Levels of evidence (I-IV) and grades of recommendation (A-C) are defined at the end of the "Major Recommendations" field.
Diagnosis
- Although the technology for diagnosing Chlamydia trachomatis continues to be a rapidly developing field, the standard of care for all cases, including medico legal cases, is a nucleic acid amplification technique (NAAT).
- NAATs are more sensitive and specific than enzyme immunoassays (EIAs) and the Department of Health has recently advised that the use of sub-optimal EIAs is no longer appropriate and has provided funding to support laboratories moving from EIAs to NAATs (Department of Health, 2003). However no test is 100% sensitive or specific (Skidmore, Horner, & Mallinson, 2006).
- Reactive tests should be confirmed in the laboratory either using the same NAAT platform but if possible a second platform is to be preferred (Skidmore, Horner, & Mallinson, 2006; Health Protection Agency, 2004). This improves specificity by countering processing errors but at the expense, which is usually judged acceptable, of a small reduction in sensitivity caused by specimens with a low organism load being missed at re-test (Skidmore, Horner, & Mallinson, 2006). Thus therapy should be offered to all patients with unconfirmed reactive NAAT results but the significance of this result must be discussed with them (Johnson et al., 2002). The laboratory report should request an additional specimen for further testing when reporting an unconfirmed reactive test, but this may be not be possible (Skidmore, Horner, & Mallinson, 2006; Health Protection Agency, 2004).
- An inhibitory control should be used for each specimen (Skidmore, Horner, & Mallinson, 2006; Health Protection Agency, 2004) as substances may be present in biological fluids which can inhibit NAATs. Failure to use an inhibitory control with each specimen will lead to false negative results (Horner et al., 2005; Mahony et al., 1998; Chong et al., 2003). The Gen-Probe APTIMA system includes a nucleic acid extraction stage which removes the majority of inhibitors and thus the manufacturers state that no inhibitory control is needed (Chong et al., 2003).
- In general NAATs are 90 to 95% sensitive with the majority of studies indicating that as either the number of sites sampled increases, or the number of different NAAT used increases, the greater the detection of C. trachomatis in any given population.
Sites to Be Sampled
Women
- A cervical swab (Grade of Recommendation B) or vulvo-vaginal swab (Grade of Recommendation C) are specimens of choice. To collect cervical specimens, a speculum examination is performed and as the sample must contain cervical columnar cells (Loeffelholz et al., 2001; Welsh, Quinn, & Gaydos, 1997), swabs should be inserted inside the cervical os and firmly rotated against the endocervix. Inadequate specimens reduce the sensitivity of NAATs.
- The vulvo-vaginal swab has a sensitivity of 90 to 95% (Carder et al., 1999; Macmillan et al., 2000; Wiesenfeld et al., 1996; Gaydos et al., 2003) and can be either taken by the patient or health care worker (Schachter et al., 2003). Studies indicate that sensitivities similar to a cervical swab are obtainable. Currently, only the APTIMA system (Gen-Probe Inc., San Diego, CA) has U.S. Food and Drug Administration (FDA) approval for this specimen type.
- If a speculum examination is not possible then urine (Grade of Recommendation B) samples can be utilized.
- Variable sensitivities (65 to 100%) have been reported using the first catch urine (FCU) specimen (McCartney, Walker, & Scoular, 2001; Schachter et al., 2003; Van Der Pol et al., 2001; Jensen, Thorsen, & Moller, 1997; Moncada et al., 2004). When processed by inexperienced staff it may perform with sensitivity <90% (Schachter et al., 2003). Patients should hold their urine for at least 1 hour (Johnson et al., 2002) (maybe 2 hours with some kits, check manufacturer's instructions) before providing a FCU specimen.
Men
- First voided urine sample is reported to be as good as a urethral swab. (Van Der Pol et al., 2001; Chernesky et al., 2005; Crotchfelt et al, 1997; Young et al, 1998; Sugunendran et al., 2001) Urine samples are easy to collect, do not cause discomfort and thus are preferable to urethral swabs. Urethral swabs should be inserted 2 to 4 cm inside the urethra and rotated once before removal (Grade of Recommendation C).
