Synonyms and related keywords: nongonococcal urethritis, nonspecific urethritis, postgonococcal urethritis, Chlamydia trachomatis, Chlamydia puerorum, Chlamydia psittaci, Chlamydia pneumoniae, C trachomatis, C puerorum, C psittaci, C pneumoniae, sexually transmitted diseases, STDs

INTRODUCTION

Background: Chlamydiae are small gram-negative obligate intracellular microorganisms that preferentially infect squamocolumnar epithelial cells.

Chlamydia trachomatis is one of the 4 species (also including Chlamydia puerorum, Chlamydia psittaci, and Chlamydia pneumoniae) in the genus Chlamydia. C trachomatis can be differentiated into 18 serovars (serologically variant strains) based on monoclonal antibody–based typing assays. Serovars A, B, Ba, and C are associated with trachoma (a serious eye disease that can lead to blindness), serovars D-K are associated with genital tract infections, and L1-L3 are associated with lymphogranuloma venereum ([LGV] see Lymphogranuloma Venereum).

Pathophysiology: The pathophysiologic mechanisms of chlamydiae are poorly understood at best. The initial response to infected epithelial cells is a neutrophilic infiltration followed by lymphocytes, macrophages, plasma cells, and eosinophilic invasion. The release of cytokines and interferons by the infected epithelial cell initializes this inflammatory cascade.

Infection with chlamydial organisms invokes a humoral cell response, resulting in secretory immunoglobulin A (IgA) and circulatory immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies and a cellular immune response. Recent studies have implicated a 40-kd major outer membrane protein (MOMP) and a 60-kd heat-shock protein (Chsp60) in the immunopathologic response, but further studies are needed to better understand these cell-mediated immune responses.

Chlamydiae have a unique biphasic life cycle that is adaptable to both intracellular and extracellular environments. In the extracellular milieu, the so-called elementary body (EB) is found. EBs are metabolically inactive infectious particles; functionally, they are spore-type structures. Once inside a susceptible host cell, the EB prevents phagosome-lysozyme fusion and then undergoes reorganization to form a reticulate body (RB).

The RB synthesizes its own DNA, RNA, and proteins but requires energy in the form of adenosine triphosphate (ATP) from the host cell. After a sufficient amount of RBs have formed, some transform back into EBs, exiting the cell to infect others.

Frequency:

• In the US: Chlamydia is the most commonly reported infectious disease in the United States—estimated at 4 million infections annually with prevalence rates of higher than 10% in sexually active adolescent females.

• Internationally: In 1995, the World Health Organization (WHO) estimated 89 million cases of C trachomatis infection worldwide.

Mortality/Morbidity: Although urogenital carriage of chlamydiae often is asymptomatic, the most common manifestation of disease is local mucosal inflammation associated with a discharge, urethritis in the male, and urethritis/vaginitis/cervicitis in the female.

• Chlamydia is one of the leading causes of pelvic inflammatory disease (PID) and infertility in women. The risk of ectopic pregnancy in women who have had PID is 7-10 times greater than that for women without a history of PID. In 15% of women who have contracted PID, chronic abdominal pain is a long-term manifestation that most likely is related to pelvic adhesions in the ovaries and fallopian tubes.

• Chlamydial infections increase the risk for acquiring HIV infection by increasing genital mucosal inflammation.

• Pregnant women infected with chlamydia can pass the infection on to their infants during delivery, which may develop into chlamydial pneumonia or chlamydial conjunctivitis.

Race: The incidence of chlamydial infection is not related to race per se but rather to the sexual histories of the individuals and, particularly, to the frequency and use (or nonuse) of barrier protection.

Sex: Although the presence of asymptomatic infection with genitourinary chlamydiae can differ, acquisition is similar for both sexes.

Age: Age factors in chlamydial genitourinary infection relate to the age of first sexual exposure and the frequency of exposure.

CLINICAL

History: C trachomatis is a sexually transmitted microorganism responsible for a wide spectrum of diseases that include cervicitis, salpingitis, endometritis, urethritis, epididymitis, conjunctivitis, and neonatal pneumonia. In contrast to gonorrhea infection, most men and women who are infected are asymptomatic, and, therefore, diagnosis is delayed until a positive screening result or upon discovering a symptomatic partner. Chlamydia has been isolated in approximately 40-60% of males presenting with nongonococcal urethritis. Recent epidemiological studies indicate a high prevalence rate of asymptomatic men who act as a reservoir for chlamydial infections. A study by Quinn et al (1996) demonstrated that transmission probability in both men and women is estimated at 68%.

