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Genital chlamydial infections

The new england journal of medicine This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author’s clinical recommendations. From the Division of Research, Department A 19-year-old woman visits her primary care provider for counseling about contracep-
tion. She became sexually active one year previously and has had a new sexual partner
munity Health, Brown University MedicalSchool and the Women and Infants Hospi- for the past three months. Her partner currently uses a condom intermittently for con-
tal, Providence, R.I. Address reprint requests traception, and she inquires about oral contraceptives. She reports no medical prob-
to Dr. Peipert at the Division of Research, lems and is in good health. Her physical examination is unremarkable. Is testing for
Women and Infants Hospital, 101 DudleySt., Providence, RI 02905, or at [email protected] Chlamydia trachomatis indicated?
Copyright 2003 Massachusetts Medical Society. Chlamydia trachomatis is the most common bacterial cause of sexually transmitted infec-tions in the United States, responsible for an estimated 3 million new infections eachyear.1,2 The cost of care for untreated chlamydial infections and their complications isestimated to exceed $2 billion annually.3 c l i n i c a l p r e s e n t a t i o n
As many as 85 to 90 percent of C. trachomatis infections in men and women are asymp-tomatic.4,5 Asymptomatic infections can persist for several months.5 Despite the fre-quent absence of symptoms, at least one third of women have local signs of infectionon examination.5 The two most commonly reported signs are mucopurulent dischargefrom the cervix and hypertrophic cervical ectopy (Fig. 1). Signs and symptoms in meninclude urethral discharge of mucopurulent or purulent material, dysuria, or urethralpruritus.
Clinical manifestations of C. trachomatis infections in women include acute urethral syndrome, urethritis, bartholinitis, cervicitis, upper genital tract infection (endometritis,salpingo-oophoritis, or pelvic inflammatory disease), perihepatitis (Fitz-Hugh–Curtissyndrome), and reactive arthritis.5 Symptoms depend on the site of infection. Infectionof the urethra and lower genital tract may cause dysuria, abnormal vaginal discharge,or postcoital bleeding, whereas infection of the upper genital tract (e.g., endometritisor salpingitis) may be manifested as irregular uterine bleeding and abdominal or pelvicdiscomfort.
In women, untreated chlamydial infection can lead to severe reproductive complica- tions. C. trachomatis is an important causal agent in pelvic inflammatory disease, withsequelae including infertility, ectopic pregnancy, and chronic pelvic pain.6 Up to twothirds of cases of tubal-factor infertility and one third of cases of ectopic pregnancy maybe attributable to C. trachomatis infection.7 Chlamydial infection during pregnancy isassociated with a number of adverse outcomes of pregnancy including preterm labor,premature rupture of the membranes, low birth weight, neonatal death, and postpartumendometritis.8,9 Chlamydial infection during pregnancy may be transmitted to the infant during de- Downloaded from www.nejm.org on November 30, 2010. For personal use only. No other uses without permission. Copyright 2003 Massachusetts Medical Society. All rights reserved. alence rates in the United States have ranged from2 to 7 percent among female college students and4 to 12 percent among women attending a familyplanning clinic to 6 to 20 percent among men andwomen attending a clinic for sexually transmit-ted diseases or persons entering correctional fa-cilities.5,12 In the United Kingdom, recent data sug-gest that the rate of infection among young womenexceeds 10 percent.13 The prevalence of C. tracho-matis infection is highest in groups of persons whoare the least likely to see a clinician. Prevalence rateshave declined in geographic areas where screening Figure 1. Cervical Ectropion (White Arrow) with Mucopu-
rulent Cervicitis (Black Arrow).
Risk factors for chlamydial infection in sexual- Photograph courtesy of Dr. Marc Steben.
