OVERVIEW: What every practitioner needs to know

Are you sure your patient has Chlamydia? What are the typical findings for this disease?

Genital infection with Chlamydia trachomatis is the most frequently reported infection in the United States. Prevalence is highest in persons younger than 25 years of age. Some female patients with uncomplicated infection of the cervix already have subclinical upper reproductive tract infection at diagnosis. Complications of genital infection can include pelvic inflammatory disease, ectopic pregnancy, and infertility. Infection of neonates can occur in infants who are exposed to the mother’s infected cervix. Neonatal infection is most commonly recognized when the infant experiences purulent conjuctivitis between 5 and 12 days of age.

Asymptomatic genital infection is common in men and women, making screening programs essential for identification of infected individuals. Symptomatic individuals may complain of urethritis. Men can experience epididymitis manifesting as testicular pain.

Cervicitis is often silent. In contrast, salpingitis, endometritis, perihepatitis (Fitz-Hugh-Curtis syndrome), and pelvic inflammatory disease are associated with moderate to severe pelvic and/or abdominal pain.

Men and women who practice receptive anal intercourse can experience symptoms of proctitis.

Infants who are infected at the time of delivery may develop conjuctivitis, cough, and dyspnea.

Infection in adolescents

Surveillance indicates that between 2% and 20% of female individuals between the ages of 15 and 24 years are infected with C. trachomatis. Genital tract infection is transmitted sexually, is often asymptomatic, and can persist for months to years. Reinfection after antibiotic treatment is common.

Lymphogranuloma venereum is a sexually transmitted infection caused by C. trachomatis serovars L1, L2, and L3. The tender suppurative inguinal or femoral lymph node seen in individuals with this infection is typically unilateral. The primary inoculation site on the genitals may be evident as an ulcerative lesion of the skin or mucous membranes.

Neonatal Infection

Neonatal chlaymidial conjuctivitis, or ophthalmia neonatorum, presents as eye discharge at several days to 2 weeks of age. The eyes become congested and edematous. Chronic infection leads to follicular keratoconjuctivitis with neovascularization and scarring of the cornea. Screening and prevention measures have largely eliminated the risk for progression with visual loss in developed countries, but ophthalmic infection with Chlamydia remains a significant cause of childhood ocular morbidity in resource-challenged areas of the world.

Pneumonia has an insidious onset between the age of 2 and 19 weeks. A staccato cough, dyspnea, tachypnea, and rales are usually present. Fever is usually absent. Peripheral blood eosinophilia has been described in infants with chlamydial pneumonia.

Infection in young children

Testing for C. trachomatis infection should be performed for all children who have been sexually abused. Any child who is found to have a sexually transmitted infection should be screened for Chlamydia.

What other disease/condition shares some of these symptoms?

Urethritis, cervicitis, pelvic inflammatory disease (PID), and epididymitis may be caused by other sexually transmitted agents, particularly Neisseria gonorrhoeae.

Neonatal conjuctivitis can also be caused by N. gonorrhoeae. Neonatal chlamydial pneumonia can mimic pertussis syndrome caused by Bordetella pertussis, Bordetella parapertussis, respiratory syncytial virus, or adenovirus.

What caused this disease to develop at this time?

C. trachomatis infection is very common in sexually active individuals, especially in the adolescent age group. Since most infections are minimally symptomatic or asymptomatic, infection goes unrecognized and spreads easily. Reinfection after appropriate treatment is common.

Screening for chlamydial infection is a standard of care during pregnancy. Identified infections should be treated to prevent complications in the woman and in her newborn. Infants born vaginally to infected mothers have a 1 in 2 chance of acquiring the organism, a 1 in 4 chance of conjuctivitis developing, and about a 1 in10 chance of pneumonia developing.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Confirmation of the diagnosis can be made by culture (the required diagnostic study in medicolegal cases of sexual abuse) or by nucleic acid amplification testing.

Several non–culture-based techniques are available for testing urethral swab specimens (from male individuals), endocervical swab specimens (from female individuals), or conjunctival swabs (from infants). Polymerase chain reaction, strand-displacement amplification tests, and transcription-mediated amplification tests can also be used to evaluate urine samples for the presence of chlamydial DNA. Liquid-base cytology specimens collected for Papanicolaou (Pap) smears might also be acceptable for testing, although sensitivity is lower than for endocervical swab or urine samples.

Non–culture-based methods are not recommended for testing urethral swabs obtained from female individuals or from swabs used to collect samples from the pharynx or rectum.

When evaluating a child for infection after sexual abuse, culture is still the only accepted diagnostic test in some legal jurisdictions.

Serum antibody testing of limited utility, and if performed will not distinguish between present or past infection.

A diagnosis of genital chlamydial infection should prompt investigation for other sexually transmitted infections (gonorrhea, syphilis, HIV, hepatitis B, hepatitis C)

Would imaging studies be helpful? If so, which ones?

