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Neisseria gonorrhoeae
Neisseria gonorrhoeae is a pathogen only of humans. Gonorrhea, one of the oldest known human illnesses, continues to result in significant morbidity; an estimated 87 million cases occur worldwide each year. In the US, gonorrhea is the second most frequently reported communicable disease after Chlamydia trachomatis. The reader is referred to organism- or syndrome-specific chapters for the overall approach to genital tract infections. The major public health impact of the sexually transmitted infection (STI) gonorrhea is acute salpingitis, which is one of the leading causes of infertility in women around the world. Gonorrhea is also a potent amplifier of the spread of human immunodeficiency virus (HIV); it increases rates of the sexual transmission of HIV up to fivefold.
Microbiology, Virulence, Immunity, And Pathogenesis
N. gonorrhoeae, an oxidase-positive, gram-negative diplococcus, primarily infects columnar or transitional epithelial cells in the human genital tract. Transmission results almost exclusively from intimate contact, such as sexual activity or parturition. Adherence to mucosal epithelium is mediated by numerous gonococcal surface structures, including pili, opacity-associated outer membrane (Opa) proteins, and lipo-oligosaccharides (LOSs), and is followed by penetration of organisms between and through epithelial cells to submucosal tissue. Cytokine release, which usually occurs in the process of invasion of male urethral cells, contributes to the symptomatic nature of gonococcal disease in men. A neutrophil response follows, with subsequent sloughing of the epithelium, pus formation, and development of submucosal microabscesses. If infection is untreated, macrophages and lymphocytes eventually replace neutrophils, and hematogenous extension can occur. In contrast, subversion of host immune function can occur in women with uncomplicated cervical infection, resulting in a lack of antibody and interleukin production. However, in a model of upper genital disease that uses organ explant culture of fallopian tubes, gonococcal endotoxin (lipopolysaccharide) impairs ciliary motility and contributes to the destruction of surrounding ciliated cells.
N. gonorrhoeae has evolved multiple mechanisms to evade host immune responses, with resulting successful adaptation to variable microenvironments (e.g., the male urogenital tract, the female lower and upper genital tracts that also vary throughout the menstrual cycle, and the human bloodstream). Although both humoral and local secretory antibodies to N. gonorrhoeae are induced during some uncomplicated infections, specific antibodies are rendered ineffective by antigenic variation of gonococcal surface molecules. For example, the organism can perform the following functions: (1) turn on or off the synthesis or shift the expression of pili, Opa proteins, and LOS; (2) vary surface immunoaccessibility of porin (Por) and LOS antigens; (3) elicit antibody responses that are not protective (e.g., antibodies to the reduction-modifiable protein [Rmp] that block bactericidal activity of other antibodies against Por and LOS); and (4) alter LOS enzymatically by sialylation, thereby causing a loss of serum bactericidal activity. The organism also resists clearance by neutrophil oxidative and nonoxidative killing mechanisms. The exact role of host defense mechanisms in modulating infection or conferring immunity to reinfection is unclear because repeated infections are common.
Epidemiology
Approximately 1.14 million new N. gonorrhoeae infections occur annually in the US. In 2019, 616,392 US cases were reported; the incidence of reported disease rose from 98 cases per 100,000 population in 2009 (a historic low) to 188 cases per 100,000 population in 2019. During 2015–2019, the rate among males increased by 60.6%, and the rate among females increased by 43.6%. In data from 2010 to 2014, the rate among men increased by 28%, whereas the rate among women decreased by 4%. The magnitude of increase among men suggests either increased transmission or increased case ascertainment (e.g., through increased extragenital screening) among gay, bisexual, and other men who have sex with men (collectively referred to as MSM). However, most jurisdictions do not routinely report the sex of the patient’s sex partner or the site of infection for gonorrhea cases, so trends in gonorrhea rates among MSM over time cannot be assessed. The highest incidence overall is among women and men 20–24 years of age ( Fig. 126.1 ). When data are examined by single-year age groups, as done for California, rates of infection are substantially higher in women 18 and 19 years of age than in women 15, 16, or 17 years of age; these findings indicate the potential for more targeted prevention and treatment efforts in settings serving older adolescents and young adults. Prevalence continues to be highest in girls and women, in the 14- to 19-year-old age group, in the non-Hispanic Black population, and in the residents of inner cities. , The risk of gonorrhea in adolescents and young adults is multifactorial, including an increased likelihood of multiple sex partners, unprotected sex, susceptibility to infection as a result of cervical ectopy (in adolescent women), and less access to STI prevention services (lack of insurance or other ability to pay, lack of transportation, discomfort with facilities designed for adults, and concerns about confidentiality). , Additional risk factors include older sexual partners and substance abuse, particularly of alcohol and marijuana. ,
The likelihood of transmission of N. gonorrhoeae depends on the anatomic site exposed and the number of exposures. A male’s risk of acquiring urethral infection after a single episode of vaginal intercourse with an infected woman is approximately 20%; the risk increases 60%–80% after 4 exposures. The risk of male-to-female transmission has not been evaluated as thoroughly but is probably ∼50%–70% after a single contact, with little evidence that risk increases with multiple exposures. , The risk of transmission by rectal or oral contact is less well defined but is thought to be relatively efficient for insertive or receptive rectal intercourse. Pharyngeal gonorrhea can be acquired easily through fellatio, which may account for 26% of cases of urethral gonorrhea in MSM. Oral sex is a highly prevalent practice among heterosexual young people, regardless of whether they have engaged in penetrative intercourse; as a result, pharyngeal gonorrhea has become increasingly prevalent, particularly among adolescents. In a study of patients between the ages of 15 and 29 years (69% of whom were <25 years) attending one of twelve public Los Angeles STI clinics, pharyngeal testing increased case finding by 39%, from 46 to 64 cases. In this group, 45% of those infected had urogenital infection only, 28% had pharyngeal infection only, and 27% had infection at both sites.
