Abstract
Introduction
Genital chlamydia is the most commonly reported bacterial sexually transmitted infection (STI) in developed 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 for men and non-pregnant women with uncomplicated genital chlamydial infection?What are the effects of antibiotic treatment for pregnant women with uncomplicated genital chlamydial infection? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2009 (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 a sexually transmitted infection (STI) 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 STI in developed countries. Over 200,000 chlamydia diagnoses were made in the UK in 2008, with 60% of cases being detected in departments of genitourinary medicine.
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 14 men and one in 11 women aged under 25 years screened as part of 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 (PID), which may result in infertility, ectopic pregnancy, or chronic pelvic pain.
Partner notification and treatment is an important part of effective management.
Chlamydia-positive individuals are at high risk of retesting positive within 1 year. There is a growing body of opinion that repeat testing at 3 to 12 months after treatment, or sooner if there is a change of sexual partner, is likely to be beneficial for public health.
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, but we don't know which regimen of erythromycin is more effective.
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.
Treatment cure rates of over 95% have been reported, and a test of cure is only considered necessary if non-compliance or re-exposure is suspected.
In pregnant women, multiple-dose regimens of erythromycin or amoxicillin seem effective in treating chlamydial infection.
One small study has also suggested that clindamycin and multiple-dose erythromycin are equally effective at 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 be used only if no adequate alternative is available.
In pregnant women, no antibiotic regimen has a microbiological cure rate of over 95%, and pregnant women should be offered a test of cure no sooner than 5 weeks after treatment was initiated to ensure that the infection has cleared.
About this condition
Definition
Genital chlamydia (Chlamydia trachomatis serotypes D–K) is a sexually transmitted infection (STI) that infects the urethra in men and the endocervix or urethra (or both) in women. It can also infect other mucosal surfaces at the rectum, conjunctiva, and nasopharynx. It is defined as uncomplicated genital infection if it has not ascended to the upper genital tract, or not caused sexually acquired reactive arthritis. 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 50% of cases. Complicated chlamydial infection includes spread to the upper genital tract (causing pelvic inflammatory disease [PID] in women [see review on PID] and epididymo-orchitis in men), or development of sexually acquired reactive arthritis. Lymphogranuloma venereum (LGV) caused by C trachomatis serovars L1–3 (predominantly serovar L2) has also emerged as an important genital tract pathogen in men who have sex with men. In most cases, men infected with LGV present with symptomatic rectal disease. Interventions for complicated chlamydial infection (including LGV) are not included in this review.
Incidence/ Prevalence
Genital chlamydia is the most common bacterial STI in developed countries, with reported cases continuing to increase annually. Over 200,000 diagnoses of chlamydia were made in the UK in 2008, with 60% of cases being detected in departments of genitourinary medicine. Based on data from genitourinary medicine clinics, this rate of diagnosis is equivalent to a population rate of 200/100,000 men and women. Infection is most common in people under 25 years, with rates decreasing thereafter. Rates of diagnosis were highest in women aged 16 to 19 years (1406/100,000) and men aged 20 to 24 years (1163/100,000). In the US, the respective figures for women and men in these age groups in 2008 were 3275/100,000 and 1056/100,000. 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. During 2007 and 2008, one in 14 men and one in 11 women aged under 25 years screened as part of the National Chlamydia Screening Programme in the UK tested positive for chlamydia. Population-based studies have observed prevalences in the range of 2% to 6%, with a higher prevalence in women aged 16 to 19 years and men aged 20 to 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 transfer. 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 PID (see review on PID). Tubal infertility has been found to occur in about 11% of women after a single episode of PID, 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. Men and women who are chlamydia-positive are at high risk of retesting positive after treatment. Although the assumption that positive tests for chlamydia after treatment are always due to re-infection, cure rates of less than 95% have been observed in prospective studies where repeat infection is unlikely. A large partner-treatment RCT found an 8% (95% CI 5% to 11%) failure rate in 289 women who had been sexually inactive 3 to 20 weeks after treatment. A subset analysis of men enrolled in an RCT and who had tested positive for chlamydia found a positive-retest rate of 36% (25/68) in chlamydia-positive men with urethritis at a median of 43 days after treatment. Interestingly, the proportion of men who tested positive for chlamydia at rescreening yet denied sexual exposure was 36% (9/25). The authors of the study concluded that this higher than expected rate of positive rescreening tests could have been the result of inaccurate reporting by the index patient or treatment failure. C trachomatis resistance to antibiotics seems to be rare. However, due to technical difficulties, limited studies have been undertaken in vivo. At high multiplicities of infection (load), in-vitro