Chlamydia (Chlamydial Genitourinary Infections)

Background

Chlamydial infection can cause disease in many organ systems, including the genitourinary tract. Chlamydiae are small gram-negative obligate intracellular microorganisms that preferentially infect squamocolumnar epithelial cells. They include the genera Chlamydia (of which the type species is Chlamydia trachomatis) and Chlamydophila (eg, Chlamydophila pneumoniae and Chlamydophila psittaci).

C trachomatis can be differentiated into 18 serovars (serologically variant strains) on the basis of monoclonal antibody–based typing assays. These serovars are associated with different medical conditions, as follows:

• Serovars A, B, Ba, and C – Trachoma, a serious eye disease endemic in Africa and Asia that is characterized by chronic conjunctivitis and can lead to blindness
• Serovars D-K – Genital tract infections
• Serovars L1-L3 – Lymphogranuloma venereum (LGV), which is associated with genital ulcer disease in tropical countries

C trachomatis infection affects the cervix, urethra, salpinges, uterus, nasopharynx, and epididymis^{[1, 2, 3]} ; it is the most commonly reported bacterial sexually transmitted disease (STD) in the United States and a leading cause of infertility in women. C trachomatis infection causes other diseases as well, including conjunctivitis, pneumonia or pneumonitis, afebrile pneumonia syndrome (in infants born vaginally to infected mothers), Fitz-Hugh-Curtis syndrome, and trachoma (the world’s leading cause of acquired blindness).^[4]

C pneumoniae infection is spread via respiratory droplets and causes pharyngitis, bronchitis, and pneumonia. C psittaci infection is spread by bird droppings and aerosols and causes psittacosis. These infections are not discussed in this article.

At present, fewer than 50% of sexually active young females in the United States are screened for the presence of chlamydiae. Nationally, the annual screening rate increased from 25.3% in 2000 to 43.6% in 2006, then decreased slightly to 41.6% in 2007.^[5]

The US Preventive Services Task Force recommends routine screening for chlamydial infections. The USPSTF recommends screening for chlamydia in sexually active females aged 24 years or younger and in older women who are at increased risk for infection. Routine Chlamydia screening of sexually active young women is recommended to prevent consequences of untreated chlamydial infection (eg, pelvic inflammatory disease (PID), infertility, ectopic pregnancy, and chronic pelvic pain).^{[6, 7]} A guideline synthesis is also available from the National Guideline Clearinghouse.^[8]

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Pathophysiology

The pathophysiologic mechanisms of chlamydial infection are poorly understood at best. Chlamydia infects columnar epithelial cells, which places the adolescent female at particular risk because of the presence of the squamocolumnar junction on the ectocervix until early adulthood. The initial response of epithelial cells to infection 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. A 40-kd major outer membrane protein (MOMP) and 10- and 60-kd chlamydial heat-shock proteins (cHSPs) have been implicated in the immunopathologic response, but further studies are needed to provide a better understanding of these cell-mediated immune responses.^[9]

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.

The bacterium is usually spread through sexual activity. An infected male has a 25% chance per sexual encounter of transmitting the infection to an uninfected female. Chlamydiae can be vertically spread as well. The transmission rate from infected mother to newborn is 50-60%, causing conjunctivitis (in most cases) or pneumonia (in 10-20% of cases; see Afebrile Pneumonia Syndrome).

Infection of the genital tract is the most common clinical presentation. The incubation period is 1-3 weeks. Approximately 50% of infected males and 80% of infected females are asymptomatic, but infection may cause a mucopurulent cervicitis in females and urethritis in males. Ascending infection can result in PID in women and is the most common cause of epididymitis in men younger than 35 years. Of women with PID, 5-10% develop perihepatitis (ie, Fitz-Hugh-Curtis syndrome).

Although patients with any STD are at increased risk of coinfection with another STD, coinfection of chlamydia and gonorrhea is most common. Forty percent of women and 20% of men with chlamydial infection are co-infected with gonorrhea. Patients with chlamydia also have a higher frequency of Reiter syndrome (ie, urethritis, conjunctivitis, reactive arthritis) than the general population.

LGV is rare in the United States but is responsible for 10% of cases of genital ulcer disease in tropical countries. Localized inguinal adenopathy and ulceration develop 2-12 weeks after exposure. Proctitis, rectal strictures, and lymphatic obstruction with secondary elephantiasis can occur in untreated disease.

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Etiology

Chlamydial transmission usually is caused by sexual contact through oral, anal, or vaginal intercourse. Neonatal infection (eg, conjunctivitis or pneumonia) may occur secondary to passage through the birth canal of an infected mother. Specific risk factors for chlamydial infection include the following:

• Nonwhite race
• Multiple sexual partners or a new sexual partner
• Age 15-24 years (especially < 19 years)
• Poor socioeconomic conditions (eg, homelessness)
• Exchange of sex for drugs or money
• Single marital status
• Intercourse without a barrier contraceptive
• History of a previous STD or current coinfection with another STD
• Certain cytokine polymorphisms – These have been associated with severe disease and risk of tubal factor infertility^[10]
• Certain variants in Toll-like receptor 1 and 4 genes – These predispose to infection^[11]
• Having been a foster child (males only)^[12]

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Epidemiology

United States statistics

Chlamydial infection is the most frequently reported infectious disease in the United States, and its prevalence is highest in persons aged 24 years or younger.^[13] The annual incidence of C trachomatis genital infections was estimated to be 2.86 million cases in the United States in 2008.^[14]

Sexually active female populations average chlamydial carriage rates of about 20%. Many patients are asymptomatic. The incidence is 2-3 times that of Neisseria gonorrhoeae.