- Patients should hold their urine at least 1 hour before being tested (Johnson et al., 2002), (maybe 2 hours with some kits, check manufacturer's instructions).
Rectal, Pharyngeal and Conjunctival Specimens, Men and Women
Medico Legal Cases
For medico legal cases a NAAT should be taken from all the sites where penetration has occurred. This guideline recommends NAAT rather than culture due to the low sensitivity (60 to 80%) of culture and its lack of availability in many centres (Grade of Recommendation D).
- A reactive NAAT result must be confirmed using a different NAAT (Johnson et al., 2002). Ideally, two swabs should be taken from each site, one for testing and one for confirmation if the initial test is positive. This avoids potential compatibility problems when retesting specimens using a different platform (Skidmore, Horner, & Mallinson, 2006). There is evidence that the Becton Dickinson ProbeTec ET strand displacement amplification (SDA) assay has a lower analytical sensitivity than Roche Cobas Amplicor PCR (Chalker et al., 2005) for some serotypes, which means that SDA may not be suitable for the confirmation of PCR results. There are also data to suggest that Gen-Probe APTIMA system has a higher sensitivity than the other two assays discussed (Schacter et al., 2005). Although, this system does have its own confirmatory assay with matching sensitivity it uses the same methodology, on the same specimen, thus theoretically some causes of false positives may not be eliminated (Johnson et al., 2002).
Cell Culture
- Sensitivity 60 to 80%
- 100% specificity
- Expertise essential
- Expensive—and only limited availability nationally
- Can be used on all specimen types
- Routine use is not recommended due to high cost and low sensitivity.
Enzyme Immunoassays (EIAs)
- The sensitivity of the majority of EIAs is probably only 40 to 70% and their use is not recommended. This guideline recommends laboratories to move to the use of NAATs utilizing Department of Health dedicated funding (Westrom, 1994).
- Should be not used on non-invasive specimens in women, nor on rectal or throat specimens in women or men.
Direct Fluorescent Antibody (DFA)
- Routine use is not recommended.
- Labour intensive, and although a >80% sensitivity is achievable, this requires skilled personnel using a cut off of 2 elementary bodies.
- Unsuitable for large numbers of specimens (>30/day).
- Will accommodate all specimen types including rectal and pharyngeal
Management
General Advice
Ideally, treatment should be effective (microbiological cure rate >95%), easy to take (not more than twice daily), with a low side effect profile, and cause minimal interference with daily lifestyle (Grade of Recommendation C). Uncomplicated genital tract infection with C. trachomatis is not an indication for removal of an intrauterine system (IUS) or intrauterine device (IUD).
Patients should be advised to avoid sexual intercourse (including oral sex) until they and their partner(s) have completed treatment (or wait 7 days if treated with azithromycin). Advice regarding appropriate action if using hormonal contraceptives is also required.
Patients should be given detailed explanation of their condition with particular emphasis on the long–term implications for them and their partner(s). This should be reinforced by giving them clear, accurate written information.
Further Investigation
All patients diagnosed with C .trachomatis should be encouraged to have screening for other sexually transmitted infections (STIs), including a human immunodeficiency virus (HIV) test and, where indicated, hepatitis B screening and vaccination (Grade of Recommendation C). If the patient is within the window period for HIV and syphilis, these should be repeated at an appropriate time interval. All contacts of C. trachomatis should be offered the same screening tests.
Treatment of Genital, Rectal and Pharyngeal Uncomplicated Infection (see appropriate guidelines for treatment of complications) and Epidemiological Treatment
Recommended Regimens (Grade of Recommendation A)
- Doxycycline 100 mg twice a day (bd) for 7 days (contraindicated in pregnancy)
or
- Azithromycin 1 g orally in a single dose
Alternative Regimens (Grade of Recommendation A)
- Erythromycin 500 mg bd for 10 to 14 days
or
- Ofloxacin 200 mg bd or 400 mg once a day for 7 days
Studies of Anti-Microbial Efficacy
Doxycycline and Azithromycin
For information on the studies of the efficacy of azithromycin and doxycycline, see the original guideline document.
