Abstract
Introduction
Genital chlamydia is the most commonly reported bacterial sexually transmitted disease (STD) in resource-rich countries. In women, infection occurs most commonly between the ages of 16 and 19 years.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of antibiotic treatment in men, non-pregnant women, and pregnant women with uncomplicated genital chlamydia infection? We searched: Medline, Embase, The Cochrane Library, and other important databases up to January 2007 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 24 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: amoxicillin, ampicillin, azithromycin, ciprofloxacin, clarithromycin, clindamycin, doxycycline, erythromycin, lymecycline, minocycline, ofloxacin, pivampicillin, rifampicin, roxithromycin, sparfloxacin, tetracycline, and trovafloxacin.
Key Points
Genital chlamydia (Chlamydia trachomatis serotypes D-K) is an STD that infects the urethra in men, and the endocervix or urethra (or both) in women. It is defined as uncomplicated if it has not ascended to the upper genital tract, or caused sexually acquired reactive arthritis.
It is the most common bacterial STD in resource-rich countries. Over 110,000 chlamydia diagnoses were made in England and Wales in 2006, most in departments of genitourinary medicine, where it accounts for 30% of all new STD diagnoses.
Infection is usually asymptomatic, particularly in women. Most people infected do not present for testing or treatment. Therefore, population rates based on routine surveillance data underestimate the true disease burden. One in 10 people aged under 25 years screened as part of the the National Chlamydia Screening Programme in the UK tested positive for chlamydia.
If untreated, chlamydial infection can ascend to the upper genital tract, causing pelvic inflammatory disease, which may result in infertilitiy, ectopic pregnancy, or chronic pelvic pain.
Multiple-dose regimens of tetracyclines (doxycycline or tetracycline) achieve microbiological cure in at least 95% of men and non-pregnant women with genital chlamydia.
Erythromycin also seems beneficial as a multiple-dose regimen, with a 2 g daily dose more effective than 1 g.
Ciprofloxacin seems less likely to lead to microbiological cure compared with doxycycline.
We don't know whether multiple-dose regimens of other antibiotics (such as other macrolides, quinolones, and penicillins) are effective, as we found few adequate studies.
A single dose of azithromycin seems as beneficial as a 7-day course of doxycycline, and produces similar rates of adverse effects.
Single-dose treatments have the obvious advantage of improving adherence.
In pregnant women, multiple-dose regimens of erythromycin or amoxicillin seem effective in treating chlamydial infection.
One small study has also suggested that multiple-dose erythromycin is as effective as clindamycin in curing infection, although the size of the study makes it hard to draw definitive conclusions.
Single-dose azithromycin may be effective in treating chlamydia in pregnant women. However, it should only be used if no adequate alternative is available.
About this condition
Definition
Genital chlamydia (Chlamydia trachomatis serotypes D-K) is an STD that infects the urethra in men, and the endocervix or urethra (or both) in women. It is defined as uncomplicated if it has not ascended to the upper genital tract, or caused sexually acquired reactive arthrtitis. Infection in women is asymptomatic in up to 70% of cases, but may cause non-specific symptoms, including vaginal discharge and intermenstrual bleeding. Infection in men causes urethral discharge and urethral irritation or dysuria, but may also be asymptomatic in up to half of cases. Complicated chlamydial infection includes spread to the upper genital tract (causing pelvic inflammatory disease in women [see review on pelvic inflammatory disease] and epididymo-orchitis in men) and extragenital sites, such as the eye, or development of sexually acquired reactive arthritis. Lymphogranuloma venereum (LGV) caused by Chlamydia trachomatis serovars L1-3 (predominantly serovar L2) has also emerged as an important genital tract pathogen in men who have sex with men. Interventions for complicated chlamydial infection are not included in this review.
