Gonorrhea

Gonorrhea is a sexually transmitted infection (STI) caused by the gram-negative bacteria Neisseria gonorrhoeae (N. gonorrhoeae). Gonorrhea may be asymptomatic but commonly manifests as cervicitis or urethritis with less common presentations such as proctitis, conjunctivitis, or pharyngitis. Without antibiotic treatment, complications can occur. Complications for men may include epididymitis, prostatitis, balanitis, and periurethral abscess. Women may develop pelvic inflammatory disease, which can cause perihepatitis and fertility issues. Disseminated gonococcal infection is associated with fever, dermatitis, tenosynovitis, septic arthritis, and (rarely) endocarditis or meningitis. Gonorrhea diagnosis is made by microscopy, culture, or nucleic acid amplification tests. Management generally involves ceftriaxone, but treatment with doxycycline should be pursued if a coinfection with Chlamydia trachomatis (C. trachomatis) is not excluded.

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Epidemiology and Etiology

Epidemiology

  • 2nd most common bacterial STI (chlamydia is the most common)
  • Worldwide annual incidence: approximately 80–100 million people:
    • Higher incidence in developing countries, including Africa and the Western Pacific
    • United States new cases in 2018: approximately 600,000
    • Incidence appears to be increasing globally.
  • Gender differences: men > women (particularly in men who have sex with men (MSM))
  • Most common age groups:
    • Men: 20–29 years old
    • Women: 15–24 years old
  • Factors sustaining gonorrhea in the population:
    • A recent reversing trend in safe sexual practices
    • Asymptomatic cases
    • Antibiotic-resistant strains
  • Gonorrhea is a notifiable disease.

Etiology

Gonorrhea is caused by the pathogen Neisseria gonorrhoeae (N. gonorrhoeae):

  • Gram-negative, nonmotile, nonspore-forming bacterium
  • Diplococcus (grows in pairs)
  • Culture and biochemical characteristics:
    • Grows best in aerobic conditions, but can grow in anaerobic conditions
    • Medium: modified Thayer-Martin (MTM) agar in 5% CO2 atmosphere:
      • Enriched chocolate agar 
      • Antimicrobial agents are used to selectively favor Neisseria growth by inhibiting the growth of fungi and other bacteria.
    • Oxidase and catalase positive: 
      • Only oxidizes glucose 
      • Produces acid, not gas (nonfermenting)

Risk factors:

  • New or multiple sexual partners
  • Unprotected sex
  • Substance abuse
  • Low educational level
  • Low socioeconomic status
  • MSM
  • History of STI
  • Gonorrhea is an independent factor for the transmission of HIV.

Pathophysiology

Transmission

  • Sexual contact with the penis, vagina, mouth, or anus of an infected individual
  • Perinatal (during vaginal delivery)

Virulence factors

  • Antigenic variation:
    • Allows expression of distinct surface antigens
    • Impedes recognition by the host’s immune system
  • Pili (fimbriae): 
    • Long, hair-like appendages on the bacterial surface
    • Able to lengthen and retract
    • Initiate attachment to host cells
    • Furnish resistance to phagocytosis
    • Provide antigenic variation among different strains 
  • Opacity-associated protein: 
    • Outer membrane protein
    • Aids in attachment to host cell receptors
  • Lipooligosaccharide (LOS) envelope protein:
    • Endotoxin
    • An oligosaccharide with a lipid A component 
    • Aids in evading the host’s defenses:
      • Can mimic a host’s glycosphingolipids
      • Able to provide antigenic variation
    • Responsible for toxicity by causing:
      • Fever
      • Ciliary loss
      • Mucosal cell death
  • Por protein: 
    • The most abundant surface protein
    • Provides aqueous channels
    • Renders some strains resistant to complement activation and deposition
    • Interferes with phagosome-lysosome fusion and may prevent intracellular killing by neutrophils
  • IgA protease: 
    • Cleaves and inactivates IgA-1 immunoglobulin 
    • Reduces the host’s immune defense

Pathogenesis

  • Bacterium adheres to the mucosal epithelium → competes with microbiota → colonizes and invades the epithelium via transcytosis with the help of pili and opacity-associated proteins
  • LOS is released → activates toll-like receptor (TLR) and nucleotide-binding oligomerization domain-containing protein (NOD) signaling in:
    • Epithelial cells
    • Macrophages
    • Dendritic cells 
  • Production of cytokines and chemokines → influx of neutrophils → phagocytosis of harmful bacteria → neutrophil-rich purulent exudate
  • Since N. gonorrhoeae has defense mechanisms to resist being killed, the bacteria-laden neutrophils act as agents of transmission to another host.
Gonorrhea Neisseria gonorrhoeae pathogenesis

Pathogenesis of N. gonorrhoeae:
DC: dendritic cell
LOS: lipooligosaccharide
TLR: toll-like receptor
NOD: nucleotide-binding oligomerization domain-containing protein
NLR: NOD-like receptor

Image by Lecturio.

Antimicrobial resistance

  • Penicillin and tetracycline resistance occurs from the acquisition of R factor (plasmid) coding for:
    • B-lactamase (penicillinase) → disrupts penicillin’s internal structure
    • TetM protein → prevents tetracycline from binding to its target 30S ribosomal subunit site
  • Quinolone resistance occurs from alterations in DNA gyrase and topoisomerase IV.
  • Macrolide (e.g., azithromycin) resistance can result from either:
    • Alterations in the ribosomal binding target
    • Under- and overexpression of influx and efflux systems
  • 3rd-generation cephalosporins (e.g, ceftriaxone): 
    • Remain highly effective as a single dose, but resistant strains have been isolated in Japan and in Europe
    • Resistant strains may have mutations in:
      • PenA gene → encodes a penicillin-binding protein
      • Multiple transferable resistance regulator (mtrR) gene → ↑ drug efflux
      • PenB gene → ↓ drug influx through por proteins

Clinical Presentation

Urogenital infection in men

  • Incubation period: 2–7 days
  • Most will be symptomatic.
  • Acute urethritis (most common presentation): 
    • Urethral discharge: 
      • Mucopurulent
      • Copious
    • Dysuria
    • Regional lymphadenopathy
  • Complications:
    • Epididymitis: 
      • Unilateral testicular swelling
      • Tenderness
    • Prostatitis: 
      • Enlarged prostate gland
      • Pain and tenderness to palpation
    • Balanitis (inflammation of the glans penis): 
      • Pain and pruritus
      • Ulceration
      • Swollen foreskin 
      • Phimosis
    • Periurethral abscess: 
      • Pain
      • Tenderness
      • Fluctuant mass
    • Cowper (bulbourethral) gland inflammation or abscess: 
      • Fever
      • Pain and tenderness to palpation of the perineum
    • Seminal vesiculitis: 
      • Dysuria
      • Fever
      • Perineal pain
      • Ejaculation of purulent material
Urethritis due to gonorrhea

Purulent penile discharge due to urogenital gonorrhea infection

Image: “4065” by CDC. License: Public Domain

Urogenital infection in women

  • Incubation period: < 10 days
  • Up to 70% of women are asymptomatic.
  • Cervicitis: 
    • Vaginal pruritus
    • Mucopurulent vaginal discharge
    • Physical examination: 
      • May be normal
      • Mucopurulent cervical discharge
      • Friable cervical mucosa
  • Urethritis:
    • Dysuria
    • Urinary urgency and frequency
  • Complications:
    • Infection of Bartholin’s or Skene’s glands:
      • Swollen glands
      • Pus may be expressed from the orifices. 
    • Pelvic inflammatory disease (PID): 
      • Occurs in 10%–20% of women with cervical gonorrhea
      • Pelvic pain
      • Lower abdominal pain and tenderness
      • Abnormal vaginal bleeding
      • Dyspareunia
      • Fever 
      • Cervical motion tenderness
      • Adnexal tenderness
    • Perihepatitis (Fitz-Hugh-Curtis syndrome): 
      • Occurs in 4% of infected women; associated with PID
      • Inflammation of the liver capsule

Extragenital infections

  • Ocular gonorrhea (conjunctivitis):
    • Usually caused by autoinoculation from a primary site of infection in adults
    • Manifestations range in severity from asymptomatic to sight threatening.
    • Signs and symptoms:
      • Eyelid edema
      • Hyperemic conjunctiva
      • Chemosis 
      • Purulent discharge
      • Photophobia
      • Pain
    • Severe complications:
      • Corneal ulceration
      • Perforation
      • Blindness
  • Pharyngeal gonorrhea (pharyngitis): 
    • Due to orogenital sexual exposure
    • Often coexists with genital infection
    • Usually mild or asymptomatic
    • Signs and symptoms:
      • Sore throat
      • Pharyngeal exudates
      • Cervical lymphadenopathy
    •  Most cases resolve spontaneously.
  • Anorectal gonorrhea (proctitis):
    • In women: 
      • Most often occurs concurrently with cervicitis
      • Usually asymptomatic
    • In men:
      • More often associated with MSM
      • More likely to exhibit symptoms
    • Possible symptoms: 
      • Rectal pain and fullness
      • Pruritus
      • Tenesmus
      • Purulent discharge
      • Rectal bleeding
Eye infection due to gonorrhea

Hyperemia, chemosis, and purulent discharge due to gonococcal conjunctivitis:
The patient developed partial blindness as a result of the infection.

Image: “Eye infection due to gonorrhea” by CDC/Arthur E. Kaye. License: Public Domain

Disseminated gonococcal infection

  • Bacteremia:
    • Fever
    • Chills
  • Purulent arthritis:
    • Abrupt onset
    • Mono- or oligoarthritis
    • Pain and swelling
    • Distal joints (e.g., knees, wrists, ankles)
  • Arthritis-dermatitis syndrome:
    • Occurs 2–3 weeks after genitourinary infection
    • Polyarthralgia:
      • Small or large joints
      • Asymmetric
      • Migratory
    • Tenosynovitis: often involves distal joints (e.g., fingers, toes, wrists, ankles)
    • Dermatitis: 
      • Painless
      • Pustular
      • Hemorrhagic papules or macules may occur.
  • Rare manifestations:
    • Endocarditis (common before antibiotics were available)
    • Myopericarditis
    • Meningitis
    • Osteomyelitis
Gonococcal lesion on skin

Close-up view of a gonococcal lesion on the skin of a patient’s arm:
A gray pustule associated with disseminated gonococcal infection

Image: “2038” by CDC/Emory University, Dr. Thomas F. Sellers. License: Public Domain

Clinical presentation in children

Newborn infections:

  • Caused by exposure to infected cervical secretions at birth
  • Ophthalmia neonatorum: 
    • Purulent conjunctivitis
    • Corneal ulcerations
    • Panophthalmitis
    • Blindness
  • Other mucosal sites of infection (usually asymptomatic): 
    • Vaginitis
    • Anorectal infection
    • Pharyngeal infection
  • Disseminated gonococcal infection:
    • Fever
    • Lethargy
    • Poor feeding
    • Vomiting
    • Arthritis (refusal to move the affected limb) 
    • Scalp abscesses
Gonococcal ophthalmia neonatorum

A newborn presenting with gonococcal ophthalmia neonatorum, caused by a maternally transmitted gonococcal infection.

Image: “Gonococcal ophthalmia neonatorum” by CDC/J. Pledger. License: Public Domain

After the neonatal period:

  • Suspect sexual abuse if gonorrhea (or any other STI) is diagnosed.
  • Vulvovaginitis is the most common manifestation.
  • Anorectal and pharyngeal infections are also common, but are usually asymptomatic.

Diagnosis

Laboratory evaluation

  • Nucleic acid amplification test:
    • The test of choice
    • > 95% sensitive and specific 
    • Amplifies N. gonorrhoeae DNA or RNA sequences
    • Specimens:
      • Endocervical or vaginal swab (women only)
      • Urethral swab (men only)
      • Oropharynx swab
      • Rectal swab
      • 1st-catch urine samples can also be analyzed for concurrent Chlamydia trachomatis (C. trachomatis).
    • Does not provide antibiotic susceptibility information
  • Gram staining: 
    • Sensitivity varies among sites:
      • > 90% in urethral exudates from men
      • 50% for endocervical exudates 
      • < 10% for joint fluid
      • Gram stain is not helpful for oropharynx or rectal samples because nonpathogenic Neisseria often colonize the sites. 
    • Findings: gram-negative intracellular diplococci
  • Cultures: 
    • Provides antibiotic susceptibility data
    • Helpful if suspicious of treatment failure
    • Sensitivity:
      • 72%–95% in symptomatic patients
      • 50%–85% in asymptomatic patients
  • Patients should also be evaluated for other STIs: 
    • C. trachomatis 
    • Syphilis
    • HIV
    • HSV
    • Hepatitis B and C

Disseminated gonococcal infection evaluation

In addition to the laboratory evaluations above, the following testing may be performed in patients suspected of having disseminated gonococcal infection:

  • Blood cultures:
    • Positive culture is diagnostic.
    • More often positive in arthritis-dermatitis syndrome than with purulent arthritis
  • Synovial fluid:
    • WBC is usually > 50,000 cells/μL.
    • ↓ Glucose
    • Cultures: 
      • Positive in only 50% of cases
      • Less likely to be positive in arthritis-dermatitis syndrome
    • Nuclear acid amplification test can be used and is more sensitive.

Management

Uncomplicated gonococcal infection management

Antibiotic management:

  • Single IM dose of ceftriaxone
  • Dual treatment with ceftriaxone and azithromycin is no longer recommended due to increased resistance.
  • Doxycycline should be added if C. trachomatis coinfection has not been excluded.

Additional measures:

  • Pharyngeal infections: 
    • More difficult to cure 
    • Retest to confirm treatment was effective.
  • Ocular gonorrhea:
    • Ophthalmology evaluation 
    • Topical fluoroquinolones
    • Saline irrigation
  • Epididymitis and proctitis: Ceftriaxone is followed by a course of doxycycline.

Disseminated gonococcal infection management

  • IV ceftriaxone
  • Perform joint drainage in patients with septic arthritis.

Management for sexual partners

  • All individuals who had sexual contact within the past 60 days with the patient should be notified for evaluation and treatment.
  • Expedited partner therapy (EPT): 
    • A prescription for cefixime is provided for sexual partners without a formal evaluation.
    • Limited to heterosexual contacts
    • Depends on individual country and state regulations
    • Not recommended for MSM due to the high risk of:
      • Coexisting infections (especially HIV)
      • Treatment failure (especially for pharyngeal infection)

Prevention and risk reduction

  • Latex condoms are one of the most effective preventative measures.
  • STI testing every year if: 
    • Multiple sex partners 
    • History of STI
  • Educate regarding the transmission of gonorrhea to other mucosal surfaces.

Complications

  • Infertility
  • Chronic pelvic pain
  • Fetal loss
  • Ectopic pregnancy
  • Urethral strictures
  • Increased risk of HIV transmission

Differential Diagnosis

  • Nongonococcal pelvic inflammatory disease: an ascending mono- or polymicrobial infection caused by C. trachomatis (most common), Mycoplasma genitalium (M. genitalium), anaerobic organisms, enteric gram-negative rods, streptococci, genital mycoplasmas, and Gardnerella vaginalis. Patients may have cervical discharge, vaginal bleeding, lower abdominal pain, and fever. Nuclear acid amplification tests and cultures of the endocervix aid in diagnosis, but management is usually with empiric antibiotics.
  • Nongonococcal cervicitis: other acute, infectious causes include Trichomonas vaginalis (T. vaginalis), C. trachomatis, or M. genitalium. Chronic cervicitis usually has a noninfectious cause, most often either mechanical or chemical irritation (e.g., tampon, diaphragm, or latex). Patients may have vaginal discharge, bleeding, and an erythematous, friable cervix. The etiology can be diagnosed by nuclear acid amplification tests: Gram stains and cultures are not as sensitive. Management involves antibiotics for the causative organism.
  • Nongonococcal urethritis in men: Gonococcal urethritis (GU) is usually more severe than nongonococcal urethritis, including those caused by C. trachomatis and M. genitalium. However, most cases of urethritis in the United States are caused by neither gonorrhea nor chlamydia. Diagnosis of GU is by gram staining and nuclear acid amplification tests. Other possible pathogens, which can be differentiated by specific laboratory testing, include Neisseria meningitidis, T. vaginalis, HSV, and syphilis.
  • Epididymitis: Acute epididymitis is usually infectious. The most common organisms responsible for acute epididymitis in men < 35 years of age are N. gonorrhoeae and C. trachomatis. Coliform (e.g., Escherichia coli) and Pseudomonas species are more frequent in older men. Viral and mycotic causes of epididymitis are rare. Nuclear acid amplification tests and cultures should be performed for diagnosis. Management depends on the etiology but can include antibiotics, scrotal elevation, ice packs, and analgesics.
  • Urinary tract infection: an infection (usually due to bacteria) of the urinary system. Patients may develop urinary frequency, urgency, and/or suprapubic pain. Urinary tract infections usually do not have vaginal discharge, but may have fever and flank pain if the kidneys are affected. Nuclear acid amplification tests, microscopic examination, and urine specimen cultures help to diagnose the disease. Management includes appropriate antibiotic coverage for the causative organism.
  • Conjunctivitis: Acute conjunctivitis usually has a viral etiology, but bacterial causes include Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus, and C. trachomatis. Patients may experience eye irritation, hyperemia, and discharge. The diagnosis of conjunctivitis is clinical. Management is usually empirical with topical and/or systemic antibiotics.

