Chlamydia and other urethritis and cervicitis

• Chlamydia is a sexually transmitted infection caused by the bacterium Chlamydia trachomatis, which also causes lymphogranuloma venereum and, through a different set of strains, the eye disease trachoma.
• In women it is often silent until it ascends to cause pelvic inflammatory disease (PID), infertility or an ectopic pregnancy; in men it commonly produces urethritis or epididymitis.
• Infants can be infected during birth, with conjunctivitis or pneumonia.
• Diagnosis rests on a nucleic acid amplification test (NAAT) on urine or a swab; doxycycline 100 mg twice daily for 7 days is first-line in adults and adolescents, while azithromycin 1 g as a single dose is used in pregnancy. ^[1]
• Cure is usual, but reinfection is common, so partners must be treated and retesting is needed.

By the end of this page you should be able to:

1. Distinguish the three C. trachomatis serovar groups and the diseases they cause.
2. Recognise chlamydial infection at each anatomic site, including rectal, pharyngeal and neonatal disease.
3. Choose the correct specimen and test, including NAAT and options when NAAT is unavailable.
4. Treat uncomplicated genital infection, LGV, proctitis, pregnancy and neonatal disease with the correct drug, dose, route and duration.
5. Manage sex partners, arrange test of cure where needed, and know when to retest.
6. Outline low-resource and syndromic management when tests or drugs are unavailable.

C. trachomatis exists as two forms. The infectious elementary body enters epithelial cells, then reorganises into a reticulate body that multiplies inside a membrane-bound inclusion. Thus the organism is neither truly extracellular nor easily cultured: it depends on living host cells for replication. This intracellular lifestyle explains both the prolonged incubation and the relative paucity of symptoms, because damage is slow and inflammation is modest until the organisms ascend.

The 18 recognised serovars (serotypes) of C. trachomatis fall into three clinically important groups, related to the site of infection. ^[5]

Serovars D to K are usually confined to mucosal surfaces and cause mild or asymptomatic infection; L1 to L3 penetrate epithelium and spread through lymphatic channels, producing tissue damage and scarring. ^[2] A person can be infected with more than one serovar, and most infections are mixed with other organisms, notably Neisseria gonorrhoeae in young adults.

Chlamydia trachomatis is the most frequently reported bacterial infectious disease in the United States and is the most common sexually transmitted infection globally. ^{[1] [4]} In 2020 the World Health Organization (WHO) estimated 128.5 million new infections among adults aged 15 to 49 years worldwide, with a global prevalence of about 4.0% in women and 2.5% in men, and higher rates in young people. ^[4] Lymphogranuloma venereum is relatively rare but has resurged in some countries, especially among men who have sex with men. ^[4]

The burden is concentrated in those under 25 years of age. ^[1] This is why every prevention programme aims at sexually active young people and why screening is directed at them even when they feel well.

Transmission is almost entirely sexual: vaginal, anal and oral intercourse. Perinatal spread occurs during delivery through an infected cervix. The organism is delicate, depending on a human host, so casual environmental transmission is essentially absent.

Risk is increased by new or multiple sex partners, a partner with concurrent partners, a partner with another sexually transmitted infection, lack of barrier protection, young age and membership of populations with high prevalence. A travel history with sexual contacts abroad is often relevant. Because both gonococcal and chlamydial infection may coexist, testing for one should be accompanied by testing for the other.

The clinical picture follows directly from the organism's behaviour. It replicates inside epithelial cells of the cervix, urethra, rectum or pharynx. The infected cell ruptures, releasing elementary bodies that infect neighbouring cells; a local inflammatory response follows, but it is often modest. This is why discharge may be scant or absent and why many infections are noticed only by screening.