• Risk factors

• Nonwhite race

• Multiple sexual partners

• Age younger than 19 years

• Poor socioeconomic conditions

• Single marital status

• Nonbarrier contraceptive use

• Neonatal risk

• Conjunctivitis

• Neonatal pneumonia

Physical:

• Women

• Easily induced endocervical bleeding

• Mucopurulent endocervical discharge

• Intermenstrual bleeding

• Cervical discharge

• Dysuria

• Abdominal pain

• Men

• Urethral discharge

• Urinary frequency and/or urgency

• Dysuria

• Scrotal pain/tenderness

• Perineal fullness (related to prostatitis)

DIFFERENTIALS

Herpes Simplex

Other Problems to be Considered:

Gonorrhea
Ureaplasma infection
Trichomonas infection
Foreign body
Periurethral abscess
Mycoplasma genitalium infection
Prostatitis

WORKUP

Lab Studies:

• Because of the possibility of multiple sexually transmitted infections, all patients with any sexually transmitted disease (STD) should be evaluated for chlamydial infection because chlamydial treatment is included in the Centers for Disease Control and Prevention (CDC) STD treatment regimens.

• Cytologic diagnosis

• This is used mainly for the diagnosis of infant inclusion conjunctivitis and in ocular trachoma by the demonstration of intracytoplasmic C trachomatis inclusions in HeLa cells (ie, continuously cultured carcinoma cell line used for tissue cultures).

• Cytologic diagnosis also is used to evaluate endocervical scrapings, but interpretation is difficult and sensitivity and specificity have been low.

• Isolation in cell culture

• C trachomatis grows well in a variety of cell lines (eg, McCoy, HeLa cells) that can be maintained in tissue culture.

• Incubation in tissue culture is 40-72 hours, depending on the cell type and specific biovar.

• Intracytoplasmic inclusions can be detected either by Giemsa stains or by immunofluorescent staining with monoclonal antibodies.

• Because of its high specificity (100%) and sensitivity, cell culture is the only test that should be used to establish the presence or absence of infections in cases with legal implications such as rape or sexual abuse.

• Antigen detection and nucleic acid hybridization

• By direct fluorescent antibody (DFA)

• By enzyme-linked immunosorbent assay

• Detection of chlamydial ribosomal RNA (rRNA) by hybridization with a DNA probe
  • Advantage: This is simpler and less expensive. Most studies report sensitivities greater than 70% and specificities of 97-99% in populations of men and women with a prevalence of infection of 5% or more. Antigen detection may well be the most appropriate diagnostic test for a primary care setting in the United States if a definitive diagnostic test is required.
  • Disadvantage: It is less sensitive when compared to tissue culture. In low-prevalence populations (ie, less than 5% infected), a highly significant proportion of positive test results are false-positive results. Therefore, verification of a positive test result is desirable in certain cases. Such verification can be by culture (eg, a second nonculture test that identifies a different chlamydial antigen or nucleic acid sequence than the first test), a blocking antibody, or competitive probe.

• Detection of chlamydial genes by DNA amplification tests

• Polymerase chain reaction (PCR)
• Ligase chain reaction (LCR)
• Specific chlamydial rRNA using transcription-mediated amplification
• Both PCR and LCR detect C trachomatis in urine or self-administered vaginal swab specimens with sensitivity comparable to that with urogenital swab specimens.

• Serology

• Complement fixation test
  • All patients with LGV or psittacosis have complement-fixing antibody titers of greater than 1:16.
  • Fifteen percent of men with urethritis and 45% of women with endocervical infection have titers 1:16 or greater.
• Microimmunofluorescence test
  • This is more sensitive than complement fixation test.
  • Results are positive in 99% or more of women with cervicitis and in 80-90% of men with urethritis.

• Antibody classes

• Antichlamydia IgM is uncommon in adults with genital tract infection.
• The prevalence of antichlamydia IgG is high in sexually active adults, even in those who do not have an active infection, and it likely is due to past infection.
• A statistically significant association exists between chlamydia-specific serum IgA and active disease.
• The sensitivity, specificity, and predictive values are not high enough to make any serology clinically useful in the diagnosis of active disease. Therefore, chlamydial serologies are not recommended for diagnosis of genital tract disease.

• The choice of the most appropriate test depends on the clinical setting, the facilities available, and the relative cost.

TREATMENT

Medical Care:

• Patients should abstain from sexual intercourse for 7 days after single-dose therapy or until the end of a longer regimen.