The prevalence of chlamydia has been reported to be as high as 14% among African American females aged 18-26 years and 17% among females with a history of gonorrhea or chlamydia in the previous 12 months. In addition, approximately 100,000 neonates are exposed to chlamydiae annually. The 2007-2012 National Health and Nutrition Examination Survey (NHANES) indicates that an estimated 1.8 million persons aged 14-39 years in the United States have a genital chlamydial infection.^[15]

International statistics

More than one million sexually transmitted infections (STIs) are acquired every day worldwide.^[16] C trachomatis genital tract infections are common, with an estimated 105.7 million new worldwide cases in 2008.^[17] Serosurveys have documented similar incidence figures in Australia,^[18] New Zealand,^[19] France,^[20] Germany,^[21] and the Netherlands.^[22] A report from the World Health Organization (WHO) Initiative for Vaccine Research (IVR) estimated that there were more than 140 million cases of C trachomatis infection worldwide.^[23]

Age-, sex-, and race-related demographics

Age factors in chlamydial genitourinary infection relate to the age of first sexual exposure and the frequency of exposure. Chlamydia is most prevalent in persons aged 15-24 years. Acquisition rates are comparable for the 2 sexes. Women are more likely to be asymptomatic than men (80% vs 50%); however, they are also more likely to develop long-term complications (eg, PID and infertility).

Data from 2011 demonstrate that the disease is most common in adolescents and young adults aged 15-24 years, with higher rates in women and African Americans than in Hispanics and non-Hispanic whites.^[24]

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Prognosis

Antibiotic treatment is 95% effective for first-time therapy. The prognosis is excellent if treatment is initiated early and the entire course of antibiotics is completed. Although 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; thus all sexual partners should be treated.

Deaths are rare and are caused by progression to salpingitis and tuboovarian abscess with rupture and peritonitis. The most significant morbidity occurs when repeated episodes of chlamydia lead to obstruction and scarring of the fallopian tubes, resulting in partial or total sterility. Chlamydia is an indirect cause of mortality from ectopic pregnancies.^[25] Mortality due to ectopic pregnancy is probably more common than is death due to tuboovarian abscess.

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Patient Education

Appropriate counseling of infected individuals must be performed. Inform patients of the possible long-term risks and complications of their infection, including the possibility of infertility. Educate them regarding the risk of other STDs. Counsel patients to take steps to prevent reinfection. They should avoid sexual contact until their treatment is completed and all partners also have been evaluated and treated. They should also consider using latex condoms to minimize the chances of reinfection.

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History

C trachomatis is a sexually transmitted microorganism that is responsible for a wide spectrum of diseases, including cervicitis, salpingitis, endometritis, urethritis, epididymitis, conjunctivitis, and neonatal pneumonia. In chlamydial infection, unlike gonorrhea, most men and women who are infected are asymptomatic; thus, diagnosis is delayed until a positive screening result is obtained or a symptomatic partner discovered. Chlamydia screening programs have been demonstrated to reduce the rates of PID in women.^{[26, 27]}

The US Preventive Services Task Force has made the following recommendations with regard to screening women for chlamydial infection^{[6, 7]} :

• Screen for chlamydial infection in all sexually active nonpregnant young women aged 24 years or younger and for older nonpregnant women who are at increased risk
• Screen for chlamydial infection in all pregnant women aged 24 years or younger and in older pregnant women who are at increased risk
• Do not routinely screen for chlamydial infection in women aged 25 years or older, regardless of whether they are pregnant, if they are not at increased risk

Chlamydia has been isolated in approximately 40-60% of males presenting with nongonococcal urethritis. Epidemiologic studies indicate a high prevalence of asymptomatic men who act as a reservoir for chlamydial infections. A 1996 study by Quinn et al (1996) estimated that the transmission probability was 68% in both men and women.^[28]

Although genitourinary carriage of chlamydiae is often asymptomatic, certain manifestations of disease are commonly seen, including local mucosal inflammation associated with a discharge, urethritis in males, and urethritis/vaginitis/cervicitis in females.

The following may be noted in all patients with chlamydial infection:

• Possible history of sexually transmitted diseases (STDs)
• Dysuria
• Yellow mucopurulent discharge from the urethra

The following may be noted in females with chlamydial infection:

• Vaginal discharge
• Abnormal vaginal bleeding (postcoital or unrelated to menses)
• Dyspareunia
• History of sexual activity without condoms or condom failure
• Proctitis, rectal discharge, or both in cases of receptive anal intercourse
• Slow onset and progression of lower abdominal pain
• Fever (in pelvic inflammatory disease [PID])
• No symptoms (in 80%)

The following may be noted in males with chlamydial infection:

• Urethral discharge
• History of sexual activity without condoms or condom failure
• Proctitis, rectal discharge, or both in cases of receptive anal intercourse
• Unilateral pain and swelling of the scrotum
• Fever
• No symptoms (in 50%)

The following may be noted in newborns with chlamydial infection:

• Symptoms of pneumonia (if present), beginning at 1-3 months
• Symptoms of conjunctivitis (if present), developing at 1-2 weeks
• In pneumonia, cough and fever (though the classic description is afebrile)
• In conjunctivitis, eye discharge, eye swelling, or both

The following may be noted in mothers diagnosed with or suspected of having a chlamydial infection during pregnancy:

• Injected conjunctivae
• Mucopurulent discharge from the eyes
• Bilateral involvement of the eyes

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Physical Examination

Signs of chlamydial infection in women may include the following:

• Cervical friability (easy bleeding on manipulation)
• Intermenstrual bleeding
• Mucopurulent cervical or vaginal discharge
• Urethral discharge (usually thin and mucoid)
• Mucopurulent rectal discharge (from anal intercourse)
• Cervical motion tenderness
• Dysuria
• Adnexal fullness or tenderness, associated with progression to PID
• Lower abdomen tender to palpation
• Upper right quadrant abdominal tenderness (Fitz-Hugh-Curtis syndrome)

Signs of chlamydial infection in men may include the following:

• Mucopurulent urethral discharge (elicited by having the examiner or patient milk the urethra)
• Mucopurulent rectal discharge (from anal intercourse)
• Urinary frequency or urgency
• Dysuria
• Scrotal pain, tenderness, or swelling (sometimes unilateral)
• Perineal fullness (related to prostatitis)

Signs of chlamydial infection in newborns may include the following:

• Fever, cough, wheezing, and crackles (in pneumonia)
• Conjunctival erythema, mucoid discharge, or periorbital swelling (in conjunctivitis), often bilateral

Signs of lymphogranuloma venereum (LGV) may include the following:

• Localized inguinal adenopathy or buboes
• Genital ulceration
• “Groove sign” – Separation of the inguinal and femoral lymph nodes by the inguinal ligament (seen in 15-20% of patients)

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Complications

Chlamydial infection is one of the leading causes of infertility in women. It is also a leading cause of PID. PID is a serious disease that often requires hospitalization for inpatient care, including intravenous (IV) antibiotics, testing to rule out tubo-ovarian abscess, and intensive counseling on the complications of recurrent infections.

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.

Fitz-Hugh-Curtis syndrome (perihepatitis) is a rare complication of PID that is 5 times more likely to be caused by Chlamydia than by N gonorrhoeae. It frequently presents without the typical examination findings associated with PID (ie, the pelvic examination is normal).

Women with a chlamydial infection (especially one caused by serotype G) are at increased risk for the development of cervical cancer; the risk is as much as 6.5 times greater than it is in women without infection. Chlamydial infections also increase the risk of acquiring HIV infection by increasing genital mucosal inflammation.

Pregnant women with a chlamydial infection can pass the infection on to their infants during delivery, and this may develop into chlamydial pneumonia or chlamydial conjunctivitis. Untreated neonatal conjunctivitis can result in blindness.

Reiter syndrome, a reactive arthritis secondary to an immune-mediated response, has been associated with a primary chlamydial infection. It may present as asymmetric polyarthritis, urethritis, inflammatory eye disease, mouth ulcers, circinate balanitis, and keratoderma blennorrhagica. Its etiology may not be completely clear, but 2 strong associations are observed: Reiter syndrome usually follows an infectious episode, and 80% of affected patients are positive for human leukocyte antigen (HLA)-B27.

Other potential complications of chlamydial infection are miscarriage,^[29] preterm delivery,^[30] and urethral scarring in men.

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Approach Considerations

Because of the possibility of multiple sexually transmitted infections, all patients with any sexually transmitted disease (STD) should be evaluated for chlamydial infection.

Endocervical, urethral, rectal, or oropharyngeal specimens should be obtained and assayed for C trachomatis infection in both males and females based on the patient’s sexual practices obtained by history.^[31] A voided urine sample, whether midstream or first-void, effectively captures the chlamydial organism for nucleic acid amplification testing (NAAT).^[32] NAATs are the most sensitive tests for these specimens and are therefore recommended for detecting C trachomatis infection.^{[33, 34]} Self-collected vaginal swab specimens are equivalent in sensitivity and specificity to those collected by a clinician using NAATs.^{[35, 36, 33]}

In infants with suspected chlamydial pneumonia, perform a nasopharyngeal swab for Chlamydia culture. Currently available rapid tests^[37] are not approved for use on such specimens. In severe or complicated cases, consider sending bronchoalveolar lavage fluid for chlamydial culture as well. A complete blood count (CBC) revealing peripheral eosinophilia in the appropriate clinical situation is additional evidence supporting C trachomatis pneumonia.

In infants with suspected chlamydial conjunctivitis, perform an antigen/DNA detection test, chlamydial culture, or both, using scrapings from the palpebral conjunctiva.

If the mother had a documented chlamydial infection during pregnancy that was untreated, presumptively treat the infant, even without confirmation of infection.

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Basic Laboratory Studies

A complete blood count (CBC) can be performed for suspected pelvic inflammatory disease (PID). The following should also be considered:

• HIV testing (coinfection is not uncommon)
• In women, a Papanicolaou (Pap) smear (the risk of cervical cancer is increased 6.5-fold)
• Testing sexual partners for Chlamydia

A pregnancy test is mandatory for females with suspected chlamydial infection. Obtaining a pregnancy test helps with early diagnosis and guidance of treatment. Because pregnancy is a contraindication for the use of doxycycline and ofloxacin, it is critical to obtain a pregnancy test before beginning treatment with these drugs.

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Pap smear showing chlamydia in the vacuoles. Magnification, 500x. Image courtesy of the National Institutes of Health, National Cancer Institute.

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Cytology and Cell Culture

Cytology is used mainly for diagnosing infant inclusion conjunctivitis and ocular trachoma through 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.

C trachomatis grows well in a variety of cell lines (eg, McCoy and 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.

Cultures are difficult to obtain; many false-negative results are returned. They are also expensive to perform, because of the expertise and laboratory resources required. In addition, they are unsuitable for large numbers of patients (eg, in the emergency department [ED]). Nevertheless, in certain clinical situations, cultures are mandatory.

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 those involving rape or sexual abuse. Cell culture is also preferred for rectal specimens because nonculture test results are difficult to interpret in the presence of stool organisms.

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This photomicrograph reveals McCoy cell monolayers with Chlamydia trachomatis inclusion bodies; magnified 200X. Image courtesy of the Centers for Dise....

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Molecular Techniques for Detecting Antigen, DNA, or RNA/Rapid Tests

Because C trachomatis grows only within columnar cells, obtaining a specimen that contains cells directly from the urethra or cervix, not on pooled vaginal secretions, is important. In obtaining cells along with discharge, attempt to apply pressure to the inside of the cervix or urethra. In males, insert collection swabs 1-2 cm into the urethra after the urethra is milked to bring down secretions. Always follow the directions of the manufacturer of the kit used for collection, and follow transport instructions.

Direct fluorescent antibody (DFA) testing is a laboratory assay for C trachomatis that has a sensitivity of 50-80% and a specificity of 99% specificity. It is the method of choice for confirming other assays. However, it is labor intensive and requires skilled personnel.

Enzyme-linked immunosorbent assay (ELISA) is a laboratory assay for C trachomatis that has a sensitivity of 40-60% and a specificity of 99%. Because it is both automatable and cost-effective, it is suitable for large numbers of patients. ELISA is the most commonly used test for Chlamydia in the emergency department (ED) and in outpatient clinics.

Detection of chlamydial DNA may be accomplished by using specific probes. Newer DNA probe kits currently are available that allow detection of C trachomatis and N gonorrhoeae from voided urine specimens, obviating the need for direct sampling in uncomplicated cases. These urine tests may also be appropriate for use in the evaluation of possible sexual abuse.^[38]

The US Food and Drug Administration (FDA) recently cleared the Cepheid GeneXpert CT/NG (Xpert) rapid polymerase chain reaction (PCR) test as a moderate-complexity test. CT/NG GeneXpert is a real-time PCR assay that can be run on demand in less than 2 hours and has a test performance that is similar to that of existing nucleic acid amplification tests (NAATs) in both low- and high-prevalence populations.^[39]

The C trachomatis nonculture tests have been largely replaced because of the superior performance of NAATs, even when performed on noninvasive specimens.

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Nucleic Acid Amplification Tests

NAATs have become the preferred diagnostic and screening test for C trachomatis genital infection in the United States because they are sensitive and can be used for noninvasive testing without the need for a pelvic examination or a urethral swab.^{[40, 41, 42]} NAATs target and amplify conserved nucleic acid sequences that are present in almost all clinical strains of C trachomatis, including the genital, LGV, and ocular serovars.

The APTIMA Combo 2 Assay for ribosomal RNA (rRNA) can be used on ThinPrep liquid-based Pap smear specimens.^[43] This has the advantage of being relatively simple and inexpensive. 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. If a definitive diagnostic test is required, antigen detection may well be the most appropriate diagnostic test for a primary care setting in the United States.

The main disadvantage of this approach is that it is less sensitive than tissue culture. In populations with a low (< 5%) prevalence of chlamydial infection, a highly significant percentage of positive test results are false positives. Accordingly, verification of a positive test result is desirable in certain cases. Such verification can be achieved by means of culture (eg, a second nonculture test that identifies a different chlamydial antigen or nucleic acid sequence from that identified in the first test), a blocking antibody, or a competitive probe.

NAATs that are cleared by the FDA are recommended for detection of genital tract infections caused by C trachomatis and N gonorrhoeae in men and women with or without symptoms.^[44] Older nonculture tests and non-NAATs have inferior sensitivity and specificity characteristics and are no longer recommended.

NAATs have not been cleared by FDA for the detection of rectal and oropharyngeal infections caused by C trachomatis. The Centers for Disease Control and Prevention (CDC) recommends NAATs to test for these extragenital infections based on increased sensitivity, ease of specimen transport, and processing. Routine repeat testing of NAAT-positive genital tract specimens is not recommended because the practice does not improve the positive predictive value of the test. C trachomatis and N gonorrhoeae culture capacity might still be needed in instances of child sexual assault in boys and extragenital infections in girls.^[44]

Although NAATs are sensitive, numerous disadvantages have been discussed. The first is that they are expensive and thus may not be affordable by health departments for comprehensive screening.^[45] Another disadvantage is that the FDA-approved NAATs cannot distinguish LGV from non-LGV strains, which is important because the duration of treatment is longer for LGV infections. In addition, NAATs detect chlamydial DNA or RNA rather than live organisms, and positive NAAT results are not uncommon 3 weeks after completion of antibiotic therapy.^[46] Thus, NAATs should not be used as a test-of-cure assay, except in pregnant women in whom it is justified to document cure at 3-4 weeks after completion of therapy in an effort to prevent infection in the infant.^[40]

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Serology

On a complement fixation test, all patients with lymphogranuloma venereum (LGV) have complement-fixing antibody titers higher than 1:16. Fifteen percent of men with urethritis and 45% of women with endocervical infection have titers of 1:16 or greater. The microimmunofluorescence test is more sensitive than the complement fixation test. Results are positive in at least 99% of women with cervicitis and in 80-90% of men with urethritis.

Antichlamydia immunoglobulin M (IgM) is uncommon in adults with genital tract infection. The prevalence of antichlamydial immunoglobulin G (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 immunoglobulin A (IgA) and active disease.

The sensitivity, specificity, and predictive values of serologic studies for Chlamydia are not high enough to make any of them 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.

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CT, Radiography, and Ultrasonography

Imaging studies are usually not required for patients with uncomplicated genital chlamydial infections. However, computed tomography (CT) and ultrasonography are useful diagnostic adjuncts in cases of complicated (upper tract) infection. For example, CT may identify Fitz-Hugh-Curtis syndrome (perihepatitis; see the images below). Ultrasonography may be performed to look for tubo-ovarian abscess.

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CT scan of adolescent with chlamydial Fitz-Hugh-Curtis syndrome demonstrating perihepatic fluid collection anterior to liver.

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CT scan of adolescent with chlamydial Fitz-Hugh-Curtis syndrome demonstrating free peritoneal fluid.

Obtain a chest radiograph for infants with suspected pneumonia. Chlamydial pneumonia may appear as a lobar or interstitial pneumonia in infants.

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Screening

The US Preventive Services Task Force recommends routine Chlamydia screening for sexually active young women to prevent consequences of untreated chlamydial infection (eg, PID, infertility, ectopic pregnancy, and chronic pelvic pain).^[5] Less than 50% of young, sexually active females in the United States are screened for Chlamydia. Nationally, the annual screening rate increased from 25.3% in 2000 to 43.6% in 2006, then decreased slightly to 41.6% in 2007.^[5]

A guideline synthesis that addresses screening recommendations is also available from the National Guideline Clearinghouse.^[8]

As a screening measure for asymptomatic males only, obtain urine for a leukocyte esterase test. This looks for white blood cells (WBCs), which are virtually diagnostic of chlamydial infection or gonorrhea in the absence of urinary tract infection (UTI) symptoms. If the leukocyte esterase test result is positive, proceed with the usual diagnostic tests.

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Approach Considerations

The keys to management of chlamydial infections are (1) arriving at the correct diagnosis and (2) ensuring that the patient complies with treatment.

Undiagnosed chlamydia can progress to pelvic inflammatory disease (PID), which may lead to relative or absolute infertility. This may be tragic if it occurs early in life before childbearing. Diagnostically evaluate all cases of suspected sexual abuse using chlamydial culture, not nonculture techniques.

Because of the personal nature and time-intensive diagnosis of sexually transmitted diseases (STDs), many physicians err by presuming that symptoms of an STI are caused by a urinary tract infection (UTI); therefore, patients often present with a history of multiple UTIs when, in fact, they may have had 1 or more STDs.

Adolescents are at high risk for noncompliance with treatment, especially if a patient is attempting to keep information away from parents. Single-dose, in-office treatment is increasingly being used to improve compliance and confidentiality. Partner treatment is crucial for prevention of reinfection.

Many clinicians err on the side of caution and hospitalize patients whenever PID is a concern or compliance with therapy is problematic. Consider PID an absolute indication for admission because of the potential for infertility and the poor compliance of many adolescents with prolonged treatment regimens.

Begin antibiotic therapy as soon as possible. Consider compliance, cost, and potential adverse effects. Consider treatment for possible gonorrhea coinfection. Send specimens from sites of infection to the lab for culture. Perform a pregnancy test; this can alter antibiotic treatment and patient follow-up care.

Consult obstetrics/gynecology for any patient with severe PID and any pregnant patient with chlamydial infection. Consult ophthalmology for patients with chlamydial conjunctivitis. Provide information and counseling to prevent future STDs, and consider referral for HIV testing. Encourage the patient to abstain from sexual intercourse until after treatment and testing of all partners is completed.

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Antibiotic Therapy

Two broad anatomical treatment categories of genital C trachomatis infection are recognized, as follows:

• C trachomatis cervicitis/urethritis/epididymitis (D-K biovars): Lower genital tract or uncomplicated
• C trachomatis salpingitis/endometritis (D-K biovars): Upper genital tract or complicated

Treatment of genitourinary chlamydial infection is clearly indicated when the infection is diagnosed or suspected. Chlamydiae are susceptible to antibiotics that interfere with DNA and protein synthesis, including tetracyclines, macrolides, and quinolones.^[47] CDC recommends azithromycin and doxycycline as first-line drugs for the treatment of chlamydial infection.^{[33, 40]} Medical treatment with these agents is 95% effective. Alternative agents include erythromycin, levofloxacin, and ofloxacin.^[33] Rifalazil, a rifamycin that is highly active against C trachomatis and has a long half-life, has shown promise as a single-dose treatment for chlamydial nongonococcal urethritis and is currently being evaluated in women with uncomplicated genital infection.^[48]

For many years, standard therapy for uncomplicated genital tract infection has been doxycycline 100 mg orally twice daily for 7 days. However, azithromycin given as a single 1-g dose is as effective as a 7-day course of doxycycline.^{[49, 50]} The FDA released a warning on March 12, 2013, that azithromycin can cause potentially life-threatening arrhythmias. Patients with known QT-interval abnormalities or who take drugs to treat arrhythmias should receive doxycycline instead. Test of cure after treatment is unnecessary, but retesting is recommended at 3 months after therapy because of the high risk of reinfection in women and men.^[40]

Azithromycin has also been shown to be effective in the treatment of nongonococcal urethritis, whether related to C trachomatis, genital mycoplasmas, or other organisms.^[51] Ofloxacin 300 mg twice daily for 7 days and levofloxacin 500 mg once daily for 7 days are included as alternative agents in the 2015 CDC treatment guidelines^[33] Azithromycin is now available as a generic drug, and its cost in the authors’ STD clinic (Indianapolis, IN) of about 60 cents per 1-g does is comparable to a 7-day course of doxycycline. A once-daily preparation of doxycycline (WC2031) was shown to be noninferior to the standard twice-daily regimen in both men and women and has been FDA approved for treatment of uncomplicated chlamydial genital infection in men and women.^[52]

Lower genital infections caused by Chlamydia can be treated with single-dose, directly observed treatment. This practice is encouraged when possible to reduce noncompliance due to cost, confidentiality issues, motivational issues, and maturity issues.

Upper genital tract disease must be vigorously sought out because potential complications are serious, especially in adolescents. With the advent of newer, more sensitive DNA and antigen detection kits that use urine specimens instead of a pelvic examination, the potential to presume a chlamydial infection in uncomplicated lower tract disease is concerning.

Inadequately treated PID can lead to sepsis, infertility, and chronic pelvic pain. Many practitioners strongly advise admission for inpatient therapy and monitoring of response whenever PID is suspected because of a tendency of adolescents to minimize or ignore symptoms and eschew follow-up.

The management of PID, even when gonorrhea is present, should always include therapy directed against C trachomatis, as well as N gonorrhoeae and anaerobic bacteria. Randomized trials have shown that parenteral and oral regimens have similar clinical efficacy for mild to moderate PID, although doxycycline is given orally if possible because intravenous infusion is painful.^[40]

With inpatient regimens for PID, evidence of significant clinical improvement and confidence in completion of medical therapy must be present before the patient is discharged. Recommended parenteral regimens include cefoxitin or cefotetan along with a 14-day course of doxycycline or, alternatively, clindamycin plus gentamicin or ampicillin-sulbactam plus doxycycline.^[40]

Outpatient regimens for PID include initial single-dose intramuscular therapy with a second- or third-generation cephalosporin plus 14 days of doxycycline, with or without metronidazole 500 mg twice daily for 14 days. Because of the emergence of quinolone-resistant N gonorrhoeae, regimens that include a quinolone are no longer recommended for PID treatment.

Chlamydial conjunctivitis and pneumonia are usually treated for a total of 14 days.

Treatment also is indicated for sexual 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 chlamydial infection is indicated for patients being treated for gonorrhea, as well.

In June 2015, the Centers for Disease Control and Prevention (CDC) updated treatment guidelines for gonococcal infection and associated conditions. Fluoroquinolone antibiotics remain not recommended to treat gonorrhea in the United States. The recommendation was based on analysis of new data from the CDC’s Gonococcal Isolate Surveillance Project (GISP), which showed that the percentage of fluoroquinolone-resistant gonorrhea cases in heterosexual men 6.7% in 2007, an 11-fold increase from 0.6% in 2001.^{[53, 40]}

Pregnancy treatment considerations

Guidelines from the CDC recommend azithromycin 1 g orally as a single dose. Alternatives include amoxicillin 500 mg orally three times a day for 7 days as the preferred drug regimens for treating chlamydial infections in pregnancy,^{[54, 55]} with erythromycin as another alternative.^{[40, 56, 57]} Doxycycline, ofloxacin, and levofloxacin are contraindicated in pregnancy. Clindamycin is only partially effective in eradicating C trachomatis in men with nongonococcal urethritis, but it appears to be as efficacious as erythromycin in pregnant and nonpregnant women with C trachomatis infection.^{[58, 59, 60]} Test-of-cure to document chlamydial eradication (preferably via NAAT) 3-4 weeks after therapy completion is recommended.

Posttherapy care

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.

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.

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Prevention

Individuals who are sexually active should be aware of the risks posed not only of genitourinary chlamydia infection but also by the whole gamut of STDs. Patients should be tested for other STDs or referred for other STD testing as appropriate. All sexual contacts should also be referred for testing and, if necessary, treatment.

In addition, patients should be aware that the most effective way of avoiding infection, other than abstaining from sexual activity, is to practice safe sex. This means using appropriate barrier protection (ie, latex condoms) with each sexual encounter.

The American College of Obstetricians and Gynecologists (ACOG) has released guidelines on expedited partner therapy for chlamydial and gonorrheal sexually transmitted diseases (STDs).^{[61, 62]} While designed to prevent reinfection with chlamydia and gonorrhea, the recommendations can also be applied to other STDs. The ACOG recommendations include the following:

• Expedited partner therapy to prevent reinfection, with legalization of expedited partner therapy
• Counsel partners to undergo screening for HIV infection and other STDs
• Expedited partner therapy contraindicated in cases of suspected abuse or compromised patient safety; pretreatment evaluation for abuse potential recommended
• Expedited partner therapy medications and protocols based on CDC, state, and/or local guidelines

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Long-Term Monitoring

Patients with PID should be rechecked in 1-2 days to look for signs of clinical improvement. All patients treated for chlamydial infection should receive follow-up care with a primary care provider to reduce the risk of further infection and to screen for cervical cancer.

Test for chlamydial cure is not strictly necessary unless the patient thinks he or she may have been reinfected. However, follow-up at 3-4 weeks to repeat the examination and test for cure is advised because recurrent or persistent cases can lead to infertility. Retesting before 3-4 weeks may lead to a false-positive result on nonculture tests as a result of the shedding of dead organisms.

Perform partner testing and treatment to prevent reinfection.

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WHO Guidelines on the Treatment of Chlamydia trachomatis Infection

Guidelines on treatment of Chlamydia trachomatis infection by the World Health Organization (WHO) are summarized below.^[63]

Uncomplicated Genital Chlamydia

WHO recommendations for the treatment of uncomplicated genital chlamydia are as follows:

• Azithromycin 1 g orally as a single dose or
• Doxycycline 100 mg orally twice a day for 7 days or one of these alternatives: tetracycline 500 mg orally 4 times a day for 7 days, erythromycin 500 mg orally twice a day for 7 days, or ofloxacin 200-400 mg orally twice a day for 7 days

Anorectal Chlamydial Infection

In anorectal chlamydial infection, the WHO recommends doxycycline 100 mg orally twice a day for 7 days over azithromycin 1 g orally as a single dose.

Chlamydial Infection in Pregnant Women

WHO recommendations for the treatment of chlamydial infection in pregnancy are as follows:

• Azithromycin recommended over erythromycin
• Azithromycin recommended over amoxicillin
• Amoxicillin recommended over erythromycin
• Azithromycin 1 g orally as a single dose or
• Amoxicillin 500 mg orally 3 times a day for 7 days or
• Erythromycin 500 mg orally twice a day for 7 days

Lymphogranuloma Venereum

WHO recommendations for the treatment of lymphogranuloma venereum (LGV) are as follows:

• In adults and adolescents with LGV, the guidelines suggest doxycycline 100 mg orally twice daily for 21 days over azithromycin 1 g orally weekly for 3 weeks.
• Good practice dictates treatment of LGV, particularly for men who have sex with men and for people with HIV infection.
• When doxycycline is contraindicated, azithromycin should be provided.
• When neither treatment is available, erythromycin 500 mg orally 4 times a day for 21 days is an alternative.
• Doxycycline should not be used in pregnant women.

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Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Agents used in the management of chlamydial genitourinary infections are treated primarily by administering antibiotics. Treatment of genitourinary chlamydial infection clearly is indicated when the infection is diagnosed or suspected; for sexual partners of the index case; and for patients being treated for gonorrhea.

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Azithromycin (Zithromax, Zmax)

• Dosing, Interactions, etc.

Clinical Context:  Azithromycin is a relatively new member macrolide antibiotic that possesses activity against various different bacterial organisms. It binds to the 50S ribosomal subunit of the bacteria, thereby inhibiting bacterial protein synthesis. Related to erythromycin, azithromycin is considered by many to be the treatment of choice for Chlamydia trachomatis genitourinary infection because it may be administered in a single dose, which improves adherence to treatment.

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Doxycycline (Adoxa, Doryx, Monodox, Avidoxy, Vibramycin)

• Dosing, Interactions, etc.

Clinical Context:  Doxycycline, a well-absorbed tetracycline derivative, is the second drug of choice for genital chlamydia infections. It has a limited spectrum of bacterial activity but is effective in treating chlamydial infections. Doxycycline binds to the 30S and, possibly, 50S ribosomal subunits of the bacteria, thereby inhibiting bacterial protein synthesis.

One week of doxycycline appears to be as effective as a single dose of azithromycin for treating genitourinary chlamydial infections. Although the course is longer than that of azithromycin, the cost is less, and doxycycline has been used in clinical practice for a much longer time. Because of the need for extended therapy, compliance is often poor.

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Levofloxacin (Levaquin)

• Dosing, Interactions, etc.

Clinical Context:  For pseudomonal infections and infections due to multidrug-resistant gram-negative organisms.

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Ofloxacin

• Dosing, Interactions, etc.

Clinical Context:  Penetrates prostate well and is effective against N gonorrhea and C trachomatis.

A pyridine carboxylic acid derivative with broad-spectrum bactericidal effect.

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Erythromycin (E.E.S., Ery-Tab, Erythrocin, EryPed, PCE)

• Dosing, Interactions, etc.

Clinical Context:  Erythromycin is a macrolide antibiotic with a large spectrum of activity. It binds to the 50S ribosomal subunit of the bacteria, thereby inhibiting bacterial protein synthesis. Generally, erythromycin is considered a recommended treatment for chlamydial genitourinary infection only in pregnant women. Some recommend it in infants as well.

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Cefoxitin (Mefoxin)

• Dosing, Interactions, etc.

Clinical Context:  Second-generation cephalosporin with activity against some gram-positive cocci, gram-negative rod infections, and anaerobic bacteria. Inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins; inhibits final transpeptidation step of peptidoglycan synthesis, resulting in cell wall death.

Infections caused by cephalosporin- or penicillin-resistant gram-negative bacteria may respond to cefoxitin.

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Ampicillin

• Dosing, Interactions, etc.

Clinical Context:  Like erythromycin, ampicillin is considered a recommended treatment for genitourinary chlamydial infection only in pregnant women. Ampicillin binds to penicillin-binding proteins, which inhibit bacterial cell wall synthesis by inhibiting the final transpeptidation step of peptoglycan synthesis in bacterial cell wall. This in turn causes the bacteria to lyse due to ongoing activity of cell wall autolytic enzymes.

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Amoxicillin (Moxatag)

• Dosing, Interactions, etc.

Clinical Context:  Because of its lower efficacy, amoxicillin is indicated only when the patient is both pregnant and erythromycin-allergic. Amoxicillin is a penicillin antibiotic with activity against gram-positive and some gram-negative bacteria. It binds to penicillin-binding proteins, thereby inhibiting bacterial cell wall growth.

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Cefotetan

• Dosing, Interactions, etc.

Clinical Context:  Second-generation cephalosporin used as single-drug therapy to provide broad gram-negative coverage and anaerobic coverage. Also provides some coverage of gram-positive bacteria. Half-life is 3.5 h. Inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins; inhibits final transpeptidation step of peptidoglycan synthesis, resulting in cell wall death.

Dosage and route of administration depends on condition of patient, severity of infection, and susceptibility of causative organism.

• References

Clindamycin (Cleocin, CLIN Single Use)

• Dosing, Interactions, etc.

Clinical Context:  Lincosamide for treatment of serious skin and soft tissue staphylococcal infections. Effective against aerobic and anaerobic streptococci (except enterococci). Inhibits bacterial growth, possibly by blocking dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest.

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Gentamicin

• Dosing, Interactions, etc.

Clinical Context:  Gentamicin is an aminoglycoside antibiotic for gram-negative coverage. It is used in combination with an agent against gram-positive organisms and one that covers anaerobes.

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Ampicillin/sulbactam (Unasyn)

• Dosing, Interactions, etc.

Clinical Context:  This combination of a beta-lactamase inhibitor and ampicillin interferes with bacterial cell wall synthesis during active replication, causing bactericidal activity against susceptible organisms.

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Metronidazole (Flagyl, Flagyl ER, Metro)

• Dosing, Interactions, etc.

Clinical Context:  Metronidazole is active against various anaerobic bacteria and protozoa. It appears to be absorbed into the cells; the intermediate metabolized compounds that are formed bind DNA and inhibit protein synthesis, causing cell death.

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Class Summary

The Centers for Disease Control and Prevention (CDC) recommends azithromycin and doxycycline as first-line drugs for the treatment of chlamydial infection. Second-line drugs (eg, erythromycin, penicillins, and sulfamethoxazole) are less effective and have more adverse effects.

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