Prevalence in a community is sustained through continued transmission by asymptomatically infected people and also by a “core group” of transmitters who are more likely than the general population to become infected and to transmit N. gonorrhoeae to their sex partners. Characteristics of core groups include demography (e.g., low socioeconomic status, geographic clustering in inner cities) and unique behavior (e.g., history of repeated gonococcal infections, drug use, multiple sex partners, prostitution, and failure to abstain from sex despite symptoms or knowledge of recent exposure). Effective control efforts for gonorrhea must target both asymptomatically infected people and infected core group members.
Antibiotic Resistance
N. gonorrhoeae is facile at developing resistance to commonly used antimicrobial agents. The epidemiology, genetics, and mechanisms of resistance have been described. , Risk factors for antibiotic resistance include travel outside the community, high-risk behaviors, and recent antibiotic use, but these risk factors are not always identified in patients infected with resistant N. gonorrhoeae . , ,
The tandem history of recommended antimicrobial therapy and development of resistance is well known. The organism has evolved to resist each single agent used formerly as first-line therapy. The emergence of cephalosporin resistance and accompanying cephalosporin treatment failures worldwide prompted designation of N . gonorrhoeae as antibiotic resistance threat level “Urgent” by the US Centers for Disease Control and Prevention (CDC) due to the potential clinical impact, economic impact, incidence, 10-year projection of incidence, transmissibility, availability of effective antibiotics, and barriers to prevention. The percentage of isolates with elevated cefixime mean inhibitory concentrations (MICs; ≥0.25 μg/mL) has varied between 0.8% and 1.4% in recent years of surveillance in the US Gonococcal Isolate Surveillance Project (GISP); elevated ceftriaxone mean MICs (≥0.125 μg/mL) have occurred in 0.1%–0.4% of isolates, but no treatment failures have yet been identified in the US. Although most definitions of cephalosporin resistance are based on ceftriaxone, important differences in susceptibility can exist across cephalosporins, thus precluding generalizability of cephalosporin susceptibility monikers. Resistance mechanisms include altered penicillin binding proteins, reduction of antimicrobial entry into cells, and active efflux. β-Lactamase has not been found in strains of N. gonorrhoeae that express relative cephalosporin resistance. The first US case of N. gonorrhoeae with reduced susceptibility to cefixime (MIC = 2.0 μg/mL) and ceftriaxone (MIC = 1.0 μg/mL) due to carriage of a mosaic penA 60 allele has now been reported; the case was identified through routine GISP surveillance and had already responded to the standard recommended treatment regimen at the time (ceftriaxone 250 mg IM combined with azithromycin 1 g PO). Of note, this particular isolate was susceptible to azithromycin (MIC = 0.25 μg/mL), although azithromycin resistance in N. gonorrhoeae is an increasing concern. Genomic epidemiology data confirm that azithromycin resistance can result from multiple mechanisms. Nationally, the percentage of N. gonorrhoeae isolates with reduced susceptibility (MIC ≥2.0 μg/mL) increased more than sevenfold over 5 years (from 0.6% in 2013 to 4.6% in 2018). Currently, the only reliable method for detecting antibiotic resistance is isolation in culture and susceptibility testing. Limitations of direct specimen testing using nucleic acid amplification tests (NAATs) are incomplete correlations among identification of specific mutations, MICs, and clinical outcomes.