ly active women include a young age (less than 25years and, in particular, less than 20 years), inter-course at an early age, having more than one sex- livery.10 An infant born to a mother with active in- ual partner, involvement with a new sexual part-fection has a risk of acquiring infection at any ana- ner, being unmarried, black race, a history of ortomical site of 50 to 75 percent. Approximately 30 coexistent sexually transmitted infection, cervicalto 50 percent of infants born to chlamydia-posi- ectopy, and inconsistent use of barrier contracep-tive mothers will have conjunctivitis, and at least tive methods.15,16 Young age is the factor that is50 percent of infants with chlamydial conjunctivi- most strongly associated with infection (relativetis will also have nasopharyngeal infection. Chla- risk among women younger than 25 years as com-mydial pneumonia develops in about 30 percent of pared with older women, 2.0 to 3.5).17 This associ-infants with nasopharyngeal infection.5 ation is largely attributable to the higher level of sex- In men, the most common clinical manifesta- ual activity among younger women. Also, in younger tion of C. trachomatis infection is nongonococcal ure- women, the squamocolumnar junction of the cer-thritis. In fact, C. trachomatis causes approximately vix often lies well out on the ectocervix, forming a35 to 50 percent of all cases of nongonococcal ure- bright red central zone of ectopic columnar epithe-thritis in heterosexual men. Symptoms of nongono- lium called an ectropion (Fig. 1); this ectopy pro-coccal urethritis may develop after an incubation vides a larger target area for chlamydial infectionperiod of 7 to 21 days and include dysuria and mild- than is present in older women.18to-moderate whitish or clear urethral discharge. Inmost cases, physical examination reveals no abnor- s t r a t e g i e s a n d e v i d e n c e malities other than the discharge. Other clinical syn-
dromes in men include acute epididymitis, acute screening
proctitis, acute proctocolitis, conjunctivitis, and Rei- Screening in Women
ter’s syndrome.5 Male infertility, chronic prostatitis, There is good evidence that screening women who
and urethral strictures are possible results of in- are at risk for C. trachomatis infection can prevent
fection. Both Reiter’s syndrome (urethritis, con- reproductive sequelae by reducing the rate of pel-
junctivitis, arthritis, and mucocutaneous lesions) vic inflammatory disease.15 The strongest evidence
and reactive tenosynovitis or arthritis (without the supporting screening in women comes from a large
other components of Reiter’s syndrome) have been randomized trial of screening and treatment at a
associated with genital C. trachomatis infection.5 In- health maintenance organization in Seattle.19 Par-
fection with C. trachomatis is also believed to be a co- ticipants were unmarried, asymptomatic women
factor for the transmission of human immunodefi- (18 to 34 years of age) who were considered to have
ciency virus in both men and women.11
a high risk of C. trachomatis infection on the basisof a scoring system that included as risk factors a e p i d e m i o l o g y o f c h l a m y d i a l i n f e c t i o n s
young age (less than 25 years), black race, nulligra- The prevalence of chlamydia depends on the char- vidity, douching, and two or more sexual partnersacteristics of the population studied. Reported prev- during the previous 12 months. By the end of the Downloaded from www.nejm.org on November 30, 2010. For personal use only. No other uses without permission. Copyright 2003 Massachusetts Medical Society. All rights reserved. The new england journal of medicine follow-up period, there were 9 verified cases of pel- and detect C. trachomatis–specific DNA or RNAvic inflammatory disease in the screened group sequences25 (including polymerase chain reaction,(8 per 10,000 woman-months of follow-up) and 33 ligase chain reaction, and transcription-mediatedcases in the usual-care group (18 per 10,000 wom- amplification of RNA) are substantially more sen-an-months; relative risk in the screened group, 0.44; sitive than the first-generation non–culture-based95 percent confidence interval, 0.20 to 0.90). Long- tests (80 to 91 percent, depending on the site fromterm adverse outcomes of chlamydial infection were which the specimen is obtained, vs. 62 to 75 per-not addressed in this study.
cent), when culture is used as the gold standard.25 In addition, two ecologic studies (studies evalu- The sensitivity is slightly lower when these newer ating associations between types of exposure and tests are performed on urine specimens rather thanoutcomes in populations rather than individual per- endocervical specimens, but the specificity is highsons), conducted in Sweden, showed that the rates for all types of specimens (range, 94 to nearly 100of both ectopic pregnancies and pelvic inflamma- percent).25 The majority of nucleic acid–amplifica-tory disease were reduced in communities after tion tests have been approved by the Food and Drugscreening for chlamydial infection was adopted.20,21 Administration for the detection of C. trachomatisHowever, it is possible that the lower prevalence of (and Neisseria gonorrhoeae) in urine from both menadverse outcomes in these studies was due to fac- and women, providing a noninvasive testing meth-tors other than screening, such as increased use of od.25 Limitations of nucleic acid–amplification testsbarrier contraceptives and reductions in risk-taking include their relatively high cost and the require-behavior.