persistence to antimicrobials (heterotypic resistance) can often be demonstrated. It has been proposed that people with high organism loads may be at increased risk of treatment failure. A systematic review of RCTs and observational studies reporting on chlamydia re-infection rates in women (38 studies; number of women not reported) found that the proportion of women re-infected with chlamydia ranged from 0% to 32%, with a median proportion of 13.9%. In women, repeat infections confer an elevated risk for PID and other complications. It has been proposed that repeat testing for chlamydia at 3 to 12 months after treatment, or sooner if there is a change of sexual partner, is likely to be of public health benefit, but this has not been evaluated as part of an RCT. All antibiotics seem to have lower efficacy in pregnant women, with no antibiotic regimen having a microbiological cure rate of over 95%. In pregnant women, a repeat test is recommended no sooner than 5 weeks after treatment, to ensure that the infection has cleared. Partner notification and treatment is an important part of effective management (see our review on partner notification). Innovative and effective partner treatment strategies have been associated with lower rates of re-infection.
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, and usually less than 5 weeks, after the end of antibiotic treatment who had a negative test for C trachomatis). However, because of the potentially prolonged life cycle of the organism, this may not indicate eradication of C trachomatis. Long-term cure rates (greater than 5 weeks) have not been studied extensively in RCTs because of high default rates and difficulty in distinguishing persistent infection from re-infection. It is beyond the scope of this review to assess the effectiveness of the listed interventions at reducing the risk of retesting positive at more than 5 weeks after treatment. Other outcomes assessed are adverse effects of treatment, including effects on the fetus. 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
Clinical Evidence search and appraisal September 2009. The following databases were used to identify studies for this systematic review: Medline 1966 to September 2009, Embase 1980 to September 2009, and The Cochrane Database of Systematic Reviews, Issue 3, 2009 (1966 to date of issue). An additional search within The Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA). 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 contributor for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews of RCTs 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. We included systematic reviews of RCTs and RCTs where harms of an included intervention were studied, applying the same study design criteria for inclusion as we did for benefits. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. RCTs of treatments 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 re-infections 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. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).The categorisation of the quality of the evidence (into high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table 1.
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 for men and non-pregnant women with uncomplicated genital chlamydial infection? | |||||||||
| 2 (190) | Cure rates | Multiple-dose doxycycline v multiple-dose ciprofloxacin | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and poor follow-up |
| 6 (877) | Cure rates | Multiple-dose doxycycline v multiple-dose antibiotics other than tetracycline, ciprofloxacin, or erythromycin | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for poor follow-up and no statistical assessment. Directness point deducted for broad range of antibiotics assessed against doxycycline |
| 1 (38) | Cure rates | Multiple-dose tetracycline v multiple-dose antibiotics other than doxycycline, ciprofloxacin, or erythromycin | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for sparse data, poor follow-up, and no statistical assessment |
| 1 (127) | Cure rates | Multiple-dose erythromycin v multiple-dose antibiotics other than doxycycline, tetracycline, or ciprofloxacin | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for sparse data, poor follow-up, and no statistical assessment |
| 2 (135) | Cure rates | Different regimens of multiple-dose erythromycin v each other | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for sparse data, poor follow-up, and no statistical assessment |
| 13 (1689) | Cure rates | Single-dose antibiotics v multiple-dose 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 erythromycin v placebo | 4 | –2 | 0 | –1 | +1 | Low | Quality points deducted for sparse data and inclusion of non-blinded RCTs. Directness point deducted for analysis of more than one antibiotic (includes clindamycin as well as erythromycin). 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 (135) | Cure rates | Multiple-dose clindamycin v placebo | 4 | –2 | 0 | –1 | +1 | Low | Quality points deducted for sparse data and inclusion of non-blinded RCTs. Directness point deducted for analysis of more than one antibiotic (includes erythromycin as well as clindamycin). Effect-size point added for odds ratio less than 0.5 |
| 1 (78) | Cure rates | Multiple-dose clindamycin v multiple-dose erythromycin | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| At least 4 (at least 290) | Cure rates | Single-dose azithromycin v multiple-dose erythromycin | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for inclusion of non-blinded RCTs |
| 2 (144) | Cure rates | Single-dose azithromycin v multiple-dose amoxicillin | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and inclusion of non-blinded RCTs. Directness point deducted for composite outcome in 1 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 (in review on Gonorrhoea)
Partner notification
PID
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.