Uncomplicated chlamydial genital infections do not require imaging. Female patients with moderate to severe pelvic or abdominal complaints should have imaging performed to evaluate for upper genital tract complications of infection (Fitz-Hugh-Curtis syndrome, salpingitis, tuboovarian abscess). A chest radiograph should be obtained in infants with suspected chlamydial pneumonia.

Confirming the diagnosis

Screening programs have reduced the prevalence of infection in women, although routine screening in men has not been widely advocated. Screening of high-risk men should be considered, however, in clinical settings of high rates of chlamydial or other sexually transmitted infections.

“Tests of cure” are not recommended unless reinfection is suspected or symptoms are persistent. Infection during pregnancy is the exception. Tests of cure are recommended in that setting, with repeat testing during the third trimester to determine if reinfection has occurred.

The majority of post-treatment infections result from reinfection because of failure to identify and treat all sexual partners or exposure to a new partner who is also infected. Repeat infections are associated with higher rates of PID and other complications. Except in pregnant women, repeat testing on completion of antimicrobial treatment is not recommended unless adherence is in question, symptoms persist, or reinfection is suspected.

Validity of repeat testing less than 3 weeks after treatment has not been established. Nucleic acid amplification tests that are performed less than 3 weeks after treatment may be sensitive enough to detect the presence of nonviable organisms, therefore yielding a false-positive result. Unlike the test of cure (less than 3 weeks after treatment), repeat testing at a later time is a priority in those who were previously infected. Therefore, infected individuals who are are treated should be retested in approximately 3 months to determine whether they may be re-infected, even in the absence of symptoms.

If you are able to confirm that the patient has infection with Chlamydia, what treatment should be initiated?

Antibiotic treatment should be prompt. Delays in treatment have been associated with an increased frequency of PID. The preferred antibiotic regimen in most circumstances is azithromycin 1 g orally as a single dose or doxycycline 100 mg twice daily for 7 days. Cure rates approach 98% with either of these strategies. Alternative regimens include erythomycin base 500 mg four times daily for 7 days, erythromycin ethylsuccinate 800 mg four times daily for 7 days, levofloxacin 500 mg once daily for 7 days, or ofloxacin 300 mg twice daily for 7 days.

For patients in whom adherence may be questionable, single-dose azithromycin is preferred. To maximize compliance, antibiotics should be provided on site, with direct observation that the patient takes the first dose.

Management of sexual partners is critical to prevent reinfection. Patients should be instructed to refer their sexual partners for evaluation and testing.

Azithromycin is the treatment of choice for pregnant women, as doxycycline and quinolone family antibiotics are contraindicated during pregnancy, and erythomycin options are not well tolerated. Another option for treatment during pregnancy is amoxicillin 500 mg three times daily for 7 days. In the setting of pregnancy, test of cure is recommended 3 weeks after therapy is completed to document eradication of the organism. Retesting during the third trimester is also recommended because reinfection is common.

Treatment of neonatal exposure and infection

Infants born to mothers who have untreated, documented chlamydial infection are are at high risk for infection, however current recommendations do not support the routine use of antibiotic prophylaxis. Instead, infants should be followed clinically, and, if symptoms develop, appropriate testing and empiric therapy initiated.

Topical antibiotic administration alone is not sufficient for the treatment of neonatal conjuctivitis, nor is it necessary when systemic antibiotics are used. The antibiotic of choice to treat neonatal chlamydial conjuctivitis or chlaymidial pneumonia is erythromycin base or erythromycin ethylsuccinate 50 mg/kg/day orally in four divided doses for a duration of 2 weeks.

Data on the use of other macrolide antibiotics in this context are limited. The results of one study involving a small number of infants suggested that a shorter course of azithromycin at 20 mg/kg/day for 3 days might be sufficient. Since treatment with erythomycin is only about 80% effective at bacterial eradication, a second course of treatment might be required. Infants should be followed clinically to determine whether re-evaluation and retreatment is necessary.

What are the adverse effects associated with each treatment option?

Azithromycin is generally well tolerated. Mild gastrointestinal complaints are most common (abdominal pain, nausea, diarrhea). Rare, serious side effects include hepatotoxicity, drug hypersensitivity reactions, and corneal erosions.

Doxycycline may cause photosensitivity, drug-induced gastrointestinal complaints (particularly erosive esophagitis), and elevated blood urea nitrogen levels. Rare, serious side effects include hepatotoxicity and drug hypersensitivity reactions.

Erythromycin base and salts are all associated with mild to moderate gastrointestinal complaints (cramping, pain, nausea, diarrhea). Episodes of torsades de pointes have been described. An association between oral erythromycin and infantile hypertophic pyloric stenosis has been reported in infants younger than 6 weeks of age who were treated with this medication. Infants who require treatment with erythomycin for chlamydial exposure or disease should be monitored for signs and symptoms of pyloric stenosis.