Although data from randomized trials of screen- The most recent addition to the testing arma- ing for chlamydial infection during pregnancy are mentarium is the use of specimens collected by pa-
lacking, there is some evidence that screening high- tients.26,27 Amplification testing of vaginal or ure-
risk women for C. trachomatis during pregnancy can thral swab specimens collected by patients has a
reduce the rate of adverse outcomes of pregnancy. sensitivity and specificity similar to those of ampli-
Two observational studies showed associations be- fication testing of specimens collected by clinicians,
tween the treatment of chlamydial infections dur- and studies indicate that patients prefer this meth-
ing pregnancy and improved outcomes of pregnan- od to the standard collection methods.28,29
cy, including lower rates of premature rupture of the
membranes, low birth weight, births of infants who treatment
were small for their gestational age, and neonatal The treatment of chlamydial infection depends on
the clinical syndrome (Table 1).2 Effective and low-cost treatments for genital chlamydial infection are available for the most common clinical syndromes The U.S. Preventive Services Task Force found no (nongonococcal urethritis in men and mucopuru-direct evidence to determine whether screening lent cervicitis in women). In a randomized trial, theasymptomatic men is effective for reducing the in- efficacy of a seven-day course of doxycycline wascidence of new infections in women, and it could equivalent to that of a single dose of azithromycin;not determine the balance of the harms and bene- both resulted in cure rates of more than 95 percentfits of screening men.15 among men and nonpregnant women.30 Sexualpartners should be notified, examined, and treated for chlamydia and any other identified or suspected The gold standard for the diagnosis of C. trachoma- sexually transmitted disease. Patients and their part-tis infection was traditionally a culture of a swab ners should be instructed to refrain from sexual in-from the endocervix in women or the urethra in tercourse until therapy is completed (specifically,men. However, the methodologic challenges of until seven days after a single-dose regimen or un-culturing this organism led to the development of til the completion of a seven-day regimen).2non–culture-based tests. Whereas early non–cul-ture-based tests, including antigen-detection tests Infection during Pregnancyand nonamplified nucleic acid hybridization, were A Cochrane review of 11 randomized trials for thelimited by their failure to detect a substantial pro- treatment of chlamydia during pregnancy conclud-portion of infections,24 newer tests that amplify ed that amoxicillin was as effective as oral erythro- Downloaded from www.nejm.org on November 30, 2010. For personal use only. No other uses without permission. Copyright 2003 Massachusetts Medical Society. All rights reserved. Table 1. Common Clinical Syndromes and Their Treatment.
Recommended Regimens
Azithromycin, 1 g orally (single dose), or doxycycline, 100 mg orally 2 times a day for 7 days Metronidazole, 2 g orally (single dose), plus erythromycin base, 500 mg orally 4 times a day for 7 days, or erythromycin ethylsuccinate, 800 mg orally 4 times a day for 7 days Ceftriaxone, 250 mg intramuscularly (single dose), plus doxycycline, 100 mg orally 2 times a day for 10 days Azithromycin, 1 g orally (single dose), or doxycycline, 100 mg orally 2 times a day for 7 days Erythromycin base, 500 mg orally 4 times a day for 7 days, or amoxicillin, 500 mg orally 3 times a day for 7 days, or azithromycin, 1 g orally (single dose) Ofloxacin, 400 mg orally 2 times a day for 14 days, or levofloxacin, 500 mg orally once a day for 14 days, with or without metronidazole, 500 mg orally 2 times a day for 14 days; otherwise, ceftriaxone, 250 mg intramuscularly (single dose), or cefoxitin, 2 g intramuscularly (single dose), plus probenecid, 1 g orally, plus doxycycline, 100 mg orally 2 times a day for 14 days, with or without metronidazole, 500 mg orally 2 times a day for 14 days Cefotetan, 2 g intravenously every 12 hours, or cefoxitin, 2 g intravenously every 6 hours, plus doxycycline, 100 mg orally or intravenously every 12 hours; otherwise, clindamycin, 900 mg intravenously every 8 hours, plus gentamicin, 2 mg per kg of body weight loading dose intravenously, then 1.5 mg per kg every 8 hours; daily administration of a single dose may be substituted * Therapy for pelvic inflammatory disease should be continued for 24 to 48 hours after clinical improvement occurs and should consist of con- tinuous oral therapy with doxycycline, 100 mg orally twice a day, or clindamycin, 450 mg orally 4 times a day, for a total of 14 days.