References
- 1.Holmes KK, Sparling PF, Mardh PA, et al, eds. Sexually transmitted diseases. 4th ed. New York: McGraw Hill Inc, 2008. [Google Scholar]
- 2.Horner P, Boag F. 2006 UK national guideline for the management of genital tract infection with Chlamydia trachomatis. BASHH. Available at http://www.bashh.org/documents/61/61.pdf (last accessed 26 March 2010). [Google Scholar]
- 3.Jebbari H, Alexander S, Ward H, et al. Update on lymphogranuloma venereum in the United Kingdom. Sex Transm Infect 2007;83:324–326. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Ward H, Alexander S, Carder C, et al. The prevalence of lymphogranuloma venereum infection in men who have sex with men: results of a multicentre case finding study. Sex Transm Infect 2009;85:173–175. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Centers for Disease Control and Prevention. Sexually transmitted disease surveillance, 2008. Available at http://cdc.gov/std/stats08/chlamydia.htm (last accessed 16 March 2010). [Google Scholar]
- 6.Health Protection Agency. STI annual data tables. Available at http://www.hpa.org.uk/HPA/Topics/InfectiousDiseases/InfectionsAZ/1201094610372 (last accessed 26 March 2010). [Google Scholar]
- 7.National Chlamydia Screening Programme, Health Protection Agency. NCSP: Five years: The fifth annual report of the National Chlamydia Screening Programme 2007/08. Available at http://www.chlamydiascreening.nhs.uk/ps/assets/pdfs/publications/reports/NCSPa-rprt-07_08.pdf (last accessed 16 March 2010). [Google Scholar]
- 8.Fenton K, Korovessis C, Johnson AM, et al. Sexual behaviour in Britain: sexually transmitted infections and prevalent Chlamydia trachomatis infection. Lancet 2001;358:1851–1854. [DOI] [PubMed] [Google Scholar]
- 9.Macleod J, Salisbury C, Low N, et al. Coverage and uptake of systematic postal screening for genital Chlamydia trachomatis and prevalence of infection in the United Kingdom general population: cross-sectional study. BMJ 2005;330:940. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Westrom L, Bengtsson LP, Mardh PA. Incidence, trends, and risks of ectopic pregnancy in a population of women. BMJ 1981;282:15–18. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Golden MR, Schillinger JA, Markowitz L, et al. Duration of untreated genital infections with Chlamydia trachomatis: a review of the literature. Sex Transm Dis 2000;27:329–337. [DOI] [PubMed] [Google Scholar]
- 12.Morré SA, van den Brule AJC, Rozendaal L, et al. The natural course of asymptomatic Chlamydia trachomatis infections: 45% clearance and no development of clinical PID after one-year follow up. Int J STD AIDS 2002;13(Suppl 2):12–18. [DOI] [PubMed] [Google Scholar]
- 13.Molano M, Meijer CJ, Weiderpass E, et al. The natural course of Chlamydia trachomatis infection in asymptomatic Colombian women: a 5-year follow-up study. J Infect Dis 2005;191:907–916. [DOI] [PubMed] [Google Scholar]
- 14.Hosenfeld CB, Workowski KA, Berman SM, et al. Repeat infection with chlamydia and gonorrhea among females: a systematic review of the literature. Sex Transm Dis 2009;36:478–489. [DOI] [PubMed] [Google Scholar]
- 15.Golden MR, Whittington WL, Handsfield HH, et al. Effect of expedited treatment of sex partners on recurrent or persistent gonorrhea or chlamydial infection.N Engl J Med2005;352:676–685. [DOI] [PubMed] [Google Scholar]
