Definition, Etiology, PathogenesisTop
1. Etiologic agent: Gram-negative bacterium, gonococcus (Neisseria gonorrhoeae) poorly resistant to environmental factors such as drying out or to disinfectants, even at low concentrations.
2. Pathogenesis: N gonorrhoeae mainly infects columnar epithelium–lined mucous membranes that have direct contact with infectious secretions. The most common sites of infection are the urethra, cervical canal, anus, throat, and conjunctiva. N gonorrhoeae use the pili (filamentous structures on the cell membrane) to adhere to mucosa in the genitourinary tract; hence their pathogenic potential. The infection leads to inflammation and production of exudate containing large numbers of bacteria and polymorphonuclear leukocytes (inflammatory exudate). The infection may spread from the primary infection site through continuity in an ascending pattern and involve other mucous membranes lined with columnar epithelium. Mucosa lined with multilayered squamous or transitional epithelium is less susceptible to infection.
3. Reservoir and transmission: The reservoir is humans. Infection is transmitted primarily through direct sexual contact (genito-genital, genito-anal, oral-genital, or oral-anal); other routes of transmission (indirect transmission) are rare. Some researchers have doubts as to whether indirect transmission is possible at all. Pregnant women with gonorrhea may transmit the infection to the newborn during delivery.
4. Risk factors: High sexual activity, multiple sexual partners, promiscuity, nonuse of condoms, use of nonbarrier contraceptives, presence of foreskin, other sexually transmitted infections (STIs).
5. Incubation and contagious period: Proximal urethritis in men, 2 to 5 days (1-14); endocervicitis, 7 to 14 days. The risk of infection is higher in women than in men. The risk for a single vaginal intercourse is estimated as 60% to 90% for women and 20% to 40% for men.
Clinical Features and Natural HistoryTop
1. In men uncomplicated gonorrhea manifests as gonococcal urethritis. The infection is typically symptomatic (~80%); in rare cases the symptoms are mild or absent (<10%).
1) Acute proximal urethritis is the most common type of urethritis in men. It manifests with urethral discharge (>80%), typically copious, initially mucopurulent and changing to purulent. In ~25% of patients the discharge may be less abundant, mucopurulent or mucous (similar as in nongonococcal urethritis). In rare cases it may appear only on compression of the urethra or following a lengthy interval in urination (eg, morning hours). Patients report dysuria (>50%) and painful erections. In acute disease they may have severe stabbing pain in the urethra worsening during urination. Meatitis (redness at the opening of the penis) is observed. If not properly treated, the infection may affect the distal urethra and spread to other segments of the genitourinary tract.
2) Distal urethritis manifests with blood in urine in the final phase of urination, malaise, low-grade fever, urinary urgency, acute pain radiating to the rectum during urination, or all of the above.
2. Women with gonorrhea usually have mild or no symptoms (≥50% of cases). Only ~20% of women seek medical attention because of symptomatic infection. The infection is usually diagnosed after the patient’s sexual partner has been infected or incidentally during a visit at the gynecologist for other reasons. Endocervicitis is the most common gonococcal disease in women. Secondary urethritis is frequent (80%-90% of cases), while proctitis is less frequently seen (35%-40% of cases). Signs and symptoms include increase in the amount or change in the character of vaginal discharge (≤50%); the discharge may be copious and purulent or scant mucopurulent or mucous (similar as in nongonococcal urethritis); hypogastric pain (≤25%); dysuria associated with urethral involvement (10%-15%), usually less pronounced than in men, likely with purulent or mucopurulent urethral discharge, appearing either spontaneously or following urethral massage (the presence of copious purulent discharge may lead to secondary irritation of the vulva and vulvitis); intermenstrual bleeding, bleeding during sexual intercourse, pronounced menstrual bleeding (rarely). Speculum examination shows red, edematous, easily bleeding exocervix and red urethral orifice.
3. Gonorrhea in both sexes:
1) Gonococcal pharyngitis: The infection is usually transmitted through oral-genital contacts. It develops mainly in women (10%-20%) and men who have sex with men (MSM; 10%-25%), typically as a secondary infection. In rare cases (~5%) the pharynx is the primary site of infection. Gonococcal pharyngitis is typically asymptomatic (~90%). If present, symptoms are nonspecific and include pharyngeal pain worsening on swallowing, redness and edema of the palatal bars and posterior pharyngeal wall, rarely slightly elevated body temperature, and enlarged regional lymph nodes.
2) In women gonococcal proctitis is usually secondary to cervicitis (in 35%-40% of cases) and rarely occurs as a primary infection resulting from anal sexual contacts (~5%). In men (non-MSM) gonococcal proctitis is very rare; in MSM, it accounts for ~40% of all cases. Additionally, infection with antibiotic-resistant N gonorrhoeae strains is common in this group. Proctitis is usually asymptomatic, particularly in women (>90%). If present, symptoms include anal discharge (mucous or mucopurulent, sometimes with blood, often noticed during defecation); burning and pruritus in the perianal area, less frequently painful abdominal pressure at defecation or dull pain worsening during defecation (if constipation is present). Perianal redness and edema are seen on physical examination. Rectoscopy reveals redness and mucosal edema in the anal canal with mucopurulent or mucous discharge.
3) Gonococcal conjunctivitis in adults: Sporadically present, usually as a secondary infection resulting from transfer of infectious discharge from the primary site of infection, typically on the fingers. In adults one eye is usually involved, and the severity of inflammation may vary from mild conjunctival irritation to severe conjunctivitis with purulent discharge.
4. Gonorrhea in newborns: The most common type of gonococcal infection in newborns is conjunctivitis. Infection is transmitted during delivery. Disseminated gonococcal infection (DGI) in newborns is rare and has manifestations resembling those in adults (cutaneous lesions, joint involvement, meningitis).
5. Other types of gonorrhea: see Complications, below.
Identification of the etiologic agent:
1) Culture is highly specific, allows for definite confirmation of the diagnosis, and is relatively inexpensive. It is also the only method of N gonorrhoeae drug susceptibility assessment (to ceftriaxone, cefixime, fluoroquinolones, spectinomycin, penicillin, and tetracyclines). Sensitivity depends on the type of specimen collected and the medium used (a selective medium with added substances inhibiting the growth of other microorganisms is preferred). Perform urethral, cervical, anal, pharyngeal, and conjunctival swab culture (urine culture is not recommended). The sensitivity of a single urinogenital culture is high (>95% for urethral discharge in symptomatic infection and 85%-95% for cervical specimens) provided that optimum conditions are maintained during specimen collection, transport, and storage, and is lower for anal and pharyngeal swabs (70%-85% and 50%-70%, respectively). Culture results are available within 24 to 48 hours.
2) Molecular tests: Nucleic acid amplification tests (NAATs) detect the DNA of N gonorrhoeae with a sensitivity >96%, which is independent of the presence or absence of symptoms or the type of material tested (it is only lower for urine samples in women). NAAT is a method of choice in asymptomatic infections and in screening for pharyngeal and rectal gonorrhea. The commercially available NAAT kits and the ones used by laboratories differ significantly, especially in specificity. Most of the tests are not designed for the diagnostic workup of pharyngeal and anorectal infections. The positive predictive value of a NAAT used in the diagnostic workup of gonorrhea should be >90%; if lower, a positive result of a test performed on a pharyngeal specimen should be confirmed with a NAAT targeting another genetic sequence of N gonorrhoeae, due to the presence of other Neisseria species in this location. Analysis of the gene encoding the DNA gyrase subunit A (gyrA) is permitted, but only in urethral or anal specimens.
3) Microscopic examination of a Gram- or methylene blue–stained specimen (1000× magnification) is the simplest, quick method of gonorrhea detection. It is highly sensitive (>95%) in symptomatic urethritis in men, that is, in the presence of infective exudate. Early in the disease or in chronic gonorrhea, N gonorrhoeae may be present outside of the white blood cells and have atypical appearance; in such cases diagnosis should be confirmed with a different method, for example, culture. The sensitivity of microscopic examination is lower in mild or asymptomatic urethritis in men, cervicitis in women (≤55%), and in proctitis (≤40%), and cannot be used to exclude infection in these clinical types. Microscopic examination is not recommended if gonococcal pharyngitis is suspected.
The International Union against Sexually Transmitted Infections (IUSTI) recommends testing for N gonorrhoeae infection:
1) In men:
a) With urethral discharge.
b) Aged <40 years or with other risk factors for sexually transmitted diseases (STDs; eg, new sexual contact in the last year or >1 sexual partner in the last year), with confirmed acute epididymo-orchitis.
2) In women:
a) With cervical o vaginal discharge, who have risk factors for an STD (age <30 years, new sexual contact in the last year or >1 partner in the last year).
b) With mucopurulent cervicitis.
3) In persons with newly diagnosed other STDs.
4) In persons who have sexual contacts with individuals with an STD or pelvic inflammatory disease (PID).
5) In persons with acute pelvic pain or symptoms of PID.
6) As part of screening for STIs in young adults (aged <25 years) or MSM.
7) As part of screening for STIs in persons with new or multiple recent sexual contacts.
8) In a newborn or adult with confirmed purulent conjunctivitis.
9) In mothers of neonates with conjunctivitis (ophthalmia neonatorum).
10) In the case of unplanned termination of pregnancy in regions with high gonorrhea prevalence.
Diagnosis of gonorrhea is established by identification of N gonorrhoeae in collected specimens.
1. Gonococcal urethritis in men: Nongonococcal urethritis, urethritis caused by mechanical injuries, genital herpes, venerophobia.
2. Gonorrhea in women: Nongonococcal cervicitis and urethritis, genital herpes, vulvovaginal candidiasis, bacterial vaginosis, trichomoniasis, cervical cancer.
3. Gonococcal proctitis: Proctitis in other STIs, genital herpes, proctitis caused by gram-negative intestinal bacilli (particularly in MSM), protozoal proctitis (Giardia lamblia, Entamoeba histolytica), anal candidiasis, anal cancers.
4. Gonococcal pharyngitis: Viral or bacterial pharyngitis.
5. Gonococcal conjunctivitis: Chlamydial conjunctivitis or conjunctivitis of other etiology (bacterial and viral).
N gonorrhoeae easily acquires resistance to antibiotics and chemotherapeutics. Treatment should at all times be followed by a test of cure (TOC) to assess eradication of the infection and identify antimicrobial resistance (AMR) (if present). If signs and/or symptoms persist after treatment completion, perform culture within 3 to 7 days (preferably supplemented by a NAAT) and assess AMR. In asymptomatic patients perform a NAAT or culture 2 weeks after completion of treatment; if the NAAT result is positive, perform culture with AMR assessment. Recommend the patient to abstain from sexual contact for 14 days (7 days if ceftriaxone therapy is used) after they and their sexual partners have completed treatment and the signs and symptoms have resolved. If this is not possible, recommend the use of condoms.
1. Treatment of uncomplicated urethritis, cervicitis, and proctitis where the antimicrobial susceptibility is unknown:
1) Preferred treatment: Ceftriaxone 1 g IM in a single dose with oral azithromycin 2 g in a single dose (if azithromycin dosed 2 g is poorly tolerated, the dose can be divided into 1-g doses administered 6-12 h apart). To reduce gastrointestinal adverse effects, azithromycin should be taken with light meals. Ceftriaxone 1 g IM monotherapy can be used in populations where susceptibility testing has shown lack of ceftriaxone resistance, followed by a TOC.
2) Alternative treatment.
a) Ceftriaxone 1 g IM monotherapy in a single dose can be used if oral azithromycin is not available or the patient is unable to take oral medications; the therapy should be followed by a TOC.
b) Oral cefixime 400 mg in a single dose with oral azithromycin 2 g in a single dose can be used if ceftriaxone is not available and IM injections cannot be made.
3) Treatment in patients with a history of severe hypersensitivity to beta-lactam antibiotics or resistance to broad-spectrum cephalosporins:
a) Spectinomycin 2 g IM in a single dose with oral azithromycin 2 g in a single dose.
b) Oral ciprofloxacin 500 g, only if the gonococci have been confirmed to be susceptible to fluoroquinolones.
c) Gentamycin 240 mg IM in a single dose with oral azithromycin 2 g in a single dose.
If the use of ceftriaxone is necessary in a patient in whom hypersensitivity has not been excluded, the patient should remain under medical surveillance for ≥30 minutes after administration.
2. Treatment of uncomplicated urogenital tract infections, proctitis, and pharyngitis where N gonorrhoeae resistance to broad-spectrum cephalosporins has been identified. Advice from specialist STI clinicians and assessment of the response to treatment are recommended:
1) Preferred treatment: IM ceftriaxone 1g in a single dose with oral azithromycin 2 g in a single dose.
2) Alternative treatment (in the case of hypersensitivity to ceftriaxone):
a) Gentamycin 240 mg IM in a single dose with oral azithromycin 2 g in a single dose; in pharyngitis and proctitis they are less effective than ceftriaxone.
b) Spectinomycin 2 g IM in a single dose with oral azithromycin 2 g in a single dose.
c) Ertapenem 1 g IM every 24 hours for 3 days.
3. Treatment of uncomplicated gonococcal pharyngitis:
1) Preferred treatment: Ceftriaxone 1g IM in a single dose with oral azithromycin 2 g in a single dose.
2) Alternative treatment:
a) Ceftriaxone 1 g IM in a single dose if azithromycin is unavailable or if the patient cannot be treated with oral agents.
b) Oral ciprofloxacin 500 mg in a single dose in patients with previous anaphylactic reaction to penicillin or allergy to cephalosporins, after resistance to fluoroquinolones has been excluded.
A number of antibiotics are less effective in eradicating N gonorrhoeae from the pharynx than from the genitourinary tract and the rectum.
4. Treatment of gonococcal conjunctivitis in adults: Ceftriaxone 1 g IM in a single dose with oral azithromycin 2 g in a single dose. Additionally, frequent saline (0.9% NaCl) irrigation of the eye should be performed.
5. Treatment of gonococcal conjunctivitis in newborns: Ceftriaxone 25 to 50 mg/kg (maximum dose: 125 mg) IV or IM in a single dose. Additionally, frequent saline (0.9% NaCl) irrigation of the eye should be performed.
6. Gonorrhea treatment during pregnancy and breastfeeding:
1) Preferred treatment: Ceftriaxone 1 g IM in a single dose with oral azithromycin 2 g in a single dose.
2) Alternative treatment:
a) Spectinomycin 2 g IM in a single dose (low effectiveness in pharyngitis) with oral azithromycin 2 g in a single dose.
b) Ceftriaxone 1 g IM in a single dose.
The safety of azithromycin in pregnancy has not been unequivocally confirmed, but it can be used where the benefits for the pregnant patient exceed the risk to the fetus. Azithromycin is excreted with breast milk.
7. Treatment of gonococcal epididymo-orchitis: Ceftriaxone 500 mg IM in a single dose with oral azithromycin 2 g in a single dose.
8. Treatment of gonococcal PID: Ceftriaxone 500 mg IM in a single dose; if coinfection with other pathogens (including anaerobes) is suspected, add oral doxycycline 100 mg bid and oral metronidazole 400 mg bid for 14 days.
9. Treatment of DGI: Hospital treatment based on antibiotic susceptibility assessment. Initial treatment: Ceftriaxone 1 g IM or IV every 24 hours, or cefotaxime 1 g IV every 8 hours, or spectinomycin 2 g IM every 12 hours for 7 days. After 24 to 48 hours and having obtained the pathogen susceptibility profile, you can switch to cefixime 400 mg bid, ciprofloxacin 500 mg, or oral ciprofloxacin 500 mg bid.
Risk factors for complications include long-lasting untreated or inadequately treated gonorrhea, maintaining sexual contacts, strenuous exercise (mainly cycling), drinking alcohol.
1. Complications in men:
1) Local complications are now relatively rare and typically resolve after treatment (the same as in uncomplicated urethritis). They include:
a) Tysonitis, which usually develops secondarily to gonococcal urethritis. Gland obstruction may result in the formation of small abscesses with purulent discharge appearing on pressure. In very rare cases it may be the only manifestation of gonorrhea.
c) Littritis, which may lead to periurethral abscess formation and postinflammatory urethral strictures.
d) Periurethral abscess may impair or block urination. The abscess may perforate through into the urethra or scrotal skin and lead to sequelae such as urethral stricture, also called watering-can perineum (a fistula between the urethra and pelvic floor, through which urine can exit).
e) Inflammation of the Cowper gland (cowperitis), with symptoms such as scrotal pain, fever (38-39 degrees Celsius), voiding abnormalities or urinary retention due to involuntary contraction of the urethral sphincter.
2) Prostatitis develops as a result of ascending spread of infection:
a) Acute prostatitis manifesting as fever (usually 38-39 degrees Celsius), chills, scrotal pain, voiding abnormalities (urinary frequency and urgency), defecation disorders (pain during defecation, constipation). Rectal examination reveals prostatic enlargement and tenderness. A prostatic abscess may form.
b) Prostatic abscess manifesting as high-grade fever, severe scrotal and suprapubic pain, and pain during defecation. The abscess may perforate through into the urethra, rectum, or scrotal skin.
c) Chronic prostatitis, usually with mild symptoms; mild, dull scrotal pain radiating to the lumbar area or testicles; mucous or mucopurulent urethral discharge, typically scant, occurring at the end of urination or during defecation; and sexual dysfunction (painful erection, painful ejaculation with blood in semen [hematospermia]). The prostate may be normal or slightly enlarged on rectal examination. Diagnosis is based on examination of urethral swab or, in chronic prostatitis, secretion obtained through prostatic massage (acute prostatitis is a contraindication to prostatic massage).
3) Epididymitis usually develops as a result of ascending spread of infection. In Europe gonorrhea is the second most frequent cause of epididymitis in men from adolescence to the age of 35 years. Gonococcal epididymitis is usually unilateral, but in rare cases the infection may affect both epididymides or the epididymis and testicle. Epididymitis is usually preceded by symptoms of gonococcal urethritis, which may be no longer present once epididymitis develops. Symptoms include high-grade fever (39-40 degrees Celsius), malaise, severe epididymal pain, often radiating along the spermatic cord to hypogastrium. Edema of the affected epididymis is observed, along with enlarged scrotum, scrotal redness, and smoothing of the scrotal skin on the affected side. Painful erection and ejaculation with purulent discharge in the semen may also be observed. Epididymitis may lead to epididymis fibrosis, spermatic cord obstruction, and eventually to infertility. The risk of infertility in patients with bilateral epididymitis is ~90%. If epididymitis is suspected, use urethral swab or urine as the diagnostic material.
4) Vesiculitis is a rare complication of gonorrhea, secondary to prostatitis or epididymitis. Manifestations include priapism and presence of blood in urine or semen.
2. Complications in women:
1) Local complications:
a) Bartholinitis, a relatively common complication (~30% of cases), usually with mild symptoms or asymptomatic. Signs and symptoms include redness and edema of the labia minora and presence of discharge on pressure. Bartholinitis may lead to the formation of a Bartholin abscess.
b) Bartholin abscess manifesting as fever and severe pain worsening when walking. Physical examination reveals a painful inflammatory mass of varying size (from a hazelnut to hen egg) beneath the skin of the labia majora.
c) Skenitis manifesting as red spots around the urethral opening, with purulent discharge appearing on pressure.