mycin.31 Several small trials comparing oral azi- should have a low threshold for the prompt insti-thromycin with these therapies have shown similar tution of treatment in women who are at risk forcure rates and acceptability for azithromycin.32,33 chlamydial infection. The delay of antibiotic thera-py is associated with an increased risk of adverse outcomes.37 The PID [Pelvic Inflammatory Disease] Although pelvic inflammatory disease is thought Evaluation and Clinical Health (PEACH) study, ato be a polymicrobial infection, C. trachomatis is one randomized trial comparing inpatient therapy con-of the more common pathogens involved. The min- sisting of cefoxitin and doxycycline with similar out-imal criteria for a diagnosis of pelvic inflammatory patient therapy, demonstrated that outpatient ther-disease include uterine–adnexal tenderness or cer- apy for uncomplicated pelvic inflammatory diseasevical-motion tenderness.2 Some studies suggest (without tubo-ovarian abscess or severe illness) wasthat atypical presentations of pelvic inflammatory as effective as intravenous inpatient therapy in termsdisease, including discomfort without appreciable of fertility and other long-term health outcomes, in-tenderness, abnormal uterine bleeding, and ab- cluding the prevention of ectopic pregnancy andnormal vaginal discharge, are often associated chronic pelvic pain.38with infection and inflammation in the upper gen-ital tract (i.e., endometritis and salpingitis).34,35 Chlamydial pelvic inflammatory disease tends tohave a more insidious onset than pelvic inflamma- There continues to be uncertainty regarding whomtory disease caused by N. gonorrhoeae or other more to screen and how frequently to do so. There is littlevirulent organisms. However, the damage to the fal- evidence of the effectiveness of screening in asymp-lopian tube can be as great or greater with chlamyd- tomatic women who are not in high-risk groups.15ia, especially with repeated infections.36 Screening on the basis of age (less than 25 years) ap- Because of the risks of infertility and other se- pears to be effective even in areas where the preva- quelae of pelvic inflammatory disease, clinicians lence of chlamydial infection is low to moderate Downloaded from www.nejm.org on November 30, 2010. For personal use only. No other uses without permission. Copyright 2003 Massachusetts Medical Society. All rights reserved. The new england journal of medicine (3 to 6 percent). In a longitudinal cohort study of ment to deliver to their sexual partners will reducescreening in 3202 high-risk, inner-city young wom- the rate of reinfection,44 but this hypothesis remainsen, chlamydial infection was detected in 24.1 per- unproven. In a recent trial in which patients werecent; the median time to new infection was slight- randomly assigned to either patient-delivered treat-ly more than 7 months, and the median time to a ment for partners (patients were asked to deliver arepeated positive test was 6.3 months. On the ba- dose of azithromycin to each of their sexual part-sis of these results, it was recommended that all ners) or self-referral (patients were asked to referyoung, sexually active women be screened every six their sexual partners for treatment), the risk of re-months.39 It is unclear, however, whether these infection was nonsignificantly lower in the groupfindings can be generalized to populations with a assigned to patient-delivered treatment (odds ratiolower prevalence of infection.
for reinfection, 0.8; 95 percent confidence interval, Level I evidence (from randomized trials) is also 0.6 to 1.1).45 lacking regarding the effectiveness of the screen-ing and treatment of pregnant women in popula- tions with a low prevalence of chlamydial infection.
In addition, the balance of benefits and harms (in- Guidelines from several professional societies, thecluding false-positive test results and the inappro- Centers for Disease Control and Prevention, and thepriate use of antibiotics) has not been assessed.15 U.S. Preventive Services Task Force are summarized Given the high prevalence of asymptomatic in- in Table 2.46-50 All groups suggest that clinicians fections in the population, some experts advocate screen routinely for C. trachomatis in all sexually ac-for the routine screening of young men as the next tive women less than 25 years of age and in otherimportant step toward reduced rates of infections asymptomatic women who are at increased risk forand complications.40,41 Although there is strong infection.