- 16.Kissinger PJ, Reilly K, Taylor SN, et al. Early repeat Chlamydia trachomatis and Neisseria gonorrhoeae infections among heterosexual men. Sex Transm Dis 2009;36:498–500. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Horner P. The case for further treatment studies of uncomplicated genital Chlamydia trachomatis infection. Sex Transm Infect 2006;82:340–343. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Hillis SD, Owens LM, Marchbanks PA, et al. Recurrent chlamydial infections increase the risks of hospitalization for ectopic pregnancy and pelvic inflammatory disease. Am J Obstet Gynecol 1997;176:103–107. [DOI] [PubMed] [Google Scholar]
- 19.Westrom LV. Sexually transmitted diseases and infertility. Sex Transm Dis 1994;21(2 Suppl):S32–S37. [PubMed] [Google Scholar]
- 20.SIGN. Management of genital Chlamydia trachomatis infection. Available at http://www.sign.ac.uk/pdf/sign109.pdf (last accessed 16 March 2010). [Google Scholar]
- 21.Scott Lamontagne D, Baster K, Emmett L, et al. Incidence and reinfection rates of genital chlamydial infection among women aged 16-24 years attending general practice, family planning and genitourinary medicine clinics in England: a prospective cohort study by the Chlamydia Recall Study Advisory Group. Sex Transm Infect 2007;83:292–303. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Chalmers I, Adams M, Dickersin K, et al. A cohort study of summary reports of controlled trials. JAMA 1990;263:1401–1405. [PubMed] [Google Scholar]
- 23.Hooton TM, Rogers ME, Medina TG, et al. Ciprofloxacin compared with doxycycline for nongonococcal urethritis. Ineffectiveness against Chlamydia trachomatis due to relapsing infection. JAMA 1990;264:1418–1421. [PubMed] [Google Scholar]
- 24.Jeskanen L, Karppinen L, Ingervo L, et al. Ciprofloxacin versus doxycycline in the treatment of uncomplicated urogenital Chlamydia trachomatis infections. A double-blind comparative study. Scand J Infect Dis Suppl 1989;60:62–65. [PubMed] [Google Scholar]
- 25.Stein GE, Mummaw NL, Havlichek DH. A preliminary study of clarithromycin versus doxycycline in the treatment of nongonococcal urethritis and mucopurulent cervicitis. Pharmacotherapy 1995;15:727–731. [PubMed] [Google Scholar]
- 26.Romanowski B, Talbot H, Stadnyk M, et al. Minocycline compared with doxycycline in the treatment of nongonococcal urethritis and mucopurulent cervicitis. Ann Intern Med 1993;119:16–22. [DOI] [PubMed] [Google Scholar]
- 27.Boslego JW, Hicks CB, Greenup R, et al. A prospective randomized trial of ofloxacin vs. doxycycline in the treatment of uncomplicated male urethritis. Sex Transm Dis 1988;15:186–191. [DOI] [PubMed] [Google Scholar]
- 28.Phillips I, Dimian C, Barlow D, et al. A comparative study of two different regimens of sparfloxacin versus doxycycline in the treatment of non-gonococcal urethritis in men. J Antimicrob Chemother 1996;37(Suppl A):123–134. [DOI] [PubMed] [Google Scholar]
- 29.McCormack WM, Dalu ZA, Martin DH, et al. Double-blind comparison of trovafloxacin and doxycycline in the treatment of uncomplicated chlamydial urethritis and cervicitis. Trovafloxacin Chlamydial Urethritis/Cervicitis Study Group. Sex Transm Dis 1999;26:531–536. [DOI] [PubMed] [Google Scholar]
- 30.Lassus AB, Virrankoski T, Reitamo SJ, et al. Pivampicillin versus doxycycline in the treatment of chlamydial urethritis in men. Sex Transm Dis 1990;17:20–22. [PubMed] [Google Scholar]