Incidence/ Prevalence
Genital chlamydia is the most common bacterial STD in resource-rich countries, with reported cases continuing to increase annually. Over 110,000 chlamydia diagnoses were made in England and Wales in 2006, most in departments of genitourinary medicine where it accounts for 30% of all new STD diagnoses. This is equivalent to a population rate of 190/100,000 men and 187/100,000 women. Infection is most common in people under 25 years, with rates decreasing thereafter. Rates of diagnosis were highest in women aged 16-19 years (1337/100,000) and men aged 20-24 years (1144/100,000). In the USA, the respective figures for women and men in 2006 were 2862/100,000 and 859/100,000. Most people infected do not present for testing or treatment. Therefore, population rates based on data obtained on routine surveillance using departments of genitourinary medicine underestimate the true disease burden. One in 10 people aged under 25 years screened as part of the the National Chlamydia Screening Programme in the UK tetsted positive for chlamydia. Population-based studies have observed prevalences in the range of 2-6%, with a higher prevalence in women aged 16-19 years and men aged 20-24 years.
Aetiology/ Risk factors
Infection is caused by the bacterium Chlamydia trachomatis serotypes D-K. It is transmitted primarily through sexual intercourse, but also perinatally and through direct or indirect oculogenital contact. Risk factors include age under 25 years, new partner or more than one partner in the past year, and failure to use condoms correctly.
Prognosis
In women, untreated chlamydial infection that ascends to the upper genital tract causes pelvic inflammatory disease (see review on pelvic inflammatory disease). Tubal infertility has been found to occur in about 11% of women after a single episode of pelvic inflammatory disease, and the risk of ectopic pregnancy is increased six- to sevenfold. Ascending infection in men causes epididymitis, but evidence that this causes male infertility is limited. Mother-to-infant transmission can lead to neonatal conjunctivitis and pneumonitis. Chlamydia may coexist with other genital infections, and may facilitate transmission and acquisition of HIV infection. For ethical reasons, there are few prospective follow-up studies of untreated people who are chlamydia-positive. Nevertheless, there is some evidence than infection can resolve spontaneously. About 50% of women test negative after 1 year, and 95% after 4 years.
Aims of intervention
To eradicate C trachomatis; to prevent the development of upper genital tract infection; to prevent further sexual transmission; and to prevent perinatal transmission, with minimal adverse effects of treatment.
Outcomes
The primary outcome assessed in most trials is short-term microbiological cure rate (calculated as the percentage of people attending a follow-up visit at least 1 week after the end of antibiotic treatment who had a negative test for C trachomatis). However, because of the prolonged life cycle of the organism, this may not indicate eradication of C trachomatis. Long-term cure rates have not been studied extensively because of high default rates and difficulty in distinguishing persistent infection from reinfection. One non-systematic review found no persistent infection up to 20 weeks after successful antibiotic treatment. In population-based studies of chlamydia screening, only one of 73 (1.4%) asymptomatic people selected at random from the community, immediately treated with azithromycin 1 g, was chlamydia-positive on retesting 6 weeks after treatment. However, a large partner-treatment RCT found an 8% (95%, CI 5% to 11%) failure rate in 289 women who had been sexually inactive 3-20 weeks after treatment, but not in men. The reason for this is unclear, and it has been argued that further treatment studies with longer follow-up are needed.Other outcomes include adverse effects of treatment, involving effects on the fetus, and incidence of pelvic infalmmatory disease and infertility. We present cure rates for pregnant women separately from those for men and non-pregnant women, because two important drug groups — tetracyclines and quinolones — are contraindicated in pregnancy.
Methods
BMJ Clinical Evidence search and appraisal January 2007. The following databases were used to identify studies for this systematic review: Medline 1966 to January 2007, Embase 1980 to January 2007, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2006, Issue 4. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and NICE. We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, at least single blinded, and containing more than 20 individuals, of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. RCTs of treatment for genital chlamydia usually compare a new antibiotic versus an existing regimen, because placebo-controlled RCTs would be considered unethical. Single trials usually have insufficient statistical power to establish equivalence, but meta-analysis is often inappropriate because of differences in the antibiotics used. Therefore, where appropriate, we present the absolute cure rates for individual antibiotics, combining results across trials. We present the range of cure rates (with exact binomial CIs) or, if there was no evidence of statistical heterogeneity between RCTs, the summary cure rate (95% CIs) weighted by the standard error. Summary rates do not include cure rates of 100%, because the standard error cannot be computed if there are no treatment failures. In one instance (ciprofloxacin), two RCTs compared the same regimen with no evidence of statistical heterogeneity, and we used a fixed-effects meta-analysis to calculate the summary odds ratio with 95% confidence intervals. Trial quality was assessed in terms of randomisation, blinding, and numbers of withdrawals from analysis. RCTs with methodological limitations have been included, but relevant problems are mentioned in the text. Categorising interventions: We considered a regimen beneficial if the summary cure rate from two or more RCTs was 95% or greater, as suggested previously, and if the lower confidence limit was also above 90%. We found insufficient data to differentiate reinfections from persistent infections. We considered regimens to be likely (or unlikely) to be beneficial on the basis of positive (or negative) results from two or more RCTs, and of unknown effectiveness if there was only one RCT, or if results were conflicting. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).