evidence that treatment can eradicate C. trachoma-tis infection in men, there are no studies demon- strating that the screening of asymptomatic men can reduce the rates of acute infection and adverseoutcomes in men or in women. Cost-effectiveness Screening for C. trachomatis infection is indicatedanalyses have suggested that there is an economic in sexually active women with risk factors for thisbenefit to society of screening for C. trachomatis, as infection, including an age of less than 25 years, in-compared with not screening, in high-risk wom- consistent use of barrier contraceptives, a new sex-en.42,43 However, the cost effectiveness of the ual partner, more than one sexual partner, cervicalscreening of men and low-risk women is debatable ectopy, and a history of or coexisting sexually trans-and will depend on the prevalence of infections, mitted disease. The patient described in the vignettethe ease and cost of specimen collection, the cost has some of these risk factors. Electing not to screenof testing, the characteristics of the diagnostic tests her would place her at risk for adverse outcomes,(e.g., their sensitivity and specificity), and the short- including ascending infection (pelvic inflamma-and long-term adverse outcomes that are prevent- tory disease) and infertility, chronic pelvic pain, anded. Additional research is needed to determine the ectopic pregnancy. Annual screening is reasonable,optimal interval between screenings and to compare although more frequent testing may be indicated inthe universal screening of all sexually active women areas of high prevalence or in women with severalyounger than 25 years of age with screening based risk factors. Information on prevalence (the rates ofon the presence of additional risk factors in popu- positive tests) can often be obtained from microbi-lations with a range of prevalence rates.
ology laboratories. The use of barrier contraception It remains uncertain whether the routine use of (e.g., condoms) as a method of prevention should urine specimens or specimens collected by patients be discussed with all patients. If a screening test iswould improve compliance with testing and treat- positive for C. trachomatis, I would treat the patientment. Also, it is unclear whether the empirical treat- with doxycycline or azithromycin. Retesting (a “testment of the sexual partners of patients with chla- of cure”) after treatment with recommended reg-mydial infections is preferable to the screening of imens is not indicated unless compliance is inthese partners. Some experts suggest that provid- question, symptoms are present, or reinfection ising patients with prescriptions for empirical treat- suspected.2 Rescreening for chlamydia is recom- Downloaded from www.nejm.org on November 30, 2010. For personal use only. No other uses without permission. Copyright 2003 Massachusetts Medical Society. All rights reserved. Table 2. Guidelines from Professional Societies and Federal Agencies.
Who Should Be Screened
Timing or Frequency of Screening
All young sexually active women and other women at Perform routinely (interval not specified) All sexually active women with risk factors (age ≤25 yr, new male sexual partner or two or more sexual part-ners in previous year, inconsistent use of barrier con-traceptives, history of sexually transmitted disease, black race, cervical ectopy) Perform during first trimester in all women, Persons in high-risk groups (sexually active women <25 yr of age, men and women with a new sexual partner or more than one partner in the previous year, women who use nonbarrier contraceptive methods) Perform during first trimester in all women All sexually active women <20 yr of age; women 20–24 yr of age if one of the following risk factors is present: inconsistent use of barrier contraceptives or a new sexual partner or multiple sexual partners during the previous 3 mo; women >24 yr of age if both risk fac-tors are present Perform during first prenatal visit in all women, third trimester if high risk (<25 yr of age or other risk factors) All sexually active women ≤25 yr of age and other asymp- Perform routinely, optimal interval uncertain tomatic women at increased risk for infection All asymptomatic pregnant women ≤25 yr of age and Perform routinely, optimal interval uncertain * The guidelines of the Centers for Disease Control and Prevention are available at http://www.cdc.gov/std/treatment/rr5106.pdf.
† The guidelines of the U.S. Preventive Services Task Force are available at http://www.ahrq.gov/clinic/uspstf/uspschlm.htm. The task force recommends routine screening in the groups listed and notes that there is insufficient evidence to make a recommendation for or against screening in asymptomatic men.
mended when patients present for care within 12 the diagnosis. Treatment for sexual partners thatmonths after a positive test.2 is delivered by the patient for the prevention of re- The timely treatment of the patient’s sexual part- peated infection has efficacy similar to that of self- ners is also essential in order to reduce the risk of referral and is a reasonable approach.
reinfection. The sexual partners should be evaluat- Supported in part by a Midcareer Investigator Award in Women’s ed, tested, and treated if they have had sexual con- Health Research from the National Institute of Child Health and tact with the patient during the 60 days preceding r e f e r e n c e s
Sexually transmitted disease surveillance, Cecil JA, Howell MR, Tawes JJ, et al. Fea- 2001. Atlanta: Centers for Disease Control tures of Chlamydia trachomatis and Neisseria tory disease and fertility: a cohort study of gonorrhoeae infection in male army recruits.
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