- 31.Lassus A, Juvakoski T, Kanerva L. Comparison between rifampicin and tetracycline in the treatment of nongonococcal urethritis in males with special reference to Chlamydia trachomatis Eur J Sex Transm Dis 1984;2:15–17. [Google Scholar]
- 32.Worm AM, Hoff G, Kroon S, et al. Roxithromycin compared with erythromycin against genitourinary chlamydial infections. Genitourin Med 1989;65:35–38. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Worm AM, Avnstorp C, Petersen CS. Erythromycin against Chlamydia trachomatis infections. A double blind study comparing 4- and 7-day treatment in men and women. Dan Med Bull 1985;32:269–271. [PubMed] [Google Scholar]
- 34.Linnemann CC Jr, Heaton CL, Ritchey M. Treatment of Chlamydia trachomatis infections: comparison of 1- and 2-g doses of erythromycin daily for seven days. Sex Transm Dis 1987;14:102–106. [PubMed] [Google Scholar]
- 35.Paavonen J, Kousa M, Saikku P, et al. Treatment of nongonococcal urethritis with trimethoprim-sulphadiazine and with placebo. A double-blind partner-controlled study. Br J Venereal Dis 1980;56:101–104. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Brihmer C, Mardh PA, Kallings I, et al. Efficacy and safety of azithromycin versus lymecycline in the treatment of genital chlamydial infections in women. Scand J Infect Dis 1996;28:451–454. [DOI] [PubMed] [Google Scholar]
- 37.Kuo CC, Wang SP, Grayston JT. Antimicrobial activity of several antibiotics and a sulfonamide against Chlamydia trachomatis organisms in cell culture. Antimicrob Agents Chemother 1977;12:80–83. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Lau CY, Qureshi AK. Azithromycin versus doxycycline for genital chlamydial infections: a meta-analysis of randomised clinical trials. Sex Transm Dis 2002;29:497–502. [DOI] [PubMed] [Google Scholar]
- 39.Brocklehurst P, Rooney G. Interventions for treating genital Chlamydia trachomatis infection in pregnancy. In: The Cochrane Library, Issue 3, 2009. Chichester, UK: John Wiley & Sons Ltd. Search date 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Pitsouni E, Iavazzo C, Athanasiou S, et al. Single-dose azithromycin versus erythromycin or amoxicillin for Chlamydia trachomatis infection during pregnancy: a meta-analysis of randomised controlled trials. Int J Antimicrob Agents 2007;30:213–221. [DOI] [PubMed] [Google Scholar]
- 41.Jacobson GF, Autry AM, Kirby RS, et al. A randomized controlled trial comparing amoxicillin and azithromycin for the treatment of Chlamydia trachomatis in pregnancy. Am J Obstet Gynecol 2001;184:1352–1356. [DOI] [PubMed] [Google Scholar]
- 42.Kacmar J, Cheh E, Montagno A, et al. A randomized trial of azithromycin versus amoxicillin for the treatment of Chlamydia trachomatis in pregnancy. Infect Dis Obstet Gynecol 2001;9:197–202. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Cooper WO, Hernandez-Diaz S, Arbogast PG, et al. Antibiotics potentially used in response to bioterrorism and the risk of major congenital malformations. Paediatr Perinat Epidemiol 2009;23:18–28. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Bar-Oz B, Diav-Citrin O, Shechtman S, et al. Pregnancy outcome after gestational exposure to the new macrolides: a prospective multi-center observational study. Eur J Obstet Gynecol Reprod Biol 2008;141:31–34. [DOI] [PubMed] [Google Scholar]
- 45.National Poisons Information Service. Toxbase. Available at http://www.toxbase.org/ (last accessed 16 March 2010). [Google Scholar]