatment with erythromycin. A test of cure earlier will miss late failures and may detect non-viable organisms.

· Compliance with clinical standards of care.

· Partner notification.

· Patient’s knowledge of chlamydia and how to reduce the risk of acquiring it.

Dr Patrick J Horner, Department of Genitourinary Medicine, The Milne Centre, Bristol Royal Infirmary; Dr E Owen Caul, Public Health Laboratory Service, Myrtle Road, Bristol

Medline searches for the years 1970 to present using keywords “Chlamydia trachomatis” in association with “polymerase chain reaction” or “PCR” or “ligase chain reaction” or “lcr” or “lcx” and “immunoenzyme techniques” or “enzyme-linked immunosorbent assay”. “Chlamydia trachomatis” combined with the following key words “detection”, “diagnosis”, “treatment”. The Cochrane library: “Chlamydia trachomatis”

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