Table.
GRADE evaluation of interventions for chlamydia (uncomplicated, genital)
| Important outcomes | Cure rates, adverse effects | ||||||||
| Number of studies (participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of antibiotic treatment in men and non-pregnant women with uncomplicated genital chlamydial infection? | |||||||||
| 12 (At least 2000 women) | Cure rates | Multiple-dose doxycyline or tetracycline v other multiple-dose antibiotics | 4 | –2 | 0 | –2 | 0 | Very low | Quality points deducted for poor follow-up, and exclusion of participants in analysis of some results. Directness points deducted for too many comparators, and no direct comparison between groups |
| 2 (258) | Cure rates | Multiple-dose erythromycin v other multiple-dose antibiotics | 4 | –2 | 0 | –2 | 0 | Very low | Quality points deducted for poor follow-up, and exclusion of participants in analysis of some results. Directness points deducted for too many comparators, and no direct comparison between groups |
| 2 (190) | Cure rates | Multiple-dose ciprofloxacin v other multiple-dose antibiotics | 4 | –3 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data, poor follow-up, and exclusion of participants in analysis of some results. Directness point deducted for no direct comparison between groups |
| 1 (70) | Cure rates | Multiple-dose trimethoprim–sulfadizine v placebo | 4 | –3 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data, poor follow-up, and exclusion of participants in analysis of some results. Directness point deducted for no direct comparison between groups |
| 16 (At least 2000 women) | Cure rates | Other multiple-dose antibiotics (including macrolides, quinolones, and penicillins) v tetracycline, doxycycline, ciprofloxacin, or erythromycin | 4 | –2 | 0 | –2 | 0 | Very low | Quality points deducted for poor follow-up and exclusion of participants in analysis of some results. Directness point deducted for too many different drugs analysed in single RCTs, no direct comparison between groups |
| 13 (1689) | Cure rates | Single doses v multiple doses of antibiotics | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for inclusion of non-blinded RCTs |
| What are the effects of antibiotic treatment for pregnant women with uncomplicated genital chlamydial infection? | |||||||||
| 1 (135) | Cure rates | Multiple-dose antibiotics (erythromycin, clindamycin) v placebo | 4 | –2 | 0 | 0 | +1 | Moderate | Quality points deducted for sparse data and incomplete reporting of results. Effect-size point added for odds ratio less than 0.5 |
| 3 (390) | Cure rates | Multiple-dose erythromycin v multiple-dose amoxicillin | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for inclusion of non-blinded RCTs |
| 1 (78) | Cure rates | Multiple-dose erythromycin v multiple-dose clindamycin | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data. |
| 4 (290) | Cure rates | Single-dose antibiotics v multiple-dose (azithromycin v erythromycin) | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for lack of blinding |
| 2 (144) | Cure rates | Single-dose antibiotics v multiple-dose (azithromycin v amoxicillin) | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and lack of blinding. Directness point deducted for composite outcome in one RCT |
Type of evidence: 4 = RCT; 2 = Observational Consistency: similarity of results across studies Directness: generalisability of population or outcomes Effect size: based on relative risk or odds ratio
Glossary
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
- Very low-quality evidence
Any estimate of effect is very uncertain.
Dual treatment for gonorrhoea and chlamydia infections (gonorrhoea)
Partner notification
Pelvic inflammatory disease
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
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