Levofloxacin and ofloxacin can both cause nausea and diarrhea. Headache is common. All fluoroquinolones, including levofloxacin and ofloxacin, are associated with an increased risk of tendonitis and tendon rupture. In addition, these medications can exacerbate muscle weakness in patients with myasthenia gravis. Cardiovascular side effects rarely include a prolonged QT interval and ventricular tachycardia. Reports of torsades de pointes have been described.

All of the above antibiotics can be associated with drug hypersensitivity reactions, including erythema multiforme.

What are the possible outcomes of chlamydial infection?

The vast majority of genital chlamydia infections are uncomplicated, especially when diagnosed and treated early. Complications are more likely when the infection is chronic or recurrent. In female patients the most serious complications include upper genital tract infection progressing to acute or chronic PID. In some cases, the inflammation and associated scarring leads to secondary infertility or an ectopic pregnancy. It is estimated that 15% of women may become sterile after a single episode of PID, and 50% will become sterile after three episodes of PID.

Like women, men with untreated chlamydial infection can experience progressive symptoms as the infection spreads to cause epididymitis and/or orchitis. Infertility secondary to severe or recurrent infection is an uncommon complication.

Neonatal chlamydial infection can lead to ophthalmia neonatorum. If left untreated, corneal scarring can develop. In neonates in whom pneumonia develops, even when treated early in the course of infection, abnormal pulmonary function tests results can be seen for several years.

Fitz-Hugh-Curtis syndrome

Fitz-Hugh-Curtis syndrome, or perihepatitis, is characterized by upper right quadrant pain that may radiate to the shoulder. Nausea, fever, and other signs and symptoms of PID may be present as well. Fitz-Hugh-Curtis syndrome is a known complication of infection with C. trachomatis or N. gonorrhoeae, or coinfection with both.

Epidemiology of Chlamydia trachomatis infection

The number of new C. trachomatis infections is estimated to exceed 4 million cases/year in the United States alone. Unlike syphilis and gonorrhea, the prevalence of chlamydial infections is not tightly associated with socioeconomic status. When studied, prevalence is consistently higher than 5% among sexually active adolescents and young adult women seeking care in outpatient clinics, regardless of geography, location of the clinic (urban or rural), and the race or ethnicity of the screened population. Trends in decreasing age of sexual debut, and later ages for marriage have contributed to the high prevalence in the age group younger than 25 years.

Chlamydial infection is sexually transmitted. Pathogenesis of infection in infants is directly related to exposure to cervicovaginal secretions at the time of delivery, at which time the newborn’s mucous membranes becomes colonized. Rarely, this infection is transmitted to younger children as a result of sexual abuse. There is no known genetic predisposition to the development of infection from C. trachomatis.

How do these pathogens/genes/exposures cause the disease?

Human to human transmission is the only route of contagion known. Sexually transmitted infection can occur during oral, vaginal, or anal sexual activity. Perinatal exposure occurs when a newborn comes into contact with infected cervicovaginal secretions.

What complications might you expect from the disease or treatment of the disease?

Complications of genital tract infection with C. trachomatis include PID, scarring of the fallopian tubes with secondary infertility, ectopic pregnancy and Fitz-Hugh-Curtis syndrome.

How can chlamydial infection be prevented?

A vaccine is not available; however the use of condoms dramatically reduces the risk of transmission. Sexual contacts of each index case should be notified of their exposure and evaluated for infection. Re-exposure and re-infection is common.

Age at sexual debut, numbers of sexual partners, and sexual habits all contribute to the frequency of infection.

Routine screening for chlamydia infection during pregnancy allows for early identification and treatment of maternal disease. This strategy is highly effective for preventing maternal-infant transmission.

What is the evidence?

Workowski, K, Berman, S. “Sexually transmitted diseases treatment guidelines, 2010”. MMWR. vol. 59. 2010. pp. RR12(This report updates 2006 guidelines with expanded diagnostic evaluations for cervicitis, clinical efficacy of azithromycin for chlamydial infections during pregnancy, diagnostic evaluation of sexual assault, and sexually transmitted disease prevention strategies. The diagnostic tests that are available for chlamydial infections are discussed.)

“U.S. Preventive Services Task Force. Screening for chlamydial infection: U.S. Preventive Services Task Force recommendation statement”. Ann Intern Med. vol. 147. 2007. pp. 128-34. (The report from this task force outlines the rationale for routine screening of all sexually active females 25 years and younger, discusses barriers to routinely including male patients in such programs, and highlights situations in which men should be screened.)

Lau, CY, Qureshi, AK. “Azithromycin versus doxycycline for genital chlamydial infections: a meta-analysis of randomized clinical trials”. Sex Trans Dis. vol. 29. 2002. pp. 497-502. (Twelve randomized trials were included in this meta-analysis providing evidence that azithromycin or doxycycline can be used as “drugs of choice” for the treatment of chlamydial infection with a 97%-98% cure rate.)

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Chlamydia trachomatis