• Patients also should refrain from sexual intercourse until all of their sex partners have been cured.

• Follow-up culture is not recommended after azithromycin or doxycycline therapy, but it may be considered in pregnancy after erythromycin or amoxicillin therapy. Nonculture tests should be avoided in this circumstance to avoid positive results from nonviable organisms.

MEDICATION

Treatment of genitourinary chlamydial infection clearly is indicated when the infection is diagnosed or suspected. Treatment also is indicated for sex partners of the index case if the time of the last sexual encounter was within 60 days of onset, and it should be considered for longer periods for the last sexual partner. Treatment of chlamydia is indicated for patients being treated for gonorrhea, as well.

Drug Category: Antibiotics — Therapy should cover all likely pathogens in the context of this clinical setting.

Drug Name	Azithromycin (Zithromax) — Relatively new member of the macrolide family of antimicrobials. Related to erythromycin, it is considered by many to be the treatment of choice of C trachomatis genitourinary infection because it may be administered as a 1-dose treatment, which improves adherence to treatment.
Adult Dose	1 g PO once
Pediatric Dose	less than 8 years: Not established >8 years or >45 kilograms: Administer as in adults
Contraindications	Documented hypersensitivity; hepatic impairment; do not administer with pimozide
Interactions	May increase toxicity of theophylline, warfarin, and digoxin; effects are reduced with coadministration of aluminum and/or magnesium antacids; nephrotoxicity and neurotoxicity may occur when coadministered with cyclosporine; can inhibit metabolism of disopyramide and pimozide, leading to cardiotoxicity; inhibition of rifabutin metabolism may lead to rifabutin toxicity
Pregnancy	B – Usually safe but benefits must outweigh the risks.
Precautions	Generally not recommended for routine use during pregnancy but can be used as an alternative if failure occurs (by followup culture) after treatment with erythromycin or amoxicillin (neither are highly efficacious treatments); site reactions can occur with IV route; bacterial or fungal overgrowth may result with prolonged antibiotic use; may increase hepatic enzymes and cholestatic jaundice; caution in patients with impaired hepatic function, prolonged QT intervals, or pneumonia; caution in hospitalized, geriatric, or debilitated patients; adverse effects are GI in origin, namely nausea, vomiting, diarrhea, and abdominal pain; less common effects include headache, dizziness, and hepatotoxicity

Drug Name	Doxycycline (Doryx, Vibramycin) — Well absorbed tetracycline antimicrobial. When administered for 1 wk, appears to be as effective as single-dose azithromycin for genitourinary chlamydial infections. Although the course is longer (7 d versus 1 dose) than azithromycin, the cost is less and it has been used in clinical practice for a much longer time.
Adult Dose	100 mg PO bid
Pediatric Dose	less than 8 years: Not recommended >8 years: Administer as in adults
Contraindications	Documented hypersensitivity; severe hepatic dysfunction
Interactions	Bioavailability minimally decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; tetracyclines can increase hypoprothrombinemic effects of anticoagulants; tetracyclines can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy
Pregnancy	D – Unsafe in pregnancy
Precautions	Photosensitivity may occur rarely; use during tooth development (last half of pregnancy through age 8 y) can cause permanent discoloration of teeth

Drug Name	Erythromycin (E.E.S., E-Mycin, Eryc, Ery-Tab, Erythrocin) — Macrolide antimicrobial agent that generally is considered the recommended treatment for chlamydial genitourinary infection only during pregnancy.
Adult Dose	500 mg erythromycin base PO qid for 7 d; alternatively, 250 mg erythromycin base PO qid for 14 d or 800 mg erythromycin ethylsuccinate PO qid for 7 d or 400 mg qid for 14 d
Pediatric Dose	less than 45 kilograms: 50 mg/kg/d erythromycin base divided PO qid for 10-14 d; this regimen also should be used for ophthalmia neonatorum and/or infant pneumonia due to chlamydia
Contraindications	Documented hypersensitivity; hepatic impairment
Interactions	As an inhibitor of the cytochrome oxidase P-450 3A4 system, can increase serum levels of atorvastatin, buspirone, carbamazepine, cerivastatin (removed from US market 8/8/01), cilostazol, cisapride, clozapine, cyclosporine, diazepam, dicumarol, dihydroergotamine, disopyramide, felodipine, fexofenadine, lovastatin, midazolam, pimozide, pravastatin, quinidine, sildenafil, triazolam, valproic acid, vinblastine, and warfarin; similar effects as doxycycline can occur with concomitant use of digoxin and oral contraceptives
Pregnancy	B – Usually safe but benefits must outweigh the risks.
Precautions	Caution in liver disease; estolate formulation may cause cholestatic jaundice; GI adverse effects are common (administer doses pc); discontinue use if nausea, vomiting, malaise, abdominal colic, or fever occur; efficacy of treatment is not as high as the standard regimens in adults; test of cure at 3 wk after completion of therapy should be considered and re-treatment may be needed