2) PID, a syndrome caused by ascending spread of infection from the cervical canal to uterine cavity, fallopian tubes, and ovaries. PID involves inflammation of pelvic organs, such as adnexitis, endometritis, pelvic peritonitis, and tubo-ovarian empyema. It is present in ~20% of women with gonorrhea and is more frequent in those aged <25 years and those who have not given birth (nulliparous women). Other risk factors include promiscuity, prostitution, history of repeated gonococcal or chlamydial infections, use of intrauterine contraceptive devices, and gynecologic procedures. PID is characterized by a wide spectrum of signs and symptoms of varying intensity, including hypogastric pain or tenderness, low-grade fever, heavy and painful menstruation, intermenstrual bleeding (more frequent in chlamydial PID), vaginal discharge, pain during sexual intercourse, dysuria. PID may cause infertility and increased risk of extrauterine pregnancy.
3. Complications in both sexes:
1) DGI develops in 0.5% to 3% of individuals with gonorrhea, more frequently in women, as a result of hematogenous spread of infection. N gonorrhoeae types AUH IA-1 and AUH IA-2 are responsible for >90% of cases. Bacteriologic confirmation of the presence of N gonorrhoeae in blood is difficult. Bacteremia is typically periodic and identified only in 20% to 30% of patients; in ~80% of cases the bacteria can be identified at the primary infection site (diagnostic specimens should be collected from the primary infection site). Types:
a) Arthritis-dermatitis syndrome (most frequent). Arthritis develops in 30% to 40% of patients; in most cases it is mild and reactive. Typically the carpal, metacarpophalangeal, ankle, and knee joints are involved, although the disease may affect other joints. The affected joints are swollen and painful, and the symptoms often resolve spontaneously. Severe septic arthritis, which was described in the pre-antibiotic era, is now rare. In this type purulent discharge containing N gonorrhea was found in the synovial fluid of mainly large joints such as the elbow, shoulder, and knee, often leading to their damage. Cutaneous lesions are observed in 50% to 75% of patients, usually early in the disease. The most typical feature of DGI is necrotic lesions with an erythematous rim, but macular, papular, bullous, or petechial lesions may also develop. Although cutaneous lesions may appear at any location, they are most frequently present in distal limbs, often above the affected joints.
b) Rarely: Endocarditis, myocarditis and pericarditis, meningitis, osteitis.
2) Fitz-Hugh–Curtis syndrome manifesting as perihepatitis with adnexitis in women. It develops in 1% to 10% of women with gonococcal PID and is due to spread of infection from the fallopian tubes, likely via the lymphatic route. Symptoms are similar as in PID, additionally with right upper abdominal pain.
1. Gonorrhea in pregnancy poses health hazard to both the mother and child. Pregnancy is a risk factor for DGI. Gonorrhea may increase the risk of premature birth and postpartum endometritis.
2. All persons with diagnosed gonorrhea and their sexual partners should be tested for other STIs: HIV infection, hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, syphilis; symptomatic individuals should undergo additional testing for Chlamydia trachomatis and Mycoplasma genitalium infections (with macrolide resistance assessment).
3. In patients treated with a regimen without azithromycin, in whom C trachomatis infection has not been excluded, the IUSTI recommends adding oral doxycycline 100 mg every 12 hours for 7 days.
In early disease and in patients with early initiated treatment, the prognosis is good. In full-blown complications the prognosis depends on their type.
Immunoprophylaxis: None available.
1. Every patient with gonorrhea should be offered specialist counseling and recommended sexual abstinence until completion of treatment and resolution of symptoms.
2. Contact investigation: Obtain information on the patient’s sexual contacts from the last 60 days preceding symptom onset or diagnosis. Try to contact all sexual partners of the patient and offer them proper diagnostic workup, treatment, and counseling.
3. Screening for other STIs such as syphilis, HIV infection, viral hepatitis B, viral hepatitis C.
4. Patient isolation: Not required.
5. Personal protective equipment (PPE) for medical staff: Standard.