Clinical Manifestations
N. gonorrhoeae typically infects susceptible columnar or transitional epithelial cells (e.g., mucous membranes of the conjunctiva, pharynx, urethra, endocervix, and rectum). Infection often remains localized to the site of inoculation but can disseminate.
Perinatal Infections
Perinatal infection is generally acquired during passage through an infected birth canal, although transmission can occur after cesarean delivery, especially following premature rupture of membranes. Infant risks for infection include lack of appropriate ophthalmic prophylaxis, lack of maternal prenatal care, and maternal history of STI or substance abuse. An infant born to a woman with cervical gonococcal infection has approximately a 30% risk of acquiring ophthalmic infection, versus a <5% risk if ocular prophylaxis is given.
Ophthalmia Neonatorum
The usual incubation period for gonococcal ophthalmia neonatorum is 2–5 days, but onset can be as early as several hours after birth (following prolonged rupture of membranes) or as late as several weeks. Prematurity and premature rupture of membranes are significant risk factors for gonococcal ophthalmia. The time of onset and clinical findings do not reliably distinguish N. gonorrhoeae conjunctivitis from C. trachomatis conjunctivitis.
Typical findings of gonococcal conjunctivitis are marked bilateral eyelid edema, chemosis, and copious purulent discharge. Asymptomatic infection or mild chronic infection with intermittent symptoms lasting for several months has also been reported. Although gonococcal conjunctivitis is generally less severe in neonates than in adults, corneal complications such as ulceration and perforation of the globe (rarely), panophthalmitis, and blindness can occur.
Other Perinatal Infections Including Systemic Infection
N. gonorrhoeae can be isolated from culture of pharyngeal swabs or orogastric fluid in approximately one third of infants with ophthalmia neonatorum. , Examples of neonatal mucosal infections include vaginitis (uncommon because neonatal vaginal mucosa is well estrogenized by circulating maternal hormone), urethritis, rhinitis, anorectal infection, and funisitis. N. gonorrhoeae scalp abscess can follow fetal electrode monitoring. , Disseminated disease is rare in neonates; pyogenic arthritis is the most common manifestation. , Clinical symptoms typically develop at 1–4 weeks of age; pseudoparalysis is characteristic and multiple joint involvement is common. Most affected infants do not have concurrent or previous conjunctivitis or other mucosal infections. Skin lesions representing septic emboli of bloodstream infection (BSI), commonly seen in adults, are not described in neonates. Neonatal infection rarely results in meningitis or endocarditis.
Mucosal Infections in Children, Adolescents, and Adults
N. gonorrhoeae causes a variety of mucosal infections in sexually active adolescents and adults, as well as in sexually abused children. Transmission by fomites or through nonsexual contact is extremely rare.
In prepubertal children, gonococcal infection usually occurs in the genital tract, and vaginitis is the most common manifestation (the nonestrogenized alkaline vaginal mucosa permits colonization). N. gonorrhoeae infection should be considered in any girl with vaginal discharge, even when sexual abuse is not suspected. In a study of 43 girls <12 years of age with vaginal discharge, 9% had gonorrhea. Sexual abuse must be considered strongly when gonococcal infection is diagnosed in prepubertal children (beyond the newborn period). Among sexually abused children, pharyngeal and anorectal gonococcal infections can occur and are often asymptomatic. Gonococcal urethritis, perihepatitis, and pelvic inflammatory disease (PID) are uncommon but possible in prepubertal children.
Most males who come to medical attention with N. gonorrhoeae infection are symptomatic. Asymptomatic or minimally symptomatic infections may be more common than appreciated, but are usually recognized only through screening programs or after symptomatic infection in a contact. In a cohort of men whose time of acquisition of the infection was defined, only 2.5% remained asymptomatic for 2 weeks. However, certain phenotypes of gonococci have been more frequently associated with asymptomatic infection. Acute urethritis is the major clinical manifestation in males who complain of dysuria or note a mucoid or mucopurulent discharge 2–5 days after infection. The discharge often becomes profuse and purulent within 24–48 hours of onset. Females are more likely than males to have asymptomatic infection or mild, sometimes unappreciated, symptoms. The endocervical canal is the predominant site of urogenital infection; urethral colonization also occurs in most cases in which the cervix is involved. The incubation period for urogenital infections in women is less certain and more variable, but in most symptomatic women, the symptoms develop within 10 days of infection. , Symptomatic females can have vaginal discharge, dysuria, abdominal pain, and intermenstrual bleeding; symptoms and signs range from mild to severe. The cervix can appear normal or can exhibit edema, erythema, or friability, as well as purulent or mucopurulent discharge.