Drug Name	Ofloxacin (Floxin) — Fluorinated quinolone recommended as an alternative regimen to azithromycin or doxycycline in adults with genitourinary chlamydial infection. Efficacy is similar to doxycycline and azithromycin but is more expensive and offers no advantage in dosing. Other quinolone antimicrobials have not been evaluated appropriately or were not adequately effective.
Adult Dose	300 mg PO bid for 7 d
Pediatric Dose	Not recommended
Contraindications	Documented hypersensitivity
Interactions	Medications that contain divalent cations (eg, aluminum, magnesium, calcium, iron) decrease absorption from the GI tract; antibiotics, including ofloxacin, may interfere with the immunological response to live typhoid vaccine if administered within 24 h; can increase serum levels of procainamide and theophylline but not caffeine
Pregnancy	C – Safety for use during pregnancy has not been established.
Precautions	Major adverse effects of ofloxacin include nausea, vomiting, diarrhea, headache, insomnia, and dizziness; fluoroquinolones, including ofloxacin, are not recommended in children, adolescents, and pregnant or breastfeeding women because of potential risk of arthropathy with the disruption of cartilage and depletion of collagen; short courses do not seem to have effects on growth; some cases of tendon rupture (most notably Achilles) have been linked to fluoroquinolone use

Drug Name	Ampicillin (Principen, Omnipen, Marcillin) — Like erythromycin, amoxicillin is considered a recommended treatment for genitourinary chlamydial infection only in pregnant women.
Adult Dose	500 mg PO tid for 7 d
Pediatric Dose	Not recommended
Contraindications	Documented hypersensitivity
Interactions	Probenecid and disulfiram elevate ampicillin levels; allopurinol decreases ampicillin effects and has additive effects on ampicillin rash; may decrease effects of oral contraceptives; coadministration with PO typhoid vaccine can affect the immunogenicity of the vaccine by inhibiting replication; methotrexate levels may be increased by penicillins
Pregnancy	B – Usually safe but benefits must outweigh the risks.
Precautions	Retesting 3 wk after therapy completion should be considered; major adverse effects include diarrhea, rash, nausea, and vomiting; Clostridium difficile infection and/or colitis may occur

FOLLOW-UP

Deterrence/Prevention:

• Individuals who are sexually active should be aware of the risk not only of genitourinary chlamydia infection but also of the whole gamut of STDs and that the best way of avoiding infection is to practice safe sex. This means using appropriate barrier protection (ie, latex condoms).

Complications:

• Reiter syndrome, a reactive arthritis secondary to an immune-mediated response has been associated (among other things) with a primary chlamydial infection.

• It may present as asymmetric polyarthritis, urethritis, inflammatory eye disease, mouth ulcers, circinate balanitis, and keratoderma blennorrhagica.

• While the etiology of Reiter syndrome may not be completely clear, 2 clear associations are observed. It usually follows an infectious episode, and 80% of affected patients are human leucocyte antigen-B27 (HLA-B27)–positive.

• Deeper pelvic complications in the female

• PID

• Potential infertility

• Spread to the newborn during parturition

Prognosis:

• Treatment failures with primary therapies are quite rare.

• Relapse may occur with alternative therapies.

• Reinfection is very common and is related to nontreatment of infected sexual partners or acquisition from a new partner.

Patient Education:

• Appropriate counseling of infected individuals must be performed.

• Counsel patients to avoid reinfection from the sexual partner by facilitating treatment of the contact prior to sexual reexposure.

• Counsel patients to use latex condoms to prevent reinfection.

• For excellent patient education resources, visit eMedicine’s Sexually Transmitted Diseases Center. Also, see eMedicine’s patient education articles Sexually Transmitted Diseases and Chlamydia.

MISCELLANEOUS

Medical/Legal Pitfalls:

• Remembering to treat patients for chlamydial genitourinary infection even when gonococcal infection is clearly diagnosed is important.

• Consider testing the cure when treatment with amoxicillin or erythromycin is used instead of the standard doxycycline or azithromycin regimens.