References

  1. Riedel, S., Hobden, J.A. (2019). In Riedel, S, Morse, S.A., Mietzner, T., Miller, S. (Eds.), Jawetz, Melnick, & Adelberg’s Medical Microbiology (28th ed, pp. 295-301).
  2. Ram, S., Rice, P.A. (2018). In Jameson, J.L., et al. (Ed.), Harrison’s Principles of Internal Medicine (20th ed. Vol 1, pp. 1122-1129). 
  3. Morris, S.R. (2020). Gonorrhea. MSD Manual Professional Edition. Retrieved January 27, 2021, from https://www.msdmanuals.com/professional/infectious-diseases/sexually-transmitted-diseases-stds/gonorrhea
  4. Cyr, S. S. (2020). Update to CDC’s treatment guidelines for gonococcal infection, 2020. MMWR. Morbidity and Mortality Weekly Report, 69. Retrieved on January 29, 2021, from https://doi.org/10.15585/mmwr.mm6950a6
  5. Infectious diseases | 2021 National Notifiable Conditions. (n.d.). Retrieved January 29, 2021, from https://wwwn.cdc.gov/nndss/conditions/notifiable/2021/infectious-diseases/
  6. Lovett, A., & Duncan, J. A. (2019). Human immune responses and the natural history of Neisseria gonorrhoeae infection. Frontiers in Immunology, 9. https://doi.org/10.3389/fimmu.2018.03187
  7. Lockwood, C.J., Magriples U. (2020). Prenatal care: Initial assessment. UpToDate. Retrieved January 30, 2021, from https://www.uptodate.com/contents/prenatal-care-initial-assessment
  8. Price, G.A., and Bash, M.C. (2019). Epidemiology and pathogenesis of Neisseria gonorrhoeae infection. In Bloom, A. (Ed.), UpToDate. Retrieved February 23, 2021, from https://www.uptodate.com/contents/epidemiology-and-pathogenesis-of-neisseria-gonorrhoeae-infection
  9. Ghanem, K.G. (2020). Clinical manifestations and diagnosis of Neisseria gonorrhoeae infection in adults and adolescents. In Bloom, A. (Ed.), UpToDate. Retrieved February 23, 2021, from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-neisseria-gonorrhoeae-infection-in-adults-and-adolescents
  10. Klausner, J.D. (2021). Disseminated gonococcal infection. In Bloom, A. (Ed.), UpToDate. Retrieved February 23, 2021, from https://www.uptodate.com/contents/disseminated-gonococcal-infection
  11. Seña, A.C., Cohen, M.S. (2021). Treatment of uncomplicated Neisseria gonorrhoeae infections. UpToDate. Retrieved January 30, 2021, from https://www.uptodate.com/contents/treatment-of-uncomplicated-neisseria-gonorrhoeae-infections
  12. Wong, B. (2018). Gonorrhea. In Chadrasekar, P.H. (Ed.), Medscape. Retrieved February 23, 2021, from https://emedicine.medscape.com/article/218059-overview

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