Other Anti-Microbials
The information from published studies on efficacy of other anti-microbials is considerably less than that available for azithromycin and doxycycline. It should not be assumed that these are more efficacious than either doxycycline or azithromycin.
Ofloxacin (Grade of Recommendation B)
- It is unknown whether 200 mg twice a day is superior to 400 mg once a day (Kitchen et al., 1990).
- Ofloxacin has similar efficacy to doxycycline and a better side-effect profile but is considerably more expensive, so is not recommended as first-line treatment.
- Resistance to ofloxacin has been demonstrated in vivo and in vitro, but appears to be rare (64).
- No long term follow up (>6 weeks) data.
Erythromycin (Grade of Recommendation A)
- Erythromycin is less efficacious than either azithromycin or doxycycline.
- When taken four times a day, 20 to 25% may experience side effects sufficient to cause the patient to discontinue treatment (Linneman, Heaton, & Ritchey, 1987).
- There are only limited data on erythromycin 500 mg twice a day, with efficacy reported to be between 73 and 95%. A 10 to 14 day course appears to be more efficacious than a 1-week course of 500 mg twice a day, with a cure rate >95% (Tobin, Harindra, & Mani, 2004; Ross, Crean, & McMillan, 1996).
- Resistance to erythromycin has been demonstrated in vivo and appears to be rare. It has not been documented to be significant in vivo.
Other Tetracyclines (Grade of Recommendation A)
- "Deteclo" (registered trademark) is probably as efficacious as doxycycline (Munday et al., 1995). However, photosensitivity occurs more frequently and there are insufficient data on efficacy if compliance is poor.
- Oxytetracycline 500 mg bd 10 days has also been shown to be effective (Tobin, Harindra, & Mani, 2004)
Pregnancy and Breast Feeding
Recommended Regimens (Grade of Recommendation A)
- Erythromycin 500 mg four times a day for 7 days
or
- Erythromycin 500 mg twice a day for 14 days
or
- Amoxicillin 500 mg three times a day for 7 days
or
- Azithromycin 1 g stat (see caution below from the British National Formulary [BNF])
Due to higher positive chlamydia tests after treatment in pregnancy, attributed to either less efficacious treatment regime, non compliance, or re-infection, it is recommended that pregnant woman must have a test of cure 5 weeks after completing therapy, 6 weeks later if given azithromycin.
- Doxycycline and ofloxacin are contraindicated in pregnancy
- Azithromycin is probably less than 95% effective (Jacobson et al., 2001; Kacmar et al., 2001; Brocklehurst & Rooney, 2000). The safety of azithromycin in pregnancy and lactating mothers has not yet been fully assessed, although available data indicate that it is safe (Brocklehurst & Rooney, 2000). World Health Organization (WHO) Guidelines recommend 1 g stat to treat C. trachomatis in pregnancy; the BNF recommends its use in pregnancy and lactation only if no alternative is available.
- Erythromycin has a significant side effect profile and is less than 95% effective. There are no trials of erythromycin 500 mg twice a day for 14 days, which would be better tolerated than four times a day although the follow-up data from the Portsmouth pilot study suggests it is efficacious (Tobin, Harindra, & Mani, 2004).
- Amoxycillin had a similar cure rate to erythromycin in a meta-analysis and had a much better side effect profile (Brocklehurst & Rooney, 2000). However, penicillin in vitro has been shown to induce latency and re-emergence of infection at a later date is a theoretical concern of some experts.
Compliance with Therapy
In general, compliance with therapy is improved if there is a positive therapeutic relationship between the patient and the doctor (Sanson-Fisher, Bowman, & Armstrong, 1992) and/or nurse.
This can probably be improved if the following are applied (Grade of Recommendation C):
Discuss with patient and provide clear written information on:
- What C. trachomatis is and how it is transmitted
- It is primarily sexually transmitted.