Pharyngeal infection occurs in approximately 3%–7% of N. gonorrhoeae infections in heterosexual men, and in approximately 10%–20% of infections in heterosexual women or MSM. Most pharyngeal infections are asymptomatic; acute tonsillopharyngitis or cervical lymphadenopathy rarely occurs. , Pharyngeal infections can progress to disseminated gonococcal infection (DGI) if untreated. Oral sex also has a role in sustaining gonorrhea in a population of MSM by providing a pool of untreated asymptomatic infections, and it may account for as much as 34% of the population attributable risk for symptomatic gonococcal urethritis in MSM.
Asymptomatic rectal infection is present in 26%–68% of women with gonococcal cervicitis; translocation of infected secretions is thought to be the mechanism because rectal infection positivity correlates with duration of infection. , In MSM, rectal mucosa can become infected after receptive anal intercourse. In contrast to MSM who experience a high proportion of rectal-only N. gonorrhoeae infections (≤86%), the rectum is the sole site of infection in a minority of women (≤44%). Anorectal infection is often asymptomatic. If present, symptoms range from painless mucopurulent discharge and scant rectal bleeding to overt proctitis with associated rectal pain and tenesmus. ,
Gonococcal conjunctivitis is rare in adults, usually results from autoinoculation, and occurs most often in people with anogenital infection. Untreated gonococcal conjunctivitis can progress rapidly to ulcerative keratitis and corneal perforation; however, mild or asymptomatic conjunctival infection also occurs. The outcome correlates closely with the severity of disease at the initiation of therapy. Gonococcal conjunctivitis has also been described in prepubertal children without laboratory evidence or a suggestive history of sexual abuse.
Of note, while not defined as an STI, N. meningitidis also can cause urogenital and rectal mucosal disease. In 2015, clusters of meningococcal urethritis in US males led to the discovery of a novel Nm clade (US_NmUC). This clade acquired genetic determinants from N. gonorrhoeae and has also been linked to recurrent meningococcal urethritis and ophthalmia neonatorum. It is now circulating in the UK and Southeast Asia.
Disseminated Gonococcal Infection
Disseminated gonococcal infection (DGI), also known as the arthritis-dermatitis syndrome, is the most common manifestation of acute systemic gonococcal infection beyond the neonatal period. In the 1970s, when gonococcal strains with a propensity to disseminate were common, DGI occurred in up to 3% of people with untreated mucosal gonorrhea; DGI is currently much less common. DGI was described more commonly in women, with an onset within 7 days of the start of menstruation in approximately one-half of cases ; however, more recent case series describe more male than female cases. , Certain strains of N. gonorrhoeae (currently uncommon in the US) are associated with disseminated infection. DGI strains often cause asymptomatic urogenital infection and are typically, although not always, penicillin G susceptible and resistant to the complement-mediated bactericidal activity of human serum. , Complement deficiency, which predisposes to gonococcal or meningococcal BSI, is found in up to 13% of patients with DGI. , Eculizumab, a monoclonal antibody inhibiting terminal complement activation, may also increase susceptibility to DGI.
The characteristic findings of acute arthritis, tenosynovitis, and dermatitis, alone or in combination, result from intermittent BSI. Less than one half of patients with DGI have N. gonorrhoeae isolated from blood, joint fluid, skin lesions, or other sterile sites, but N. gonorrhoeae can be isolated from a mucosal site or from a sex partner in approximately 80% of cases. , Dermatitis occurs in approximately 75% of patients with DGI. The classic skin lesions are discrete, tender necrotic pustules on erythematous bases located distally on an upper extremity. Macules, papules, petechiae, bullae, or ecchymoses also have been described. Results of culture or Gram stain of lesions are positive for N. gonorrhoeae in only approximately 10%–15% of cases. Migratory polyarthralgia or tenosynovitis (especially in the flexor and extensor tendon sheaths) affecting smaller joints is an early finding. Pyogenic monoarticular or polyarticular arthritis develops later in approximately one third of patients; the wrist, metacarpophalangeal, ankle, and knee joints are involved most commonly. , , ,
Gonococcal endocarditis is a rare complication, occurring in approximately 1%–3% of patients with DGI. , , The aortic valve is affected most often; valvular damage can progress rapidly if infection is untreated. Hepatitis and meningitis are uncommon complications of DGI.
Laboratory Findings And Diagnosis
Laboratory confirmation of N. gonorrhoeae infection is essential in children because of the legal implications of potential sexual abuse. Confirmation is also critical in adolescents and adults to improve adherence to therapy and referral of sex partners.
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