Ascending infection is the dangerous step. In women the organism moves from the cervix to the endometrium, fallopian tubes and ovaries, producing pelvic inflammatory disease. Inflammation and scarring of the tubes are the mechanism behind both tubal factor infertility and ectopic pregnancy. In men the organism may ascend in the vas and epididymis. Rarely it produces disseminated infection, presenting as reactive arthritis with conjunctival inflammation.

Coinfection and repeat infection matter: the organism does not induce reliable immunity, so reinfection after treatment is well documented and each episode adds to the risk of tissue damage.

Women (cervicitis). Many women have no symptoms at all. Those who do may notice an abnormal vaginal discharge, intermenstrual or post-coital bleeding, dysuria, vaginal pruritus or mild lower abdominal pain. ^[3] On examination there may be a purulent or mucopurulent endocervical exudate and bleeding induced by a swab; often there is nothing to see, which is why screening is essential.

Men (urethritis). Typically a mild dysuria, meatal irritation or pruritus with a mucoid, mucopurulent or scanty watery discharge. Meatal inflammation may be visible. ^[3] Prostatitis with perineal pain or pelvic discomfort can also occur.

Rectal infection with genital serovars D to K is frequently asymptomatic. When symptoms occur there may be anal discomfort, discharge or bleeding. In contrast, LGV serovars cause severe proctocolitis: rectal pain, mucoid or bloody discharge, tenesmus, fever and malaise; the picture can resemble inflammatory bowel disease. ^[2] Rectal infection is common in men who have sex with men and should be sought at that site rather than inferred from urogenital tests. ^[5]

Oropharyngeal infection is common and almost always asymptomatic; it sometimes comes to light during routine gonorrhoea screening because many NAAT platforms detect both organisms from one specimen. Clinical features, if any, are mild sore throat or pharyngeal exudate.

In a sexually active man under about 40 years with acute scrotal pain and swelling, chlamydial infection is a leading cause of epididymitis, often with urethral symptoms and only mild systemic upset. This is one of the few settings in which a man is brought to medical attention while still infectious, so partner management is particularly important.

PID may be acute with lower abdominal pain, deep dyspareunia, fever and adnexal tenderness, but it is often subtle, and subclinical upper tract infection can be present at the time a diagnosis of uncomplicated cervicitis is made. ^[1] The risk of future infertility rises with repeated or delayed infection.

Chlamydia is the most common infectious trigger of reactive arthritis, a seronegative inflammatory arthritis that can develop after urogenital infection. The classic clinical cluster is arthritis (often an asymmetric oligoarthritis of the lower limbs), inflammation of the eye (conjunctivitis or uveitis) and urethral symptoms. Not every component need be present, and the triad is not specific, but the pattern should prompt chlamydial testing and treatment. Additional features can include keratoderma blennorrhagicum, circinate balanitis and enthesitis. ^[4]

In a small proportion of women with PID, infection spreads from the pelvis to the surface of the liver, producing perihepatitis: sharp right upper quadrant pain, often pleuritic and worsened by movement, sometimes with no obvious pelvic symptoms. C. trachomatis is one of its most common causes. ^[6] It should enter the differential diagnosis of right upper quadrant pain in young, sexually active women.

NAAT is the test of choice for C. trachomatis. It is the most sensitive and specific direct test and has replaced culture as the diagnostic gold standard. ^[5] Specimens can be taken from urine and swabs of the urogenital, rectal or pharyngeal mucosa; they do not require viable organisms, which eases transport. Preferred specimens are first-catch urine for men and vaginal swabs for women. ^{[1] [5]} Rectal and pharyngeal infection should be tested at those sites because urine would miss them. ^[5] Urine is still less sensitive than a swab in women, so a vaginal or endocervical swab is preferred. ^[4]

Point-of-care antigen tests (for example lateral-flow immunochromatographic tests) have too low a sensitivity to be recommended; NAAT-based point-of-care tests have performance close to laboratory NAATs and are suitable where turn-around time matters. ^[5]

Culture and DFA are seldom used now; culture depends on viable organisms and is insensitive, and non-culture antigen tests perform poorly. DFA and culture are used in specific situations such as neonatal conjunctivitis, where NAATs are not FDA-cleared for conjunctival swabs.

Serology is not useful for acute infection but may support a diagnosis of invasive disease (LGV, PID complicated by Fitz-Hugh-Curtis syndrome) or reactive arthritis, when organisms are no longer recoverable from swabs. ^[5]

When any test is positive, also test for gonorrhoea, syphilis and HIV.

There is no severity score. Diagnosis is established by detecting C. trachomatis at the exposed site. Clinical syndromes define how aggressively to treat:

• Uncomplicated urethritis or cervicitis: standard 7-day course.
• LGV (genital ulcer with bubo, or proctitis with bloody discharge, tenesmus or ulcers): extended 21-day course.
• Fitz-Hugh-Curtis syndrome or complicated PID: management as PID, usually with multi-agent regimens.
• Neonatal conjunctivitis or pneumonia: systemic treatment of the infant plus treatment of the mother and her partners.

For adolescents and adults with chlamydial urethritis, cervicitis, rectal infection or pharyngeal infection, the recommended regimen is doxycycline 100 mg orally twice daily for 7 days. ^[1] Alternatives are azithromycin 1 g orally as a single dose or levofloxacin 500 mg orally once daily for 7 days. ^[1] In practice doxycycline is the preferred first-line agent; a Cochrane review and meta-analysis of randomised trials found higher microbiologic failure with azithromycin than with doxycycline in men, and doxycycline performs better for rectal infection, which may be present alongside urogenital infection in women and in men who have sex with men. ^[1] Where poor adherence is likely, azithromycin given as a single directly observed dose remains useful and is always made available. ^[1] One also should: ^[3]

• Tell patients to abstain from sexual intercourse for 7 days after single-dose therapy, or until completion of the 7-day regimen and resolution of symptoms. ^[1]
• Give the first dose on site and dispense all doses.
• Test for HIV, gonorrhoea and syphilis at diagnosis. ^[1]

When a patient presents with urethritis or cervicitis and no test is immediately available, the recommended treatment covers both gonococcal and chlamydial infection. For nongonococcal urethritis, doxycycline 100 mg twice daily for 7 days is recommended. ^[3] For cervicitis, doxycycline 100 mg twice daily for 7 days is recommended, with concurrent treatment for gonococcal infection when the patient is at increased risk. ^[3] Presumptive treatment should be provided at diagnosis when follow-up cannot be ensured or when NAAT is unavailable. ^[3] If the woman is at lower risk of sexually transmitted infection, deferring treatment until results are available is an option. ^[3]

LGV requires 21 days of doxycycline 100 mg twice daily. ^[2] Alternatives are azithromycin 1 g once weekly for 3 weeks or erythromycin base 500 mg four times daily for 21 days. ^[2] The 21-day course is based on long-standing clinical practice, is estimated to cure greater than 98.5% of cases, and is supported by pharmacokinetic rather than trial data. ^[2] Shorter 7-day courses appear adequate for asymptomatic rectal infection. ^[2] In addition:

• Treat buboes by aspiration through intact skin if needed to prevent rupture and scarring; incision and drainage may be required. ^[2]
• Treat proctitis presumptively when severe features (bloody discharge, tenesmus or ulcers) are present, before NAAT results return. ^[2]
• Extend the course in complicated disease (fistulas, buboes, strictures). ^[2]
• Rectal LGV is often associated with HIV; test for other sexually transmitted infections and offer HIV pre-exposure prophylaxis to HIV-negative people. ^[2]

Azithromycin 1 g orally as a single dose is the recommended regimen in pregnancy; amoxicillin 500 mg three times daily for 7 days is the alternative. ^[1] Doxycycline is contraindicated in the second and third trimesters because of the risk of fetal tooth discolouration, and levofloxacin is avoided because of concern about cartilage damage in the neonate. ^[1] In addition: ^[3]

• Document eradication with a NAAT test of cure at approximately 4 weeks after completion of therapy, because of the risk of sequelae to mother and neonate. ^[1]
• Retest at 3 months, and again in the third trimester or at delivery when risk persists. ^[1]
• Screen all pregnant women under 25, and those at increased risk, at the first prenatal visit; women with untreated at-risk chlamydia are common in adolescents and young adults. ^[1]
• Treat the woman and her partners promptly; an untreated infection at delivery can lead to neonatal disease. ^[1]

Neonates acquire C. trachomatis during passage through an infected cervix. Conjunctivitis is the most frequent presentation, developing 5 to 12 days after birth, and a subacute, afebrile pneumonia with staccato cough may develop at 1 to 3 months. ^[1] Topical treatment alone is inadequate, and oral treatment is required.

Recommended regimen for neonatal chlamydial infection (ophthalmia or pneumonia) is erythromycin base or ethylsuccinate 50 mg per kg body weight per day orally, in four divided doses, for 14 days. ^[1] Because erythromycin is only about 80% effective for ophthalmia, a second course may be needed and follow-up is essential. ^[1] Limited data suggest azithromycin suspension 20 mg per kg per day for 3 days may be effective, and presumptive therapy for asymptomatic infants of at-risk mothers is not recommended; they should be monitored and treated if disease develops. ^[1] In older infants and children, azithromycin or doxycycline (in those aged 8 years or more) are used at doses in the CDC guideline. ^[1]

For non-pregnant adolescents and adults, a test of cure 4 weeks after treatment is not recommended unless adherence is in question, symptoms persist or reinfection is suspected. ^[1] The reason is that nonviable organisms can give false-positive NAAT results in the first 4 weeks. ^[1] Retest all treated men and women at approximately 3 months, because the majority of apparent failures represent reinfection rather than drug failure. ^[1]

Sex partners should be referred for evaluation, testing and presumptive treatment if they had sexual contact within the 60 days before the onset of symptoms or diagnosis; the most recent partner should be treated even if the last contact was more than 60 days earlier. ^[1] Where partner services are unavailable and the provider is concerned that the partner cannot access care, expedited partner therapy, where permitted by law, is an effective alternative. ^[1] All partners should abstain from sexual intercourse until both parties have completed treatment and symptoms have resolved.

• Pelvic inflammatory disease with tubal inflammation and occlusion.
• Infertility, usually tubal factor, and ectopic pregnancy.
• Fitz-Hugh-Curtis syndrome (perihepatitis, a complication of PID). ^[6]
• Chronic pelvic pain.
• Epididymitis, prostatitis and scrotal complications in men. ^[3]
• Reactive arthritis, which can include conjunctival inflammation and urethritis. ^{[3] [4]}
• Sterility in women after severe or recurrent disease, and rare male infertility after epididymo-orchitis. ^[4]
• Adverse pregnancy outcomes: preterm birth, low birth weight and neonatal conjunctivitis or pneumonia. ^[4]
• LGV sequelae: chronic pain, fistula, stricture and lymphoedema if treatment is delayed.

Uncomplicated chlamydial infection is curable and prognosis is excellent when treatment is prompt, partners are treated and reinfection is avoided. The risk of lasting damage rises steeply with delay: repeated or untreated infection produces tubal scarring. This is why the strongest recommendations in every guideline concern early treatment, partner management and retesting at 3 months.

Prevention combines barrier protection with early detection; there is no vaccine.

• Screen all sexually active women under 25 years of age annually, and those 25 or older at increased risk (new partner, multiple partners, partner with concurrent partners or a partner with a sexually transmitted infection). ^[1]
• Screening programs for women have been shown to reduce PID rates. ^[1]
• In men, routine universal screening is not recommended in adults at low risk; screening should be offered to young men in settings with high prevalence and to populations such as men who have sex with men. ^[1]
• Screen all MSM at exposed anatomic sites at least annually; for high-risk individuals, more frequently. ^[1]
• Screen pregnant women at risk at the first prenatal visit and rescreen in the third trimester. ^[1]
• Take a sexual history that includes sites of contact, and test at the appropriate site; rectal and pharyngeal infection will otherwise be missed.

Pregnancy. Azithromycin as above, with a 4-week NAAT test of cure and 3-month retest. ^[1] Prenatal screening and treatment are the main method of preventing neonatal disease. ^[1]

Infants and children. Chlamydial infection in a child should raise the question of perinatal transmission (possible up to 2 to 3 years later) or sexual abuse; test appropriately and treat according to age and weight. ^[1]

Older adults and the immunocompromised. Expect more atypical or extragenital disease and apply the same regimens with a low threshold for testing and referral.

HIV infection. The same treatment regimens apply. ^[1]

Much chlamydia care can be delivered with simple resources, but several principles matter.

• Where NAATs are unavailable, use syndromic case management: treat urethritis and cervicitis presumptively with doxycycline as above, covering gonococcal infection when indicated. ^{[3] [4]}
• Urine and self-collected swabs are feasible where laboratory capacity is limited; many finger-prick or cartridge-based point-of-care NAATs are now approaching laboratory performance. ^[5]
• Trachoma (serovars A to C) remains the leading infectious cause of blindness in endemic regions and is treated and prevented by the WHO SAFE strategy; it is not a sexually transmitted infection. ^[5]
• LGV may be missed where molecular typing is unavailable; treat severe proctitis or inguinal buboes empirically for 21 days. ^[2]
• Fitz-Hugh-Curtis syndrome may be under-diagnosed where imaging and laboratory tests are scarce; maintain a high index of suspicion in reproductive-age women with right upper quadrant pain and treat for chlamydia and gonorrhoea on clinical grounds. ^[6]
• Partner treatment is the single most effective intervention to prevent reinfection in any setting.
• Always test for HIV, syphilis and gonorrhoea when possible; syndromic care should not stop other prevention services.

• Chlamydia is caused by Chlamydia trachomatis, with 18 serovars in three groups: A to C (trachoma), D to K (genital and neonatal infection) and L1 to L3 (LGV). ^{[5] [2]}
• It is the most commonly reported bacterial infection in many settings; in 2020 WHO estimated 128.5 million new infections worldwide. ^[4]
• Infection is frequently asymptomatic in both sexes. ^[4]
• Complications (PID, infertility, ectopic pregnancy, epididymitis, reactive arthritis, neonatal conjunctivitis and pneumonia) come from delayed or untreated infection. ^{[1] [4]}
• Diagnosis rests on NAAT; urine suffices for men, vaginal swabs are preferred for women, and rectal or pharyngeal sites must be tested where indicated. ^{[1] [5]}
• First-line treatment is doxycycline 100 mg twice daily for 7 days; azithromycin 1 g once is preferred in pregnancy. ^[1]
• LGV is treated for 21 days with doxycycline. ^[2]
• Neonatal infection is treated systemically with erythromycin; topical therapy alone is inadequate. ^[1]
• Test of cure at 4 weeks is recommended only in pregnancy or in cases of poor adherence; otherwise retest all patients at 3 months. ^[1]
• Partners within the previous 60 days should be evaluated, tested and treated. ^[1]
• Low-resource settings rely on syndromic care, partner treatment and a high index of suspicion for complications. ^{[3] [4] [6]}

Chlamydial epidemiology and screening; nongonococcal urethritis; gonococcal infections; pelvic inflammatory disease; infertility and ectopic pregnancy; epididymo-orchitis; sexually transmitted infection syndromic management; reactive arthritis; neonatal conjunctivitis and pneumonia; trachoma; antimicrobial resistance and stewardship. ^[3]