- If asymptomatic there is evidence that it could have persisted for months or years.
- The diagnosis of C. trachomatis, particularly
- It is often asymptomatic in both men and women.
- Whilst tests are accurate, no test is absolutely so.
- The complications of untreated C. trachomatis
- Side effects and importance of complying fully with treatment and what to do if a dose is missed
- Advice regarding antibiotics and hormonal contraception
- The importance of their sexual partner(s) being evaluated and treated
- Advice to abstain from sexual intercourse until they and their partner(s) have completed therapy (and waited 7 days if treated with azithromycin)
- Advice on safer sexual practices, including advice on correct, consistent condom use
Reducing the Risk of Individuals Retesting Chlamydia-Positive Following Treatment
Recommendations
- Advise (and document that advice given) no genital, oral, or anal sex, even with a condom, until both index patient and their partner(s) have completed treatment or if the partner(s) choose testing only until the partner(s) have a negative test.
- Abstain as above from sexual activity, for one week after azithromycin 1 g stat.
Management of Sexual Partners
- All patients identified with C. trachomatis should have partner notification discussed at treatment by a health care professional.
- The method of partner notification agreed for each partner/contact identified should be documented, as should partner notification outcomes.
- All sexual partners should be offered, and encouraged to take up a full STI screen, including HIV test and if indicated hepatitis B screening +/- vaccination.
- Epidemiological treatment for C. trachomatis should be offered. If declined, patients must be advised to abstain from sex until they have received a negative result. If found to be positive, any other potentially exposed partner(s) needs screening and the offer of epidemiological treatment.
Look Back Period
Only limited evaluation has taken place of the incubation period following exposure to the development of symptoms. In the United Kingdom a cut-off of 4 weeks is used to identify those sexual partner(s) potentially at risk if the index patient is symptomatic. If the index case is asymptomatic, an arbitrary cut off of 6 months, or until the last previous sexual partner (whichever is the longer time period), is used. Common sense needs to be used in assessing which sexual partner(s) may have been at risk in these situations.
Those at risk should be informed and invited to attend for evaluation and epidemiological treatment even if tests are negative. This may be patient led or provider led.
Follow Up
Follow up by phone may be both more efficacious and cost effective than by re-attendance.
This is an important part of the management of chlamydial infection and it has a number of objectives including:
- Following up partner notification
- Reinforcing health education
- Ensuring compliance with treatment and abstinence from sexual intercourse until partner(s) have completed antibiotics (if treated with azithromycin waiting seven days)
- There is evidence to suggest that follow-up by phone may be more efficacious than asking the patient to re-attend. It is therefore likely that the former method is more cost effective (Apoola, Boothby, & Radcliffe, 2004).
- Re-treat non-compliant and/or re-exposed individuals
Test of Cure
A test of cure is not routinely recommended but should be performed in pregnancy or if non-compliance or re-exposure is suspected. It should be deferred for 5 weeks (6 weeks if azithromycin given) after treatment is completed.
Definitions:
Grading of Recommendations
A (Evidence Levels Ia, Ib)
- Requires at least one randomised controlled trial as part of the body of literature of overall good quality and consistency addressing the specific recommendation
B (Evidence Levels IIa, IIb, III)
- Requires availability of well conducted clinical studies but no randomised clinical trials on the topic of recommendation
C (Evidence Level IV)
- Requires evidence from expert committee reports or opinions and/or clinical experience of respected authorities
- Indicates absence of directly applicable studies of good quality
Levels of Evidence
Ia
- Evidence obtained from meta-analysis of randomised controlled trials
Ib
- Evidence obtained from at least one randomised controlled trial
IIa
- Evidence obtained from at least one well designed controlled study without randomisation
IIb
- Evidence obtained from at least one type of well designed quasi-experimental study
III
- Evidence obtained from well designed, non-experimental descriptive studies, such as comparative studies, correlation studies, and case control studies
IV
- Evidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities
